The dynamics of cross-orientation masking at monocular and interocular sites.
We investigated the temporal properties of monocular and dichoptic cross-orientation masking (XOM) mediating suppressive or facilitatory cross-channel interactions between the neural detectors for the test and orthogonal mask stimuli. We measured the evolution of masking as a function of the duration of the test and mask stimuli to determine its time constant, and determined its dependence on stimulus onset asynchrony (SOA), for three contrast combinations: color-only (red-green color test and mask), luminance-only (luminance test and mask) and color-luminance (color test and luminance mask). Results show that the temporal properties of monocular and dichoptic masking differ markedly from each other and across contrast type. For the color-only condition, the dichoptic suppressive interaction is significantly longer than for the monocular one and both are largely independent of SOA. For the luminance-only condition, the suppressive interactions in both presentations are faster than for color, have similar time constants, but have different dependencies on SOA. For the color-luminance condition under the monocular conditions, cross-orientation facilitation (XOF) occurs with the luminance mask speeding up the processing of the color test with greatest XOF when the luminance mask precedes the color test by around 22 ms. No significant effects are observed for the dichoptic condition. Effects are invariant across spatial frequency. These strongly differential dynamic effects suggest that there is separate encoding of color contrast, luminance contrast, and their combination at the relatively early within-eye stage of processing, which is distinct from the dichoptic site.


Germline genetics of prostate cancer.
An important fraction (>/~10%) of men with high-risk, localized prostate cancer and metastatic prostate cancer carry germline (heritable) pathogenic and likely pathogenic variants (also known as mutations) in DNA repair genes. These can represent known or suspected autosomal dominant cancer predisposition syndromes. Growing evidence suggests that pathogenic variants in key genes involved in homologous recombination and mismatch DNA repair are important in prostate cancer initiation and/or the development of metastases. Here we provide a comprehensive review regarding individual genes and available literature regarding risks for developing prostate cancer, and discuss current national guidelines for germline genetic testing in the prostate cancer population and treatment implications. The association with prostate cancer risk and treatment implications is best understood for those with germline mutations of BRCA2, with emerging data supporting associations with ATM, CHEK2, BRCA1, HOXB13, MSH2, MSH6, PALB2, TP53 and NBN. Treatment implications in the metastatic castration resistant prostate cancer setting include rucaparib and olaparib, and pembrolizumab with potential clinical trial opportunities in earlier disease settings. The data summarized in this review has led to the expansion of national guidelines for germline genetic testing in prostate cancer. We review these guidelines, and discuss the importance of cascade genetic testing of relatives, diverse populations with attention to inclusion, as well as prostate cancer screening updates and clinical trial opportunities for men who carry genetic risk factors for prostate cancer.


Short-latency drinking and increased Na appetite after intracerebral microinjections of NGF in rats.
NERVE GROWTH FACTOR (NGF) is a polypeptide trophic factor for peripheral sympathetic and sensory neurones(1,2). Apparent NGF(3-5) and NGF receptors(6,7) have also been identified in the brain, and intracerebral administration of NGF in the adult rat produces marked biochemical(8) and morphologica(9,10) changes in brain tissue. These findings, taken together with the observations that central injections of NGF facilitate behavioural recovery from brain damage(11,12), indicate that this polypeptide may have an important role in brain function. It has been observed that rats given intraventricular injections of up to 2.3 microg NGF drink copiously (M.E.L. and G. Guroff, unpublished observations). Perkins et al.(13) reported that diencephalic application of crystalline NGF (1-15 microg) resulted in an intense polydipsia. The present report confirms the observations of M.E.L. and Guroff, and extends the findings of Perkins et al.(13) by using solutions of NGF instead of crystals. It also describes for the first time a second phenomenon produced by intracranial administration of NGF, namely an intense appetite for aversive concentrations of sodium solutions.


Robust, Self-Healing Superhydrophobic Fabrics Prepared by One-Step Coating of PDMS and Octadecylamine.
A robust, self-healing superhydrophobic poly(ethylene terephthalate) (PET) fabric was fabricated by a convenient solution-dipping method using an easily available material system consisting of polydimethylsiloxane and octadecylamine (ODA). The surface roughness was formed by self-roughening of ODA coating on PET fibers without any lithography steps or adding any nanomaterials. The fabric coating was durable to withstand 120 cycles of laundry and 5000 cycles of abrasion without apparently changing the superhydrophobicity. More interestingly, the fabric can restore its super liquid-repellent property by 72 h at room temperature even after 20000 cycles of abrasion. Meanwhile, after being damaged chemically, the fabric can restore its superhydrophobicity automatically in 12 h at room temperature or by a short-time heating treatment. We envision that this simple but effective coating system may lead to the development of robust protective clothing for various applications.


Microwave assisted sample preparation for determining water-soluble fraction of trace elements in urban airborne particulate matter: evaluation of bioavailability.
The feasibility of using two different microwave-based sample preparation methods was investigated to determine the total and water-soluble trace metal fraction in airborne particulate matter. The extraction techniques were then applied to urban particulate matter of different sizes in order to evaluate their bioavailability of associated trace metals. While a combination of HNO3-HF-H2O2 was used for the total trace metal fraction of particulate matter, water was employed for the microwave-assisted extraction of water-soluble trace metal fractions. Inductively coupled plasma-mass spectrometry (ICP-MS) was used for the analysis of trace elements. The experimental protocol for the microwave assisted digestion was established using two different SRMs (1648, urban particulate matter and 1649a, urban dust). In the case of water-soluble trace metal fraction, the quantities extracted from the SRMs were compared between ultrasonic and microwave-assisted extractions, and there was a good agreement between the two extraction methods. Blanks values and limits of detection (LODs) for total and water-soluble trace metal concentrations were determined for three different filter substrates (Teflon, Zeflour, and Quartz). Subsequently, the proposed digestion method was evaluated for its extraction efficiency with these filter substrates. Finally, the real-world application of the proposed microwave-based sample preparation methods was demonstrated by analyzing trace elements in airborne particulate samples collected from different outdoor environments in Singapore. The solubility of 11 trace elements detected in the particulate samples is quantified.


Prevalence of Cigarette Smoking Among Adult Emergency Department Patients in Canada.
Tobacco smoking is a priority public health concern, and a leading cause of death and disability globally. While the daily smoking prevalence in Canada is approximately 9.7%, the proportion of smokers among emergency department (ED) patients has been found to be significantly higher. The purpose of this survey study was to determine the smoking prevalence of adult ED patients presenting to three urban Canadian hospitals, and to determine whether there was an increased prevalence compared to the general public. A verbal questionnaire was administered to adult patients aged 18 years and older presenting to Royal University Hospital, St. Paul's Hospital, and Saskatoon City Hospital in Saskatoon, Saskatchewan. We compared patients' smoking habits to Fagerström tobacco dependence scores, readiness to quit smoking, chief complaints, Canadian Triage Acuity Scale scores, and willingness to partake in ED-specific cessation interventions. A total of 1190 eligible patients were approached, and 1078 completed the questionnaire. Adult Saskatoon ED patients demonstrated a cigarette smoking prevalence of 19.6%, which is significantly higher than the adult Saskatchewan public at 14.65% (P<0.0001). Out of the smoking cohort, 51.4% indicated they wanted to quit smoking and would partake in ED-specific cessation counselling, if available. Of the proposed interventions, ED cessation counselling was most popular among patients (62.4%), followed by receiving a pamphlet (56.2%), and referral to a smokers' quit line (49.5%). The higher smoking prevalence demonstrated among ED patients highlights the need for a targeted intervention program that is feasible for the fast-paced ED environment. Training ED staff to conduct brief cessation counselling and referral to community supports for follow-up could provide an initial point of contact for smokers not otherwise receiving cessation assistance.


Seroprevalence of Toxoplasma gondii infection in sheep and goats from different geographical regions of the world: Systematic review and meta-analysis.
The Toxoplasma gondii is an obligate intracellular protozoan parasite which significantly impact small ruminant productivity, international animal trade and transboundary movement of animal across the globe. The seroprevalence of T. gondii infection (toxoplasmosis) in sheep and goats is widely studied in many parts of the world and there is a lack of comprehensive information on prevalence estimates considering the global and regional perspectives. The aim of the study was to use systematic review and meta-analysis methods to estimate the global and regional pooled seroprevalence of T. gondii infection in sheep and goats, as well as factors that influence prevalence estimations. Relevant articles reporting the seroprevalence of toxoplasmosis in sheep and/goats were searched in five electronic databases, including PubMed, Web of Science, Scopus, Embase and ProQuest. After the publications were checked to verify they fit the inclusion criteria, a total of 225 articles were included in the systematic review and meta-analysis, reflecting data from 70 countries/regions. The pooled prevalence was estimated using a random effect meta-analysis model. Overall, the seroprevalence of T. gondii infection was 33.86% (95% CI: 30.47-37.25%) in sheep and 31.78% (95% CI: 28.99-34.58%) in goats, with significant variation in prevalence estimates across geographical locations (p < .001). Substantial heterogeneity (I2 > 75%) was observed in most pooled seroprevalence estimates. The T. gondii infection in global sheep and goat population showed uptrend over the period. This information would be useful for epidemiologist, health authorities and farmers in order to plan future T. gondii survey and infection management strategies both locally and internationally.


Tolerance to the procholinergic action of the D1 receptor full agonist dihydrexidine.
It has been well established that dopamine D1 receptor agonists increase acetylcholine (ACh) release in the brain, an effect that has been suggested to contribute to their procognitive properties. We sought to examine whether the ACh-releasing action of the D1 receptor full agonist dihydrexidine HCl (DHX) is altered after repeated administration. DHX dose-dependently (3, 9, 18, and 36 mg/kg, i.p.) increased ACh efflux in the hippocampus of freely moving rats through D1 receptor stimulation, as the D1 receptor antagonist SCH 23390 (0.3 mg/kg, i.p.) abolished the effect of DHX (18 mg/kg, i.p.). Daily injections of DHX (18 mg/kg, i.p.) over 14 days did not significantly affect basal hippocampal ACh concentrations, but they significantly curtailed the stimulatory action of a challenge injection of DHX (18 mg/kg, i.p.) on ACh efflux. Tolerance to the procholinergic action of DHX develops with repeated administration.


Mood disorder in a patient with a benign thalamic cystic lesion: a case report.
The thalamus is increasingly gaining importance in psychiatric disorders. There are case reports in the literature of neuropsychiatric symptoms associated with thalamic infarcts. The present report elucidates the complexities of linking neuropsychiatric symptoms to a benign thalamic brain lesion, and its impact on management. We present the case of a Caucasian man in his early 30s, who presented with a difficult to treat bipolar illness and coexisting thalamic lesion. In this report we explore the possible links between our patient's symptoms and his brain lesion. We discuss the possible neuronal mechanisms that may be involved and debate the most appropriate management strategies. We hope this report will assist further insights into the role of the thalamus in psychiatric disorders.


