Evaluation of minimally invasive surgical staging for esophageal cancer.
Conventional imaging studies (computed tomography and endoscopic esophageal ultrasonography) used for preoperative evaluation of patients with esophageal cancer can be inaccurate for detection of small metastatic deposits. We evaluated the efficacy of minimally invasive surgical (MIS) staging as an additional modality for evaluation of patients with esophageal cancer. Between December 1998 and February 2001, 33 patients with esophageal cancer were evaluated for surgical resection. Conventional imaging studies demonstrated operable disease in 31 patients and equivocal findings in 2 patients. All patients then underwent MIS staging (laparoscopy, bronchoscopy, and ultrasonography of the liver). We compared the results from surgical resection and MIS staging with those from conventional imaging. MIS staging altered the treatment plan in 12 (36%) of 33 patients; MIS staging upstaged 10 patients with operable disease and downstaged 2 patients with equivocal findings. MIS staging accurately determined resectability in 97% of patients compared with 61% of patients staged by conventional imaging. The specificity and negative predictive value for detection of unsuspected metastatic disease in MIS staging were 100% and 96%, respectively, compared with 91% and 65%, respectively, for conventional imaging studies. In addition to conventional imaging studies, MIS staging should be included routinely in the preoperative work-up of patients with esophageal cancer.


Does myectomy convey survival benefit in hypertrophic cardiomyopathy?
Obstructive hypertrophic cardiomyopathy (HCM) can be treated by transaortic subaortic myectomy, which has been shown to improve patients' symptoms and abolish left ventricular outflow tract obstruction. Different options, such as dual chamber pacing and septal ethanol ablation, are now available for the management of obstructive HCM, and it is important to evaluate the risks and benefits of myectomy, especially its impact on survival. In this article, the authors review the clinical course of obstructive HCM and the early and long-term results of surgery. They examine the outcomes of obstructive HCM in patients after surgical versus conservative therapy. In addition, they review the studies that have compared other techniques to surgery for the management of obstructive HCM.


The reversed forearm flap using scarred skin in hand reconstruction.
A reverse forearm flap was used in the reconstruction of the hands of two epileptic patients, who had sustained deep dermal burns of the right hand and forearm. The base of both flaps consisted of scarred, transplanted skin. Furthermore one flap was split. Venous drainage was preserved. A good result was observed in both cases.


Image analysis of HER2 immunohistochemical staining. Reproducibility and concordance with fluorescence in situ hybridization of a laboratory-validated scoring technique.
Image analysis of the HER2 immunohistochemical (IHC) stain can help determine which breast cancer patients may benefit from HER2-targeted therapy. We studied the concordance of HER2 IHC and fluorescence in situ hybridization (FISH) as well as reproducibility of surgical pathologist (SP) and cytotechnologist (CT) interpretations using manual and image analysis methodologies on 154 IHC cases. Concordances with FISH were good for IHC negative (0, 1+) cases (range, 97%-100%) and positive (3+) cases (range, 87%-100%). Image analysis had fewer equivocal (2+) results (10.4%) than CT (14.9%) and SP (16.2%) manual methods, with higher concordances to FISH (31%, 26%, and 20% for image analysis, CT manual, and SP manual, respectively). CT manual (κ = 0.747) and image analysis (κ = 0.779) methods had better interobserver reproducibility than SP manual (κ = 0.697). CT image analysis had better intraobserver reproducibility (κ = 0.882) than CT (κ = 0.828) and SP (κ = 0.766) manual methods. HER2 IHC analysis performed by image analysis can produce accurate results with improved reproducibility.


Fatal Kikuchi-Fujimoto disease associated with SLE and hemophagocytic syndrome: a case report.
Kikuchi-Fujimoto disease (KFD) or histiocytic necrotizing lymphadenitis is a rare, benign, autoimmune condition characterized by lymphadenopathy, fever, and neutropenia. KFD can frequently mimic various diseases including infection, malignancy, and autoimmune disease. KFD has also been infrequently reported in association with SLE, which can be diagnosed previously, simultaneously, or after the diagnosis of SLE. The author presents here the first case of fatal KFD simultaneously occurred with SLE complicated with hemophagocytic syndrome and severe infection. The recognition of this association is of significance for management of affected patients with early intensive immunosuppressive therapy for favorable outcome.


Estimating the Risk of Death from COVID-19 in Adult Cancer Patients.
During the coronavirus disease 2019 (COVID-19) pandemic, organisations have produced management guidance for cancer patients and the delivery of cytotoxic chemotherapy, but none has offered estimates of risk or the potential impact across populations. We combined data from four countries to produce pooled age-banded case fatality rates, calculated the sex difference in survival and used data from four recent studies to convert case fatality rates into age/sex-stratified infection fatality rates (IFRs). We estimated the additional risk of death in cancer patients and in those receiving chemotherapy. We illustrate the impact of these by considering the impact on a national incident cancer cohort and analyse the risk-benefit in some clinical scenarios. We obtained data based on 412 985 cases and 41 854 deaths. The pooled estimate for IFR was 0.92%. IFRs for patients with cancer ranged from 0 to 29% and were higher in patients receiving chemotherapy (0.01-46%). The risk was significantly higher with age and in men compared with women. 37.5% of patients with a new diagnosis of cancer in 2018 had an IFR ≥5%. Survival benefits from adjuvant chemotherapy ranged from 5 to 10% in some common cancers, compared with the increased risk of death from COVID-19 of 0-3%. Older male patients are at a higher risk of death with COVID-19. Patients with cancer are also at a higher risk, as are those who have recently received chemotherapy. We provide well-founded estimates to allow patients and clinicians to better balance these risks and illustrate the wider impact in a national incident cohort.


A single-parameter model of the immune response to bacterial invasion.
The human immune response to bacterial pathogens is a remarkably complex process, involving many different cell types, chemical signals, and extensive lines of communication. Mathematical models of this system have become increasingly high-dimensional and complicated, as researchers seek to capture many of the major dynamics. In this paper, we argue that, in some important instances, preference should be given to low-dimensional models of immune response, as opposed to their high-dimensional counterparts. One such model is analyzed and shown to reflect many of the key phenomenological properties of the immune response in humans. Notably, this model includes a single parameter that, when combined with a single set of reference parameter values, may be used to quantify the overall immunocompetence of individual hosts.


The stroma-vascular fraction of rat inguinal and epididymal adipose tissue and the adipoconversion of fat cell precursors in primary culture.
The stroma-vascular fraction (SVF) of inguinal and epididymal fat pads of 4 week-old rats was studied by electron microscopy. Among the various cell types, endothelial cells and preadipocytes were found in both SVF, while mesothelial cells were only detected in the epididymal SVF. The resulting heterogeneity of primary culture and the adipoconversion of the fat cell precursors were studied in a serum-supplemented medium enriched with insulin (14.5 nM) and exogenous triglycerides. Despite the heterogeneity of the inoculum, the primary cultures were rather homogeneous, fat cell precursors being the main cell type. Distinctive contaminant fibroblast-like cells were observed in both cultures, whereas epithelial-like cells, which correspond most probably to mesothelial cells, were only found in epididymal cultures. Differentiation of fat cell precursors was assessed by the appearance of lipoprotein lipase (LPL) and glycerol-3-phosphate dehydrogenase (GPDH). LPL activity was found in the same level in cells of both deposits while GPDH activity was elevated in inguinal vs epididymal derived stroma-vascular cells. The different adipose conversion pattern of both cultures was confirmed by morphological quantification: the maturation of epididymal fat cell precursors was faster but less extensive. These differences could be related mainly to regional localization rather than to different maturation of the two fat deposits.


Patterns of extracellular norepinephrine in the paraventricular hypothalamus: relationship to circadian rhythm and deprivation-induced eating behavior.
In order to clarify the physiological role of norepinephrine (NE) in the hypothalamic paraventricular nucleus (PVN), changes in extracellular levels of endogenous NE were measured in 11 freely-moving rats using microdialysis and high pressure liquid chromatography with electrochemical detection. To determine whether there was a circadian pattern of extracellular NE in freely-eating subjects, samples of dialysate from the vicinity of the PVN were collected and assayed for NE every 2 hrs for 48 hrs. The pattern of NE averaged across subjects was similar during both 24-hr periods, with a reliable peak at the beginning of the dark cycle and relatively stable levels at all other times. When these animals were subsequently deprived of food for 24 hrs, a gradual rise in extracellular NE was observed, ultimately increasing to 215% of the predeprivation level. When the animals were refed and NE measurements were continued at more frequent intervals, extracellular levels were found to decline during the first 20 min of eating, as well as over the next 3 hrs as food intake diminished. These patterns of extracellular NE, together with previous evidence, suggest that endogenous NE in the PVN plays a role in the initiation and/or maintenance of normal eating behavior at the beginning of the nocturnal feeding period, as well as after food deprivation.


Identification of cardiovascular and molecular prognostic factors for the morbidity and mortality in COVID-19-sepsis (ICROVID): Protocol for a prospective multi-centre cohort study.
Severe COVID-19 constitutes a form of viral sepsis. Part of the specific pathophysiological pattern of this condition is the occurrence of cardiovascular events. These include pulmonary embolism, arrhythmias and cardiomyopathy as manifestations of extra-pulmonary organ dysfunction. Hitherto, the prognostic impact of these cardiovascular events and their predisposing risk factors remains unclear. This study aims to explore this question in two cohorts of viral sepsis-COVID-19 and influenza-in order to identify new theragnostic strategies to improve the short- and long-term outcome of these two diseases. In this prospective multi-centre cohort study, clinical assessment will take place during the acute and post-acute phase of sepsis and be complemented by molecular laboratory analyses. Specifically, echocardiography and cardiovascular risk factor documentation will be performed during the first two weeks after sepsis onset. Aside from routine haematological and biochemical laboratory tests, molecular phenotyping will comprise analyses of the metabolome, lipidome and immune status. The primary endpoint of this study is the difference in 3-month mortality of patients with and without septic cardiomyopathy in COVID-19 sepsis. Patients will be followed up until 6 months after onset of sepsis via telephone interviews and questionnaires. The results will be compared with a cohort of patients with influenza sepsis as well as previous cohorts of patients with bacterial sepsis and healthy controls. Approval was obtained from the Ethics Committee of the Friedrich Schiller University Jena (2020-2052-BO). The results will be published in peer-reviewed journals and presented at appropriate conferences. DRKS00024162.


