[Traditional medicine seen from the perspective of Western medicine during the late 19th and early 20th century in Korea].
From the 18th century traditional medicine began to be criticised by some of Korean intellectuals who attained the knowledge of Western medicine through the imported books on Western science. In the early 20th century, Western medical doctors in Korea generally had critical attitude toward traditional medicine. Their critical opinions on traditional medicine are typically recognizable in the debate between two camps that occurred in 1930s. However, some exceptional doctors such as Chang Ki-moo and Bang Hap-shin had special interest in traditional medicine despite their education in Western medicine. It was their clinical experience of the limitation of Western medicine which led them to study traditional medicine. Both of them were particularly attracted by the School of Old Prescriptions, which was a school of Japanese traditional medicine. The medical theory of the school was characterized by the simplification of vague and complicated theory of traditional medicine. The school held the theory that all diseases are caused by one poison. Consequently, treatment of all diseases consists in eliminating the poison. He also put forward a theory of one prescription for one disease, and therefore the same remedy should be applied to a disease with the same cause even though it might manifest various symptoms. Given the fact that their theory of diseases is very similar to that of Western medicine, it is understandable that they were attracted to the School of Old Prescriptions. As the doctors trained in Western medicine, they were possibly more familiar with the doctrine of the School of Old Prescriptions than the traditional medicine based on Yin Yang and Five-Phase theory.


The symbiotic phenotypes of exopolysaccharide-defective mutants of Rhizobium sp. strain TAL1145 do not differ on determinate- and indeterminate-nodulating tree legumes.
Three classes of exopolysaccharide (EPS) defective mutants were isolated by Tn3Hogus -insertion mutagenesis of Rhizobium sp. strain TAL1145, which nodulates tree legumes. The class I and class III mutants produced 10-22% of the EPS produced by TAL1145 and appeared partially mucoid while the class II mutants formed small, opaque and non-mucoid colonies. Size-fractionation of the soluble EPSs made by these mutants in the culture supernatant indicated that the class I and the class III mutants produced reduced levels of both highland low-molecular-mass EPSs while the class II mutants lacked both these EPSs but produced a small amount of a medium-molecular-mass anthrone-reactive EPS. The succinyl and acetyl substituents observed in the TAL1145 EPS were absent in the EPS of the class II mutants. When examined under UV, the class I and class III mutants grown on Calcofluor-containing YEM agar showed dim blue fluorescence, compared to the bright blue fluorescence of the wild-type strain, whereas the class II mutants did not fluoresce. While the dim blue fluorescence of the class III mutants changed to yellow-green after 10 d, the fluorescence of the class I mutants did not change after prolonged incubation. Unlike the EPS-defective mutants of other rhizobia, these mutants did not show different symbiotic phenotypes on determinate- and indeterminate-nodulating tree legumes. The class I and the class III mutants formed small ineffective nodules on both types of legumes whereas the class II mutants formed normal nitrogen-fixing nodules on both types. The genes disrupted in the class I and class III mutants form a single complementation group while those disrupted in the class II mutants constitute another. All the three classes of EPS-defective mutants were located within a 10.8 kb region and complemented by two overlapping cosmids.


Opioid dose and drug-related mortality in patients with nonmalignant pain.
Opioids are widely prescribed for chronic nonmalignant pain, often at doses exceeding those recommended in clinical practice guidelines. However, the risk-benefit ratio of high-dose opioid therapy is not well characterized. The objective of this study was to characterize the relationship between opioid dose and opioid-related mortality. We conducted a population-based nested case-control study of Ontario, Canada, residents aged 15 to 64 years who were eligible for publicly funded prescription drug coverage and had received an opioid from August 1, 1997, through December 31, 2006, for nonmalignant pain. The outcome of interest was opioid-related death, as determined by the investigating coroner. The risk of opioid-related death was compared among patients treated with various daily doses of opioids. Among 607,156 people aged 15 to 64 years prescribed an opioid over the study period, we identified 498 eligible patients whose deaths were related to opioids and 1714 matched controls. After extensive multivariable adjustment, we found that an average daily dose of 200 mg or more of morphine (or equivalent), was associated with a nearly 3-fold increase in the risk of opioid-related mortality (odds ratio [OR], 2.88; 95% confidence interval [CI], 1.79-4.63) relative to low daily doses (<20 mg of morphine, or equivalent). We found significant but attenuated increases in opioid-related mortality with intermediate doses of opioids (50-99 mg/d of morphine: OR, 1.92; 95% CI, 1.30-2.85; 100-199 mg/d of morphine: OR, 2.04; 95% CI, 1.28-3.24). Among patients receiving opioids for nonmalignant pain, the daily dose is strongly associated with opioid-related mortality, particularly at doses exceeding thresholds recommended in recent clinical guidelines.


Discourse connectedness in manic and schizophrenic patients: associations with derailment and other clinical thought disorders.
The language performance of hospitalised manic ( n = 12) and schizophrenic (n=15) patients was compared in order to test hypotheses based on previous models of communication disorder in these patient groups. It was hypothesised that the derailments of manic and schizophrenic patients were discriminable by virtue of differences in the level of connectedness of the speech during this type of language disorder. Previous hypotheses have suggested that manics derail because they discuss multiple concurrent topics and schizophrenics derail as a pattern of general vagueness and poorly interconnected speech. These hypotheses were supported by the finding that manic patients manifested a higher level of overall discourse connectedness during derailments, even when the overall increased amount of speech was accounted for. Manics were not simply more competent overall, because they failed to differ from schizophrenics in their discourse connectedness during nondisordered segments. These results are discussed in terms of their implications for clinical and linguistic differentiation of the language of psychotic patients.


The Impact of Income on Emergency General Surgery Outcomes in Urban and Rural Areas.
Emergency general surgery (EGS) accounts for more than 2 million U.S. hospital admissions annually. Low-income EGS patients have higher rates of postoperative adverse events (AEs) than high-income patients. This may be related to health care segregation (a disparity in access to high-quality centers). The emergent nature of EGS conditions and the limited number of EGS providers in rural areas may result in less health care segregation and thereby less variability in EGS outcomes in rural areas. The objective of this study was to assess the impact of income on AEs for both rural and urban EGS patients. The National Inpatient Sample (2007-2014) was queried for patients receiving one of 10 common EGS procedures. Multivariate regression models stratified by income quartiles in urban and rural cohorts adjusting for sociodemographic, clinical, and other hospital-based factors were used to determine the rates of surgical AEs (mortality, complications, and failure to rescue [FTR]). 1,687,088 EGS patients were identified; 16.60% (n = 280,034) of them were rural. In the urban cohort, lower income quartiles were associated with higher odds of AEs (mortality OR, 1.21 [95% CI, 1.15-1.27], complications, 1.07 [1.06-1.09]; FTR, 1.17 [1.10-1.24] P < 0.001). In the rural context, income quartiles were not associated with the higher odds of AE (mortality OR, 1.14 [0.83-1.55], P = 0.42; complications, 1.06 [0.97-1,16], P = 1.17; FTR, 1.12 [0.79-1.59], P = 0.52). Lower income is associated with higher postoperative AEs in the urban setting but not in a rural environment. This socioeconomic disparity in EGS outcomes in urban settings may reflect health care segregation, a differential access to high-quality health care for low-income patients.


Vaccine-induced immune thrombotic thrombocytopenia.
In response to the COVID-19 pandemic, vaccines for SARS-CoV-2 were developed, tested, and introduced at a remarkable speed. Although the vaccine introduction had a major impact on the evolution of COVID-19, some potential rare side-effects of the vaccines were observed. Within a short period, three scientific groups from Norway, Germany, and the UK reported cerebral venous sinus thrombosis with thrombocytopenia and anti-platelet factor 4 (anti-PF4) antibodies in individuals following AstraZeneca-Oxford vaccination and named this new syndrome vaccine-induced immune thrombotic thrombocytopenia (VITT). This syndrome was subsequently reported in individuals who received Johnson & Johnson vaccination. In this Viewpoint, we discuss the epidemiology, pathophysiology, and optimal diagnostic and therapeutic management of VITT. Presentation of an individual with possible VITT should raise prompt testing for anti-PF4 antibodies and initiation of treatment targeting autoimmune processes with intravenous immunoglobulin and prothrombotic processes with non-heparin anticoagulation.


Mechanism and kinetics of electrochemical degradation of uric acid using conductive-diamond anodes.
Uric acid (UA) is one of the principal effluents of urine wastewaters, widely used in agriculture as fertilizer, which is potentially dangerous and biorefractory. Hence, the degradation of UA (2,6,8-trihydroxy purine) in aqueous solution of pH 3.0 has been studied by conductive-diamond electrochemical oxidation. Hydroxyl radicals formed from water oxidation at the surface of boron-doped diamond anodes were the main oxidizing agents. Effects of current density and supporting electrolyte on the degradation rate and process efficiency are assessed. Results show that the increase of current density from 20 to 60 mA cm(-2) leads to a decrease in the efficiency of the electrochemical process. In addition, the best degradation occurred in the presence of NaCl as conductive electrolyte. Interestingly, an almost total mineralization of 50 ppm UA was obtained when anodic oxidation was performed at low current densities (20 mA cm(-2)) and in the presence of NaCl. This result confirmed that the electrolysis using diamond anodes is a very interesting technology for the treatment of UA. The identification of UA transformation products was performed by high-performance liquid chromatography (HPLC). HPLC analysis of treated solutions revealed that oxalic acid and urea were the two intermediates found. Oxalic acid was the most persistent product. Based on detected intermediates and bibliographic research, a mechanism of UA mineralization by anodic oxidation has been proposed. Ionic chromatography analysis confirmed the release of [Formula: see text] and [Formula: see text] ions during UA mineralization.


