Wingspan stent-assisted coiling of intracranial aneurysms with symptomatic parent artery stenosis: experience in 35 patients with mid-term follow-up results.
There is a potential risk of aneurysm rupture after parent artery revascularization because of increased blood flow. The purpose of this study is to assess the efficacy and safety of Wingspan stent-assisted coil embolization in the treatment of intracranial aneurysms with symptomatic parent artery stenosis. Thirty-five consecutive patients (19 men, 16 women; age range, 48-79 years; mean age, 60.4 years) harboring 35 unruptured wide-necked or fusiform intracranial aneurysms (mean size 6.8mm; range 2.5-18 mm.) with symptomatic parent artery stenosis (mean degree 71.1%; range 50-92%) were treated with the Wingspan stent-assisted coiling. Twenty-four lesions were located in the anterior circulation and eleven in the posterior circulation. Patients were premedicated with antiplatelet therapy consisting of aspirin 300 mg and clopidogrel 75 mg for at least 3 days before the procedure. Following pre-dilatation and stent placement, a coiling microcatheter entered the aneurysm through the interstices of the stent, and then coiling was performed. After the procedure, clopidogrel 75 mg daily was recommended for an additional 30 days, and aspirin 100mg was recommended throughout follow-up. For all patients, clinical follow-up was conducted by clinic visitation, or telephone interview. Angiographic follow-up with DSA was recommended at 6 months and 1 year after the procedure. Angiography follow-up (mean time 10.6 months) was obtained in 31 cases (88.6%). The technical feasibility of the procedure, procedure-related complications, angiographic results, clinical outcome and follow-up angiography were evaluated. In every case, technical success was achieved. The degree of stenosis was reduced from 71.1% to 17.4% after balloon angioplasty and stenting. Immediate angiography demonstrated complete occlusion in 25 cases (71.4%), neck remnant in 7 cases (20.0%), and incomplete occlusion in 3 cases (8.6%). Procedure-related morbidity occurred in two patients (5.7%), including thromboembolism (n=1) and occlusion of small penetrating arteries (n=1). At follow-up (mean time 18.3 months), two additional cases of ischemic stroke occurred. The overall frequency of any stroke, intracranial hemorrhage, or death within 30 days or ipsilateral stroke beyond 30 days was 11.4%. No rehemorrhage of treated aneurysm occurred. At angiographic follow-up, four cases demonstrated ≥ 50% in-stent restenosis (12.9%), one of which was symptomatic, and two aneurysms (6.4% of the follow-up angiograms) demonstrated recanalization. We found that the Wingspan stent-assisted coil embolization was helpful in the treatment of intracranial aneurysms with parent artery stenosis.


The 1942 fire at Boston's Cocoanut Grove nightclub.
The year 1992 marked the 50th anniversary of one of the worst civilian disasters in American history. On November 28, 1942, fire destroyed Boston's Cocoanut Grove nightclub, killing 491 people and sending hundreds more to area hospitals. The disaster came at a unique time in the history of burn care and resulted in a number of important advances in burn treatment, including the first comprehensive descriptions of inhalation injury, improvements in topical treatment of burn wounds, resuscitation of shock, use of antibiotics, and understanding of the metabolic response to injury. In addition, the fire stimulated organization of burn care facilities, public safety legislation, and burn prevention. The history of the fire is reviewed, emphasizing its role in stimulating advances that formed some of the foundations of modern burn treatment.


Impact of renal function on hydroxyurea exposure in sickle-cell disease patients.
This prospective study aimed to develop a population pharmacokinetics (PK) model of hydroxyurea (HU) in patients with sickle cell disease. This model can be used to determine the impact of glomerular filtration rate (GFR) on HU kinetics. We included 30 patients. They underwent HU pharmacokinetics analyses of plasma and urine. Six underwent PK analyses in 2 periods with and without angiotensin-converting enzyme inhibitor. HU was assayed with a validated high-performance liquid chromatography-UV method. Noncompartmental PK analysis was conducted and a population PK model built with Monolix. This model was validated externally on another 56 patients. HU PK was simulated as a function of GFR. The HU PK model was constructed as a 2-compartment model with first-order absorption and elimination. The quality criteria were good, including for external validation. We found that estimated GFR (eGFR) and body weight affected HU PK, with lower eGFR or body weight associated with a higher HU area under the curve. We recommend the monitoring of HU through eGFR and body weight, which together account for 47% of its variability. Urinary HU fractions and renal clearance were higher in the glomerular hyperfiltration group and lower in the moderate chronic kidney disease group, respectively. No differences in nonrenal HU clearance were observed. Estimated GFR has an impact on the kinetics of hydroxyurea, and HU dose should be adapted accordingly. Angiotensin-converting enzyme inhibitor seems to have minor effect on HU PK in adults with sickle cell disease.


Evaluation of patient care interventions and recommendations by a transitional care pharmacist.
A "transitional care pharmacist" (TCP) was deployed within an acute care setting to identify opportunities for improved continuity of care. The provision of medication reconciliation services, drug consultation, patient counseling and planning for after-hospital care was time consuming but also fruitful, resulting in roughly nine interventions per patient. Areas with the greatest potential for morbidity reduction were the resumption of home medications during the acute stay and at discharge. Allergy identification was a key contribution at admission, as was the provision of a detailed follow-up plan at discharge. Targeting high-risk patients and spreading portions of the work to other disciplines could achieve added efficiency in this service. Results have value to hospitals implementing medication reconciliation programs.


Detection and assessment of alpha-synuclein in Parkinson disease.
Different studies have reported varying alpha-synuclein values in the cerebrospinal fluid (CSF), serum, and plasma, making determination of the alpha-synuclein cutoff value for Parkinson's disease difficult and rendering identifying the cause of variation essential. We searched PubMed from inception to June 2021 and identified 76 eligible studies. Included studies reported data on total, phosphorylated, and oligomeric alpha-synuclein in the CSF, serum, or plasma from individuals with Parkinson's disease and healthy controls. The mean or median alpha-synuclein values from the included studies were summarized and categorized through laboratory assays to visualize potential trends. The enzyme-linked immunosorbent assay (ELISA) is the most common assay used to determine alpha-synuclein concentrations. Less common assays include Luminex, single molecule arrays, electrochemiluminescence, and immunomagnetic reduction (IMR). IMR is a single-antibody and wash-free immunoassay designed for determining the extremely low concentration of bio-molecules. For patients with Parkinson's disease, the median or mean testing values ranged from 60.9 to 55,000 pg/mL in the CSF, 0.446 to 1,777,100 pg/mL in plasma, and 0.0292 to 38,200,000 pg/mL in serum. The antibody selection was diverse between studies. The tendency of distribution was more centralized among studies that used the same kit. Studies adopting specific antibodies or in-house assays contribute to the extreme values. Only a few studies on phosphorylated and oligomeric alpha-synuclein were included. The type of assay and antibody selection in the laboratory played major roles in the alpha-synuclein variation. Studies that used the same assay and kit yielded relatively unanimous results. Furthermore, IMR may be a promising assay for plasma and serum alpha-synuclein quantification. A consensus on sample preparation and testing protocol unification is warranted in the future.


Exploring the Relationship Between Schizophrenia and Cardiovascular Disease: A Genetic Correlation and Multivariable Mendelian Randomization Study.
Individuals with schizophrenia have a reduced life-expectancy compared to the general population, largely due to an increased risk of cardiovascular disease (CVD). Clinical and epidemiological studies have been unable to unravel the nature of this relationship. We obtained summary-data of genome-wide-association studies of schizophrenia (N = 130 644), heart failure (N = 977 323), coronary artery disease (N = 332 477), systolic and diastolic blood pressure (N = 757 601), heart rate variability (N = 46 952), QT interval (N = 103 331), early repolarization and dilated cardiomyopathy ECG patterns (N = 63 700). We computed genetic correlations and conducted bi-directional Mendelian randomization (MR) to assess causality. With multivariable MR, we investigated whether causal effects were mediated by smoking, body mass index, physical activity, lipid levels, or type 2 diabetes. Genetic correlations between schizophrenia and CVD were close to zero (-0.02-0.04). There was evidence that liability to schizophrenia causally increases heart failure risk. This effect remained consistent with multivariable MR. There was also evidence that liability to schizophrenia increases early repolarization pattern, largely mediated by BMI and lipids. Finally, there was evidence that liability to schizophrenia increases heart rate variability, a direction of effect contrasting clinical studies. There was weak evidence that higher systolic blood pressure increases schizophrenia risk. Our finding that liability to schizophrenia increases heart failure is consistent with the notion that schizophrenia involves a systemic dysregulation of the body with detrimental effects on the heart. To decrease cardiovascular mortality among individuals with schizophrenia, priority should lie with optimal treatment in early stages of psychosis.


[Effect of preoperative paromomycin therapy on the course of wound healing after colonic intervention. A prospective blind study].
156 patients undersent colorectal surgery during a prospective blind study at the Städt. Krankenhaus München-Harlaching. The study showed that administration of 4,0 g Paromomycin (= Humatin) on each of the two preoperative days combined with mechanical cleansing of the intestine has a beneficial effect. Our test group showed significantly lower incidence of wound complications at the abdominal laparotomies (p less than 0,05; X2) and at the anastomoses (p less than 0,01; X2 than the control group. Anastomic leakage (major leaks) and following septical complications occurred nearly exclusively in our "Not-Humatin-group". The lethality of the entire group was 13,1% (n = 20).


Genome-wide analysis displays marked induction of EBI3/IL-27B in IL-18-activated AML-derived KG1 cells: critical role of two kappaB binding sites in the human EBI3 promotor.
The cell line KG1 is derived from a patient with acute myeloid leukemia. Activation of KG1 cells by interleukin (IL)-18 is associated with induction of key Th1 signature parameters such as T-bet and interferon-gamma. Here we set out to characterize the genome-wide mRNA expression profile under the condition of short-term stimulation (4h) with IL-18 using the Affymetrix GeneChip((R)) Array System. Besides the chemokines CXCL10, CXCL11, and CCL1 we identified Epstein-Barr virus induced gene-3 (EBI3)/IL-27B as being among those genes that are profoundly upregulated by IL-18 in KG1 cells. Thorough investigation revealed that IL-18-induced EBI3 mRNA efficiently translates into protein. Electromobility shift analysis and mutational analysis of the human EBI3 promoter identified two nuclear factor-kappaB binding sites as being crucial for induction by pro-inflammatory cytokines like IL-18. In addition, we demonstrate that KG1 cells express the Type A IL-27 receptor chain (WSX-1) and display STAT-1, -3 activation as well as induction of SOCS-3 under the influence of IL-27. IL-18 shows therapeutic potential in murine leukemia and is currently being evaluated in phase II clinical trials for the treatment of immunologically sensitive cancers. Since IL-27 mediates anti-cancer bioactivity in animal models, data presented herein may add a novel facet to tumorsuppressive characteristics of IL-18.


