Radioactive iodine in the management of medullary carcinoma of the thyroid.
Although it is generally accepted that medullary thyroid cancer (MTC) cells do not take up iodine, there are reports indicating that this can occur. Additionally, the potential for radioactive iodine (RAI) to reduce the risk of recurrence within the thyroid bed following thyroid remnant ablation in MTC is uncertain. A systematic review was therefore undertaken. Studies of patients with MTC of any age or stage receiving RAI, either as adjuvant postoperative treatment or primary treatment for unresectable disease, or as treatment for recurrent or metastatic disease were eligible for inclusion. Randomised and non-randomised studies were identified by electronic searching of Medline and Embase databases. A risk of bias assessment (ROBINS-I) was carried out for each study. Outcome measures sought included overall survival, locoregional relapse-free survival, rates of locoregional recurrence, and changes in serum calcitonin. A protocol was registered with PROSPERO before the systematic review was undertaken. There were no randomised studies. Ten non-randomised studies (525 patients) and ten case reports (21 patients) met the inclusion criteria, with all studies containing a high risk of bias. There were case reports reporting responses to RAI, both as adjuvant treatment and for recurrent/metastatic disease. The proportion of metastatic or recurrent MTC which take up iodine remains unknown. A possible role of RAI ablation for patients with localised MTC and raised calcitonin post-thyroidectomy should be explored. Although there is insufficient data to recommend changes to current treatment policies, this review suggests avenues for further research.


A Comparison of Adrenalectomy and Eplerenone on Vascular Function in Patients with Aldosterone-producing Adenoma.
It remains unclear whether adrenalectomy has more beneficial effects than treatment with a mineralocorticoid receptor antagonist on vascular function in patients with aldosterone-producing adenoma (APA). The aim of this study was to compare the effects of adrenalectomy and treatment with eplerenone on vascular function in patients with APA. Flow-mediated vasodilation (FMD), as an index of endothelium-dependent vasodilation, and nitroglycerine-induced vasodilation (NID), as an index of endothelium-independent vasodilation, were measured to assess vascular function before and after a 3-month treatment with eplerenone and at 3 months after adrenalectomy in 23 patients with APA. Flow-mediated vasodilation and NID after adrenalectomy were significantly higher than those before treatment with eplerenone (5.4 ± 2.6% vs 2.7 ± 1.9% and 14.8 ± 4.7% vs 9.6 ± 4.6%, P < 0.01, respectively) and those after treatment with eplerenone (5.4 ± 2.6% vs 3.1 ± 2.3% and 14.8 ± 4.7% vs 11.0 ± 5.3%, P < 0.01 and P = 0.03, respectively), while treatment with eplerenone did not alter FMD and NID compared with those before treatment with eplerenone. After adrenalectomy, the increase in FMD and NID were significantly correlated with a decrease in plasma aldosterone concentration and a decrease in the aldosterone-renin ratio. There were no significant relationships between FMD and changes in other parameters or between NID and changes in other parameters. Adrenalectomy, but not treatment with eplerenone, improved vascular function in patients with APA. Adrenalectomy may be more effective than treatment with eplerenone for reducing the incidence of future cardiovascular events in patients with APA. Clinical Trial Information: URL for the clinical trial: http://UMIN; Registration Number for the clinical trial: UMIN000003409.


Characteristics and health impacts of volatile organic compounds in photocopy centers.
This study investigates the indoor air quality of typical photocopy centers in Taiwan to evaluate the human health risk following inhalation exposure. Both personal and area samplings were conducted at seven photocopy centers in the Tainan area from July 2002 to March 2003, which covered both summer and winter seasons in Taiwan. The benzene, toluene, ethylbenzene, xylenes, and styrene (BTEXS) measurements indicated no difference between personal and area samplings (P>0.05) and found that air conditioning improves indoor air quality. The additive factor at each photocopy center was significantly below 1.0, based on the current BTEXS permissible exposure limits in Taiwan. However, the mean benzene and styrene levels in the current study were 138 and 18 times, respectively, higher than those in another study conducted in the United States. Comparison of mass ratios of BTEXS with those of several chamber studies revealed that the photocopier is not the only volatile organic compound (VOC) source in photocopy centers. The lifetime cancer and noncancer risks for workers exposed to VOCs were also assessed. Results show that all seven centers in this study had a lifetime cancer risk exceeding 1x10(-6) (ranging from 2.5x10(-3) to 8.5x10(-5)). Regarding noncancer risk, levels of toluene, ethylbenzene, xylenes, and styrene were below the reference levels in all photocopy centers; however, the hazard indices for all still exceeded 1.0 (range 26.2-1.8) because of the high level of benzene in the photocopy centers.


Prompt closure versus gradual weaning of external ventricular drainage for hydrocephalus following aneurysmal subarachnoid haemorrhage: Protocol for the DRAIN randomised clinical trial.
Aneurysmal subarachnoid haemorrhage (aSAH) is a life-threatening disease caused by rupture of an intracranial aneurysm. A common complication following aSAH is hydrocephalus, for which placement of an external ventricular drain (EVD) is an important first-line treatment. Once the patient is clinically stable, the EVD is either removed or replaced by a ventriculoperitoneal shunt. The optimal strategy for cessation of EVD treatment is, however, unknown. Gradual weaning may increase the risk of EVD-related infection, whereas prompt closure carries a risk of acute hydrocephalus and redundant shunt implantations. We designed a randomised clinical trial comparing the two commonly used strategies for cessation of EVD treatment in patients with aSAH. DRAIN is an international multi-centre randomised clinical trial with a parallel group design comparing gradual weaning versus prompt closure of EVD treatment in patients with aSAH. Participants are randomised to either gradual weaning which comprises a multi-step increase of resistance over days, or prompt closure of the EVD. The primary outcome is a composite outcome of VP-shunt implantation, all-cause mortality, or ventriculostomy-related infection. Secondary outcomes are serious adverse events excluding mortality, functional outcome (modified Rankin scale), health-related quality of life (EQ-5D) and Fatigue Severity Scale (FSS). Outcome assessment will be performed 6 months after ictus. Based on the sample size calculation (event proportion 80% in the gradual weaning group, relative risk reduction 20%, type I error 5%, power 80%), 122 patients are needed in each intervention group. Outcome assessment for the primary outcome, statistical analyses and conclusion drawing will be blinded. ClinicalTrials.gov identifier: NCT03948256.


Worsening of Seizures After Asparagine Supplementation in a Child with Asparagine Synthetase Deficiency.
Asparagine synthetase deficiency is an autosomal recessive neurometabolic disorder characterized clinically by severe congenital microcephaly, global developmental delay, intractable epilepsy, and motor impairment in the form of spastic quadriparesis. Diagnosis is confirmed by findings of low cerebral spinal fluid or plasma asparagine in addition to a mutation of the subsequently in ASNS gene. There is no documented trial of asparagine as a treatment for this disorder. We present a child with asparagine synthetase deficiency whose mental status improved slightly from a vegetative state to a minimally conscious state after starting asparagine supplementation. He subsequently became irritable, developed sleep disturbance, and experienced worsening seizures, requiring discontinuation of the asparagine supplements. Asparagine supplementation may be not effective in controlling the seizures in asparagine synthetase deficiency, and it is likely to make them worse.


Development and validation of an LC-MS/MS method for quantification of favipiravir in human plasma.
Favipiravir (FVP) is a broad-spectrum antiviral that selectively inhibits viral RNA-dependent RNA polymerase, first trialled for the treatment of influenza infection. It has been shown to be effective against a number of RNA virus families including arenaviruses, flaviviruses and enteroviruses. Most recently, FVP has been investigated as a potential therapeutic for severe acute respiratory syndrome coronavirus 2 infection. A liquid chromatography tandem mass spectrometry method for the quantification of FVP in human plasma has been developed and validated for use in clinical trials investigating favipiravir as treatment for coronavirus disease-2019. Samples were extracted by protein precipitation using acetonitrile, using 13C, 15N- Favipiravir as internal standard. Elution was performed on a Synergi Polar-RP 150 × 2.1 mm 4 µm column using a gradient mobile phase programme consisting of 0.2% formic acid in water and 0.2% formic acid in methanol. The assay was validated over the range 500-50,000 ng/mL; this method was found to be precise and accurate and recovery of FVP from the matrix was high. Stability experiments confirmed and expanded on the known stability of FVP, including under heat treatment and for a period of 10 months at - 80 °C.


Building Perinatal Case Manager Capacity Using Quality Improvement.
Improving breastfeeding rates among Black women is a potential strategy to address disparities in health outcomes that disproportionately impact Black women and children. This quality improvement (QI) initiative aimed to improve perinatal case manager knowledge and self-efficacy to promote breastfeeding among Black, low-income women who use services through Boston Healthy Start Initiative. QI methodology was used to develop and test a two-part strategy for perinatal case managers to promote and support breastfeeding. A positive change was observed in infant feeding knowledge and case manager self-efficacy to promote breastfeeding. Among the 24 mothers participating in this QI initiative, 100% initiated and continued breastfeeding at 1 week postpartum, and 92% were breastfeeding at 2 weeks postpartum.


Reversible obstructive hydrocephalus from hypertensive encephalopathy.
Diffuse edema involving the posterior fossa may be seen with hypertensive encephalopathy and has rarely been reported to cause hydrocephalus. We present three such cases and review the literature to better delineate this uniquely reversible syndrome. Case reports and review of literature. Three patients with hypertensive encephalopathy presented to our institutions with clinical and radiographic features of obstructive hydrocephalus associated with brainstem and cerebellar edema. This required transient external drainage of cerebrospinal fluid (CSF) in two of the three patients. However, with recognition of this unusual syndrome and aggressive management of elevated blood pressure, both edema and hydrocephalus resolved. All patients made complete recoveries and did not require permanent CSF shunting. A review of the literature yielded 15 additional case reports describing reversible obstructive hydrocephalus related to hypertensive encephalopathy. All had mean arterial pressures above 130 mmHg and presented primarily with altered mental status. While half required ventriculostomy, only one required shunting. Excluding a patient who died from sepsis, all recovered neurologically once blood pressure was controlled. It is imperative to recognize such cases where hypertension causes edema within the posterior fossa resulting in secondary hydrocephalus. Focusing management on lowering blood pressure avoids unnecessary or prolonged CSF diversion.