The influence of lobeline on nucleus accumbens dopamine and locomotor responses to nicotine in nicotine-pretreated rats.
In vivo brain microdialysis was used to investigate the influence of lobeline on dopamine (DA) and dihydroxyphenylacetic acid (DOPAC) overflow in the core of the nucleus accumbens of freely-moving rats pretreated with nicotine (0.4 mg x kg(-1), s.c., once per day for 5 days). Locomotion was also recorded. Lobeline, at doses of 0.7, 4.0 and 10.0 mg x kg(-1), i.p., failed to elicit any significant changes in extracellular dopamine or dihydroxyphenylacetic acid levels during the 60 min following its administration and did not stimulate locomotor. The dopamine responses to nicotine (0.4 mg x kg(-1), s.c.), were abolished (P<0.01) if the nicotine challenge was administered 10 min but not 60 min, after lobeline doses of 4.0 and 10.0 mg kg(-1), i.p., but were unaffected following lobeline at the lowest dose tested (0.7 mg x kg(-1), i.p.) at either time. The increase in locomotor activity was significantly attenuated (P<0.01), to a similar extent, when the nicotine was injected 10 min, but not 60 min, after all three doses of lobeline (0.7, 4.0 and 10.0 mg kg(-1), i.p.) when compared with the saline-treated rats. The results suggest that lobeline is a short-acting antagonist of the nicotinic AChRs which mediate the effects of nicotine on mesolimbic dopamine activity and locomotor stimulation.


Effect of an external nasal dilator strip on cytologic characteristics of bronchoalveolar lavage fluid in Thoroughbred racehorses.
To determine the effects of an external nasal dilator strip on cytologic characteristics of bronchoalveolar lavage (BAL) fluid in racing Thoroughbreds. Clinical trial. 23 Thoroughbred racehorses in active training. Each horse raced on 2 occasions: once while wearing an external nasal dilator strip and once while not. Bronchoalveolar lavage was performed 12 to 18 hours after each race, and BAL fluid was analyzed for RBC and leukocyte counts and hemosiderin content. Mean +/- SEM count of RBCs in BAL fluid when horses raced without the nasal dilator strip (84.6 +/- 275 cells/microL) was not significantly different from count when they raced with it (41.7 +/- 12.2 cells/microL). Horses were grouped as having mild or severe bleeding on the basis of RBC count in BAL fluid after horses raced without the nasal dilator strip. Mean count when horses with severe bleeding raced without the nasal dilator strip (271.0 +/- 63.7 cells/microL) was significantly higher than mean count when these horses raced with the strip (93.8 +/- 376 cells/microL). Mean count of lymphocytes in BAL fluid was significantly lower after horses raced with the external nasal dilator strip. Results suggest that use of an external nasal dilator strip in Thoroughbred racehorses may decrease pulmonary bleeding, particularly in horses with severe exercise-induced pulmonary hemorrhage.


[Initial experiences with implanted drug pumps for continuous intrathecal calcitonin therapy in therapy-resistant pain].
The hormone calcitonin has proved itself for some years in the treatment of chronic pain syndromes. In addition to its known influence on calcium exchange it gives vise to an analgesic effect within the central nervous system and this follows systemic administration or after bolus intrathecal injection. Two patients with chronic non malignant pain are presented in whom continuous delivery pumps have been used for intrathecal Lachs-Calcitonin (Karil, Fa. Sandoz).


MRI evaluation of complex renal cysts using the Bosniak classification: a comparison to CT.
The purpose of this study was to compare the ability of magnetic resonance imaging (MRI) and computed tomography (CT) to discriminate between benign and malignant cystic renal lesions utilizing the Bosniak classification. We retrospectively searched our Radiological Information System using renal/kidney cysts as entries. The search retrieved 2929 patients and 525 complex renal cysts. After exclusions, 42 complex cysts, from 37 patients, with CT and MRI, up to six months apart, were included. Surgery and pathology report and follow-up of at least 24 months were used as a standard of reference. The mean age of patients was 51.4 years, ranging from 11 to 82 years old. Twenty-nine lesions were classified as Bosniak I, II or II-F by CT and/or MRI and 13 as Bosniak III or IV, by one of the methods. The interobserver agreement for Bosniak classification for CT was 0.87 and 0.93 for MRI. Fifteen lesions had higher Bosniak categories on MRI, included six with change in management. Only two lesions had a higher category on CT, one with change in management. The frequency of malignancy for Bosniak III was 50 % (2/4) for CT and 20% for MRI (1/5), as Bosniak upgrades by MRI resulted in surgery for benign lesions. Both methods had 100 % frequency of malignancy for category 4. MRI led to category migration and management change of complex renal cysts in a significant proportion of cases, likely due to its superior soft tissue and contrast resolution. The impact of MRI on detection and outcomes of malignant complex renal cysts still requires further investigation.


Changing one's focus of attention alters the structure of movement variability.
Substantial evidence supports the beneficial effect of an external (vs. internal) focus of attention on task performance during goal-directed movements. Counter-intuitively, an external focus has also been shown to increase joint-level movement variability. To determine whether shifting attentional focus can alter the structure of movement variability, thereby offering a probable mechanistic explanation for how adopting an external focus of attention might confer its benefits. Thirty-five healthy adults (age 23-55) performed unipedal hopping under three different attentional foci: natural (no directed focus), internal focus, and external focus. Uncontrolled manifold analysis was used to examine the structure of movement variability with respect to stabilization of leg orientation and vertical leg length during hopping. Takeoff/landing event bin and stance phase integrals of performance-irrelevant and performance-destabilizing variability were compared across focus conditions. Accuracy of hopping in place improved with both external and internal foci compared to the natural condition (.004 ≤ p ≤ .035). External focus, to a greater degree than internal focus, destabilized leg orientation at takeoff and landing compared to the natural condition (.001 ≤ p ≤ .038). External focus increased - but internal focus decreased - leg length stabilization throughout stance compared to the natural condition (p < .001). External focus was superior to internal and natural focus conditions in terms of increasing flexibility within the system to orient the leg differently at takeoff and landing to compensate for unintentional drift during hopping. An external focus increased leg length stabilization in stance by preferentially increasing the subset of variability that explores multiple successful performance options. These results provide an understanding of the mechanism underlying external focus benefits - improving movement variability/coordination.


Recognition between a short unstructured peptide and a partially folded fragment leads to the thioredoxin fold sharing native-like dynamics.
Thioredoxins (TRXs) constitute attractive α/β scaffolds for investigating molecular recognition. The interaction between the recombinant fragment spanning the sequence 1-93 of full-length TRX (TRX1-93) and the synthetic peptide comprising residues 94-108 (TRX94-108), plus a C-terminal tyrosine tag (the numbering scheme used in entry pdb 2TRX is used throughout the article, two complementary moieties of E. coli TRX, brings about the consolidation of a native-like complex. Despite its reduced thermodynamic stability, this complex is able to acquire fine structural features remarkably similar to those characteristic of full-length TRX, namely, hydrodynamic behavior, assessed by diffusion-ordered spectroscopy (DOSY)-NMR; the pattern of secondary structure, as revealed by three-bond HNHα coupling constants and secondary shifts for Hα/CO/Cα/Cβ; native-like tertiary structural signatures revealed by near-UV circular dichroism (CD) spectroscopy. The complex exhibits a relaxation behavior compatible with that expected for a native-like structure. However, heteronuclear nuclear Overhauser effect (NOE)s reveal an enhanced dynamics for the complex by comparison with full-length TRX. Furthermore, higher R(2) values for residues 43-50 and 74-89 would likely result from an exchange process modulated by the peptide at the interface region. The slow kinetics of the consolidation reaction was followed by CD and real-time NMR. Equilibrium titration experiments by NMR yield a K(D) value of 1.4 ± 1.0 μM and a second low-affinity (>150 μM) binding event in the vicinity of the active site. Molecular dynamics simulations of both the isolated fragment TRX1-93 and the complex suggest the destabilization of α2 and α3 helical elements and the persistence of β-structure in the absence of TRX94-108. Altogether, structural and dynamic evidence presented herein points to the key role played by the C-terminal helix in establishing the overall fold. This critical switch module endows reduced TRX with the ability to act as a cooperative folding unit.


Efficacy of mindfulness- and acceptance-based cognitive-behavioral therapies for bodily distress in adults: a meta-analysis.
Bodily distress, i.e., somatoform disorders and associated functional somatic syndromes, is highly prevalent, often persistent and highly disabling. It has been proposed that "third wave" therapies may be beneficial variants of cognitive behavioral treatments. However, evidence on their efficacy is scarce. This meta-analysis examines the efficacy of "third wave" psychotherapies (mindfulness-based cognitive therapy [MBCT], mindfulness-based stress reduction [MBSR], and acceptance and commitment therapy [ACT]) in adults with bodily distress. We included randomized controlled trials (RCTs) treating adults with bodily distress using MBCT, MBSR, and ACT compared to inactive and non-specific control groups. A random effects model was used. The primary outcome was somatic symptom severity. Secondary outcomes were degrees of depression and of anxiety, health anxiety, perceived health status, mindfulness, psychological inflexibility, and pain acceptance. Sixteen RCTs with 1,288 participants were included in the analysis (k = 4 MBCT, k = 7 MBSR, k = 5 ACT; k = 7 fibromyalgia, k = 5 irritable bowel syndrome, k = 1 chronic fatigue syndrome, k = 2 bodily distress, k = 1 medically unexplained symptoms). However, not all studies provided data for each of the relevant outcomes. The analyses revealed that "third wave" therapies were more effective than control conditions in reducing somatic symptom severity (k = 15, n = 1,100, g = -0.51, 95%CI -0.69; -0.32). Heterogeneity was moderate (I 2 = 52.8%, 95%CI 15.1 to 73.8). Effects for secondary outcomes were small to moderate with varying degrees of heterogeneity. We did not find differences between the different therapy approaches (mindfulness- vs. acceptance-based therapies); neither therapy dosis (i.e., total duration of therapy sessions) nor number of sessions were significant moderators of efficacy. The therapies addressing mindfulness and acceptance proved to be more effective than control conditions. Hence, they are promising treatment approaches for bodily distress. However, there is still need for research on which patient groups may benefit from these psychological approaches. https://osf.io/g7hby, identifier: 10.17605/OSF.IO/4RZGC.


Regulation of the GLUT4/muscle-fat glucose transporter mRNA in adipose tissue of insulin-deficient diabetic rats.
Previous studies have documented that streptozotocin-induced insulin deficiency results in a marked decrease in adipose tissue GLUT4 glucose transporter mRNA levels (Sivitz, W.I., DeSautel, S.L., Kayano, T., Bell, G.I., and Pessin, J.E. (1989) Nature 340, 72-74). In this study, nuclear run-on analysis performed on diabetic and insulin-treated diabetic rats demonstrated that the decrease in GLUT4 mRNA occurs via a diabetes-induced decrease in GLUT4 transcription rate. The decrease in GLUT4 mRNA levels could be prevented by treatment of the diabetic animals with the adenosine receptor agonist phenylisopropyl-adenosine (PIA). Under these conditions, PIA completely blocked the elevation of intracellular cAMP levels associated with insulin deficiency. Surprisingly, isolation of primary rat adipocytes from control animals resulted in a rapid decrease (approximately 20-fold) in GLUT4 mRNA levels by 24 h with a concomitant increase (approximately 70-fold) in GLUT1 mRNA levels. This rapid loss of GLUT4 expression did not correlate with changes in adipocyte cAMP levels and was not prevented by treatment of the cells with either insulin and/or PIA. These data demonstrate that the decrease in GLUT4 transcription induced by insulin deficiency in vivo predominantly results from an increase in intracellular cAMP levels. In contrast, although GLUT4 transcription also decreases in adipocytes when removed from their normal physiological environment, this occurs independent of changes in cAMP levels.


