Perinatal outcome and congenital malformations in in-vitro fertilization babies from the Bourn-Hallam group.
The perinatal outcome and congenital malformations in children born between 1978 and 1987 in Great Britain after in-vitro fertilization (IVF) at Bourn Hall Clinic and the Hallam Medical Centre are presented. The average maternal age was 34.2 years. Multiple births were frequent, constituting 23% of all deliveries; 19% were twins and 4% triplets. There were no quadruplet or higher order multiple births during that period. Twenty-five per cent of all deliveries were preterm. The mean birth weight was 2793 g and was strongly related to multiplicity of pregnancy and gestational age. Overall, 32% of babies had a low birthweight (less than 2500 g) with 6% having a very low birthweight (less than 1500 g). The overall stillbirth and infant mortality rates were two to three times higher than those of infants born after natural conception in England and Wales; this is attributed to the high incidence of multiple births. The stillbirth rates were 5.07, 20.8 and 24.7 per thousand total births in singletons, twins and triplets respectively. The corresponding figures for perinatal mortality were 13.5, 38.2 and 37 per thousand. Overall, 2.5% of the babies had one or more major congenital malformations diagnosed within one week of life. This was within the range of expected values in the United Kingdom and there was no significant increase in any specific malformation.


Falls following discharge after an in-hospital fall.
Falls are among the most common adverse events reported in hospitalized patients. While there is a growing body of literature on fall prevention in the hospital, the data examining the fall rate and risk factors for falls in the immediate post-hospitalization period has not been well described. The objectives of the present study were to determine the fall rate of in-hospital fallers at home and to explore the risk factors for falls during the immediate post-hospitalization period. We identified patients who sustained a fall on one of 16 medical/surgical nursing units during an inpatient admission to an urban community teaching hospital. After discharge, falls were ascertained using weekly telephone surveillance for 4 weeks post-discharge. Patients were followed until death, loss to follow up or end of study (four weeks). Time spent rehospitalized or institutionalized was censored in rate calculations. Of 95 hospitalized patients who fell during recruitment, 65 (68%) met inclusion criteria and agreed to participate. These subjects contributed 1498 person-days to the study (mean duration of follow-up = 23 days). Seventy-five percent were African-American and 43% were women. Sixteen patients (25%) had multiple falls during hospitalization and 23 patients (35%) suffered a fall-related injury during hospitalization. Nineteen patients (29%) experienced 38 falls at their homes, yielding a fall rate of 25.4/1,000 person-days (95% CI: 17.3-33.4). Twenty-three patients (35%) were readmitted and 3(5%) died. One patient experienced a hip fracture. In exploratory univariate analysis, persons who were likely to fall at home were those who sustained multiple falls in the hospital (p = 0.008). Patients who fall during hospitalization, especially on more than one occasion, are at high risk for falling at home following hospital discharge. Interventions to reduce falls would be appropriate to test in this high-risk population.


Phase and amplitude correlations in resting-state activity in human stereotactical EEG recordings.
Inter-areal interactions of neuronal oscillations may be a key mechanism in the coordination of anatomically distributed neuronal processing. In humans, invasive stereo-electroencephalography (SEEG) is emerging as a reference method for electrophysiological recordings because of its excellent spatial and temporal resolution. It could thus be also considered an optimal method for mapping neuronal inter-areal interactions. However, the common bipolar (BP) referencing of SEEG data may both confuse signals from distinct sources and suppress true neuronal interactions whereas the alternative monopolar (MP) reference yields data contaminated by volume conduction. We advance here a novel referencing scheme for SEEG data where electrodes in grey matter are referenced to closest white-matter (CW) electrodes. Using a 22 subject cohort and these three referencing schemes, we observed that both inter-areal phase and amplitude correlations decayed as function of distance and frequency but remained significant and stable across distances up to 10cm. Furthermore, we found that deep and superficial cortical laminae exhibit distinct spectral profiles of oscillation power as well as distinct patterns of inter-areal phase and amplitude interactions. These effects were qualitatively similar in MP and CW but distorted with BP referencing. Importantly CW was not influenced by the apparent large-scale volume conduction inherent to MP. We thus demonstrate here that with CW referencing, the superior anatomical accuracy of SEEG can be leveraged to yield accurate quantification and qualitatively novel insight into phase and amplitude interactions in human brain activity.


Prenatal and early postnatal fatty acid status and neurodevelopmental outcome.
The present review addresses the effect of pre- and postnatal supplementation of nutrition with long-chain polyunsaturated fatty acids (LCPUFA) on neurodevelopmental outcome. The few studies which addressed the effect of prenatal LCPUFA status or prenatal LCPUFA supplementation suggest that a better prenatal arachidonic acid (AA) and doxosahexaenoic acid (DHA) status might be related to a better neurodevelopmental outcome until at least 18 months of age. A review of the few randomized controlled trials on formula supplementation with LCPUFA in preterm infants did not provide evidence for a significant beneficial effect of LCPUFA on developmental outcome. A review of the trials on formula supplementation with LCPUFA in term infants revealed that supplementation with LCPUFA, in particularly supplementation with >or=0.30% DHA, has a beneficial effect on neurodevelopmental outcome until 4 months. The studies could not demonstrate a consistent positive effect beyond that age. It was concluded that the relatively subtle effects of LCPUFA supplementation on neurodevelopmental outcome do not only depend on dosage but also on the gestational period during which the nutritional components are supplied: supplementation prior to term seems to have more effect than that after term.


Antibody to human adenovirus early antigens during acute adenovirus infections.
The antibody (Ab) response to human adenovirus (AV) early antigens (EA) in acute AV infections was studied by the immunoperoxidase antibody technique for determining virus-specific immunoglobulin G (IPA-IgG). AV-EA-Ab appeared about 5 days after the onset of clinical symptoms, reached a peak 15 to 30 days later, and declined in titer after a few months. The staining pattern in the IPA-IgG reaction was usually nuclear; however, in most primary infections sera obtained 2 to 3 weeks after the onset of infection also showed cytoplasmic staining. According to the recent deoxyribonucleic acid homology classification of human AV in five groups (A, B, C, D, and E), the EA-Ab response in primary human infections was found to be group specific for groups A to D, with consistent cross-reactions with group E. In AV type 4 (group E) infections, EA-Ab appeared to be directed against all groups, although at different titers. Comparable results were obtained using AV type-specific animal antisera. Thus, it was concluded that group E shares EA with all the other groups. Furthermore, in each individual with remote AV infections, the current infection elicited an anamnestic EA-Ab response to all AV groups responsible for previous infections. In diagnostic virology these findings can be applied to the rapid diagnosis of a current for recent) AV infection on a single serum sample and to the rapid group identification of clinical isolates by using type-specific animal antisera containing EA-Ab (one for each group) or sera from patients with primary AV infections.


Molecular Characterization of Chitin Synthase Gene of Demodex canis from Mizoram, India.
Canine demodicosis is a parasitic condition affecting the skin of dogs. The present study was designed to characterize chitin synthase gene of Demodex canis. The molecular technique was used for better understanding of this gene. A total of 75 dogs which are reared as pets with or without showing any skin lesions were examined during the study period. Skin scrapings were examined by indirect method using 10% potassium hydroxide solution under 10 × microscope. DNA samples were extracted from positive skin samples and were subjected to PCR for molecular identification. A total of 25 dogs irrespective of age, sex, breed or coat showed positive result for D. canis. The PCR revealed a single amplified product of 339 bp length which exactly matched with D. canis. The chitin synthase gene was amplified by PCR, subsequently cloned, sequenced, and compared with available data in GenBank for the particular gene of D. canis. Only one single nucleotide polymorphism (SNP) was noticed at 231 position of the chitin synthase gene sequence when compared to other isolates. The molecular technique confirms with the morphological identity of D. canis. This report signifies the value of peculiar tool to identify 'follicular mite' even from apparently healthy skin.


Pharmacogenetic aspects of the use of tacrolimus in renal transplantation: recent developments and ethnic considerations.
Tacrolimus (Tac) is effective in preventing acute rejection but has considerable toxicity and inter-individual variability in pharmacokinetics and pharmacodynamics. Part of this is explained by polymorphisms in genes encoding Tac-metabolizing enzymes and transporters. A better understanding of Tac pharmacokinetics and pharmacodynamics may help to minimize different outcomes amongst transplant recipients by personalizing immunosuppression. The pharmacogenetic contribution of Tac metabolism will be examined, with a focus on recent discoveries, new developments and ethnic considerations. The strongest and most consistent association in pharmacogenetics is between the CYP3A5 genotype and Tac dose requirement, with CYP3A5 expressers having a ~ 40-50% higher dose requirement compared to non-expressers. Two recent randomized-controlled clinical trials using CYP3A5 genotype, however, did not show a decrease in acute rejections nor reduced toxicity. CYP3A4*22, CYP3A4*26, and POR*28 are also associated with Tac dose requirements and may be included to provide the expected improvement of Tac therapy. Studies focusing on the intracellular drug concentrations and on calcineurin inhibitor-induced nephrotoxicity also seem promising. For all studies, however, the ethnic prevalence of genotypes should be taken into account, as this may significantly impact the effect of pre-emptive genotyping.


Comparison of a 550,000 dalton cartilage matrix glycoprotein in cartilage from immature and mature dogs.
Cartilage matrix glycoprotein is a disulfide bonded 550,000 dalton protein found in cartilage and in the vitreous of the eye. Immunofluorescence studies using a specific antiserum to this glycoprotein have previously demonstrated a difference between the topographic distribution of staining for cartilage matrix glycoprotein in cartilage from immature and mature animals. Using a polyclonal antiserum to cartilage matrix glycoprotein, we studied this protein in cartilage from normal immature and mature dogs to determine if it changes with maturation. Cartilage matrix glycoprotein from immature canine cartilage migrates as a doublet, with apparent molecular weights of 100-116,000, regardless of its state of reduction, and is immunologically cross reactive with cartilage matrix glycoprotein from adult canine cartilage. Cartilage matrix glycoprotein from mature canine cartilage is disulfide bonded before reduction with 2-mercaptoethanol and its 116,000 Da subunit migrates as a single band after reduction.