Amyloid fibers are water-filled nanotubes.
A study of papers on amyloid fibers suggested to us that cylindrical beta-sheets are the only structures consistent with some of the x-ray and electron microscope data. We then found that our own 7-year-old and hitherto enigmatic x-ray diagram of poly-L-glutamine fits a cylindrical sheet of 31 A diameter made of beta-strands with 20 residues per helical turn. Successive turns are linked by hydrogen bonds between both the main chain and side chain amides, and side chains point alternately into and out of the cylinder. Fibers of the exon-1 peptide of huntingtin and of the glutamine- and asparagine-rich region of the yeast prion Sup35 give the same underlying x-ray diagrams, which show that they have the same structure. Electron micrographs show that the 100-A-thick fibers of the Sup35 peptide are ropes made of three protofibrils a little over 30 A thick. They have a measured mass of 1,450 Da/A, compared with 1,426 Da/A for a calculated mass of three protofibrils each with 20 residues per helical turn wound around each other with a helical pitch of 510 A. Published x-ray diagrams and electron micrographs show that fibers of synuclein, the protein that forms the aggregates of Parkinson disease, consist of single cylindrical beta-sheets. Fibers of Alzheimer A beta fragments and variants are probably made of either two or three concentric cylindrical beta-sheets. Our structure of poly-L-glutamine fibers may explain why, in all but one of the neurodegenerative diseases resulting from extension of glutamine repeats, disease occurs when the number of repeats exceeds 37-40. A single helical turn with 20 residues would be unstable, because there is nothing to hold it in place, but two turns with 40 residues are stabilized by the hydrogen bonds between their amides and can act as nuclei for further helical growth. The A beta peptide of Alzheimer's disease contains 42 residues, the best number for nucleating further growth. All these structures are very stable; the best hope for therapies lies in preventing their growth.


In vivo tendon forces correlate with activity level and remain bounded: evidence in a rabbit flexor tendon model.
While some tendons and ligaments in the lower extremity develop peak forces proportional to the intensity of activity (Komi 1990; Komi et al., 1992; Korvick et al., 1996), others maintain a steady force regardless of activity level (Herzog et al., 1993; Prilutsky et al., 1994). Investigators (Biewener et al., 1988; Korvick et al., 1996) have also shown that peak knee and ankle tendon forces approach one-quarter to one-third of ultimate or failure force values. In the rabbit flexor digitorum profundus (FDP) tendon model we tested several hypotheses, chiefly that peak in vivo forces not only increase with increasing activity but do not exceed one-third of their ultimate or failure values. The FDP tendon was instrumented in three animals, and each rabbit subjected to an experimental design involving three activity levels. Peak tensile forces and rates of rise and fall in tendon force increased significantly with increasing activity (p < 0.01). Further, the tendon maintained a non-zero force level throughout all trials. For the most vigorous activity, inclined hopping, tensile forces and stresses were, on average, within 30% of the tendon's ultimate force and stress values, respectively. Such in vivo measurements in different tendon systems should help investigators better understand the recruitment and contribution of important muscle-tendon units to joint stability and gait.


Travel for medical or dental care by race/ethnicity and rurality in the U.S.: Findings from the 2001, 2009 and 2017 National Household Travel Surveys.
The travel burden for medical or dental care is a well-documented barrier to healthcare access, particularly in rural areas. There is limited research providing national estimates of the travel trends for medical/dental care, particularly among racial/ethnic groups, and among rural and urban populations. We analyzed data from the 2001, 2009, and 2017 National Household Travel Surveys. Main outcomes were the average travel distance (in miles), average travel time (in minutes), and travel burden, characterized as the percentage of trips lasting ≥ 30 miles or minutes for medical/dental care. We used ordinary least squares and multivariable logistic regressions to examine trends in the travel time/distance and travel burden, controlling for socio-demographic and travel dynamics. Among rural residents, the average travel distance for medical/dental care increased by 17.8% between 2001 and 2017, while no increase was observed among urban residents. Thirty-six percent of trips among rural residents lasted ≥ 30 minutes in 2001 but increased to 47.4% in 2017. Logistic regression estimates show that though Blacks experienced higher odds of a travel time burden compared to Whites, the burden lessened over time. In 2017, urban Blacks (OR = 0.41, 95% C.I. = 0.26,0.66), and rural Blacks (OR = 0.16, 95% C.I. = 0.05,0.55) were less likely to spend ≥ 30 minutes traveling for medical/dental care compared to Whites, using the year 2001 as the baseline. The travel distance and time for medical/dental care have increased in rural areas. However, the travel burden among rural and urban Black residents has decreased. Continuing to alleviate excess burdens of transportation may be beneficial.


Novel prediction score including pre- and intraoperative parameters best predicts acute kidney injury after liver surgery.
A recently published score predicts the occurrence of acute kidney injury (AKI) after liver resection based on preoperative parameters (chronic renal failure, cardiovascular disease, diabetes, and alanine-aminotransferase levels). By inclusion of additional intraoperative parameters we aimed to develop a new prediction model. A series of 549 consecutive patients were enrolled. The preoperative score and intraoperative parameters (blood transfusion, hepaticojejunostomy, oliguria, cirrhosis, diuretics, colloids, and catecholamine) were included in a multivariate logistic regression model. We added the strongest predictors that improved prediction of AKI compared to the existing score. An internal validation by fivefold cross validation was performed, followed by a decision curve analysis to evaluate unnecessary special care unit admissions. Blood transfusions, hepaticojejunostomy, and oliguria were the strongest intraoperative predictors of AKI after liver resection. The new score ranges from 0 to 64 points predicting postoperative AKI with a probability of 3.5–95 %. Calibration was good in both models (15 % predicted risk vs. 15 % observed risk). The fivefold cross-validation indicated good accuracy of the new model (AUC 0.79 (95 % CI 0.73–0.84)). Discrimination was substantially higher in the new model (AUCnew 0.81 (95 % CI 0.76–0.86) versus AUCpreoperative 0.60 (95 % CI 0.52–0.69), p < 0.001). The new score could reduce up to 84 unnecessary special care unit admissions per 100 patients depending on the decision threshold. By combining three intraoperative parameters with the existing preoperative risk score, a new prediction model was developed that more accurately predicts postoperative AKI. It may reduce unnecessary admissions to the special care unit and support management of patients at higher risk.


The effect of tranexamic acid in patients with TBI: a systematic review and meta-analysis of randomized controlled trials.
To conduct a systematic review and meta-analysis and evaluate the effect of tranexamic acid in patients with traumatic brain injury. PubMed, EMBASE, and CENTRAL (Cochrane Central Register of Controlled Trials) were searched to identify randomized controlled trials and evaluate the effect of tranexamic acid in traumatic brain injury patients. The primary outcome was mortality. Two reviewers extracted the data independently. The random effect meta-analysis was used to estimate the aggregate effect size of 95% confidence intervals. Six randomized controlled trials investigating tranexamic acid versus placebo and 30073 patients were included. Compared with placebo, tranexamic acid decreased the mortality (RR = 0.92; 95% CI, 0.87-0.96; p < 0.001) and growth of hemorrhagic mass (RR = 0.78; 95% CI, 0.61-0.99; p = 0.04). However, tranexamic acid could not decrease disability or independent, neurosurgery, vascular embolism, and stroke. Current evidence suggested that compared with placebo, tranexamic acid could reduce mortality and growth of hemorrhagic mass. This finding indicated that patients with traumatic brain injury should be treated with tranexamic acid.


Interstitial pneumonitis associated with ifosfamide therapy.
Ifosfamide and cyclophosphamide have many toxicities in common. Interstitial pneumonitis has not been reported previously as a side effect of ifosfamide therapy. The authors report the case of a 58-year-old woman who was treated with ifosfamide for soft tissue sarcoma. After the fifth cycle of chemotherapy she developed clinical evidence of interstitial pneumonitis, a diagnosis that was later confirmed at autopsy. The authors suggest that ifosfamide therapy was directly related to this patient's fatal case of interstitial pneumonitis.


Colour stability of provisional crown and bridge restoration materials.
In an in vitro study to determine the colour stability of provisional restoration materials, the PMMA synthetics Trimm and Cronsin and the bis-acrylic composites Protemp Garant, Protemp Garant NF, Protemp II and Provipont DC were investigated. The colour changes of the cylindrical untreated samples were measured in comparison with samples after 24 and 72 hours of artificial ageing in a Suntest CPS+ UV ageing device using the Minolta CM 3500d spectrophotometer according to the CIE-L*a*b* system. Trimm (light), Cronsin (brown, yellow and universal), Provipont DC (yellow) and Protemp Garant NF (extra light) displayed the greatest discoloration with values > or = 4-21 delta E, where discoloration toward yellow could be discerned. The remaining materials showed lower luminance reflectance values of < or = 1-4 delta E, and therefore greater colour stability. Because of their colour stability the materials Cronsin (grey), Protemp Garant (yellow), Protemp II (light), Protemp Garant NF (yellow, light and extra light) could also be used as long-term interim prosthetics.


Psychopharmacology: the bridge between psychiatry and biology.
The current enthusiasm for biologic approaches to psychiatric problems stems from the practical applications of clinical psychopharmacology. Effective drugs led to more efficient and humane treatment of patients with such disorders. Still, our present drugs leave much to be desired. As we have learned more about how they may ameliorate various types of mental disorders, we generate hypotheses about the possible causes of the disorders we treat. Thus we try to lift ourselves by our bootstraps; drugs generate hypotheses that one hopes will lead to better drugs. Although at times progress seems to be agonizingly slow, if we consider the great progress of the past 35 years one cannot be less than enthusiastic about the prospects for the next three decades. It has been my good fortune to have been connected closely with the developments of the past, a few of which have been discussed in this personal odyssey. It will be the good fortune of my younger colleagues to see the future realization of many of our hopes for better treatment and understanding of psychiatric disorders.