In vivo Study on the Corrosion Behavior of Magnesium Alloy Surface Treated with Micro-arc Oxidation and Hydrothermal Deposition.
To study the corrosion behavior of magnesium alloy surface treated with micro-arc oxidation and hydrothermal deposition in living animals. A magnesium oxide (MgO) layer was prepared on Mg alloy using micro-arc oxidation technology, and then a composite coating composed of magnesium hydroxide, hydroxyapatite, and MgO was coated on the MgO layer using the hydrothermal deposition method for 2 h and 24 h. Male 3-month-old white New Zealand rabbits (n = 48) weighting 2200-2300 g, were divided into four groups randomly. The prepared Mg alloy samples with composite coatings were implanted into the femoral medullary cavity of rabbits. For the Mg group, bare Mg samples without any treatment were implanted; for the MgO group, bare Mg samples undergoing MAO treatment were implanted; for the HT2h group, samples of the MgO group undergoing hydrothermal treatment (HT) for 2 h were implanted; and for the HT24h group, samples of group MgO undergoing HT for 24 h were implanted. Then the in vivo corrosion behaviors of implants were evaluated by X-ray observation, micro-CT analysis and serum Mg2+ examination. The X-ray showed that samples implanted in animals were decreased as time went by. The micro-CT showed that on the fourth week, the residual volume percentages (RVP) of samples of the Mg, MgO, HT2h, and HT24h groups were 72.81% ± 2.10%, 71.68% ± 1.49%, 81.14% ± 1.54%, and 82.04% ± 0.89%, respectively; on the eighth week, the RVP of four groups were 29.45% ± 1.06%, 41.82% ± 1.13%, 53.92% ± 0.37%, and 62.53% ± 2.06%, respectively; while on the 12th week, RVP were 8.45% ± 0.49%, 9.97% ± 0.75%, 37.09% ± 0.89%, 46.71% ± 1.87%. The RVP of the HT2h group and the HT24h group were higher than for the Mg group and the MgO group for all three time points (P < 0.05); the RVP for HT24h was higher than for HT2h at 8 and 12 weeks, and the differences were significant, indicating that the degradation of Mg alloy slowed down after composite coating. In addition, the composite-coated Mg alloy by 24-h hydrothermal treatment exhibited a slower degradation than that treated by 2 h. Serum Mg2+ concentration results showed that on the second week, the Mg2+ concentrations of the Mg, MgO, HT2h, and HT24h groups were 2.24 ± 0.10 mmol/L, 2.12 ± 0.07 mmol/L, 2.06 ± 0.11 mmol/L, and 2.15 ± 0.12 mmol/L, respectively. On the fourth week, these concentrations were 1.99 ± 0.33 mmol/L, 2.18 ± 0.06 mmol/L, 2.17 ± 0.09 mmol/L, and 2.13 ± 0.14 mmol/L, respectively. On the eighth week, the concentrations were 2.22 ± 0.09 mmol/L, 2.20 ± 0.17 mmol/L, 2.06 ± 0.11 mmol/L, and 2.14 ± 0.07 mmol/L, respectively. On the 12th week, the concentrations were 2.18 ± 0.04 mmol/L, 2.20 ± 0.08 mmol/L, 2.09 ± 0.02 mmol/L, and 2.16 ± 0.11 mmol/L. The combination of micro-arc oxidation and hydrothermal deposition can greatly improve the anti-corrosion behavior of Mg alloy, and Mg alloy coated with this composite coating is a promising biomaterial with a satisfactory degradation rate.


Heat inactivation of Salmonella spp. in fresh poultry compost by simulating early phase of composting process.
The purpose of this study was to determine the effect of moisture on thermal inactivation of Salmonella spp. in poultry litter under optimal composting conditions. Thermal inactivation of Salmonella was studied in fresh poultry compost by simulating early phase of composting process. A mixture of three Salmonella serotypes grown in Tryptic soy broth with rifampin (TSB-R) was inoculated in fresh compost with 40 or 50% moisture at a final concentration of c. 7 log CFU g(-1). The inoculated compost was kept in an environmental chamber which was programmed to rise from room temperature to target composting temperatures in 2 days. In poultry compost with optimal moisture content (50%), Salmonella spp. survived for 96, 72 and 24 h at 50, 55 and 60°C, respectively, as compared with 264, 144 and 72 h at 50, 55 and 60°C, respectively, in compost with suboptimal moisture (40%). Pathogen decline was faster during the come-up time owing to higher ammonia volatilization. Our results demonstrated that Salmonella spp. survived longer in fresh poultry compost with suboptimal moisture of 40% than in compost with optimal moisture of 50% during thermophilic composting. High nitrogen content of the poultry compost is an additional factor contributing to Salmonella inactivation through ammonia volatilization during thermal exposure. This research validated the effectiveness of the current composting guidelines on Salmonella inactivation in fresh poultry compost. Both initial moisture level and ammonia volatilization are important factors affecting microbiological safety and quality of compost product.


Determination of the titratable acidity and the pH of wine based on potentiometric flow injection analysis.
A FIA system using a pH-sensitive detector based on a graphite/quinhydrone/silicone composite electrode was applied to determine sequentially the titratable acidity and the pH of wine, as well as the sum of calcium and magnesium ions. For all measurements the same FIA configuration was used employing different carrier solutions. The results for the determination of acidity and pH are in good agreement with those obtained by classical potentiometric titrations and by pH measurements using a conventional glass electrode. The standard deviation was less than 1.5% for both kinds of measurements and the sample volume was 150 μL. The method allows about 40 determinations of titratable acidity per hour and 30 pH measurements per hour. The titration method can be adjusted to the legal requirements in USA and Europe.


Designed protein logic to target cells with precise combinations of surface antigens.
Precise cell targeting is challenging because most mammalian cell types lack a single surface marker that distinguishes them from other cells. A solution would be to target cells using specific combinations of proteins present on their surfaces. In this study, we design colocalization-dependent protein switches (Co-LOCKR) that perform AND, OR, and NOT Boolean logic operations. These switches activate through a conformational change only when all conditions are met, generating rapid, transcription-independent responses at single-cell resolution within complex cell populations. We implement AND gates to redirect T cell specificity against tumor cells expressing two surface antigens while avoiding off-target recognition of single-antigen cells, and three-input switches that add NOT or OR logic to avoid or include cells expressing a third antigen. Thus, de novo designed proteins can perform computations on the surface of cells, integrating multiple distinct binding interactions into a single output.


Disparity issues in coronary artery surgery.
Coronary artery disease is the third leading cause of mortality worldwide. Coronary artery surgery is an important treatment option. Certain groups such as people of color, those from lower socioeconomic backgrounds and women tend to have lower rates of receiving the surgery they need ( Fig. 1 ). Still there are disparities in treatment options for coronary artery disease among different groups, due to geographic location, economical situation, institutional tradition and sex. Through continued research, awareness and utilization of innovative technologies, we can improve access and equity in healthcare for all patients, including patients in need of coronary surgery.


The position of the crossed and uncrossed optic axons, and the non-optic axons, in the optic tract of the rat.
The position of the crossed and uncrossed optic axons, and of the non-optic axons, within the optic tract was determined in the adult hooded rat. Horseradish peroxidase histochemistry and lesion-induced degeneration of axonal profiles were independently used to study the position of the three relevant populations of axons within the optic tract. The boundaries of the optic tract are distinct at all but its caudomedial border, where it abuts the supra-optic commissures running parallel to the fibres of the optic tract. Labelling the crossed population of optic axons, or inducing their degeneration, both demonstrate a clear caudomedial border of the optic tract, although a number of optic axons stray out of the optic tract and course within the supra-optic commissures immediately caudomedial to the tract. The uncrossed optic axons are, as a population, positioned relatively deep in the optic tract, towards its dorsal border. A few occur at further ventral positions, but their density is greatly reduced there. There is also a very thin region along the dorsalmost edge of the optic tract free of uncrossed optic axons. The relative position of the uncrossed to the crossed optic axons is discussed in the context of the mammalian optic tract as a chronological map: spatial position in the tract may reflect temporal order of axonal arrival during early development. A large population of non-optic axons belonging to Gudden's commissure courses within the boundaries of the optic tract at a relatively ventral position. They are most frequent caudomedially, and are absent rostrolaterally. Hence, axons of the optic tract and Gudden's commissure are substantially intermingled in the caudomedial half of the optic tract. These non-optic axons greatly outnumber the uncrossed optic axons, and will consequently distort counts of uncrossed optic axons based on intact profiles that remain after removal of the opposite eye. However, they are still a minority in comparison to the crossed optic axons in this region.


[Surgical treatment of the Dumping-syndrome (author's transl)].
We observed 106 patients suffering from severe dumping syndrome after gastric resection. For remedying the authors performed Billroth-I reconstruction, the Sacharov-Henley operation, antiperistaltic interposition of a short jejunal segment and practiced a new method of their own: interposition of a long iliac segment. The results obtained are reported.


Progenitor competence: genes switching places.
Drosophila neural progenitor cells are competent to give rise to certain neuronal cell types only during a limited period of time. Kohwi et al. link the termination of early competence to changes in subnuclear organization of chromatin.


Diverse roles of hepatocyte growth factor activator inhibitor type 1 (HAI-1) in the growth of glioblastoma cells in vivo.
Hepatocyte growth factor activator inhibitor type-1 (HAI-1) is an integral-membrane proteinase inhibitor. In this study, we examined the effects of HAI-1 on human glioblastoma cells. Two glioblastoma cell lines (YKG-1, U251) were stably transfected with expression plasmid harboring mature membrane-form or truncated secreted-form HAI-1. Culture characteristics were not altered by the expression of HAI-1, whereas in vitro invasiveness of U251 was suppressed. On the other hand, the expression of membrane-form HAI-1 resulted in significantly enhanced tumorigenicity of both cell lines in vivo. In contrast, secreted-form HAI-1 did not promote the tumorigenicity. These results suggest that HAI-1 may play complex roles in progression of glioblastoma cells, and membrane-form HAI-1 may mediate an undefined important signaling in the cells.


[Changes in the spatial organization and structure of the smooth-muscle cells of the tunica media of the major arteries during lengthwise stretching in situ].
It has been shown that in vivo stretching of the arterial wall leads to the loss of cell-cell contacts between medial smooth muscle cells (SMC), and to the change in the cell cooperation type. It is accompanied by the increase in SMC proliferative activity, and by changes in their shape and phenotype, from the contractile to the synthetic one. The increase in the number of extracellular connective tissue structures occurs in the intercellular space.