Immune Cell Infiltrate in Chronic-Active Antibody-Mediated Rejection.
Background: Little is known about immune cell infiltrate type in the kidney allograft of patients with chronic-active antibody-mediated rejection (c-aABMR). Methods: In this study, multiplex immunofluorescent staining was performed on 20 cases of biopsy-proven c-aABMR. T-cell subsets (CD3, CD8, Foxp3, and granzyme B), macrophages (CD68 and CD163), B cells (CD20), and natural killer cells (CD57) were identified and counted in the glomeruli (cells/glomerulus) and the tubulointerstitial (TI) compartment [cells/high-power field (HPF)]. Results: In the glomerulus, T cells and macrophages were the dominant cell types with a mean of 5.5 CD3+ cells/glomerulus and 4 CD68+ cells/glomerulus. The majority of T cells was CD8+ (62%), and most macrophages were CD68+CD163+ (68%). The TI compartment showed a mean of 116 CD3+ cells/HPF, of which 54% were CD8+. Macrophage count was 21.5 cells/HPF with 39% CD68+CD163+. CD20+ cells were sporadically present in glomeruli, whereas B-cell aggregates in the TI compartment were frequently observed. Natural killer cells were rarely identified. Remarkably, increased numbers of CD3+FoxP3+ cells in the TI compartment were associated with decreased graft survival (p = 0.004). Conclusions: Renal allograft biopsies showing c-aABMR show a predominance of infiltrating CD8+ T cells, and increased numbers of interstitial FoxP3+ T cells are associated with inferior allograft survival.


Quantitative analysis of nonlinear optical input/output of a quantum-dot network based on the echo state property.
The echo state property, which is related to the dynamics of a neural network excited by input driving signals, is one of the well-known fundamental properties of recurrent neural networks. During the echo state, the neural network reveals an internal memory function that enables it to remember past inputs. Due to the echo state property, the neural network will asymptotically update its condition from the initial condition and is expected to exhibit temporally nonlinear input/output. As a physical neural network, we fabricated a quantum-dot network that is driven by sequential optical-pulse inputs and reveals corresponding outputs, by random dispersion of quantum-dots as its components. In the network, the localized optical energy of excited quantum-dots is allowed to transfer to neighboring quantum-dots, and its stagnation time due to multi-step transfers corresponds to the hold time of the echo state of the network. From the experimental results of photon counting of the fluorescence outputs, we observed nonlinear optical input/output of the quantum-dot network due to its echo state property. Its nonlinearity was quantitatively verified by a correlation analysis. As a result, the relation between the nonlinear input/outputs and the individual compositions of the quantum-dot network was clarified.


Quality of life in spanish patients with liver transplant.
Liver transplantation is the optimal method of treatment in patients with end-stage liver failure. Transplantation medicine has significantly progressed in the last time, but some psychology and psychosomatic problems still remain unsolved. Health-Related Quality of Life (HRQL) in liver transplant is considered a useful measure of evolutionary process of the illness. The authors analyzed the evolution of HRQL in pre-transplant (waiting-list patients) and post-transplant (first year after liver transplant) periods of liver transplant Spanish patients. A prospective and longitudinal study was carried out among patients who received a liver transplant from a deceased donor. They were assessed in four phases: at the time of inclusion on the transplant waiting-list, and 3, 6, and 12 months after receiving the graft. We used a structured interview and SF-36 and Euroqol-5D (EQ-5D) Health Questionnaires. The greater differences were found between pre-transplant and post-transplant stages with less well-being in the stage before the transplant. No significantly differences were observed when comparing the 3, 6 and 12 months from post-transplant stage. The HQRL of liver patients improved after the transplant, being appreciated a tendency to the stabilization from three months onwards. We suggest that the psychological intervention, in liver patients, should be conducted in waiting-list patients and in the first 3 months post-transplant, periods with a poor mental health (anxiety, depression, and stress by fear to the unknown thing) and a low adhesion to the treatment that can generate a smaller graft and/or patient survival.


The radiographic fate of the syndesmosis after trans-syndesmotic screw removal in displaced ankle fractures.
The purpose of this study was to evaluate the radiographic changes of the tibiofibular position and the ankle mortise after removal of trans-syndesmotic fixation to determine if there is loss or maintenance of correction. In addition, the effect of the type of rotational injury, early weight bearing, and the number of trans-syndesmotic screws used on the integrity of the inferior tibiofibular articulation or ankle mortise after screw removal were evaluated. An analysis was conducted of 86 patients, with an unstable rotational ankle fracture requiring open reduction with syndesmosis screw stabilization. Routine radiographic parameters were measured just after open reduction and just before syndesmotic screw removal. There was a high correlation of loss of the integrity of the syndesmotic parameters after screw removal. However, the medial clear space of the ankle changed an insignificant amount, suggesting that although there appears to be some loss of maintenance, the talus did not shift laterally at the expense of a mobile syndesmosis. Ankle injuries requiring stabilization of syndesmotic instability with use of temporary trans-syndesmotic fixation achieve a stable ankle mortise after removal. Tibiofibular diastasis is commonplace upon removal of the syndesmotic hardware, but the ankle mortise remains unchanged. Based on the radiographic criteria described in this study, the postoperative change in medial clear space or tibiofibular diastasis has no bearing on fracture type, deltoid injury, or the use of 1 or 2 cortical screws. As such, other unknown mechanisms affecting the integrity of the syndesmosis after screw removal are in place.


Evaluation of traumatic subarachnoid hemorrhage using susceptibility-weighted imaging.
SWI is an MR imaging technique that is very sensitive to hemorrhage. Our goal was to compare SWI and CT to determine if SWI can show traumatic SAH in different parts of the subarachnoid space. Twenty acute TBI patients identified by CT with SAH underwent MR imaging scans. Two neuroradiologists analyzed the CT and SWI data to decide whether there were SAHs in 8 anatomical parts of the subarachnoid space. Fifty-five areas with SAH were identified by both CT and SWI. Ten areas were identified by CT only and 13 by SWI only. SAH was recognized on SWI by its very dark signal intensity surrounded by CSF signal intensity in the sulci or cisterns. Compared with the smooth-looking veins, SAH tended to have a rough boundary and inhomogeneous signal intensity. In many instances, blood in the sulcus left an area of signal intensity loss that had a "triangle" shape. SWI showed 5 more cases of intraventricular hemorrhage than did CT. SAH can be recognized by SWI through its signal intensity and unique morphology. SWI can provide complementary information to CT in terms of small amounts of SAH and hemorrhage inside the ventricles.


Haemodynamic outcome at four-dimensional flow magnetic resonance imaging following valve-sparing aortic root replacement with tricuspid and bicuspid valve morphology.
To provide a more complete characterization of aortic blood flow in patients following valve-sparing aortic root replacement (VSARR) compared with presurgical cohorts matched by tricuspid and bicuspid valve morphology, age and presurgical aorta size. Four-dimensional (4D) flow magnetic resonance imaging (MRI) was performed to analyse three-dimensional (3D) blood flow in the thoracic aorta of n = 13 patients after VSARR with reimplantation of native tricuspid aortic valve (TAV, n = 6) and bicuspid aortic valve (BAV, n = 7). Results were compared with presurgical age and aortic size-matched control cohorts with TAV (n = 10) and BAV (n = 10). Pre- and post-surgical aortic flow was evaluated using time-resolved 3D pathlines using a blinded grading system (0-2, 0 = small, 1 = moderate and 2 = prominent) analysing ascending aortic (AAo) helical flow. Systolic flow profile uniformity in the aortic root, proximal and mid-AAo was evaluated using a four-quadrant model. Further analysis in nine analysis planes distributed along the thoracic aorta quantified peak systolic velocity, retrograde fraction and peak systolic flow acceleration. Pronounced AAo helical flow in presurgical control subjects (both BAV and TAV: helix grading = 1.8 ± 0.4) was significantly reduced (0.2 ± 0.4, P < 0.001) in cohorts after VSARR independent of aortic valve morphology. Presurgical AAo flow was highly eccentric for BAV patients but more uniform for TAV. VSARR resulted in less eccentric flow profiles. Systolic peak velocities were significantly (P < 0.05) increased in post-root repair BAV patients throughout the aorta (six of nine analysis planes) and to a lesser extent in TAV patients (three of nine analysis planes). BAV reimplantation resulted in significantly increased peak velocities in the proximal AAo compared with root repair with TAV (2.3 ± 0.6 vs 1.6 ± 0.4 m/s, P = 0.017). Post-surgical patients showed a non-significant trend towards higher systolic flow acceleration as a surrogate measure of reduced aortic compliance. VSARR restored a cohesive flow pattern independent of native valve morphology but resulted in increased peak velocities throughout the aorta. 4D flow MRI methods can assess the clinical implications of altered aortic flow dynamics in patients undergoing VSARR.


Development of EEG activity after ten days of electrocerebral inactivity: ten days of electrocerebral inactivity: a case report in a premature neonate-hydranencephaly or massive ventricular enlargement.
This premature girl demonstrated electrocerebral inactivity in four records over a ten day period. After another eight days with no records, low voltage activity was present at a time when clinical responsiveness increased although the child never developed a prognostically favorable clinical state. The clinical responses never became well developed and the outlook never appeared favorable. If electrocerebral inactivity can be followed by active cortical function in a child who at best had islands of neurons on a deafferented cortex, then some recovery may potentially be possible in the premature child with post bleeding distress and electrocerebral inactivity with apparently present hemisphere tissue. It must be emphasized that "cerebral death" is a syndrome requiring more than electrocerebral inactivity alone. The presently accepted criteria of a single inactive EEG record is not sufficient evidence in itself to predict lack of potential survival in neonates. On the other hand, the return of EEG activity does not predict potential for recovery but only demonstrates a change in CNS function which has to be considered in conjunction with, but not in isolation of, other clinical data to assist the clinician.


Biochanin A Induces S Phase Arrest and Apoptosis in Lung Cancer Cells.
Lung cancer is among the most common malignancies with a poor 5-year survival rate reaching only 16%. Thus, new effective treatment modalities and drugs are urgently needed for the treatment of this malignancy. In this study, we conducted the first investigation of the effects of Biochanin A on lung cancer and revealed the mechanisms underlying its potential anticancer effects. Biochanin A decreased cell viability in a time-dependent and dose-dependent manner and suppressed colony formation in A549 and 95D cells. In addition, Biochanin A induced S phase arrest and apoptosis and decreased mitochondrial membrane potential (ΔΨm) in A549 and 95D cells in a dose-dependent manner. Our results of subcutaneous xenograft models showed that the growth of Biochanin A group was significantly inhibited compared with that of control groups. Finally, P21, Caspase-3, and Bcl-2 were activated in Biochanin A-treated cells and Biochanin A-treated xenografts which also demonstrated that Biochanin A induced cell cycle arrest and apoptosis in lung cancer cells by regulating expression of cell cycle-related proteins and apoptosis-related proteins. In conclusion, this study suggests that Biochanin A inhibits the proliferation of lung cancer cells and induces cell cycle arrest and apoptosis mainly by regulating cell cycle-related protein expression and activating the Bcl-2 and Caspase-3 pathways, thus suggesting that Biochanin A may be a promising drug to treat lung cancer.