Investigation of mode coupling in strained and unstrained multimode step-index POFs using the Langevin equation.
The Langevin equation (LE) is used to evaluate mode coupling in multimode step-index polymer optical fiber (SI POF) that is both unstrained and strained. The numerical solution of the LE matches the numerical solution of the power flow equation (PFE). Strain-induced mode coupling is noticeably stronger in strained fiber than in unstrained fiber of the same types. Therefore, compared to similar lengths for unstrained fibers, the coupling length of the equilibrium mode distribution (EMD) is attained and the length of fiber required to produce a steady-state distribution (SSD) are both much shorter for strained fibers. We have demonstrated that the mode coupling in strained and unstrained multimode SI POFs that comes from the random perturbations (RPs) of the fiber can be successfully treated by the LE. The study's findings can be used to improve communication and sensory systems that use multimode SI POFs under different bending circumstances. Additionally, it is crucial to be able to compute the modal distribution of the SI POFs used in the optical fiber sensory system at a specific length and under various bending scenarios.


Comprehensive Serology Based on a Peptide ELISA to Assess the Prevalence of Closely Related Equine Herpesviruses in Zoo and Wild Animals.
Equine herpesvirus type 1 (EHV-1) causes respiratory disorders and abortion in equids while EHV-1 regularly causes equine herpesvirus myeloencephalopathy (EHM), a stroke-like syndrome following endothelial cell infection in horses. Both EHV-1 and EHV-9 infections of non-definitive hosts often result in neuronal infection and high case fatality rates. Hence, EHV-1 and EHV-9 are somewhat unusual herpesviruses and lack strict host specificity, and the true extent of their host ranges have remained unclear. In order to determine the seroprevalence of EHV-1 and EHV-9, a sensitive and specific peptide-based ELISA was developed and applied to 428 sera from captive and wild animals representing 30 species in 12 families and five orders. Members of the Equidae, Rhinocerotidae and Bovidae were serologically positive for EHV-1 and EHV-9. The prevalence of EHV-1 in the sampled wild zebra populations was significantly higher than in zoos suggesting captivity may reduce exposure to EHV-1. Furthermore, the seroprevalence for EHV-1 was significantly higher than for EHV-9 in zebras. In contrast, EHV-9 antibody prevalence was high in captive and wild African rhinoceros species suggesting that they may serve as a reservoir or natural host for EHV-9. Thus, EHV-1 and EHV-9 have a broad host range favoring African herbivores and may have acquired novel natural hosts in ecosystems where wild equids are common and are in close contact with other perissodactyls.


[Analgesia with remifentanil in spontaneously breathing patients undergoing brief but painful radiological procedures].
Percutaneous transhepatic biliary drainage (PTBD) and stenting are very painful procedures in interventional radiology and require potent analgesia; employing remifentanil in spontaneously breathing patients may be one possible strategy. The study group was composed of 18 men and 2 women with a mean age of 63+/-10 (mean+/-SD) years. Pain intensity was measured with a VAS score before the procedure, after local anesthesia on the rib cage, after stenting and after the radiology procedure. Remifentanil infusion (dosage: 0.12-0.30 microg/kg body weight/min) was infused throughout the entire radiology procedure according to physical status, past medical history, individual pain, and clinical assessment. During insufflation of 10l O(2)/min via a venturi mask, oxygen saturation did not fall below 96% at any time-point during the procedure. In the VAS score, we noted a decrease after starting the remifentanil infusion towards the end of procedure. All patients were able to move into bed without help. Postoperatively, no analgesics and no antiemetics were needed. Employing a remifentanil infusion for brief interventional radiology procedures in palliative treatment of patients resulted in high patient and radiologist comfort.


Correction: Krivonogov et al. Microbial Diversity and Authigenic Mineral Formation of Modern Bottom Sediments in the Littoral Zone of Lake Issyk-Kul, Kyrgyz Republic (Central Asia). Biology 2023, 12, 642.
Sergei Krivonogov was not included as an author in the original publication [...].


Enhancement of vascular action of arginine vasopressin by diminished extracellular sodium concentration.
The present study was undertaken to examine the effects of diminished extracellular sodium concentration on the vascular action of arginine vasopressin (AVP) in cultured rat vascular smooth muscle cells (VSMC). The preincubation of cells with the 110 mM extracellular Na+ ([Na+]e) solution supplemented with 30 mM choline chloride for 60 minutes enhanced the effect of AVP- (1 x 10(-8) M) induced VSMC contraction. The treatment of 110 mM [Na+]e solution also enhanced the cellular contractile response to the protein kinase C (PKC) activators, phorbol 12-myristate 13-acetate and 1-oleoyl-2-acetyl-glycerol. Furthermore, preincubation with the 110 mM [Na+]e solution also potentiated the effect of 1 x 10(-8) M AVP, but not 1 x 10(-6) M, to increase the cytosolic-free Ca2+ ([Ca2+]i) concentration. The 110 mM [Na+]e media decreased the basal intracellular Na+ concentration and increased intracellular 45Ca2+ accumulation, basal [Ca2+]i and AVP-produced 45Ca2+ efflux. These effects of 110 mM [Na+]e solution to enhance the vascular action of AVP were abolished by using Ca(2+)-free 110 mM [Na+]e solution during the preincubation period. The preincubation with the 110 mM [Na+]e solution did not change either the Kd and Bmax of AVP V1 receptor of VSMC or the AVP-induced production of inositol 1,4,5-trisphosphate. The present in vitro results therefore indicate that the diminished extracellular fluid sodium concentration within a range observed in clinical hyponatremic states enhances the vascular action of AVP.(ABSTRACT TRUNCATED AT 250 WORDS)


Safety, efficacy, and DIVA feasibility on a novel live attenuated classical swine fever marker vaccine candidate.
Classical swine fever virus (CSFV) is the etiological agent of classical swine fever, a highly contagious disease that causes significant economic losses to the swine industry. Systemic prophylactic immunization with the live attenuated vaccine, the C-strain vaccine, is one of the effective measures for CSF control. However, one of the limitations of the C-strain vaccine is that the field strains-infected animals cannot be differentiated from the C-strain vaccinated herds by serological tests (DIVA). This constraint hampers the practical usage of the C-strain vaccine to eradicate the CSF in China. In the current study, a novel CSF modified live marker vaccine candidate was constructed based on the attenuation of the prevalent 2.1 genotype strain by the deletion of two virulence associated functional residues in the CSFV Erns, H79, and C171. Meanwhile, four residues S14, G22, E24, and E25 were identified specifically for the 6B8 mAb binding to the CSFV E2 as the novel conformational epitope. Then four substitutions of S14K, G22A, E24R, and G25D were further incorporated in the double deletion construct as a negative serological marker. Finally, the double-deletion marker MLV candidate GD18-ddErnHC-KARD was rescued, and its safety and efficacy profiles were evaluated in piglets. The safety study results indicated that the candidate did not induce fever, clinical signs, or pathological lesions with a high dose of 105.0 TCID50, and in addition, no virus shedding was detected until 21 days post-inoculation. Meanwhile, the efficacy study results demonstrated that at a low dose of 103.0 TCID50, it conferred complete clinical protection and no virus shedding was detected after the challenge with a highly virulent Shimen strain. Importantly, the infected animals were differentiated using the accompanied DIVA ELISA. These results constitute a proof-of-concept for rationally designing a CSF antigenically marked modified live vaccine candidate.


Diastolic flow velocity pattern of the left anterior descending coronary artery in hypertrophied heart, with special reference to the difference between hypertrophic cardiomyopathy and hypertensive left ventricular hypertrophy.
This study aimed to clarify the characteristics of diastolic flow velocity pattern of the left anterior descending coronary artery (LAD) in patients with left ventricular hypertrophy (LVH), and the difference in diastolic LAD flow velocity pattern between hypertensive LVH and hypertrophic cardiomyopathy (HCM). The flow velocity pattern was recorded at the mid-portion of the LAD by high-frequency transthoracic Doppler echocardiography in 22 patients with HCM, 10 hypertensive patients with LVH [LVH(+)HT], and 9 hypertensive patients without LVH [LVH(-)HT]. The diastolic flow pattern was analyzed. Standard two-dimensional echocardiogram and apexcardiogram (ACG) were also recorded. The interventricular septal thickness (IVST) and the sum of the IVST and LV posterior wall thickness (PWT) (IVST + PWT) were greater in HCM than in HT (p < 0.01) patients. Early diastolic upstroke time (D-UT) of the LAD flow velocity wave was longest in HCM, and was longer in LVH(+)HT than in LVH(-)HT (p < 0.01) patients. Direct correlation was found between D-UT and IVST, IVST + PWT in patients with LVH(+)HT and LVH(-)HT (r = 0.80, 0.79, respectively; p < 0.01), but no correlation was found between these parameters in HCM. Late-diastolic step (LDS) formation of the LAD flow velocity wave was observed in 68% of HCM, 20% of LVH(+)HT, but none of the LVH(-)HT patients. The A wave ratio of ACG was higher in patients with LDS than in those without (p < 0.01). The LDS occurred coincidently with the A wave of ACG. The diastolic LAD flow velocity pattern in hypertrophied heart is characterized by slow acceleration and LDS formation, reflecting impaired relaxation and increased stiffness of the LV, respectively. These abnormalities correlate with the degree of hypertrophy in hypertensive heart, but do not correlate with that in HCM.


Antigen binding to GM1 ganglioside results in delayed presentation: minimal effects of GM1 on presentation of antigens internalized via other pathways.
Plasma membrane rafts are sphingolipid- and cholesterol-rich patches that function as membrane trafficking and surface signalling regions. Ganglioside GM1 is an integral component of these microdomains, and Escherichia coli enterotoxin B subunit (EtxB) is a pentamer that binds with high affinity to GM1 resulting in GM1 cross-linking. We previously demonstrated that antigen coupled directly to EtxB resulted in enhanced presentation relative to antigen taken up by fluid-phase endocytosis. Here we demonstrate a new role for GM1 in antigen presentation by examining the effects of cross-linking GM1 on the kinetics of presentation and processing of antigen by the B-cell receptor (BCR), fluid-phase endocytosis and GM1-targeted antigen. EtxB bound to B cells does not augment the subsequent kinetics or magnitude of presentation of either BCR-internalized antigen or soluble antigen. Moreover, presentation of GM1-bound antigen is significantly slower than antigen presentation following BCR-mediated uptake. In contrast to the rapid internalization of BCR-bound antigen (which has a half life of 60 min), the majority of EtxB-bound antigen forms a plasma membrane depot detectable for many hours after initial incubation (and with a half life of 12 hr). We conclude that cross-linking of GM1 by EtxB minimally affects the processing and presentation of antigens internalized via other pathways. Nevertheless, binding of antigens to GM1 results in delayed presentation that has important implications for in vivo immunization using GM1-targeted adjuvants.