Differential pulse voltammetry in brain tissue: III. Mapping of the rat serotoninergic raphe nuclei by electrochemical detection of 5-HIAA.
Differential pulse voltammetry using a new type of carbon fiber electrode, electrochemically treated, is described. The working electrode contains 3 pyrolytic carbon fibers, and passes more current, thus giving a greater sensitivity (with the PRG5 Tacussel polarographic system) than the original monofiber electrodes. It is now possible to investigate brain areas where the monofiber electrodes, working near the limit of PRG5 sensitivity, showed too small a signal. These electrodes have, in addition, better mechanical resistance and can be used (after trypsin cleaning and further electrochemical treatment) for several experiments. Electrochemical measurements made in the nucleus raphe dorsalis before and after treatment with p-chlorophenylalanine, reserpine, clorgyline and clorgyline followed by reserpine, suggest that as in the striatum 5-hydroxyindoleacetic acid (5-HIAA) is mainly responsible for peak 3. The map of the raphe system made with this technique is well correlated with the serotoninergic system of the raphe: the highest peak heights are recorded in the raphe dorsalis.


Risks of chronic steroid or immunosuppressive therapy on total shoulder arthroplasty patients.
Patients on chronic corticosteroids/immunosuppressants (SI) undergoing orthopaedic surgery are at an increased risk for surgical complications and worse outcomes. However, whether or not chronic preoperative SI use increases the risk for 30-day complications in patients undergoing primary total shoulder arthroplasty (SA) has yet to be explored. From 2006 to 2019, the National Surgical Quality Improvement Program (NSQIP) database was used to identify all patients who underwent primary SA (anatomic TSA and reverse TSA). Patients were stratified into two cohorts: chronic preoperative SI users and those without use. Bivariate and multivariate analyses were utilized in this study. Of the 26,979 patients who underwent primary SA, 25,656 (95.1%) patients did not have SI usage whereas 1323 (4.9%) patients had chronic preoperative SI usage. Following adjustment on multivariate analyses, compared to the non-SI usage cohort, patients who used SI had an increased risk of urinary tract infections (UTIs) (OR 1.87; p = 0.009) and septic shock (OR 7.14; p = 0.002). There were no differences in mortality between the two cohorts (p = 0.058). Chronic pre-operative SI use is an independent risk factor for septic shock and UTIs following primary SA. Surgeons and patients should be aware of these risks to better inform patient counseling and surgical decision making.


Prebiotically plausible oligoribonucleotide ligation facilitated by chemoselective acetylation.
The recent synthesis of pyrimidine ribonucleoside-2',3'-cyclic phosphates under prebiotically plausible conditions has strengthened the case for the involvement of ribonucleic acid (RNA) at an early stage in the origin of life. However, a prebiotic conversion of these weakly activated monomers, and their purine counterparts, to the 3',5'-linked RNA polymers of extant biochemistry has been lacking (previous attempts led only to short oligomers with mixed linkages). Here we show that the 2'-hydroxyl group of oligoribonucleotide-3'-phosphates can be chemoselectively acetylated in water under prebiotically credible conditions, which allows rapid and efficient template-directed ligation. The 2'-O-acetyl group at the ligation junction of the product RNA strand can be removed under conditions that leave the internucleotide bonds intact. Remarkably, acetylation of mixed oligomers that possess either 2'- or 3'-terminal phosphates is selective for the 2'-hydroxyl group of the latter. This newly discovered chemistry thus suggests a prebiotic route from ribonucleoside-2',3'-cyclic phosphates to predominantly 3',5'-linked RNA via partially 2'-O-acetylated RNA.


Antenatal and perinatal antecedents of moderate and severe spastic cerebral palsy.
Routinely collected perinatal morbidity data were abstracted for 204 cases of moderate and severe spastic cerebral palsy and 816 matched controls. Separate analyses were conducted for cases with birth-weight > or = 2,500 g and birth-weight < 2,500 g. The presence of a congenital abnormality was an important risk factor for cerebral palsy in both groups and further analyses were conducted after dividing the groups according to presence or absence of a congenital abnormality. In the < 2,500 g group, resuscitation needed was clearly identified as a risk factor for cerebral palsy in the group with no congenital abnormalities (adjusted OR=3.4; 95% CI=1.6-7.5) while in the group with congenital abnormalities, none of the risk factors were clearly associated with an increased risk of cerebral palsy. Among the cases with birth-weight > or = 2,500 g, intrauterine hypoxia/birth asphyxia was clearly associated with an increased risk of cerebral palsy (adjusted OR=18.1; 95% CI=1.8-186) in the group with no congenital abnormalities while in the group with congenital abnormalities, none of the factors were clearly associated with an increased risk of cerebral palsy.


Structural Requirements of Abscisic Acid (ABA) and its Impact on Water Flow During Radial Transport of ABA Analogues Through Maize Roots.
The effect of (+) (ABA) and (?)-abscisic acid and nine ABA metabolites, precursors or derivatives on radial water movement through maize roots, was investigated using a suction technique (Freundl and others 1998). (+)-ABA, (+)- and (?)-abscisyl aldehyde, (+)-8?-hydroxymethyl ABA, (+)-8?-methylene, and (+)-8?-acetylene ABA stimulated radial water transport. (?)-ABA, phaseic acid, and (+)-8?-acetylene methyl ABA were ineffective. ELISA analysis for ABA detected and apparent increase of free ABAxyl in xylem sap of excised root systems that were perfused with either (+)-abscisyl aldehyde, (+)-8?-methylene, (+)8?-acetylene-ABA, or ABA-glucose ester. The analogues (+)-8?-hydroxymethyl ABA and (?)-abscisyl aldehyde passed the cortex of maize roots without changing the ABAxyl. The data from this study permit conclusions about the structural requirements for hormonal regulation of hydraulic conductivity.


Nociceptive and antinociceptive responses to intrathecally administered nicotinic agonists.
Activation of spinal nicotinic receptors evokes a prominent algogenic response. Recently, epibatidine, a potent nicotinic agonist, was found to display an antinociceptive response after systemic administration. To examine the spinal component of this action, effects of three nicotinic agonists epibatidine, cytisine and nicotine--were given intrathecally (IT) and their antinociceptive activity was subsequently assessed. All agents elicited dose-dependent algogenic activity, characterized at lower doses by touch-evoked hyperactivity and at higher doses by intermittent vocalization and marked behavioral activity, with the rank order of potency being epibatidine > cytisine > nicotine. In addition, intrathecal epibatidine elicited a short-lasting, dose-dependent thermal antinociception. In contrast, the other nicotinic agonists at the highest usable dose failed to produce a significant antinociception. Mecamylamine, a nicotinic channel blocker, completely abolished the antinociceptive and algogenic responses of epibatidine. The competitive antagonist, alpha-lobeline, blocked both the analgesic and algogenic responses, but methyllycaconitine inhibited only the algogenic effects of epibatidine. Dihydro-beta-erythroidine, also a competitive antagonist, had no effect on the initial intense algogenic responses. The analgesic response to epibatidine was neither inhibited by naloxone nor by atropine. 2-Amino-5-phosphopentanoic acid, a competitive N-methyl-D-aspartate receptor antagonist, did not affect the analgesic response to intrathecal epibatidine or the intense initial algogenic response. Upon repeated administration (30-min interval), epibatidine (1 microg, IT) exhibited marked and rapid desensitization to both the analgesic and algogenic responses which recovered within 8 h. Pretreatment with two consecutive doses of cytisine (5 microg, IT, 30-min apart) inhibited the agitation and analgesic actions of intrathecal epibatidine. Thus, we contend that in addition to the typical nociceptive response elicited by spinal nicotinic agonists, intrathecal epibatidine also exhibits a pronounced but short-lasting antinociception. The analgesic and algogenic responses to intrathecal epibatidine may be mediated by distinct subtypes of spinal nicotinic receptors as suggested by the antagonist studies.


Ecosystem services mapping for green infrastructure planning-The case of Tehran.
Cities are responsible for more than 70% of carbon-related energy emissions. In order to cope with the widespread effects of these emissions-in addition to improving technology and the use of green energy-it is necessary to reduce the volume of emissions with the help of green spaces at the point of origin. Green spaces provide extensive ecosystem services that improve the quality of life and urban ecosystem livability. Due to the expansion of urban areas, the volume of ecological resources has declined and these resources have become more disconnected. The ongoing reduction of these ecological resources makes their management and planning a critical necessity. We need to evaluate the multiple benefits of urban ecosystem services for appropriate ecosystem management and integrate those ecological benefits with the social characteristics of neighborhoods. This paper provides some analysis, as the first step, to assess the ecosystem services (ES) provided by the green spaces (supply analyses) and the social-ecological needs in these spaces (needs analyses). Next, these assessments are used to find the urban areas with the highest social-ecological needs and with the lowest supply of green spaces in order to provide a reliable basis for the multi-functional planning of green spaces. These assessments are also used to analyze the status of services provided in the environment and the services needed to respond to the people's cultural and ecological needs.


Ethanol stimulates prostacyclin biosynthesis by human neutrophils and potentiates anti-platelet aggregatory effects of prostacyclin.
Previous reports on the direct effects of ethanol on human platelet aggregation function have been inconsistent. Ethanol ingestion produces vasodilation and raises intracellular cyclic AMP concentrations, effects similar to those of prostacyclin. We, therefore, hypothesized that ethanol may influence biosynthesis and/or bioactivity of prostacyclin. In our experiments, ethanol in concentrations up to 400 mg% had no consistent inhibitory effect on platelet aggregation in response to epinephrine, ADP, or combination of subthreshold concentrations of epinephrine plus ADP. However, ethanol in concentrations as low as 10 mg% potentiated the platelet aggregation inhibitory effects of prostacyclin. In addition, ethanol (20 mg%) decreased formation of thromboxane A2 in whole blood by 41% and stimulated formation of prostacyclin by 160% (both P less than 0.01). Additional studies using isolated human cells demonstrated synthesis of prostacyclin by neutrophils in the presence of platelets, and this neutrophil prostacyclin formation was enhanced in the presence of ethanol. These effects of alcohol in concentrations achieved after moderate intake may relate to the hemodynamic, biochemical, and cardioprotective effects of ethanol.