Subjective and novel objective radiographic evaluation of inflatable bone tamp treatment of articular calcaneus, tibial plateau, tibial pilon and distal radius fractures.
There is a growing need to develop tools that allow for better reductions of difficult to treat fractures in minimally disruptive ways. One such technique has been developed using the inflatable bone tamp and a fast setting calcium phosphate. KYPHON(®) XPANDER Inflatable Bone Tamp and the KYPHON(®) Osteo Introducer(®) System were used to reduce the articular fractures and a fast-setting calcium phosphate was introduced into those voids and metal hardware was applied as deemed necessary. Subjects were skeletally mature patients treated for articular fractures of the calcaneus, tibial plateau, tibial pilon, or distal radius. Post-operative day zero and week 12 radiographs were objectively and subjectively evaluated by three independent orthopaedic surgeons. Their objective scores were then translated into subjective categories based on the Heiney-Redfern scaled scoring (H-R score) system established herein. Overall, the thorough radiographic analysis by independent reviewers indicates that the technique is capable of obtaining and maintaining articular reductions in a good or adequate manner at 12-weeks post-operatively. Introduced is a potential novel evaluation scale scoring system for these articular fractures that evaluates the important anatomic considerations reproducibly in fracture reductions. There are many potential benefits that remain speculative to this type of tool within a procedure, and therefore this tool and technique warrants further research.


Effect of serum albumin on dynamic force-area curve of dipalmitoyl lecithin.
In line with previous findings at 25 degrees C, solutions of serum albumin in the subphase stabilized the surface activity of DPL spread films at 25 degrees C as well as 37 degrees C. In contrast, films adsorbed from mixtures of DPL and albumin exhibitied a marked inhibitory action of the albumin on DPL activity. The inhibitory effect increased with the relative protein concentration but, with albumin/DPL ratios smaller than 2, the DPL activity was regained gradually with cycling. With larger albumin/DPE negative effect of albumin was counteracted by higher temperatures (37 degrees C vs 25 degress C) and modest cholesterol concentrations; with greater cholesterol concentrations the known inhibitory effect of cholesterol prevailed. The inhibitory effect of albumin was potentiated by humidity; saturation of the atmosphere with water vapor at 37 degrees C abolished the DPL character of DPL-RSA mixtures and prevented its return (zero surface tension) upon reversal of the atmosphere from saturated water vapor to dry air. The data are important in the interpretation of the surface activity of pulmonary washings and other pulmonary extracts.


Epidemiology of the new HIV infections in a large university hospital of Southern Italy: the importance of increasing the culture of the HIV screening test in the prevention of late diagnosis.
the delay of HIV diagnosis represents an important risk of spreading HIV infection within the community and, at the same time, a loss of opportunity for undiagnosed subjects to start the antiretroviral therapy. to evaluate the difference, over time, between early and late HIV diagnosis in a large University Hospital of Southern Italy and to emphasize the importance of spreading the culture of prevention, based on the improvement of the HIV screening test adherence, in order to reduce the incidence of late HIV diagnosis. retrospective cross-sectional study. all the HIV screening tests performed in the six-year period 2013-2018 by the HIV laboratory of a third-level University hospital of Sicily (Southern Italy) were considered. The tests were performed on four categories of patients: voluntary HIV screening participants, inpatients, outpatients, and healthcare workers. number of performed HIV tests and frequency of early and late HIV diagnosis in the studied categories of subjects. in the considered period, 16,290 HIV tests were performed and the new diagnosis, considering all the four categories of patients, were in total 72, of which the highest percentage (45.8%) concerned voluntary HIV screening participants showing a mean CD4+ level >350/μL (threshold to discriminate early or late infection), followed by inpatients (27.8%) and outpatients (26.4%) with a mean CD4+ levels <350/μL. Moreover, from 2013 to 2018, the detection of serological positivity on voluntary HIV screening participants showed a decrease of 12.5%, while there was a parallel increase of 18.2% in the inpatients group. In the outpatients, the serological positivity remains quite stable. Concerning sexual habits, in the voluntary HIV screening participants, more than half (55.5%) of the HIV positive subjects were homo-bisexuals, while in the inpatients and outpatients' groups the highest percentage (83.3%) were heterosexuals. in this study, the majority (45.8%) of the new HIV diagnosis were detected on voluntary HIV screening participants in an earlier phase of infection. However, adding the percentages of inpatients and outpatients, it results that more than half (54.2%) of the new diagnosis occurred in a more advanced phase of infection. For these reasons, it appears necessary to stress the importance of an early diagnosis, reachable only by the spread of an HIV screening culture through health education campaigns addressed to the entire population and, especially, to heterosexual category that was the most interested group in the late diagnosis.


Estimation of the number of synapses in the hippocampus and brain-wide by volume electron microscopy and genetic labeling.
Determining the number of synapses that are present in different brain regions is crucial to understand brain connectivity as a whole. Membrane-associated guanylate kinases (MAGUKs) are a family of scaffolding proteins that are expressed in excitatory glutamatergic synapses. We used genetic labeling of two of these proteins (PSD95 and SAP102), and Spinning Disc confocal Microscopy (SDM), to estimate the number of fluorescent puncta in the CA1 area of the hippocampus. We also used FIB-SEM, a three-dimensional electron microscopy technique, to calculate the actual numbers of synapses in the same area. We then estimated the ratio between the three-dimensional densities obtained with FIB-SEM (synapses/µm3) and the bi-dimensional densities obtained with SDM (puncta/100 µm2). Given that it is impractical to use FIB-SEM brain-wide, we used previously available SDM data from other brain regions and we applied this ratio as a conversion factor to estimate the minimum density of synapses in those regions. We found the highest densities of synapses in the isocortex, olfactory areas, hippocampal formation and cortical subplate. Low densities were found in the pallidum, hypothalamus, brainstem and cerebellum. Finally, the striatum and thalamus showed a wide range of synapse densities.


Monostatic all-fiber rangefinder system.
A rangefinder based on a fiber-coupled, monostatic system that transmits and receives through the same aperture has been developed. Some of the advantageous characteristics include elimination of the requirement for precision alignment of the receiver detector and smaller size than bistatic systems using separate transmit and receive apertures. Because there is no parallax between transmit and receive beam paths, optimum receiver alignment is maintained for all ranges. The system operates at 50 kpps and uses a 27 mm diameter/40 mm focal length transmit/receive lens. The standard deviation range precision of the system is 7.8 mm at 50 m with 3.3 μJ pulses.


Application of nano TiO(2) towards polluted water treatment combined with electro-photochemical method.
A novel composite reactor was prepared and studied towards the degradation of organic pollutants in this work. In the reactor, a UV lamp was installed to provide energy to excite nano TiO(2), which served as photocatalyst, leading to the production of hole-electron pairs, and a three-electrode electrolysis system was used to accumulate H(2)O(2) which played an important role in the degradation process. The reactor was evaluated by the degradation process of rhodamine 6G (R-6G), and the data obtained in the experiments showed that the combination of the photochemical and electrochemical system raised the degradation rate of R-6G greatly; the working mechanism of the reactor was also discussed in the article. The prepared reactor was also utilized to treat polluted water from dyeing and printing process. After continuous treatment for 0.5h, chemical oxygen demand biochemical oxygen demand, quantity of bacteria and ammonia nitrogen of the polluted water were reduced by 93.9%, 87.6%, 99.9% and 67.5%, respectively, which indicated that the method used here could be used for effective organic dyes degradation.


Tangentially migrating GABAergic cells of subpallial origin invade massively the pallium in developing sharks.
We studied the development of the GABAergic system in the telencephalon of the dogfish Scyliorhinus canicula using GABA and glutamate decarboxylase (GAD) immunocytochemistry. The earliest GABA-expressing cells appeared in the basal telencephalon (subpallium) of stage 24 embryos. Shortly after, the subpallium showed abundant GABA-expressing neuroblasts near the meningeal surface or migrating radially in the neuroepithelium. The limit between the GABA-expressing region and the remainder of the telencephalon (pallium) was sharp and coincides with the pallial/subpallial boundary. At stage 28, GABA-expressing cells with the morphology of tangentially migrating cells (showing a thick growth cone-like leading process) migrate from a dome-shaped protrusion of the lateral subpallium and extended laterally and rostrodorsally into the pallium following either a superficial route or coursing periventricularly. At later stages, abundant GABA-expressing cells were seen in various pallial regions and strings of GABA-expressing cells, possibly migrating, were also noted. The colonization of the dogfish pallium by GABA-expressing cells, originating from the subpallium, is strongly reminiscent of the palliopetal tangential migrations of GABA-expressing cells demonstrated in the telencephalon of mammals and follows similar routes. These results strongly suggest that tangential migrations of GABA-expressing cells appeared very early in vertebrate forebrain evolution.


Inter-molecular β-sheet structure facilitates lung-targeting siRNA delivery.
Size-dependent passive targeting based on the characteristics of tissues is a basic mechanism of drug delivery. While the nanometer-sized particles are efficiently captured by the liver and spleen, the micron-sized particles are most likely entrapped within the lung owing to its unique capillary structure and physiological features. To exploit this property in lung-targeting siRNA delivery, we designed and studied a multi-domain peptide named K-β, which was able to form inter-molecular β-sheet structures. Results showed that K-β peptides and siRNAs formed stable complex particles of 60 nm when mixed together. A critical property of such particles was that, after being intravenously injected into mice, they further associated into loose and micron-sized aggregates, and thus effectively entrapped within the capillaries of the lung, leading to a passive accumulation and gene-silencing. The large size aggregates can dissociate or break down by the shear stress generated by blood flow, alleviating the pulmonary embolism. Besides the lung, siRNA enrichment and targeted gene silencing were also observed in the liver. This drug delivery strategy, together with the low toxicity, biodegradability, and programmability of peptide carriers, show great potentials in vivo applications.


Oncogenic signaling-mediated regulation of chromatin during tumorigenesis.
Signaling pathways play critical roles in executing and controlling important biological processes within cells. Cells/organisms trigger appropriate signal transduction pathways in order to turn on or off intracellular gene expression in response to environmental stimuli. An orchestrated regulation of different signaling pathways across different organs and tissues is the basis of many important biological functions. Presumably, any malfunctions or dysregulation of these signaling pathways contribute to the pathogenesis of disease, particularly cancer. In this review, we discuss how the dysregulation of signaling pathways (TGF-β signaling, Hippo signaling, Wnt signaling, Notch signaling, and PI3K-AKT signaling) modulates chromatin modifications to regulate the epigenome, thereby contributing to tumorigenesis and metastasis.