Lonapegsomatropin: Pediatric First Approval.
Lonapegsomatropin (lonapegsomatropin-tcgd; SKYTROFA®), a long-acting prodrug of somatropin (human growth hormone), is in development by Ascendis Pharma as a treatment for growth hormone deficiency in pediatric and adult patients. Lonapegsomatropin received its first approval in August 2021 in the USA for the treatment of pediatric patients at least 1 year of age (and weighing ≥ 11.5 kg) with growth failure due to inadequate secretion of endogenous growth hormone. Lonapegsomatropin is administered as a once-weekly subcutaneous injection; the sustained release of somatropin from lonapegsomatropin eliminates the need for daily somatropin injections. This article summarizes the milestones in the development of lonapegsomatropin leading to this first pediatric approval for the treatment of growth hormone deficiency.


Implementing neural network approach to create carbon-based optical nanosensor of heavy metal ions in liquid media.
The present study is devoted to the creation of multifunctional optical carbon dots-based nanosensor to simultaneously measure concentrations of metal ions (Cu2+, Ni2+, Cr3+) and NO3- anion in liquid media. Such nanosensor operates on the basis of its fluorescence (FL) change under the influence of ions in the medium. However, the absence of analytical model, describing CD FL mechanism, the superposition of various luminescence quenching mechanisms during the interaction of carbon dots (CD) with cations, hampers the usage of classical approaches to solve this inverse multiparametric spectroscopic problem. To solve it neural networks were used that analyzed complex fluorescence signal from CD aqueous suspensions comprising Cu2+, Ni2+, Cr3+, NO3- ions in the concentration range from 0 to 4.95 mM. The following neural network architectures ensured optical spectroscopy inverse problem solution: multilayer perceptrons, 1D and 2D convolutional neural networks. The developed sensor enables simultaneous determination of the concentrations of heavy metal ions Cu2+, Ni2+, Cr3+ with a root mean squared error of 0.28 mM, 0.79 mM, 0.24 mM respectively. Based on the data given in the literature we can assert that the accuracy of the studied nanosensor satisfies the needs of monitoring the composition of waste and technological water. The developed nanosensor has a unique multimodality: with the simplicity of the synthesis protocol the sensor enables simultaneous determination of three heavy metal ions concentrations, while analogues are being developed mainly to measure the concentration of one (in rare cases two) heavy metal ions.


Information complexity of neural networks.
This paper studies the question of lower bounds on the number of neurons and examples necessary to program a given task into feed forward neural networks. We introduce the notion of information complexity of a network to complement that of neural complexity. Neural complexity deals with lower bounds for neural resources (numbers of neurons) needed by a network to perform a given task within a given tolerance. Information complexity measures lower bounds for the information (i.e. number of examples) needed about the desired input-output function. We study the interaction of the two complexities, and so lower bounds for the complexity of building and then programming feed-forward nets for given tasks. We show something unexpected a priori--the interaction of the two can be simply bounded, so that they can be studied essentially independently. We construct radial basis function (RBF) algorithms of order n3 that are information-optimal, and give example applications.


Changes in premovement activity in primary somatosensory cortex differ when monkeys make hand movements in response to visual vs vibratory cues.
Rhesus monkeys were taught to make identical wrist flexion and extension movements in response to either a visual cue or to vibratory cues. Changes in firing rates that were not stimulus-associated but preceded the movements were measured for each primary somatosensory cortical neuron recorded under the two stimulus cued conditions. The onset of the premovement activity changes and the magnitude of these changes differed when visually cued trials were compared with vibratory cued trials that resulted in the same behavioral response. In general, the magnitudes of premovement activity changes were less and the onset of these changes occurred earlier for vibratory cued trials than for the corresponding trials triggered by the visual stimulus. These findings support the hypothesis that centrally generated modulatory influences arriving at primary somatosensory cortical neurons prior to movement onset may differ, depending upon the modality of the stimulus which signals that a movement may be initiated.


Attenuated long-term Arc expression in the aged fascia dentata.
One prominent component of aging is a defect in memory stabilization. To understand how the formation of enduring memories is altered in the aged brain, long-term markers of the biological events that may mediate memory consolidation were used to examine the activity dynamics of hippocampal circuits over extended intervals. The immediate early gene Arc, which is implicated in both durable memory and synaptic plasticity, is expressed in the fascia dentata (FD) for long periods following behavioral experience. To test the hypothesis that aging alters long-term Arc transcription in the FD, a region critical for spatial memory and impaired with progressive age, young and aged rats explored a novel environment twice, separated by an 8-hour interval, and FD Arc transcription was assessed. Relative to young rats, (a) fewer granule cells in the aged FD transcribe arc 8 hours after spatial exploration, and (b) this decrease is correlated with impaired spatial memory. These findings are consistent with behavioral evidence of age-related decline in hippocampal-dependent memory processing long after an event is to be remembered, and reaffirm the integral role of the FD in the neural circuits supporting durable memory.


A new sesquineolignan and four new neolignans isolated from the leaves of Piper betle, a traditional medicinal plant in Myanmar.
One new sesquineolignan, piperneolignan A (1), four new neolignans, piperneolignans B-E (2-5), and eight known compounds were isolated from the leaves of Piper betle (Piperaceae) collected from Myanmar. These new structures were determined by analysis of MS and NMR data, and the absolute configuration of piperneolignan A was elucidated by electronic circular dichroism (ECD) calculations. Piperneolignan A (1), piperneolignan B (2), hydroxychavicol (6), p-hydroxycinnamaldehyde (10), and diallylcatechol (13) possessed anti-inflammatory activity against nitric oxide (NO) production in lipopolysaccharide (LPS)-activated murine macrophage RAW 264.7 cells with IC50 values of 9.87, 45.94, 4.80, 26.40, and 40.45 μM, respectively, compared with the positive control NG-monomethyl-l-arginine (l-NMMA, IC50 = 33.84 μM). The two hydroxy groups in the structure of hydroxychavicol are essential for activity, and dimerization or trimerization of hydroxychavicol decreases activity.


Magnitude and factors associated with birth preparedness and complication readiness among pregnant women in Wolaita Zone, Ethiopia.
To assess the magnitude and factors associated with birth preparedness and complication readiness (BPCR) among pregnant women in Humbo district, Wolaita Zone, Ethiopia. A community-based cross-sectional study was conducted from August 1 to 30, 2020. A total of 506 pregnant women were randomly selected and interviewed using a questionnaire. Data were entered using EpiData version 4.6.0, and analysis was made using SPSS version 24. An adjusted odds ratio (aOR) with a 95% confidence interval (CI) was calculated. The magnitude of BPCR in the Humbo district was 26.0%. The odds of being prepared for birth and its complications were higher among women who had a history of obstetric complications (aOR 2.77; 95% CI 1.18-6.52), participated in pregnant women's conferences (aOR 3.84; 95% CI 2.13-6.93), received advice on BPCR (aOR 2.39; 95% CI 1.36-4.22), and were knowledgeable on labor and childbirth danger signs (aOR 2.64; 95% CI 1.55-4.49). The magnitude of birth preparedness and complication readiness was low in the study area. The healthcare provider should encourage the women to participate in conferences and provide continuous counseling during their prenatal care visits.


Fixators dynamization for delayed union and non-union of femur and tibial fractures: a review of techniques, timing and influence factors.
The optimal balance between mechanical environment and biological factors is crucial for successful bone healing, as they synergistically affect bone development. Any imbalance between these factors can lead to impaired bone healing, resulting in delayed union or non-union. To address this bone healing disorder, clinicians have adopted a technique known as "dynamization" which involves modifying the stiffness properties of the fixator. This technique facilitates the establishment of a favorable mechanical and biological environment by changing a rigid fixator to a more flexible one that promotes bone healing. However, the dynamization of fixators is selective for certain types of non-union and can result in complications or failure to heal if applied to inappropriate non-unions. This review aims to summarize the indications for dynamization, as well as introduce a novel dynamic locking plate and various techniques for dynamization of fixators (intramedullary nails, steel plates, external fixators) in femur and tibial fractures. Additionally, Factors associated with the effectiveness of dynamization are explored in response to the variation in dynamization success rates seen in clinical studies.


Structural, Hirshfeld surface and three-dimensional inter-action-energy studies of 1,3,5-triethyl 2-amino-3,5-di-cyano-4,6-bis-(4-fluoro-phen-yl)cyclo-hex-1-ene-1,3,5-tri-carboxyl-ate.
In the title compound, C29H27F2N3O6, which crystallizes in the monoclinic space group P21/c, the cyclo-hexenone ring is puckered and adopts an envelope conformation. The crystal structure features various inter-molecular inter-actions, such as N-H⋯O, C-H⋯N and C-H⋯O. These inter-actions were investigated using Hirshfeld surface analysis and the three-dimensional inter-action energies were calculated using the B3LYP/6-31 G(d,p) energy density model.


Parental hypertension and 24 h-blood pressure in children prior to diabetic nephropathy.
In a search for predictors of nephropathy development, albumin excretion rate (AER), ambulatory blood pressure, and parental hypertension were assessed in 40 type 1 diabetic patients and 27 normal siblings (age<18 years) during a 2-year follow-up period. A double-antibody kit and an automated device were used for measuring 24-h AER and ambulatory blood pressure monitoring (ABPM), respectively. Patients had higher 24-h and daytime diastolic blood pressure (DBP), diastolic load, and daytime heart rate than siblings. Patients with hypertensive parents had higher 24-h DBP and diastolic load than patients with normotensive parents and all siblings. Non-dipping was more frequent in children with hypertensive parents ( P<0.05). Both diabetes ( P<0.001) and parental hypertension ( P<0.05) had independent effects on longitudinal AER (average AER during follow-up). Patients with intermittent or persistent microalbuminuria showed a trend towards higher diastolic load ( P<0.05); the latter group had higher 24-h DBP ( P<0.01). Longitudinal AER correlated with 24-h DBP ( P<0.01) and maternal mean blood pressure ( P<0.05). Since changes in blood pressure preceded persistent microalbuminuria, ABPM might help to identify diabetic children prone to nephropathy.