DIS3L2 knockdown impairs key oncogenic properties of colorectal cancer cells via the mTOR signaling pathway.
DIS3L2 degrades different types of RNAs in an exosome-independent manner including mRNAs and several types of non-coding RNAs. DIS3L2-mediated degradation is preceded by the addition of nontemplated uridines at the 3'end of its targets by the terminal uridylyl transferases 4 and 7. Most of the literature that concerns DIS3L2 characterizes its involvement in several RNA degradation pathways, however, there is some evidence that its dysregulated activity may contribute to cancer development. In the present study, we characterize the role of DIS3L2 in human colorectal cancer (CRC). Using the public RNA datasets from The Cancer Genome Atlas (TCGA), we found higher DIS3L2 mRNA levels in CRC tissues versus normal colonic samples as well as worse prognosis in patients with high DIS3L2 expression. In addition, our RNA deep-sequencing data revealed that knockdown (KD) of DIS3L2 induces a strong transcriptomic disturbance in SW480 CRC cells. Moreover, gene ontology (GO) analysis of significant upregulated transcripts displays enrichment in mRNAs encoding proteins involved in cell cycle regulation and cancer-related pathways, which guided us to evaluate which specific hallmarks of cancer are differentially regulated by DIS3L2. To do so, we employed four CRC cell lines (HCT116, SW480, Caco-2 and HT-29) differing in their mutational background and oncogenicity. We demonstrate that depletion of DIS3L2 results in reduced cell viability of highly oncogenic SW480 and HCT116 CRC cells, but had little or no impact in the more differentiated Caco-2 and HT-29 cells. Remarkably, the mTOR signaling pathway, crucial for cell survival and growth, is downregulated after DIS3L2 KD, whereas AZGP1, an mTOR pathway inhibitor, is upregulated. Furthermore, our results indicate that depletion of DIS3L2 disturbs metastasis-associated properties, such as cell migration and invasion, only in highly oncogenic CRC cells. Our work reveals for the first time a role for DIS3L2 in sustaining CRC cell proliferation and provides evidence that this ribonuclease is required to support the viability and invasive behavior of dedifferentiated CRC cells.


Long noncoding RNA H19 - a new player in the pathogenesis of liver diseases.
The liver is a vital organ that controls glucose and lipid metabolism, hormone regulation, and bile secretion. Liver injury can occur from various insults such as viruses, metabolic diseases, and alcohol, which lead to acute and chronic liver diseases. Recent studies have demonstrated the implications of long noncoding RNAs (lncRNAs) in the pathogenesis of liver diseases. These newly discovered lncRNAs have various functions attributing to many cellular biological processes via distinct and diverse mechanisms. LncRNA H19, one of the first lncRNAs being identified, is highly expressed in fetal liver but not in adult normal liver. Its expression, however, is increased in liver diseases with various etiologies. In this review, we focused on the roles of H19 in the pathogenesis of liver diseases. This comprehensive review is aimed to provide useful perspectives and translational applications of H19 as a potential therapeutic target of liver diseases.


Transcript expression in endometrial cancers from Black and White patients.
Previous studies suggest that differences in molecular features of endometrial cancers between racial groups may contribute to the poorer survival in Blacks. The objective of this investigation was to determine whether gene expression among endometrial cancers is different between Blacks and Whites. Fresh frozen tumors from 25 Black patients were matched by stage, grade, and histology to endometrial cancer specimens from 25 White patients. Each case was macrodissected to produce specimens possessing a minimum of 75% cancer cellularity. A subset of 10 matched pairs was also prepared using laser microdissection (LMD) to produce specimens possessing a minimum of 95% cancer cells. Total RNA isolated from each sample was analyzed using the Affymetrix Human Genome U133 Plus 2.0 arrays. Data were analyzed using principal component analysis and binary class comparison analyses. Unsupervised analysis of the 50 endometrial cancers failed to identify global gene expression profiles unique to Black or White patients. In a subset analysis of 10 matched pairs from Blacks and Whites prepared using LMD and macrodissection, unsupervised analysis did not reveal a unique gene expression profile associated with race in either set, but associations were identified that relate to sample preparation technique, histology and stage. Our microarray data revealed no global gene expression differences and identified few individual gene differences between endometrial cancers from Blacks and Whites. More comprehensive methods of transcriptome analysis could uncover RNAs that may underpin the disparity of outcome or prevalence of endometrial cancers in Blacks and Whites.


High quality metaphases from solid ovarian tumors.
Cytogenetic studies of human solid tumor tissue are hampered by poor quality preparations. Using a method of short-term tissue culture developed for ovarian carcinoma specimens, we have obtained large numbers of high quality metaphases suitable for analysis from 19 of 28 ovarian tumors studied.


Measuring interregional functional connectivity using coherence and partial coherence analyses of fMRI data.
Understanding functional connectivity within the brain is crucial to understanding neural function; even the simplest cognitive operations are supported by highly distributed neural circuits. We developed a novel method to measure task-related functional interactions between neural regions by applying coherence and partial coherence analyses to functional magnetic resonance imaging (fMRI) data. Coherence and partial coherence are spectral measures that estimate the linear time-invariant (LTI) relationship between time series. They can be used to generate maps of task-specific connectivity associated with seed regions of interest (ROIs). These maps may then be compared across tasks, revealing nodes with task-related changes of connectivity to the seed ROI. To validate the method, we applied it to an event-related fMRI data set acquired while subjects performed two sequence tapping tasks, one of which required more bimanual coordination. Areas showing increased functional connectivity with both tasks were the same as those showing increased activity. Furthermore, though there were no significant differences in mean activity between the two tasks, significant increases in interhemispheric coherence were found between the primary motor (M1) and premotor (PM) regions for the task requiring more bimanual coordination. This increase in interhemispheric connectivity is supported by other brain imaging techniques as well as patient studies.


[Controlled study comparing mechanical and manual esophago-jejunostomy following gastrectomy].
40 patients with gastric malignancies were entered into a prospective randomised study of mechanical stapling (EEA) vs. manual single layer suturing of the esophago-jejunostomy following total gastrectomy. The groups were well matched with respect to clinical features, medical risk factors and tumor stage. Following manual technique, no anastomotic leak was observed. In the group with automatic mechanical suturing one technical failure and one insufficiency was seen. This difference, however, is not statistically significant. One patient died (cardiac infarction). The analysis of operating time, morbidity and hospital stay showed no significant differences. These results indicate that by use of a precise standardized conventional suture technique the same security performing an esophago-jejunostomy can be achieved as with mechanical staplers.


His bundle electrograms in 51 patients requiring permanent transvenous pacemakers.
Fifty-one patients required the implantation of a Cordis Omnis-Stanicor permanent pacemaker. His bundle electrograms studies, which included right atrial pacing and sinoatrial (SA) node postsuppression recovery times, were performed prior to the implantations. Pacing and sensing thresholds were obtained in all patients. Syncope or episodes of dizziness were the presenting symptoms in virtually every patient. Twenty-eight of the 51 patients had the sick sinus syndrome. Only nine patients were in complete heart block, and an additional nine were in second-degree heart block. The His bundle electrogram technique was not particularly helpful in selecting the potential pacemaker candidate. The symptomatic patient with second- or third-degree heart block requires a pacemaker. In the sick sinus syndrome, the His bundle electrogram was a disappointing tool in detecting abnormalities. In chronic bundle branch block, the His bundle electrogram appears to play a major role. A prolonged H-V interval in a symptomatic patient, in whom a specific noncardiac cause cannot be identified, signifies that a pacemaker is required.


Reduction in Severity of All-Cause Gastroenteritis Requiring Hospitalisation in Children Vaccinated against Rotavirus in Malawi.
Rotavirus is the major cause of severe gastroenteritis in children aged <5 years. Introduction of the G1P[8] Rotarix® rotavirus vaccine in Malawi in 2012 has reduced rotavirus-associated hospitalisations and diarrhoeal mortality. However, the impact of rotavirus vaccine on the severity of gastroenteritis presented in children requiring hospitalisation remains unknown. We conducted a hospital-based surveillance study to assess the impact of Rotarix® vaccination on the severity of gastroenteritis presented by Malawian children. Stool samples were collected from children aged <5 years who required hospitalisation with acute gastroenteritis from December 2011 to October 2019. Gastroenteritis severity was determined using Ruuska and Vesikari scores. Rotavirus was detected using enzyme immunoassay. Rotavirus genotypes were determined using nested RT-PCR. Associations between Rotarix® vaccination and gastroenteritis severity were investigated using adjusted linear regression. In total, 3159 children were enrolled. After adjusting for mid-upper arm circumference (MUAC), age, gender and receipt of other vaccines, all-cause gastroenteritis severity scores were 2.21 units lower (p < 0.001) among Rotarix®-vaccinated (n = 2224) compared to Rotarix®-unvaccinated children (n = 935). The reduction in severity score was observed against every rotavirus genotype, although the magnitude was smaller among those infected with G12P[6] compared to the remaining genotypes (p = 0.011). Each one-year increment in age was associated with a decrease of 0.43 severity score (p < 0.001). Our findings provide additional evidence on the impact of Rotarix® in Malawi, lending further support to Malawi's Rotarix® programme.


Estimating canopy stomatal conductance and photosynthesis in apple trees by upscaling parameters from the leaf scale to the canopy scale in Jinzhong Basin on Loess Plateau.
The estimations of stomatal conductance and photosynthesis performed by upscaling the parameters from the leaf scale to the canopy scale are key points in the fields of forest ecohydrology and physiology. The foundation for solving this scientific problem is determining the optimal models for calculating the leaf stomatal conductance (gl) and photosynthetic rate (Pl). In this study, we used the Jarvis model combined with modification factors, including leaf-air temperature (ΔT) and CO2 concentration inside and outside the stomata (ΔC), to estimate gl and the new Ye light-response model to estimate the Pl of apple trees in Jinzhong Basin on Loess Plateau. The results show that the modified Jarvis (JarvisΔT-ΔC) model and the new Ye light-response model could estimate gl and Pl, respectively, with very high accuracy, with R2 values of 0.926 and 0.959 for the former, and 0.987 and 0.983 for the latter in 2019 and 2021, respectively. Then, we estimated the canopy stomatal conductance (gc) and photosynthetic rate (Pc) by first dividing the apple tree canopy into sunlit and shaded leaves and then summing the contribution of sunlit and shaded gl, Pl and leaf area index. Our efforts will be a valid reference for estimating the gc and Pc of other tree or crop species in the future.


Environmental dietary factors in colorectal cancer. Some unresolved issues.
Unresolved epidemiologic issues in large bowel cancer include reasons for changes in incidence rates, differences in epidemiology of cancer in the distal and proximal colon and rectal cancer, and the optimal fat and fiber levels for low rates. The authors examined questions of suitable procedures for the assessment of intake of specific key nutrients and mode of cooking. International data by site and nutritional factors were compared. Fat and fiber intake in the United States, Japan, and Finland related to differences in rates. Laboratory animal model studies indicated that type of fat affected carcinogenesis. Colon cancer rates in men in the United States increased slightly, but started to decline slightly, as in women. Dietary factors play a key role in causation and prevention of large bowel cancer, with a diet of 25% fat and 25 g fiber recommended. Comprehensive school health education should be used to modify the nutritional habits of children.


