Decreasing efficacy of repeated intravitreal triamcinolone injections in diabetic macular oedema.
Intravitreal triamcinolone (IVTA) results in transient improvements in diabetic macular oedema (DMO), necessitating repeated injections. The authors report a case series of 10 eyes of 10 patients with DMO, who received a repeat injection of 4 mg IVTA, at least 26 weeks after the first injection of the same dose. Pre-injection and at 2, 4, 9, and 17 weeks post-injection, best corrected visual acuity (BCVA) and central foveal thickness (CFT) on optical coherence tomography, after the first and repeat injections, were compared using paired t test. Side effects were monitored. BCVA, CFT, intraocular pressure (IOP), and cataract scores were not significantly different before initial and repeat injections (given at 32.5 (SD 3.5) weeks after the first injection). Transient improvements of BCVA and CFT were achieved after both injections. However, after the repeat injection, the BCVA was significantly worse at all time points (p<0.05) and so were the best achieved CFT and the CFT at 4 weeks post-injection (p = 0.034 and 0.011 respectively), compared with the initial injection. Post-injection maximum IOPs and increase in cataract scores were not significantly different between the two injections. A repeat injection of 4 mg of IVTA may not be as effective as an initial injection for the treatment of DMO.


A study of the physiology of Bacillus anthracis Sterne during manufacture of the UK acellular anthrax vaccine.
To analyse the growth of Bacillus anthracis during simulations of the UK anthrax vaccine manufacturing process. Simulated vaccine production runs were performed using the toxigenic, acapsulate Sterne 34F(2) strain of B. anthracis in semi-defined medium. After rising during the logarithmic growth phase, the pH of the culture starts to fall at about 18 h from pH 8.7 to reach <7.6 at 26 h, coincident with consumption of glucose and optimal production of protective antigen (PA; 7.89 g ml(-1), SD 1.0) and lethal factor (LF; 1.85 g ml(-1), SD 0.29). No increased breakdown of toxin antigens was seen over the 26-32 h period. When glucose was exhausted, amino acids (principally serine) were utilized as an alternative carbon source. Sporulation was not observed during the 32 h. PA and LF, the principal constituents in the UK anthrax vaccine, undergo little degradation during vaccine fermentation. The vaccine manufacturing process is robust and reproducible. This is the first detailed analysis of the manufacturing process used for the UK acellular anthrax vaccine; insight gained into the process will support continued and safe vaccine manufacture.


D-glucaro 1,4-lactone and resveratrol as antioxidants in blood platelets.
The aim of our work was to study the anti-aggregatory and antioxidative effects of natural dietary products, D-glucaro 1,4-lactone (1,4-GL) in combination with phenolic compound resveratrol (trans-3,4',5-trihydroxystilbene). Our results in vitro showed that 1,4-GL alone slightly inhibits platelet aggregation induced by thrombin. The combination of resveratrol (0.1 microM) with 0.5 mM of 1,4-GL caused a significant decrease of thrombin-induced platelet aggregation; however separately, neither of studied compound at used concentrations was not effective. When platelets were treated with 1,4-GL (at the concentration of 0.1 mM and higher) and resveratrol (0.1 microM), similar synergistic action of both tested compound on markers of oxidative stress formation was observed. We measured the levels of different specific markers of oxidative stress, e.g., superoxide anion radicals O(2)(-)*, thiobarbituric acid-reactive substances and carbonyl group formation. Both tested compounds inhibited also the generation of O(2)(-)* and malondialdehyde that represents enzymatical peroxidation of arachidonic acid leading to thromboxane A(2) (TXA(2)) formation in platelets after thrombin stimulation. The obtained in vitro results demonstrate that anti-platelet and antioxidative properties of resveratrol may be significantly augmented by another dietary agent such as 1,4-GL, but mechanism synergistic action of these compounds is not yet known.


Relationship between semen quality and human sperm penetration of zona-free hamster ova.
Spermatozoa from 22 presumably fertile donors and from the male partners of 43 infertile couples were evaluated for their ability to fertilize zona pellucida-free hamster ova. All "fertile" donors gave positive results ion the interspecies in vitro fertilization test; 26% of the male partners (patients) gave negative results. Correlations of in vitro fertilization rates and standard semen analysis results indicate that, except for extremely low semen values, sperm fertilizing capacity in vitro could not be predicted accurately from ejaculate sperm number, motility, or morphology. Sperm motility evaluation agreed better with in vitro fertilization test results than did either sperm number or morphology; however, 9 of 31 patients (29%) with normal sperm motility in the ejaculate were judged subfertile in vitro. Also, although higher in vitro fertilization rates were related to greater numbers of normal parameters in a semen sample, 8 of 25 male patients (32%) appraised as "normal" according to the usual semen analysis yielded below-normal in vitro fertilization results. These results support the idea that deficient sperm fertilizing capacity often is a characteristic of poor-quality semen. However, deficiencies in fertilizing capacity also were observed in patient semen samples with excellent properties. Therefore, the interspecies in vitro fertilization test might be useful as an additional tool in clinical investigations of the fertility of the male partners of childless couples, particularly in cases in which infertility continues for no readily apparent reason.


Prefrontal cortex projections to the basilar pons in rhesus monkey: implications for the cerebellar contribution to higher function.
The feedforward limb of the cerebrocerebellar system is directed largely through the corticopontine pathway. We determined the extent to which higher order corticopontine projections are derived from prefrontal associative cortices by injecting anterograde tracers into multiple prefrontal regions in rhesus monkeys. Most prefrontopontine projections were derived from the dorsolateral and dorsomedial convexities, including areas 8A, 46 dorsal, 9, and 10; and lighter projections arose from medial and ventrolateral cortices. These findings strengthen the observation that the cerebrocerebellar system incorporates associative cerebral regions, and they enhance the notion that the cerebellum participates in the organization of cognitive function.


First Reported Use of Radiofrequency Identification (RFID) Technique for Targeted Excision of Suspicious Axillary Lymph Nodes in Early Stage Breast Cancer - Evaluation of Feasibility and Review of Current Recommendations.
The purpose of this study was to evaluate, whether radio frequency identification (RFID) labeling of axillary lymph nodes (LNs) for the use of targeted resection is feasible in primary breast cancer patients with suspicious LNs. We analyzed 10 consecutive patients where RFID technique was used for intraoperative detection of suspicious LNs without preceding neoadjuvant chemotherapy (NACT). We compared the specifics of these procedures to 10 consecutive sentinel lymph node biopsies (SLNB) in the cN0 situation. Intraoperative detection rate (DR) for the RFID-labeled target lymph node (TLN) was 100%. Perioperative complications were infrequent and comparable to SLNB. Average time for location of the RFID labeled TLN was quicker than for the SLN. In 71.4% the chip bearing TLN equaled a SLN. The use of the RFID technique for intraoperative localization of axillary LNs for targeted excision seems feasible. RFID technique for targeted axillary dissection (TAD) following NACT should be investigated in a prospective manner.


APP mediates tau uptake and its overexpression leads to the exacerbated tau pathology.
Alzheimer's disease (AD), as the most common type of dementia, has two pathological hallmarks, extracellular senile plaques composed of β-amyloid peptides and intracellular neurofibrillary tangles containing phosphorylated-tau protein. Amyloid precursor protein (APP) and tau each play central roles in AD, although how APP and tau interact and synergize in the disease process is largely unknown. Here, we showed that soluble tau interacts with the N-terminal of APP in vitro in cell-free and cell culture systems, which can be further confirmed in vivo in the brain of 3XTg-AD mouse. In addition, APP is involved in the cellular uptake of tau through endocytosis. APP knockdown or N-terminal APP-specific antagonist 6KApoEp can prevent tau uptake in vitro, resulting in an extracellular tau accumulation in cultured neuronal cells. Interestingly, in APP/PS1 transgenic mouse brain, the overexpression of APP exacerbated tau propagation. Moreover, in the human tau transgenic mouse brain, overexpression of APP promotes tau phosphorylation, which is significantly remediated by 6KapoEp. All these results demonstrate the important role of APP in the tauopathy of AD. Targeting the pathological interaction of N-terminal APP with tau may provide an important therapeutic strategy for AD.