Microporous Carbon Nanofibers Derived from Poly(acrylonitrile-co-acrylic acid) for High-Performance Supercapacitors.
Carbon nanofiber (CNF)-based supercapacitors have promising applications in the field of energy storage. It is desirable, but remains challenging, to develop CNF electrode materials with large specific surface area (SSA), high specific capacitance (SC), and high power density, as well as excellent cycling stability and high reliability. Herein, acrylonitrile-acrylic acid copolymer P(AN-co-AA) was synthesized for the preparation of nitrogen-doped microporous CNFs. Thermal degradation of the AA segment leads to the formation of micropores that are distributed not only on the CNF surface, but also inside the material. The microporous structure and nitrogen content can be manipulated at the molecular level by adjusting the weight ratio between AN and AA, and the SSA and SC could reach as high as 1099 m2 g-1 and 156 F g-1 , respectively. After KOH activation, the activated CNFs have an extremely high SSA of 2117 m2 g-1 and SC of 320 F g-1 , which are among the highest values ever reported for electric double-layer supercapacitors with an alkaline electrolyte. Furthermore, the capacitance retention, which can be maintained at 99 % even after 16 000 cyclic tests, reveals outstanding durability and repeatability.


Molecular Epidemiology of Human Papillomavirus Infection Among Chinese Women With Cervical Cytological Abnormalities.
Virtually all invasive cervical cancers are caused by persistent genital human papillomavirus (HPV) infection. Therefore, HPV-based screening becomes an essential tool as one of the cervical prevention strategies to reduce the disease burden. Population-specific epidemiologic information on HPV infection among women with cytological abnormalities is essential to inform the strategy of HPV-based screening programme. The study also explored the presence of cutaneous HPV types (Beta-β and Gamma-γ) in cervical infections. A cross-sectional study on Chinese women aged ≥25 years who were referred to public specialist out-patient clinics for colposcopy or further management of cervical cytological abnormalities were recruited between 2015 and 2016 in Hong Kong. HPV was detected and typified by the novel PCR-based Next-Generation Sequencing (NGS) strategies. The overall HPV infection rate was 74% and detected in 222 of the 300 respondents, with the prevalence of cutaneous HPV infection being 2.3%. The overall prevalence of HPV infection among women with current cytological abnormalities was 79.1% (197/249). The age-specific prevalence of HPV (any-type HPV infection) among women with cytological abnormalities reached the first peak with 87.9% in the age group of 35-39 years and gradually declined to 56.0% at 55-59 years. While a second peak occurred at 65 years or above (92.9%). HPV58 (13.7%), HPV52 (11.7%), HPV53 (11.2%), HPV16 (10.0%), HPV18 (5.2%), and HPV51 (5.2%) were the top five high-risk HPV genotypes among women with cytological abnormalities. Any-HPV type infection was significantly associated with an abnormal cervical smear (OR = 3.7; 95% CI 2.0-7.1), and high-risk HPV infection was also significantly associated with an abnormal cervical smear (OR = 6.3; 95% CI 3.0-13.5). New evidence on the second peak of HPV infection at ≥65 years old suggests the necessity to review the current guideline for the cervical screening program extending to age 65 and above. Moreover, the high prevalence of two HPV genotypes-high-risk HPV51 and potential high-risk HPV53, among women with cytological abnormalities-suggests further research work is needed to confirm the contributory role of HPV51 and HPV53 in cervical cancer and the need for inclusion in the next generation of the HPV vaccine.


Genomic Resistance Patterns to Second-Generation Androgen Blockade in Paired Tumor Biopsies of Metastatic Castration-Resistant Prostate Cancer.
Patients with castration-resistant prostate cancer (CRPC) receive second-generation androgen-deprivation therapy, but frequently experience relapse or do not respond. Understanding the genetic mechanisms of resistance will help to identify strategies and biomarkers that are essential for the next line of therapy. We analyzed whole exomes of patient-matched pre- and post-treatment tumors from patients with CRPC. These patients had received the secondary androgen-deprivation therapy agent, abiraterone, which suppresses androgens to below castration levels, or enzalutamide, which competitively inhibits the key androgen signaling effector, androgen receptor. We observed that abiraterone-resistant tumors harbored alterations in AR and MYC, whereas enzalutamide-resistant tumors gained alterations in cell-cycle pathway genes, such as mutation in cyclin-dependent kinase N2A (CDKN2A) or amplification of CDK6. Experimentally, overexpressing cell-cycle kinases promoted enzalutamide resistance in androgen-sensitive LnCAP cells that was mitigated via CDK4/6 blockade-palbociclib and ribociclib. CDK4/6-mediated resistance observed in preclinical experiments suggests that CDK4/6 amplifications may sufficiently promote enzalutamide resistance in CRPC, and that these patients may respond to palbociclib or ribociclib. The overall observations suggest that, in genomically selected advanced CRPC, clinical strategies against abiraterone- or enzalutamide-resistant tumors may require treatment strategies that are tailored to the resistance mechanisms that are specific to those patient subpopulations.


Acute Distal Migration and Shortening of the Flow-Redirection Endoluminal Device: A Case Report.
The flow diverter (FD) is a promising device. Apart from two main complications, hemorrhagic and ischemic ones, stent migration is reportedly an unusual complication. In particular, distal migration of the FD has rarely been reported. We report a case of asymptomatic acute distal migration of the flow-redirection endoluminal device (FRED). A 50-year-old woman was incidentally diagnosed with an unruptured right internal carotid-ophthalmic artery aneurysm with a maximum diameter of 8.0 mm, and she subsequently underwent endovascular treatment with FRED. Based on the vessel diameter (3.8 mm proximal and 3.6 mm distal to the aneurysm), a 4.0-mm-diameter and 18-mm-long FRED was deployed without postoperative complications. However, on MRA 12 months after treatment, the aneurysm was not occluded; angiography showed distal migration of the FRED. The postoperative MRA and skull X-ray images were retrospectively reviewed to determine the period of the migration. The skull X-ray images and the signal loss area due to the FRED on MRA 1 day after the treatment had already demonstrated the migration of the FRED. In the second treatment, a 4.0-mm-diameter and 23-mm-long FRED was deployed in an overlapping fashion up to the proximal part of the carotid siphon. Prompt identification of distal migration of the FD without neurologic signs could be challenging. It is important to follow up meticulously with MRA and skull X-ray images after FD treatment for detecting stent migrations as early as possible.


Technological innovation of Continuous Glucose Monitoring (CGM) as a tool for commercial aviation pilots with insulin-treated diabetes and stakeholders/regulators: A new chance to improve the directives?
Civil aviation pilots who develop insulin-treated diabetes and want to renew a Commercial Pilot License (CPL) represent a medical, social and regulatory problem. This depends on justified concerns about hypoglycemia, the most threatening event for people who carry out jobs requiring a high level of concentration and reliability. This negatively affects social and working aspects of pilots' lives, who have a high profile and a high-cost professional qualification. It could be possible now to revise this attitude thanks to the availability of Continuous Glucose Monitoring (CGM) devices. CGM clearly showed to prevent hypoglycemic events in insulin-treated diabetic patients by allowing strict monitoring and trend prediction of glucose levels. By systematizing available data on such devices and present regulations in CPL issuance worldwide, our review can be used as handy tool for a fruitful discussion among the scientific community, national and international civil aviation regulators, stakeholders and pilots, aimed at evaluating the evidence-based opportunity to revise CPL issuance criteria for insulin-treated diabetic pilots. For the above-mentioned reasons, there are, among the regulatory administrations of Civil Aviation around the globe, several different approaches and limitations set for the subjects with insulin-treated diabetes who want to obtain, or renew, a CPL.


Oral health: The first step to sustainable development goal 3.
The 17 sustainable development goals (SDGs) were established by the United Nations Agenda 2030 plan of action to achieve peace, prosperity, and well-being for all by 2030. SDG 3 aims to ensure healthy lives and promote well-being for all at all ages. However, oral health is not specifically mentioned and targeted in SDG 3. Numerous studies have demonstrated a connection between oral health and general health. Oral disease and the common non-communicable diseases have the co-existing modifying risk factors. In addition, oral health is associated with social, economic, cultural, and environmental problems. By the implementation of oral health care, oral health promotion, and universal health coverage, these could not only be good for oral health but also benefit for general health and well-being. Taken together, oral health is the first step to SDG 3.


GPCR activation and GRK2 assembly by a biased intracellular agonist.
Phosphorylation of G-protein-coupled receptors (GPCRs) by GPCR kinases (GRKs) desensitizes G-protein signalling and promotes arrestin signalling, which is also modulated by biased ligands1-6. The molecular assembly of GRKs on GPCRs and the basis of GRK-mediated biased signalling remain largely unknown owing to the weak GPCR-GRK interactions. Here we report the complex structure of neurotensin receptor 1 (NTSR1) bound to GRK2, Gαq and the arrestin-biased ligand SBI-5537. The density map reveals the arrangement of the intact GRK2 with the receptor, with the N-terminal helix of GRK2 docking into the open cytoplasmic pocket formed by the outward movement of the receptor transmembrane helix 6, analogous to the binding of the G protein to the receptor. SBI-553 binds at the interface between GRK2 and NTSR1 to enhance GRK2 binding. The binding mode of SBI-553 is compatible with arrestin binding but clashes with the binding of Gαq protein, thus providing a mechanism for its arrestin-biased signalling capability. In sum, our structure provides a rational model for understanding the details of GPCR-GRK interactions and GRK2-mediated biased signalling.


Diagnostic accuracy of hand-assisted laparoscopy in predicting resectability of peritoneal carcinomatosis from gynecological malignancies.
Residual disease after excision surgery is the main prognostic factor in advanced ovarian cancer. Open surgery can delay neoadjuvant chemotherapy initiation. Therefore, a minimally invasive method for evaluating resectability would be of great interest. Aim of our study is to evaluate a new technique for assessing the extent of peritoneal carcinomatosis, combining manual palpation and standard laparoscopy. Prospective single-center study from October 2008 to January 2010. Patients with peritoneal carcinomatosis from gynecological malignancies were investigated by standard laparoscopy followed by laparoscopy plus manual palpation using Lapdisc(®) (Ethicon Inc.), at 43 abdominopelvic sites. When both techniques indicated resectability, standard cytoreduction surgery was performed via a midline laparotomy. The Fagotti, modified Fagotti, and Sugarbaker scores were computed. The diagnostic performance of each evaluation criterion was assessed by computing sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and area under the receiver-operating characteristic curves (ROC-AUCs). Of the 29 included patients, 18 (62.1%) were considered to have resectable disease. Fourteen (14/18, 77.8%) had macroscopically complete cytoreduction. With Lapdisc(®), sensitivity was 100%, specificity 73.3%, PPV 77.8%, NPV 100%, and ROC-AUC 0.87. Corresponding values were as follows: laparoscopy, 100%, 40%, 60.9%, 100%, and 0.70; Fagotti and modified Fagotti scores, 100%, 46.7%, 63.6%, 100%, and 0.73; Sugarbaker score, 64.3%, 93.3%, 90%, 73.7%, and 0.79. The ROC-AUCs showed significantly better performance of Lapdisc(®) than of standard laparoscopy (P = 0.008). Hand-assisted laparoscopy may perform better than laparoscopy alone for predicting the resectability of peritoneal carcinomatosis by increasing the number of sites evaluated.