Bromocriptine-induced inhibition of hydroxylase/lyase activity of adult rat Leydig cells.
The present in vitro studies using a suspension of Leydig cells from adult rat testis demonstrated that bromocriptine (BR, 2 x 10(-5)M) inhibits hCG-stimulated testosterone production (in the presence of submaximal and maximal doses of hCG), while basal production was unaffected. When the cells were exposed to 8-bromo-cAMP either in the presence or absence of hCG, the inhibitory effect of BR was not reversed. In intact cells, BR inhibited conversion of progesterone and 17-hydroxy-progesterone to testosterone while conversion of androstenedione was not affected. Incubation of homogenates of Leydig cells in the presence of limiting NADPH concentrations (< or = 0.1 mM) resulted in significant BR-induced inhibition of conversion of progesterone (10 microM) to testosterone, while in the presence of "high" concentrations of NADPH (> or = 0.5 mM) BR was without effect. Present results suggest that BR inhibits androgen production at the level of the microsomal enzymes 17 alpha-hydroxylase and/or 17,20-lyase. The inhibitory effect of BR using homogenates of Leydig cells was evident only in the presence of limiting NADPH concentrations that suggests a competitive-like pattern of inhibition, but mechanisms by which BR decreases activity of microsomal enzymes remain to be determined.


The role of lactogenic hormones in maternal behavior in female rats.
Most mammals display an immediate onset of maternal care towards their offspring at parturition. In contrast, inexperienced, nulliparous females are often slow responders and show less intensity in their maternal responses. The transition from a slow responder in non-parous females to a rapid response at parturition is facilitated by the endocrine state of pregnancy. The present report reviews recent evidence from my laboratory demonstrating a role for prolactin in the stimulation of maternal behavior in the rat and presents new findings suggesting tht the conceptus, through its secretion of placental lactogens, helps prime the maternal brain (one site being the medial preoptic area) to respond maternally at parturition.


Distinct functions of interferon-gamma for chemokine expression in models of acute lung inflammation.
Challenge of the immune system with bacterial superantigens or endotoxin induces the systemic release of cytokines followed by lethal septic shock. The lung is particularly susceptible to systemic toxin exposure resulting in acute leucocyte infiltration and vascular damage. In the present study, the functions of interferon-gamma (IFN-gamma) and tumour necrosis factor (TNF) for chemokine regulation during acute lung inflammation were examined. Following administration of the superantigen, staphylococcal enterotoxin B (SEB), lung mRNA levels of the chemokines cytokine-induced neutrophil chemo-attractant (KC), lipopolysaccharide-induced CXC chemokine (LIX), macrophage chemotactic protein-1 (MCP-1), macrophage inflammatory protein (MIP)-1alpha and MIP-2 were increased to a similar extent both in controls and in mice deficient for the IFN-gamma or 55 000 MW TNF receptors. In contrast, interferon-inducible protein-10 (IP-10) and monokine induced by IFN-gamma (Mig) mRNA expression was markedly reduced in mice deficient for IFN-gamma or IFN-gamma receptor, but not in 55 000 MW TNF receptor knockout mice. In situ hybridization experiments demonstrated that IP-10 was highly expressed in lung interstitial macrophages of C57BL/6, but not of IFN-gamma receptor-deficient mice. In contrast to SEB administration, treatment with lipopolysaccharide resulted in a strong induction of IP-10 and Mig in IFN-gamma receptor-deficient mice. Together, these results establish a critical function of IFN-gamma for chemokine induction in acute lung inflammation that is dependent on the nature of the inflammatory stimulus.


DFT study on the reactivity of iron porphyrins tuned by ring substitution.
The effect of beta-substituents (-NO2, -Br, -OCH3) in the reactivity of Fe(II) and Fe(III) porphyrins is studied by means of density functional theory (DFT) calculations. The binding of nitric oxide, carbon monoxide and dioxygen (NO, CO, O2) was explored due to the relevance of their interactions in the chemistry of heme proteins and in biomimetic catalysis. The binding capability (BC) of the porphyrins was found to be strongly modulated both by the donor and attractor substituents used in the work. Unexpectedly, we found that the BC of Fe(II) porphyrins is mainly decreased for the diatomic ligands, when both donor or withdrawing substituents were considered. This effect was particularly significant when the ligand was oxygen. The correlation of Fe-X and X-O (X=N, C, O) bond distances is explained in terms of backdonation effects.


Pemphigus-like antibodies: a report of two cases.
Two patients with high titres of circulating intercellular antibodies are described. One had bullous mycosis fungoides and the other had bullous impetigo. In each case, as the underlying disease responded to treatment, the titre of antibodies fell.


Statins and Risk of Thrombosis in Critically ill Patients with COVID-19: A Multicenter Cohort Study.
Coagulation abnormalities are one of the most important complications of severe COVID-19, which might lead to venous thromboembolism (VTE). Hypercoagulability with hyperfibrinogenemia causes large vessel thrombosis and major thromboembolic sequelae. Statins are potentially a potent adjuvant therapy in COVID-19 infection due to their pleiotropic effect. This study aims to evaluate the effectiveness of statins in reducing the risk of thrombosis among hospitalized critically ill patients with COVID-19. A multicenter, retrospective cohort study of all critically ill adult patients with confirmed COVID-19 admitted to Intensive Care Units (ICUs) between March 1, 2020, and March 31, 2021. Eligible patients were categorized based on their usage of statins throughout their ICU stay and were matched with a propensity score. The primary endpoint was the odds of all cases of thrombosis; other outcomes were considered secondary. A total of 1039 patients were eligible; following propensity score matching, 396 patients were included (1:1 ratio). The odds of all thrombosis cases and VTE events did not differ significantly between the two groups (OR 0.84 (95% CI 0.43, 1.66), P = 0.62 and OR 1.13 (95% CI 0.43, 2.98), P = 0.81, respectively. On multivariable Cox proportional hazards regression analysis, patients who received statin therapy had lower 30-day (HR 0.72 (95 % CI 0.54, 0.97), P = 0.03) and in-hospital mortality (HR 0.67 (95 % CI 0.51, 0.89), P = 0.007). Other secondary outcomes were not statistically significant between the two groups except for D-dimer levels (peak) during ICU stay. The use of statin therapy during ICU stay was not associated with thrombosis reduction in critically ill patients with COVID-19; however, it has been associated with survival benefits.


Mg-Prompted Polyfluoroarene C-H Functionalization: Formal Synthesis of Transfluthrin, Fenfluthrin, and Tefluthrin.
Directing group and transition metal free C-H bond functionalization of a simple molecule is an ideal but challenging chemical transformation. Herein, we report a general Mg-prompted approach to synthesize versatile polyfluoroaryl carbinols at ambient temperature via polyfluoroarene C-H bond addition to aldehydes, which featured excellent monoaddition selectivity and broad functional group compatibility. The usefulness of this practical and efficient method was demonstrated in gram-scale formal synthesis of pyrethroid insecticides transfluthrin, tefluthrin, and fenfluthrin.


Determination of ethnicity in children in The Netherlands: two methods compared.
The aim of this study was to investigate whether names (surnames and the combination of surnames and first names) are adequate to identify Turkish, Moroccan and Surinamese children in a Dutch population. Parents visiting the Emergency Department of the Sophia Children's Hospital with their child filled in a questionnaire about their ethnic background, socio-economic factors and cultural factors. Patients' names were classified by students with a Turkish, Moroccan and Surinamese (Hindustanic and Creole) background. A combined name-method (surnames in combination with first names) and surnames only were compared with a reference method (ethnicity by parents' country of birth). The validity of both name methods and the measurements of agreement (kappa) of both comparisons were analysed. Turkish names showed good validity measurements between the combined name-method and the reference method (sensitivity of 81% and a positive predictive value of 86%). The Arabic names were distinguishable with a sensitivity of 77%, specificity of 99% and positive predictive value of 87%. Surinamese names were less easy to distinguish from the other names (69, 96 and 69% respectively). Overall, the measurement of agreement showed a kappa of 0.69 in the comparison between the classification of the combined names and the classification by parent's country of birth. The classification of the combined names was slightly better than the classification by surnames only. Names can be used to identify Turkish and Arabic (Moroccan) children in a routinely registered database of Dutch children. For Surinamese names this method is less suitable.


Parkinson's Disease Master Regulators on Substantia Nigra and Frontal Cortex and Their Use for Drug Repositioning.
Parkinson's disease (PD) is among the most prevalent neurodegenerative diseases. Available evidences support the view of PD as a complex disease, being the outcome of interactions between genetic and environmental factors. In face of diagnosis and therapy challenges, and the elusive PD etiology, the use of alternative methodological approaches for the elucidation of the disease pathophysiological mechanisms and proposal of novel potential therapeutic interventions has become increasingly necessary. In the present study, we first reconstructed the transcriptional regulatory networks (TN), centered on transcription factors (TF), of two brain regions affected in PD, the substantia nigra pars compacta (SNc) and the frontal cortex (FCtx). Then, we used case-control studies data from these regions to identify TFs working as master regulators (MR) of the disease, based on region-specific TNs. Twenty-nine regulatory units enriched with differentially expressed genes were identified for the SNc, and twenty for the FCtx, all of which were considered MR candidates for PD. Three consensus MR candidates were found for SNc and FCtx, namely ATF2, SLC30A9, and ZFP69B. In order to search for novel potential therapeutic interventions, we used these consensus MR candidate signatures as input to the Connectivity Map (CMap), a computational drug repositioning webtool. This analysis resulted in the identification of four drugs that reverse the expression pattern of all three MR consensus simultaneously, benperidol, harmaline, tubocurarine chloride, and vorinostat, thus suggested as novel potential PD therapeutic interventions.