Assessing mitochondrial morphology and dynamics using fluorescence wide-field microscopy and 3D image processing.
Mitochondrial morphology and length change during fission and fusion and mitochondrial movement varies dependent upon the cell type and the physiological conditions. Here, we describe fundamental wide-field fluorescence microscopy and 3D imaging techniques to assess mitochondrial shape, number and length in various cell types including cancer cell lines, motor neurons and astrocytes. Furthermore, we illustrate how to assess mitochondrial fission and fusion events by 3D time-lapse imaging and to calculate mitochondrial length and numbers as a function of time. These imaging methods provide useful tools to investigate mitochondrial dynamics in health, aging and disease.


Activation of peroxisome proliferator-activated receptor-gamma by curcumin blocks the signaling pathways for PDGF and EGF in hepatic stellate cells.
During hepatic fibrogenesis, reduction in the abundance of peroxisome proliferator-activated receptor-gamma (PPARgamma) is accompanied by activation of mitogenic signaling for platelet-derived growth factor (PDGF) and epidermal growth factor (EGF) in hepatic stellate cells (HSCs), the major effector cells. We previously reported that curcumin, the yellow pigment in curry, interrupted PDGF and EGF signaling, stimulated PPARgamma gene expression, and enhanced its activity, leading to inhibition of cell proliferation of activated HSC in vitro and in vivo. The aim of this study was to elucidate the underlying mechanisms. We hypothesized that the enhancement of PPARgamma activity by curcumin might result in the interruption of PDGF and EGF signaling. Our experiments demonstrated that curcumin, with different treatment strategies, showed different efficiencies in the inhibition of PDGF- or EGF-stimulated HSC proliferation. Further experiments observed that curcumin dose dependently reduced gene expression of PDGF and EGF receptors (ie, PDGF-betaR and EGFR), which required PPARgamma activation. The activation of PPARgamma by its agonist suppressed pdgf-betar and egfr expression in HSC. In addition, curcumin reduced the phosphorylation levels of PDGF-betaR and EGFR, as well as their downstream signaling cascades, including ERK1/2 and JNK1/2. Moreover, activation of PPARgamma induced gene expression of glutamate-cysteine ligase, the rate-limiting enzyme in de novo synthesis of the major intracellular antioxidant, glutathione. De novo synthesis of glutathione was required for curcumin to suppress pdgf-betar and egfr expression in activated HSCs. Our results collectively demonstrated that enhancement of PPARgamma activity by curcumin interrupted PDGF and EGF signaling in activated HSCs by reducing the phosphorylation levels of PDGF-betaR and EGFR, and by suppressing the receptor gene expression. These results provide novel insights into the mechanisms of curcumin in the inhibition of HSC activation and the suppression of hepatic fibrogenesis.


Communication: Infrared spectroscopy of protonated allyl-trimethylsilane: Evidence for the β-silyl effect.
β-trimethylsilyl-2-propyl cation has been formed by the gas phase protonation of allyl-trimethylsilane and characterized by infrared multiple photon dissociation spectroscopy. The experimental Cβ-Cα (+) stretching feature at 1586 cm(-1), remarkably blue-shifted with respect to a C-C single bond stretching mode, is indicative of high double bond character, a signature of β-stabilizing effect due to hyperconjugation of the trimethylsilyl group in the β-position with respect to the positively charged carbon. Density functional theory calculations at the B3LYP∕6-311++G(2df,2p) level yield the optimized geometries and IR spectra for candidate isomeric cations and for neutral and charged reference species.


[Obliterating frontal sinus operation with abdominal fat. Follow-up with imaging methods].
Between 1983 and 1991 ten patients with chronic frontal sinus disease underwent frontal osteoplastic flaps with fat obliteration. In order to judge operative success on a long-term basis all patients were called for postoperative follow-up. They then completed a questionnaire, in which they were asked about postoperative complaints. Additionally, sinuses were examined by computed tomographic (CT) and magnetic resonance imaging (MR). Among the patients evaluated seven had no complaints, and no evidence of disease could be found by medical examination. CT scans showed complete obliteration of the frontal sinuses in all patients. In these patients, two-thirds of the fat had been replaced by connective tissue. MR was used in an attempt to show evidence for suppurative disease in the frontal sinus, but the MR images failed to correlate with symptoms. Additional results could not be obtained when compared to CT. Overall operating success could only be determined by clinical assessment and confirmed the value of the frontal osteoplastic flap with fat obliteration.


Results of a pediatric sedation program on head MRI scan success rates and procedure duration times.
The purpose of this study was to determine if a pediatric sedation program improved head magnetic resonance imaging (MRI) scan success rates and procedure duration times compared with the year preceding the program. Sedation was successful in 189 (85.1%) of 222 children before the program compared with 211 (98.1%) of 215 children during the program (P < 0.001). Mean procedure duration times for head MRI scans with and without contrast were shorter in the program compared with before the program (58.7 +/- 1.4 min versus 71.8 +/- 3.0 min, P < 0.001, and 46.7 +/- 1.2 min versus 58.5 +/- 1.9 minutes, P < 0.001, respectively). No major complications occurred during the 15-month period in the sedation program. We conclude that sedation for pediatric MRI, managed by an organized pediatric sedation program, is highly successful, efficient, and safe.


Kinetics of iron reduction of ferritin cores and of a low molecular weight hydroxy-iron polymer.
The kinetics of reduction by dithionite of iron cores in ferritin and of iron cores after removal of the protein shell (isolated cores) has been analysed along with that of a low molecular weight hydroxy-iron polymer. Spectrophotometric measurements have shown that the time course of the reaction approximates a pseudo first-order behaviour. In the case of ferritin cores the pseudo first-order rate constant reaches an asymptotic value which markedly increases when the cores are isolated. In contrast, in the low molecular weight hydroxy-iron polymer, no clear asymptotic value is reached. Thus, the rate of reduction appears to be determined both by the presence of the protein shell and by the crystallite surface area. Kinetic light scattering experiments show that in ferritin and in the isolated cores a rapid drop in molecular weight occurs during the first stages of reduction, suggesting a fragmentation of the iron crystallite.


A retrospective study of the rate of postoperative septic arthritis following 353 elective arthroscopies.
To report the rate of postoperative septic arthritis following elective diagnostic and surgical arthroscopy in small animals within a clinical setting. A retrospective case review from the case log of one veterinary surgeon. Of the 353 procedures included, performed on 305 animals, there were three cases of postoperative sepsis (0.85%). Interventional arthroscopy including both diagnostic and surgical arthroscopy in small animals is a safe technique and poses a risk of postoperative sepsis of approximately 1%.


Design and evaluation of universal 16S rRNA gene primers for high-throughput sequencing to simultaneously detect DAMO microbes and anammox bacteria.
To develop universal 16S rRNA gene primers for high-throughput sequencing for the simultaneous detection of denitrifying anaerobic methane oxidation (DAMO) archaea, DAMO bacteria, and anaerobic ammonium oxidation (anammox) bacteria, four published primer sets (PS2-PS5) were modified. The overall coverage of the four primer pairs was evaluated in silico with the Silva SSU r119 dataset. Based on the virtual evaluation, the two best primer pairs (PS4 and PS5) were selected for further verification. Illumina MiSeq sequencing of a freshwater sediment and a culture from a DAMO-anammox reactor using these two primer pairs revealed that PS5 (341b4F-806R) was the most promising universal primer pair. This pair of primers detected both archaea and bacteria with less bias than PS4. Furthermore, an anaerobic fermentation culture and a wastewater treatment plant culture were used to verify the accuracy of PS5. More importantly, it detected DAMO archaea, DAMO bacteria, and anammox bacteria simultaneously with no false positives appeared. This universal 16S rRNA gene primer pair extends the existing molecular tools for studying the community structures and distributions of DAMO microbes and their potential interactions with anammox bacteria in different environments.


Expression of Toll-like receptors and downstream genes in lipopolysaccharide-induced porcine alveolar macrophages.
The aim of the present study was to determine the age-related kinetic changes of Toll-like receptors (TLRs) and downstream genes expression, and secretion of cytokine in lipopolysaccharide (LPS) stimulated porcine alveolar macrophages (AM). For this purpose, AMs were isolated from 5-day-old newborn piglets and 120-day-old young pigs. mRNA expression and cytokine measurement was determined by quantitative real-time PCR and ELISA, respectively. First, AMs were incubated for 24 h in the absence or presence of increasing concentrations of LPS. Results showed the up-regulation of TLRs 2, 4, 5 and 9 mRNA from all concentrations of LPS used, as compared to non-stimulated cells, and TLR4 was the highest expression in both ages (P<0.05). Furthermore, quantitative analysis demonstrated increased expression of mRNAs encoding TLRs 2, 4, 5 and 9, LBP, CD14, MD2, MyD88, IRAK4 and TRAF6 in both ages in a time-dependant manner (P<0.05). Overall, LPS inducible mRNA for TLR4, LBP, CD14 and MyD88 had higher expression in newborn piglets compared with those of young pigs (P<0.05). The level of cytokine protein IL6 and TNFα in supernatant fluid significantly varied with time of incubation and age of animals. Their concentration increased immediately at 1 h after LPS stimulation and remained significantly higher up to 48 h in both ages. Production of pro-inflammatory cytokine protein IL6 and TNFα in supernatant was significantly higher in young pigs than those of piglets. This study suggests that differential age-related changes in the expression of TLRs and downstream genes, and pro-inflammatory cytokine could contribute to a different age-related innate immune response during pulmonary infection. Further investigation is warranted to determine the precise effects of LPS on porcine AMs by means of a functional study across a wider age range.


ACAT as a drug target for Alzheimer's disease.
Accumulation of beta-amyloid peptide (Abeta) in the brain regions responsible for memory and cognitive functions is a neuropathological hallmark of Alzheimer's disease. Cholesterol may be involved in many aspects of Abeta metabolism. It affects generation, aggregation and clearance of Abeta in the brain. Not only the amount but also the distribution of cholesterol within cells appears to modulate Abeta biogenesis. ACAT is an enzyme that regulates subcellular cholesterol distribution by converting membrane cholesterol to cholesteryl esters for storage and transport. We have used various cell- and animal based models to show that inhibition of ACAT strongly reduces Abeta generation and protects from amyloid pathology. Here, we discuss data supporting ACAT inhibition as a strategy to treat Alzheimer's disease.