Theileria annulata-infected cells produce abundant proteases whose activity is reduced by long-term cell culture.
Lysates of Theileria annulata-infected bovine lymphoblastoid cells and their uninfected counterparts were tested for protease activity using gelatin substrate SDS-PAGE. The infected cells produced a number of extra activities at pH 8.0 in the presence of Ca2+. Calcium was found to enhance the activities but was not an absolute requirement. Studies using inhibitors, including E64, 3,4-dichloroisocoumarin, pepstatin and 1, 10-phenanthroline suggested that the activities were metalloproteases. We analysed two vaccine lines; the Ode line from India and the Ankara Pendik line from Turkey. In the Ode line the later passage had very much reduced levels of the enzyme activities. In the case of the Ankara Pendik line both stages analysed had very low protease activities, but a reduction from the early to late passage was also observed. The reduction in the level of protease activity was also observed as a gradual process during on-going culture of lines derived from the Hissar and Ode stocks. In the Ode line we demonstrated a parallel decrease in the production of microschizonts upon temperature shift in vitro.


Fetal heart rate monitoring during fetoscopic repair of open spinal neural tube defects: a single-centre observational cohort study.
During fetal surgery, the haemodynamic stability of the fetus depends on the haemodynamic stability of the mother. The primary objective of this study was to assess changes in fetal heart rate (FHR) throughout the different stages of surgery. The secondary objective was to assess potential changes in maternal physiological parameters and their association with FHR. This was a single-center observational cohort study conducted between 2015 and 2019 in 26 women undergoing intra-uterine fetoscopic repair of open spina bifida. The primary outcome was FHR. Maternal physiologic parameters were measured at the beginning, during and after surgery. The linear mixed-effects model fitted by maximum likelihood was used to assess changes in each variable at specific times throughout the surgery, and the repeated measures correlation coefficient was used to study the association between FHR and maternal physiological parameters. One (3.8%) case of fetal bradycardia (FHR <110 beats per minute) required the administration of intramuscular atropine. No other significant FHR changes were observed during surgery. Maternal oesophageal temperature (P <0.001), lactate levels (P=0.002), and mean arterial pressure (P=0.016) changed significantly during surgery, although none of these changes was clinically relevant. The FHR showed a significant association with maternal carbon dioxide tension (r=0.285, 95% CI 0.001 to 0.526) and maternal heart rate (r=0.302, 95% CI 0.025 to 0.535). The FHR remained stable during intra-uterine fetoscopic repair of open spina bifida. Maternal carbon dioxide tension and heart rate may have a mild influence on FHR.


Gastric Lavage for Prevention of Feeding Intolerance in Neonates Delivered Through Meconium-Stained Amniotic Fluid: A Systematic Review and Meta-Analysis.
The role of gastric lavage in neonates delivered through meconium-stained amniotic fluid remains unclear. This study evaluated the effects of gastric lavage, compared to no gastric lavage, on the incidences of feeding intolerance, respiratory distress, meconium aspiration synd-rome, time to establish breastfeeding, hospitalization and pro-cedure-related complications in late-preterm and term neonates delivered through meconium-stained amniotic fluid. Systematic review and meta-analysis. MEDLINE, EMBASE, CENTRAL, and other databases were searched for randomized controlled trials and quasi-randomized controlled trials using search terms: neonate OR newborn infant, meconium OR meconium-stained amniotic fluid, and lavage OR gastric lavage from inception to May 2020. Data were pooled in RevMan and analyzed in GRADE. Pooled effects (9 randomized controlled trials, number=3668), showed a significant reduction in the incidence of feeding intolerance (relative risk 0.70; 95% confidence interval 0.58,0.85, I2=0) after gastric lavage. No difference was observed for the incidence of meconium aspiration syndrome (4 studies) or procedure-related complications (7 studies). Only one study, reporting the proportion of neonates with low oxygenation (SpO2<85%), did not find any significant difference. No study evaluated the effects of gastric lavage on respiratory distress, breastfeeding, and hospitalization. Low-quality evidence supported the role of gastric lavage for the prevention of feeding intolerance in late-preterm and term neonates born through meconium-stained amniotic fluid. Applicability of results was limited by the high risk of bias. Well-conducted randomized controlled trials with important patient outcomes are needed before recommending the practice of gastric lavage.


Estimation of critical and viscous frequencies for Biot theory in cancellous bone.
The use of Biot theory for modelling ultrasonic wave propagation in porous media involves the definition of a "critical frequency" above which both fast and slow compressional waves will, in principle, propagate. Critical frequencies have been evaluated for healthy and osteoporotic cancellous bone filled with water or marrow, using data from the literature. The range of pore sizes in bone gives rise to a critical frequency band rather than a single critical frequency, the mean of which is lower for osteoporotic bone than normal bone. However, the critical frequency is a theoretical concept and previous researchers considered a more realistic "viscous frequency" above which both fast and slow waves may be experimentally observed. Viscous frequencies in bone are found to be several orders of magnitude greater than calculated critical frequencies. Whereas two waves may well be observed at all ultrasonic frequencies for water-filled cancellous bone at 20 degrees C, it is probable megahertz frequencies would be needed for observation of two waves in vivo.


Do Optimally Tuned Range-Separated Hybrid Functionals Require a Reparametrization of the Dispersion Correction? It Depends.
For ground- and excited-state studies of large molecules, it is the state of the art to combine (time-dependent) DFT with dispersion-corrected range-separated hybrid functionals (RSHs), which ensures an asymptotically correct description of exchange effects and London dispersion. Specifically for studying excited states, it is common practice to tune the range-separation parameter ω (optimal tuning), which can further improve the accuracy. However, since optimal tuning essentially changes the functional, it is unclear if and how much the parameters used for the dispersion correction depend on the chosen ω value. To answer this question, we explore this interdependency by refitting the DFT-D4 dispersion model for six established RSHs over a wide range of ω values (0.05-0.45 a0-1) using a set of noncovalently bound molecular complexes. The results reveal some surprising differences among the investigated functionals: While PBE-based RSHs and ωB97M-D4 generally exhibit a weak interdependency and robust performance over a wide range of ω values, B88-based RSHs, specifically LC-BLYP, are strongly affected. For these, even a minor reduction of ω from the default value manifests in strong systematic overbinding and poor performance in the typical range of optimally tuned ω values. Finally, we discuss strategies to mitigate these issues and reflect the results in the context of the employed D4 parameter optimization algorithm and fit set, outlining strategies for future improvements.


Targeting therapy-resistant lung cancer stem cells via disruption of the AKT/TSPYL5/PTEN positive-feedback loop.
Cancer stem cells (CSCs) are regarded as essential targets to overcome tumor progression and therapeutic resistance; however, practical targeting approaches are limited. Here, we identify testis-specific Y-like protein 5 (TSPYL5) as an upstream regulator of CSC-associated genes in non-small cell lung cancer cells, and suggest as a therapeutic target for CSC elimination. TSPYL5 elevation is driven by AKT-dependent TSPYL5 phosphorylation at threonine-120 and stabilization via inhibiting its ubiquitination. TSPYL5-pT120 also induces nuclear translocation and functions as a transcriptional activator of CSC-associated genes, ALDH1 and CD44. Also, nuclear TSPYL5 suppresses the transcription of PTEN, a negative regulator of PI3K signaling. TSPYL5-pT120 maintains persistent CSC-like characteristics via transcriptional activation of CSC-associated genes and a positive feedback loop consisting of AKT/TSPYL5/PTEN signaling pathway. Accordingly, elimination of TSPYL5 by inhibiting TSPYL5-pT120 can block aberrant AKT/TSPYL5/PTEN cyclic signaling and TSPYL5-mediated cancer stemness regulation. Our study suggests TSPYL5 be an effective target for therapy-resistant cancer.


The value of MR angiography techniques in the detection of head and neck paragangliomas.
The objective of this study was to compare three-dimensional phase-contrast angiography (3D PCA), 2D time-of-flight (2D TOF), and 3D TOF magnetic resonance (MR) angiography and a proton density weighted technique in terms of their ability to detect head and neck paragangliomas. 14 patients with 29 paragangliomas were examined at 1.5 T. Three MR angiography sequences (3D PCA, 2D TOF, and multi-slab 3D TOF) and a proton density (PD) weighted sequence were reviewed by four neuroradiologists. The gold standard was digital subtraction angiography. Presence of tumor was assessed in five grades of confidence. Sensitivity and specificity were calculated after dichotomizing the results. Data was analyzed using the logistic regression method. Mean sensitivity and specificity for the four observers were for PD: 72%/97%, for 3D PCA: 75%/90%, for 2D TOF: 66%/93%, and for 3D TOF: 90%/92%. Sensitivity was significantly better for 3D TOF MRA (P < 0.001). No substantial between-observer variation for tumor detection was present. Our results demonstrate that, using 3D TOF MRA, paragangliomas in the head and neck region can be detected with high sensitivity and specificity. Further investigation is necessary to judge the value of 3D TOF MR angiography against fat suppressed contrast enhanced T1 weighted and fat suppressed T2 weighted MR sequences to find the optimal imaging sequence for paragangliomas.