Musculoskeletal Ultrasound to Identify Subclinical Joint and Periarticular Involvement in Patients With Inflammatory Bowel Disease: A Systematic Literature Review.
Musculoskeletal ultrasonography identifies subclinical joint and entheseal inflammation, and it might be of value in patients with inflammatory bowel diseases (IBD), which are at higher risk of inflammatory arthropathy and disability. Our aim was to retrieve the evidence on the applications of ultrasound in patients with non-arthropathic IBD. Studies enrolling patients with IBD without arthritis, undergoing ultrasound of joints, tendons or entheses were eligible. The outcomes of interest encompassed the frequency of ultrasound-detected lesions, their accuracy in diagnosing arthritis, their prognostic role and sensitivity to change. All study types, excluding case reports, case series and narrative reviews, were included. Search strategies were applied in PubMed and Embase. Abstract and full-texts were evaluated by pairs of reviewers. The risk of bias was evaluated through the Newcastle-Ottawa scale or the Quality Assessment of Diagnostic Accuracy Studies (QUADAS) 2. The protocol was registered in PROSPERO (CRD42021264972). Out of 2,304 records, eight studies were included, all reporting the frequency of lesions, while only three evaluated also the diagnostic accuracy. All studies had a cross-sectional design, with no evidence on prediction or follow-up. All studies evaluated the entheses, while only three the joints. The most common chronic lesions were entheseal thickening (up to 81.5%) and enthesophytes (67.9%), while entheseal erosions were present in 16%-17% of patients. Among inflammatory lesions, power Doppler was reported in 14%-67% of patients. There were no differences among Crohn's disease or ulcerative colitis and depending on disease activity, while there were contrasting results on different disease durations. When evaluating the diagnostic performance, the best specificity for a diagnosis if IBD was 0.88 (95%CI, 0.8-0.94) for joint abnormalities. Also, the best sensitivity was 0.88 (95%CI, 0.76-0.95) for entheseal lesions. No studies assessed of the combination of lesions. Due to the limited number of studies, meta-analyses were not performed. Despite the possible value of ultrasound in IBD, there is limited evidence deriving from cross-sectional studies. Longitudinal studies are needed to clarify the role of this technique, while its current placement might be that of complementing clinical assessment, in particular in early intestinal disease.


Application of ultrasound-guided tumescent local anesthesia in prepectoral pacemaker implantation: A detailed procedural report.
Ultrasound image-guided tumescent local analgesia (TLA) is an effective technique in prepectoral pacemaker implantation surgery. The technique provides enough analgesic effect, at the same time, the pocket creation procedures become easy because of the hydrodissection effect of TLA solution. This technique relieves patients from intra-operative pain and relieves physicians from stresses during pocket creation.


Role of Body Composition in the Prediction of Skeletal Fragility Induced by Hormone Deprivation Therapies in Cancer Patients.
This review paper is intended to show that changes in body composition are key in the pathogenesis of bone fragility amongst patients with breast and prostate cancer receiving hormone deprivation therapies (HDTs) and that the mechanism is based on the development of alterations in bone quality rather than in bone quantity. Preclinical and clinical data suggest a tight connection amongst bone, adipose and muscular tissues by means of several soluble mediators, potentially leading to (1) bone resorption and bone quality deterioration in sarcopenic obese subjects, (2) bone mineral deposition in healthy trained subjects. Cancer patients treated with HDTs frequently fall into the first condition, named osteosarcopenic obesity. Current clinical guidelines for the prevention of treatment-induced osteoporosis focus on bone mineral density (BMD) as a main predictive factor for fracture risk; however, the pathophysiology underlying HDT-induced bone fragility differs from that of primary and postmenopausal osteoporosis, suggesting a prevalent role for bone quality alterations. Focusing on available data from clinical trials, in our review we suggest osteosarcopenic obesity as a common target for the prevention and treatment of HDTs-related metabolic and skeletal complications, beyond a BMD-centred approach.


Vision-based Nano Robotic System for High-throughput Non-embedded Cell Cutting.
Cell cutting is a significant task in biology study, but the highly productive non-embedded cell cutting is still a big challenge for current techniques. This paper proposes a vision-based nano robotic system and then realizes automatic non-embedded cell cutting with this system. First, the nano robotic system is developed and integrated with a nanoknife inside an environmental scanning electron microscopy (ESEM). Then, the positions of the nanoknife and the single cell are recognized, and the distance between them is calculated dynamically based on image processing. To guarantee the positioning accuracy and the working efficiency, we propose a distance-regulated speed adapting strategy, in which the moving speed is adjusted intelligently based on the distance between the nanoknife and the target cell. The results indicate that the automatic non-embedded cutting is able to be achieved within 1-2 mins with low invasion benefiting from the high precise nanorobot system and the sharp edge of nanoknife. This research paves a way for the high-throughput cell cutting at cell's natural condition, which is expected to make significant impact on the biology studies, especially for the in-situ analysis at cellular and subcellular scale, such as cell interaction investigation, neural signal transduction and low invasive cell surgery.


Tissue-specific expression of keratin proteins in human esophageal and epidermal epithelium and their cultured keratinocytes.
In contrast to the simplified keratin content of bovine, rabbit, and rat esophageal epithelium (composed mainly of a 57 and 46 or 51 kD keratin, depending on the animal species), human esophageal epithelium contained a quantitatively different array of keratin proteins, ranging in molecular weight from 37 to 61 kD. The pattern of keratin proteins from human esophageal epithelium differed qualitatively and quantitatively from that of human epidermis. Human esophageal epithelium lacked the 63, 65, and 67 kD keratins characteristic of human epidermis, consistent with the absence of a granular layer and an anucleate stratum corneum. Moreover, human esophageal epithelium contained a distinctive 61 kD keratin protein which was either not present or present in only small amounts in human epidermis and variable amounts of a 37 kD keratin. Whereas the 56, 59, and 67 kD keratins were the most abundant keratins in human epidermis, the 52, 57, and 61 kD keratins predominated in human esophageal epithelium. During in vitro cultivation, both human epidermal and esophageal keratinocytes produce colonies which are stratified, but the morphologic appearance of these cultured epithelia differs. Only cultured human epidermal keratinocytes contain keratohyalin granules in the outermost layers and a prominent 67 kD keratin on immunoprecipitation. Otherwise the keratin contents appear similar. In conclusion, human esophageal epithelium exhibited intertissue and interspecies differences in the pattern of keratin proteins. During in vitro cultivation, human esophageal keratinocytes retained some aspects of their distinctive program of differentiation.


The endothelin A receptor antagonist LU 135252 protects the myocardium from neutrophil injury during ischaemia/reperfusion.
Endothelin-1 (ET-1) is not only a potent vasoconstrictor but also a stimulator of polymorphonuclear leukocyte (PMN) aggregation and adhesion. The aim of this study was to investigate whether an ETA receptor antagonist attenuates the PMN-mediated contractile dysfunction following myocardial ischaemia. Isolated rat hearts were perfused according to the Langendorff method. The hearts were subjected to global ischaemia and reperfused with buffer solution only, or human PMNs dissolved in rat plasma (HNRP). In an initial study, the ETA receptor antagonist LU 135252 (1 and 10 mumol/l) or ET-1 (1 and 10 nmol/l) did not significantly affect the recovery of left ventricular developed pressure (LVDP), end-diastolic pressure (LVEDP), the first derivative of left ventricular pressure (dP/dt) or the rate pressure product (RPP) during reperfusion with buffer solution only compared to a vehicle group. In a second study on hearts reperfused with HNRP, administration of LU 135252 (10 mumol/l) significantly enhanced the recovery of LVDP, dP/dt and RPP in hearts reperfused with HNRP. LVEDP was 20 mmHg lower in hearts given LU 135252 than vehicle in combination with HNRP (P < 0.05). The outflow of PMNs in the coronary effluent during reperfusion was 41 +/- 8% in hearts given LU 135252 compared to 9 +/- 5% in vehicle-treated hearts (P < 0.01). There was a significant correlation between the myocardial functional recovery and the outflow of PMNs. Administration of ET-1 (0.1 and 1 nmol/l) in combination with HNRP resulted in complete loss of contractile function and no outflow of PMNs during reperfusion. The ETA receptor antagonist LU 135252 protects from ischaemia/reperfusion injury in the isolated rat heart in the presence of PMNs. It is suggested that inhibition of PMN-induced injury during reperfusion is an important cardioprotective action of LU 135252.


Mechanism of immortalization.
Model systems implementing various approaches to immortalize cells have led toward further understanding of replicative senescence and carcinogenesis. Human diploid cells have a limited life span, termed replicative senescence. Because cells are terminally growth arrested during replicative senescence, it has been suggested that it acts as a tumor suppression mechanism as tumor cells exhibit an indefinite life span and are immortal. The generation of immortal cells lines, by the introduction of SV40 and human papillomavirus (HPV) sequences into cells, has provided invaluable tools to dissect the mechanisms of immortalization. We have developed matched sets of nonimmortal and immortal SV40 cell lines which have been useful in the identification of novel growth suppressor genes (SEN6) as well as providing a model system for the study of processes such as cellular aging, apoptosis, and telomere stabilization. Thus, their continued use is anticipated to lead to insights into other processes, which are effected by the altered expression of oncogenes and growth suppressors.


Operation Open Heart--Rwanda.
In October 2007, five Intensive Care Nurses who trained at Epworth Hospital went to Rwanda to participate in a foreign aid program called "Operation Open Heart", run by the Sydney Adventist Hospital, Wahroonga, New South Wales Australia. The program was based at the King Faisal Hospital in Kigali, Rwanda and is part of a health care outreach project that sends teams of specialist doctors and health professionals to perform open heart surgery on children and adults with congenital heart abnormalities in under-developed countries.


Estimated prevalence of mental disorders and the desire for social distance--results from population surveys in two large German cities.
The study is focused on two research questions: What are the public's estimates of the prevalence of depression, schizophrenia, bulimia nervosa and anorexia nervosa? What is the relationship between the estimated prevalence of the mental disorders and the public's desire for social distance? Analyses are based on a telephone survey in two large German cities (Hamburg and Munich, N=2014, response rate 51%). Vignettes with typical signs and symptoms suggestive of a depression, schizophrenia, bulimia nervosa and anorexia nervosa were presented. Respondents were asked about the lifetime prevalence of the mental disorders and their desire for social distance. Across all four disorders under study the respondents markedly overestimate the rates of lifetime prevalence. Increasing prevalence estimation is associated with a significant decrease in the desire for social distance in case of schizophrenia. As for depression, anorexia nervosa and bulimia nervosa there are no significant associations. Many campaigns aimed at reducing stigma emphasize the high prevalence of mental disorders. The assumption of these campaigns is that reduction of the perceived distinction leads to a decrease of the desire for social distance towards those afflicted. Our results indicate that this may not generally be an effective way to reduce stigma.