Risk of symptomatic dengue for foreign visitors to the 2014 FIFA World Cup in Brazil.
Brazil will host the FIFA World Cup™, the biggest single-event competition in the world, from June 12-July 13 2014 in 12 cities. This event will draw an estimated 600,000 international visitors. Brazil is endemic for dengue. Hence, attendees of the 2014 event are theoretically at risk for dengue. We calculated the risk of dengue acquisition to non-immune international travellers to Brazil, depending on the football match schedules, considering locations and dates of such matches for June and July 2014. We estimated the average per-capita risk and expected number of dengue cases for each host-city and each game schedule chosen based on reported dengue cases to the Brazilian Ministry of Health for the period between 2010-2013. On the average, the expected number of cases among the 600,000 foreigner tourists during the World Cup is 33, varying from 3-59. Such risk estimates will not only benefit individual travellers for adequate pre-travel preparations, but also provide valuable information for public health professionals and policy makers worldwide. Furthermore, estimates of dengue cases in international travellers during the World Cup can help to anticipate the theoretical risk for exportation of dengue into currently non-infected areas.


catena-Poly[[bis(cis-1-tert-butyltetrazole-kappaN4)copper(II)]-di-micro-chloro].
The title polymeric compound, [CuCl(2)(C(5)H(10)N(4))(2)](n), is the first structurally characterized complex with a bulky 1-alkyltetrazole ligand. The coordination polyhedron of the Cu atom is an elongated octahedron. The equatorial positions of the octahedron are occupied by the two Cl atoms, with Cu-Cl distances of 2.2920 (8) and 2.2796 (9) A, and by the two N-4 atoms of the tetrazole ligands, with Cu-N distances of 2.023 (2) and 2.039 (2) A. Two symmetry-related Cl atoms occupy the axial positions, at distances of 2.8244 (8) and 3.0174 (8) A from the Cu atom. The [CuCl(2)(C(5)H(10)N(4))(2)] units form infinite chains extended along the b axis, linked together only by van der Waals interactions. The skeleton of each chain consists of Cu and Cl atoms.


Relationship between lymph nodes examined and survival benefits with postoperative radiotherapy in oral cavity squamous cell carcinoma patients with stage T1-2N1M0.
This study aims to explore the relationship between the lymph nodes examined and survival benefits of postoperative radiotherapy in oral cavity squamous cell carcinoma patients with stage T1-2N1M0. This study retrieved patients who underwent dissection of the primary site and neck lymph nodes for pT1-2N1M0 oral cavity squamous cell carcinoma without adverse nodal features from the Surveillance, Epidemiology, and End Results database from 2004 to 2015. Propensity score matching analysis was conducted, and the best cutoff value of the lymph nodes examined was determined by X-tile. Cancer-specific survival was the primary outcome. Univariable and multivariable analyses were performed to assess the relation between postoperative radiotherapy and cancer-specific survival, adjusting for other prognostic factors. A total of 469 patients were finally enrolled according to our exclusion criteria, and then 119 pairs of patients were matched by propensity score matching analysis. The best cutoff value of the lymph nodes examined was determined by X-tile, stratifying patients into lymph nodes examined ≤16 group and lymph nodes examined >16 group. For the whole matched cohort, the choice of postoperative radiotherapy had no correlation with other factors (all p's > 0.05), and postoperative radiotherapy made no contribution to a better survival outcome for patients (p = 0.289). After stratified by the lymph nodes examined, in the lymph nodes examined ≤16 group, significantly improved CSS was found for those who undertook postoperative radiotherapy compared to those who just received surgery (unadjusted hazard ratio, 0.541; 95% confidence interval, 0.333-0.878; p = 0.013). Our study revealed that pT1-2N1M0 oral cavity squamous cell carcinoma patients were more likely to benefit from postoperative radiotherapy when unsatisfactory neck dissection was conducted, indicating that the number of lymph nodes examined might be a factor when clinicians do therapeutic planning for early-stage oral cavity squamous cell carcinoma patients.


A test of the psychosocial vulnerability and health behavior models of hostility: results from an 11-year follow-up study of Mexican Americans.
Previous research has shown that interpersonal conflict and depression are cross-sectionally associated with hostility. Our objective was to determine whether hostility is longitudinally predictive of interpersonal distress and depression and to replicate previous research that suggests that hostility is a risk factor for other health behaviors (e.g., smoking and excessive alcohol use) and psychosocial health problems. We use data from the youngest generation of a three-generation, 11-year follow-up study of Mexican Americans, that represent 251 Mexican Americans between the ages of 18 and 42 years. Our indicator of hostility was the irritability subscale from the Buss-Durkee Hostility Inventory. After statistically controlling for marital status, language acculturation, education, age, and sex, irritability was found to predict subsequent heavy drinking, somatic symptoms associated with depression, psychosomatic symptoms, infectious disease, divorce, marital separation, ending a serious nonmarital relationship, not being married at the follow-up, and more negative feelings associated with divorce, marital separation, and ending a serious relationship. Our research supports theory and research suggesting that hostility is predictive of physical symptoms, poor health habits, and interpersonal conflict.


Effects of Moisture-Proof Back Passivation Layers of Al2O3 and AlxTi1-xOy Films on Efficiency Improvement and Color Modulation in Transparent a-Si:H Solar Cells.
In this study, the back passivation layers (BPLs) were developed to protect hydrogenated amorphous silicon (a-Si:H) thin films of transparent solar cells from humidity and contaminants. Metal oxide compound films with Al (Al2O3) and Ti (AlxTiyOz (ATO)) were fabricated by plasma-enhanced atomic layer deposition for the BPLs on transparent solar cells. The BPLs of Al2O3 films applied to the transparent solar cells were deposited in different thicknesses to evaluate the performance, and the ATO film thickness was fixed at 30 nm. Even at the thinnest thickness of 30 nm, the water vapor transmission rates of BPLs were very low at 1.96 × 10-3 (Al2O3) and 1.23 × 10-2 g/m2·day (ATO). In addition to moisture protection, measures of cell performance, including open-circuit voltage and short-circuit current density, were improved by blocking the leakage current and through the optical interference effects of the BPLs. The solar cell with ATO BPLs exhibited an increase in efficiency of more than 12% compared with those of conventional reference cells. Furthermore, by varying the refractive index and thickness of the BPLs, the reflection and transmission spectra were modulated to implement various cell colors without serious loss in cell efficiency.


Increased intracellular and extracellular oxidant production in phagocytes of rheumatic patients treated with biological therapy - whole blood quantification.
Infectious complications, resulting from reduced activity of immune cells, are the most severe and common adverse effects of biological therapy. This study analyzed the effect of biological therapy on blood phagocytes, focusing on the formation of reactive oxygen species (ROS), an important factor in the defence against invading pathogens. Intra- and extracellular ROS production were recorded separately, on the basis of luminol and isoluminol chemiluminescence in patients treated with antibodies against tumor necrosis factor-α or against interleukin-6 receptor. In comparison to healthy donors or to rheumatic patients treated with classical immunosuppressive drugs, biological therapy increased ROS formation in both compartments. This indicates that the anti-microbial activity of blood phagocytes was not reduced by TNFα- or IL-6-neutralizing therapy, at least in terms of ROS. The method presented does not require blood fractionation, which could modify activity of phagocytes and cause loss of some subpopulations of these cells. The technique is simple, requires microliter volumes of blood and is thus well applicable to clinical studies.


Steered molecular dynamics and stability analysis on PAH dimerisation and condensation on fullerene and soot surfaces.
The mechanism of how a soot nucleus is impacted by polycyclic aromatic hydrocarbons (PAHs) and then grows through PAH condensation remains unclear. Using steered molecular dynamics (SMD), the non-bonding interaction between PAHs and soot was quantitatively studied using the free energy distribution during the dimerisation and condensation. The results showed that only two dimers (A7-A10 and 2 A10) remained stable at 1000 K. The simulations showed that PAH condensation on a fullerene should not be ignored in soot mass growth. For fullerenes with a diameter not less than 1.8 nm (C540), even A4 condenses at temperatures of 1500 K, and A10 condenses stably on the surface of fullerenes even at 2000 K. The effects of multilayers and hydrogenated fullerenes on the free energy of PAH condensation are different. The stability of PAH dimers and PAH condensation pairs was discussed through free energy and chemical equilibrium. The results show that larger dimers are more stable than small ones at flame temperatures. Condensation is far more important than nucleation in mass growth at flame temperatures. Furthermore, the larger the PAH is, the higher the transformation ratio of the PAH in condensation on soot and thus the more stable the condensation product is. Finally, both the stability analysis of an upper temperature limit for condensation and simulation results of ReaxFF-MD cross-confirm that pyrene stably condensates on a simplified nascent soot (C540) and a simulated soot (C658H319O9), respectively, at 1500 K, but not at higher temperatures over 1800 K.


Reduced Insulin Clearance Differently Relates to Increased Liver Lipid Content and Worse Glycemic Control in Recent-Onset Type 2 and Type 1 Diabetes.
Diabetes may feature impaired insulin kinetics, which could be aggravated by altered hepatic metabolism and glycemic control. Thus, we examined insulin clearance and its possible determinants in individuals with recent-onset diabetes. Participants of the German Diabetes Study (GDS) with type 1 diabetes (T1D) (n = 306), type 2 diabetes (T2D) (n = 489), or normal glucose tolerance (control [CON]) (n = 167) underwent hyperinsulinemic-euglycemic clamps for assessment of whole-body insulin sensitivity (M value) and insulin clearance (ICCLAMP). Insulin clearance rates were further calculated during intravenous glucose tolerance tests (ICIVGTT) and mixed-meal tests (ICMMT). Hepatocellular lipid content (HCL) was quantified with 1H-MRS. Both T1D and T2D groups had lower ICCLAMP (0.12 ± 0.07 and 0.21 ± 0.06 vs. 0.28 ± 0.14 arbitrary units [a.u.], respectively, all P < 0.05) and ICMMT (0.71 ± 0.35 and 0.99 ± 0.33 vs. 1.20 ± 0.36 a.u., all P < 0.05) than CON. In T1D, ICCLAMP, ICIVGTT, and ICMMT correlated negatively with HbA1c (all P < 0.05). M value correlated positively with ICIVGTT in CON and T2D (r = 0.199 and r = 0.178, P < 0.05) and with ICMMT in CON (r = 0.176, P < 0.05). HCL negatively associated with ICIVGTT and ICMMT in T2D (r = -0.005 and r = -0.037) and CON (r = -0.127 and r = -0.058, all P < 0.05). In line, T2D or CON subjects with steatosis featured lower ICMMT than those without steatosis (both P < 0.05). Insulin clearance is reduced in both T1D and T2D within the first year after diagnosis but correlates negatively with liver lipid content rather in T2D. Moreover, insulin clearance differently associates with glycemic control and insulin sensitivity in each diabetes type, which may suggest specific mechanisms affecting insulin kinetics.