ST-Elevation Magnitude Correlates With Right Ventricular Outflow Tract Conduction Delay in Type I Brugada ECG.
The substrate location and underlying electrophysiological mechanisms that contribute to the characteristic ECG pattern of Brugada syndrome (BrS) are still debated. Using noninvasive electrocardiographical imaging, we studied whole heart conduction and repolarization patterns during ajmaline challenge in BrS individuals. A total of 13 participants (mean age, 44±12 years; 8 men), 11 concealed patients with type I BrS and 2 healthy controls, underwent an ajmaline infusion with electrocardiographical imaging and ECG recordings. Electrocardiographical imaging activation recovery intervals and activation timings across the right ventricle (RV) body, outflow tract (RVOT), and left ventricle were calculated and analyzed at baseline and when type I BrS pattern manifested after ajmaline infusion. Peak J-ST point elevation was calculated from the surface ECG and compared with the electrocardiographical imaging-derived parameters at the same time point. After ajmaline infusion, the RVOT had the greatest increase in conduction delay (5.4±2.8 versus 2.0±2.8 versus 1.1±1.6 ms; P=0.007) and activation recovery intervals prolongation (69±32 versus 39±29 versus 21±12 ms; P=0.0005) compared with RV or left ventricle. In controls, there was minimal change in J-ST point elevation, conduction delay, or activation recovery intervals at all sites with ajmaline. In patients with BrS, conduction delay in RVOT, but not RV or left ventricle, correlated to the degree of J-ST point elevation (Pearson R, 0.81; P<0.001). No correlation was found between J-ST point elevation and activation recovery intervals prolongation in the RVOT, RV, or left ventricle. Magnitude of ST (J point) elevation in the type I BrS pattern is attributed to degree of conduction delay in the RVOT and not prolongation in repolarization time.


Rerouting Hearing Aid Systems for Overcoming Simulated Unilateral Hearing in Dynamic Listening Situations.
Unilateral hearing loss increases the risk of academic and behavioral challenges for school-aged children. Previous research suggests that remote microphone (RM) systems offer the most consistent benefits for children with unilateral hearing loss in classroom environments relative to other nonsurgical interventions. However, generalizability of previous laboratory work is limited because of the specific listening situations evaluated, which often included speech and noise signals originating from the side. In addition, early studies focused on speech recognition tasks requiring limited cognitive engagement. However, those laboratory conditions do not reflect characteristics of contemporary classrooms, which are cognitively demanding and typically include multiple talkers of interest in relatively diffuse background noise. The purpose of this study was to evaluate the potential effects of rerouting amplification systems, specifically a RM system and a contralateral routing of signal (CROS) system, on speech recognition and comprehension of school-age children in a laboratory environment designed to emulate the dynamic characteristics of contemporary classrooms. It was expected that listeners would benefit from the CROS system when the head shadow limits audibility (e.g., monaural indirect listening). It was also expected that listeners would benefit from the RM system only when the RM was near the talker of interest. Twenty-one children (10 to 14 years, M = 11.86) with normal hearing participated in laboratory tests of speech recognition and comprehension. Unilateral hearing loss was simulated by presenting speech-shaped masking noise to one ear via an insert earphone. Speech stimuli were presented from 1 of 4 loudspeakers located at either 0°, +45°, -90°, and -135° or 0°, -45°, +90°, and +135°. Cafeteria noise was presented from separate loudspeakers surrounding the listener. Participants repeated sentences (sentence recognition) and also answered questions after listening to an unfamiliar story (comprehension). They were tested unaided, with a RM system (microphone near the front loudspeaker), and with a CROS system (ear-level microphone on the ear with simulated hearing loss). Relative to unaided listening, both rerouting systems reduced sentence recognition performance for most signals originating near the ear with normal hearing (monaural direct loudspeakers). Only the RM system improved speech recognition for midline signals, which were near the RM. Only the CROS system significantly improved speech recognition for signals originating near the ear with simulated hearing loss (monaural indirect loudspeakers). Although the benefits were generally small (approximately 6.5 percentage points), the CROS system also improved comprehension scores, which reflect overall listening across all four loudspeakers. Conversely, the RM system did not improve comprehension scores relative to unaided listening. Benefits of the CROS system in this study were small, specific to situations where speech is directed toward the ear with hearing loss, and relative only to a RM system utilizing one microphone. Although future study is warranted to evaluate the generalizability of the findings, the data demonstrate both CROS and RM systems are nonsurgical interventions that have the potential to improve speech recognition and comprehension for children with limited useable unilateral hearing in dynamic, noisy classroom situations.


Maternal-fetal medicine fellowship obstetrical ultrasound experience: results from a fellowship survey.
To assess maternal-fetal medicine (MFM) fellowship obstetrical ultrasound training, scope of practice and research. A 52-item prenatal diagnosis survey was e-mailed to 458 associate members of the Society for Maternal-Fetal Medicine on two separate occasions. Associate members include both MFM fellows and recent graduates who are not yet board certified in MFM. A total of 148 associate members completed the survey (32% response rate), 92% of whom were at least in their second year of fellowship. A total of 58% of fellows spend at least 20% of their fellowship time performing prenatal ultrasounds, and most begin their ultrasound training in their first year. Most fellows describe being comfortable performing routine fetal anatomy surveys, growth ultrasounds and umbilical artery Doppler measurements, but only 48% are nuchal translucency (NT) certified, most through Nuchal Translucency Quality Review. A total of 7% of fellows do not receive structured training in 2D ultrasound, 39% receive no structured training in 3D/4D ultrasound, and 28% receive no structured training in fetal echocardiography. Only 38% can identify an ultrasound mentor during fellowship. Most fellows are trained in ultrasound during their first year of fellowship and feel comfortable performing routine exams. However, ultrasound mentorship, structured training and research in prenatal ultrasound are limited in some programs.


Bibliometric profile of global scientific research on digoxin toxicity (1849-2015).
Digoxin is a cardiac glycoside derived from the common foxglove digitalis purpurea and has been available for several centuries as a medicinal agent. Despite extensive patient experience over many years, there remains some controversy regarding the possibility that digoxin might have a deleterious effect on survival. This study was constructed to assess trends in digoxin toxicity research using well-established qualitative and quantitative bibliometric indicators. The current study is based on publications that have been indexed in Scopus. Articles referring to the subject of digoxin toxicity between 1849 and 2015 were assessed according to the document type, publication language, countries/territories, institutions, journal, impact factors, total number of citations, h-index, average number of citations per publication, and international collaborations. There were 2900 publications that included 2542 (87.7%) original research articles, while 5.3% were reviews and 4.6% letters. The country of origin was the USA in 849 publications, Germany in 241, the UK in 150, and France in 143. The USA and the UK had the highest number of international collaborations. The average number of citations per publications related to digoxin toxicity was 8.1, and the h-index was 59. The USA and Canada had the highest h-indices by country at 46 and 22, respectively. This study presents the first bibliometric analysis on digoxin toxicity publications. The USA was the most important contributors to digoxin toxicity literature with the greatest international collaboration, largest number of articles and highest h-index, followed by Germany and the UK. There has been a trend towards reduced publication numbers related to digoxin toxicity at global level, although it is still an important issue and we present the current research themes related to digoxin toxicity that were identified.


Customized web-based sound therapy for tinnitus.
Traditional masking efforts have presented broadband noises, most typically white noise. Targeted (customized) sound therapies have been introduced to overcome the limitations of traditional maskers. To evaluate the efficacy of a web-based delivery of customized sound therapy in reducing tinnitus loudness and increasing the residual inhibition. Thirty-two subjects matched their tinnitus frequency using a web-based protocol. A customized Harmonic Sound Therapy file was produced by the web-based software and downloaded by the patient onto an MP3 player. The subjects listened to the sound file for one hour. Tinnitus loudness mean was 6.0 ± 2.3 standard deviation (SD) which decreased to 3.3 ± 1.9 SD after one hour of sound therapy. Some reduction in loudness was seen in 81%, while 72% experienced a reduction of 25% or more. Tinnitus annoyance decreased from an average of 6.1 ± 2.6 SD to 3.1 ± 2.0 SD. Median duration of residual inhibition was 32.5 minutes, with an average of 75 minutes ± 132 SD. Customized sound therapy can be delivered via the internet. Harmonic Sound Therapy is effective in reducing the loudness and annoyance of tinnitus.


Improvements in Neck Pain and Disability Following C1-C2 Posterior Cervical Instrumentation and Fusion for Atlanto-Axial Osteoarthritis.
Symptomatic Atlanto-axial (C1-2) osteoarthritis (AAOA) is a common phenomenon in elderly patients; however, there is a paucity of data on the effectiveness of posterior atlanto-axial fusion (PAAF) for this condition. To this end, here we assess changes in patient-reported outcomes and neck-related disability in adult patients undergoing PAAF for symptomatic C1-2 AAOA. In this retrospective study, the clinical records of consecutive patients with symptomatic AAOA who underwent PAAF between 2004 and 2017 were reviewed. Patient demographics, comorbidities, intraoperative and postoperative variables, and complication rates were collected. Neck Disability Index (NDI) scores were recorded at baseline and 6 weeks, 6 months, 1 year, and 2 years postoperatively. Forty-two patients (average age, 72.04 ± 8.56 years; 26.19% males) met the study's inclusion criteria. In this cohort, 19.04% had previous subaxial cervical spine surgery, 35.71% had a history of smoking (all had stopped smoking before surgery), and 11.90% had type II diabetes. At baseline, the majority of patients had a normal neurologic exam. The average preoperative NDI score was 26.88 ± 24.85, which improved to 10.59 ± 14.88 at the 1-year follow-up and 13.20 ± 14.96 at the 2-year follow-up (P = 0.004). At baseline, 18% of the patients reported severe disability based on NDI score; this percentage decreased to 2% at 1 year and 0 at 2 years (P = 0.01). Importantly, a high percentage (11.90%) of patients had undergone previous subaxial cervical fusion for their pain due to a mistaken diagnosis for this condition, without symptom relief. In appropriately selected patients, PAAF may decrease neck pain and improve functional disability in patients with AAOA. Future prospective longitudinal studies are needed to corroborate these findings.