Investigation of the biochemical controls on mercury uptake and mobility in trees.
Atmospheric elemental mercury (Hg(0)) enters plant stomata, becomes oxidized, and is then transferred to annual growth rings providing an archive of air Hg(0) concentrations. To better understand the processes of Hg accumulation and translocation, the foliage of quaking aspen and Austrian pine were exposed to Hg(0), and methylmercury (MeHg) or Me198Hg via roots, in controlled exposures during the summer. Isotopic measurements demonstrated, in a laboratory setting, that the natural mass-dependent fractionation observed was the same as that measured in field studies, with the lighter isotopes being preferentially taken up by the leaves. Hg was measured in plant tissues across seasons. Aspen trees moved Hg into new growth immediately after exposure, resorbed Hg in the fall, and then distributed Hg to new growth tissues in the spring. Austrian pine did not reallocate Hg. Mercury measured in aspen leaf fractions of trees exposed to Hg(0) demonstrated that 85 % of Hg was in the cell wall. It was also found that redox-active molecules, such as H2O2, could potentiate the release of cell wall-bound Hg from aspen leaves, providing a potential mechanism for remobilization. Regardless of the mechanism, the ability of aspen to reallocate Hg to new tissues indicates that Hg distribution in tree rings from aspen do not provide a reliable record of yearly changes in atmospheric Hg(0).


Effects of Wastewater from Oil Exploration on Soil Mesofauna.
Wastewater from oil exploration may contain substances that can alter the diversity of soil organisms. This study evaluated whether produced water treated by filtration or reverse osmosis and glutaraldehyde from reverse osmosis treatments negatively affected the mesofauna in an irrigated area. In the field, irrigation with produced water treated by reverse osmosis and filtration influenced Hymenoptera and Cosmochthonius sp., while Entomobryomorpha springtails were affected only by the reverse osmosis water. In the ecotoxicological tests, reproduction in the springtail Folsomia candida was inhibited by the reverse osmosis treatment, while reproduction in the earthworm Enchytraeus crypticus was affected by both water treatments. Although glutaraldehyde did not affect the survival of F. candida, the reproduction was inhibited (EC50 = 44.4 mg/L). No adverse effect of glutaraldehyde was observed on reproduction or survival of E. crypticus. These results indicate that produced water, when used in irrigated agriculture, may affect soil functional mesofauna.


Luteolin protects dopaminergic neurons from inflammation-induced injury through inhibition of microglial activation.
Parkinson's disease is a neurodegenerative disorder characterized by progressive degeneration of dopaminergic neurons in the substantia nigra. Accumulating evidence has suggested that inflammation in the brain participates in the pathogenesis of Parkinson's disease. Luteolin, a polyphenolic compound found in foods of plant origin, belongs to the flavone subclass of flavonoids, and has been shown to possess antimutagenic, antitumorigenic, antioxidant and antiinflammatory properties. In this study, we found that luteolin concentration-dependently attenuated the lipopolysaccharide (LPS)-induced decrease in [(3)H]dopamine uptake and loss of tyrosine hydroxylase-immunoreactive neurons in primary mesencephalic neuron-glia cultures. Moreover, luteolin also significantly inhibited LPS-induced activation of microglia and excessive production of tumor necrosis factor-alpha, nitric oxide and superoxide in mesencephalic neuron-glia cultures and microglia-enriched cultures. Our results demonstrate that luteolin may protect dopaminergic neurons from LPS-induced injury and its efficiency in inhibiting microglia activation may underlie the mechanism.


[Diffuse atrophy of the choroid--a case report].
The authors present a case of the 66-year-old female patient suffering from the diffuse atrophy of the choroid. The 66-year-old woman was referred to the Ophthalmological Clinic in Krakow with the diagnosis of choroideremia. The patient developed central vision problems (mainly in the left eye) and night blindness. We performed following investigations: distance and near visual acuity with Snellen charts, Amsler grid test, the investigation of the anterior and posterior segments of both eyes, and the fluorescein angiography as well as the infrared photo of the fundus. The assessment of ornithine serum level was performed. The ophthalmological examination revealed: the distance visual acuity in the RE=0.5, and in the LE=0.25. The near visual acuity in the RE=0.5, in the LE=0.75. The Amsler grid test in the RE showed no pathology but in the LE revealed in the nasal aspect of the central visual field a relative scotoma. Fundoscopy, fluorescein angiography and infrared imaging revealed the broad patch form atrophy of the RPE and choriocapillaris within the whole fundus and also within the macula. The serum level of ornithine was within the normal limits. Based on the results of performed investigations the definitive diagnosis of a very rare dystrophy--a diffuse atrophy of the choroid was established.


Potential for advice from doctors to reduce the number of patients referred to emergency departments by NHS 111 call handlers: observational study.
To determine the effect of using experienced general practitioners (GPs) to review the advice given by call handlers in NHS 111, a national service giving telephone advice to people seeking medical care. Observational study following the introduction of GPs to review call handlers' decisions which had been made using decision support software. NHS 111 call centre covering Cambridgeshire and Peterborough. When a call handler using standard NHS 111 decision support software would have advised the caller to attend the hospital accident and emergency (A&E) department, the decision was reviewed by an experienced GP. Percentage of calls where an outcome other than A&E attendance was recommended by the GP. Of 1474 cases reviewed, the GP recommended A&E attendance in 400 cases (27.1%). In the remainder of cases, the GP recommended attendance at a primary care out-of-hours centre or minor injury unit in 665 cases (45.2%) and self-management or some alternative strategy in 409 (27.8%). Fewer callers to NHS 111 would be sent to emergency departments if the decision was reviewed by an experienced GP. Telephone triage services need to consider whether using relatively unskilled call handlers supported by computer software is the most cost-effective way to handle requests for medical care.


Influences of children's and adolescents' action-control processes on school achievement, peer relationships, and coping with challenging life events.
Self-regulation represents a core aspect of human functioning that influences positive development across the life span. This chapter focuses on the action-control model, a key facet of self-regulation during childhood and early adolescence. The authors discuss the development of action-control beliefs, paying particular attention to their relationship to indices of positive development. They then discuss how linking the action-control model with other theories of self-regulation can inform our understanding of self-regulation across the life span.


Liver graft harbouring hydatid disease: how far can we extend our donor pool?
As the current demand for liver transplantation exceeds our donor pool, the donor search is shifted towards the extended donor criteria. The livers harbouring hydatid disease are a controversial source of grafts. We report the use of a liver graft harbouring hydatid disease in urgent liver transplantation in a patient with autoimmune hepatitis. Corroborated with previous experiences, we show that the liver grafts harbouring hydatid cysts provide a rare but valuable source of organs.


Surface accessibility of 13C-labeled lysine residues in membrane-bound myelin basic protein.
Surface-exposed regions of membrane-bound myelin basic protein--the major extrinsic membrane protein of central nervous system myelin--have been implicated as possible antigenic sites in diseased myelin. With the goal of determining the extent and nature of these regions, we have prepared basic protein modified with 13CH3-enriched acetyl groups at 7 of its 13 lysine residues. The resulting protein was placed in a membrane environment and studied by NMR spectroscopy to determine the location and rates of molecular motion of the labeled side chains with respect to lipid bilayers of the membrane. When 13C NMR spectra were obtained of the acetylated protein bound to multilamellar vesicles prepared from dimyristoylphosphatidic acid in the gel state (T = 33 degrees C), conditions under which reduced motion in the lipid bilayer broadens methylene and methyl 13C resonances of the membrane beyond detection (i.e. greater than 75-100 Hz), line widths of membrane-bound protein were measured to be 7.8 Hz, an increase of 4 Hz versus free protein. A reduction of 25-30% in integrated intensity observed in protein acetyl resonances upon membrane interaction was shown to be attributable to a population of protein-aggregated liposomes whose resonances were similarly too broad to be observed. Thus, the epsilon-acetyllysyl probes distributed throughout the protein do not penetrate the dimyristoylphosphatidic acid bilayer, but must reside in the interstitial aqueous spaces at or between membrane surfaces. These findings suggest an overall surface accessibility of membrane-bound myelin basic protein and are therefore incompatible with a model for the protein involving membrane-embedded loops or regions of functional significance.


Pinocembrin alleviates pyroptosis and apoptosis through ROS elimination in random skin flaps via activation of SIRT3.
Random skin flap grafting is the most common skin grafting technique in reconstructive surgery. Despite progress in techniques, the incidence of distal flap necrosis still exceeds 3%, which limits its use in clinical practice. Current methods for treating distal flap necrosis are still lacking. Pinocembrin (Pino) can inhibit reactive oxygen species (ROS) and cell death in a variety of diseases, such as cardiovascular diseases, but the role of Pino in random flaps has not been explored. Therefore, we explore how Pino can enhance flap survival and its specific upstream mechanisms via macroscopic examination, Doppler, immunohistochemistry, and western blot. The results suggested that Pino can enhance the viability of random flaps by inhibiting ROS, pyroptosis and apoptosis. The above effects were reversed by co-administration of Pino with adeno-associated virus-silencing information regulator 2 homolog 3 (SIRT3) shRNA, proving the beneficial effect of Pino on the flaps relied on SIRT3. In addition, we also found that Pino up-regulates SIRT3 expression by activating the AMP-activated protein kinase (AMPK) pathway. This study proved that Pino can improve random flap viability by eliminating ROS, and ROS-induced cell death through the activation of SIRT3, which are triggered by the AMPK/PGC-1α signaling pathway.


CDC20 contributes to the development of human cutaneous squamous cell carcinoma through the Wnt/β‑catenin signaling pathway.
Cell division cycle 20 (CDC20) is a regulatory molecule and serves critical roles at multiple points of the cell cycle. Recent evidence indicates that CDC20 may serve an oncogenic role in a number of human cancer types. However, the role of CDC20 in primary cutaneous squamous cell carcinoma (cSCC) has not been studied, to the best of our knowledge. The aim of the present study was to investigate whether and how CDC20 is involved in the tumorigenesis of cSCC. The results revealed that CDC20 expression was significantly increased in cSCC tissues and cell lines, and its expression was associated with pathological differentiation. Downregulation of CDC20 inhibited cell proliferation, induced cell cycle arrest, promoted apoptosis and reduced migratory ability through inhibition of the Wnt/β‑catenin signaling pathway. Furthermore, all‑trans‑retinoic acid treatment significantly downregulated CDC20 expression in cSCC. The present results revealed that CDC20 may serve a crucial role in human cSCC, and suggested that CDC20 may be a novel biomarker for the prevention, diagnosis and treatment of cSCC.


[Dynamic release of tinidazole from the degradable PLLA-tinidazole blend gel].
To determine the dynamic release of tinidazole from the degradable poly-lactic acid (PLLA)-tinidazole blend gel (a periodontal local drug delivery) by high-performance liquid chromatography (HPLC) in vitro and to observe the polylactic acid (as a vector of tinidazole) how to affect the release of tinidazole. HPLC analysis was conducted. The operating conditions were C18-ODS-A column, water-methanol-acetic acid as mobile phase at a flow rate of 1.5 ml/min and a detection wavelength at 310 nm and a column temperature at 30 degrees C. The retention time of tinidazole was about 12 min. There was good linear relationship between the concentrations of tinidazole in blend gel and their peak areas in the ranges of 5 - 500 mg/L. The regression reaction was y = 0.836 + 8.452 2 x 10(-5) x (r = 0.998 6). RSD was 0.2%. Polylactic acid had no influence on the determination of tinidazole. The daily average release of tinidazole was 5.60%. The cumulative release of tinidazole was about 78.40% in 14 days. The in vitro drug release analysis is an useful method in evaluating the performance of local drug delivery system. HPLC analysis is a simple and accurate method with good reproducibility.