Insufficient production of IL-10 from M2 macrophages impairs in vitro endothelial progenitor cell differentiation in patients with Moyamoya disease.
Moyamoya disease (MMD) is well known to be caused by insufficient cerebral vascular formation. However, the essential pathogenesis has not yet been identified. Using our recently developed technique of generating vasculogenic and anti-inflammatory cultures, we investigated endothelial progenitor cell (EPC) expansion and differentiation under the cytokine milieu generated by the peripheral blood mononuclear cells (PBMNCs) of the operated and non-operated MMD patients. EPC colony forming assay of the cultured PBMNCs disclosed the decline of the definitive EPC colony numbers in the both MMD patients. The level of interleukin-10 (IL-10) was lower in secretory cytokines from the cultured PBMNCs of MMD patients than that in that of controls using a cytometric bead array. The addition of human recombinant IL-10 to PBMNCs cultured from MMD patients restored the EPC colony forming potential of MMD PBMNCs. Following phorbol myristate acetate stimulation of the cultured PBMNCs, flow cytometry revealed a decrease in intracellular IL-10 storage in the main cell populations of the PBMNCs cultured from MMD patients relative to those cultured from controls. The present data provide the expected mechanism of vascular malformation in MMD pathogenesis originated from the insufficient production of IL-10 secreting cells from PBMNCs fostering EPC expansion and differentiation.


A specific early eluting peak in Bio-Rad Variant II cation-exchange high-performance liquid chromatography (CE-HPLC) for the screening of alpha-thalassaemia in a Chinese population.
The early eluting peaks in the first minute of cation-exchange high-performance liquid chromatography (CE-HPLC) are often not analysed in haemoglobin pattern studies, except for haemoglobin (Hb) Bart's and Hb H peaks. In this study, we described the presence of a specific α-thalassaemia early eluting peak (αEEP) at the retention time of 0.24 min generated by Variant II CE-HPLC (β-Thalassaemia Short Program; Bio-Rad Laboratories). We have evaluated the utility of αEEP for the screening of α-thalassaemia trait in our local Chinese population in comparison to the Hb H inclusion body test. A total of 303 blood samples presenting with microcytosis were sent for haemoglobin pattern study and were analysed for the presence or absence of αEEP and Hb H inclusions. Twenty cases with a normal mean corpuscular volume were assessed as a control. Discordant results between the αEEP and the Hb H inclusion test were reviewed with the α-globin genotyping test performed. The concordance rate of the αEEP and the Hb H inclusion body test was 96.0% (κ=0.921, p<0.001). Eight of 303 cases (2.6%) were initially negative for the Hb H inclusion test but positive for the αEEP. All eight cases were found to have occasional Hb H inclusion bodies upon review. Four of 303 cases (1.3%) were negative for the αEEP but positive for the Hb H inclusion test. Of these four cases, two (50%) showed heterozygous Southeast Asian (SEA) type deletion, one (25%) showed Hb Quong Sze mutation, and one (25%) showed no mutation detected upon molecular testing. All the Hb E trait cases with no Hb H inclusions and the negative control group showed the absence of the αEEP. The sensitivity and specificity of αEEP for detecting SEA deletion were 93.8% and 100% respectively, which is superior to the Hb H inclusion test (sensitivity 81.3%, specificity 95.2%). The αEEP is found to be a more sensitive method than the Hb H inclusion body test in the screening of α-thalassaemia trait in our Chinese population, in which SEA type deletion is prevalent. Further study is needed to explore the utility of the αEEP in the screening of α-thalassaemia traits in other populations. The exact nature of the αEEP is yet to be defined.


Promoting advance care planning among community-based older adults: A randomized controlled trial.
To test an intervention designed to motivate older adults in documenting their healthcare preferences in advance, and to guide proxies in making hypothetical decisions that match those of the older adult. The trial involved 235 older adults, of which half were assisted in communicating their wishes to their proxy. Hypothetical vignettes were used at baseline and twice after the intervention to elicit older adults' preferences and assess their proxy's ability to predict them. By the end of the trial, 80% of older adults allocated to the experimental group had documented their wishes. Changes over time in mean accuracy scores did not differ between groups for any hypothetical situations, except when limiting the sample to dyads that were highly discordant at baseline. The intervention motivated a large proportion of older adults to express their preferences but had little effect on proxies' ability to predict them. Educational tools developed for this study will assist healthcare providers in helping older adults to record their wishes in advance. Clients must be informed of the challenge of making substitute decisions and of the need to discuss the amount of leeway the proxy should have in interpreting expressed wishes.


Systematic review on the cost-effectiveness of self-management education programme for type 2 diabetes mellitus.
A review of cost-effectiveness studies on self-management education programmes for Type 2 diabetes mellitus. Cochrane, PubMed and PsycINFO databases were searched for papers published from January 2003 through September 2015. Further hand searching using the reference lists of included papers was carried out. In total, 777 papers were identified and 12 papers were finally included. We found eight programmes whose effectiveness analyses were based on randomised controlled trials and whose costs were comprehensively estimated from the stated perspective. Among these eight, four studies showed a cost per unit reduction in clinical risk factors (HbA1c or BMI) of US$491 to US$7723 or cost per glycaemic symptom day avoided of US$39. In three studies the cost per QALY gained, as estimated from a life-time model, was less than US$50,000. However, one study found the programme was not cost-effective despite a gain in QALYs at the one-year follow up. A small number of cost-effectiveness studies were identified with only eight of sufficiently good quality. The cost of a self-management education programme achieving reduction in clinical risk factors seems to be modest and is likely to be cost-effective in the long-term.


Allostery and the lac Operon.
The ability to regulate gene expression is essential for controlling metabolic events in a cell. Proteins that function like molecular switches respond to fluctuations in the environment to maintain homeostasis. The operon model, proposed by Jacob and Monod, provides a cogent depiction for how gene expression is regulated. A molecular mechanism for the regulation followed shortly with the theory for allosteric transition. Over the past half-century, the details of the lac operon and the allosteric model have been tested using genetic, biochemical, and structural techniques. Remarkably, the principles originally put forward 50 years ago remain essentially unchanged. Models for the operon and the theory of allosteric transitions are two of the most profound discoveries of molecular biology.


A method for fast automated microscope image stitching.
Image stitching is an important technology to produce a panorama or larger image by combining several images with overlapped areas. In many biomedical researches, image stitching is highly desirable to acquire a panoramic image which represents large areas of certain structures or whole sections, while retaining microscopic resolution. In this study, we develop a fast normal light microscope image stitching algorithm based on feature extraction. At first, an algorithm of scale-space reconstruction of speeded-up robust features (SURF) was proposed to extract features from the images to be stitched with a short time and higher repeatability. Then, the histogram equalization (HE) method was employed to preprocess the images to enhance their contrast for extracting more features. Thirdly, the rough overlapping zones of the images preprocessed were calculated by phase correlation, and the improved SURF was used to extract the image features in the rough overlapping areas. Fourthly, the features were corresponded by matching algorithm and the transformation parameters were estimated, then the images were blended seamlessly. Finally, this procedure was applied to stitch normal light microscope images to verify its validity. Our experimental results demonstrate that the improved SURF algorithm is very robust to viewpoint, illumination, blur, rotation and zoom of the images and our method is able to stitch microscope images automatically with high precision and high speed. Also, the method proposed in this paper is applicable to registration and stitching of common images as well as stitching the microscope images in the field of virtual microscope for the purpose of observing, exchanging, saving, and establishing a database of microscope images.


Speed of capsular bend formation at the optic edge of acrylic, silicone, and poly(methyl methacrylate) lenses.
To evaluate how and how fast a capsular bend is created clinically at the optic edge of an intraocular lens (IOL) after cataract surgery. Jinshikai Medical Foundation, Nishi Eye Hospital, Osaka, Japan. Capsular bend formation was observed by slitlamp after maximum pupil dilation in 45 eyes of 45 patients with senile cataract. Fifteen eyes each received an AcrySof MA60BM acrylic (Alcon), PhacoFlex II SI-40NB silicone (Allergan), or UV26T poly(methyl methacrylate) (PMMA) (Menicon) IOL. Patients were evaluated prospectively at 1 day and 1, 2, and 4 weeks and retrospectively (15 eyes per IOL) 1 year after cataract surgery. A capsular bend index was developed to document and categorize the capsular bend formation process at the IOL optic edge. The anterior and posterior capsules adhered, with the latter attracted to the former. The adhesion always progressed from the periphery to the optic edge so that the posterior capsule eventually wrapped around the posterior optic edge, although not fully circumferentially in all cases. The process took place in 4 stages. Capsular bend formation was complete 1 month after surgery with the foldable IOLs (AcrySof, PhacoFlex II) but was significantly delayed with the PMMA IOL. After 1 year, the capsular wrapping was firm and fully circumferential at the optic edge with all IOL types in all cases. Capsular bend formation progressed in the same fashion but at significantly different speeds among the IOLs, suggesting that the process depends on IOL material and design. Fast, early capsular bend formation may be 1 reason AcrySof and PhacoFlex II IOLs prevent PCO statistically better than PMMA IOLs. The results indicate that PCO is prevented by the sharp capsular bend created by sharp optic edges and by quick bend formation.


Dependence of wetting on cavitation during the spreading of a filler droplet on the ultrasonically agitated Al substrate.
The cavitation characteristics during the spreading of a pure Sn liquid droplet subjected to ultrasonication were studied for the first time through high-speed photography to reveal the wetting mechanism. Ultrasonic vibration realized the spreading of Sn droplet on the nonwetting pure Al substrate. However, the oxide layer of the substrate at the spreading front is difficult to remove. The high-speed photography result shows that a noncavitation region consistently appears at the spreading front, because the acoustic pressure is below the cavitation threshold of 1.26 MPa. In particular, the width of the noncavitation region gradually increases as the size of the spreading area increases. Such a result accounts for the condition wherein the oxide layer at the spreading front is difficult to remove. Furthermore, the bubble density during spreading gradually decreases due to the decreased acoustic pressure of the thinned liquid. Finally, the bubble dynamics were calculated to verify the wetting mechanism.


Modification of the chemically induced inflammation assay reveals the Janus face of a phenol rich fulvic acid.
Inflammation is an essential process as a reaction towards infections or wounding. Exposure to hazardous environmental pollutants can lead to chronic inflammations, where the resolving phase is delayed or blocked. Very contradictory studies have been reported on the pro- and anti-inflammatory effects of humic substances (HSs) leading to significant disagreements between researchers. To a certain extent, this can be attributed to the chemical heterogeneity of this group of xenobiotics. Here we show for the first time that pro- and anti-inflammatory effects can occur by one HSs. We adapted an assay that uses green fluorescence-labeled zebrafish larvae and CuSO4 to indue an inflammation. In wild-type larvae, exposure to 50 µM CuSO4 for 2 h activated the production of reactive oxygen species, which can be monitored with a fluorescence dye (H2DCFDA) and a microplate reader. This allows not only the use of wild-type fish but also a temporal separation of copper exposure and inflammatory substance while retaining the high throughput. This modified assay was then used to evaluate the inflammatory properties of a fulvic acid (FA). We found, that the aromatic structure of the FA protects from inflammation at 5 and 50 mg C/L, while the persistent free radicals enhance the copper-induced inflammation at ≥ 300 mg C/L.