Radiofrequency ablation is a thyroid function-preserving treatment for patients with bilateral benign thyroid nodules.
To evaluate the efficacy and safety of radiofrequency (RF) ablation for treatment of bilateral thyroid nodules as well as preservation of thyroid function. Between January 2007 and October 2012, 18 patients (16 women and 2 men; mean age, 49.9 y; median age, 44 y; age range, 27-81 y) with bilateral thyroid nodules treated by RF ablation were included in this study. The inclusion criteria included bilateral thyroid nodules, pressure symptoms or cosmetic problems, cytologic confirmation of benignancy without atypical cells, and patient refusal of surgery. We used an RF generator (Cool-tip RF system [Covidien, Boulder, Colorado] or SSP-2000, Taewoong Medical Co, Ltd [Gyeonggi-do, Republic of Korea]) and an 18-gauge internally cooled electrode with 1-cm active tips (Cool-tip [Covidien] or Well-Point RF electrode [Taewoong Medical Co, Ltd]). RF ablation was conducted using the moving shot technique and a trans-isthmic approach. RF ablation was performed in separate sessions for nodules in each lobe. Follow-up ultrasound examinations were performed at 1-6 months, 6-12 months, and during the last month of follow-up. The diameter and volume of the nodule and clinical problems including cosmetic and symptom scores were evaluated before and after the procedure. The mean initial nodule size was 4.1 cm ± 1.9, although there was a significant decrease by the time of the last follow-up examination (range, 1-48 mo; mean, 18.1 mo ± 12.8; P < .001, 2.5 cm ± 1.4). The initial nodule volume was 24.4 mL ± 32.2 and was decreased at the last follow-up (6.3 mL ± 19.0, P < .001), with a mean volume reduction of 75.9% ± 19.0. The symptom (P < .001) and cosmetic (P < .001) scores were decreased. Serum hormone levels did not differ significantly before treatment and at the last follow-up (P > .05). RF ablation improves cosmetic problems and symptoms and preserves thyroid function in patients with bilateral thyroid nodules.


Diffusion-weighted magnetic resonance imaging in focal breast lesions: analysis of 78 cases with pathological correlation.
This study assessed the usefulness of magnetic resonance diffusion-weighted imaging (DWI) in distinguishing between benign and malignant breast lesions. Gadolinium-enhanced magnetic resonance imaging (MRI) and DWI with determination of the apparent diffusion coefficient (ADC) were performed on 78 women, each with a focal breast lesion at least 7 mm in diameter, which was studied by cytology or histology. Final diagnoses were obtained by cytology in 29 cases and histology in 49 (11 percutaneous biopsies and 38 surgical specimens). There were 43 benign lesions (13 fibrocystic disease, eight fibroadenoma, seven adenosis, five normal breast tissue, four inflammatory lesions, three intramammary lymph nodes, two scleroelastosis and one fat necrosis) and 35 malignant lesions (30 invasive ductal carcinoma, two invasive lobular carcinoma, one ductal carcinoma in situ, one carcinomatous mastitis and one metastasis from neuroendocrine carcinoma). The mean ADC values were 1.677±0.151 for benign lesions and 1.298±0.129 for malignant lesions (p<0.001). With an ADC cutoff value of 1.48, DWI had 88.6% sensitivity [confidence interval (CI) 78.1%-99.1%] and 95.3% specificity (CI 88.9%-100%), with 31 true positives, four false negatives (three invasive ductal carcinoma and one carcinomatous mastitis), 41 true negatives and two false positives (one fat necrosis and one fibroadenoma). With the cutoff value set at 1.52, DWI sensitivity (35 true positive, no false negative) was 100% and specificity was 86% (CI 75.7%-96.3%) due to 37 true negatives and six false positives (an additional two fibroadenoma and two fibrocystic disease compared with those recorded with the cutoff set at 1.48). The overall accuracy of DWI considering both cutoff values (72 correct evaluations out of 78 cases) was 92.3% (CI 86.4%-98.2%). DWI is a reliable tool for characterising focal breast lesions.


Prevalence of Helicobacter pylori in asymptomatic patients at surgical outpatient department: Harare hospitals.
Helicobacter pylori infection is present in more than 50% of the world's population. The estimated life time risk of peptic ulcer disease is 20 percent and of gastric cancer is 1-2 percent. A cross sectional study was done at two Central hospitals in Harare, Zimbabwe, with the objective being to estimate the prevalence of Helicobacter pylori infection in asymptomatic individuals. Other objectives were to determine the association of the Helicobacter pylori infection with potential risk factors.Four hundred and fifty patients visiting the outpatient surgical clinics for other complaints other than upper gastrointestinal symptoms were recruited in the study. Drops of whole blood were obtained by fingertip puncture from each patient. The Onsite H. pylori Combo Rapid Test was used to confirm the presence or absence of antibodies against Helicobacter pylori. A questionnaire was used to record the sociodemographics of the participants. Three hundred patients, 186 males (62%) and 114 females (38%) participated. The prevalence of Helicobacter pylori infection was 67.7 percent (203/300). The prevalence of H pylori infection was significantly correlated with increasing age (p = 0.012), sharing of a bed with siblings during childhood (p = 0.013) and the mode of sanitation methods (p = 0.023). There was no association found between H pylori infection and other risk factors such as; gender, level of education, employment status or number of rooms in a house. H. pylori infection prevalence was significantly associated with increasing age, sharing of a bed with siblings during childhood and the mode of sanitation used. Clinicians and the public have to be aware of the important role of H pylori in upper gastrointestinal disease. Use of better sanitation methods, appropriate hygiene, avoidance of over-crowding amongst other measures should be encouraged as a means to reduce the acquisition and transmission of H pylori.


Early Onset Acute Coronary Artery Occlusion After Pembrolizumab in Advanced Non-Small Cell Lung Cancer: A Case Report.
Myocarditis, arrhythmia, and cardiomyopathy are the most reported acute cardiotoxicities in cancer patients receiving immune checkpoint inhibitor (ICI) therapy. But it is not clear whether ICI can cause acute coronary occlusive disease. We reported acute coronary artery occlusion in an 83-year-old male non-small cell lung cancer (NSCLC) patient after 2 days of pembrolizumab infusion. This patient had a server-underlying three-vessel coronary artery disease without symptoms. The patient was discharged from the hospital two weeks after percutaneous coronary intervention. Pembrolizumab may cause destabilization of severely stenosed atherosclerotic plaques, which contributes to acute myocardial infarction. We should take more caution about lung cancer patients with baseline coronary disease when treat with ICI. CRP may be a useful predictor factor of early-onset coronary events in these patients.


The prevalence of menstrual disorders and premenstrual syndrome among adolescent girls living in North Borneo, Malaysia: a questionnaire-based study.
This study aimed to determine menstrual characteristics and related morbidities among adolescent girls living in Sabah, North Borneo, a less-developed state in Malaysia. Data were obtained from a quantitative survey conducted in three government high schools located in Ranau, Sabah. The participants were adolescent girls who had attained menarche between the ages of 14 and 19. Based on the analysis of questionnaires completed by 757 adolescent girls, the mean age at the time of the survey was 17 ± 1.4 years, and the mean menarche age was 12.2 ± 1.1 years. Our data demonstrated that 85.7% of the participants experienced dysmenorrhoea, of which at least 42.1% (mean pain score ± SD: 4.81 ± 0.76, 95% confidence interval (CI) 4.72, 4.90) experienced moderate dysmenorrhoea, and 11.2% (mean pain score ± SD: 7.86 ± 0.94, 95% CI 7.64, 8.08) experienced severe dysmenorrhoea. Over 70% of these girls complained of tiredness, headache, and appetite changes during menses. The prevalence of menstrual disorders and related morbidities was high among the girls residing in Sabah. Reproductive health issues in rural and socioeconomically deprived areas remains poorly addressed. The main consequence of neglecting menstrual disorders and their related morbidities is impaired future sexual reproductive health in adults. Thus, addressing adolescent reproductive health issues is crucial, especially for girls living in areas where access to healthcare is difficult. The information gathered from this study can be used to strategize effective interventions to improve adolescents' reproductive health status in rural areas.