Measurement of carbon storage in landfills from the biogenic carbon content of excavated waste samples.
Landfills are an anaerobic ecosystem and represent the major disposal alternative for municipal solid waste (MSW) in the U.S. While some fraction of the biogenic carbon, primarily cellulose (Cel) and hemicellulose (H), is converted to carbon dioxide and methane, lignin (L) is essentially recalcitrant. The biogenic carbon that is not mineralized is stored within the landfill. This carbon storage represents a significant component of a landfill carbon balance. The fraction of biogenic carbon that is not reactive in the landfill environment and therefore stored was derived for samples of excavated waste by measurement of the total organic carbon, its biogenic fraction, and the remaining methane potential. The average biogenic carbon content of the excavated samples was 64.6±18.0% (average±standard deviation), while the average carbon storage factor was 0.09±0.06g biogenic-C stored per g dry sample or 0.66±0.16g biogenic-C stored per g biogenic C.


Utility of history, physical examination, electrocardiogram, and chest radiograph for differentiating normal from decreased systolic function in patients with heart failure.
To determine whether clinical parameters alone can differentiate normal versus decreased systolic left ventricular function in patients with heart failure. Detailed clinical data were collected prospectively from 225 consecutive patients who were hospitalized with heart failure. Findings in patients with normal (ejection fraction > or =45%) or decreased (ejection fraction <45%) left ventricular function were compared. Systolic function was normal in 104 patients (46%) and decreased in 121 patients (54%). Patients with normal function were older (mean [+/- SD] age, 59 +/- 13 years vs. 54 +/- 13 years, P = 0.007) and more likely to be female (56% vs. 35%, P = 0.001), obese (body mass index > or =30 kg/m(2), 62% vs. 48%, P = 0.04), have marked systolic (> or =160 mm Hg, 50% vs. 27%, P <0.001) and diastolic (> or =110 mm Hg, 25% vs. 13%, P = 0.02) hypertension, and use calcium antagonists (34% vs. 14%, P = 0.001). Patients with decreased function were more likely to use alcohol (37% vs. 20%, P = 0.007), angiotensin-converting enzyme (ACE) inhibitors (85% vs. 62%, P <0.001), and digoxin (57% vs. 27%, P <0.001); and more likely to have tachycardia (51% vs. 32%, P = 0.004), rales (89% vs. 80%, P = 0.05), electrocardiographic left ventricular hypertrophy (42% vs. 22%, P = 0.002), left atrial abnormality (52% vs. 22%, P <0.001), or flow cephalization on chest radiograph (91% vs. 79%, P = 0.02). Only sex, tachycardia, and use of digoxin and ACE inhibitors were associated with ventricular function in multivariable analysis. However, the sensitivity, specificity, and predictive values for all clinical variables were low. Differences in clinical parameters in heart failure patients with decreased versus normal systolic function cannot predict systolic function in these patients, supporting recommendations that heart failure patients should undergo specialized testing to measure ventricular function.


Knowledge, attitudes and practices towards COVID-19: Community survey in southern Ethiopia.
Being well informed about the pandemic and how the virus spreads help to prevent and control the pandemic. Health authorities should monitor community practice to prevent the pandemic to identify gaps and minimize risks. This study was, therefore, designed to assess community knowledge, attitude and practices (KAP) related to COVID-19 prevention and its associated factors in urban settings. Community based cross-sectional study was conducted in southern Ethiopia. Twelve towns with high population density and mobility and 1162 participants were included in the study using multi-stage sampling. Semi-structured questionnaire was used to collect data. Mask use was assessed by observation while social distancing and handwashing were assessed by interview. Good practice was defined as wearing face mask, keeping social distance and handwashing. Data was collected by health professionals who have BSc and above (in nursing and public health) and analyzed using SPSS version 25. Descriptive statistics and binary logistic regression at 95% confidence level were performed. From 1162 respondents, about three fifths, 714 (61.4%), were females and 829 (64.2%) were married. The mean knowledge score was 69.7 (SD±17.87) while mean score for attitude was 80.6 (SD±6.29). Only about one third, 380 (32.7%), had good practice. Occupation, age and overall knowledge about COVID-19 and its prevention were associated with good COVID-19 prevention measures. Knowledge and attitude related to COVID-19 prevention and control were moderate while practice was low. The risk communication strategy should be strengthened using precautionary advocacy.


Changes in the Severity of Frailty Among Older Adults After 12 Months of Supervised Home-Based Physical Exercise: A Randomized Clinical Trial.
To investigate the effects of 12 months of physiotherapist-supervised, home-based physical exercise on the severity of frailty and on the prevalence of the 5 frailty phenotype criteria, using secondary analyses. Randomized clinical trial, with 1:1 allocation into 12-month home-based physical exercise, or usual care. The multicomponent exercise sessions (60 minutes) were supervised by the physiotherapist and included strength, balance, functional, and flexibility exercises twice a week at participants' homes. Home-dwelling older adults aged ≥65 years who were frail (meeting 3-5 criteria) or prefrail (1-2 criteria) according to frailty phenotype criteria. The severity of frailty (nonfrail, prefrail, or frail) was assessed using frailty phenotype criteria, and the prevalence of each frailty criterion (weight loss, low physical activity, exhaustion, weakness, and slowness) were assessed at baseline and at 12 months. Two hundred ninety-nine persons were included in the analyses, of whom 184 were prefrail and 115 were frail at baseline. Their mean age was 82.5 (SD 6.3) years, and 75% were women. There was a significant difference between the exercise and usual care groups' transitions to different frailty states from baseline to 12 months among those who at baseline were prefrail (P = .032) and frail (P = .009). At 12 months, the mean number of frailty criteria had decreased in the exercise group (-0.27, 95% CI -0.47, -0.08) and remained unchanged in the usual care group (0.01, 95% CI -0.16, 0.18; P = .042). The prevalence of the exhaustion (P = .009) and the low physical activity (P < .001) criteria were lower at 12 months in the exercise group than in the usual care group. The severity of frailty can be reduced through 12-month supervised home-based exercise training. Exercise should be included in the care of older adults with signs of frailty.


Malignant hyperthermia: molecular defects in membrane permeability.
Malignant hyperthermia (MH), a genetically inherited disorder of skeletal muscle, is due to molecular defect in membrane permeability. The alteration in membrane permeability is suggested to be due to enhanced phospholipase A2 activity which is responsible for the increased level in sarcoplasmic Ca2+. The excess Ca2+ is responsible for muscle hyper-rigidity and enhanced rate of glycolysis, resulting in a rapid rate of lactic acid production and a low pH in MH muscle.


Versatility of chitosan/BmNPV bacmid DNA nanocomplex as transfection reagent of recombinant protein expression in silkworm larvae.
To examine the feasibility of chitosan as an alternative transfection reagent candidate for protein expression in Bm5 cells and silkworm larvae using recombinant BmNPV bacmid DNA. Chitosan 100 and recombinant Bombyx mori nucleopolyhedrovirus (BmNPV) bacmid DNA, in amino group/phosphate group (N/P) ratios of 0.1-10, were used for formation of chitosan/DNA nanocomplexes. The chitosan/BmNPV bacmid DNA nanocomplexes showed higher specific activity of GFPuv-β1,3-N-acetylglucosaminyltransferase 2 (β3GnT2) fusion protein (GGT2) expressed in silkworm larvae than DMRIE-C, a conventional silkworm transfection reagent. In particular, the composition of chitosan and BmNPV bacmid DNA nanocomplexes formed by an N/P ratio of 8 or 10, respectively, showed the highest specific activity of β3GnT2 in the silkworm larvae hemolymph. In addition, three different proteins were expressed in silkworm larvae to the same extent using chitosan as that using DMRIE-C. This is the first finding that chitosan/BmNPV bacmid DNA nanocomplexes can rival the performance of commercially available transfection reagents for the expression of recombinant proteins in Bm5 cells and silkworm larvae.


Microtremor data and HVSR method in the kaligarang fault zone Semarang, Indonesia.
The data presented contains a collection of microtremor measurement data in the Kaligarang Fault zone, Indonesia. This study aims to present data regarding the structure and lithology of the rocks in the Kaligarang Fault zone. Data was obtained using a triaxial geophone VHL PS 2B and recorded with a data logger type GL 240 with a duration of 10 minutes. The data in this study are primary data taken using a single-station microtremor device with a total of 75 acquisition points in the Kaligarang Fault zone. This data can then be used in the analysis of the Horizontal to Vertical Spectral Ratio (HVSR) which will later produce the hv curve. The vp, vs, density and thickness profiles of each data were obtained from carrying out the inversion process using dinver.


Gene therapy for chronic granulomatous disease.
Mutations in phagocyte NADPH oxidase cause CGD, resulting in recurrent infections and granulomatous inflammation. Hematopoietic stem cell (HSC) transplant can cure CGD, but most patients lack a suitable donor. We conducted a clinical trial of ex vivo autologous HSC gene transfer as salvage therapy for three patients with X-linked CGD (X-CGD) who had incurable infection. Patients received nonmyeloablative busulfan conditioning and then were infused with amphotropic MFGS-gp91phox murine retrovirus vector-transduced autologous HSC, resulting in early gene marking and high-level oxidase function correction of 24%, 5%, and 4% of circulating neutrophils. Subjects #1 and #3 fully resolved infection and have maintained gene marking at 5 years at 0.7% and 0.03% oxidase-normal neutrophils. Subject #2 lost gene marking by 4 weeks and at 6 months succumbed to his infection. The two surviving subjects have normal blood count and bone marrow exam, with no evidence for clonal dominance of vector inserts. We conclude that gene therapy salvage treatment for severe infection unresponsive to conventional therapy can provide life-saving clinical benefit to CGD patients lacking a suitable donor. We are developing lentivectors for our next generation gene therapy of CGD. We are also exploring novel alternate approaches to gene therapy using zinc finger nuclease-mediated gene targeting of induced pluripotent stem cells derived from CGD patients.


Vasorelaxant and antihypertensive effects of methanolic fraction of the essential oil of Alpinia zerumbet.
Alpinia zerumbet is used in folk medicine in Brazil to treat hypertension. However, several pathways involved in the mechanism of vasorelaxation are still unclear. This study was designed to verify the antihypertensive effect of the methanolic fraction of the essential oil of A. zerumbet (MFEOAz) and to characterize its mechanism of action. The thoracic aortic rings from the Wistar rats were perfused in the organ chambers filled with Kreb's solution, where the tension of each ring was measured. The antihypertensive effect of MFEOAz was assessed in rats submitted to chronic hypertension by inhibition of nitric oxide synthesis by indirect measurement of blood pressure with indirect tail cuff method. MFEOAz relaxed phenylephrine and KCl-induced contraction of either endothelium-intact or endothelium-denuded rat aortic rings in a concentration-dependent manner. Pre-incubation with MFEOAz (100 and 300 μg/mL) in Ca(2+)-free Krebs solution attenuated phenylephrine- or caffeine-induced contraction. Pre-incubation with L-NAME, ODQ, wortmannin, atropine, indomethacin, catalase, SOD, TEA, 4-aminopyridine, glibenclamide, apamin, charybdotoxin, or iberiotoxin did not affect MFEOAz-induced relaxation. The intragastric administration of MFEOAz induced an antihypertensive effect. MFEOAz it seems inhibited the calcium influx via voltage-operated calcium channels and receptor-operated calcium channels, as well as inhibition of calcium mobilization from intracellular stores.