Carbon and Nitrogen Dynamics, and CO2 Efflux in the Calcareous Sandy Loam Soil Treated with Chemically Modified Organic Amendments.
In Saudi Arabia, more than 335,000 tons of cow manure is produced every year from dairy farming. However, the produced cow manure is usually added to the agricultural soils as raw or composted manure; significant nitrogen losses occur during the storage, handling, and application of the raw manure. The recovery of ammonia from cow manure through thermochemical treatments is a promising technique to obtain concentrated nitrogen fertilizer and reducing nitrogen losses from raw manure. However, the byproduct effluents from the recovery process are characterized by different chemical properties from the original raw manure; thus, its impact as soil amendments on the soil carbon and nitrogen dynamics is unknown. Therefore, a 90-day incubation experiment was conducted to study the impact of these effluents on CO2 efflux, organic C, microbial biomass C, available NH4+, and NO3- when added to agricultural soil. In addition to the two types of effluents (produced at pH 9 and pH 12), raw cow manure (CM), composted cow manure (CMC), cow manure biochar (CMB), and control were used for comparison. The application of CM resulted in a considerable increase in soil available nitrogen and CO2 efflux, compared to other treatments. Cow manure biochar showed the lowest CO2 efflux. Cumulative CO2 effluxes of cow manure effluents were lower than CM; this is possibly due to the relatively high C:N ratio of manure effluent. The content of P, Fe, Cu, Zn, and Mn decreased as incubation time increased. Soil microbial biomass C for soil treated with cow manure effluents (pH 12 and 7) was significantly higher than the rest of the soil amendments and control.


[Indicators of preoperative anxiety and anxiolysis from the anesthesiological viewpoint].
In recent times preoperative anxiety is again discussed as an important influential factor for perioperative complications. The anaesthesiologist may be important to identify and control the patients' anxiety although his time while on premedication visit is rather limited. The present article deals with the different aspects of preoperative anxiety, argues about possible psychological and physiological characteristics of anxiety and describes conventionally used psychophysiological testing for the identification of anxiety. Referring to the literature, different therapeutical options are given. Psychological techniques for reducing and controlling preoperative anxiety might be an important topic for further research, especially as far as their influence on perioperative morbidity and mortality is concerned.


Telomere length and telomere repeating factors: Cellular markers for post-traumatic stress disorder-like model.
The aim of the present study was to explore the telomere length of peripheral blood leukocytes from a rat model of post-traumatic stress disorder (PTSD), as well as the expression level of telomere-binding protein in the hippocampal CA1 region. The PTSD model was established with 42 adult male Wistar rats. The relative telomere length of the leukocytes was measured by real-time fluorescence quantitative polymerase chain reaction, and the expression levels of telomere repeating factor 1 (TRF1) and telomere repeating factor 2 (TRF2) in the hippocampal CA1 region of the PTSD rat model were determined by immunofluorescence technology. The covariance analysis of repeated measurements by the mixed model approach was used for the telomere length analysis. The comparison of averaged data among groups was performed using least significant difference and analysis of variance. The Student's t test or the Mann-Whitney U test was used for intragroup comparison. The association study among groups was conducted using the Spearman test. The shortening speed of telomere length significantly accelerated in rats after Single Prolonged Stress (SPS) stimulation (P<0.05). The expression levels of TRF1 and TRF2 increased with the progress of PTSD, and the expression peak was shown in day 14, which was significantly different from the control group (P<0.05). The shortening speed of the telomere length of peripheral blood leukocytes accelerated in PTSD rats, and the expression levels of TRF1 and TRF2 increased in hippocampus, both of which were closely associated with the pathological progress of the PTSD-like model and unfavorable prognosis.


Can Computer-Assisted Total Knee Arthroplasty Support the Prediction of Postoperative Three-Dimensional Kinematics of the Tibiofemoral and Patellofemoral Joints at the Replaced Knee?
The aim of this study was to analyze the extent to which postoperative patellofemoral joint (PFJ) kinematics assessed at 6-month follow-up after total knee arthroplasty (TKA) mimics the intraoperative kinematics after final component implantation. The study hypothesis, already proved in terms of tibiofemoral joint (TFJ) kinematics, is that the intraoperative assessment of PFJ kinematics after component implantation is also capable of predicting postoperative knee kinematics during activities of daily living. Twenty patients selected for TKA with patellar resurfacing were implanted using surgical navigation, including patellar component positioning via a novel computer-assisted procedure. This allowed for intraoperative TFJ and PFJ kinematic assessment after final component implantation. At 6-month follow-up, all patients were contacted for follow-up control; in addition to clinical examination, this implied postoperative kinematics assessments by three-dimensional video fluoroscopy of the replaced knee during standard activities of daily living. Several traditional PFJ, as well as TFJ, rotations and translations were calculated intra- and postoperatively and then statistically compared. Good postoperative replication of the intraoperative measurements was observed for most of PFJ variables analyzed, as well as those for TFJ. Relevant statistical analysis also supported the significant consistency between the intra- and postoperative measurements. Pertaining to the present findings on a statistical basis, intraoperative measurements performed at both TFJ and PFJ kinematics using a surgical navigation system under passive conditions, are predictive of the overall knee kinematics experienced at postoperative follow-ups by the same replaced knees in typical activities of daily living.


[Reflection of the plastic properties of 2 neurons with a common monosynaptic input in the statistical characteristics of their impulse activity].
Changes of cross-correlation histograms (CCH) of impulse trains and of mean interspike intervals (ISI) of neurones N1 and N2 with a common monosynaptic excitatory or inhibitory-excitatory input from N3, at changes of efficiency of interneuronal connections, neurone excitability and summate action on them of independent random afferent synaptic inflows were studied by methods of mathematical and biomathematical modelling of neuronal interaction. It was shown that the increase of amplitude of the central peak (trough) of a normalized CCH of N1-N2 accompanied by reduction of mean ISI of N1 and N2, is either a sign of an increase of the amplitude of postsynaptic potentials of N1 and N2 elicited by impulses of the nonrecorded N3 or a sign of an increase of mean ISI of N3.


Amino acid requirement of growing pigs depending on amino acid efficiency and level of protein deposition 1st communication: lysine.
The study was conducted to evaluate the variability of efficiency of lysine utilisation in different feed proteins for growing pigs including wheat, unprocessed soybean flakes (SF), hydrothermal processed SF, corn gluten meal (CGM), two batches of soybean protein concentrate (SPC-1, SPC-2), different batches of peas (Pisum sativum) and field beans (Vicia faba). Data about efficiency of lysine are important for further conclusions related to lysine requirement in dependence on level of daily protein deposition. In N-balance studies 161 growing barrows (40-65 kg BW) of the genotype [Piétrain x (Duroc x Landrace)] were randomly allotted into 23 experimental treatments (n = 7) with diets in which lysine was the first limiting amino acid. Data from the N-balance trials were used to calculate efficiency of lysine and consequently lysine requirement based on an exponential N-utilisation model. Results from the present studies indicate that efficiency of lysine in different feed proteins varies in a very wide range and this variation greatly affected the calculated lysine requirement. Therefore, the variation in efficiency of lysine should be taken into account in requirement calculations and consequently in diet formulation for pigs. The results of model calculation for the lysine requirement depending on daily protein deposition (130, 145 and 160 g/d) and efficiency of lysine are given for different standards for comparison (g x kg(-0.67) x d(-1), g x d(-1) and percentage of lysine in the diet). The calculated lysine requirement of growing barrows (50 kg BW) corresponding to an average lysine efficiency was 15.5, 18.0 and 21.1 g/d for daily protein deposition of 130, 145 and 160 g, respectively. The results of the model calculation for 145 or 160 g daily protein deposition are in agreement with actual studies and recommendations of NRC (1998) and DLG (2002) for lysine supply.


Interleukin-6 Facilitates Acute Myeloid Leukemia Chemoresistance via Mitofusin 1-Mediated Mitochondrial Fusion.
Acute myeloid leukemia (AML), an aggressive hematopoietic malignancy, exhibits poor prognosis and a high recurrence rate largely because of primary and secondary drug resistance. Elevated serum IL6 levels have been observed in patients with AML and are associated with chemoresistance. Chemoresistant AML cells are highly dependent on oxidative phosphorylation (OXPHOS), and mitochondrial network remodeling is essential for mitochondrial function. However, IL6-mediated regulation of mitochondrial remodeling and its effectiveness as a therapeutic target remain unclear. We aimed to determine the mechanisms through which IL6 facilitates the development of chemoresistance in AML cells. IL6 upregulated mitofusin 1 (MFN1)-mediated mitochondrial fusion, promoted OXPHOS, and induced chemoresistance in AML cells. MFN1 knockdown impaired the effects of IL6 on mitochondrial function and chemoresistance in AML cells. In an MLL::AF9 fusion gene-induced AML mouse model, IL6 reduced chemosensitivity to cytarabine (Ara-C), a commonly used antileukemia drug, accompanied by increased MFN1 expression, mitochondrial fusion, and OXPHOS status. In contrast, anti-IL6 antibodies downregulated MFN1 expression, suppressed mitochondrial fusion and OXPHOS, enhanced the curative effects of Ara-C, and prolonged overall survival. In conclusion, IL6 upregulated MFN1-mediated mitochondrial fusion in AML, which facilitated mitochondrial respiration, in turn, inducing chemoresistance. Thus, targeting IL6 may have therapeutic implications in overcoming IL6-mediated chemoresistance in AML. IL6 treatment induces MFN1-mediated mitochondrial fusion, promotes OXPHOS, and confers chemoresistance in AML cells. Targeting IL6 regulation in mitochondria is a promising therapeutic strategy to enhance the chemosensitivity of AML.