The correlation between genetic factors and freezing of gait in patients with Parkinson's disease.
Clinical-related risk factors to freezing of gait (FOG) in Parkinson's disease (PD) have been identified. Still, the influence of genetic variations on the FOG occurrence has been poorly studied thus far. We aimed to evaluate the association of six selected polymorphisms of DRD2, ANKK1, and COMT genes with the FOG occurrence and explore the influence of ANNK1/DRD2 haplotypes on the onset of FOG in the group of PD patients. PD patients (n = 234), treated with levodopa for at least two years, were genotyped for the rs4680 in COMT, rs6277, rs1076560, and rs2283265 in DRD2, and rs1800497 and rs2734849 polymorphisms in ANKK1 genes. FOG was evaluated by posing a direct question. In addition, a comprehensive set of clinical scales was applied to all patients. FOG occurred in 132 (56.4%) PD patients in our cohort. Freezers were younger at PD onset, had longer disease duration, used higher levodopa daily doses and dopaminergic agents, and had higher motor and non-motor scales scores than non-freezers. FOG was more frequent among AA rs4680 COMT carriers than AG and GG rs4680 COMT carriers. Independent predictors of FOG were: disease duration of more than ten years, levodopa daily dose higher than 500 mg/day, motor status, and COMT AA genotype. AGGAA and GGAAA haplotypes were revealed as protective and vulnerability factors for FOG occurrence. In addition to previously identified disease- and therapy-related risk factors, our results suggested a possible contribution of dopamine-related genes to the FOG occurrence.


Action insight: the role of the dorsal stream in the perception of grasping.
In this issue of Neuron, Shmuelof and Zohary use functional magnetic resonance imaging (fMRI) to demonstrate differential sensitivity of the ventral and dorsal cortical streams of visual processing to images of objects and grasping hands, respectively.


Modelling the electrodialytic recovery of sodium lactate.
The recovery of sodium lactate from model solutions by ED (electrodialysis) was studied using a sequential experimental procedure so as to assess the main engineering parameters (i.e. ion transport numbers in solution and electro-membranes, effective solute and water transport numbers, effective membrane surface area, surface resistances and limiting current intensity) affecting ED stack design and/or optimization. Of the major factors that determine the performance of this ED process, Omega (the current efficiency) was about 88% in the constant-current region, while epsilon (the specific energy consumption) increased from 0.14 to 0.31 kWh x kg(-1) for a solute recovery yield of 95% and j (current density) increasing from 112 to 337 A x m(-2). The specific-resistance values of the anion- or cation-exchange membranes were found to be five or two times greater respectively than those extracted from literature and measured in aqueous NaCl solutions.


Composites of Bacillus megaterium H16 derived poly-3-hydroxybutyrate as a biomaterial for skin tissue engineering.
Composite films of Bacillus megaterium H16 derived PHB with 1%Poly-L-lactic acid (PLLA), 1%Poly-ε-caprolactone (PCL), and 0.3 % graphene nanoplatelets (GNP) were produced by solvent cast method. The composite films were characterized by SEM, DSC-TGA, XRD, and ATR-FTIR. The ultrastructure of PHB and its composites depicted an irregular surface morphology with pores after the evaporation of chloroform. The GNPs were seen to be integrated inside the pores. The B. megaterium H16 derived-PHB and its composites demonstrated good biocompatibility which was evaluated in vitro on HaCaT and L929 cells by MTT assay. The cell viability was best for PHB followed by PHB/PLLA/PCL > PHB/PLLA/GNP > PHB/PLLA. PHB and its composites were highly hemocompatible as it resulted in <1 % hemolysis. The PHB/PLLA/PCL and PHB/PLLA/GNP composites can serve as ideal biomaterials for skin tissue engineering.


Unfavorable biological behavior and treatment response of neuroendocrine ovarian metastases of midgut neuroendocrine tumors.
Neuroendocrine ovarian metastases (NOM) predominantly derive from midgut neuroendocrine tumors (NETs) and develop in about 25% of women with advanced stage of this malignancy. Little is known of the growth rate and treatment response of NOM. We therefore evaluated the efficacy of different management options for patients with NOM, including peptide receptor radionuclide therapy (PRRT), somatostatin analogues (SSAs) and oophorectomy. Records were screened for patients with well-differentiated NOM of midgut origin that presented in our NET referral center between 1991 and 2022. Progression-free survival (PFS) and tumor growth rate (TGR) of ovarian and extra-ovarian metastases were determined using RECIST (response evaluation criteria in solid tumors) 1.1. In 12 available patients undergoing PRRT, NOM were associated with a shorter PFS than extra-ovarian metastases (P = 0.003). While PRRT induced a similar decrease in TGR for ovarian and extra-ovarian lesions in nine patients with available data (-2.3 vs -1.4, P > 0.05), only the TGR of NOM remained positive after PRRT. In 16 patients treated with SSAs, the TGR of NOM was almost three times that of extra-ovarian lesions during treatment (2.2 vs 0.8, P = 0.011). Oophorectomy was performed in 46 of the 61 included patients and was significantly associated with a prolonged OS (115 vs 38 months, P < 0.001). This association persisted after propensity score matching and correction for tumor grade and simultaneous tumor debulking. In conclusion, NOM have a higher TGR compared to extra-ovarian metastases, resulting in a shorter PFS after PRRT. Bilateral salpingo-oophorectomy should be considered for postmenopausal women with NOM undergoing surgery for metastatic midgut NETs.


Ventricular function and infarct size: the Western Washington Intravenous Streptokinase in Myocardial Infarction Trial.
The Western Washington Intravenous Streptokinase in Acute Myocardial Infarction Trial randomized 368 patients with symptoms and signs of acute myocardial infarction of less than 6 h duration to either conventional care or 1.5 million units of intravenous streptokinase. The mean time to randomization was 209 min and 52% of patients were randomized within 3 h of symptom onset. Quantitative, tomographic thallium-201 infarct size and radionuclide ejection fraction were measured at 8.2 +/- 7.5 weeks in 207 survivors who lived within a 100 mile radius of a centralized laboratory. Overall, infarct size as a percent of the left ventricle was 19 +/- 13% for control subjects and 15 +/- 13% for treatment patients (p = 0.03). For anterior infarction in patients entered within 3 h of symptom onset, infarct size was 28 +/- 13% in the control group versus 19 +/- 15% for the treatment group (p = 0.09). Left ventricular ejection fraction was 47 +/- 15% in the control versus 51 +/- 15% in the treatment group (p = 0.08). For anterior infarction of less than 3 h duration, the ejection fraction was 38 +/- 16% in the control versus 48 +/- 20% in the treatment group (p = 0.13). By statistical analysis incorporating the nonsurvivors, p values for all of these variables were less than or equal to 0.08. There was no benefit for patients with inferior infarction or for anterior infarction of greater than 3 h duration. It is concluded that intravenous streptokinase, when given within 3 h of symptom onset to patients with anterior infarction, reduces infarct size and improves ventricular function.


Utility of salivary gland biopsy in diagnosing Sjogren's syndrome in a POTS patient population.
POTS patients undergo labial salivary gland biopsies (LSGB) for histologic confirmation of Sjogren's syndrome (SS). Predictive features of positive results are unknown. 161 POTS patients underwent LSGB. Their charts were reviewed for antibody and diagnostic testing results. Only 11% (17/161) of POTS patients were SS positive. There were more positive ANA antibodies in those with positive LSGB (65% v 28%, p = .0026). Positive skin nerve biopsy for small fiber neuropathy (SFN) was associated with positive LSGB (p = .046). A positive ANA and skin biopsy for SFN are two helpful features in selecting POTS patients for LSGB.


Intermolecular complexes between three human CD1 molecules on normal thymus cells.
The first cluster of differentiation (CD1) defines at least three distinct human thymic cell-surface differentiation antigens-CD1a, CD1b, and CD1c. We looked for structural homology of the three CD1 heavy chains at their peptide level by two-dimensional peptide maps. We show here that the CD1a Mr 49,000 heavy chain and the CD1b Mr 45,000 heavy chain appear to be more homologous to each other than to the CD1c Mr 43,000 heavy chain and that only one tyrosil peptide is common to the three heavy chains. Study of the CD1 heavy chains from several individuals reveals a very limited polymorphism of these molecules. We also demonstrate here that CD1a or CD1a-like molecules and other CD1 molecules can form intermolecular complexes on the surface of normal thymus cells. Molecules that are structurally very similar to CD1a molecules are associated noncovalently either with CD1c molecules or with CD1b molecules, and only CD1a molecules can associate covalently with CD8 molecules. In contrast, we could not find these intermolecular complexes on the surface of leukemic T-cell lines in culture.


Stable, Nonviral Expression of Mutated Tumor Neoantigen-specific T-cell Receptors Using the Sleeping Beauty Transposon/Transposase System.
Neoantigens unique to each patient's tumor can be recognized by autologous T cells through their T-cell receptor (TCR) but the low frequency and/or terminal differentiation of mutation-specific T cells in tumors can limit their utility as adoptive T-cell therapies. Transfer of TCR genes into younger T cells from peripheral blood with a high proliferative potential could obviate this problem. We generated a rapid, cost-effective strategy to genetically engineer cancer patient T cells with TCRs using the clinical Sleeping Beauty transposon/transposase system. Patient-specific TCRs reactive against HLA-A*0201-restriced neoantigens AHNAK(S2580F) or ERBB2(H473Y) or the HLA-DQB*0601-restricted neoantigen ERBB2IP(E805G) were assembled with murine constant chains and cloned into Sleeping Beauty transposons. Patient peripheral blood lymphocytes were coelectroporated with SB11 transposase and Sleeping Beauty transposon, and transposed T cells were enriched by sorting on murine TCRβ (mTCRβ) expression. Rapid expansion of mTCRβ(+) T cells with irradiated allogeneic peripheral blood lymphocytes feeders, OKT3, interleukin-2 (IL-2), IL-15, and IL-21 resulted in a preponderance of effector (CD27(-)CD45RA(-)) and less-differentiated (CD27(+)CD45RA(+)) T cells. Transposed T cells specifically mounted a polyfunctional response against cognate mutated neoantigens and tumor cell lines. Thus, Sleeping Beauty transposition of mutation-specific TCRs can facilitate the use of personalized T-cell therapy targeting unique neoantigens.