Thinking about Causation: A Thought Experiment with Dominos.
We argue that population attributable fractions, probabilities of causation, burdens of disease, and similar association-based measures often do not provide valid estimates or surrogates for the fraction or number of disease cases that would be prevented by eliminating or reducing an exposure because their calculations do not include crucial mechanistic information. We use a thought experiment with a cascade of dominos to illustrate the need for mechanistic information when answering questions about how changing exposures changes risk. We suggest that modern methods of causal artificial intelligence (CAI) can fill this gap: they can complement and extend traditional epidemiological attribution calculations to provide information useful for risk management decisions.


Interface-mediated fabrication of bowl-like and deflated ballon-like hollow carbon nanospheres.
In our work, two kinds of hollow carbon nanospheres with controlled morphologies have been successfully prepared from low-cost and nontoxic glucose as the sole carbon precursor under neutral aqueous medium via a simple hydrothermal route. During the process, sodium dodecylbenzene sulfonate (SDBS) and triblock copolymer P123 ((EO)20(PO)70(EO)20) was skillfully selected as the structure-directing agent, respectively. SEM, TEM and AFM results revealed that the two products showed bowl-like and deflated-balloon-like morphology with uniform particle sizes, respectively. Based on the experimental observations, a possible formation mechanism was also discussed, in which the growth of the carbon nanospheres involved an interface-medicated assembly process. The present method was easy, green and mild. Apart from the unique nanostructure, the obtained bowl-like hollow carbon nanospheres exhibited excellent biocompatibility. In particular, it should be mentioned that the open window formed by the bowl-like morphology can facilitate ion transport, thus improving their performances.


Correction to: Differences in Characteristics and Outcome of Patients with Penetrating Injuries in the USA and the Netherlands: A Multi-institutional Comparison.
In the original article Dennis Den Hartog's name was tagged incorrectly. It is correct as reflected here.


Binding of autoimmune cardiolipin-reactive antibodies to heparin: a mechanism of thrombosis?
Autoimmune CL-rA need a plasma protein, beta 2GPI, to bind anionic PL. While beta 2GPI could be the true antigen, beta 2GPI binding to solid phase heparin did not determine its recognition by CL-rA when using patient plasmas. We tested plasmas from four patients with antiphospholipid syndrome in this study and no CL-rA binding to heparin sepharose was obtained. On the contrary, when CL-rA were first purified from the plasmas by means of a CL-octyl sepharose column, the purified material bound to the heparin sepharose column. Thus, after recognizing beta 2 GPI, CL-rA bind heparin. 'In vivo' CL-rA binding to heparin like-substances could inhibit the anti-thrombotic properties of endothelial cells.


Results of cable graft technique in repair of large nerve trunk lesions.
Cable grafting was reintroduced in the beginning of the 1980's as a modified method for repair of large polyfascicular nerves without group arrangement such as trunks and cords of the brachial plexus, sciatic nerve and its divisions, or the other main nerve trunks. We used this method in 25 patients with brachial plexus injury and 29 patients with injuries to the sciatic nerve. Results were analyzed according to the individual nerve elements and were available for 32 elements of the brachial plexus and for 19 tibial and 19 peroneal divisions of the sciatic nerve. We defined useful functional recovery according to the priorities in repair of the brachial plexus and sciatic nerve with lower limits M3 for relevant muscles and functions and S2 for sensory function. Results were especially favourable for the brachial plexus with a total rate of recovery 84% and for tibial division with the same total rate of recovery. On the basis of the results obtained we were able to conclude that the results of the modified cable grafting were at least similar to those of interfascicular nerve grafting and that this method could be useful for repair of large polyfascicular nerve trunks. However, the main advantage of this technique is a considerable gain in operative time.


Quantification of NMDAR Subunit Genes Expression by qRT-PCR.
Transcription is the initial and generally the most sensitive step to cellular needs and environmental cues. Thus, it serves as a major mechanism controlling gene expression. Using reverse-transcription quantitative polymerase chain reaction technology (RT-qPCR), we will present how to quantify the transcriptional expression of NMDARs subunits during brain development and in both healthy and pathological conditions.


Toxicity of 4-nonylphenol in spiked sediment to three populations of Chironomus riparius.
Nonylphenols (NPs) are the primary stable metabolites of alkylphenol polyethoxylates (APEs), a family of compounds widely used in industry and in some domestic products. As NPs accumulate in sediments in aquatic environments, the risk to benthic organisms needs to be assessed. In this study 4NP-spiked sediments were tested on larvae of the dipteran Chironomus riparius. First instar larvae obtained from populations at three different sources were used. To spike the sediments, an equilibration procedure between water and sediment was adopted to avoid the use of solvents. Lower 10-d LC50 values were determined for two populations of C. riparius from clean environments (315-465 and 315-350 microg g(-1) d.w., respectively) than those of a strain deriving from a population collected in a polluted river (600-680 microg g(-1) d.w.). Larval growth always decreased with increasing 4NP concentration but without any defined trend. The results of this study suggest that tolerance to the toxicant can be developed in populations of polluted environments and that testing procedures should be standardised.


Chemical composition and antioxidant activities of Jeddah corniche algae, Saudi Arabia.
The increased use of natural product in the pharmaceutical industry has led to an increase in demand for screening for bioactive compounds in marine algae. An important economic algae, through chemical composition analysis and their antioxidant activities were investigated in this study. Chemical composition analysis of three algal samples from the Chlorophyta Ulva lactuca (U), Phaeophyta Sargassum crassifolia (S) and Rhodophyta Digenea simplex (D) was tested. Main components were sugars (57.40-185.13 mg/g dry weight), uronic acids (29.3-45.26 mg/g dry weight), sulfate (94.7-181.2 mg/g dry weight), amino acids (7.6-16.7 mg/g dry weight) and small amounts of betaines (2.38-8.47 mg/g dry weight). Hydrolyzed chemical composition analysis fractions of algal extract was shown a great proportion of sugars plus sulfate (as polysaccharide composed) ranges between 332 and 538.2 mg/g dry weight with trace amounts of uronic acids (⩽9%). All three algal extract showed antioxidant activities on lipoxygenase, DPPH and on Ames test. Two of aqueous extracts (U and D) inhibited lipoxygenase activity by less than 50%, where as the methanolic extract (S) caused 76% inhibition of the control. In all cases, the methanolic extract were more inhibitory than the aqueous extract. The (S) showed the highest antioxidant activity with DPPH (69%) in aqueous extract and in methanol extract with Ames test (85%). Both U and D showed antioxidant activity with DPPH in hexane by less of 25% where as in both aqueous and methanolic extracts by less than 50% of the control. Aqueous and methanolic extracts of U and D showed high inhibition by Ames test which caused 70% and 75% respectively. IR spectra of algal extracts (U; D and S) range from 1450 to 750 cm(-1) were very similar absorption band at 1430, 1370, 1250, 1130, 1110, 1050 and 1020 cm(-1). Absorption bands were due to uronic acids, glucosides and sulfate. The presence of sulfated polysaccharide material in the fractions UF2, DF2 and SF2 were found as cell wall storage of marine algae, confirmed by (13)C NMR spectroscopy. It is concluded that the algal species probably have a different components and can be used in the activities of antioxidant enzymes as reduced the risks of enzymes. But the correlation between the chemical composition and antioxidant activities of algal extracts needs further investigation.


Innate immune reactivity of the ileum-liver axis in nonalcoholic steatohepatitis.
Over-proliferation and bacterial translocation of Gram-negative bacilli within the intestinal flora, and increased portal venous levels of endotoxins, are involved in nonalcoholic steatohepatitis (NASH). To evaluate the innate immune response in the small intestine and liver using the rat NASH model. We produced the NASH model by administering a choline-deficient amino acid-defined diet to F344 rats. We analyzed the serum and liver tissue to assess the effects of innate immune reactivity in this NASH model. Significant increases were detected in serum ALT levels and in the portal venous serum and whole-liver levels of TNF-α and IFN-γ in the NASH group. Strong Sirius red staining and TNF-α immune staining were seen in the NASH group, and real-time PCR revealed significantly increased expression of TNF-α and TLR4 mRNA in the NASH group. Higher TNF-α levels were detected in the Kupffer cells isolated culture supernatant in the NASH group than in the control group. Immune staining of the ileal tissue specimens resulted in greater staining of TNF-α, TLR4, and macrophage/dendritic cells, mainly in the submucosa, in the NASH group than in the control group. In the small intestine and liver of the rat NASH model, the possibility that enhancement of the innate immune response, mediated by the TLR4 signal, led to increased production of TNF-α was suggested. This interaction between the small intestine and liver may be involved in the onset and progression of NASH.


Short report. Cooking for autism: a pilot study of an innovative culinary laboratory for Italian adolescents and emerging adults with autism spectrum disorder.
Adolescence and emerging adulthood are critical periods for young people with autism spectrum disorder (ASD). However, there is a lack of appropriate and affordable services available. The Il Tortellante® is an Italian project aimed at promoting adaptive behavior and social skills, and at reducing the severity of symptomatology through a culinary group intervention in which young people with ASD learn to make fresh pasta by hand. A longitudinal study was conducted. Before and after the intervention, 20 participants were assessed based on the severity of symptoms, social skills, and adaptive behaviors. According to our findings, severity of symptoms and daily living skills improved significantly. A culinary intervention may be useful for adolescents and young adults with ASD to improve daily living skills and reduce ASD-related symptomatology. Services and associations may consider developing a culinary laboratory for people with ASD to improve group intervention proposals for adolescents and emerging adults. WHAT THIS PAPER ADDS?: This paper offers one of the first investigations of the impact of a culinary laboratory on ASD symptoms, social skills, and adaptive behavior in adolescents and young adults diagnosed with ASD. This group intervention could contribute to expand the range of interventions targeted at adolescents and young adults with ASD, to reduce the severity of symptoms, and to promote adaptive behaviors.


[Age and changes in the hematocrit in the mesenteric capillaries of the white rat].
The dynamics of the capillary hematocrit in 4-5-, 7- and 11-week rats involved its reduction with ageing from 0.17 l/l in 4-5-week rats to 0.10 l/l in 7- and 11-week ones in spite of considerable variability in each animal group. The reduction of the hematocrit seems to be due to the growth of capillary net in mesentery.


Serum biotin in Japanese children: Enzyme-linked immunosorbent assay measurement.
Biotin deficiency has been reported in Japanese infants fed special formulas for medical reasons, including those with milk allergy and congenital metabolic diseases, because these formulas contain little biotin. Serum biotin measurement is useful for diagnosing biotin deficiency. We applied a simple and rapid method to analyze serum biotin, and established normal ranges for children and adults. Serum biotin in 188 healthy Japanese children aged 0-4 years and in 25 healthy adults was analyzed using a Biotin ELISA Kit (immundiagnostik). The effects of various conditions on the measurement of serum biotin were also examined. Median biotin in children aged 0-4 years was 10.4 ng/dL (IQR, 7.9-13.4 ng/dL), and that in adults was 12.9 ng/dL (IQR, 10.8-15.8 ng/dL). Normal range was 4.7-22.0 ng/dL in children and 8.4-20.5 ng/dL in adults (calculated using two-sided 95%CI). Measurements obtained with this method were not affected by frozen storage, freeze-thaw, or hemolysis, indicating that serum biotin can be analyzed accurately under these conditions, with a possible application to plasma samples. Serum biotin was significantly lower in children than in adults, with the normal range being 4.7-22.0 ng/dL in children and 8.4-20.5 ng/dL in adults. This simple and accurate enzyme-linked immunosorbent assay method is useful for diagnosing biotin deficiency.