Human Papillomavirus Vaccination in Male and Female Adolescents Before and After Kidney Transplantation: A Pediatric Nephrology Research Consortium Study.
Background: Kidney transplant (KT) recipients have higher incidence of malignancies, including Human Papillomavirus (HPV)-associated cancers. Thus, HPV vaccines may have an important role in preventing HPV-related disease in this population; however, immunogenicity and safety data are lacking. Objective: To examine the immunological response and tolerability to HPV vaccination in pediatric KT recipients compared to future KT candidates. Methods: The quadrivalent HPV vaccine was administered to girls and boys age 9-18 recruited from seven centers part of the Pediatric Nephrology Research Consortium. Subjects were recruited for three groups: (1) CKD: chronic kidney disease stages 3, 4, and 5 not on dialysis; (2) Dialysis; (3) KT recipients. The outcome consisted of antibody concentrations against HPV 6, 11, 16, and 18. Geometric mean titers (GMTs) and seroconversion rates were compared. Vaccine tolerability was assessed. Results: Sixty-five participants were recruited: 18 in the CKD, 18 in the dialysis, and 29 into the KT groups. KT patients had significantly lower GMTs after vaccination for all serotypes. The percentages of subjects who reached seroconversion were overall lower for the KT group, reaching statistical significance for HPV 6, 11, and 18. Comparing immunosuppressed subjects (anyone taking immunosuppression medications, whether KT recipient or not) with the non-immunosuppressed participants, the former had significantly lower GMTs for all the HPV serotypes and lower seroconversion rates for HPV 6, 11, and 18. KT females had higher GMTs and seroconversion rates for certain serotypes. There were no adverse events in either group. Conclusions: HPV vaccine was well-tolerated in this population. Pediatric KT recipients had in general lower GMTs and seroconversion rates compared to their peers with CKD or on dialysis. Immunosuppression played a role in the lack of seroconversion. Our results emphasize the importance of advocating for HPV vaccination prior to KT and acknowledge its safety post transplantation. Future studies are needed to investigate the effect of a supplemental dose of HPV vaccine in KT recipients who do not seroconvert and to evaluate the long-term persistence of antibodies post-KT.


Keratinocyte growth stimulation by granulocyte-macrophage colony-stimulating factor (GM-CSF).
Human granulocyte-macrophage colony stimulating factor (GM-CSF) is a 22 kD glycoprotein derived from activated T cells, endothelial cells, fibroblasts and macrophages. It stimulates the proliferation and differentiation of haematopoietic cells and certain nonhaematopoietic cells. This study investigated the effect of GM-CSF on cultured human keratinocytes and determined whether these cells express GM-CSF receptors. Measurement of keratinocyte growth by image analysis showed that GM-CSF mildly stimulated the growth of keratinocytes. With 4 ng/ml GM-CSF the growth of primary keratinocytes and subcultured keratinocytes was only stimulated up to 25% and 18% of the control cell level, respectively. Human keratinocytes were incubated with GM-CSF at 4 ng/ml for 4 days to induce receptor expression. These cells showed only a weak positive reaction on affinity labelling using digoxigenated GM-CSF. We conclude that keratinocyte growth may be stimulated by GM-CSF but that the presence of GM-CSF receptors on these cells is equivocal.


Epigenetic regulation of cancer-associated genes in ovarian cancer.
The involvement of epigenetic aberrations in the development and progression of tumors is now well established. However, most studies have focused on the epigenetic inactivation of tumor suppressor genes during tumorigenesis and little is known about the epigenetic activation of cancer-associated genes, except for the DNA hypomethylation of some genes. Recently, we reported that the overexpression of cancer-promoting genes in ovarian cancer is associated with the loss of repressive histone modifications. This discovery suggested that epigenetic derepression may contribute to ovarian tumorigenesis by constituting a possible mechanism for the overexpression of oncogenes or cancer-promoting genes in tumors. The emerging importance of epigenetic aberrations in tumor initiation and in the regulation of cancer-initiating cells, suggests that epigenetically regulated genes may be promising therapeutic targets and biomarkers. Given that the current challenges in ovarian cancer include the identification of biomarkers for early cancer detection and the discovery of novel therapeutic targets for patients with recurrent malignancies undergoing chemotherapy, understanding the epigenetic changes that occur in ovarian cancer is crucial. This review looks at epigenetic mechanisms involved in the regulation of cancer-associated genes, including the contribution of epigenetic derepression to the activation of cancer-associated genes in ovarian cancer. In addition, possible epigenetic therapies targeting epigenetically dysregulated genes are discussed. A better understanding of the epigenetic changes in ovarian cancer will contribute to the improvement of patient outcomes.


The nucleus pararaphales in the human, chimpanzee, and macaque monkey.
The human cerebral cortex and cerebellum are greatly expanded compared to those of other mammals, including the great apes. This expansion is reflected in differences in the size and organization of precerebellar brainstem structures, such as the inferior olive. In addition, there are cell groups unique to the human brainstem. One such group may be the nucleus pararaphales (PRa); however, there is disagreement among authors about the size and location of this nucleus in the human brainstem. The name "pararaphales" has also been used for neurons in the medulla shown to project to the flocculus in the macaque monkey. We have re-examined the existence and status of the PRa in eight humans, three chimpanzees, and four macaque monkeys using Nissl-stained sections as well as immunohistochemistry. In the human we found a cell group along the midline of the medulla in all cases; it had the form of interrupted cell columns and was variable among cases in rostrocaudal and dorsoventral extent. Cells and processes were highly immunoreactive for non-phosphorylated neurofilament protein (NPNFP); somata were immunoreactive to the synthetic enzyme for nitric oxide, nitric oxide synthase, and for calretinin. In macaque monkey, there was a much smaller oval cell group with NPNFP immunoreactivity. In the chimpanzee, we found a region of NPNFP-immunoreactive cells and fibers similar to what was observed in macaques. These results suggest that the "PRa" in the human may not be the same structure as the flocculus-projecting cell group described in the macaque. The PRa, like the arcuate nucleus, therefore may be unique to humans.


Technical note: A vacuum-assisted approach for biopsying the mammary glands of various species.
Biopsy of the mammary glands is a technique used in both research and clinical diagnosis. A vacuum-assisted approach that enables the collection of tissue from the mammary glands of various species is described, along with methods for biopsying cows and pigs. The procedure involves tissue penetration via blunt dissection with a sharpened trocar. Tissue cores are excised and collected via the vacuum-assisted handpiece followed by a saline lavage and wound closure. This approach yields tissue cores of approximately 100 mg, is well suited for use in various species, and affords the potential to reduce postoperative complications.


Epidermal nerve fiber density and sural nerve morphometry in peripheral neuropathies.
To study intraepidermal nerve fiber (IENF) density in distal leg skin biopsies, sural nerve morphometry, electrophysiology, and clinical features in patients with peripheral neuropathies. We studied 26 patients with neuropathic complaints who had undergone clinical evaluation, nerve conduction studies, distal leg skin biopsy, and sural nerve biopsy. We quantified densities of IENF and of myelinated and unmyelinated fibers in the sural nerve. Associations among skin and sural nerve morphometric measures and sensory nerve action potential (SNAP) amplitudes were examined nonparametrically. Morphometric measures were examined with respect to diagnostic category of neuropathy. IENF density correlated with the densities of sural nerve total myelinated (r = 0.57, p = 0.0011), small myelinated (r = 0.53, p = 0.0029), and large myelinated fibers (r = 0.49, p = 0.0054). There was a trend toward an association between IENF and sural nerve unmyelinated fiber densities (r = 0.32, p = 0.054). Sural SNAP amplitude and large myelinated fiber densities were highly correlated (r = 0.87, p < 0.0001). IENF density and sural nerve small fiber measures were concordant in 73% of patients. Reduced IENF density was the only indicator of small fiber depletion in 23% of cases. It was usually normal in acquired demyelinating neuropathies and where clinical suspicion for neuropathy was low. Distal leg Intraepidermal nerve (IENF) density may be more sensitive than sural nerve biopsy in identifying small fiber sensory neuropathies. Assessments of IENF density and large fiber measures on biopsy and electrophysiology are both useful for characterizing sensory and sensorimotor neuropathies.


[Effects of iron ion additional introduction in radiation therapy of tumor-bearing animals].
The gender differences of the transplantable glioma-35 growth were revealed in tumor-bearing rats. The effect of mineral iron containing water (ICW) as drinking water was studied during radiation therapy (RT) in tumor bearing male rats. It was shown that ICW used separately had a weak anti cancer effect. The ICW use after irradiation caused no significant changes in hematological reactions as compared with RT only. The mineral water administration before irradiation resulted in the reduction of the supercoiled DNA index on the 1st and 21st day after irradiation, as well as in monocytopeny and a definite decrease in the tumor volume on the 21st day of the experiment as compared with control, which is associated with the ferroptosis effect of ICW. It was established that the reaction peculiarities of the blood DNA structure index in irradiated rats at the early stage of glioma growth may serve an express marker of the efficiency of RT.


Mechanisms involved in persistent facilitation of neuromuscular synapses in aplysia.
Synaptic plasticity can last from a fraction of a second to weeks depending on how it was induced. The mechanisms that underlie short-, intermediate-, and long-term plasticity have been intensively studied at central synapses of both vertebrates and invertebrates; however, peripheral plasticity has not received as much attention. In this study, we investigated the mechanisms that contribute to a persistent form of plasticity at neuromuscular synapses in buccal muscle I3a of Aplysia. These synapses are reversibly facilitated by the small cardioactive peptide (SCP), a peptide cotransmitter that is intrinsic to the motor neurons, and persistently facilitated by serotonin (5HT) released from modulatory neurons that are extrinsic to the motor circuit. Many of the short-term effects of 5HT and SCP are mediated by the cAMP pathway, but little is known about the mechanisms that underlie persistent modulation. We were able to eliminate several possible mechanisms. One of these was the possibility that the apparent reversal of SCP's effects was due to desensitization of the SCP receptor. Superfusion for longer periods or with higher concentrations of SCP indicate that the SCP receptors do not desensitize. We also determined that new protein synthesis is not required for the persistent facilitation of EJPs. Another possibility was that 5HT was taken up and slowly re-released. Our results suggest that this mechanism is also unlikely. Activation of the cAMP pathway does not appear to mediate persistent effects; however, 5HT as well as SCP does cause persistent increases in cAMP levels that can prime I3a synapses and increase the effectiveness of activators of the cAMP pathway. Instead, the persistent effects of 5HT are mimicked by phorbol, suggesting that protein kinase C or an Aplysia homologue of unc13 may mediate these effects. These results, in combination with results from experiments on the sensory neurons that contribute to withdrawal reflexes in Aplysia, suggest that the mechanisms for intermediate- and long-term facilitation may reside in all of the synapses involved in the sensory to motor response reflex.