Differential effects of microtubule-altering agents on beta-cells during development.
The effect of microtubule-altering agents on the insulin secretory response to glucose during the perinatal period was investigated with an in vitro perifusion system. Rat pancreatic mince from day 17 of gestation (D17G) to day 6 postnatally (D6PN) were perifused for 60 min in basal glucose followed by 45 min with high glucose (3.5 mg/ml) or with high glucose plus 10 mM arginine (D17G). The two phases of insulin secretion in response to high glucose developed in an age-dependent and asynchronous manner. The first phase matured between D17G and D18G, and maturation of the second phase occurred subsequently. Vinblastine (VB) (20 or 100 microM) had a differential effect on the insulin secretory response. VB did not inhibit stimulated insulin release at D17G. This absence of an inhibitory effect of VB at D17G could not be explained by the absence of polymerized tubulin because microtubules were present in the control beta-cells and, in addition, VB treatment resulted in the formation of paracrystalline deposits. Subsequently in development, and with isolated islets of the adult, VB inhibited stimulated insulin release. Heavy water (deuterium oxide, D2O) inhibited stimulated insulin secretion at D17G but blocked completely insulin release from the near-term beta-cell. The inhibition of insulin secretion by D2O was rapidly reversed when water replaced D2O in the perifusion media. The results indicate that the maturation of the second phase of insulin secretion coincides with the ability of the microtubule-altering agents to modify the insulin secretory response. One possible explanation for these findings is that at D17G the microtubules are not coupled physicochemically to other molecules or structures necessary for their role in insulin secretion to be expressed fully.


Yawning: role of hypothalamic paraventricular nitric oxide.
Yawning is a phylogenetically old, stereotyped event that occurs alone or associated with stretching and/or penile erection in humans, in animals from reptiles to birds and mammals, under different conditions. Several neurotransmitters and neuropeptides are involved in its control at the central level. One of these at the level of the paraventricular hypothalamic nucleus (PVHN) is nitric oxide (NO). First, NO synthase inhibitors injected into this hypothalamic nucleus prevent yawning induced by dopamine agonists, oxytocin or N-methyl-D-aspartic acid (NMDA), which induce yawning by activating PVHN oxytocinergic neurons projecting to extra-hypothalamic brain areas. The inhibitory effect of NO synthase inhibitors was not observed when these compounds were given concomitantly with L-arginine, the precursor of NO. Second, dopamine agonists, NMDA and oxytocin given at doses that induce yawning, increase NO production in the PVHN, as determined by in vivo microdialysis. Conversely, the opiate morphine, which prevents yawning induced by dopamine agonists, oxytocin and NMDA, also prevents the increase in the paraventricular NO production induced by these compounds. Third, NO donors, such as nitroglycerin, sodium nitroprusside and hydroxylamine, induce yawning when injected into the PVHN apparently by activating oxytocinergic transmission. Since guanylate cyclase inhibitors and NO scavengers (hemoglobin) injected into the PVHN do not prevent drug-induced yawning, nor 8-Br-cGMP injected into the PVHN induces this behavioral response, it is likely that NO acts as an intracellular rather than an intercellular modulator inside the PVHN oxytocinergic neurons in which NO is formed to facilitate the expression of this phylogenetically old event by guanylate cyclase-independent mechanisms.


Blood component transfusion in critically ill patients.
This review summarizes the current evidence base for commonly transfused blood components with a particular focus on the nonacutely bleeding patient. There remains little definitive evidence to guide transfusion practices in the critically ill. The most rigorous evidence to guide red blood cell (RBC) transfusion practice is derived from the Transfusion in Critical Care Trial (TRICC Trial) that was published in 1999. Specific subgroups of patients may be at particular risk of the adverse effects of anemia, and require further study. There are no randomized controlled trials addressing clinically important outcomes evaluating frozen plasma, platelet thresholds, or impaired platelet activity in the critically ill. As all blood components have some level of risk, the general approach to transfusion should be one of minimization. For the nonacutely bleeding critically ill patient, a RBC transfusion trigger of 70 g/l is clinically acceptable. For patients at potentially higher risk of adverse effects related to anemia such as those with septic shock, severe and/or acute ischemic heart disease, or brain injury, a higher threshold (80-90 g/l) may be considered. There is insufficient evidence to recommend specific thresholds for transfusion of frozen plasma or platelets in the critically ill.


Chicamycin, a new antitumor antibiotic. I. Production, isolation and properties.
Chicamycin is a new antitumor antibiotic produced by a strain of Streptomyces albus, No. J576 -99. The antibiotic is extractable into organic solvents from the fermentation broth and is obtained in two active forms, chicamycins A and B, depending upon the isolation procedure used. Chicamycin A is not a natural antibiotic but the methanol adduct of naturally produced chicamycin B. Both forms of the antibiotic have weak antibacterial activity against some Gram-positive and acid-fast bacteria. They inhibit the growth of experimental tumors such as P388 mouse leukemia.


[Activation of brain K+-phosphatase and Mg2+, Na+, K+-AtPase by sodium alkyl sulfates].
K+-dependent phosphatase and Mg2+, Na+, K+-ATPase were studied under the activating effect of surfactant homologs of the alkyl sulphate series with the hydrocarbon radical long chain C4-C15. The homologs are shown to activate the enzymes when they are in the molecular-disperse but not in micellar state. A clear regularity is observed in the effect of these surfactants on K+-phosphatase depending on the length of the hydrocarbon radical chain: the degree of the activating effect rises with the chain lengthening, reaching the maximum value when the number of carbon atoms is 12. The lower and upper bounds of the alkyl sulphate hydrocarbon radical chain length necessary for manifestation of the activating effect shift somewhat for K+-dependent phosphatase as compared with Mg2+, Na+, K+-ATPase. The data obtained evidence for a stronger stability of the phosphatase to a destructive effect of the surfactants as compared with transport ATPase.


Efficacy of a Bicistronic Vector for Correction of Sandhoff Disease in a Mouse Model.
GM2 gangliosidoses are a family of severe neurodegenerative disorders resulting from a deficiency in the β-hexosaminidase A enzyme. These disorders include Tay-Sachs disease and Sandhoff disease, caused by mutations in the HEXA gene and HEXB gene, respectively. The HEXA and HEXB genes are required to produce the α and β subunits of the β-hexosaminidase A enzyme, respectively. Using a Sandhoff disease mouse model, we tested for the first time the potential of a comparatively lower dose (2.04 × 1013 vg/kg) of systemically delivered single-stranded adeno-associated virus 9 expressing both human HEXB and human HEXA cDNA under the control of a single promoter with a P2A-linked bicistronic vector design to correct the neurological phenotype. A bicistronic design allows maximal overexpression and secretion of the Hex A enzyme. Neonatal mice were injected with either this ssAAV9-HexB-P2A-HexA vector or a vehicle solution via the superficial temporal vein. An increase in survival of 56% compared with vehicle-injected controls and biochemical analysis of the brain tissue and serum revealed an increase in enzyme activity and a decrease in brain GM2 ganglioside buildup. This is a proof-of-concept study showing the "correction efficacy" of a bicistronic AAV9 vector delivered intravenously for GM2 gangliosidoses. Further studies with higher doses are warranted.


Molecular chaperone Hsp90 is a therapeutic target for noroviruses.
Human noroviruses (HuNoV) are a significant cause of acute gastroenteritis in the developed world, and yet our understanding of the molecular pathways involved in norovirus replication and pathogenesis has been limited by the inability to efficiently culture these viruses in the laboratory. Using the murine norovirus (MNV) model, we have recently identified a network of host factors that interact with the 5' and 3' extremities of the norovirus RNA genome. In addition to a number of well-known cellular RNA binding proteins, the molecular chaperone Hsp90 was identified as a component of the ribonucleoprotein complex. Here, we show that the inhibition of Hsp90 activity negatively impacts norovirus replication in cell culture. Small-molecule-mediated inhibition of Hsp90 activity using 17-DMAG (17-dimethylaminoethylamino-17-demethoxygeldanamycin) revealed that Hsp90 plays a pleiotropic role in the norovirus life cycle but that the stability of the viral capsid protein is integrally linked to Hsp90 activity. Furthermore, we demonstrate that both the MNV-1 and the HuNoV capsid proteins require Hsp90 activity for their stability and that targeting Hsp90 in vivo can significantly reduce virus replication. In summary, we demonstrate that targeting cellular proteostasis can inhibit norovirus replication, identifying a potential novel therapeutic target for the treatment of norovirus infections. HuNoV are a major cause of acute gastroenteritis around the world. RNA viruses, including noroviruses, rely heavily on host cell proteins and pathways for all aspects of their life cycle. Here, we identify one such protein, the molecular chaperone Hsp90, as an important factor required during the norovirus life cycle. We demonstrate that both murine and human noroviruses require the activity of Hsp90 for the stability of their capsid proteins. Furthermore, we demonstrate that targeting Hsp90 activity in vivo using small molecule inhibitors also reduces infectious virus production. Given the considerable interest in the development of Hsp90 inhibitors for use in cancer therapeutics, we identify here a new target that could be explored for the development of antiviral strategies to control norovirus outbreaks and treat chronic norovirus infection in immunosuppressed patients.


Microvascular structure as a prognostically relevant endpoint.
Remodelling of subcutaneous small resistance arteries, as indicated by an increased media-to-lumen ratio, is frequently present in hypertensive, obese, or diabetic patients. The increased media-to-lumen ratio may impair organ flow reserve. This may be important in the maintenance and, probably, also in the progressive worsening of hypertensive disease. The presence of structural alterations represents a prognostically relevant factor, in terms of development of target organ damage or cardiovascular events, thus allowing us a prediction of complications in hypertension. In fact, media-to-lumen ratio of small arteries at baseline, and possibly their changes during treatment may have a strong prognostic significance. However, new, non-invasive techniques are needed before suggesting extensive application of the evaluation of remodelling of small arteries for the cardiovascular risk stratification in hypertensive patients. Some new techniques for the evaluation of microvascular morphology in the retina, currently under clinical investigation, seem to represent a promising and interesting future perspective. The evaluation of microvascular structure is progressively moving from bench to bedside, and it could represent, in the near future, an evaluation to be performed in all hypertensive patients, to obtain a better stratification of cardiovascular risk, and, possibly, it might be considered as an intermediate endpoint in the evaluation of the effects of antihypertensive therapy, provided that a demonstration of a prognostic value of non-invasive measures of microvascular structure is made available.