About the assumption of linearity in soil-to-plant transfer factors for uranium and thorium isotopes and 226Ra.
The linearity assumption for soil and plant concentrations of radionuclides is usually a good approximation for use in food-chain models. To verify this assumption, different samples of plant and substrate were collected from a granitic zone located near a disused uranium mine in order to cover a large range of concentrations. In all of the samples, the activity concentration of 226Ra and of different isotopes of uranium (238U and 234U) and thorium (232Th, 230Th and 228Th) were determined. The results indicate that the linearity assumption can be considered valid when the range of concentrations taken into account is large (approx. two orders of magnitude). Otherwise, there is a clear deviation from linearity. Also, the influence of different stable elements on the soil-plant transfer factors was studied by using multivariate regression methods. The uptake of uranium, thorium and radium was found to be mainly associated with the concentration of iron in the plant and the phosphorus and alkaline earths in the substrate.


Binding parameters and thermodynamics of the interaction of imino sugars with a recombinant human acid alpha-glucosidase (alglucosidase alfa): insight into the complex formation mechanism.
Recently, enzyme enhancement therapy (EET) for Pompe disease involving imino sugars, which act as potential inhibitors of acid alpha-glucosidases in vitro, to improve the stability and/or transportation of mutant acid alpha-glucosidases in cells was studied and attracted interest. However, the mechanism underlying the molecular interaction between the imino sugars and the enzyme has not been clarified yet. We examined the inhibitory and binding effects of four imino sugars on a recombinant human acid alpha-glucosidase, alglucosidase alfa, by means of inhibition assaying and isothermal titration calorimetry (ITC). Furthermore, we built structural models of complexes of the catalytic domain of the enzyme with the imino sugars bound to its active site by homology modeling, and examined the molecular interaction between them. All of the imino sugars examined exhibited a competitive inhibitory action against the enzyme, 1-deoxynojirimycin (DNJ) exhibiting the strongest action among them. ITC revealed that one compound molecule binds to one enzyme molecule and that DNJ most strongly binds to the enzyme among them. Structural analysis revealed that the active site of the enzyme is almost completely occupied by DNJ. These biochemical and structural analyses increased our understanding of the molecular interaction between a human acid alpha-glucosidase and imino sugars.


Roles of alternatively activated M2 macrophages in allergic contact dermatitis.
Alternatively activated macrophages (M2 macrophages) play key roles in the suppression of Th1 cell responses and the orchestration of tissue repair. However, recent studies have shown that M2 macrophages have potentials to produce high levels of proinflammatory cytokines such as IL-1β, IL-6, and TNF-α, suggesting that M2 macrophages may exacerbate inflammation in some settings. In this regard, we have recently shown that large numbers of M2 macrophages accumulate in the sites of hapten-induced contact hypersensitivity (CHS), an animal model of allergic contact dermatitis, and that M2 macrophages exacerbate hapten-induced CHS by producing matrix metalloproteinase 12 (MMP12). We have also shown that suppressor of cytokine signaling-3 (SOCS3), a member of SOCS family proteins that are cytokine-inducible negative regulators of the JAK/STAT signaling pathways, is highly and preferentially expressed in M2 macrophages in hapten-induced CHS and that SOCS3 expressed in M2 macrophages is involved in the attenuation of CHS by suppressing MMP12 production. These findings underscore the importance of M2 macrophage-derived MMP12 in the development of CHS, and suggest that inhibition of M2 macrophages or MMP12 could be a potential therapeutic strategy for the treatment of allergic contact dermatitis.


Microelectronic sensors for simultaneous measurement of PO2 and pH.
Sensors capable of simultaneous measurement of pH and PO2 in an aqueous solution have been fabricated in planar form using microelectronic technology. Separate potentiometric metal-metal oxide pH and three electrode amperemetric PO2 sensors have been fabricated together on a silicon chip with active surface of 2 x 3 mm. Rhodium-rhodium oxide electrodes operating in a cyclic voltammetry mode have also been studied and show sensitivity to both pH and PO2 in different regions of the voltage swept curve.


Clinical significance of proliferative potential of occult metastatic cells in bone marrow of patients with breast cancer.
There is increasing statistical evidence that the presence of tumour cells in bone marrow detected by immunocytochemistry represents an important prognostic indicator in breast cancer, but their individual capacity to become clinical metastases is unknown. The aim of this study was to assess the proliferative capacity of these occult metastatic cells in the bone marrow of patients with various stages of breast cancer. We obtained bone marrow aspirates from 60 patients with breast cancer before treatment with chemotherapy: 17 stage II, 12 stage III and 31 stage IV. After bone marrow culture for 6-34 days (median: 17 days) under specific cell culture conditions, viable epithelial cells were detected by cytokeratin staining in 40 patients (66%). Expansion of tumour cells was poorly correlated with tumour cell detection on primary screening (P=0.06). There was a nonsignificant correlation between the number and the presence of expanded tumour cells and the UICC stage of the patients. On primary screening, tumour cell detection was positive in 56% of patients and was correlated with clinical UICC stage (P=0.01). However, with a median follow-up of 23 months, expansion of tumour cells from bone marrow was associated with decreased patient survival (P=0.04), whereas the survival difference according to detection of CK-positive cells on primary screening was not statistically significant. In conclusion, viable tumour cells can be detected in the bone marrow of breast cancer patients. Their proliferative potential could be predictive of outcome and deserves further investigation.


Endoscopic fluorescence detection of dysplasia in patients with Barrett's esophagus, ulcerative colitis, or adenomatous polyps after 5-aminolevulinic acid-induced protoporphyrin IX sensitization.
Surveillance of patients with Barrett's esophagus or ulcerative colitis for dysplasia is confined to biopsy specimens taken randomly during endoscopy because dysplasia remains undetectable by visual inspection. We attempted to visualize dysplastic tissue during endoscopy after sensitization with 5-aminolevulinic acid (5-ALA) leading to accumulation and formation of protoporphyrin IX and induction of characteristic red fluorescence of the latter substance using blue light illumination. Six patients with histologically proven low- or high-grade dysplasia (Barrett's esophagus 2, ulcerative colitis 1, Billroth-II stomach 1, rectal polyps 2) were treated with oral administration of different concentrations of 5-ALA (10 to 20 mg/kg) or by local instillation of 3 gm 5-ALA in the rectum. Endoscopic fluorescence detection was performed 1 to 6 hours after sensitization using a blue light source and compared with conventional white light endoscopy. Biopsies of fluorescent and nonfluorescent areas were compared with histologic findings. Normal duodenal mucosa and squamous epithelium showed more intense 5-ALA-induced background red fluorescence compared with normal mucosa in the stomach or Barrett's mucosa. Histologically, dysplasia was exclusively found in areas with red fluorescence. False-positive fluorescence was associated with microscopic inflammation of the mucosa or feces in the colon. 5-ALA-induced protoporphyrin IX fluorescence may be useful in the detection of dysplasia in the gastrointestinal tract by enhancement of endoscopic surveillance of patients at a high risk for dysplasia.


Efficient application of monolithic silica column to determination of illicit heroin street sample by HPLC.
In this paper, an HPLC method is proposed for a routine, rapid and simple analysis of heroin samples confiscated from the illicit market, based on a new type of packing for HPLC columns (monolithic silica). Acetonitrile and pH 3.5 phosphate buffer solution were used under both isocratic and gradient conditions. Under our analytical conditions, all the components of a typical mixture of an illicit heroin sample proved to be fully separated into well-resolved peaks in 7 min. Analytical linearity and accuracy of the method were also studied for all analytes using tetracaine hydrochloride as the internal standard.


Macrocyclic glycohybrid toolbox identifies novel antiangiogenesis agents from zebrafish assay.
A practical and modular approach to obtain a diverse set of 14-membered macrocyclic compounds from carbohydrates is developed that utilizes functional groups at C-1 and C-5. The evaluation of this toolbox in various zebrafish assays led to the identification of 2.7f as an antiangiogenesis agent.


Pre-hospital benzodiazepines associated with improved outcomes in out-of-hospital status epilepticus: A 10-year retrospective cohort study.
Outcomes of status epilepticus have not substantially changed over the last decade. Given onset is most often in the community, early termination strategies that are implementable outside of hospitals are of public health importance. This 10-year retrospective single-centre cohort study aimed to determine whether pre-hospital benzodiazepine administration is associated with improved health outcomes in patients with out-of-hospital onset status epilepticus. We reviewed the medical records of all patients admitted with status epilepticus between 2008 and 2018 at St Vincent's Hospital Melbourne. Data regarding onset setting, medical history, management and outcomes were extracted. 72 patients meeting inclusion criteria were identified. Onset of status epilepticus was out-of-hospital for 74% (53/72) of patients, 66% (35/53) of whom were administered a benzodiazepine before reaching hospital, most often by ambulance officers (30/35, 86%). Pre-hospital benzodiazepine administration was associated with a 90% reduction in duration time to seizure cessation (0.65 vs 5.8 days, p = 0.012) and 50% reduction in length of hospital stay (7.6 vs 15.8 days, p = 0.045). In-hospital onset status epilepticus was associated with higher mortality than out-of-hospital onset (26% vs 4%, RR 6.5, p = 0.004). Pre-hospital benzodiazepines shorten the time to seizure control and length of hospital stay in patients with out-of-hospital status epilepticus, although is under-utilised by both ambulance staff and home carers. Health policy measures to improve ambulance officer and home carer administration skills and confidence may address these issues.