Ti-substituted O3-type layered oxide cathode material with high-voltage stability for sodium-ion batteries.
O3-type layered transition metal oxides (NaxTMO2) have attracted extensive attention as a promising cathode material for sodium-ion batteries because of their high capacity. However, the irreversible phase transition especially cycled under high voltage remains a concerning challenge for NaxTMO2. Herein, a Ti-substituted NaNi0.5Co0.2Mn0.3O2 cathode with strongly suppressed phase transition and enhanced storage stability is investigated. The Ti substitution effectively inhibits the irreversible phase transition and alleviates the structural change even charged to 4.3 V during the repeated Na+ deintercalation process. After storing in air or water, the original O3 phase structure of the material is integrally maintained without the generation of impurity phase. As a result, the as-prepared material shows excellent long-term cycle stability and rate performance when charged to a high voltage of 4.3 V.


History and Technical Approaches and Considerations for Ablative Surgery for Epilepsy.
The history of epilepsy surgery is generally noted to have begun in 1886 with Victor Horsley's first report of craniotomies for posttraumatic epilepsy. With increased understanding of brain function and development of electroencephalographic methods, nonlesional epilepsy began to be treated with resection in the 1950s. Methodological improvements and increased understanding of pathophysiology followed, and the advent of stereotaxy and ablative technology in the 1960s and 1970s heralded a new era of minimally invasive, targeted procedures for lesional and nonlesional epilepsy. Current techniques combine stereotactic methods, improved ablative technologies, and electroencephalographic methods for a multidisciplinary approach to the neurosurgical treatment of epilepsy.


Evaluations and comparisons of microbial diversities in four types of body fluids based on two 16S rRNA gene sequencing methods.
Body fluids are one of the common biological traces at crime scenes. Understanding the types of these biological traces could provide key clues for the investigations of the forensic cases. In recent years, partial hypervariable regions of 16S rRNA gene sequencing and full-length 16S rRNA gene sequencing have attracted the interests of researchers and we intend to explore which method can be better applied to forensic researches. In this study, the 16S rRNA gene V3-V4 (short-read) sequencing based on next-generation sequencing and the full-length 16S rRNA gene sequencing based on single molecule real-time sequencing were used to classify microbes in saliva, peripheral blood, vaginal secretion and menstrual blood samples. Alpha diversity metrics in short-read sequencing were larger than those of full-length sequencing. Phylum-level bacteria in four kinds of body fluids obtained from the two platforms were similar, while their abundances were different. The results of principal coordinates analysis and analysis of molecular variance indicated the microbial compositions of vaginal secretion and menstrual blood samples were similar, and the microbial compositions among saliva, peripheral blood, vaginal secretion or menstrual blood samples were significantly different. The linear discriminant analysis effect size showed the differential bacteria screened among the four kinds of body fluids were variant in two sequencing results. Both sequencing methods could be used to detect bacterial diversities in four different types of body fluids and provide potential tools for microbes to identify the four kinds of body fluids in forensic investigation, in which full-length sequencing could provide more accurate taxonomy.


Two tripartite classification systems of CD86+ and CD206+ macrophages are significantly associated with tumor recurrence in stage II-III colorectal cancer.
The prognostic value of tumor-associated macrophages remains unclear in colorectal cancer (CRC). Two tripartite classification systems, namely, ratio and quantity subgroups, were investigated as the prognostic stratification tools for stage II-III CRC. We assessed the infiltration intensity of CD86+ and CD206+ macrophages in 449 cases with stage II-III disease by immunohistochemical staining. Ratio subgroups were defined by the lower- and upper-quartile points of CD206+/(CD86++CD206+) macrophage ratio, including the low-, moderate-, and high-ratio subgroups. Quantity subgroups were defined by the median points of CD86+ and CD206+ macrophages and included the low-, moderate-, and high-risk subgroups. The main analysis was recurrence-free survival (RFS) and overall survival (OS). Ratio subgroups (RFS/OS: HR=2.677/2.708, all p<0.001) and quantity subgroups (RFS/OS: HR=3.137/3.250, all p<0.001) could serve as independent prognostic indicators that effectively predicted survival outcomes. More importantly, log-rank test revealed that patients in the high-ratio (RFS/OS: HR=2.950/3.151, all p<0.001) or high-risk (RFS/OS: HR=3.453/3.711, all p<0.001) subgroup exhibited decreased survival outcomes after adjuvant chemotherapy. The predictive accuracy of the quantity subgroups within 48 months was higher than that of the ratio subgroups and tumor stage (all p<0.05). Ratio and quantity subgroups could serve as independent prognostic indicators that could potentially be incorporated into the tumor staging algorithm to improve prognostic stratification and provide better predictions of survival outcomes in stage II-III CRC after adjuvant chemotherapy.


Uridine diphosphate-glucuronosyltransferase activities in rat brain microsomes.
The glucuronidation capacity of rat brain microsomes was investigated using a series of chemically related phenolic compounds and fatty acids which are usually glucuronidated in vivo. Most of the phenols assayed were glucuronidated, but no glucuronide formation was detected for stearic and alpha-linolenic acids, 4-methylphenol, bilirubin, morphine, dopamine and serotonin. The activity of uridine diphosphate-glucuronosyltransferase (UGT) towards 1-naphthol represented 0.28% of that obtained with liver microsomes. The inhibitory effects on the formation of 1-naphthol glucuronide of some endogenous and exogenous substances were investigated. The results suggest that only the isoform of UGT conjugating 1-naphthol is present in rat brain.


Large-scale gene expression analysis in molecular target discovery.
The evolution of simple arrays consisting of a few genes to ones composed of thousands of genes and/or ESTs has allowed investigators unprecedented views of the molecular mechanisms within cells. Due to the enormous quantities of information derived from microarray analysis, new types of problems have surfaced, such as where to store all of the data. The ability to solve database or statistical problems has required the bench biologist to collaborate with database developers, software designers and statisticians to determine solutions for storage, analysis and interpretation of microarray data. The collaborative effort between these extremely diverse disciplines has led to the development of creative database query and gene expression analysis tools, producing significant reductions in the time required by researchers to filter through the datasets and discover the key processes perturbed by the diseases of interest. Both unsupervised and supervised analysis methods have been applied to gene expression data leading to the discovery of novel therapeutic targets and diagnostic markers. Furthermore, tumor classification based on their respective molecular fingerprints has led to the classification of cancer subtypes and the discovery of novel molecular taxonomies that may eventually lead to improved patient stratification and superior therapeutic strategies.


Factors affecting aerosol performance during nebulization with jet and ultrasonic nebulizers.
Nebulization of aqueous solutions is a convenient delivery system to deliver drugs to the lungs because it can produce droplets small enough to reach the alveolar region. However, the droplet size might be affected by the changes in the temperature and the concentration of the nebulizing solution in the reservoir during nebulization. In this study, the changes in the droplet size over the nebulization time using a PariBoy air-jet and a Multisonic ultrasonic nebulizer have been studied. The findings were related to changes in the temperature, concentration, surface tension, viscosity and saturated vapour pressure of the nebulizing solution. By using the jet nebulizer, an increase in the droplet size followed by a decrease has been observed. This observation could be attributed to the approx. 7 degrees C reduction of the temperature during the first 2 min in the jet nebulizer reservoir which increased the viscosity of the nebulizing solution. After this initial period of time, the increasing drug concentration induced a reduction of the surface tension and, consequently, a decrease in the droplet size. However, with the ultrasonic nebulizer a temperature increase of approx. 20 degrees C during the first 6 min in the nebulizing solution was observed leading to a decrease in droplet size, viscosity and surface tension and an increasing saturated vapour pressure. This again led to smaller average droplet sizes.


Adriamycin in combination for the treatment of breast cancer: a Southwest Oncology Group study.
Patients with advanced breast cancer who had not previously received chemotherapy were treated on a three-arm prospective study: adriamycin day 1 plus 5-FU on day 1 and 8 (AF), adriamycin day 1, plus 5-FU day 1 and 8, and cyclophosphamide day 1 (AFC), and adriamycin day 1 plus 5-FU day 1 and 8, cyclophosphamide day 1 and methotrexate day 1 (AFCM). These courses were repeated every 21 days. The response rate was 44/105 (42%) AF, 44/103 (43%) AFC and 52/105 (49%) AFCM. The length of response was 22, 33 and 35 weeks, respectively, for AF, AFC and AFCM (P = 0.21). The median survival, 64 weeks, was equal in all three limbs. The major toxicity was leukopenia. Twenty-eight percent developed a WBC of less than 2,000/microliter, which resulted in seven deaths (2.2%).


Approach to Ureterovaginal Fistula: Examining 13 Years of Experience.
We describe the management and outcomes of ureterovaginal fistulas over a 13-year period and present a treatment algorithm. We performed a review of ureterovaginal fistula cases between January 2005 and December 2017 at our tertiary academic center. Demographics, diagnostic approaches, and treatment outcomes were assessed. Nineteen cases of ureterovaginal fistula were identified. Fistulas developed after hysterectomy in 18 cases and cesarean delivery in 1 case. Our primary treatment was conservative management with ureteral stenting in 12 and reimplantation in 6 cases. There was 1 case of spontaneous resolution. Ureteral stenting was successful in 11 (92%) of 12 patients. Stents were left in place for an average of 66 days (27-92 days). Complications of stents included pyelonephritis in 2 cases (18%) and stricture in 1 case (9%). Ultimately, conservative management was successful in treating ureterovaginal fistulas in 10 (83%) of 12 cases. The indications for primary ureteral reimplantation were concurrent vesicovaginal fistula in 3 cases, history of ureteral injury with surgical repair during the index surgery in 2 cases, and a 1-year delay in diagnosis in 1 case. A variety of follow-up surveillance methods were used, including tampon tests, computed tomographic urograms, retrograde pyelograms, and MAG-3 Lasix renal scans. In carefully selected patients, ureteral stenting results in high cure rates for posthysterectomy ureterovaginal fistulas and should be considered first-line therapy. Complicated ureterovaginal fistulas may be best managed by primary ureteral reimplantation.