Thromboembolism profiles associated with cyclin-dependent kinase 4/6 inhibitors: a real-world pharmacovigilance study and a systematic review.
Thrombosis is the second leading cause of mortality in cancer patients. This study aimed to investigate the association between cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) and thrombosis. A retrospective pharmacovigilance analysis based on real-world data combined with a systematic review was used to explore the thrombotic risk profiles of CDK4/6i. The study has been registered with Prospero (CRD42021284218). In the pharmacovigilance analysis, CDK4/6i showed a higher rate of reported venous thromboembolism (VTE) (ROR = 2.78, 95% CI = 2.64-2.92), with the highest signal for trilaciclib (ROR = 27.55, 95% CI = 13.43-56.52) but only 9 cases, followed by abemaciclib (ROR = 3.73, 95% CI = 3.19-4.37). For arterial thromboembolism (ATE), only ribociclib increased the reporting rate (ROR = 2.14, 95% CI = 1.91-2.41). In the meta-analysis, palbociclib, abemaciclib, and trilaciclib all increased the risk of VTE (OR = 2.23, 3.17, and 3.90). In the subgroup analysis, only abemaciclib increased the risk of ATE (OR = 2.11, 95% CI = 1.12-3.99) . CDK4/6i had different profiles of thromboembolism. Palbociclib, abemaciclib, or trilaciclib increased the risk of VTE. Ribociclib and abemaciclib showed a weak association with the risk of ATE.


Synthesis of cholestane saponins as mimics of OSW-1 and their cytotoxic activities.
To fulfill the structure-activity relationship (SAR) of OSW-1, and aim at finding the simplest structural part while maintaining most of the biological activities, six cholestane saponins were synthesized by introducing OSW-1 disaccharide (2-O-4-methoxybenzoyl-β-D-xylopyranosyl-(1→3)-2-O-acetyl-α-L-arabinopyranosyl) and its 1→4-linked analogue to the 7-hydroxy or 16-hydroxy of steroidal sapogenins. Cytotoxic activities of the products were tested. Compounds 1 and 3 exhibited potent cytotoxicities against five types of human tumor cells, with minimum IC(50) of 2.0 and 75 nM, respectively. And due to its high activity and easy accessibility compound 1 could be a potential candidate for new anti-tumor agents.


Molecular physiology and functional morphology of SO₄²⁻ excretion by the kidney of seawater-adapted eels.
Marine teleosts actively excrete SO₄²⁻ and keep the plasma concentration of this ion much lower than that of environmental seawater (SW). We used the eel as a model to study the excretory mechanism of SO₄²⁻ because this euryhaline species changes SO₄²⁻ regulation drastically after transfer from freshwater (FW) to SW. Time-course studies showed that plasma SO₄²⁻ concentration decreased 3 days after transfer of eels from FW to SW, while urine SO₄²⁻ concentration increased on 1 day. Detailed analyses showed that urine SO₄²⁻ concentration increased linearly from 6 h after SW transfer; however, this did not immediately translate to increased SO₄²⁻ excretion because the volume of urine was decreased. We identified five SO₄²⁻ transporters in the eel kidney. Three of these (Slc26a1, Slc26a6b and Slc26a6c) are expressed in both SW- and FW-acclimated eels while Slc26a6a and Slc13a1 are expressed in SW-acclimated eels and FW-acclimated eels, respectively. We showed that changes in Slc26a6a and Slc13a1 gene expression occurred 1-3 days after SW transfer. In SW eel kidneys, immunohistochemistry using specific antisera against each transporter protein showed that Slc26a6a and Slc26a6c are localized on the apical membrane of the P1 segment of the proximal tubule, while Slc26a6b is localized on the apical membrane and Slc26a1 on the basolateral membrane of the P2 segment. The current study revealed complex molecular mechanisms of SO₄²⁻ excretion in the SW eel kidney that involve segment-specific localization of multiple Slc transporters in proximal tubules and modulation of their expression in different SO₄²⁻ environments. This precise regulatory mechanism may endow the eel with euryhalinity.


Carbon black nanoparticle exposure during middle and late fetal development induces immune activation in male offspring mice.
Increasing exposure to nanoparticles (NPs) has raised concerns regarding their health and safety profiles in humans and animals, especially in developing organisms, which may display increased sensitivity to NP toxicity. The present study examined the effects of gestational exposure to carbon black NP (CB-NP) on the development of the offspring immune system. Pregnant mice were exposed to CB-NP (95μg/kg body weight) by intranasal instillation on gestational days 9 and 15. The thymus and spleen were collected from their offspring mice on postnatal day (PND) 1, 3 and 5. Thymocyte and splenocyte phenotypes were examined by determining the expression of cell-surface molecules using flow cytometry. Gene expression in the thymus and spleen was examined using quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Prenatal exposure to CB-NP increased total thymocytes and their immunophenotypes (CD4(-)CD8(-) and CD4(+)CD8(+) cells). It also induced an increase in total lymphocytes, and CD4(-)CD8(-), particularly CD3(-)B220(-)cells, at PND 5 in the spleen of newborn male offspring, reflecting the stimulation of immature splenocytes. Furthermore, mRNA expression of genes related to the induction of peripheral tolerance (i.e. thymic Traf6) was upregulated. These data suggest that respiratory exposure to CB-NP during middle and late gestation may have allergic or inflammatory effects in male offspring, and may provide initial information on the potential developmental immunotoxicity of nanoparticles.


Neuropeptide Y increases differentiation of human olfactory receptor neurons through the Y1 receptor.
Olfactory dysfunction significantly impedes the life quality of patients. Neuropeptide Y (NPY) is not only a neurotrophic factor in the rodent olfactory system but also an orexigenic peptide that regulates feeding behavior. NPY increases the olfactory receptor neurons (ORNs) responsivity during starvation; however, whether NPY can promote differentiation of human ORNs remains unexplored. This study investigates the effect of NPY on the differentiation of human olfactory neuroepithelial cells in vitro. Human olfactory neuroepithelium explants were cultured on tissue culture polystyrene dishes for 21 days. Then, cells were cultured with or without NPY at the concentration of 0.5 ng/mℓ for 7 days. The effects of treatment were assessed by phase contrast microscopy, immunocytochemistry and western blot analysis. The further mechanism was evaluated with NPY Y1 receptor-selected antagonist BIBP3226. NPY-treated olfactory neuroepithelial cells exhibited thin bipolar shape, low circularity, low spread area, and long processes. The expression levels of Ascl1, βIII tubulin, GAP43 and OMP were significantly higher in NPY-treated cells than in controls (p < 0.05). NPY-treated olfactory neuroepithelial cells expressed more components of signal transduction apparatuses, Golf and ADCY3, than those without NPY treatment. Western blot analysis also further confirmed these findings (p < 0.05). Additionally, the expression levels of Ascl1, βIII2 tubulin, GAP43, OMP, ADCY3, and Golf in BIBP3226 + NPY and controls were comparable (p > 0.05). NPY not only increases expressions of protein markers of human olfactory neuronal progenitor cells, but also promotes differentiation of ORN and enhances formation of components of olfactory-specific signal transduction pathway through Y1 receptors.


Programming Fluorogenic DNA Probes for Rapid Detection of Steroids.
The ability of aptamers to recognize a variety of different molecules has fueled their emergence as recognition agents to probe complex media and cells. Many detection strategies require aptamer binding to its target to result in a dramatic change in structure, typically from an unfolded to a folded state. Here, we report a strategy based on forced intercalation (FIT) that increases the scope of aptamer recognition by transducing subtle changes in aptamer structures into fluorescent readouts. By screening a library of green-fluorescent FIT-aptamers whose design is guided by computational modeling, we could identify hits that sense steroids like dehydroepiandrosterone sulfate (DHEAS) down to 1.3 μM with no loss in binding affinity compared to the unmodified aptamer. This enabled us to study DHEAS in clinical serum samples with several advantages over gold standard methods, including rapid readout (<30 min), simple instrumentation (plate-reader), and low sample volumes (10 μL).


A Better Zn-Ion Storage Device: Recent Progress for Zn-Ion Hybrid Supercapacitors.
As a new generation of Zn-ion storage systems, Zn-ion hybrid supercapacitors (ZHSCs) garner tremendous interests recently from researchers due to the perfect integration of batteries and supercapacitors. ZHSCs have excellent integration of high energy density and power density, which seamlessly bridges the gap between batteries and supercapacitors, becoming one of the most viable future options for large-scale equipment and portable electronic devices. However, the currently reported two configurations of ZHSCs and corresponding energy storage mechanisms still lack systematic analyses. Herein, this review will be prudently organized from the perspectives of design strategies, electrode configurations, energy storage mechanisms, recent advances in electrode materials, electrolyte behaviors and further applications (micro or flexible devices) of ZHSCs. The synthesis processes and electrochemical properties of well-designed Zn anodes, capacitor-type electrodes and novel Zn-ion battery-type cathodes are comprehensively discussed. Finally, a brief summary and outlook for the further development of ZHSCs are presented as well. This review will provide timely access for researchers to the recent works regarding ZHSCs.