Evaluation of enzyme immunoassays in the diagnosis of camel (Camelus dromedarius) trypanosomiasis: a preliminary investigation.
Three enzyme immunoassays were used for the serodiagnosis of Trypanosoma evansi in camels in the Sudan in order to evaluate their ability to discriminate between infected and non-infected animals. Two assays were used for the detection of trypanosomal antibodies, one using specific anti-camel IgG conjugate and another using a non-specific Protein A conjugate. The third assay detected the presence of trypanosomal antigens using anti-T. evansi antibodies in a double antibody sandwich assay. Inspection of the frequency distribution of assay results suggested that the ELISA for circulating trypanosomal antibodies using specific antisera and the ELISA for circulating antigens can distinguish between non-infected camels and infected camels exhibiting patent infections or not. The ELISA using Protein A conjugate to bind non-specifically to camel immunoglobulin did not appear to discriminate between infected and non-infected animals.


Epidemiology of acutely decompensated systolic heart failure over the 2003-2013 decade in Douala General Hospital, Cameroon.
Acutely decompensated heart failure (HF) (ADHF) is a common cause of hospitalization and mortality worldwide. This study explores the epidemiology and prognostic factors of ADHF in Cameroonian patients. This was a retrospective study conducted between January 2003 and December 2013 from the medical files of patients followed at the intensive care and cardiovascular units of Douala General Hospital in Cameroon. Clinical, electrocardiographic, echocardiographic, and biological data were collected from 142 patients (58.5% men; mean age 58 ± 14 years) hospitalized for ADHF with reduced ejection fraction (HFrEF), whose left ventricular ejection fraction was <50%, or alternatively whose shortening fraction was <28%, both assessed by echocardiography. The commonest risk factors associated with HFrEF were hypertension (59.2%), diabetes mellitus (16.2%), tobacco use (14.1%), and dyslipidaemia (7.7%), respectively. The major causes of HF in hospitalized patients were hypertensive heart disease (40%, n = 57); hypertrophic cardiomyopathy (33.8%, n = 48); and ischemic heart disease (21.8%, n = 31). The most frequent comorbid conditions were atrial fibrillation (25.4%, n = 36) and chronic kidney disease (18.3%, n = 26). Major biological abnormalities included increased bilirubinemia >12 mg/L (87.5%, n = 124); hyperuricaemia >70 mg/L (84.9%, n = 121); elevated serum creatinine (65.6%, n = 93); anaemia (59.1%, n = 84); hyperglycaemia on admission >1.8 g/L (42.3%, n = 60); and hyponatraemia <135 mEq/L (26.8%, n = 38). At admission, 33.8% (n = 48) of patients had no pharmacological treatment for HF. The most frequently used therapies upon admission included furosemide (50%, n = 71), angiotensin-converting enzyme inhibitors (ACEIs; 40.1%, n = 57); spironolactone (35.2%, n = 50); digoxin (26%, n = 37); beta-blockers (17.7%, n = 25); angiotensin-receptor blockers (ARBs; 7%, n = 10); and nitrates (7.0%). The overall in-hospital mortality rate was 20.4%. Factors associated with poor prognosis were systolic blood pressure <90 mmHg [odds ratio (OR) 3.88; confidence interval (CI) 1.36-11.05, P = 0.011], left ventricular ejection fraction <20% (OR 7.48; CI 2.84-19.71, P < 0.001), decreased renal function (OR 1.03; CI 1.00-1.05, P = 0.026), dobutamine use for cardiogenic shock (OR 2.74;CI 1.00-7.47, P = 0.049), pleural fluid effusion (OR 3.46; CI 1.07-11.20, P = 0.038), and prothrombin time <50% (OR 3.60; CI 1.11-11.68, P = 0.033). The use of ACEIs/ARBs was associated with reduced in-hospital mortality rate (OR 0.17; CI 0.02-0.81, P = 0.006). Hypertensive heart disease, hypertrophic cardiomyopathy, and ischemic heart disease are the commonest causes of HF in this Cameroonian population. ADHF is associated with high in-hospital mortality in Cameroon. Hypotension, severe left ventricular systolic dysfunction, renal function impairment, and dobutamine administration were associated with worst acute HF outcomes. ACEIs/ARBs use was associated with improved survival.


Stressors and development: a reciprocal relationship.
In this article we have attempted to delineate the importance of developmental levels in a young person's response to stressors and, conversely, the effect of stressors on levels of development. In so doing, we isolated specific lines of development from their context. We neglected the important roles of rewards and punishments, permissions and prohibitions, family and community dynamics, values, stories and myths. Even in this simplified schema, we have not addressed the importance of protective and risk factors, neither of which are found in isolation; but all of these issues are the subject of articles elsewhere in this issue.


[Major malformation syndrome and apparently balanced chromosomal abnormality: holoprosencephaly and 5p; 12q translocation].
Observation of holoprosencephaly associated to chromosomic aberration (balanced translocation 5p; 12q); genetic council may be difficult in case of familial translocation.


Cystine/cysteine metabolism in cultured Sf9 cells: influence of cell physiology on biosynthesis, amino acid uptake and growth.
Spodoptera frugiperda (Sf9) insect cells proliferate in a cystine-free medium, with the same growth rate, reaching the same final cell density, as in a cystine-containing medium, provided that the inoculum is taken from a pre-culture sufficiently early, at 47-53 h. With an inoculum from a 103 h culture an extended lag phase accompanied by cell death was observed during the first 50 h of cystine-free culture, even though the culture had been adapted to cystine-free conditions for 10 passages. Cystine-free cultures seeded with a 103 h inoculum had lower growth rates and reached lower final cell densities than corresponding cystine-supplied cultures. Cysteine biosynthesis occurs from methionine via the β-cystathionine pathway. More methionine was consumed by the cells in cystine-free media, and cystathionine was secreted when methionine and cystine were supplied in excess. The data suggest that cysteine biosynthesis is up-regulated in proliferating cells but down-regulated when the cells enter the stationary phase.In cultures supplied with cystine (10-100 mg 1(-1)), the specific uptake rate and total consumption of cystine, as well as the uptake of glutamate, glutamine and glucose increased with increasing cystine concentrations. These results are interpreted in view of system x (c) (-) , a concentration dependent amino acid transporter. Similarly, the consumption of amino acids transported by system L (ile, leu, val, tyr) was enhanced in cystine-containing cultures, as compared to cystine-free cultures. Uptake of cystine, methionine and system L amino acids ceases abruptly in all cultures, even before growth ceased. The specific growth rate starts to decline early during the growth phase, but this growth behaviour could not be correlated to the depletion of nutrients. We therefore propose that the observed growth pattern is a result of (auto)regulatory events that control both proliferation and metabolism.


Approaches to fast MR imaging.
Fast MR scanning may be accomplished through a number of strategies as discussed below. Each technique accomplishes improvements in scan time at the expense of signal and noise, spatial resolution, contrast resolution or other imaging artifacts. The scanning strategies discussed are in a variety of stages of clinical implementation, although several are already in wide spread use. All the existing techniques offer improvements in scan time, but they are still far from the theoretical limits imposed by the physics of MR scanning and further reduction in MR scanning time maybe expected in the future.


Evaluation on the generalization of a learned convolutional neural network for MRI reconstruction.
Recently, deep learning approaches with various network architectures have drawn significant attention from the magnetic resonance imaging (MRI) community because of their great potential for image reconstruction from undersampled k-space data in fast MRI. However, the robustness of a trained network when applied to test data deviated from training data is still an important open question. In this work, we focus on quantitatively evaluating the influence of image contrast, human anatomy, sampling pattern, undersampling factor, and noise level on the generalization of a trained network composed by a cascade of several CNNs and a data consistency layer, called a deep cascade of convolutional neural network (DC-CNN). The DC-CNN is trained from datasets with different image contrast, human anatomy, sampling pattern, undersampling factor, and noise level, and then applied to test datasets consistent or inconsistent with the training datasets to assess the generalizability of the learned DC-CNN network. The results of our experiments show that reconstruction quality from the DC-CNN network is highly sensitive to sampling pattern, undersampling factor, and noise level, which are closely related to signal-to-noise ratio (SNR), and is relatively less sensitive to the image contrast. We also show that a deviation of human anatomy between training and test data leads to a substantial reduction of image quality for the brain dataset, whereas comparable performance for the chest and knee dataset having fewer anatomy details than brain images. This work further provides some empirical understanding of the generalizability of trained networks when there are deviations between training and test data. It also demonstrates the potential of transfer learning for image reconstruction from datasets different from those used in training the network.


Pediatric primary diffuse large cell lymphoma of bone with t(3;22)(q27;q11).
A child with a primary lymphoma of bone (PLB) with a t(3;22)(q27;q11) is described. An 11-year-old boy had a 5-week history of back pain and a destructive lesion of S1 that contained an epidural component. Histologic evaluation of a biopsy confirmed the diagnosis of diffuse large B-cell non-Hodgkin lymphoma. Karyotypic analysis disclosed a t(3;22)(q27;q11), but the amount of tumor tissue was insufficient for molecular studies of the BCL-6 gene. The patient remains free of disease 4 years after completion of intensive systemic chemotherapy and intrathecal chemotherapy. The lymphoma in the patient described in this report is highly unusual because of the coexistence of pediatric PLB and a t(3;22)(q27q11).


Genotoxicity testing of aqueous extracts of Mahwangyounpae-tang, a polyherbal formula.
Mahwangyounpae-tang (MT), consisting of 22 types of herbal extracts has been used for thousands of years in Korean traditional medicine for the oral treatment of respiratory diseases including asthma. As part of a safety evaluation of MT extracts for use in asthma, the potential genotoxicity of an aqueous MT extract was evaluated using the standard battery of tests (bacterial reverse mutation assay; chromosomal aberrations assay; mouse micronucleus assay) recommended by Korea Food and Drug Administration (KFDA). The MT extract was determined not to be genotoxic under the conditions of the reverse mutation assay, chromosomal aberrations assay and mouse micronucleus assay. Use of MT is presently expected to be safe, as anticipated intake is small compared to the doses administered in the genotoxicity assays and may, after further toxicity research, prove to be a useful anti-asthma agent.