Impact of therapeutic regimen and clinical presentation on overall survival in CNS lymphoma.
The authors present a retrospective analysis of 45 patients who underwent treatment of CNS lymphoma (both primary and secondary) at a single institution between 2005 and 2012. This study involves 21 female and 24 male patients with a mean age of 59.2 years. All medical records and pathology reports were reviewed for each patient. Univariate and multivariate analyses of overall survival were performed. Presentation with altered mental status was a significant risk factor for worse overall survival. An HIV infection, deep lesion location, and age over 60 did not impact survival. A survival benefit was demonstrated with the use of systemic therapy, specifically rituximab, and radiation. The CNS Lymphoma Score was derived from this cohort, which proved a powerful predictive tool for overall survival. The surgical complication rate in this series was 17.8 %. This study highlights the prognostic importance of presenting mental status on outcomes in CNS lymphoma and demonstrates a summative benefit of rituximab and whole brain radiation therapy. Considering these factors together provides an easily applicable and meaningful stratification for this patient population. The surgical complication rate in this patient population is not negligible. The high percentage of wound-related surgical complications suggests the need for a waiting period between surgery and initiation of chemotherapy to allow for wound healing.


Spatial and temporal baseline of perfluorooctanesulfonic acid retained in sediment core samples from Puget Sound, Washington, USA.
Per- and poly-fluorinated alkyl substances (PFAS) are a group of highly persistent synthetic chemicals utilized in many industrial and consumer products, and - significantly toward introduction to the marine environment - in fire-fighting foams. Recently, PFAS have been linked to adverse health effects, prompting the need to better understand transport, lability, and fate. Perfluorooctanesulfonic acid (PFOS), a manufactured PFAS and biodegradation product, partitions to marine sediments and thus can be used as a primary indicator toward regulatory efforts. The current study offers a spatial and temporal analysis of Puget Sound from cores collected adjacent Tacoma and Seattle, WA, as well as cores from central Hood Canal and Carr Inlet. Temporal fluxes reflected releases into the environment corresponding with initial production and subsequent increases in use. Biologically active layers ranged from 434 pg/g (Carr Inlet) to 824 pg/g (Hood Canal) PFOS, producing benthic community risk quotients between 0.11 and 0.17.


Backtracking by single RNA polymerase molecules observed at near-base-pair resolution.
Escherichia coli RNA polymerase (RNAP) synthesizes RNA with remarkable fidelity in vivo. Its low error rate may be achieved by means of a 'proofreading' mechanism comprised of two sequential events. The first event (backtracking) involves a transcriptionally upstream motion of RNAP through several base pairs, which carries the 3' end of the nascent RNA transcript away from the enzyme active site. The second event (endonucleolytic cleavage) occurs after a variable delay and results in the scission and release of the most recently incorporated ribonucleotides, freeing up the active site. Here, by combining ultrastable optical trapping apparatus with a novel two-bead assay to monitor transcriptional elongation with near-base-pair precision, we observed backtracking and recovery by single molecules of RNAP. Backtracking events ( approximately 5 bp) occurred infrequently at locations throughout the DNA template and were associated with pauses lasting 20 s to >30 min. Inosine triphosphate increased the frequency of backtracking pauses, whereas the accessory proteins GreA and GreB, which stimulate the cleavage of nascent RNA, decreased the duration of such pauses.


Clinical experience with infants with Robin sequence: a prospective study.
To study the clinical course of patients with Robin sequence (RS) during the first 6 months of life. A longitudinal prospective study of children with RS. Hospital de Reabilitação de Anomalias Craniofaciais, Universidade de São Paulo, Bauru-SP, Brazil, 1997 and 1998. Sixty-two children were studied from hospital admission to 6 months of age. Thirty-three (53.2%) presented with probable isolated RS (PIRS), 25 (40.3%) presented with syndromes or other malformations associated with RS, and 4 (6.5%) presented with RS with neurological involvement. The type of respiratory tract obstruction was defined by nasopharyngoscopy. The patients with type 1 and type 2 obstruction underwent nasopharyngeal intubation (NPI), and glossopexy was indicated in patients with type 1 obstruction who did not show clinical improvement with this procedure. Tracheostomy was indicated in patients with type 2 obstruction who did not show a good course after NPI, in patients with type 1 obstruction who did not show good course after glossopexy, and in patients with type 3 and type 4 obstruction. Prone position treatment (PPT) or NPI was the definitive treatment in 25 cases (75.8%) of PIRS and in 13 cases (52%) of syndromes or other malformations. Among the children with type 1 obstruction, 24 (51.1%) were submitted exclusively to PPT and 12 (25.5%) to NPI. With the type 2 groups, only one (12.5%) received PPT, and three (37.5%) were treated exclusively with NPI. All 15 infants treated exclusively with NPI (24.4%) presented with good weight, length, and neuromotor development. Most patients with PIRS and type 1 obstruction improved without surgical intervention. NPI should be the initial treatment in all patients with RS with type 1 and type 2 obstruction who present with important respiratory and feeding difficulties.


Metformin increases the PGC-1alpha protein and oxidative enzyme activities possibly via AMPK phosphorylation in skeletal muscle in vivo.
AMP-activated protein kinase (AMPK), which was activated by an antihyperglycemic drug metformin, has been hypothesized to mediate metabolic adaptations. The purposes of the present study were 1) to confirm whether acute metformin administration induced AMPK phosphorylation and 2) to determine whether chronic metformin treatment increased the peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) protein expression, glycolytic and oxidative enzyme activities, and cytochrome c and glucose transporter-4 (GLUT4) protein expressions in the rat soleus and red and white gastrocnemius muscles. The single oral administration of metformin (300 mg/kg body wt) enhanced the AMPK phosphorylation at 5 and/or 6 h after treatment. In the chronic study, rats were fed either normal chow or chow containing 1% metformin for 14 days. Metformin treatment resulted in a mean daily metformin intake of 631 mg.kg body wt(-1).day(-1). Metformin increased the PGC-1alpha content in all three muscles. Metformin increased the hexokinase activity in the white gastrocnemius, the citrate synthase activity in all three muscles, and the beta-hydroxyacyl-CoA dehydrogenase activity in the soleus. The cytochrome c protein content in the soleus muscle also increased. The GLUT4 content was unchanged by metformin. These results suggest that metformin enhances the PGC-1alpha expression and mitochondrial biogenesis possibly at least in part via AMPK phosphorylation in the skeletal muscle. Metformin has thus been proposed to possibly ameliorate insulin resistance, at least partially, by means of such metabolic effects.


Underrepresentation of underrepresented minorities in academic medicine: the need to enhance the pipeline and the pipe.
The number of underrepresented minorities (URMs; black or African American, Hispanic or Latino, American Indian or Alaska Native, Native Hawaiian or other Pacific Islander) among US medical school faculty is markedly low when compared with their respective percent representation of the US population. Women URMs are doubly underrepresented, particularly as the academic rank advances from the instructor to the professor level, and gender discrepancies occur more prominently among white female faculty. Although the percent of white faculty has decreased over the past 5 years, the low percentage of black and Hispanic faculty has not changed proportionately. Furthermore, the 2008-2009 pipeline of URM trainees is unlikely to reverse the current trends. Several measures are suggested for consideration by medical schools and the National Institutes of Health, and recommendations that URM faculty and students may wish to consider are also discussed. The major issues to address include increasing the pipeline of predoctoral URMs, promoting the success and retention of junior URM faculty, enhancing the support of senior URM faculty to serve as needed mentors, and building a pool of URM and non-URM mentors for URM trainees. Therefore, issues pertaining to both the pipeline and the pipe need to be overcome.


Microtubules as antiparasitic drug targets.
Parasitic diseases including malaria, leishmaniasis and schistosomiasis take a terrible toll of human life, health and productivity, especially in tropical and subtropical regions, and are also highly significant in animal health worldwide. Antiparasitic drugs are the mainstays of control of most of these diseases, but in many cases current therapies are inadequate and in some the situation is deteriorating because of drug resistance. Microtubules, as essential components of almost all eukaryotic cells, are proven drug targets in many helminth diseases and show promise as targets for the development of new antiprotozoal drugs. This article reviews the chemistry of the microtubule inhibitors in current use and under investigation as antiparasitic agents, their activities against the major parasites and their mechanisms of action. New directions in both inhibitor chemistry and biological evaluation are discussed. The most promising immediate avenues for discovery and design appear to lie in development of novel benzimidazoles for helminth parasites and compounds based on antimitotic herbicides for protozoal parasites. New understanding from functional genomics, structural biology and microtubular imaging will help accelerate the development of completely novel antiparasitic drugs targeting microtubules.


Neonatal research: the parental perspective.
To investigate the recollections of parents consenting for their infants to be research subjects and determine their views about the need for consent. Parents of 154 sick newborn infants enrolled in a randomised trial in the early neonatal period. All parents had given written consent and received printed information. A questionnaire and accompanying letter was sent to the parental home 18 months later. Non-responders were sent a further questionnaire and letter. Response rate was 64% (99/154). Some respondents (12%) did not remember being asked to consent to their baby joining a study, and a further 6% were unsure. Most of the respondents (79%) were happy, 13% neutral, and 8% unhappy with their decision to give consent. None felt heavy pressure to agree. Entering the trial caused 24% of respondents to feel more anxious, 56% neutral, and 20% less anxious about their baby. Most of the respondents (83%) would be unhappy to forgo the consent process for trials passed by the institutional ethics committee. A significant proportion of parents who give written consent for a trial in the early neonatal period do not later remember having done so. Parents who have had experience of neonatal research would be unhappy for their baby to be enrolled in a study that had ethics committee approval without their consent being obtained.


Is ambient temperature associated with risk of infant mortality? A multi-city study in Korea.
Although numerous studies have shown increased risk of mortality from elevated temperatures for adults, limited studies have examined temperature's effect on mortality for infants. Our study investigated the city-specific and overall effects of ambient temperature on infant mortality in seven major cities in Korea, 2004-2007. Birth cohort using a linked birth and death records included 777,570 births with 557 all-cause deaths. We estimated city-specific hazard ratios for each city using an extended Cox proportional hazards model with time-dependent covariates. Then we combined city-specific hazard ratios to generate overall hazard ratio across the seven cities using a Bayesian hierarchical model. Stratified analyses were conducted by cause of death (total and SIDS), exposure period (whole gestation, each trimester, lifetime, 1 month before death, and 2 weeks before death), sex, and maternal characteristics. Overall across the cities, we found significantly positive associations between ambient temperature during 1 month before death or 2 weeks before death and infant mortality from total or SIDS. The overall hazard ratio of infant mortality from total deaths and SIDS for a 1°C increase during 1 month before death was 1.52 (95% CI, 1.46-1.57) and 1.50 (95% CI, 1.35-1.66), respectively. We also found suggestive evidence that some factors such as mother's age may modify the association. Our findings have implications for establishment of policy to reduce the risk of infant mortality from high ambient temperature under climate change.