A systematic review of potential biomarkers for bacterial burden and treatment efficacy assessment in TB platform-based clinical trials.
Adaptive platform trials can be more efficient than classic trials for developing new treatments. Moving from culture-based to simpler- or faster-to-measure biomarkers as efficacy surrogates may enhance this advantage. We performed a systematic review of treatment efficacy biomarkers in adults with tuberculosis. Platform trials can span different development phases. We grouped biomarkers as: α, bacterial load estimates used in phase 2a trials; β, early and end-of treatment endpoints, phase 2b-c trials; γ, post-treatment or trial-level estimates, phase 2c-3 trials. We considered as analysis unit (biomarker entry) each combination of biomarker, predicted outcome, and their respective measurement times or intervals. Performance metrics included: sensitivity, specificity, area under the receiver-operator curve (AUC), and correlation measures, ,and classified as poor, promising, or good. Eighty-six studies included 22864 participants. From 1356 biomarker entries, 318 were reported with the performance metrics of interest, with 103 promising and 41 good predictors. Group results: α, mycobacterial RNA and Lipoarabinomannan in sputum, and host metabolites in urine; β, mycobacterial RNA and host transcriptomic or cytokine signatures for early treatment response; γ, host transcriptomics for recurrence. A combination of biomarkers from different categories could help designing more efficient platform trials. Efforts to develop efficacy surrogates should be better coordinated.


Effects of pulse methylprednisolone on bone and marrow tissues: corticosteroid-induced osteonecrosis in rabbits.
To investigate the effects of pulse methylprednisolone acetate on bone and bone marrow tissues and to clarify the causal factors of corticosteroid-induced osteonecrosis (ON) by using an experimental animal model. Male adult Japanese white rabbits were injected once with 20 mg/kg of methylprednisolone into the right gluteus medius muscle. Seven rabbits were killed at 4 weeks, 4 at 6 weeks, 4 at 8 weeks, and 6 at 10 weeks. Both histopathologic and hematologic studies were performed every week. By 4 weeks after the steroid injection, 43% of the rabbits studied had developed multifocal ON lesions in the femur and/or humerus. In 1 rabbit, a thrombus was detected in an arteriole adjacent to the necrotic area at 4 weeks. After 6 weeks, there was also progressive histologic evidence of revascularization, with granulation tissue, and osteoblastic repair, with appositional bone formation. Hyperlipemia, fatty liver, and intraosseous fat embolism were observed in conjunction with thrombocytopenia and hypofibrinogenemia. A single injection of high-dose corticosteroids was found to be capable of inducing thrombocytopenia, hypofibrinogenemia, and hyperlipemia with multifocal ON in several bones.


Evaluating deep learning predictions for COVID-19 from X-ray images using leave-one-out predictive densities.
Early detection of the COVID-19 virus is an important task for controlling the spread of the pandemic. Imaging techniques such as chest X-ray are relatively inexpensive and accessible, but its interpretation requires expert knowledge to evaluate the disease severity. Several approaches for automatic COVID-19 detection using deep learning techniques have been proposed. While most approaches show high accuracy on the COVID-19 detection task, there is not enough evidence on external evaluation for this technique. Furthermore, data scarcity and sampling biases make difficult to properly evaluate model predictions. In this paper, we propose stochastic gradient Langevin dynamics (SGLD) to take into account the model uncertainty. Four different deep learning architectures are trained using SGLD and compared to their baselines using stochastic gradient descent. The model uncertainties are also evaluated according to their convergence properties and the leave-one-out predictive densities. The proposed approach is able to reduce overconfidence of the baseline estimators while also retaining predictive accuracy for the best-performing cases.


Exploring calcium ion-dependent effect on the intermolecular interaction between human secreted phospholipase A2 and its peptide inhibitors in coronary artery disease.
Human secreted phospholipase A2 (hsPLA2) is a small calcium ion (Ca2+)-regulatory protein secreting from platelets, eosinophils and T-lymphocytes, which has been established as an important biomarker and potential target for the diagnosis and therapy of coronary artery disease. Short peptide inhibitors are used to competitively suppress the enzymatic activity of hsPLA2. Here, Ca2+ effect on the intermolecular recognition and interaction between hsPLA2 and its peptide inhibitors is investigated systematically by using molecular modeling and bioinformatics analysis. Dynamics simulations reveal that the hsPLA2 structure bound with Ca2+ is rather stable and has low thermal motion; removal of Ca2+ considerably increases structural flexibility and intrinsic disorder of the protein. Energetics calculations suggest that presence of Ca2+ can effectively promote the interaction of hsPLA2 with peptide inhibitors. In particular, the local substructures of hsPLA2 such as helix H1, loop L2 and double-stranded β-sheet DS that participate in peptide recognition are involved in or nearby Ca2+-coordinating site and can be directly stabilized by the Ca2+. In addition, a significant concentration-dependent effect of Ca2+ on peptide-hsPLA2 binding is observed in vitro, that is, a little of Ca2+ can largely improve peptide binding affinity, but high Ca2+ concentration does not increase the affinity substantially. The correlation between calculated free energy and experimental binding affinity over different peptide inhibitors is improved considerably by adding Ca2+ to hsPLA2. Specifically, the FLSYK peptide can generally bind to Ca2+-bound hsPLA2 with a moderate or high affinity (Kd ranges between 56 and 210 μM), but have only a modest affinity or even nonbinding to Ca2+-free hsPLA2 (Kd > 400 μM or = n.d.).


Bistable perception alternates between internal and external modes of sensory processing.
Perceptual history can exert pronounced effects on the contents of conscious experience: when confronted with completely ambiguous stimuli, perception does not waver at random between diverging stimulus interpretations but sticks with recent percepts for prolonged intervals. Here, we investigated the relevance of perceptual history in situations more similar to everyday experience, where sensory stimuli are usually not completely ambiguous. Using partially ambiguous visual stimuli, we found that the balance between past and present is not stable over time but slowly fluctuates between two opposing modes. For time periods of up to several minutes, perception was either largely determined by perceptual history or driven predominantly by disambiguating sensory evidence. Computational modeling suggested that the construction of unambiguous conscious experiences is modulated by slow fluctuations between internally and externally oriented modes of sensory processing.


Local governments' decade of organisational change to promote child health and wellbeing: a Western Australian qualitative study.
We aim to reflect on the introduction of risk-based approaches to public health, driven by legislation outlining the expected local government public health functions and roles by identifying factors that most influenced organisational change within the Western Australia local government sector when developing and submitting child and young people's health and social policy to an annual Awards program. This paper uses 10 years of data from a WA-based Local Government Policy Awards scheme to identify planned organisational change within the local government sector by applying a tangible organisational change model to develop a change narrative to describe factors that influenced local governments to address public health. Semi-structured interviews of 83 local government officers over the 10 years since implementation were used to create the narrative and identify factors that strengthened or hindered policy development and implementation at the local organisational level. Participant interviews highlighted that the Policy Award Scheme contributed to steps outlined in the Pettigrew et al. (1992) stepped model of organisational change theory to support policy development. Implications for public health: Few studies have explored these elements in their own right. We argue that advocacy for structured policy development is continually needed to support and promote internal policy prioritisation and implementation in practice.


Intraoperative management of distal tracheal rupture with selective bronchial intubation.
Patients with tracheal rupture present a considerable challenge to the anesthesiologist. The most important aspect in anesthesiology in such cases is to maintain oxygenation and ventilation without compromising surgical repair. We report a case of a woman who suffered a chemical perforation of the carina and left bronchus after ingesting hydrochloric acid during a suicide attempt. We describe the intraoperative management strategies, with emphasis on the use of bilateral bronchial intubation to provide selective lung ventilation. Alternative modes of ventilation and the use of cardiopulmonary bypass are discussed.