Clinical implications of angiogenesis in cancers.
Angiogenesis plays an important role in the growth and progression of cancer. The regulation of tumor angiogenesis depends on a net balance of angiogenic factors and antiangiogenic factors, which are secreted by both tumor cells and host-infiltrating cells. Numerous studies have indicated that assessment of angiogenic activity by either microvessel density or expression of angiogenic factors in cancer can provide prognostic information independent of conventional clinicopathological factors such as tumor staging. Some studies also suggested that assessment of tumor angiogenesis may predict cancer response to chemotherapy or radiotherapy. However, the most important clinical implication of tumor angiogenesis is the development of a novel strategy of anticancer therapy targeting tumor vessels instead of cancer cells. Antiangiogenic therapy aims to inhibit the growth of tumor, and current evidence suggests that it works best in combination with conventional cytotoxic chemotherapy. Recently, a monoclonal antibody against vascular endothelial growth factor, which is one of the most potent angiogenic factors, has been approved for clinical use in colorectal cancer patients after a clinical trial confirmed that combining the antibody with standard chemotherapy regimen could prolong patient survival. The clinical implications of angiogenesis in cancer are reviewed in this article.


Single-slice rebinning method for helical cone-beam CT.
In this paper, we present reconstruction results from helical cone-beam CT data, obtained using a simple and fast algorithm, which we call the CB-SSRB algorithm. This algorithm combines the single-slice rebinning method of PET imaging with the weighting schemes of spiral CT algorithms. The reconstruction is approximate but can be performed using 2D multislice fan-beam filtered backprojection. The quality of the results is surprisingly good, and far exceeds what one might expect, even when the pitch of the helix is large. In particular, with this algorithm comparable quality is obtained using helical cone-beam data with a normalized pitch of 10 to that obtained using standard spiral CT reconstruction with a normalized pitch of 2.


Challenges to Global Standardization of Outcome Measures.
Global standardization of outcome measures for disease states can help researchers and healthcare providers compare healthcare institutions' and populations' health outcomes. Despite the creation of standardized outcome sets, clinical institutions' adoption of these sets is not common. A literature review shows that among the challenges to standardizing outcome measures include the difficulties of achieving consensus in the working groups creating these outcome sets, the tradeoffs made when selecting outcome measurement tools, and the high costs of implementing a new or different set of outcome measures. The duplication of effort to create these standard sets can also limit standardization, which could be minimized through increased transparency of how these standard sets are developed. We propose some approaches to improve how to create and implement standard sets to broaden their usability across institutions.


Cues for sound localization are encoded in multiple aspects of spike trains in the inferior colliculus.
To localize sound, information from three cues--interaural timing differences (ITDs), interaural level differences (ILDs), and spectral notch cues (SNs)--must be properly integrated. The inferior colliculus (IC) receives convergent input from neurons encoding all three cues. Using virtual space stimuli and information theoretic techniques, we investigated the coding of the various localization cues in single neurons of the IC under different encoding schemes. Here we focus on the analysis of information encoded by first-spike latency, in comparison to previous results on discharge rate and ongoing spike timing. The results show that the localization cues converge to different degrees in particular neurons. ITD information is conveyed most strongly by spike rate, with small amounts of independent information in latency and ongoing spike timing. ILD information shows a similar pattern, with larger mutual information values for all three cues. For these cues, ongoing spike timing does not typically contribute independent information over that captured by a joint rate/first-spike latency code. SNs are coded by both rate and first-spike latency, but ongoing spike timing significantly enhances their representation in a best frequency-dependent manner, as long as the temporal envelope of the stimulus can be used in the decoder. The differential coding of the localization cues suggests that information about multiple cues could be multiplexed onto the responses of single neurons.


Treatment of recent-onset rheumatoid arthritis: lessons from the BeSt study.
To determine the efficacy, toxicity, utilities, and costs of 4 treatment strategies for patients with recent-onset rheumatoid arthritis (RA). 508 patients with recent-onset active RA [mean Disease Activity Score (DAS) 4.4, mean Health Assessment Questionnaire score 1.4] were randomized into 4 strategy groups: (1) sequential monotherapy; (2) step-up to combination therapy [both starting with methotrexate (MTX)]; (3) initial combination therapy with MTX, sulfasalazine, and prednisone; (4) initial combination therapy with MTX and infliximab. Treatment adjustments were based on 3-monthly calculations of the DAS (target DAS ? 2.4), by research nurses who were blinded to the strategy group. They also collected data on treatment toxicity, functional ability, costs, and utilities. Yearly anonymized radiographs of hands and feet were scored in random order by 2 independent physicians, using the Sharp/van der Heijde score. Functional ability improved significantly earlier in Groups 3 and 4 than in Groups 1 and 2, but was comparable among the groups at the end of the first year of treatment. Radiographic joint damage progression was significantly lower in Groups 3 and 4 than in Groups 1 and 2, but low in all groups compared to other RA populations, probably due to DAS-driven treatment adjustments in all groups. More patients in Groups 3 and 4 than in Groups 1 and 2 achieved clinical remission (DAS 1.6), and patients who achieved early continued remission in Groups 3 and 4 had significantly less joint damage progression than those who achieved the same in Groups 1 and 2. More patients could taper and stop all antirheumatic drugs and still retained remission in Group 4 (17% at t = 3 years) than in the other groups (10%, 5%, 9%, respectively). Toxicity was comparable between groups. Quality of life measures were significantly higher in Group 4 than in the other groups, but costs of treatment were also the highest in Group 4. Depending on the method used, higher productivity in Group 4 compensated for the higher medical costs. In patients with recent-onset RA, initial combination therapy including prednisone or infliximab results in earlier clinical improvement and less joint damage progression than initial monotherapy. Initial treatment with infliximab resulted in the highest quality of life, highest productivity, and highest medical costs. DAS-driven treatment adjustments were effective to suppress disease activity and damage progression in all groups.


Selecting and applying indicators of ecosystem collapse for risk assessments.
Ongoing ecosystem degradation and transformation are major threats to biodiversity. Measuring ecosystem change toward collapse relies on monitoring indicators that quantify key ecological processes. Yet little guidance is available on selection and use of indicators for ecosystem risk assessment. We reviewed indicator use in ecological studies of ecosystem collapse in marine pelagic and temperate forest ecosystems. We examined indicator-selection methods, indicator types (geographic distribution, abiotic, biotic), methods of assessing multiple indicators, and temporal quality of time series. We compared how these factors were applied in the ecological studies with how they were applied in risk assessments by using the International Union for Conservation of Nature's Red List of Ecosystems (RLE), for which indicators are used to estimate risk of ecosystem collapse. Ecological studies and RLE assessments rarely reported how indicators were selected, particularly in terrestrial ecosystems. Few ecological studies and RLE assessments quantified ecosystem change based on all 3 indicator types, and indicators types used differed between marine and terrestrial ecosystems. Several studies used indices or multivariate analyses to assess multiple indicators simultaneously, but RLE assessments did not because as RLE guidelines advise against them. Most studies and RLE assessments used time-series data that spanned at least 30 years, which increases the probability of reliably detecting change. Limited use of indicator-selection protocols and infrequent use of all 3 indicator types may hamper accurate detection of change. To improve the value of risk assessments for informing policy and management, we recommend using explicit protocols, including conceptual models, to identify and select indicators; a range of indicators spanning distributional, abiotic, and biotic features; indices and multivariate analyses with extreme care until guidelines are developed; time series with sufficient data to increase ability to accurately diagnose directional change; data from multiple sources to support assessments; and explicitly reporting steps in the assessment process.


Hsa-miR-196a2 functional SNP is associated with the risk of ESCC in individuals under 60 years old.
The miR-196a2 gene contains a C/T polymorphism (rs11614913). Its presence could change the conformation of secondary structure of miR-196a2 RNA, and directly affect the binding to target mRNAs and the miRNA maturation process. Both of which eventually alter protein expression and contributed to cancer susceptibility. This study assessed whether the rs11614913 single nucleotide polymorphism (SNP) could affect an individual's susceptibility to esophageal squamous cell carcinomas (ESCC). SNP rs11614913 was genotyped by polymerase chain reaction ligase detection reaction (PCR-LDR) in 597 ESCC patients and 597 control subjects. Overall, there were no significant differences in the frequency of the miRNA-196a2 SNP rs11614913 genotype between the ESCC cases and the controls (χ(2) = 1.395, p = 0.498). The TT genotype, CT genotype and CT/TT combined genotype (dominant model) did not modify the risk of ESCC as compared with the CC genotype. Comparisons of the TT genotype to the CT/CC combined genotype did not reveal a significant association to ESCC, too. However, further analyses revealed an increased risk of ESCC in the dominant model (OR = 1.56, 95% CI = 1.08-2.26) and the allele frequency comparison (OR = 1.31, 95% CI = 1.06-1.63) in the ≤60-year-old group. These results suggest that the miRNA-196a2 functional polymorphism rs11614913 might be an effective genetic marker for ESCC risk assessment in individuals younger than 60 years of age from a region of high ESCC incidence in northern China.


Effect of forskolin and acetylcholine on calcium current in single isolated cardiac myocytes.
The effect of extracellular and intracellular application of forskolin on the voltage-sensitive calcium current, ICa, was studied in myocytes isolated from frog ventricle. Myocytes were isolated by enzymatic dissociation, and ICa was measured using the whole-cell configuration of the patch clamp technique modified to permit intracellular perfusion of various substances. Intracellular perfusion with forskolin (0.1 to 10 microM) had a negligible effect on ICa: ICa was increased 15 +/- 13% (mean +/- SE; N = 5). In contrast, superfusion of the cell with forskolin increased ICa significantly. The EC50 for the forskolin effect was 0.4 microM. A maximal 4.5-fold increase in ICa occurred with 3 microM forskolin. This is somewhat less than the maximal response to isoprenaline seen in this same series of experiments. The effects of forskolin, isoprenaline, and intracellular cAMP were not additive. In contrast, the effects of isoprenaline or intracellular cAMP and calcium channel agonists, such as Sandoz (+)202-791, were additive. This supports the hypothesis that the positive inotropic effects of forskolin are at least partly mediated by an increase in intracellular cAMP and a stimulation of ICa. The effects of forskolin were antagonized by acetylcholine (1 microM) or intracellular perfusion with cGMP. Acetylcholine on the average decreased forskolin-stimulated ICa 57 +/- 11% (N = 17). The relevance of these results to the suggestion that acetylcholine acts by mechanisms other than inhibition of adenylate cyclase is discussed.