Disruption of estrogen receptor alpha-p53 interaction in breast tumors: a novel mechanism underlying the anti-tumor effect of radiation therapy.
Inactivation of tumor suppressor p53 is one of the most frequent events in cancer. Unlike many other cancers, however, p53 gene mutations are infrequent in breast cancers, as about 80% of breast tumors contain wild type p53. The mechanisms underlying functional inactivation of wild type p53 in breast cancer have remained elusive. Besides, how p53 gets activated in breast tumors subjected to radiation therapy remains unknown. We recently reported that in MCF-7 breast cancer cells, estrogen receptor alpha (ERalpha) directly binds to p53 and represses its function. Furthermore, the ERalpha-p53 interaction was disrupted by ionizing radiation. These observations have important translational implications especially as there are no reliable cellular or molecular criteria for rational radiotherapy for breast cancer. Here we report our studies towards addressing this important issue, using an MCF-7 breast cancer xenograft model in mice. Radiation effectively inhibits growth of these tumors and stabilizes p53, but has no observable effect on ERalpha protein level. Importantly, chromatin immunoprecipitation (ChIP) assays demonstrated that ERalpha interacts with p53 bound to endogenous target gene promoters in tumors in vivo, and this interaction is considerably reduced in response to radiotherapy although p53 level is increased. Concomitant with its effect on ERalpha-p53 interaction, radiation increases p53-mediated transcriptional activation of several target genes and increases p53-mediated transcriptional repression of survivin. Our studies show that disruption of ERalpha-p53 interaction in vivo resulting in restoration of functional p53 is a cellular response to radiation. Radiation could be affecting ERalpha and/or p53 directly or it could be influencing other proteins associated with the ERalpha-p53 complex. To the best of our knowledge, this is the first report on analysis of DNA-protein-protein interaction occurring on endogenous gene promoters in vivo in breast tumor tissues. These findings suggest that alleviating the inhibitory effect of ERalpha on p53 could be one of the molecular mechanisms underlying activation of p53 by radiation in breast tumors, and therefore, could be exploited to develop more effective ways of combining radiation therapy with systemic therapies such as hormonal therapy and chemotherapy.


Nonmyeloablative allogeneic peripheral blood stem cell transplantation for multifocal extramedullary plasmacytomas progressing after autologous transplantation.
Multifocal extramedullary plasmacytomas (EMP) are an uncommon manifestation of plasma cell malignancies. We report two patients with multiple EMP who developed rapidly progressive and ultimately fatal disease shortly after undergoing nonmyeloablative, matched-related donor allogeneic peripheral blood stem cell transplantation (PBSCT). We have not observed a similar course in patients transplanted for multiple myeloma without extramedullary manifestations and hypothesize that the intense immunosuppression associated with the fludarabine, busulfan and anti-thymocyte globulin conditioning regimen may have contributed to rapid disease progression in the two EMP patients. Our observations support the assertion that extramedullary disease is a marker for an aggressive, refractory plasma cell malignancy and suggest that patients should be treated intensively from the time of diagnosis. The utility of a graft-versus-tumor effect and the role of nonmyeloablative allogeneic PBSCT is yet to be defined in patients with extramedullary plasma cell malignancies, but it is logical to consider using it at the time of minimal residual disease rather than at disease relapse or progression. Nevertheless, we recommend circumspection in the administration of highly immunosuppressive conditioning regimens to patients with refractory EMP and encourage further clinical research in this area.


Reduced expression of glyoxalase-1 mRNA in mood disorder patients.
Glyoxalase-1 (Glo1) is an antioxidant enzyme which detoxifies alpha-ketoaldehydes to prevent the accumulation of pro-oxidant compounds, such as methylglyoxal, in all cell types. Glo1 has been suggested to be involved in anxiety disorders, autism, and Alzheimer's disease. Mood disorders have a high rate of comorbidity with anxiety disorders although, to date, little is known of the involvement of Glo1 in the pathophysiology of these conditions. In the present study, we examined the expression levels of Glo1 mRNA in peripheral white blood cells of mood disorder patients to understand the role of Glo1 in mood disorders. Quantitative real-time polymerase chain reaction experiments revealed that reduced expression of Glo1 mRNA was observed in major depressive and bipolar disorder patients in a current depressive state, as compared with healthy control subjects. In contrast, the expression of Glo1 mRNA in major depressive and bipolar patients, in a remissive state, showed no significant alteration when compared with healthy control subjects. These results suggest that the aberrant expression of Glo1 might be involved in the pathophysiology of mood disorders.


Differences in clinical and endocrine features between obese and non-obese subjects with polycystic ovary syndrome: an analysis of 263 consecutive cases.
Two hundred and sixty-three women with ultrasound-diagnosed polycystic ovary syndrome were studied of whom 91 (35%) were obese (BMI greater than 25 kg/m2). Obese women with PCOS had a greater prevalence of hirsutism (73% compared with 56%) and menstrual disorders than non-obese subjects. Total testosterone and androstenedione concentrations in serum were similar in the two subgroups but SHBG concentrations were significantly lower, and free testosterone levels higher, in obese compared with lean subjects. In addition, concentrations of androsterone glucuronide, a marker of peripheral 5 alpha-reductase activity, were higher in obese than in non-obese women with PCOS. There were no significant correlations of either SHBG or free testosterone with androsterone glucuronide suggesting that obesity has independent effects on transport and on metabolism of androgen. There were no significant differences between the subgroups in either baseline gonadotrophin concentrations or the pulsatile pattern of LH and FSH secretion studied over an 8-h period. There was, however, an inverse correlation of FSH with BMI, but only in the obese subgroup. In conclusion, the increased frequency of hirsutism in obese compared with lean women with PCOS is associated with increased bio-availability of androgens to peripheral tissues and enhanced activity of 5 alpha-reductase in obese subjects. The mechanism underlying the higher prevalence of anovulation in obese women remains unexplained.


Mapping high-grade glioma immune infiltration to 5-ALA fluorescence levels: TCGA data computation, classical histology, and digital image analysis.
Resection of high-grade gliomas has been considerably improved by 5-aminolevulinic acid (5-ALA). However, not all neurobiological properties of 5-ALA are fully understood. Specifically, potential differences in immune infiltration have not been conclusively examined, despite recent reports that immune cells might play a role. Thus, we here provide a systematic mapping of immune infiltration of different 5-ALA fluorescence levels. Tumor-associated macrophages (CD68, CD163), cytotoxic T cells (CD8), and regulatory T cells (FoxP3) were quantified via three methods. First, data from The Cancer Genome Atlas (TCGA) of 172 patients was examined for correlations between 5-ALA fluorescence-related mRNA expression signatures and immune markers. Second, as classical histology, 508 stained slides from 39 high-grade glioma patients were analysed semi-quantitatively by two independent reviewers, generating 1016 data points. Third, digital image analysis was performed with automated scanning and algorithm-based cell quantification. TCGA mRNA data from 172 patients showed a direct, significant correlation between 5-ALA signatures and immune markers (p < 0.001). However, we were not able to confirm this finding in the here studied initial set of 39 patient histologies where we found a comparable immune infiltration in different fluorescence levels. Digital image analysis correlated excellently with standard histology. With mapping the immune infiltration pattern of different 5-ALA categories, we are adding fundamental basic insights to the field of 5-ALA and glioma biology. The observation that a significant correlation in TCGA data did not fully translate to detectable differences in immune infiltration in first histology data warrants further investigation in larger cohorts.


Cell density-dependent increase in prolyl hydroxylase activity in cultured L-929 cells requires de novo protein synthesis.
Prolyl hydroxylase activity in cultured L-929 cells was found to increase when cells grew from log phase to stationary phase and when cells were harvested at the mid-log phase and replated at higher cell densities. Cycloheximide and actinomycin D inhibited the cell density-dependent increase in prolyl hydroxylase activity indicating that the increase in prolyl hydroxylase activity required de novo synthesis of protein and RNA. Prolyl hydroxylase was purified from cultured L-929 cells and antibodies against the protein were raised in rabbits. The antibodies were used to demonstrate that L-929 cells contained two forms of prolyl hydroxylase: an enzymatically active, tetrameric form consisting of two alpha and two beta polypeptide chains and an enzymatically inactive form containing immunologically cross-reacting protein. The polypeptide chains alpha, beta and cross-reacting protein were obtained by immunoadsorption. Peptide map analysis indicated that cross-reacting protein was similar if not identical to beta in primary structure, and alpha was different from both beta and cross-reacting protein. The results suggested that the prolyl hydroxylase levels in cells or tissues may be regulated by new protein and/or RNA synthesis.


Habitat selection by capercaillie in summer and autumn: Is bilberry important?
The use of habitat by female and male adult capercaillie Tetrao urogallus during summer and autumn was studied by comparing the distribution of radio locations of birds with the availability of habitat at forest stand, home range and landscape level in an area of the Bavarian Alps, Germany. Capercaillie preferred forests with structural features typical of their main distribution range, the boreal forest: they selected large patches of old forest with moderate canopy cover of about 50%, and a well developed field layer with high proportions of bilberry Vaccinium myrtillus. Hens selected both home ranges and sites within home ranges in old forest. Ranges selected by cocks did not differ from availability in the study area, but they preferred old forest within their ranges. The size of home ranges was negatively related to bilberry cover both in hens and cocks. The distribution of bilberry also determined habitat use by capercaillie at the landscape scale. The study demonstrated that bilberry is the major determinant of the selection of habitat by capercaillie in landscapes with sparse and fragmentary cover of ericaceous shrubs, such as central Europe.


miR-449a inhibits proliferation and invasion by regulating ADAM10 in hepatocellular carcinoma [Retraction].
[This retracts the article on p. 2609 in vol. 8, PMID: 27398144.].


Ingested prey increase risks of visual predation in transparent Chaoborus larvae.
Transparency reduces the chances of detection of large planktonic animals by visual predators. An important constraint on the transparency of planktonic animals may be ingested food which could be seen through the body, thereby increasing the vulnerability of transparent zooplankton to visual predators. To test this hypothesis, we presented fed and un-fed Chaoborus larvae to juvenile coho salmon (Oncorhynchus kisutch). Overall, the presence of prey in the gut of Chaoborus increased their probability of capture by 68%. Predation risks due to the visibility of ingested food increased in proportion to meal size: larvae with nearly full gut were captured about three times faster on the average than larvae which had little food in their gut. Although Chaoborus larvae may be able to reduce this increased predation risk by migrating downward to low light levels, this behavior would reduce feeding opportunities by removing the larvae from surface waters where prey density is generally high. In this way, visual predators may limit the growth and the maximum size that can be achieved by transparent animals.