A randomized controlled trial on a self-guided Internet-based intervention for gambling problems.
The majority of individuals with problematic and pathological gambling remain untreated, and treatment barriers are high. Internet-based interventions can help to address existing barriers, and first studies suggest their potential for this target group. Within a randomized controlled trial (N = 150) with two assessment times (baseline and post-intervention), we aimed to investigate the feasibility, acceptance, and effectiveness of a self-guided Internet-based intervention targeted at gambling problems. We expected a significant reduction in gambling symptoms (primary outcome) and depressive symptoms as well gambling-specific dysfunctional thoughts (secondary outcomes) in the intervention group (IG) compared to a wait-list control group with access to treatment-as-usual (control group, CG) after the intervention period of 8 weeks. Results of the complete cases, per protocol, intention-to-treat (ITT), and frequent user analyses showed significant improvements in both groups for primary and secondary outcomes but no significant between-group differences (ITT primary outcome, F(1,147) = .11, p = .739, ηp2 < .001). Moderation analyses indicated that individuals in the IG with higher gambling and depressive symptoms, older age, and comorbid anxiety symptoms showed significant improvement relative to the CG. The intervention was positively evaluated (e.g., 96.5% rated the program as useful). Possible reasons for the nonsignificant between-group differences are discussed. Future studies should include follow-up assessments and larger samples to address limitations of the present study. Trial Registration ClinicalTrials.gov (NCT03372226), http://clinicaltrials.gov/ct2/show/NCT03372226 , date of registration (13/12/2017).


Role of host factors in SARS-CoV-2 entry.
The zoonotic transmission of highly pathogenic coronaviruses into the human population is a pressing concern highlighted by the ongoing SARS-CoV-2 pandemic. Recent work has helped to illuminate much about the mechanisms of SARS-CoV-2 entry into the cell, which determines host- and tissue-specific tropism, pathogenicity, and zoonotic transmission. Here we discuss current findings on the factors governing SARS-CoV-2 entry. We first reviewed key features of the viral spike protein (S) mediating fusion of the viral envelope and host cell membrane through binding to the SARS-CoV-2 receptor, angiotensin-converting enzyme 2. We then examined the roles of host proteases including transmembrane protease serine 2 and cathepsins in processing S for virus entry and the impact of this processing on endosomal and plasma membrane virus entry routes. We further discussed recent work on several host cofactors that enhance SARS-CoV-2 entry including Neuropilin-1, CD147, phosphatidylserine receptors, heparan sulfate proteoglycans, sialic acids, and C-type lectins. Finally, we discussed two key host restriction factors, i.e., interferon-induced transmembrane proteins and lymphocyte antigen 6 complex locus E, which can disrupt SARS-CoV-2 entry. The features of SARS-CoV-2 are presented in the context of other human coronaviruses, highlighting unique aspects. In addition, we identify the gaps in understanding of SARS-CoV-2 entry that will need to be addressed by future studies.


Do We Know Where They Go? Obtaining Travel History in Pediatric Patients.
To determine how often travel histories are obtained in pediatric patients. A retrospective medical record review was performed at a single tertiary care children's hospital for patients aged 2 months to 18 years who were admitted October 2015-December 2017 with International Classification of Diseases, 10th Revision codes for potential travel-related illnesses. Demographic information and travel history documentation were obtained, along with travel-related testing. From May to June 2018, prospective, single-blinded, direct observation of a convenience sample of pediatric residents was performed during the initial patient encounter to determine the frequency and quality of travel histories obtained regardless of documentation. Of 249 charts reviewed, 27 (10.8%) patients had a travel history query documented. Patients with complex chronic conditions were significantly less likely to have a travel history documented (37% vs 67%; P = 0.005). Age, sex, length of stay, race, payer status, and critical care admission did not significantly differ between groups. Those with a travel history documented were more likely to have a documented exposure history (100% vs 52%; P < 0.001) and additional testing performed (56% vs 13%, P < 0.001). During this time, a simulation course with residents featuring travel-related diagnoses led to a significant increase in documented travel histories (5% prior versus 21% after, P = 0.03). A total of 37 patient encounters were observed; travel history was asked for 4 times (4/37, 10.8%). Travel histories are rarely asked for in pediatric patients. Missed diagnoses may not only affect the patient but also have broader public health implications. Simulation is an effective tool to improve history-taking skills, yet more work is still needed.


Selected neurotrophins, neuropeptides, and cytokines: developmental trajectory and concentrations in neonatal blood of children with autism or Down syndrome.
Using a double-antibody immunoaffinity assay (Luminex) and ELISA technology, we measured concentrations of certain neurotrophins, neuropeptides, and cytokines in pooled samples (one to three subjects per sample) eluted from archived neonatal blood of children with later-diagnosed autism, Down syndrome, very preterm birth, or term control infants. We also measured analytes in blood from healthy adult controls. Case or control status for infant subjects was ascertained by retrospective review of service agency medical records. We observed inhibitory substances in eluates from archived bloodspots, especially marked for measurement of BDNF. Concentrations in control subjects differed by age: BDNF rose markedly with age, while NT-3 and NT-4/5 concentrations were lower in adults than in newborn infants. IL-8 concentrations were higher in newborn infants, preterm and term, than in adults. Considered by diagnostic group, total protein was higher in Down syndrome than in either autism or control subjects. In infants with Down syndrome, concentrations of IL-8 levels were higher than in controls, whether or not corrected for total protein; NT-3 and CGRP were lower and VIP higher. In samples from autistic subjects, NT-3 levels were significantly lower than controls and an increase in VIP approached statistical significance. Concentrations of NT-4/5 and CGRP were correlated in infants with autism but not in Down syndrome or controls. Some of these results differ from earlier findings using a single-antibody recycling immunoaffinity chromatography (RIC) system. We discuss interrelationships of VIP, NT-3 and IL-8 and their potential relevance to features of the neuropathology of autism or Down syndrome.


Studies on the energy metabolism of the pregnant sow. 1. Uterus and mammary tissue development.
Twenty-six gilts were used in an experiment to study the effects of level of feed intake on the growth and chemical composition of the gravid uterus and mammary tissue at several stages of gestation. The animals were given either 1.8 or 2.5 kg feed/d (20 or 30 MJ metabolizable energy (ME) respectively) and were slaughtered at intervals between days 40 and 110 of gestation. The gravid uterus was dissected into fetal, placental, fluid and empty uterus components. From day 70 of gestation the mammary tissue was also dissected. The fresh weight and dry matter (DM), energy and nitrogen contents of the various tissues were determined. With the exception of the fluid component, there was a significant increase (P less than 0.01) in the fresh weight of each tissue with both stage of gestation and level of feeding. At comparable litter sizes the total weight of the fetuses in late gestation was 16% higher with the higher feed intake. The DM content of the individual uterine tissues increased significantly (P less than 0.01) with increase in stage of gestation so that the mean DM content of the gravid uterus increased from 74.6 g/kg at day 50 to 103.1 and 159.0 g/kg at days 90 and 110 of gestation respectively. Neither stage of gestation nor feeding level influenced the respective energy contents of the individual uterine tissues, when expressed per g DM. The mean energy content of the total gravid uterus was 19.5 kJ/g DM. The N content (g/g fresh weight) of the tissues increased with stage of gestation and was generally higher at the higher feeding level. The mean N contents (g/g DM) of the fetal, placental, fluid and empty uterine tissues were 0.090, 0.101, 0.098 and 0.128 respectively. The mammary tissue was the most variable of all the tissues investigated. Whereas the fresh weight and N content increased with stage of gestation, both the DM and energy content decreased. Gompertz equations were fitted to describe the effects of stage of gestation, level of feed intake and liter size on the fresh weight and chemical content of the individual uterine tissues, total gravid uterus and mammary tissue. The use of these equations for calculating the nutrient requirements of pregnancy is demonstrated. It was calculated that between days 50 and 110 of gestation the ME requirement for reproduction increased from 3 to 12% of maternal energy intake. The calculated requirement for protein was from 7 to 41% of maternal dietary protein intake respectively.


Differences in protein digestibility and quality of liquid concentrate and powder forms of milk-based infant formulas fed to rats.
Protein and amino acid digestibility and protein quality of liquid concentrate and/or powder forms of infant formulas were studied by rat balance and growth methods. Casein plus methionine (control) and eight formulas were fed to weanling rats as the sole source of protein in diets containing 8% protein (nitrogen X 6.25). Values for true digestibility of protein, lysine, methionine, or cystine (85-92%) in liquid concentrates were up to 13% lower than those in powders. Similarly, the 2-wk relative protein-efficiency ratio values (64-85%) or the relative net protein ratio values (78-94%) of liquid concentrates were up to 25% lower than those for powders. Lower levels of bioavailable lysine and methionine plus cystine in liquid concentrates compared with powders (prepared by the same manufacturer) would suggest that inferior protein quality of liquid concentrates may be due to more heat treatment involved in their preparation.