Genome-wide identification and expression analysis of the JMJ-C gene family in melon (Cucumis melo L.) reveals their potential role in fruit development.
Proteins with the jumonji (JMJ)-C domain belong to the histone demethylase family and contribute to reverse histone methylation. Although JMJ-C family genes have an essential role in regulating plant growth and development, the characterization of the JMJ-C family genes in melon has not been uncovered. In this study, a total of 17 JMJ-C proteins were identified in melon (Cucumis melo L.). CmJMJs were categorized into five subfamilies based on the specific conserved domain: KDM4/JHDM3, KDM5/JARID1, JMJD6, KDM3/JHDM2, and JMJ-C domain-only. The chromosome localization analyses showed that 17 CmJMJs were distributed on nine chromosomes. Cis-acting element analyses of the 17 CmJMJ genes showed numerous hormone, light, and stress response elements distributed in the promoter region. Covariance analysis revealed one pair of replicated fragments (CmJMJ3a and CmJMJ3b) in 17 CmJMJ genes. We investigated the expression profile of 17 CmJMJ genes in different lateral organs and four developmental stages of fruit by RNA-seq transcriptome analysis and RT-qPCR. The results revealed that most CmJMJ genes were prominently expressed in female flowers, ovaries, and developing fruits, suggesting their active role in melon fruit development. Subcellular localization showed that the fruit-related CmJMJ5a protein is specifically localized in the cell nucleus. This study provides a comprehensive understanding of the gene structure, classification, and evolution of JMJ-C in melon and supports the clarification of the JMJ-C functions in further research.


Rationale and design of the DARWIN-T2D (DApagliflozin Real World evIdeNce in Type 2 Diabetes): A multicenter retrospective nationwide Italian study and crowdsourcing opportunity.
Randomized controlled trials (RCTs) in the field of diabetes have limitations inherent to the fact that design, setting, and patient characteristics may be poorly transferrable to clinical practice. Thus, evidence from studies using routinely accumulated clinical data are increasingly valued. We herein describe rationale and design of the DARWIN-T2D (DApagliflozin Real World evIdeNce in Type 2 Diabetes), a multicenter retrospective nationwide study conducted at 50 specialist outpatient clinics in Italy and promoted by the Italian Diabetes Society. The primary objective of the study is to describe the baseline clinical characteristics (particularly HbA1c) of patients initiated on dapagliflozin from marketing authorization approval to the end of 2016. Secondary and exploratory objectives will evaluate the changes in glycaemic and extraglycaemic efficacy parameters after initiation of dapagliflozin or after initiation of comparator glucose lowering medications (DPP-4 inhibitors, gliclazide extended release, and long-acting GLP-1 receptor agonists). An automated software will extract relevant data from the same electronic chart system at all centres, thereby minimizing data treatment and human intervention. The study is expected to collect an enormous dataset of information on dapagliflozin- and comparator-using patients. After study completion, the Italian Diabetes Society will launch an open crowdsourcing call on the DARWIN-T2D database, challenging diabetes researchers to apply their ideas and approaches to address new unmet needs and knowledge gaps in diabetes. We believe this will move DARWIN-T2D to the next generation of real world studies.


Optimum Baseline Clinical Severity Scale Cut Points for Prognosticating Intracerebral Hemorrhage: INTERACT Studies.
The optimal cut point of baseline National Institutes of Health Stroke Scale (NIHSS) and Glasgow Coma Scale scores for prognosticating acute intracerebral hemorrhage (ICH) is unknown. Secondary analyses of participant data are from the INTERACT (Intensive Blood Pressure Reduction in Acute Intracerebral Hemorrhage Trials) 1 and 2 studies. Receiver operating characteristic analyses were used to compare the predictive performance of baseline NIHSS and Glasgow Coma Scale scores, ICH score, and max-ICH score. Optimal cut points for predicting 90-day clinical outcomes (death or major disability [defined as modified Rankin Scale scores 3-6], major disability [defined as modified Rankin Scale scores 3-5], and death alone) were determined using the Youden index. Logistic regression models were adjusted for age, sex, hematoma volume, and other known risk factors for poor prognosis. We validated our findings in the INTERACT1 database. There were 2829 INTERACT2 patients (age, 63.5±12.9 years; male, 62.9%; ICH volume, 10.96 [5.77-19.49] mL) included in the main analyses. The baseline NIHSS score (area under the curve, 0.796) had better prognostic utility for predicting death or major disability than the Glasgow Coma Scale score (area under the curve, 0.650) and ICH score (area under the curve, 0.674) and was comparable to max-ICH score (area under the curve, 0.789). Similar findings were observed when assessing the outcome of major disability. A cut point of 10 on baseline NIHSS optimally (sensitivity, 77.5%; specificity, 69.2%) predicted death or major disability (adjusted odds ratio, 4.50 [95% CI, 3.60-5.63]). The baseline NIHSS cut points that optimally predicted major disability and death alone were 10 and 12, respectively. The predictive effect of NIHSS≥10 for poor functional outcomes was consistent in all subgroups including age and baseline hematoma volume. Results were consistent when analyzed in the independent INTERACT1 validation database. In patients with mild-to-moderate ICH, a baseline NIHSS score of ≥10 was optimal for predicting poor outcomes at 90 days. Prediction based on baseline NIHSS is better than baseline Glasgow Coma Scale score. URL: https://www.clinicaltrials.gov; Unique identifiers: NCT00226096 and NCT00716079.


Escherichia coli O157:H7 super-shedder and non-shedder feedlot steers harbour distinct fecal bacterial communities.
Escherichia coli O157:H7 is a major foodborne human pathogen causing disease worldwide. Cattle are a major reservoir for this pathogen and those that shed E. coli O157:H7 at >104 CFU/g feces have been termed "super-shedders". A rich microbial community inhabits the mammalian intestinal tract, but it is not known if the structure of this community differs between super-shedder cattle and their non-shedding pen mates. We hypothesized that the super-shedder state is a result of an intestinal dysbiosis of the microbial community and that a "normal" microbiota prevents E. coli O157:H7 from reaching super-shedding levels. To address this question, we applied 454 pyrosequencing of bacterial 16S rRNA genes to characterize fecal bacterial communities from 11 super-shedders and 11 contemporary pen mates negative for E. coli O157:H7. The dataset was analyzed by using five independent clustering methods to minimize potential biases and to increase confidence in the results. Our analyses collectively indicated significant variations in microbiome composition between super-shedding and non-shedding cattle. Super-shedders exhibited higher bacterial richness and diversity than non-shedders. Furthermore, seventy-two operational taxonomic units, mostly belonging to Firmicutes and Bacteroidetes phyla, were identified showing differential abundance between these two groups of cattle. The operational taxonomic unit affiliation provides new insight into bacterial populations that are present in feces arising from super-shedders of E. coli O157:H7.


Developing and Testing a Web-Based Provider Training for Cognitive Behavioral Therapy of Insomnia.
Chronic insomnia is a common and debilitating disease that increases risk for significant morbidity and workplace difficulties. Cognitive behavioral therapy for insomnia (CBT-I) is the first-line treatment, but there is a critical lack of behavioral health providers trained in CBT-I because, in part, of a bottleneck in training availability and costs. The current project developed and evaluated a web-based provider training course for CBT-I: CBTIweb.org. Subject matter experts developed the content for CBTIweb.org. Then, trainees completed alpha testing (n = 24) and focus groups, and the site was improved. Next, licensed behavioral health providers and trainees completed beta testing (n = 41) and the site underwent another round of modifications. Finally, to compare CBTIweb.org to an in-person workshop, licensed behavioral health providers were randomly assigned to CBTIweb.org (n = 21) or an in-person workshop (n = 23). All participants were CBT-I naïve and completed the following assessments: Computer System Usability Questionnaire, Website Usability Satisfaction Questionnaire, Website Content Satisfaction Questionnaire, and Continuing Education knowledge acquisition questionnaires. Alpha and beta testers of CBTIweb.org reported high levels of usability and satisfaction with the site and showed significant within-group knowledge acquisition. In the pilot comparison study, linear fixed-effects modeling on the pre-/postquestionnaires revealed a significant main effect for time, indicating a significant increase in knowledge acquisition from 69% correct at baseline to 92% correct at posttraining collapsed across in-person and CBTIweb.org groups. The interaction effect of Time by Condition was nonsignificant, indicating equivalence in knowledge gains across both groups. CBTIweb.org appears to be an engaging, interactive, and concise provider training that can be easily navigated by its users and produce significant knowledge gains that are equivalent to traditional in-person workshops. CBTIweb.org will allow for worldwide dissemination of CBT-I to any English-speaking behavioral health providers. Future research will work on translating this training to other languages and extending this web-based platform to the treatment of other sleep disorders (e.g., nightmares) and populations (e.g., pediatric populations with insomnia).


Prolonged viral shedding and new mutations of COVID-19 could complicate the control of the pandemic.
The studies of coronavirus disease 2019 (COVID-19) have mainly focused on epidemiological and clinical features of patients, but transmission dynamics of SARS-CoV-2 virus after patients have recovered is still poorly understood. Here we report a case with prolonged viral shedding of COVID-19 in Kaohsiung, Taiwan. This patient started to show myalgia and malaise in Wuhan, and the onset of the fever was on days 7-14 of the illness. All clinical and radiological results returned to normal after day 26, however, viral shedding was still evident 14 days later. Sequence analysis of the genome of the Taiwanese SARS-CoV-2 isolate from this patient reveals new mutations in viral replicase and ORF3a, indicating that COVID-19 evolves very quickly. Prolonged viral shedding and new mutations in the viral genome could potentially complicate the control of the COVID-19 pandemic.