Genetic elements of Thermococcales.
This minireview summarizes our current knowledge about archaeal genetic elements in the hyperthermophilic order Thermococcales in the phylum Euryarchaeota. This includes recent work on the first virus of Pyrococcus, PAV1, the discovery of novel unique virus morphotypes in hot deep-sea environments, and preliminary observations on novel cryptic plasmids. We also review the work accomplished over the last 5 years in the development of genetic tools for members of the Pyrococcus and Thermococcus genera, mainly in our laboratories.


Pediatric neurosurgical implications of the amniotic band disruption complex. Case reports and review of the literature.
Defects caused by the amniotic band disruption complex (ABDC) may vary from simple malformations caused by digital constriction to major scalp, craniofacial, and visceral malformations. ABDC may cause 7-14% of stillbirths. The etiology is unclear, but the most commonly accepted mechanism involves rupture of the amnion followed by fetal malformation, deformation, and compression. This mechanism does not adequately explain all anomalies such as hydrocephalus and holoprosencephaly that are seen in the ABDC. The use of prenatal ultrasound has allowed the diagnosis of the ABDC in utero. Since 1980, four children with the ABDC who required neurosurgical intervention were seen at the University of California, San Francisco; the presentation and subsequent surgical treatment of 2 of these children are discussed. A combined craniofacial team approach to the management of these children can maximize reconstructive and neurologic outcome.


History in the interpretation of the pattern of p49a,f TaqI RFLP Y-chromosome variation in Egypt: a consideration of multiple lines of evidence.
The possible factors involved in the generation of p49a,f TaqI Y-chromosome spatial diversity in Egypt were explored. The object was to consider explanations beyond those that emphasize gene flow mediated via military campaigns within the Nile corridor during the dynastic period. Current patterns of the most common variants (V, XI, and IV) have been suggested to be primarily related to Middle Kingdom and New Kingdom political actions in Nubia, including occasional settler colonization, and the conquest of Egypt by Kush (in upper Nubia, northern Sudan), thus initiating the Twenty-Fifth Dynasty. However, a synthesis of evidence from archaeology, historical linguistics, texts, distribution of haplotypes outside Egypt, and some demographic considerations lends greater support to the establishment, before the Middle Kingdom, of the observed distributions of the most prevalent haplotypes V, XI, and IV. It is suggested that the pattern of diversity for these variants in the Egyptian Nile Valley was largely the product of population events that occurred in the late Pleistocene to mid-Holocene through the First Dynasty, and was sustained by continuous smaller-scale bidirectional migrations/interactions. The higher frequency of V in Ethiopia than in Nubia or upper (southern) Egypt has to be taken into account in any discussion of variation in the Nile Valley.


Serious injuries to Australian veterinarians working with cattle.
To describe the factors associated with serious injuries sustained during cattle-associated activities by veterinarians responding to the Health Risks of Australian Veterinarians (HRAV) survey. Responses from the HRAV survey were reviewed and the factors associated with serious injuries reported by veterinarians while working with cattle were analysed. All veterinarians who had graduated from Australian veterinary schools between 1960 and 2000 were eligible for inclusion in the survey. The survey identified 474 serious injuries sustained while undertaking cattle-associated activities. Most cattle-associated injuries (82%) were sustained in stock or handling yards and 57% of reported injuries were sustained while undertaking pregnancy testing or undertaking examinations. Nearly 80% of all cattle-associated injuries were sustained as a result of the veterinarian being kicked or struck (49%) or pushed against or stepped on (30%). The part of the body most commonly injured was the upper limbs. Fractures were the most common type of serious injury sustained. The use of safety precautions at the time of the injury was reported by 62% of those veterinarians reporting injury. This study describes factors associated with serious injuries while working with cattle, as reported by veterinarians responding to the HRAV survey. Findings from this study will facilitate discussions aimed at addressing injury prevention for cattle veterinarians, including improving the awareness of safe handling practices and safety precautions.


Financial Planning Among Parents of Children With Intellectual and Developmental Disabilities.
Families of children with intellectual and developmental disabilities (IDD) experience significant financial hardship, which could improve through financial planning and utilization of accounts such as the Achieving a Better Life Experience (ABLE). Unfortunately, current rates of banking are low among individuals with disabilities, and no study has examined this phenomenon specifically among families of children with IDD. In this cross-sectional study, 176 parents shared their financial planning and utilization experience. Findings indicate that parents worry about their child's financial future, however, paradoxically, are not engaging in financial planning. Utilization of ABLE, checking and savings accounts, and special needs trusts are also low. Parents reported several programmatic and personal barriers which could inform immediate programmatic changes and long-term policy considerations.


Quantitative trait loci for a neurocranium deformity, lack of operculum, in gilthead seabream (Sparus aurata L.).
Lack of operculum, a neurocranial deformity, is the most common external abnormality to be found among industrially produced gilthead seabream (Sparus aurata L.), and this entails significant financial losses. This study conducts, for the first time in this species, a quantitative trait loci (QTL) analysis of the lack of operculum. A total of 142 individuals from a paternal half-sibling family (six full-sibling families) were selected for QTL mapping. They had previously shown a highly significant association with the prevalence of lack of operculum in a segregation analysis. All the fish were genotyped for 106 microsatellite markers using a set of multiplex PCRs (ReMsa1-ReMsa13). A linear regression methodology was used for the QTL analysis. Four QTL were detected for this deformity, two of which (QTLOP1 and QTLOP2) were significant. They were located at LG (linkage group) nine and LG10 respectively. Both QTL showed a large effect (about 27%), and furthermore, the association between lack of operculum and sire allelic segregation observed was statistically significant in the QTLOP1 analysis. These results represent a significant step towards including marker-assisted selection for this deformity in genetic breeding programmes to reduce the incidence of the deformity in the species.


Serum antibody responses in pigs trickle-infected with Ascaris and Trichuris: Heritabilities and associations with parasitological findings.
A humoral immune response following helminth infection in pigs is well documented. However, it has been difficult to confirm the existence of antibody mediated resistance against the large roundworm, Ascaris suum, and whipworm, Trichuris suis, in experimental settings by correlating worm burdens or egg excretion with specific antibody levels. We set out to investigate the association between worm load and T. suis and A. suum specific serum antibody levels (IgG1, IgG2 and IgA) against excretory-secretory products of adults and third stage larvae, respectively, measured at 0, 7 and 14 weeks p.i. in a trickle-infected F1-resource-population of crossbred pigs (n=195). Furthermore, we wanted to determine the heritability of these antibody isotypes during the course of infection. Most pigs remained infected with A. suum throughout the experiment while they expelled T. suis between 7 and 14 weeks post infection (p.i.). Parasite specific IgG1 and IgA were significantly (P<0.001) elevated after 7 and 14 weeks of infection, whereas parasite specific IgG2 levels only changed slightly at 14 weeks p.i.. However, the observed association between specific antibody isotype levels and faecal egg counts and macroscopic worm load was weak. The relative heritabilities of the different parasite specific isotypes were assessed and resulted in significant heritability estimates for parasite specific IgG1 and IgA. The highest heritabilities were found for A. suum specific IgG1 (h(2)=0.41 and 0.46 at 7 and 14 weeks p.i., respectively). Thus, the present study demonstrates that host genetic factors influence the IgG1 and IgA antibody isotype responses specific to two of the most common gastrointestinal nematodes of swine whereas specific antibody levels were poorly associated with egg excretion and the presence of macroscopic worms.


Effects of oregano oil brine enhancement on quality attributes of beef longissimus dorsi and semimembranosus muscles from various age animals.
The study reports whether or not oregano oil can reduce lipid oxidation and evaluate palatability variations in beef longissimus dorsi and semimembranosus muscles from various age animals (approximately 18 mo; 18 M, 30 to 60 mo; 30 M, and >60 mo; 60 M). Six muscles of each age group were halved and enhanced with a control brine containing no antioxidants (CN) or a brine containing oregano oil (OR), cut into steaks, and stored in modified atmosphere packaging for 0, 4, 7, and 11 d. Each sampling day, surface color (Minolta L, a, b), lipid oxidation (TBARS), cook yield, sensory analysis, and Warner-Bratzler shear force (WBSF) were measured. OR enhancement decreased TBARS values and slowed the rate of decline in a values (P < 0.05), but had no effect on WBSF, or sensory tenderness and juiciness scores (P > 0.05) compared to CN steaks. OR steaks had less rancidity detection, more off-flavor, lower overall acceptability in sensory analysis (P < 0.05). This indicated oregano oil can effectively reduce lipid oxidation and extend shelf-life of meat products, but further investigation would be needed to avoid off-flavor and acceptability of product quality. Decreases in meat consumption have led the meat industry to become more innovative in product development. Reducing lipid oxidation is a viable method to reduce rancidity, and improving product acceptability. Our research indicated that although oregano oil did reduce lipid oxidation, the adverse effects of flavor were too great, and thus would not be tolerable in fresh meat products at this concentration. However, there is potential to use oregano oil at lower concentrations and in a variety of processed products which could be beneficial to further the use of natural antioxidants.


Outcomes Associated with Lower Doses of Ketamine by Emergency Medical Services for Profound Agitation.
Ketamine is commonly used to treat profound agitation in the prehospital setting. Early in ketamine's prehospital use, intubation after arrival in the emergency department (ED) was frequent. We sought to measure the frequency of ED intubation at a Midwest academic medical center after prehospital ketamine use for profound agitation, hypothesizing that intubation has become less frequent as prehospital ketamine has become more common and prehospital dosing has improved. We conducted a retrospective cohort study of adult patients receiving ketamine in the prehospital setting for profound agitation and transported to a midwestern, 60,000-visit, Level 1 trauma center between January 1, 2017-March 1, 2021. We report descriptive analyses of patient-level prehospital clinical data and ED outcomes. The primary outcome was proportion of patients intubated in the ED. A total of 78 patients received ketamine in the prehospital setting (69% male, mean age 36 years). Of the 42 (54%) admitted patients, 15 (36% of admissions) were admissions to the intensive care unit. Overall, 12% (95% confidence interval [CI]), 4.5-18.6%)] of patients were intubated, and indications included agitation (n = 4), airway protection not otherwise specified (n = 4), and respiratory failure (n = 1). Endotracheal intubation in the ED after prehospital ketamine use for profound agitation in our study sample was found to be less than previously reported.