Growth of gram-positive and gram-negative bacteria in platelet concentrates.
In 1986 the allowable platelet storage time was reduced from 7 to 5 days because of a recent increase in septic deaths associated with platelet transfusion. In this study, the growth curves of two gram-positive and two gram-negative organisms in platelets stored for 7 days in CLX and PL-732 bags were evaluated. Platelets in CLX bags were inoculated with 10(1), 10(2), and 10(3) organisms and 10(2) organisms were introduced into PL-732 bags. Test organisms were inoculated into trypticase soy broth as a control. All four bacteria grew rapidly in trypticase soy broth, reaching 10(9) organisms per mL within 48 hours. In both CLX and PL-732 bags, the growth pattern of gram-positive organisms was generally logarithmic during the first few days of storage. A concentration of 10(8) organisms per mL was present by Day 3 or 4, after which further proliferation was inhibited by the high density of bacteria in the platelets. In PL-732 bags, the proliferation of gram-negative organisms followed a pattern similar to that of the gram-positive bacteria. However, gram-negative organisms grew less well in CLX bags.(ABSTRACT TRUNCATED AT 250 WORDS)


Long-Term Efficacy and Safety of the Long-Acting Complement C5 Inhibitor Ravulizumab for the Treatment of Atypical Hemolytic Uremic Syndrome in Adults.
Atypical hemolytic uremic syndrome (aHUS) is a rare, complex, multisystem disease of dysregulated complement activity, characterized by progressive thrombotic microangiopathy (TMA), acute kidney injury, and multiorgan dysfunction, which often progresses to chronic kidney disease. Results from the prospective clinical trial of ravulizumab (NCT02949128) reveal rapid resolution of TMA in patients with aHUS, with sustained efficacy and safety in a 26-week initial evaluation period. The aim of this analysis was to characterize the long-term efficacy and the safety profile of ravulizumab in adults with aHUS who had completed the initial evaluation period of the trial. Complete TMA response, hematologic and kidney functions, and safety were evaluated for all patients available for follow-up in the extension period (median follow-up: 76.7 weeks; range: 0.6-118.3). This trial included a total of 58 patients, 49 of whom entered the extension period. A total of 4 additional patients achieved complete TMA response during the follow-up period. Normalization of platelet count, serum lactate dehydrogenase (LDH), and hemoglobin observed in the 26-week initial evaluation period was sustained until the last available follow-up, as were the improvements in the estimated glomerular filtration rate (eGFR) and patient quality of life. All efficacy endpoints were correlated with the sustained inhibition of complement C5. Most adverse events (AEs) occurred early during the initial evaluation period and decreased substantially during the extension period. No patient developed a meningococcal infection or died during the extension period. This analysis reveals that ravulizumab administered every 8 weeks is efficacious with an acceptable safety profile for the long-term treatment of adults with aHUS and provides additional clinical benefit beyond 6 months of treatment.


Microarray profile of circular RNAs identifies hsa_circ_000455 as a new circular RNA biomarker for deep vein thrombosis.
Deep vein thrombosis is a type of severe venous thromboembolism that can result in high mortality and morbidity. The expression alternation of circular RNAs (circRNAs) has been found in various diseases. However, the function of circRNAs in deep vein thrombosis still remains unknown. The blood samples of deep vein thrombosis patients and health control were selected, circRNA microarray was performed, and qPCR was used to verify the expression of circRNAs. Also, GO/KEGG analysis was performed, and hsa_circ_RNA_000455-targeted miRNA-mRNA network was predicted. Here, we found that 303 circRNAs were differentially expressed in deep vein thrombosis using microarray, of which 83 circRNAs were upregulated and 220 circRNAs were downregulated. The expression of five circRNAs verified by quantitative real-time PCR was consistent with the result of microarray. GO analysis showed that the top 100 differentially expressed circRNAs in deep vein thrombosis patients were closely related to protein transport, cytoplasm, and Adenosine Triphosphate (ATP) binding. The most significantly enriched pathways by KEGG analysis included thyroid hormone-signaling pathway, endocytosis, proteoglycans in cancer, Fc gamma R-mediated phagocytosis, focal adhesion, insulin-signaling pathway, p53-signaling pathway, biosynthesis of antibiotics, bacterial invasion of epithelial cells, and AMP-activated protein kinase-signaling pathway. Then, hsa_circ_000455 was selected, and the function of hsa_circ_000455 in the pathogenesis of deep vein thrombosis was analyzed via circRNA-miRNA-mRNA network. We therefore hypothesized that hsa_circRNA_000455/hsa-miR-22-3p/NLRP3 may involve in the development of deep vein thrombosis. This study provided valuable information on circRNA profile in deep vein thrombosis for the first time and gave clues on the possible role and mechanism of hsa_circRNA_000455 in deep vein thrombosis.


Graft patency and progression of coronary artery disease after CABG assessed by angiography-derived fractional flow reserve.
Graft occlusion after coronary artery bypass graft surgery (CABG) has been associated with native coronary artery competitive flow. The present study aims to characterize the functional progression of coronary artery disease (CAD) in native vessels after CABG, and to assess the relationship between preoperative FFR as derived from angiography and graft occlusion. Multicenter study of consecutive patients undergoing CABG between 2013 and 2018, in whom a follow-up angiogram had been performed. Serial vessel-fractional flow reserve (vFFR) analyses were obtained in each major native coronary vessel before and after CABG, excluding post-anastomotic segments and graft conduits. In 73 patients, serial angiograms were suitable for vFFR analysis, including 118 grafted (86 arterial and 32 saphenous grafts) and 64 non-grafted vessels. The median time between CABG and follow-up angiography was 2.4 years [IQR 1.5, 3.3]. Functional CAD progression, by means of decline in vFFR, was observed in grafted but not in non-grafted vessels (delta vFFR in grafted vessels 0.10 [IQR 0.05, 0.18] vs. 0.01 [IQR -0.01, 0.03], in non-grafted vessels, p < 0.001). Preoperative vFFR predicted graft occlusion (AUC: 0.66, 95% CI 0.52 to 0.80, p = 0.031). In patients undergoing CABG, preoperative vFFR derived from conventional angiograms without use of pressure wire was able to predict graft occlusion. Graft occlusion was more frequent in vessels with high vFFR values. Grafted native coronary vessels exhibited accelerated functional CAD progression, whereas in non-grafted native coronaries the functional status remained unchanged.


Lack of Neuroprotection with a Single Intravenous Infusion of Human Amnion Epithelial Cells after Severe Hypoxia-Ischemia in Near-Term Fetal Sheep.
Hypoxic-ischemic encephalopathy (HIE) around the time of birth results from loss of oxygen (hypoxia) and blood supply (ischemia). Exogenous infusion of multi-potential cells, including human amnion epithelial cells (hAECs), can reduce hypoxic-ischemic (HI) brain injury. However, there are few data on treatment of severe HI in large animal paradigms at term. The aim of the current study was to determine whether infusion of hAECs early after injury may reduce brain damage after ischemia in near-term fetal sheep. Chronically instrumented fetal sheep (0.85 gestation) received 30 min of global cerebral ischemia followed by intravenous infusion of hAECs from 2 h after the end of ischemia (ischemia-hAEC, n = 6) or saline (ischemia-vehicle, n = 7). Sham control animals received sham ischemia with vehicle infusion (sham control, n = 8). Ischemia was associated with significant suppression of EEG power and spectral edge frequency until the end of the experiment and a secondary rise in cortical impedance from 24 to 72 h, which were not attenuated by hAEC administration. Ischemia was associated with loss of neurons in the cortex, thalamus, striatum and hippocampus, loss of white matter oligodendrocytes and increased microglial numbers in the white matter, which were not affected by hAEC infusion. A single intravenous administration of hAECs did not reduce electrographic or histological brain damage after 30 min of global cerebral ischemia in near-term fetal sheep.