SKOR1 has a transcriptional regulatory role on genes involved in pathways related to restless legs syndrome.
Restless legs syndrome (RLS) is a common sleep-related sensory-motor disorder. It is characterized by uncomfortable sensations in the legs during the evening or at night. The symptoms can be partially relieved by movement, so typically affected individual needs to walk during rest time; this interferes with sleep. GWAS have identified 19 RLS-associated loci. Among the first to be reported and most significant and robustly replicated reports are variants in the SKOR1 noncoding regions. SKOR1 is highly expressed in the CNS of humans and mice. Skor1 acts as a corepressor of Lbx1 transcription factor in mice and these two genes act together to regulate the cell fate of interneurons in the dorsal horn of the spinal cord. Based on this data we investigated the regulatory role of SKOR1 using a global RNA-sequencing approach in human cell lines where SKOR1 was either overexpressed or silenced. For this work we generated and validated a new poly-clonal anti-SKOR1. Pathway and gene set enrichment analyses of the differentially expressed genes showed, among others, enrichment of genes involved in neurodevelopment and iron metabolism, two RLS relevant pathways that were previously found to be enriched in the latest RLS GWAS meta-analysis. Analysis of our different datasets further supports and highlights the regulatory role of SKOR1, which when dysregulated might represent a key pathogenic element of RLS. A better understanding of SKOR1 and its activity could open new avenues of investigation for the development of a much-needed therapy.


The study of transient protein-nanoparticle interactions by solution NMR spectroscopy.
The rapid development of novel nanoscale materials for applications in biomedicine urges an improved characterization of the nanobio interfaces. Nanoparticles exhibit unique structures and properties, often different from the corresponding bulk materials, and the nature of their interactions with biological systems remains poorly characterized. Solution NMR spectroscopy is a mature technique for the investigation of biomolecular structure, dynamics, and intermolecular associations, however its use in protein-nanoparticle interaction studies remains scarce and highly challenging, particularly due to unfavorable hydrodynamic properties of most nanoscale assemblies. Nonetheless, recent efforts demonstrated that a number of NMR observables, such as chemical shifts, signal intensities, amide exchange rates and relaxation parameters, together with newly designed saturation transfer experiments, could be successfully employed to characterize the orientation, structure and dynamics of proteins adsorbed onto nanoparticle surfaces. This review provides the first survey and critical assessment of the contributions from solution NMR spectroscopy to the study of transient interactions between proteins and both inorganic (gold, silver, and silica) and organic (polymer, carbon and lipid based) nanoparticles. This article is part of a Special Issue entitled: Physiological Enzymology and Protein Functions.


ADXS31142 Immunotherapy ± Pembrolizumab Treatment for Metastatic Castration-Resistant Prostate Cancer: Open-Label Phase I/II KEYNOTE-046 Study.
ADXS31-142 is an attenuated Listeria monocytogenes-based immunotherapy targeting prostate-specific antigen (PSA), being evaluated as monotherapy and combined with pembrolizumab for metastatic castration-resistant prostate cancer (mCRPC). The 2-part phase I/II KEYNOTE-046 study enrolled men with mCRPC who have progressed after 2 or fewer prior systemic treatment regimens in the metastatic setting. In Part A, intravenous ADXS31-142 monotherapy was given every 3 weeks (q3w) to 3 dose-escalation cohorts. In Part B, ADXS31-142 (1 × 109 colony-forming units) plus pembrolizumab (200 mg) was administered intravenously q3w for 3 doses with a fourth pembrolizumab dose 3 weeks later (12-week cycles) for up to 24 months or until progression/toxicity. Endpoints included safety, overall response rate, progression-free survival (PFS), overall survival (OS), and immunogenicity. Fifty patients received ADXS31-142 alone (n = 13) or with pembrolizumab (n = 37). Among the 37 RECIST-evaluable patients (n = 8 Part A; n = 29 Part B), there were no objective responses. Median PFS was 2.2 months (95% CI: 0.8-7.4) with monotherapy and 5.4 months (95% CI: 2.3-7.9) with the combination; median OS was 7.8 months (95% CI: 4.4-18.5) and 33.7 months (95% CI: 15.4-not evaluable), respectively. Promising OS benefit was observed in combination-treated patients who had received prior docetaxel (16.0 months, 95% CI: 6.4-34.6; n = 20) and those with visceral metastasis (16.4 months, 95% CI 4.0-not evaluable; n = 11). All patients had ≥1 treatment-related adverse event, mostly grade 1/2 manageable events. No additive toxicity was observed with combination treatment. Combining ADXS31-142 with pembrolizumab was safe and well tolerated. The observed OS in mCRPC warrants further testing of this combination. NCT02325557.


Development of nocturia in relation to health, age and the menopause.
To analyse the relationship between nocturia, age, the menopausal transition, parturition and hormone replacement treatment (HRT) in women. A questionnaire study was carried out in 3669 randomly selected women (out of 6000 invited) in the County of Jämtland, Sweden. Questions were asked about health, the occurrence of somatic diseases and symptoms, habits, health care and medication. In univariate analyses age, menopausal state and HRT, but not parturition, were associated with increased nocturia. In a multiple logistic regression analysis, independent correlates for two or more nocturnal micturition episodes versus no more than one episode were: health, poor versus good 2.9 (2.1-3.8); <5 years after the menopause versus before 1.8 (1.3-2.5); 5-9 years after the menopause versus before 2.1 (1.5-3.0); > or =10 years after the menopause versus before 3.1 (2.3-4.2). Age and HRT were deleted by the logistic regression model. The present data indicate that menopausal state, but not age, parturition and HRT are independent correlates of nocturia in 40-64-year-old women.


Insignificant C1 effects cannot be called 'marginally significant'.
Slotnick (this issue) proposes that the earliest ERP C1 component, evoked by visual stimuli, may be affected by attention if certain experimental parameters are used. My opinion on this paper is that some results of previous papers are forced to appear significant even though they were not. This commentary focuses on Slotnick's description of my cited papers and clarifies that there were not in fact any significant C1 attention effects present. Even though the C1 was often numerically larger in the attended condition, the statistical tests of these effects were far from significance.


The effects of detergents on the composition of postsynaptic densities.
A method of purifying postsynaptic densities (PSD) of Cohen et al. (1977) has been modified, primarily by the substitution of octyl glucoside as the detergent used to solubilize synaptosomal fractions. Subsequent extraction with other detergents resulted in the selective removal of specific polypeptides. In particular sulphobetaine 3-14 removed most of the beta-tubulin but not alpha-tubulin. Sodium N-lauroyl sarcosinate completely destroyed the structural integrity of the PSD when the in vitro formation of intermolecular disulphide bonds was minimized. These results suggest that the structure of PSDs is more labile than previously thought and demonstrate a technique for further examining their composition.


In vivo production of neuraminidase by Pasteurella multocida A:3 in goats after transthoracic challenge.
Six goats were injected transthoracically with live Pasteurella multocida A:3 to examine if an extracellular enzyme, neuraminidase, was produced in vivo during infection with this organism. The principal group of goats (n = 6) each received 1 ml of live 7.5 x 10(4) cfu of P. multocida mixed with polyacrylate beads transthoracically in the left lung on day 0 and 1 ml of live P. multocida (2.2 x 10(8) cfu) mixed with polyacrylate beads transthoracically in the left lung on day 22. Six goats were used as negative controls and received 0.3 g of polyacrylate beads subcutaneously in the right flank on days 0 and 22. Serum was obtained from all animals on days 0, 7, 14, 22, 29, and 36. Preimmune sera from all animals showed no detectable antibody to P. multocida A:3 neuraminidase in an enzyme neutralization assay. None of the sera from the negative control animals demonstrated a significant antibody titer against the P. multocida A:3 neuraminidase. On day 36, serum samples from the six infected animals possessed complete enzyme-neutralizing activity. Anti-neuraminidase antibody could be detected as early as day 14 in the infected animals. These data show that neuraminidase is produced in vivo during an active P. multocida A:3 lobar infection.


Mechanisms of age-dependent response to winter temperature in perennial flowering of Arabis alpina.
Perennial plants live for more than 1 year and flower only after an extended vegetative phase. We used Arabis alpina, a perennial relative of annual Arabidopsis thaliana, to study how increasing age and exposure to winter cold (vernalization) coordinate to establish competence to flower. We show that the APETALA2 transcription factor, a target of microRNA miR172, prevents flowering before vernalization. Additionally, miR156 levels decline as A. alpina ages, causing increased production of SPL (SQUAMOSA PROMOTER BINDING PROTEIN LIKE) transcription factors and ensuring that flowering occurs in response to cold. The age at which plants respond to vernalization can be altered by manipulating miR156 levels. Although miR156 and miR172 levels are uncoupled in A. alpina, miR156 abundance represents the timer controlling age-dependent flowering responses to cold.


Surface plasmon resonance biosensor detects the downstream events of active PKCbeta in antigen-stimulated mast cells.
Surface plasmon resonance (SPR) biosensors detect large changes of angle of resonance (AR) when RBL-2H3 mast cells are cultured on a sensor chip and stimulated with antigen. However, the detail of molecular events that are responsible for such large changes of AR remained unknown. In this study, we investigated the relationship between intracellular signaling events induced by antigen and the change of AR, by genetic manipulation of intracellular signaling molecules; spleen tyrosine kinase (Syk), src-like adaptor protein (SLAP), linker for activation of T cells (LAT), growth-factor-receptor-bound protein 2 (Grb2), Grb2-related adaptor protein (Gads), and isotypes of protein kinase C (PKC). RBL-2H3 mast cells overexpressing dominant-negative Syk or SLAP, which both interfere with active Syk, exhibited only minimal increase of AR in response to antigen stimulation. Likewise, the interference of the activation of LAT and Gads, by expressing dominant-negative LAT and Gads, respectively, resulted in nearly complete suppression of the antigen-induced increase of AR. The cells overexpressing PKCs, apart from PKCbeta, showed a reduced extent of increase of AR in response to antigen stimulation. Moreover, the introduction of the small interfering RNA targeted against PKCbeta suppressed the antigen-induced increase of AR. These results indicate that the activation of Syk, LAT, Gads, and subsequent PKCbeta is indispensable for the antigen-induced increase of AR of mast cells detected by SPR biosensors.