Incidence and prognostic value of spindles in post-traumatic coma.
One hundred and thirty-three EEGs were analysed from 80 comatose patients with signs of brain stem impairment due to head/brain injury. Seventy EEGs were taken in acute coma on day 1 or 2 after brain injury. Sixty-three EEGs were recorded in prolonged coma 3-12 days after brain injury. Brain stem involvement was divided by neurological signs and by CT scan into secondary lesions due to supratentorial mass displacement and primary lesions due do direct violence to the brain stem. Different EEG patterns were observed, but spindle activity was of special interest. Spindles were classified as typical (easily recognizable, well organized, 12-14 c/sec activity) or atypical (hardly recognizable, distorted form, 6-11 c/sec activity). Furthermore, asymmetries of spindles were noted. The spindles and their alterations were related to different stages of outcome. Spindles were seen in 91% of the EEGs in acute coma and in 30% in prolonged coma. In acute coma due to secondary brain stem involvement a good outcome was heralded by the occurrence of typical symmetrical spindles combined with early stages of secondary brain stem impairment at neurological examination. In cases of primary brain stem involvement typical spindles also suggested a good prognosis despite the observation of serious clinical signs (decerebrate posturing). The percentage of spindle activity decreased, and distortion and asymmetry of spindles increased with the worsening of outcome. Severe intracerebral lesions (confirmed by clinical and CT scan examinations) led to distortion, asymmetry and finally disappearance of spindles. In prolonged coma spindle activity was markedly reduced regardless of the final outcome. When spindles were present atypical and asymmetric forms significantly increased in patients with bad outcome. There were no significant differences in spindle activity in the different outcome categories, if primary and secondary brain stem lesions were compared.


Congenital contracture of the infraspinous muscle. A case report.
Posterior subluxation of the glenohumeral joint and a posterior, winged scapular deformity have been reported in a patient with congenital contracture of the infraspinous muscle. The present case was successfully treated by resection of the contracted band within the infraspinous muscle, glenoid osteotomy, reverse Putti-Platt, and resection of the protruding part of the scapula. To our knowledge, this is the first case reported of congenital contracture of the infraspinous muscle. The pathogenesis of the deformity in this case is discussed.


Unraveling allostery within the angiotensin II type 1 receptor for Gαq and β-arrestin coupling.
G protein-coupled receptors engage both G proteins and β-arrestins, and their coupling can be biased by ligands and mutations. Here, to resolve structural elements and mechanisms underlying effector coupling to the angiotensin II (AngII) type 1 receptor (AT1R), we combined alanine scanning mutagenesis of the entire sequence of the receptor with pharmacological profiling of Gαq and β-arrestin engagement to mutant receptors and molecular dynamics simulations. We showed that Gαq coupling to AT1R involved a large number of residues spread across the receptor, whereas fewer structural regions of the receptor contributed to β-arrestin coupling regulation. Residue stretches in transmembrane domain 4 conferred β-arrestin bias and represented an important structural element in AT1R for functional selectivity. Furthermore, we identified allosteric small-molecule binding sites that were enclosed by communities of residues that produced biased signaling when mutated. Last, we showed that allosteric communication within AT1R emanating from the Gαq coupling site spread beyond the orthosteric AngII-binding site and across different regions of the receptor, including currently unresolved structural regions. Our findings reveal structural elements and mechanisms within AT1R that bias Gαq and β-arrestin coupling and that could be harnessed to design biased receptors for research purposes and to develop allosteric modulators.


Wnt5a and Wnt11 interact in a maternal Dkk1-regulated fashion to activate both canonical and non-canonical signaling in Xenopus axis formation.
Wnt signaling in development and adult tissue homeostasis requires tight regulation to prevent patterning abnormalities and tumor formation. Here, we show that the maternal Wnt antagonist Dkk1 downregulates both the canonical and non-canonical signaling that are required for the correct establishment of the axes of the Xenopus embryo. We find that the target Wnts of Dkk activity are maternal Wnt5a and Wnt11, and that both Wnts are essential for canonical and non-canonical signaling. We determine that Wnt5a and Wnt11 form a previously unrecognized complex. This work suggests a new aspect of Wnt signaling: two Wnts acting in a complex together to regulate embryonic patterning.


Antihypertensive effects of immunosuppressive therapy in autoimmune disease.
Systemic lupus erythematosus (SLE) is a chronic multisystem autoimmune disorder that primarily affects women of childbearing age. While immune system dysfunction has been implicated in the development of hypertension (HTN) in SLE, the effect of immunomodulatory drugs on blood pressure (BP) control in SLE patients is unknown. In the present study, we hypothesized that first-line immunomodulatory therapies prescribed to SLE patients would have a beneficial impact on BP. We retrospectively analyzed the Research Data Warehouse containing de-identified patient data (n = 1,075,406) from the University of Mississippi Medical Center for all patients with a clinical diagnosis of SLE. BP responses were analyzed in SLE patients that were initially prescribed a single therapy (methotrexate, hydroxychloroquine, azathioprine, mycophenolate mofetil (MMF), or prednisone). Of the 811 SLE patients who met criteria, most were hypertensive (56%), female (94%), and black (65%). Individuals prescribed MMF or hydroxychloroquine had significantly decreased BP and improved BP control at follow-up (>7 days and <3 months after initial visit). Our results suggest that MMF and hydroxychloroquine have beneficial effects on BP, independent of adjunctive antihypertensive therapies and existing renal disease.


Trends in laboratory-confirmed bacterial meningitis (2012-2019): national observational study, England.
Bacterial meningitis is associated with significant morbidity and mortality worldwide. We aimed to describe the epidemiology, aetiology, trends over time and outcomes of laboratory-confirmed bacterial meningitis in England during 2012-2019. UK Health Security Agency routinely receives electronic notifications of confirmed infections from National Health Service hospital laboratories in England. Data were extracted for positive bacterial cultures, PCR-positive results for Neisseria meningitidis or Streptococcus pneumoniae from cerebrospinal fluid and positive blood cultures in patients with clinical meningitis. During 2012-19, there were 6554 laboratory-confirmed cases. Mean annual incidence was 1.49/100,000, which remained stable throughout the surveillance period (p = 0.745). There were 155 different bacterial species identified, including 68.4% (106/1550) Gram-negative and 31.6% (49/155) Gram-positive bacteria. After excluding coagulase-negative staphylococci (2481/6554, 37.9%), the main pathogens causing meningitis were Streptococcus pneumoniae (811/4073, 19.9%), Neisseria meningitidis (497/4073, 12.2%), Staphylococcus aureus (467/4073, 11.5%), Escherichia coli (314/4073, 7.7%) and group B streptococcus (268/4073, 6.6%). Pneumococcal meningitis incidence increased significantly during 2012-9, while meningococcal, group A streptococcal and tuberculous meningitis declined. Infants aged <3 months had the highest mean incidence (55.6/100,000; 95% CI, 47.7-63.5) driven mainly by group B streptococci, followed by 3-11 month-olds (8.1/100,000; 95% CI 7.1-9.0), where pneumococcal and meningitis predominated. The 30-day case-fatality rate (CFR) was 10.0% (71/6554). Group A streptococcal meningitis had the highest CFR (47/85, 55.3%). The probability of surviving at 30 days was 95.3% (95% CI, 93.4-97.3%) for infants and 80.0% for older adults (77-84%). The incidence of bacterial meningitis has remained stable. The high CFR highlights a need for prevention through vaccination. PHE.


Abnormal expression of class II MHC antigens in placentae from patients with pemphigoid gestationis: analysis of class II MHC subregion product expression.
Abnormal expression of class II MHC antigens was consistently observed in an immunohistological study on placentae from patients with pemphigoid gestationis. The area affected in all the placentae was the chorionic villi adjacent to the maternal decidua. The villous stroma, and in some cases the chorionic fetal endothelium, had abnormal expression of class II MHC antigens. Monoclonal antibodies specific for the class II MHC subregion products (DR, DP and DQ) were used to analyse the class II MHC antigen expression. Differential expression of the class II MHC subregion products was observed on the villous stroma and chorionic fetal endothelium; DR and DP were always expressed but DQ in some cases was heterogeneous. This abnormal expression of class II MHC antigens may reflect an immunological attack on the placenta in pemphigoid gestationis.


Computed Tomography Angiography Spot Sign as an Indicator for Ultra-Early Stereotactic Aspiration of Intracerebral Hemorrhage.
Ultra-early surgical clot removal relieves mechanical compression on adjacent normal brain tissue and limits the toxic effects of a hematoma, which might improve the outcomes in patients with intracerebral hemorrhage (ICH); however, hematoma expansion frequently occurs within 20 hours after the ictus, and this limits the use of ultra-early surgery. Computed tomography angiography spot sign was recently validated as an important predictor of hematoma expansion in patients with ICH. Fifty-nine patients with ICH and negative spot sign who received ultra-early stereotactic aspiration (<6 hours after ictus; n = 32 [Ultra-early group]) or routine stereotactic aspiration (≥6 hours after ictus; n = 27 [Routine group]) were included in retrospective analysis. The percentage of rebleeding was not significantly different between the 2 groups. Perihematoma edema 7 days after surgery in the Ultra-early group was significantly less frequent than that in the Routine group. For long-term outcomes, the proportion of patient fatalities and Glasgow Outcome Scale score were not significantly different between the 2 groups; however, for patients with severe symptoms, the rate of good neurological outcome in the Ultra-early group was higher than that in the Routine group. Ultra-early stereotactic aspiration might decrease the volume of perihematoma edema and improve the functional outcomes to some extent, without increasing the recurrence of ICH and patient fatalities. Our findings suggest that using negative spot sign as an indicator for performing ultra-early stereotactic aspiration could be a safe and effective protocol for ICH patients.


Quantitative Histogram Analysis on Intracranial Atherosclerotic Plaques: A High-Resolution Magnetic Resonance Imaging Study.
Intracranial atherosclerosis is one of the main causes of stroke, and high-resolution magnetic resonance imaging provides useful imaging biomarkers related to the risk of ischemic events. This study aims to evaluate differences in histogram features between culprit and nonculprit intracranial atherosclerosis using high-resolution magnetic resonance imaging. Two hundred forty-seven patients with intracranial atherosclerosis who underwent high-resolution magnetic resonance imaging sequentially between January 2015 and December 2016 were recruited. Quantitative features, including stenosis, plaque burden, minimum luminal area, intraplaque hemorrhage, enhancement ratio, and dispersion of signal intensity (coefficient of variation), were analyzed based on T2-, T1-, and contrast-enhanced T1-weighted images. Step-wise regression analysis was used to identify key determinates differentiating culprit and nonculprit plaques and to calculate the odds ratios (ORs) with 95% CIs. In total, 190 plaques were identified, of which 88 plaques (37 culprit and 51 nonculprit) were located in the middle cerebral artery and 102 (57 culprit and 45 nonculprit) in the basilar artery. Nearly 90% of culprit lesions had a degree of luminal stenosis of <70%. Multiple logistic regression analyses showed that intraplaque hemorrhage (OR, 16.294 [95% CI, 1.043-254.632]; P=0.047), minimum luminal area (OR, 1.468 [95% CI, 1.032-2.087]; P=0.033), and coefficient of variation (OR, 13.425 [95% CI, 3.987-45.204]; P<0.001) were 3 significant features in defining culprit plaques in middle cerebral artery. The enhancement ratio (OR, 9.476 [95% CI, 1.256-71.464]; P=0.029), intraplaque hemorrhage (OR, 2.847 [95% CI, 0.971-10.203]; P=0.046), and coefficient of variation (OR, 10.068 [95% CI, 2.820-21.343]; P<0.001) were significantly associated with plaque type in basilar artery. Coefficient of variation was a strong independent predictor in defining plaque type for both middle cerebral artery and basilar artery with sensitivity, specificity, and accuracy being 0.79, 0.80, and 0.80, respectively. Features characterized by high-resolution magnetic resonance imaging provided complementary values over luminal stenosis in defined lesion type for intracranial atherosclerosis; the dispersion of signal intensity in histogram analysis was a particularly effective predictive parameter.