Prolonged survival and milder impairment of motor function in the SOD1 ALS mouse model devoid of fibroblast growth factor 2.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by selective motoneuron loss in brain and spinal cord. Mutations in the superoxide dismutase (SOD) 1 gene account for 10-20% of familial ALS patients. The ALS-mouse model over-expressing a mutant human SOD1 (G93A) gene closely mimics human ALS disease. The cause for the selective death of motoneurons is still unclear, but among several pathomechanisms discussed, loss of neurotrophic factors is one possibility. Basic fibroblast growth factor 2 (FGF-2) plays a prominent role in the motor system. In order to evaluate a role of FGF-2 in ALS pathogenesis, double mouse mutants transgenic for the human SOD1 mutation and lacking the endogenous FGF-2 gene were generated. Both heterozygous and homozygous FGF-2 deficient mutant SOD1 mice showed a significant delay in disease onset and less impaired motor performance in comparison to mutant SOD1 mice with normal FGF-2 levels. Survival of the double mouse mutants was significantly prolonged for two weeks. Motoneuron numbers were significantly higher in the double mutants and astrocytosis was diminished at disease endstage. While one would initially have expected that FGF-2 deficiency deteriorates the phenotype of mutant SOD1 animals, our results revealed a protective effect of FGF-2 reduction. In search of the underlying mechanisms, we could show up-regulation of other neurotrophic factors with proven protective effects in the ALS mouse model, ciliary neurotrophic factor (CNTF) and glial derived neurotrophic factor (GDNF) in muscle and spinal cord tissue of double mutant animals.


Inhibitory effects of bisbenzylisoquinolines on synthesis of the inflammatory cytokines interleukin-1 and tumour necrosis factor-alpha.
Synthesis of IL-1beta and TNFalpha by human monocytesmacrophages was significantly inhibited by eleven bisbenzylisoquinolines and one half-molecule (benzylisoquinoline), with IC(50) values in the muM range. The results indicate that these compounds may have value in the therapy of human diseases where these inflammatory cytokines have a central role in pathogenesis.


Debate: whether abdominal aortic aneurysm surgery should be centralized at higher-volume centers.
Volume-outcome relationships in vascular surgery have become increasingly relevant in recent years. At the individual surgeon level, increased experience has been linked with improved patient outcomes after volume-outcome and learning curve analyses. At the hospital level, further analyses have generally shown a similar relationship linking the busier hospitals with improved outcomes. However, is this relationship sufficient and robust enough to support important health care delivery decisions regarding centralization of care? In England, such information has helped to shape the vascular surgery reorganization process in London. The following discussion presents the advantages and disadvantages of the practical use of such information.


Cholangiocytes express an isoform of soluble adenylyl cyclase that is N-linked glycosylated and secreted in extracellular vesicles.
Soluble adenylyl cyclase (sAC)-derived cAMP regulates various cellular processes; however, the regulatory landscape mediating sAC protein levels remains underexplored. We consistently observed a 85 kD (sAC85 ) or 75 kD (sAC75 ) sAC protein band under glucose-sufficient or glucose-deprived states, respectively, in H69 cholangiocytes by immunoblotting. Deglycosylation by PNGase-F demonstrated that both sAC75 and sAC85 are N-linked glycosylated proteins with the same polypeptide backbone. Deglycosylation with Endo-H further revealed that sAC75 and sAC85 carry distinct sugar chains. We observed release of N-linked glycosylated sAC (sACEV ) in extracellular vesicles under conditions that support intracellular sAC85 (glucose-sufficient) as opposed to sAC75 (glucose-deprived) conditions. Consistently, disrupting the vesicular machinery affects the maturation of intracellular sAC and inhibits the release of sACEV into extracellular vesicles. The intracellular turnover of sAC85 is extremely short (t1/2 ~30 min) and release of sACEV in the medium was detected within 3 h. Our observations support the maturation and trafficking in cholangiocytes of an N-linked glycosylated sAC isoform that is rapidly released into extracellular vesicles.


Dobutamine stress echocardiography prior to aortic surgery: long-term cardiac outcome.
This study was undertaken to evaluate the efficacy of dobutamine stress echocardiography (DSE) in predicting not only perioperative but also long-term cardiac events. One hundred fifty-nine patients who were evaluated for elective abdominal aortic surgery were screened preoperatively with DSE from January 1, 1992 to December 31, 1993. We concluded that DSE is useful for preoperative assessment of cardiac risk prior to elective aortic surgery to minimize the need for cardiac intervention and still maintain acceptable perioperative MI and death rates. A selective approach for coronary revascularization is justified by the higher mortality in the subgroup requiring sequential procedures. DSE also allowed us to identify those high-risk patients who are best excluded from aortic surgery. Patients with abnormal DSE results are at higher risk for late cardiac events, require cardiology follow-up, and may require late coronary intervention.


Concise review of green algal genus Monostroma Thuret.
Monostroma (Ulotrichales, Chlorophyta) is the most intensively cultivated genus among green seaweeds, accounting for over 90% of total green algal cultivation. It is commonly found in the eulittoral zones of marine and estuarine habitats, thus contributing significantly to the ecology of the coastal ecosystem. Morphologically, the frond of Monostroma is blade-like with eponymous one-cell thickness; therefore, it is also known as "Slender sea lettuce". Monostroma nitidum is often used for salad ingredients, boiled tsukudani, soups, etc., due to its health benefits. Monostroma kuroshiense is commercially cultivated in East Asia and South America for the edible product "hitoegusa-nori" or "hirohano-hitoegusa nori", popular sushi wraps. This genus remains one of the well-studied seaweed genera for ecophysiology, habitat-dependent seasonality of its growth pattern, gametangial ontogeny and phylogenetics. Moreover, rhamnan sulfate (RS), a sulfated polysaccharide, is the main component of the fiber extracted from M. nitidum and studied for various biological activities. This review presents the taxonomy, morphology, anatomy, life history, distribution, ecology, physiology, cultivation and harvesting, chemical composition, and biotechnological applications of this genus.


Lipopolysaccharide and interferon gamma activate nuclear factor kappa B and induce cyclo-oxygenase-2 in equine vascular smooth muscle cells.
Equine endotoxaemia is an important cause of morbidity and mortality in horses caused by the interaction of bacterial lipopolysaccharide (LPS) with cells such as macrophages and vascular smooth muscle. In this study we isolated equine vascular smooth muscle from a variety of vessels and stimulated it with LPS and human interferon (hIFN)-gamma. Using reverse transcriptase polymerase chain reaction (rt-PCR) and Western blot analysis we show that cyclooxygenase-2 (COX-2) is readily expressed in equine vascular smooth muscle. Vascular smooth muscle cells produced prostaglandin E2 in response to LPS and hIFNgamma. Using similar approaches we saw very limited expression of inducible nitric oxide synthase (iNOS) in only one vascular smooth muscle preparation. LPS and IFNgamma caused translocation of the transcription factor nuclear factor kappa B (NfkappaB) to the nucleus in equine cells suggesting the limited iNOS production seen in our cells is not due to deficits in this signal transduction pathway. These data suggest that in equine vascular smooth muscle COX-2 and NfkappaB are likely to play important roles in the pathogenesis of equine endotoxaemia.


Effect of bupivacaine intraperitoneal and intra-abdominal bicarbonate in reducing postoperative pain in laparoscopic cholecystectomy: a double-blind randomized clinical trial study.
We aimed to compare the effect of bupivacaine intraperitoneal with intra-abdominal bicarbonate in reducing postoperative pain in laparoscopic cholecystectomy. In this double-blind randomized clinical trial study, 58 patients underwent laparoscopic cholecystectomy referred to a hospital in Tehran, Iran (2019), were assigned into three groups: at the end of the surgery, spraying 50 cc of bupivacaine 0.2% through the laparoscopic port; or rinsing the abdomen with 5.7% bicarbonate dissolved in 1000 cc of normal saline; or abdominal lavage with normal saline. Pain of patients was evaluated according to visual analogue scale criteria and means Ramsay score in recovery times, 2, 8 and 24 h and post-operative analgesia satisfaction score at 2 and 24 h were also evaluated. The mean age of range was 44.26 ± 13.13 years, 44 female patients and 14 male patients. The mean Ramsay score in recovery, 2, 8 and 24 h postoperative times was not significantly different among the groups. Comparing post-operative analgesic satisfaction scores in recovery, 2 and 24 h revealed no significant difference among the groups. We found that use of bupivacaine intraperitoneal and intra-abdominal bicarbonate decreased pain after laparoscopic cholecystectomy but the decrease was more in bupivacaine group than bicarbonate group. Retrospectively registered, IRCT20180723040570N1; date of registration: 2019-06-24.


Application of ion mobility spectrometry in cases of forensic interest.
Ion mobility spectrometry (IMS) has been known as an analytical technique since the late 1960s and early 1970s. To date, it has been successfully utilized for the detection of environmental pollutants, warfare agents, explosives, herbicides, pesticides, petroleum products as well as for the detection of prescription and illicit drugs. In this paper the authors describe the use of the IMS technology in cases of forensic interest in Salzburg, Austria. We report the use of the IMS methodology for the rapid analysis of hallucinogenic mushroom material as well as for the analysis of samples taken after an explosion. A new application of the IMS technology for the analysis of postmortem sweat samples for drugs is also presented.


Daily and seasonal activity in woodland ants.
Daily and seasonal foraging patterns are described for nine species of ants occupying a temperate zone woodland. Two common dominant species, Prenolepis imparis and Formica subsericea, are active at different times of day and during different parts of the year. They appear to be limited by physical factors (temperature and light, respectively) while the subordinate species show a wider tolerance of physical conditions. The subordinate species exhibit peak foraging periods which overlap in large part with most dominant species. This temporal pattern of species activity is discussed in relation to the competitive relationships within this ant guild.


Simultaneous bilateral ranula in an edentulous patient. Rare presentation with a brief review of the literature.
A ranula is a large mucocele located in the floor of the mouth. Ranulas is usually a mucous extravasation phenomenon due to injury to sublingual salivary gland. unilateral presentation has been reported in many cases but bilateral presentation and that too in an edentulous patient is quite uncommon. This is a case report of bilateral ranula in an edentulous patient and its management along with a brief review of pertinent literature.


Predicting 30-Day Readmissions in an Asian Population: Building a Predictive Model by Incorporating Markers of Hospitalization Severity.
To reduce readmissions, it may be cost-effective to consider risk stratification, with targeting intervention programs to patients at high risk of readmissions. In this study, we aimed to derive and validate a prediction model including several novel markers of hospitalization severity, and compare the model with the LACE index (Length of stay, Acuity of admission, Charlson comorbidity index, Emergency department visits in past 6 months), an established risk stratification tool. This was a retrospective cohort study of all patients ≥ 21 years of age, who were admitted to a tertiary hospital in Singapore from January 1, 2013 through May 31, 2015. Data were extracted from the hospital's electronic health records. The outcome was defined as unplanned readmissions within 30 days of discharge from the index hospitalization. Candidate predictive variables were broadly grouped into five categories: Patient demographics, social determinants of health, past healthcare utilization, medical comorbidities, and markers of hospitalization severity. Multivariable logistic regression was used to predict the outcome, and receiver operating characteristic analysis was performed to compare our model with the LACE index. 74,102 cases were enrolled for analysis. Of these, 11,492 patient cases (15.5%) were readmitted within 30 days of discharge. A total of fifteen predictive variables were strongly associated with the risk of 30-day readmissions, including number of emergency department visits in the past 6 months, Charlson Comorbidity Index, markers of hospitalization severity such as 'requiring inpatient dialysis during index admission, and 'treatment with intravenous furosemide 40 milligrams or more' during index admission. Our predictive model outperformed the LACE index by achieving larger area under the curve values: 0.78 (95% confidence interval [CI]: 0.77-0.79) versus 0.70 (95% CI: 0.69-0.71). Several factors are important for the risk of 30-day readmissions, including proxy markers of hospitalization severity.