Vancomycin-Resistant Enterococcus Acquisition in a Tertiary Care Hospital: Testing the Roles of Antibiotic Use, Proton Pump Inhibitor Use, and Colonization Pressure.
Vancomycin-resistant Enterococcus (VRE) is a leading cause of healthcare-associated infections, and asymptomatic colonization precedes infection. VRE continues to spread despite widespread application of pathogen-specific control guidelines. A better understanding of the risk factors for transmission is needed. A retrospective matched case-control study was performed from June 2013 through December 2016 in a single institution. Patients in 6 intensive care units, 1 hematology and oncology unit, and 1 bone marrow transplant unit were screened by means of rectal swab sampling on admission and weekly thereafter. Case patients had a negative swab sample followed by a positive sample >3 days after admission. Controls were closely matched to case patients based on time from admission to the second swab sample, unit in which the second sample was obtained, and date of admission. Comorbidity data, procedures, healthcare settings and exposures, culture data, and duration of antibiotic and proton pump inhibitor (PPI) therapy were abstracted from the electronic medical record. A multivariable risk factor model for conversion was generated using purposeful selection. A total of 551 case patients were matched with controls. The largest modifiable effects on VRE acquisition were ≥1 day of vancomycin therapy (odd ratio, 1.98; P < .001), ≥1 day of aerobic antibiotic therapy (1.90; P < .001), and a dose-dependent effect of PPI therapy (odds ratio per day of therapy, 1.09; P < .001). Colonization pressures from patients identified to be carriers and placed in contact precautions did not confer increased risk. Decreasing PPI use and preventing the inappropriate initiation of antibiotic therapy are modifiable targets to decrease VRE transmission in the hospital.


Dacryocystorhinostomy. Diagnosis and treatment of nasolacrimal canal obstructions.
Since Toti's original description of the dacryocystorhinostomy (CDR) in 1904, most surgery for relief of lacrimal obstruction has been performed through an external incision. Although the endonasal approach was for the first time introduced by Caldwell in 1893, its use stayed limited due to difficulties in visualizing the endonasal structures during the operation. The advance of the operating microscope and later a rigid endoscope into the surgery awakened interest for the endonasal approach. Endonasal DCR surgery has the advantages of preventing a scar on the skin and preserving the pump function of the naslacrimal sac. If the surgeon is experienced in endoscopic or microscopic surgery, correct localization of the window and addressing possible other nasal pathologies is possible in the same session. The endonasal laser DCR is not the first operation to be preferred due to the high cost, longer operation time, and less satisfactory results. It may be an alternative in cases with a tendency to bleeding. Endonasal surgery can not help canalicular problems. In these cases external surgery should be preferred. In revision cases, the endonasal approach is preferred by almost all authors. Even in external surgery, endoscopy may accompany the external approach to check the site of the fistula. Silicone intubation may be used routinely for two months to have better results, but no longer than 3 months to avoid complications. Silicone intubation is especially recommended in canalicular stenosis, small scarred lacrimal sacs and in reoperations. In this review article, diagnostic tests and various surgical methods, the advantages and disadvantages, were compared. Reasons for failure after surgery are also discussed.


[The effects of the ablation of atrial flutter in patients with and without a clinical history of paroxysmal atrial fibrillation].
Although the safety and effectiveness of radiofrequency (RF) transcatheter ablation in patients with atrial flutter (AFL) is well established, little attention is paid to previous history of associated paroxysmal atrial fibrillation (AF) and the recurrence of AFL after RF ablation. In addition, it is not known whether the elimination of AFL can modify the natural history of AF in patients who experience both of these arrhythmias. Accordingly, the aim of this study was to evaluate the effect of RF ablation of AFL in patients with or without a previous history of AF in terms of the incidence of both arrhythmias in the follow-up. RF ablation of the atrial isthmus between tricuspid ring, coronary sinus os and inferior vena cava was performed in 27 patients (23 males, 4 females; mean age 61 +/- 9 years) according to the technique described by Cosio. Based on ECG pattern, twenty patients exhibited common or type 1 AFL (negative F waves in the inferior leads with a sawtooth morphology), while seven patients had both common and uncommon AFL (various surface F wave morphologies, generally positive F waves in the inferior leads). A history of association between AFL and paroxysmal AF was documented in 48% of patients, but AFL was the major arrhythmia. After ablation, the patients were followed up and the clinically documented occurrence of arrhythmias was determined. Based on clinical history before ablation, we compared patients with an association between AFL and AF (Gr AFL + AF; n = 13) vs patients with only AFL (Gr AFL; n = 14). The characteristics of the two groups were similar regarding age, sex, duration of symptom, structural heart disease, left atrial size, P-wave duration, AFL interruption during RF procedure, antiarrhythmic treatment before and after RF procedure, and duration of follow-up. During a follow-up of 12 +/- 6 months, AFL recurred in 10 patients (37%), 4 from Gr AFL + AF, and 6 from Gr AFL (p = NS). Episodes of paroxysmal AF occurred in 6 patients (22%), 5 from Gr AFL + AF and 1 from Gr AFL (p < 0.05). In Gr AFL + AF, the incidence of AF after ablation was significantly lower (1.8 +/- 0.6 vs. 0.7 +/- 1 episodes/year; p < 0.02). Characteristics of patients with or without AFL recurrence in the follow-up were similar. The percentage of patients with the occurrence of AFL or AF, associated or unassociated in the follow-up, was 55%. A history of paroxysmal AF before RF ablation of AFL is not predictive of long-term success or failure of the procedure when considering the recurrence of AFL alone. Nevertheless, the general results are disappointing because the majority of patients have arrhythmias, AFL or AF, associated or unassociated in the follow-up. A clinical history of AF before ablation is correlated with a higher incidence of AF in the follow-up. In any event, the incidence of AF episodes is lower in the follow-up, indicating a possible beneficial effect of AFL ablation on AF mechanisms.


Arterial Injury to the Profunda Femoris Artery following Internal Fixation of a Neck of Femur Fracture with a Compression Hip Screw.
We report the case of an 82-year-old woman who developed extensive proximal thigh swelling and persistent anaemia following internal fixation of an extracapsular neck of femur fracture with a dynamic hip screw (DHS). This was revealed to be a pseudoaneurysm of a branch of profunda femoris artery on angiography. Her case was further complicated by a concurrent pulmonary embolism (PE). She underwent endovascular coil embolisation of the pseudoaneurysm. An IVC filter was inserted and the patient was fully anticoagulated once it had been ensured that there was no active bleeding. In this case, we review the potential for anatomical variations in the blood supply to this region and discuss treatment options for a complicated patient. We recommend that a pseudoaneurysm should be part of a differential diagnosis for postoperative patients with anaemia refractory to blood transfusion so as not to miss this rare but potentially serious complication.


VEGF receptor signaling in tumor angiogenesis.
The growth of human tumors and development of metastases depend on the de novo formation of blood vessels. The formation of new blood vessels is tightly regulated by specific growth factors that target receptor tyrosine kinases (RTKs). Vascular endothelial growth factor (VEGF) and the Flk-1/KDR RTK have been implicated as the key endothelial cell-specific factor signaling pathway required for pathological angiogenesis, including tumor neovascularization. Inhibition of the VEGF tyrosine kinase signaling pathway blocks new blood vessel formation in growing tumors, leading to stasis or regression of tumor growth. Advances in understanding the biology of angiogenesis have led to the development of several therapeutic modalities for the inhibition of the VEGF tyrosine kinase signaling pathway. A number of these modalities are under investigation in clinical studies to evaluate their potential to treat human cancers.


SUMO4 small interfering RNA attenuates invasion and migration via the JAK2/STAT3 pathway in non-small cell lung cancer cells.
Small ubiquitin-like modifier 4 (SUMO4) is the latest member of the sumoylation family, which enhances the stability of protein, regulates the distribution and localization of the protein, and affects the transcription activity of the protein. However, the role of SUMO4 in non-small cell lung cancer (NSCLC) has not yet been reported. The present study first demonstrated that SUMO4 was upregulated in a number of tissues from patients with NSCLC. Immunohistochemistry was performed to demonstrate the expression level of SUMO4 in lung cancer tumor tissues. Following the transfection, The EMT status and signaling pathway activation regulated by SUMO4-siRNA was assessed by western blotting. The Transwell and wound healing assays were performed to investigate the regulatory effect of SUMO4-siRNA on cell migration and invasion. Cell Counting Kit-8 assay was performed to investigate whether SUMO4-siRNA affected the chemosensitivity of the NSCLC cells to cisplatin. Statistical analysis of immunohistochemical results from the tissues showed that the overexpression of SUMO4 was significantly associated with sex, tumor type, history of smoking, T stage and poor prognosis. It was also identified that SUMO4 small interfering RNA attenuated invasion and migration in NSCLC cell lines, as well chemosensitivity to cisplatin via the inhibition of the JAK2/STAT3 pathway. In conclusion, SUMO4 may play an important role in the poor prognosis of patients with NSCLC. The present study indicates that SUMO4 may be a potential therapeutic target for NSCLC.


Cardiorespiratory fitness alters the influence of a polygenic risk score on biomarkers of AD.
To examine whether a polygenic risk score (PRS) derived from APOE4, CLU, and ABCA7 is associated with CSF biomarkers of Alzheimer disease (AD) pathology and whether higher cardiorespiratory fitness (CRF) modifies the association between the PRS and CSF biomarkers. Ninety-five individuals from the Wisconsin Registry for Alzheimer's Prevention were included in these cross-sectional analyses. They were genotyped for APOE4, CLU, and ABCA7, from which a PRS was calculated for each participant. The participants underwent lumbar puncture for CSF collection. β-Amyloid 42 (Aβ42), Aβ40, total tau (t-tau), and phosphorylated tau (p-tau) were quantified by immunoassays, and Aβ42/Aβ40 and tau/Aβ42 ratios were computed. CRF was estimated from a validated equation incorporating sex, age, body mass index, resting heart rate, and self-reported physical activity. Covariate-adjusted regression analyses were used to test for associations between the PRS and CSF biomarkers. In addition, by including a PRS×CRF term in the models, we examined whether these associations were modified by CRF. A higher PRS was associated with lower Aβ42/Aβ40 (p < 0.001), higher t-tau/Aβ42 (p = 0.012), and higher p-tau/Aβ42 (p = 0.040). Furthermore, we observed PRS × CRF interactions for Aβ42/Aβ40 (p = 0.003), t-tau/Aβ42 (p = 0.003), and p-tau/Aβ42 (p = 0.001). Specifically, the association between the PRS and these CSF biomarkers was diminished in those with higher CRF. In a late-middle-aged cohort, CRF attenuates the adverse influence of genetic vulnerability on CSF biomarkers. These findings support the notion that increased cardiorespiratory fitness may be beneficial to those at increased genetic risk for AD.