Comparison of performance of serum and plasma in panbio dengue and Japanese encephalitis virus enzyme-linked immunosorbent assays.
We examined the comparative performance of serum and plasma (in dipotassium EDTA) in Panbio Dengue enzyme-linked immunosorbent assays (ELISAs) for detection of non-structural protein 1 (NS1), IgM, and IgG, and a dengue/Japanese encephalitis virus (JEV) combination IgM ELISA in a prospective series of 201 patients with suspected dengue in Laos. Paired comparisons of medians from serum and plasma samples were not significantly different for Dengue IgM, and NS1 which had the highest number of discordant pairs (both 2%; P = 0.13 and P = 0.25, respectively). Comparison of qualitative final diagnostic interpretations for serum and plasma samples were not significantly different: only 1.5% (3 of 201 for Dengue/JEV IgM and Dengue IgG) and 2.0% (4 of 201; IgM and NS1) showed discordant pairs. These results demonstrate that plasma containing EDTA is suitable for use in these ELISAs.


Climate-driven shifts in adult sex ratios via sex reversals: the type of sex determination matters.
Sex reversals whereby individuals of one genetic sex develop the phenotype of the opposite sex occur in ectothermic vertebrates with genetic sex-determination systems that are sensitive to extreme temperatures during sexual differentiation. Recent rises in global temperatures have led researchers to predict that sex reversals will become more common, resulting in the distortion of many populations' sex ratios. However, it is unclear whether susceptibility to climate-driven sex-ratio shifts depends on the type of sex determination that varies across species. First, we show here using individual-based theoretical models that XX/XY (male-heterogametic) and ZZ/ZW (female-heterogametic) sex-determination systems can respond differentially to temperature-induced sex reversals. Interestingly, the impacts of climate warming on adult sex ratio (ASR) depend on the effects of both genotypic and phenotypic sex on survival and reproduction. Second, we analyse the temporal changes of ASR in natural amphibian populations using data from the literature, and find that ASR shifted towards males in ZZ/ZW species over the past 60 years, but did not change significantly in XX/XY species. Our results highlight the fact that we need a better understanding of the interactions between genetic and environmental sex-determining mechanisms to predict the responses of ectotherms to climate change and the associated extinction risks.This article is part of the themed issue 'Adult sex ratios and reproductive decisions: a critical re-examination of sex differences in human and animal societies'.


[Mitral valve fibrous ring calcinosis in ischemic heart disease].
Calcinosis of the mitral fibrous ring (CMFR) was detected echocardiographically in 11.7% of the examinees with ischemic heart disease (IHD) at the age over 60 years. In CMFR the mitral opening significantly narrows, maximal transmitral diastolic gradient rises, mitral regurgitation becomes more pronounced. In one-third of the patients calcinosis involves the posterior wall disturbing its kinematics. Narrowing of the mitral opening in IHD patients accompanying CMFR is considered to be moderate nonvalvular mitral stenosis.


Receptor-specific activity of heteromeric thyrotropin (TSH) analogs: development of synthetic TSH antagonists.
In an attempt to create potent and specific inhibitors of the interaction of thyrotropin (thyroid-stimulating hormone [TSH]) with its receptor, we designed a series of 18 synthetic peptides containing sequences of both alpha and beta subunits that were shown previously to interact with the TSH receptor. These "heteromeric" peptide analogs included amino acid residues from alpha 26-46, beta 31-52, beta 88-95 and beta 101-112 that were arranged variously and were separated from each other by artificial amino acid spacers. Each peptide was tested for its ability to interact with the TSH receptor in a radio-receptor assay (TSH-RRA) using porcine thyroid membranes and a bio-assay for TSH using FRTL-5 cells. Twelve of the 18 peptides showed binding activity in the TSH-RRA. None of the analogs demonstrated thyroid stimulatory activity, but five inhibited TSH bioactivity and were, thus, pure antagonists, the most potent possessing EC50 values in the 3-5 microM range. Specificity of the antagonists was tested by measuring their ability to inhibit hCG binding to ovarian membranes, hCG-stimulated progesterone production in MA-10 rat Leydig tumor cells and FSH binding to testicular membranes. Only those peptides that included the alpha-subunit sequence CFSR or CCFSR exhibited binding activity for the heterologous receptors, and that activity was 10-fold lower than in the TSH assays. None of the heteromeric peptides showed activity in the hCG bioassays, further demonstrating their specificity as TSH antagonists. These studies illustrate the utility of a synthetic peptide approach in the development of analogs of peptide hormones. Future alterations that significantly enhance the potency of these antagonists may result in substances with clinical efficacy in diseases such as Graves' disease and differentiated thyroid cancer that involve the thyrotropin receptor.


Turnover Rates of Intermediate Sulfur Species (Sx2-, S0, S2O32-, S4O62-, SO32-) in Anoxic Freshwater and Sediments.
The microbial reduction of sulfate to sulfide coupled to organic matter oxidation followed by the transformation of sulfide back to sulfate drives a dynamic sulfur cycle in a variety of environments. The oxidative part of the sulfur cycle in particular is difficult to constrain because the eight electron oxidation of sulfide to sulfate occurs stepwise via a suite of biological and chemical pathways and produces a wide variety of intermediates (Sx2-, S0, S2O32-, S4O62-, and SO32-), which may in turn be oxidized, reduced or disproportionated. Although the potential processes affecting these intermediates are well-known from microbial culture and geochemical studies, their significance and rates in the environment are not well constrained. In the study presented here, time-course concentration measurements of intermediate sulfur species were made in amended freshwater water column and sediment incubation experiments in order to constrain consumption rates and processes. In sediment incubations, consumption rates were Scolloidal0> Sx2-> SO32-≈ S4O62-> S2O32-, which is consistent with previous measurements of SO32-, S4O62-, and S2O32- consumption rates in marine sediments. In water column incubations, however, the relative reactivity was Scolloidal0> SO32-> Sx2-> S2O32-> S4O62-. Consumption of thiosulfate, tetrathionate and sulfite was primarily biological, whereas it was not possible to distinguish between abiotic and biological polysulfide consumption in either aqueous or sediment incubations. Scolloidal0 consumption in water column experiments was biologically mediated, however, rapid sedimentary consumption was likely due to reactions with iron minerals. These experiments provide important constraints on the biogeochemical reactivity of intermediate sulfur species and give further insight into the diversity of biological and geochemical processes that comprise (cryptic) environmental sulfur cycling.


Predictors of participant adherence and retention in the African American Study of Kidney Disease and Hypertension.
The African American Study of Kidney Disease and Hypertension (AASK) was conducted over a 7-year period at 21 clinical centers across the United States to investigate whether one of two levels of blood pressure control and/or one of three classes of antihypertensive medications was more effective at slowing the rate of renal disease in African Americans with renal insufficiency presumed secondary to hypertension. Analysis at the end of the study revealed an overall participant retention rate of 90% (still alive and not on dialysis); defined as having had at least one 125I-iothalamate GFR, the primary data collection element, measured in the final year of the study. Adherence, defined as not missing 3 consecutive protocol visits (6 months) during the study, was 77%. Adherence to protocol visits showed that participants assigned to a low blood pressure goal (mean arterial pressure [MAP] of 92 mm/Hg or lower) had a 30% (95% CI, 9%-45%) lower risk of nonadherence as compared to those assigned to the usual goal [MAP of 102-107] (p = 0.006). No statistically significant difference was observed between randomized drug assignments. Higher baseline systolic (p = 0.0001) and diastolic (p = 0.007) blood pressures were associated with a higher risk of nonadherence. Declining to provide an annual income is associated with a higher risk of nonadherence compared to those with incomes of $15,000 or higher (p = 0.04). In discussing the identifying factors that may predict nonadherence and the strategies that assisted in improving adherence and retention, this article offers insights for researchers in achieving high levels of participation in long-term clinical studies.


Information flows from hippocampus to auditory cortex during replay of verbal working memory items.
The maintenance of items in working memory (WM) relies on a widespread network of cortical areas and hippocampus where synchronization between electrophysiological recordings reflects functional coupling. We investigated the direction of information flow between auditory cortex and hippocampus while participants heard and then mentally replayed strings of letters in WM by activating their phonological loop. We recorded local field potentials from the hippocampus, reconstructed beamforming sources of scalp EEG, and - additionally in four participants - recorded from subdural cortical electrodes. When analyzing Granger causality, the information flow was from auditory cortex to hippocampus with a peak in the [4 8] Hz range while participants heard the letters. This flow was subsequently reversed during maintenance while participants maintained the letters in memory. The functional interaction between hippocampus and the cortex and the reversal of information flow provide a physiological basis for the encoding of memory items and their active replay during maintenance.


Expectations for tonal cadences: Sensory and cognitive priming effects.
Studies examining the formation of melodic and harmonic expectations during music listening have repeatedly demonstrated that a tonal context primes listeners to expect certain (tonally related) continuations over others. However, few such studies have (1) selected stimuli using ready examples of expectancy violation derived from real-world instances of tonal music, (2) provided a consistent account for the influence of sensory and cognitive mechanisms on tonal expectancies by comparing different computational simulations, or (3) combined melodic and harmonic representations in modelling cognitive processes of expectation. To resolve these issues, this study measures expectations for the most recurrent cadence patterns associated with tonal music and then simulates the reported findings using three sensory-cognitive models of auditory expectation. In Experiment 1, participants provided explicit retrospective expectancy ratings both before and after hearing the target melodic tone and chord of the cadential formula. In Experiment 2, participants indicated as quickly as possible whether those target events were in or out of tune relative to the preceding context. Across both experiments, cadences terminating with stable melodic tones and chords elicited the highest expectancy ratings and the fastest and most accurate responses. Moreover, the model simulations supported a cognitive interpretation of tonal processing, in which listeners with exposure to tonal music generate expectations as a consequence of the frequent (co-)occurrence of events on the musical surface.