2nd postoperative day discharge after full sternotomy off pump coronary artery bypass grafting surgery - A report of 2 consecutive rapid discharges.
Very early discharge after coronary artery bypass grafting (CABG), defined as discharge in ≤4 days after surgery, is considered safe and comes with a host of benefits including lower costs and earlier return to work. I present two consecutive cases of off pump coronary artery bypass grafting (OPCAB) performed through conventional full sternotomy that were discharged on the second post-operative day (at 36 and 42 h after surgery), the former being the earliest described in medical literature till date. From my early experience, I list out all the factors that facilitated such ultra fast-track recovery and present a checklist to enable rapid (<2 days) discharge after CABG. Enhanced recovery after cardiac surgery (ERACS) is feasible and holds great promise in optimizing patient care and outcomes.


Intraoperative local hemodynamic quantitative analysis of direct revascularization in patients with moyamoya disease.
Direct bypass surgery improves blood flow in patients with moyamoya disease (MMD) as well as causes local flow relocation and disturbance. This study aimed to describe the characteristics and changes of quantitative blood flow in MMD patients. Sixty-four consecutive MMD patients (67 hemispheres) who underwent STA-MCA anastomosis between August 2013 and September 2017 were included in this study. Intraoperative blood flow of superficial temporal artery and middle cerebral artery was measured with a noninvasive, ultrasound flowprobe, before and after the bypass. All data were collected prospectively. Before the bypass, 67 hemispheres were measured and 45 hemispheres acquired post-bypass measurements. Thirty-three (49.3%) had anterograde flow and 34 (50.7%) had retrograde. Retrograde blood flow was significantly higher than anterograde blood flow in MCA-M4 section (3.71 ± 2.78 ml/min vs 2.39 ± 1.71 ml/min, P = 0.023). Thirty-eight (56.7%) patients had local cerebrovascular reactivity, whereas 29 (43.3%) lost it. After bypass, blood flow was changed into three patterns: anterograde flow (1, 2.2%), retrograde flow (3, 6.7%), and bi-direction flow (41, 91.1%). Flow of M4 was significantly improved in both proximal (13.64 ± 9.16 vs 3.28 ± 2.57, P < 0.001) and distal (7.17 ± 7.21 vs 3.28 ± 2.57, P = 0.002) sides to the bypass. Postoperative infarctions occurred in 4 (8.9%) patients. All postoperative infarctions (n = 4) happened in those patients who did not have change of flow direction in M4 section distal to the bypass (P = 0.040). Direct bypass surgery improves local blood flow after bypass surgery in both sides of the anastomosis. Flow direction was usually changed after the surgery into a bi-direction pattern: anterograde flow in M4 distal to the bypass, and retrograde flow in M4 proximal to the bypass. Proximal side acquired around 5.4 times of flow than the distal side. Patients with change of flow direction in distal M4 were related with lower risks of postoperative infarctions.


Comparison of Computed and Acquired DWI in the Assessment of Rectal Cancer: Image Quality and Preoperative Staging.
The aim of the study was to evaluate the computed diffusion-weighted images (DWI) in image quality and diagnostic performance of rectal cancer by comparing with the acquired DWI. A total of 103 consecutive patients with primary rectal cancer were enrolled in this study. All patients underwent two DWI sequences, namely, conventional acquisition with b = 0 and 1,000 s/mm2 (aDWIb1,000) and another with b = 0 and 700 s/mm2 on a 3.0T MR scanner (MAGNETOM Prisma; Siemens Healthcare, Germany). The images (b = 0 and 700 s/mm2) were used to compute the diffusion images with b value of 1,000 s/mm2 (cDWIb1,000). Qualitative and quantitative analysis of both computed and acquired DWI images was performed, namely, signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), and signal intensity ratio (SIR), and also diagnostic staging performance. Interclass correlation coefficients, weighted κ coefficient, Friedman test, Wilcoxon paired test, and McNemar or Fisher test were used for repeatability and comparison assessment. Compared with the aDWIb1,000 images, the cDWIb1,000 ones exhibited significant higher scores of subjective image quality (all P <0.050). SNR, SIR, and CNR of the cDWIb1,000 images were superior to those of the aDWIb1,000 ones (P <0.001). The overall diagnostic accuracy of computed images was higher than that of the aDWIb1,000 images in T stage (P <0.001), with markedly better sensitivity and specificity in distinguishing T1-2 tumors from the T3-4 ones (P <0.050). cDWIb1,000 images from lower b values might be a useful alternative option and comparable to the acquired DWI, providing better image quality and diagnostic performance in preoperative rectal cancer staging.


Gastroprotective activities of Turnera diffusa Willd. ex Schult. revisited: Role of arbutin.
Turnera diffusa Willd. ex Schult. has been used for the treatment of several human disorders including peptic ulcer. The current study is an attempt to evaluate the anti-ulcerogenic activities of arbutin, a major constituent of Turnera diffusa on two ulcer models. The possible involvement of lipid peroxidation, nitric oxide, IL-6, IL-10, TNF-α and mucus barrier mechanism has been investigated. Effects of arbutin on ulcer index, gastric juice acidity, mucus content and histochemistry, gross and histological gastric lesions, nitric oxide, cytokines levels (IL-6, IL-10 and TNF-α), and thiobarbituric acid reactive substances (TBARS), were evaluated in aspirin or ethanol-induced ulcer in vivo. Acute toxicity of arbutin was also examined in rodent model. MTT assay was used to assess the cytotoxicity of the compound on normal liver cells (WRL-68). Pre-treatment with arbutin or omeprazole protected the gastric mucosa as seen by reduction in ulcer area and mucosal content, reduced or absence of edema, inflammation and leucocytes infiltration on both models. Arbutin significantly (P<0.05) lowered the elevated TBARS level into gasteric homogenate. Arbutin did not produce significant inhibition of NO. This natural compound has modulated the levels of interleukin-6, interleukin-10 and TNF-α. No in vitro or in vivo toxicities for arbutin were observed. Thus it can be concluded that Turnera diffusa possesses anti-ulcer activity, which could be attributed to lipid peroxidation inhibitory, immuno modulatory and anti-oxidant mechanisms of arbutin but not to the intervention with nitric oxide inflammation pathway.


Cryo-EM structure of NPF-bound human Arp2/3 complex and activation mechanism.
Actin-related protein (Arp) 2/3 complex nucleates branched actin networks that drive cell motility. It consists of seven proteins, including two actin-related subunits (Arp2 and Arp3). Two nucleation-promoting factors (NPFs) bind Arp2/3 complex during activation, but the order, specific interactions, and contribution of each NPF to activation are unresolved. Here, we report the cryo-electron microscopy structure of recombinantly expressed human Arp2/3 complex with two WASP family NPFs bound and address the mechanism of activation. A cross-linking assay that captures the transition of the Arps into the activated filament-like conformation shows that actin binding to NPFs favors this transition. Actin-NPF binding to Arp2 precedes binding to Arp3 and is sufficient to promote the filament-like conformation but not activation. Structure-guided mutagenesis of the NPF-binding sites reveals their distinct roles in activation and shows that, contrary to budding yeast Arp2/3 complex, NPF-mediated delivery of actin at the barbed end of both Arps is required for activation of human Arp2/3 complex.


Tumour infiltrating lymphocytes correlate with improved survival in patients with esophageal squamous cell carcinoma.
We undertook a study of tumour infiltrating lymphocytes (TILs) in a large and relatively homogeneous group of patients with completely resected esophageal squamous cell carcinoma (ESCC). Hematoxylin and eosin-stained sections of 235 ESCC tumours were evaluated for density of TILs in intratumoural (iTIL) and stromal compartments (sTIL). Foxp3+, CD4+, and CD8+ T cells in tumoural and stromal areas were evaluated by immunohistochemistry. Of the 235 tumours, high sTIL (>10%), and iTIL (>10%) were observed in 101 (43.0%) and 98 (41.7%), respectively. The median follow-up period was 36.0 months (95% CI 29.929-42.071). Univariate analysis revealed that sTIL (>10%), iTIL (>20%), vessels involvement, lymph node metastasis, and clinical stage were significantly associated with postoperative outcome. In multivariate analysis, high sTIL (HR: 0.664, P = 0.019 for Disease free survival; HR: 0.608, P = 0.005 for Overall survival) was identified as independent better prognostic factor. Further analysis, sTIL was identified as independently prognostic factor in Stage III-IVa disease, which was not found in Stage I-II disease. Our study demonstrated that sTIL was associated with better ESCC patients' survival, especially in Stage III-IVa disease. Assessment of sTIL could be useful to discriminate biological behavior for ESCC patients.


Impact of the COVID-19 pandemic on juvenile idiopathic arthritis presentation and research recruitment: results from the CAPRI registry.
The COVID-19 pandemic has disrupted healthcare delivery and clinical research worldwide, with data from areas most affected demonstrating an impact on rheumatology care. This study aimed to characterize the impact of the pandemic on the initial presentation of JIA and JIA-related research in Canada. Data collected from the Canadian Alliance of Pediatric Rheumatology Investigators JIA Registry from the year pre-pandemic (11 March 2019 to 10 March 2020) was compared with data collected during the first year of the pandemic (11 March 2020 to 10 March 2021). Outcomes included time from symptom onset to first assessment, disease severity at presentation and registry recruitment. Proportions and medians were used to describe categorical and continuous variables, respectively. The median time from symptom onset to first assessment was 138 (IQR 64-365) days pre-pandemic vs 146 (IQR 83-359) days during the pandemic. The JIA category frequencies remained overall stable (44% oligoarticular JIA pre-pandemic, 46.8% pandemic), except for systemic JIA (12 cases pre-pandemic, 1 pandemic). Clinical features, disease activity (cJADAS10), disability (CHAQ) and quality of life (JAQQ) scores were similar between the two cohorts. Pre-pandemic, 225 patients were enrolled, compared with 111 in the pandemic year, with the greatest decrease from March to June 2020. We did not observe the anticipated delay in time to presentation or increased severity at presentation, suggesting that, within Canada, care adapted well to provide support to new patient consults without negative impacts. The COVID-19 pandemic was associated with an initial 50% decrease in registry enrolment but has since improved.