In vitro inhibitory properties of sesquiterpenes from Chloranthus serratus on cell motility via down-regulation of LIMK1 activation in human breast cancer.
LIM kinase 1 plays an important role in tumor cell invasion and metastasis by regulating architecture of actin cytoskeleton, and inhibiting activity of this kinase may be a promising strategy to prevent cancer cells from distant spread. In our previous studies, we found several extracts from the medical herbs in genus Chloranthus to exhibit anti-metastatic effects. The aim of this study is to find LIMK1 inhibitors from Chloranthus serratus, a medical herb from genus Chloranthus and to evaluate their effects on cell motility. Three sesquiterpenes, chloranthalactone E (compound 1), serralactone A (compound 2, SERA is used in the further testing), and 8β, 9α-dihydroxylindan-4(5), 7(11)-dien-8α, 12-olide (compound 3) were isolated from Chloranthus serratus, and the anti-LIMK1 activities of these compounds were investigated by kinase-Glo® luminescent kinase assay. Then, the anti-LIMK1 properties of SERA were verified by kinase-Glo® luminescent kinase assay and western blot assay. The effects of SERA on F-actin polymerization and cell migration were investigated by Phalloidin dying, AP 48 chamber system and ORIS™ cell migration assay. Furthermore, the inhibitory effects of SERA on LIMK1 were confirmed by overexpression of LIMK1 and small interfering RNA (siRNA) mediated gene silencing. we reported here that among the three sesquiterpenes, SERA showed significantly inhibition on LIMK1 activity, and the IC50 values on MDA-MB-231 and MDA-MB-468 cells were 3.14 μM and 4.64 μM, respectively. Furthermore, it was also found that SERA significantly suppressed LIMK1 and cofilin1 phosphorylation, F-actin polymerization and also cell migration. Data from LIMK1 overexpression and RNA interfering assay confirmed that the inhibitory effects of SERA on LIMK1 was antagonized and enhanced by the overexpression and knockdown of LIMK1. collectively, it was concluded that SERA exhibited significant inhibitory effects on breast cancer cells migration, and these effects of this sesquiterpene are due to its properties reducing the activation of LIM kinase 1.


Treatment research for children and youth exposed to traumatic events: moving beyond efficacy to amp up public health impact.
Population-based demands for trauma services have accelerated interest in the rapid deployment of efficacious interventions to address the diverse mental health consequences of traumatic experiences. However, optimal strategies for supporting either implementation or dissemination of trauma-focused interventions within healthcare or mental healthcare systems are underdeveloped. This work offers suggestions for adapting treatment research parameters in order to advance the science on the implementable and practical use of trauma-focused interventions within a public health framework. To this end, we briefly examine the current status of research evidence in this area and discuss efficacy and effectiveness treatment research parameters with specific attention to the implications for developing the research base on the implementation and dissemination of effective trauma practices for children and adolescents. Examples from current studies are used to identify approaches for developing, testing and enhancing strategies to roll out effective treatment practices in real-world settings. New approaches that reflect the contexts in which these practices are implemented may enhance the feasibility, acceptability, replicability and sustainability of trauma treatments and services, and thus improve outcomes for a broader population of youth and families.


Development of a Protocol for Objectively Measuring Digital Device Use in Youth.
Screen time is predominantly measured using questionnaires assessing a limited range of activities. This project aimed to develop a coding protocol that reliably identified screen time, including device type and specific screen behaviors, from video-camera footage. Screen use was captured from wearable and stationary PatrolEyes video cameras in 43 participants (aged 10-14 years) within the home environment (May-December 2021, coding in 2022, statistical analysis in 2023). After extensive piloting, the inter-rater reliability of the final protocol was determined in 4 coders using 600 minutes of footage from 18 participants who spent unstructured time on digital devices. Coders independently annotated all footage to determine 8 device types (e.g., phone, TV) and 9 screen activities (e.g., social media, video gaming) using Observer XT (behavioral coding software). Reliability was calculated using weighted Cohen's κ for duration per sequence (meets criteria for total time in each category) and frequency per sequence (meets criteria for total time in each category and order of use) for every coder pair on a per-participant and footage type basis. Overall reliability of the full protocol was excellent (≥0.8) for both duration per sequence (κ=0.89-0.93) and the more conservative frequency per sequence (κ=0.83-0.86) analyses. This protocol reliably differentiates between different device types (κ=0.92-0.94) and screen behaviors (κ=0.81-0.87). Coder agreement ranged from 91.7% to 98.8% across 28.6-107.3 different instances of screen use. This protocol reliably codes screen activities in adolescents, offering promise for improving the understanding of the impact of different screen activities on health.


Human endogenous oxytocin and its neural correlates show adaptive responses to social touch based on recent social context.
Both oxytocin (OT) and touch are key mediators of social attachment. In rodents, tactile stimulation elicits the endogenous release of OT, potentially facilitating attachment and other forms of prosocial behavior, yet the relationship between endogenous OT and neural modulation remains unexplored in humans. Using a serial sampling of plasma hormone levels during functional neuroimaging across two successive social interactions, we show that contextual circumstances of social touch influence not only current hormonal and brain responses but also later responses. Namely, touch from a male to his female romantic partner enhanced her subsequent OT release for touch from an unfamiliar stranger, yet females' OT responses to partner touch were dampened following stranger touch. Hypothalamus and dorsal raphe activation reflected plasma OT changes during the initial social interaction. In the subsequent interaction, precuneus and parietal-temporal cortex pathways tracked time- and context-dependent variables in an OT-dependent manner. This OT-dependent cortical modulation included a region of the medial prefrontal cortex that also covaried with plasma cortisol, suggesting an influence on stress responses. These findings demonstrate that modulation between hormones and the brain during human social interactions can flexibly adapt to features of social context over time.


A prospective randomized trial of the cut-and-sew Maze procedure in patients undergoing surgery for rheumatic mitral valve disease.
To evaluate the safety and efficacy of the addition of the cut-and-sew Maze III procedure (CSM) for mitral valve replacement (MVR) in patients with atrial fibrillation (AF) associated with rheumatic mitral valve disease (RMVD). A total of 130 patients with persistent or long-standing persistent AF associated with RMVD were assigned at random to either the CSM plus MVR (Maze III) group or MVR alone (non-Maze) group. The primary endpoint was a composite of freedom from stroke and death at 1 year. There were no significant differences between the Maze III and non-Maze groups in terms of major complications and in-hospital mortality. One-year freedom from stroke or death was better in the Maze III group compared with the non-Maze group (P = .0028; hazard ratio, 0.2653; 95% confidence interval, 0.1122 to 0.6270). The risk of AF recurrence in the Maze III group was 0.002-fold that in non-Maze group (P = .000). Addition of the CSM to an MVR procedure can decrease the risk of stroke or death and high sinus rhythm at 1 year without increasing the operative risk. CSM is a safe and effective approach to treating AF associated with RMVD.


Patch testing with patients' own cosmetics and toiletries--results of the IVDK*, 1998-2002.
Patch test results with products brought in by the patients collected by the members of the Information Network of Departments of Dermatology (IVDK) between 1998 and 2002 were analysed. 5911 patients were patch tested with their own cosmetics and toiletries during this period. The 34 082 single test preparations applied to these 5911 patients were manually assigned to 1 of 26 categories, based on the EU Classification Annex I to 76/768/EEC, which had been further refined. The leave-on product category most commonly tested was 'creams, emulsions, lotions, gels and oils for the skin' (n = 3621 tested, n = 312 positive). The rinse-off product type most commonly tested was 'bath and shower preparations' (n = 1333 tested, n = 71 positive). In one-third of patients tested positive to these products, no other positive test result was observed. In the remainder, positive reactions to the fragrance mix, Myroxylon pereirae resin, methyldibromo glutaronitrile, (chloro-)methylisothiazolinone, 2-bromo-2-nitropropane-1,3-diole and further ingredients of cosmetics and toiletries were more common than in product-negative patients. However, in view of the potential for false-positive reactions mainly to rinse-off products, the results must be interpreted with caution. In conclusion, testing of patients' own products can be regarded as efficient and safe, if in accordance with current recommendations.


[Assessment of the sensitizing potency of cosmetic ingredients and commodities. How will the ingredients of cosmetics and commodities be tested in Europe today and tomorrow?].
Cosmetics and certain commodities are applied or used by consumers directly on the skin. Creams may remain on the skin for longer periods, hair is dyed multiple times per year, nickel ions can be released from studs and piercings in areas of skin damage or migrate from toy materials into the skin of children. Accordingly, using or handling such products always entails a risk for developing a contact allergy. Moreover, daily usage and repeated contacts to certain cosmetics and commodities might lead to repeated elicitation of contact eczema in people already sensitized against allergenic ingredients. Unfortunately, contact allergy is not curable. For the assessment of the allergenic potential of chemicals, only testing based on animal experiments was available in the past. In 2003, the 7(th) amendment of the Cosmetics Directive 76/768/EWG laid down a ban on animal testing of cosmetic ingredients and from 2013 a general marketing ban of such products as well. Therefore, the development and validation of non-animal methods for assessing the toxicological endpoint sensitization/allergenic potency of chemicals is a major task for the years ahead and remains equally a challenge for industry and regulatory agencies.


Massive contralateral pneumonia following thoracotomy for lung resection.
Separation of the lungs with a double-lumen endobronchial tube facilitates the surgical approach and protects the bronchial system from contamination by pus or blood from the operated lung. We report a case of a 49-year-old man who suffered a gram-negative pneumonia requiring mechanical ventilatory support and prolonged hospitalization after pulmonary resection. Contamination of the ventilated-dependent lung was documented intraoperatively. Current information on postoperative infectious complications and preventive measures are discussed.