Comparison of neuroendocrine tumor detection and characterization using DOTATOC-PET in correlation with contrast enhanced CT and delayed contrast enhanced MRI.
We evaluated the rate of successful characterization of gastroenteropancreatic neuroendocrine tumors (NETs) present with an increased somatostatin receptor, comparing CE-CT with CE-MRI, each in correlation with DOTATOC-PET. 8 patients with GEP-NET were imaged using CE-MRI (Gd-EOB-DTPA), CE-CT (Imeron 400) and DOTATOC-PET. Contrast-enhancement of normal liver-tissue and metastasis was quantified with ROI-technique. Tumor delineation was assessed with visual-score in blind-read-analysis by two experienced radiologists. Out of 40 liver metastases in patients with NETs, all were detected by CE-MRI and the lesion extent could be adequately assessed, whereas CT failed to detect 20% of all metastases. The blind-read-score of CT in arterial and portal phase was median -0.65 and -1.4, respectively, and 2.7 for delayed-MRI. The quantitative ROI-analysis presented an improved contrast-enhancement-ratio with a median of 1.2, 1.6 and 3.3 for CE-CT arterial, portal-phase and delayed-MRI respectively. Late CE-MRI was superior to CE-CT in providing additionally morphologic characterization and exact lesion extension of hepatic metastases from neuroendocrine tumor detected with DOTATOC-PET. Therefore, late enhanced Gd-EOB-DTPA-MRI seems to be the adequate imaging modality for combination with DOTATOC-PET to provide complementary (macroscopic and molecular) tumor characterization in hepatic metastasized NETs.


Plasma norepinephrine and epinephrine responses to glucagon in patients with suspected pheochromocytomas.
Plasma norepinephrine and epinephrine levels were measured before and after glucagon administration in 28 patients suspected of having a pheochromocytoma: three patients were subsequently found to have tumors. The norepinephrine response predicted the presence or absence of a tumor in 27 of the 28 patients. Epinephrine levels doubled, on the average, in patients who did not have pheochromocytomas, and were not useful in distinguishing the patients with or without tumors. A comparison of the response to glucagon and a placebo indicated that changes in plasma catecholamine levels were hormone-related and not the result of side-effects accompanying injection. The glucagon provocation test, with measurement of plasma norepinephrine and epinephrine levels, may be a useful adjunctive tool for evaluating patients suspected of having a pheochromocytoma when performed according to a standardized protocol and interpreted in relation to appropriate controls.


Selective sparing of hippocampal CA3 cells following in vitro ischemia is due to selective inhibition by acidosis.
A brief global ischemic insult to the brain leads to a selective degeneration of the pyramidal neurons in the hippocampal CA1 region while the neurons in the neighbouring CA3 region are spared. The reason for this difference is not known. The selective vulnerability of CA1 neurons to ischemia can be reproduced in vitro in murine organotypic slice cultures, if the ion concentrations in the medium during the anoxic/aglycemic insult are similar to that in the brain extracellular fluid during ischemia in vivo. As acidosis develops during ischemia, we studied the importance of extracellular pH for selective vulnerability. We found that cell death in the CA1 and CA3 regions was equally prevented by removal of calcium from the medium or following blockade of the N-methyl-D-aspartate (NMDA) receptor by D-2 amino-5-phosphonopentanoic-acid (D-APV). On the other hand, damage to the CA3 neurons markedly decreased with decreasing pH following in vitro ischemia, while the degeneration of CA1 neurons was less pH dependent. Patch-clamp recordings from pyramidal neurons in the CA1 and CA3 regions, respectively, revealed a pronounced inhibition of NMDA-receptor mediated excitatory postsynaptic currents (EPSCs) at pH 6.5 that was equally pronounced in the two regions. However, when changing pH from 6.5 to 7.4 the recovery of the EPSCs was significantly slower in the CA3 region. We conclude that acidosis selectively protects CA3 pyramidal neurons during in vitro ischemia, and differentially affects the kinetics of NMDA receptor activation, which may explain the difference in vulnerability between CA1 and CA3 pyramidal neurons to an ischemic insult.


The role of neurohormonal blockers in the primary prevention of acute-, early-, and late-onset anthracycline-induced cardiotoxicity.
Anthracycline-induced cardiotoxicity has been classified based on its onset into acute, early, and late. It may have a significant burden on the quality and quantity of life of those exposed to this class of medication. Currently, there are several ongoing debates on the role of different measures in the primary prevention of cardiotoxicity in cancer survivors. Our article aims to focus on the role of neurohormonal blockers in the primary prevention of anthracycline-induced cardiotoxicity, whether it is acute, early, or late onset. PubMed and Google Scholar database were searched for the relevant articles; we reviewed and appraised 15 RCTs, and we found that angiotensin-converting enzyme inhibitors (ACEI) and B-blockers were the most commonly used agents. Angiotensin II receptor blockers (ARBs) and mineralocorticoid receptor antagonists (MRAs) were used in a few other trials. The follow-up period was on the range of 1-156 weeks (mode 26 weeks). Left ventricular ejection fraction (LVEF), left ventricular diameters, and diastolic function were assessed by either echocardiogram or occasionally by cardiac magnetic resonance imaging (MRI). The occurrence of myocardial injury was assessed by troponin I. It was obvious that neurohormonal blockers reduced the occurrence of LVEF and myocardial injury in 14/15 RCTs. Beta-blockers, especially carvedilol and ACEI, especially enalapril, should be considered for the primary prevention of acute- and early-onset cardiotoxicity. ARB and MRA are suitable alternatives when patients are intolerant to ACE-I and B-blockers. We recommend further studies to explore and establish the role of neurohormonal blockers in the primary prevention of the acute-, early-, and late-onset cardiotoxicity.


A Cross-sectional Study of Stretched Penile Length in Boys from West Bengal, India.
Short penile length is a commonly encountered problem in clinical practice. Detection of abnormal stretched penile length (SPL) warrants appropriate endocrine evaluation. Ethnicity-specific SPL data are required to detect these abnormalities. There is a dearth of such data in India. This study aims to establish normative values of SPL in boys from West Bengal. This is a cross-sectional study. SPL, testicular volume (TV), height/length, and weight were measured in 460 boys aged 1 to 13 years from the schools located at urban, suburban, and rural areas in the state of West Bengal, India. Similar data were collected from 36 healthy neonates within 1-3 days of full-term delivery at IPGME and R and SSKM Hospital, Kolkata, West Bengal, India. The 5th percentile, median, and 95th percentile of SPL were 1.7, 2.0, and 2.7 cm for neonates; 3.5, 4.4, and 6.4 cm for the children aged 1 Y-2 Y 11 M; 4.0, 5.5, and 7.0 cm for the age group 3 Y-4 Y 11 M; 4.2, 6.0, and 7.2 cm for the age group 5 Y-6 Y 11 M; 4.3, 6.0, and 7.6 cm for the age group 7 Y-8 Y 11 M; 4.4, 6.5, and 9.0 cm for the age group 9 Y-10 Y 11 M; and 4.8, 7.0, and 11.0 cm for the age group 11 Y-12 Y 11 M, respectively. SPL showed significant positive correlation with TV [r = 0.365, P < 0.0005] and height of the children [r = 0.516, P < 0.0005], but not with BMI. Our study provides normative data of SPL in neonate and children aged 1 to 13 years from the eastern part of India. SPL value correlated positively with TV and height of children.


Annealing to sequences within the primer binding site loop promotes an HIV-1 RNA conformation favoring RNA dimerization and packaging.
The 5' untranslated region (5' UTR) of HIV-1 genomic RNA (gRNA) includes structural elements that regulate reverse transcription, transcription, translation, tRNA(Lys3) annealing to the gRNA, and gRNA dimerization and packaging into viruses. It has been reported that gRNA dimerization and packaging are regulated by changes in the conformation of the 5'-UTR RNA. In this study, we show that annealing of tRNA(Lys3) or a DNA oligomer complementary to sequences within the primer binding site (PBS) loop of the 5' UTR enhances its dimerization in vitro. Structural analysis of the 5'-UTR RNA using selective 2'-hydroxyl acylation analyzed by primer extension (SHAPE) shows that the annealing promotes a conformational change of the 5' UTR that has been previously reported to favor gRNA dimerization and packaging into virus. The model predicted by SHAPE analysis is supported by antisense experiments designed to test which annealed sequences will promote or inhibit gRNA dimerization. Based on reports showing that the gRNA dimerization favors its incorporation into viruses, we tested the ability of a mutant gRNA unable to anneal to tRNA(Lys3) to be incorporated into virions. We found a ∼60% decrease in mutant gRNA packaging compared with wild-type gRNA. Together, these data further support a model for viral assembly in which the initial annealing of tRNA(Lys3) to gRNA is cytoplasmic, which in turn aids in the promotion of gRNA dimerization and its incorporation into virions.


Structural and dynamical analysis of an engineered FhuA channel protein embedded into a lipid bilayer or a detergent belt.
Engineered channel proteins are promising nano-components with applications in nanodelivery and nanoreactors technology. Because few of the engineered channel proteins have been crystallized, solution studies based on Neutron Scattering, Circular Dichroism and NMR play a major role. Consequently, the understanding of membrane proteins dynamics in water/detergent solutions or when embedded in a lipid membrane, can clarify how the environment affects protein behavior. In this study, molecular dynamics simulations of the FhuA Escherichia coli outer membrane channel protein and its engineered FhuA Δ1-159 variant have been performed in two different environments: a DNPC (1,2-dinervonyl-sn-glycero-3-phosphocholine) lipid bilayer and a water/OES (N-octyl-2-hydroxyethyl sulfoxide) detergent solution. Furthermore the FhuA Δ1-159 variant has been simulated in the open and closed states, the last induced by the presence of six 3-(2-pyridyldithio)-propionic-acid in the channel inner core. Differences in protein structural and dynamical behavior between the two environments have been found. Considering the FhuA protein characterized by an elliptical-cylindrical symmetry: (a) neither variations on the secondary structure nor axial deformation have been observed in any of the systems; (b) the ellipticity of the channel section (open state) and its fluctuations are enhanced in presence of water/OES, while diminished or suppressed in the DNPC bilayer; (c) the insertion of hydrophobic pyridyl groups into the FhuA Δ1-159 channel (closed state) induces a higher ellipticity in water/OES solution, while shifting to a circular section in the DNPC membrane; (d) the cork domain represented by the first 159 amino acids does not play a major role for protein stability.