Particles act as 'specialty centers' with expanded enzymatic function throughout the water column in the western North Atlantic.
Heterotrophic bacteria initiate the degradation of high molecular weight organic matter by producing an array of extracellular enzymes to hydrolyze complex organic matter into sizes that can be taken up into the cell. These bacterial communities differ spatially and temporally in composition, and potentially also in their enzymatic complements. Previous research has shown that particle-associated bacteria can be considerably more active than bacteria in the surrounding bulk water, but most prior studies of particle-associated bacteria have been focused on the upper ocean - there are few measurements of enzymatic activities of particle-associated bacteria in the mesopelagic and bathypelagic ocean, although the bacterial communities in the deep are dependent upon degradation of particulate organic matter to fuel their metabolism. We used a broad suite of substrates to compare the glucosidase, peptidase, and polysaccharide hydrolase activities of particle-associated and unfiltered seawater microbial communities in epipelagic, mesopelagic, and bathypelagic waters across 11 stations in the western North Atlantic. We concurrently determined bacterial community composition of unfiltered seawater and of samples collected via gravity filtration (>3 μm). Overall, particle-associated bacterial communities showed a broader spectrum of enzyme activities compared with unfiltered seawater communities. These differences in enzymatic activities were greater at offshore than at coastal locations, and increased with increasing depth in the ocean. The greater differences in enzymatic function measured on particles with depth coincided with increasing differences in particle-associated community composition, suggesting that particles act as 'specialty centers' that are essential for degradation of organic matter even at bathypelagic depths.


Towards a sociology of disease.
We argue for a sociology of health, illness, and disease. Under the influence of Talcott Parsons, the social study of health began as medical sociology and then morphed into sociology of health and illness, focusing largely on the social aspects of health-related topics. Social scientists have been reluctant to tackle disease in its physiological and biological manifestations. The result is an impoverishment of sociological analysis on at least three levels: social scientists have rarely made diseases central to their inquiries; they have been reluctant to include clinical endpoints in their analysis; and they have largely bracketed the normative purpose of health interventions. Consequently, social scientists tend to ignore what often matters most to patients and health care providers, and the social processes social scientists describe remain clinically unanchored. A sociology of disease explores the dialectic between social life and disease; aiming to examine whether and how social life matters for morbidity and mortality and vice versa. Drawing from specific advances in science and technology studies and social epidemiology, we point to ways that sociologists can participate as health researchers.


Energy self-sufficiency for hawaii.
Currently, Hawaii is almost totally dependent for energy on imported oil. The island state has a wide variety of renewable energy resources, however, and for the past decade has supported the development of these resources as substitutes for seaborne petroleum. Sufficient progress has been made to date in commercializing a number of these alternative energy sources to give cause for optimism tIhat Hawaii will be able to achieve energy self-sufficiency with its indigenous renewable resources.


Nobiletin, a flavone from Citrus depressa, induces gene expression and increases the protein level and activity of neprilysin in SK-N-SH cells.
Neprilysin (NEP) is one of the candidate amyloid β protein (Aβ) degrading enzymes affecting brain Aβ clearance. This enzyme declines in the brain with age, which leads to the increased Aβ deposition in Alzheimer's disease (AD). Pharmacological activation of NEP during the aging process, therefore, represents a potential strategy to prevent the development of AD. To examine the influence of nobiletin on neprilysin activity, we measured cellular NEP activity in SK-N-SH cells. Moreover, NEP expression was examined by using reverse transcription - polymerase chain reaction and Western blotting. Measurement of cellular NEP activity showed that nobiletin stimulated this in a dose- and time-dependent manner in SK-N-SH cells. Moreover, nobiletin increased the expression of NEP mRNA, and then the levels of NEP protein, also in a dose- and time-dependent manner. Our findings showed that nobiletin promoted NEP gene and protein expression, resulting in enhancement of cellular NEP activity in SK-N-SH cells. This compound could be a novel Aβ-degrading compound for use in the development of disease-modifying drugs to prevent and (or) cure AD.


An efficient synthesis of N-methyl amino acids by way of intermediate 5-oxazolidinones.
N-Methyl amino acids occur in many natural products. Experimental strategies are presented for a unified approach to the synthesis of N-methyl derivatives through 5-oxazolidinones of the 20 common l-amino acids. The amino acids with reactive side chains that required protecting groups or devoted syntheses for side chain construction for N-methylation to proceed included serine, threonine, tyrosine, cysteine, methionine, tryptophan, asparagine, histidine, and arginine. The studies have provided improved methods for the preparation of N-methyl serine, threonine, and tyrosine. All 20 of the common l-amino acids are now available in suitable forms for solid or solution-phase peptide synthesis.


Trends in Web Searches About the Causes and Treatments of Autism Over the Past 15 Years: Exploratory Infodemiology Study.
Ninety percent of adults in the United States use the internet, and the majority of internet users report looking on the web for health information using search engines. The rising prevalence of autism spectrum disorder (ASD), uncertainty surrounding its etiology, and variety of intervention approaches contribute to questions about its causes and treatments. It is not known which terms people search most frequently about ASD and whether web search queries have changed over time. Infodemiology is an area of health informatics research using big data analytics to understand web search behavior. The objectives were to (1) use infodemiological data to analyze trends in web-based searches about the causes and treatments of ASD over time and (2) inform clinicians and ASD organizations about web queries regarding ASD. Google Trends was used to analyze web searches about the causes and treatments of ASD in the United States from 2004 to 2019. The search terms analyzed for queries about causes of ASD included vaccines, genetics, environmental factors, and microbiome and those for therapies included applied behavior analysis (ABA), gluten-free diet, chelation therapy, marijuana, probiotics, and stem cell therapy. Google Trends results are normalized on a scale ranging from 0 to 100 to represent the frequency and relative interest of search topics. For searches about ASD causes, vaccines had the greatest frequency compared to other terms, with an initial search peak observed in 2008 (scaled score of 81), reaching the highest frequency in 2015 (scaled score of 100), and a current upward trend. In comparison, searches about genetics, environmental factors, and microbiome occurred less frequently. For web searches about ASD therapies, ABA consistently had a high frequency of search interest since 2004, reaching a maximum scaled score of 100 in 2019. The analyses of chelation therapy and gluten-free diet showed trending interest in 2005 (scaled score of 68) and 2007 (scaled score of 100), respectively, followed by a steady decline since (scaled scores of only 10 and 16, respectively, in 2019). Searches related to ASD and marijuana showed a rise in 2009 (scaled score of 35), and they continue to trend upward. Searches about probiotics and stem cell therapy have been relatively low (scaled scores of 22 and 18, respectively), but are gradually gaining interest. Web search volumes for stem cell therapy in 2019 surpassed both gluten-free diet and chelation therapy as web-searched interventions for ASD. Google Trends is an effective infodemiology tool to analyze large-scale web search trends about ASD. The results showed informative variation in search trends over 15 years. These data are useful to inform clinicians and organizations about web queries on topics related to ASD, identify knowledge gaps, and target web-based education and knowledge translation strategies.


[Methodologic problems in studies of pressure in the venous sinuses of the brain].
The adequacy of the indirect method for the liquorodynamic evaluation of intrasinusal pressure has been established. It was found that in patients with parasagittal meningiomas intrasinusal pressure does not depend on the size of the tumour and its relation to the superior sagittal sinus, or on intracranial hypertension (up to 28 mm Hg). In the phase of decompensation of intracranial hypertension the effective pressure of resorption increases. The quantitative characteristics of venous cerebral circulation and of liquorodynamics is of importance in evaluating the condition of compensatory mechanisms of the cerebrospinal system in various forms of neurosurgical pathology.


Cyclin D1 expression and early breast cancer recurrence following lumpectomy and radiation.
The purpose of this study was to determine the prognostic significance of cyclin D1 (cycD1) levels in ipsilateral breast tumor recurrence (IBTR) following lumpectomy and radiation therapy. A total of 98 patients (49 patients with IBTR and 49 matched cases without IBTR) selected from our conservatively treated breast cancer population served as the patient population for the current study. All patients were treated with lumpectomy followed by radiation therapy to the intact breast to a total median dose of 64 Gy. The patients were followed in our clinic with a median follow-up of 13 years. Immunohistochemical analysis of cycD1 in these 98 early-stage breast cancer patients was performed using a polyclonal antibody generated against the human cycD1 protein. All clinical, pathologic, and molecular variables were entered into a computerized data base for statistical analysis. Low levels of immunohistochemically detected cycD1 protein correlated with IBTR (p = 0.001), but there was no association between cycD1 protein levels and metastatic disease, axillary lymph node involvement, distant disease-free survival (DDFS), and overall survival (OS). Subgroup analysis revealed that for early breast tumor relapses (within 4 years of initial breast tumor diagnosis), low levels of cycD1 were associated with IBTR (p = 0.004), but cycD1 expression was not prognostic for IBTR from breast cancer patients with late relapses (p = NS). These studies provide in vivo evidence for the prognostic and biologic significance of cycD1 expression in determining response to radiation therapy in breast cancer patients.


* Tissue Engineering Strategies to Improve Osteogenesis in the Juvenile Swine Alveolar Cleft Model.
Alveolar (gumline) clefts are the most common congenital bone defect in humans, affecting 1 in 700 live births. Treatment to repair these bony defects relies on autologous, cancellous bone transfer from the iliac crest. This harvest requires a second surgical site with increased surgical time associated with potential complications, while providing only limited cancellous bone. Improvements in treatment protocols that avoid these limitations would be beneficial to patients with clefts and other craniofacial bone defects. There have been steady advances in tissue-engineered (TE) solutions for long-bone defects and adult patients, but advances for the pediatric craniofacial skeleton have been slower to emerge. This study utilizes a previously established juvenile swine model with a surgically created, critical size alveolar defect to test the efficacy of umbilical cord (UC) mesenchymal stem cells (MSCs) treatments on nano-microfiber scaffolds. At 1 month after implanting our TE construct, mineralized tissue in the surgical gap was quantified through computed tomography (CT), and histology, and excised tissue was subjected to mechanical testing. Both undifferentiated and predifferentiated (toward an osteogenic lineage) UC MSCs generated bone within the cleft on a scale comparable to iliac crest cancellous bone, as evidenced by histology and CT scans. All of the pigs treated with scaffold/stem cell combinations had mineralized tissue within the defect, although without filling the entire defect. Several of the experimental animals exhibited poor and/or asymmetric maxillary growth 1 month after the initial surgery, especially if the surgical defect was located on the smaller side of an already asymmetric pig. Our results demonstrate that tissue engineering approaches using UC MSCs are a promising alternative for repair of the alveolar cleft. Data in the pig model demonstrate that implanted scaffolds are at least as good as the current gold standard treatment based on harvesting cancellous bone from the iliac crest, regardless of whether the cells seeded on the scaffold are precommitted to an osteogenic fate.