Frontier issues in international ocean governance: Japan's discharge of nuclear contaminated water into the sea.
This paper aimed at explore international ocean governance issues through the perspective of Japan's nuclear contaminated water discharge to the sea. This paper analyzes the core issue of Japan's plan to discharge nuclear contaminated water into the ocean from the perspectives of Japan's international legal obligation, law enforcement issues, and judicial issues after integrated analyzing academic research paper and cases. Japan has obligations such as timely notification, information disclosure, environmental impact assessment, and avoidance of transboundary harm. Intergovernmental and non-governmental international organizations, such as IAEA, IMO and WHO should play a role in setting up an international group of experts to carry out monitoring and assessment, and whose positions and attitudes are important references for judging Japan's behavior. Cases heard before ICJ, ITLOS, and advisory opinion proceeding could provide reference from the judicial perspective on the issue of transboundary harm and proof of damages. Furthermore, this paper discusses the response strategies that the international community especially the opponents may adopt, including promoting the adoption of relevant treaties, take a combination of requesting advisory opinion and file arbitration, establish effective international monitoring mechanism, and engage in close communication with stakeholders.


The risk of COVID-19 infection among nurses working with COVID-19 patients.
Working with 2019 coronavirus disease (COVID-19) patients is currently considered one of the main fears and challenges that face healthcare workers (HCWs), especially nurses. This challenge can jeopardize the quality of health care services for those patients and cause a serious mental burden to HCWs. To understand and estimate the risk of COVID-19 infection among HCWs who directly serve COVID-19 patients. Before the community spread of the disease, 270 nurses who worked with COVID-19 wards were followed for 11 weeks to report the COVID-19 cases. On the other hand, during the community spread of the disease, 981 registered nurses (300 worked in COVID-19 wards and 681 worked in non-COVID wards) were followed for up to 16 weeks to report the COVID-19 cases. Before the community spread of COVID-19, none of the nurses who worked with the COVID-19 patients got the infection. On the other hand, during the community spread of the COVID-19 infection, 30% of the 300 nurses who worked in the COVID-19 wards got the COVID-19 infection, while 64% of the 681 HCWs who worked in the non-COVID wards got the infection. The relative risk of getting COVID-19 infection among HCWs who worked in the COVID-19 wards was reduced to about half in comparison to other HCWs who worked in the non-COVID wards (RR = 0.469). HCWs should not fear working with COVID-19 patients. Considering appropriate personal protective measures and infection control standards, the risk of infection transmission from the community is higher than that of COVID-19 patients, if any.


Human vascular endothelial cells stimulate memory but not naive CD8+ T cells to differentiate into CTL retaining an early activation phenotype.
Endothelial cell (EC)-selective alloreactive CTL may mediate alloimmune vascular injury. In the present study, EC-selective CTL were generated in cocultures of purified human CD8+ T cells with allogeneic EC and were compared with conventional CTL against corresponding B lymphoblastoid cells (BLC). EC caused activation and expansion of memory but not naive CD8+ T cells, which differentiated into EC-selective CTL that retained high surface expression of CD69, CD25, and CD62L and displayed low intracellular perforin content. In contrast, BLC-stimulated CTL could be generated from naive or memory CD8+ T cells and showed a more mature phenotype (low CD69, CD25, and CD62L with higher levels of perforin). The expansion of alloreactive T cells by EC stimulation was 5- to 20-fold less effective than in corresponding BLC-stimulated cultures, accounting for a reduction in the assayable cytotoxicity of individual microcultures. In these IL-2-supplemented cocultures, no effect on CTL generation or phenotype was observed by mAb blocking of costimulation provided by LFA-3, ICAM-1, or CD40, by addition of comitogenic anti-CD28 mAb, or by preactivation of EC with CD40 ligand. Cyclosporine inhibited CTL expansion and cytotoxicity similarly in both EC- and BLC-stimulated cultures but did not affect the phenotype of those CTL that did emerge. This study extends the characterization of endothelium as an immunoregulatory cell type distinct from conventional APC and may explain why graft rejection within the arterial intima, an anatomic compartment in which EC may be the primary type of APC, is separable from rejection in the graft parenchyma.


Anti-Inflammatory Effects of Endogenously Released Adenosine in Synovial Cells of Osteoarthritis and Rheumatoid Arthritis Patients.
Exogenous adenosine and its metabolite inosine exert anti-inflammatory effects in synoviocytes of osteoarthritis (OA) and rheumatoid arthritis (RA) patients. We analyzed whether these cells are able to synthesize adenosine/inosine and which adenosine receptors (ARs) contribute to anti-inflammatory effects. The functionality of synthesizing enzymes and ARs was tested using agonists/antagonists. Both OA and RA cells expressed CD39 (converts ATP to AMP), CD73 (converts AMP to adenosine), ADA (converts adenosine to inosine), ENT1/2 (adenosine transporters), all AR subtypes (A1, A2A, A2B and A3) and synthesized predominantly adenosine. The CD73 inhibitor AMPCP significantly increased IL-6 and decreased IL-10 in both cell types, while TNF only increased in RA cells. The ADA inhibitor DAA significantly reduced IL-6 and induced IL-10 in both OA and RA cells. The A2AAR agonist CGS 21680 significantly inhibited IL-6 and induced TNF and IL-10 only in RA, while the A2BAR agonist BAY 60-6583 had the same effect in both OA and RA. Taken together, OA and RA synoviocytes express the complete enzymatic machinery to synthesize adenosine/inosine; however, mainly adenosine is responsible for the anti- (IL-6 and IL-10) or pro-inflammatory (TNF) effects mediated by A2A- and A2BAR. Stimulating CD39/CD73 with simultaneous ADA blockage in addition to TNF inhibition might represent a promising therapeutic strategy.


The genetic overlap between mood disorders and cardiometabolic diseases: a systematic review of genome wide and candidate gene studies.
Meta-analyses of genome-wide association studies (meta-GWASs) and candidate gene studies have identified genetic variants associated with cardiovascular diseases, metabolic diseases and mood disorders. Although previous efforts were successful for individual disease conditions (single disease), limited information exists on shared genetic risk between these disorders. This article presents a detailed review and analysis of cardiometabolic diseases risk (CMD-R) genes that are also associated with mood disorders. First, we reviewed meta-GWASs published until January 2016, for the diseases 'type 2 diabetes, coronary artery disease, hypertension' and/or for the risk factors 'blood pressure, obesity, plasma lipid levels, insulin and glucose related traits'. We then searched the literature for published associations of these CMD-R genes with mood disorders. We considered studies that reported a significant association of at least one of the CMD-R genes and 'depression' or 'depressive disorder' or 'depressive symptoms' or 'bipolar disorder' or 'lithium treatment response in bipolar disorder', or 'serotonin reuptake inhibitors treatment response in major depression'. Our review revealed 24 potential pleiotropic genes that are likely to be shared between mood disorders and CMD-Rs. These genes include MTHFR, CACNA1D, CACNB2, GNAS, ADRB1, NCAN, REST, FTO, POMC, BDNF, CREB, ITIH4, LEP, GSK3B, SLC18A1, TLR4, PPP1R1B, APOE, CRY2, HTR1A, ADRA2A, TCF7L2, MTNR1B and IGF1. A pathway analysis of these genes revealed significant pathways: corticotrophin-releasing hormone signaling, AMPK signaling, cAMP-mediated or G-protein coupled receptor signaling, axonal guidance signaling, serotonin or dopamine receptors signaling, dopamine-DARPP32 feedback in cAMP signaling, circadian rhythm signaling and leptin signaling. Our review provides insights into the shared biological mechanisms of mood disorders and cardiometabolic diseases.


Intranasal vaccination of humans with recombinant cholera toxin B subunit induces systemic and local antibody responses in the upper respiratory tract and the vagina.
Forty-five volunteers were vaccinated twice intranasally with 10, 100, or 1,000 microg of cholera toxin B subunit (CTB). Blood and nasal and vaginal secretions were collected before and 1 week after the second vaccination from all volunteers, and the specific and total immunoglobulin A (IgA) and IgG titers were determined by enzyme-linked immunosorbent assay. Samples were also taken 6 months (n = 16) and 1 year (n = 14) after the vaccination. The 10- and 100-microg doses were well tolerated by the volunteers, but the 1,000-microg dose induced increased secretions from the nose and repetitive sneezings for several hours. The CTB-specific serum IgA and IgG increased 21- and 7-fold, respectively, 1 week after vaccination with the medium dose and increased 61- and 37-fold, respectively, after the high dose. In nasal secretions the specific IgA and IgG increased 2- and 6-fold after the medium dose and 2- and 20-fold after the high dose, respectively. In vaginal secretions the specific IgA and IgG increased 3- and 5-fold after the medium dose and 56- and 74-fold after the high dose, respectively. The lowest dose did not induce any significant antibody titer increases in serum or in secretions. The specific IgA and IgG levels in secretions were still elevated after 6 months but were decreasing 1 year after the vaccination. These results show that intranasal vaccination of humans with CTB induces strong systemic and mucosal antibody responses and suggest that CTB may be used as a carrier for antigens that induce protective immunity against systemic as well as respiratory and genital infections.


Chromosomal superkiller mutants of Saccharomyces cerevisiae.
Yeast strains carrying a 1.5 X 10(6)-dalton double-stranded RNA in virus-like particles secrete a protein toxin which is lethal to strains not carrying this species of double-stranded RNA. We find that recessive mutations in any of four chromosomal genes result in the superkiller phenotype, i.e., increased secretion of killer toxin activity by strains carrying the killer genome. These genes are designated ski1 through ski4 (for superkiller), ski3 and ski4 are located on chromosome XIV, and ski1 is on chromosome VII. A ski1 mutation results in a decreased rate of cell growth. The kex1 and kex2 mutations are epistatic to each ski mutation.