Blockade effect of mu and kappa opioid antagonists on the anti-nociception induced by intra-periaqueductal grey injection of oxytocin in rats.
Intra-periaqueductal grey (PAG) injection of 1 nmol of oxytocin induced significant increases in hindpaw withdrawal latency (HWL) to thermal and mechanical stimulation in rats. The anti-nociceptive effect of oxytocin was attenuated significantly by subsequent intra-PAG injection of the mu opioid antagonist beta-funaltrexamine (beta-FNA) and the kappa opioid antagonist nor-binaltorphimine (nor-BNI), but not by the delta antagonist naltrindole. The results demonstrated that mu and kappa opioid receptors, not delta receptors, were involved in the oxytocin-induced anti-nociception in PAG of rats.


Differential effects of dopamine and psychoactive drugs on dopamine transporter phosphorylation and regulation.
The dopamine transporter (DAT) is a phosphoprotein whose activity and phosphorylation state are acutely regulated by both protein kinase C (PKC) and substrate transport. DAT is a major site of action for psychostimulant and therapeutic drugs that either block transport or are transported substrates, but the effects of such drugs on DAT phosphorylation and regulation are not well understood. To examine these issues we subjected rDAT LLC-PK(1) cells to acute in vitro pretreatments with the endogenous, psychostimulant, and therapeutic compounds dopamine (DA), (-)-cocaine, 2 beta-carbomethoxy-3beta-(4-fluorophenyl)tropane (beta-CFT), GBR 12909, mazindol, and methylphenidate (MPH), in the presence or absence of the PKC activator phorbol 12 myristate 13 acetate (PMA), followed by analysis of DAT metabolic phosphorylation and transport activity. Basal phosphorylation of DAT was not affected by any of the uptake blockers tested, and PMA-stimulated phosphorylation was not affected by cocaine, beta-CFT, mazindol or MPH, but was strongly suppressed by GBR 12909. Pretreatment of cells with cocaine or MPH had no effect on subsequent DA transport activity or the extent of PMA-induced transport down-regulation, whereas GBR 12909 inhibited PMA-induced DAT internalization. These findings indicate that these DAT phosphorylation and down-regulation properties are unaffected by some classes of uptake blocking drugs, but that differential regulatory effects may be exerted by GBR compounds. Pretreatment of cells with DA had no obvious effect on basal or PMA-stimulated DAT phosphorylation but led to cocaine-blockable transport down-regulation. DA-induced down-regulation was blocked by the PKC inhibitor bisindoylmaleimide I and was not additive with down-regulation induced by PMA, consistent with PKC serving as a common step and point of integration for these DA and PMA induced processes. The results of this study provide information on the potential for endogenous and psychoactive compounds to modulate or be modulated by DAT phosphorylation-mediated regulatory mechanisms that may contribute to drug behavioral or therapeutic properties.


Production and secretion of platelet-derived growth factor AB by cultured human keratinocytes: regulatory effects of phorbol 12-myristate 13-acetate, etretinate, 1,25-dihydroxyvitamin D3, and several cytokines.
Platelet-derived growth factor (PDGF) is a potent mitogen for several mesenchymal cells and plays an important role in wound repair. Three PDGF isoforms, PDGF-AA, PDGF-BB, and PDGF-AB, have been found to be generated in various tissues. PDGF-AB production by normal human keratinocytes (NHKs), by human squamous cell carcinoma cell line (HSC-1) cells, and by human dermal fibroblasts (HDFs) was studied in the presence of agents which influence cell growth. Both NHKs and HSC-1 cells spontaneously produced and secreted PDGF-AB. NHKs grown in keratinocyte growth medium produced more PDGF-AB than did those grown in keratinocyte basic medium. Phorbol 12-myristate 13-acetate inhibited PDGF-AB production in NHKs but promoted its production in HSC-1 cells. 1,25-dihydroxyvitamin D3 up-regulated PDGF-AB production, whereas etretinate did not. High levels of calcium in the culture medium induced little change in cellular PDGF-AB levels. Prostaglandin E1 slightly inhibited PDGF-AB production, transforming growth factor beta 1 promoted PDGF-AB production and interferon-gamma, interleukin-1 alpha, and tumor necrosis factor-alpha failed to exert any influence at all. Cultured HDFs did not produce any detectable PDGF-AB. These results suggest that keratinocytes are a major source of cutaneous PDGF and that this factor may therefore play an important role in wound repair and in certain proliferative skin diseases.


Altered subgroups of regulatory T cells in patients with primary Sjögren's syndrome.
Primary Sjögren syndrome (pSS) is a systemic autoimmune inflammatory disease. Up to now, the role of regulatory T cells (Tregs) and their subgroups in pSS is still in controversial. In this study we tried to elucidate the roles of Tregs and its subgroups in pSS. Total 43 pSS patients and 23 health persons as control were enrolled in this study. We grouped the pSS patients according to the anti-SSa/SSb and the EULAR Sjögren's syndrome disease activity index (ESSDAI). Among the 43 pSS patients, 14 patients were followed after treatment. The percentage of rTregs (resting Treg cells) among Tregs was increased in the pSS group, and decreased after treatment. In the high disease activity subpopulation (ESSDAI ≥ 5), the percentage of rTregs among Tregs decreased after treatment. On the contrary, the percentage of aTregs (activated Treg cells) increased after treatment. It was in an inverse correlation between the percentage of aTreg and rTreg in pSS patients. The Tregs are co-cultured with responder T cells. Tregs from pSS patients showed poorer proliferation inhibitory function. Our results show that the percentages of Tregs and their subgroups altered in pSS patients. The percentage of aTreg and the percentage of rTreg have an inverse correlation in pSS patients. Compared to the control group, the percentage of rTregs among Tregs was increased in the pSS patients and decreased after the treatment. Our study also showed that The Tregs from pSS patients may have poorer inhibitory functions.


Comment on Bunmaprasert et al. Reducible Nonunited Type II Odontoid Fracture with Atlantoaxial Instability: Outcomes of Two Different Fixation Techniques. Int. J. Environ. Res. Public Health 2021, 18, 7990.
I read with great interest the paper of Bunmaprasert et al. [...].


Protein damage by photoproducts of merocyanine 540.
Exposure of certain photoactive dyes to light prior to their use in biological systems (preactivation) has been shown to result in formation of long-lived cytotoxic photoproducts. The cytotoxic species responsible for the biological activity of preactivated merocyanine 540 (pMC540) appears to be a hydroperoxide generated by oxidation of ground-state dye by singlet molecular oxygen, formed via energy transfer from triplet excited-state dye to oxygen. A positive correlation (r = .93) exists between the levels of hydroperoxides and percent of tumor cells killed upon exposure to pMC540. Exposure of bovine serum albumin (BSA) (0.5 mg/mL) to pMC540 (0.2 mg/mL-1 mg/mL) results in loss of tryptophan fluorescence and 345 nm emission, suggesting a probable role of either hydroxyl (.OH) or .OH + superoxide (O2-). Polyacrylamide gel electrophoresis indicates fragmentation of treated BSA. Aggregation of pMC540-treated BSA is not detected. Bityrosine production is not observed. A dose-dependent decrease in BSA solubility is observed in treated samples, suggesting an increase in hydrophobicity. Amino acid analysis of BSA treated with pMC540 shows loss of some amino acids residues. The data presented here suggest that photoproducts of MC540 derived via the process of preactivation may mediate their effect (at least in part) by reactive oxygen species.


Neoareolar wise pattern reduction in patients requiring central partial mastectomy.
Oncoplastic surgery integrates breast cancer resection with tissue transfer techniques to preserve breast cosmesis. With the novel methods developed in the oncoplastic movement, we are capable of performing larger resections with clear margins while minimizing the cosmetic deformity caused by more traditional surgical techniques. Central and retroareolar breast cancers continue to be a cosmetic challenge because removal of the central portion of the breast can be particularly deforming. An inferior pedicle Wise pattern reduction mammoplasty is performed. The inferior pedicle is de-epithelized except for a circular disc of skin superiorly, which will become the neoareola. The breast cancer is removed along with the nipple-areolar complex (NAC). Part of the NAC may be preserved if tumor resection can be performed with sufficient margins. A standard reduction is performed, removing more tissue as indicated by cosmetic need. The reduction is completed in standard fashion using the neoareola as a replacement for the previously removed NAC. The video demonstrates the feasibility of this technique, highlighting both preservation of breast shape and contour, and creation of a substitute for the NAC. Complex reduction techniques have been reported in the literature as feasible options for breast conservation surgery. The neoareolar Wise pattern reduction mammoplasty offers an option that allows for oncologically sound cancer surgery while simultaneously preserving cosmesis.


Improving end-of-life outcomes in nursing homes by targeting residents at high-risk of mortality for palliative care: program description and evaluation.
The objectives were (1) to describe the Making Advance Planning a Priority (MAPP) program, a program designed to identify nursing home (NH) residents at high risk of death and (2) to evaluate end-of-life care outcomes for NH residents at high risk of death. PROGRAM DESCRIPTION and evaluation using a retrospective chart review before and after implementation of the MAPP program. NH residents who died 1 year before program implementation compared to NH residents who died 1 year after program implementation (n = 72). The MAPP program was designed to: (1) identify residents at high risk of death, (2) inform the attending physician of the residents' mortality risk, (3) obtain palliative care or, if the prognosis was 6 months of less, a hospice consultation, and (4) improve advance care planning documentation. Site of death (hospital versus nursing home), presence of an advance directive, presence of an order for cardiopulmonary resuscitation, proportion of NH residents with palliative care and/or hospice consultation prior to death, length of palliative care and/or hospice services before death. Following implementation of the MAPP program, we hypothesized that there would be a reduction in hospitalizations, an increase in hospice/palliative care referrals, an increase hospice/palliative care length of service, an increase the utilization of advance directives, but no difference in days in the hospital before death. Following implementation of the MAPP program intervention, residents were less likely to die in the hospital (48.2% preintervention versus 8.9% postintervention, p < 0.0001). Every resident who died after implementation of the MAPP program had an advanced directive (p = 0.03). Residents were more also more likely to get palliative care referrals (7.4% preintervention versus 31.1% postintervention, p = 0.02). An intervention designed to address the end-of-life needs of NH residents at high risk of death improves end-of-life outcomes with a reduction in terminal hospitalizations, an increase in palliative care referrals and improvement of advance directive completion.


Developmental changes in rat adrenocortical cell membrane potential.
Resting membrane potentials of zona fasciculata-reticularis cells of the rat adrenal gland varied with age. The mean membrane potentials of newborn rat adrenal cells was -56.4 +/- 0.7 mV in the first week of life. The mean potential increased slightly to -61.9 +/- 0.8 mV in the second week and then decreased with age to a mean of -38.5 +/- 0.8 mV in 25--50 week old rats and of -25.9 +/- 1.9 mV in 100 week old rats. The changes in membrane potential may correlate with the indices of adrenocortical growth and activity.