Evaluation of antimutagenic activity and mechanisms of action of beta-glucan from barley, in CHO-k1 and HTC cell lines using the micronucleus test.
Due to the need to identify new antimutagenic agents and to determine their mechanism of action, the present study examined the mechanism of action of the beta-glucan with regard to antimutagenicity using the micronucleus assay in CHO-k1 and HTC cell lines. The mutagenicity experiments were performed with three different concentrations of beta-glucan (5, 10, and 20 microg/mL), in wich only the highest dose showed mutagenic activity. In the antimutagenicity experiments, the same concentrations of beta-glucan were combined with a mutagenic agent, methylmethane sulfonate, or 2-aminoanthracene, using four different treatment protocols: pre-treatment, simultaneous treatment (simple and with pre-incubation), and post-treatment. The results indicate that the CHO-k1 cell line treated with MMS presented a chemopreventive activity for all the doses of beta-glucan in the different treatment protocols, except for the lowest dose in post-treatment. When HTC cell line treated with MMS is analysed, a chemopreventive activity can be verified for the highest dose in both pre- and post-treatment. For the simple simultaneous treatment, the three doses demonstrated efficacy, while for the simultaneous treatment with pre-incubation only the intermediate concentration was effective. In HTC treated with 2AA both the lowest dose in the pre-treatment protocol and the post-treatment protocol did not show efficacy in preventing DNA damage. The evaluation of the different protocols and the damage decrease percentages observed suggest that beta-glucan has both desmutagenic and bioantimutagenic activity. It is necessary, however, to note that efficacy and mechanism of action are subject to variation when compared the two cell lines, since in HTC, representing a drug-metabolizing system, this substance can show a diminished chemopreventive capacity.


Qualitative Perceptions of an Anticipated Fresh Food Prescription Program.
Food insecurity (FI) is a growing public health problem. Produce prescriptions are known to improve healthy eating and decrease FI; however, few studies have incorporated community voice prior to its implementation. In this study, we aimed to elicit perspectives of individuals at risk for FI and the potential impact of a fresh food prescription (FFRx) program. We conducted this qualitative descriptive study through an academic medical center in collaboration with community partners. We conducted focus groups involving Latinx (N = 16) and African-American (N = 8) adults in community settings. Data were interpreted using an inductive thematic analysis. Three overarching themes emerged: (1) fresh food accessibility was limited by cost, household size, and transportation but enhanced by food pantries, budgeting, and education; (2) cooking behaviors were curbed by time constraints and unfamiliarity but propagated by passion, traditions, and communal practices; and (3) health and wellness deterrents included unhealthy diets driven by cultural and familial norms; however, weight loss and awareness of comorbidities were positive motivators. Participants shared their preference for local produce and cooking classes as components of a FFRx program while raising concerns about low participation due to the stigma of receiving aid. Our findings illuminated interest in engaging in a FFRx program and learning ways to prepare healthy foods. A program distributing fresh produce and healthy lifestyle education could close gaps identified in African-American and Latinx communities at risk for FI.


EVOLUTION OF GENERALISTS AND SPECIALISTS IN SPATIALLY HETEROGENEOUS ENVIRONMENTS.
Quantitative genetic models are used to investigate the evolution of generalists and specialists in a coarse-grained environment with two habitat types when there are costs attached to being a generalist. The outcomes for soft and hard selection models are qualitatively different. Under soft selection (e.g., for juvenile or male-reproductive traits) the population evolves towards the single peak in the adaptive landscape. At equilibrium, the population mean phenotype is a compromise between the reaction that would be optimal in both habitats and the reaction with the lowest cost. Furthermore, the equilibrium is closer to the optimal phenotype in the most frequent habitat, or the habitat in which selection on the focal trait is stronger. A specialist genotype always has a lower fitness than a generalist, even when the costs are high. In contrast, under hard selection (e.g., for adult or female-reproductive traits) the adaptive landscape can have one, two, or three peaks; a peak represents a population specialized to one habitat, equally adapted to both habitats, or an intermediate. One peak is always found when the reaction with the lowest cost is not much different from the optimal reaction, and this situation is similar to the soft selection case. However, multiple peaks are present when the costs become higher, and the course of evolution is then determined by initial conditions, and the region of attraction of each peak. This implies that the evolution of specialization and phenotypic plasticity may not only depend on selection regimes within habitats, but also on contingent, historical events (migration, mutation). Furthermore, the evolutionary dynamics in changing environments can be widely different for populations under hard and soft selection. Approaches to measure costs in natural and experimental populations are discussed.


The rs4783961 and rs708272 genetic variants of the CETP gene are associated with coronary artery disease, but not with restenosis after coronary stenting.
We evaluated whether cholesteryl ester transfer protein (CETP) gene polymorphisms are associated with the presence of coronary artery disease (CAD) and/or restenosis in patients with coronary stent. Two polymorphisms of the CETP gene [-971 A/G (rs4783961), and Taq1B A/G (rs708272)] were genotyped by 5'exonuclease TaqMan assays in 219 patients with CAD (66 patients with restenosis and 153 without restenosis) and 607 control individuals. The distribution of polymorphisms was similar in patients with and without restenosis. However, when the whole group of patients (with and without restenosis) was compared to healthy controls, under dominant model, the G allele of the Taq1B A/G polymorphism was associated with increased risk of CAD (odds ratio [OR] = 1.48, pCDom = 0.032). In the same way, under codominant, dominant, and additive models, the A allele of the -971 A/G polymorphisms was associated with an increased risk of developing CAD (OR = 2.03, pCCo-dom = 0.022, OR = 1.83, pCDom = 0.008, and OR = 1.39, pCAdd = 0.011, respectively). In addition, the linkage disequilibrium showed that the "AG" haplotype was associated with increased risk of developing CAD (OR = 1.28, p = 0.03). This study demonstrates that CETP Taq1B A/G and CETP -971 A/G polymorphisms are associated with an increased risk of developing CAD, but no association with restenosis was observed.


Natural pseurotins inhibit proliferation and inflammatory responses through the inactivation of STAT signaling pathways in macrophages.
Natural pseurotins, secondary metabolites of fungi, commonly produced by various species such as Aspergillus flavus with suggested significant biological effects. However, little is known about effects of pseurotins on immune system functions. Effects of pseurotin A and D on proliferation and viability of macrophage RAW 264.7 cells were evaluated together with mitochondrial respiration and glycolysis. Macrophage response to lipopolysaccharide was analyzed based on determination of nitric oxide (NO) production, expression of inducible NO synthase (iNOS), interleukin 6 (IL-6) and tumor necrosis factor production. Activation of selected signaling pathways, particularly STAT and MAPK, as well as expression of cyclins were determined. Natural pseurotins A and D in concentrations of up to 50 μM significantly inhibit proliferation of RAW 264.7 macrophages which was not complemented by induction of cell toxicity. The inhibition of cell proliferation was accompanied by downregulation of expression of cyclins and mitochondrial respiration via inhibition of particularly STAT3 phosphorylation. Both pseurotins significantly inhibited production of NO, expression of iNOS and IL-6 production. Our results advance the current mechanistic understanding of the pseurotin-induced inhibition of proliferation, metabolic respiration and functional responses in macrophages by linking the effect to JAK/STAT signaling pathway.


A quantitative microassay of carbohydrate-mediated cell adhesion to glycoconjugates immobilized on polystyrene plates.
A microadhesion assay that allows the quantitative determination of carbohydrate-mediated cell adhesion to glycoconjugates immobilized on 96-well polystyrene plates has been developed. After dislodging nonadherent cells by centrifugation, specifically bound cells are quantified by colorimetric analysis of a blue formazan product generated from the dye 3-(4,5-dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide by enzymatic reduction. Carbohydrate specificity of the cell adhesion was demonstrated by inhibition analyses and the general applicability of the assay was proved with indicator cells of three different origins: mouse fibrosarcoma cells, Chang liver cells, and human breast carcinoma cells (MDA-MB 231).


Health-related Quality of Life for Abiraterone Plus Prednisone Versus Enzalutamide in Patients with Metastatic Castration-resistant Prostate Cancer: Results from a Phase II Randomized Trial.
Abiraterone and enzalutamide are associated with side effects that may impair health-related quality of life (HRQoL). To assess patient-reported HRQoL, depression symptoms, and cognitive function for abiraterone versus enzalutamide. We randomized 202 patients in a phase II study of abiraterone versus enzalutamide for first-line treatment of metastatic castration-resistant prostate cancer (ClinicalTrials.gov: NCT02125357). Patients completed Functional Assessment of Cancer Therapy-Prostate (FACT-P) and Patient Health Questionnaire-9 (PHQ-9) questionnaires, and Montreal Cognitive Assessment (MoCA) cognitive assessments at baseline and on treatment. To compare the change in FACT-P scores over time between treatment arms, we used a mixed model for repeated measures (MMRM). For FACT-P domains where there was an interaction between the treatment arm and age, we constructed separate models for patients aged <75 and ≥75yr. We compared the proportion of patients with clinically meaningful change from baseline for FACT-P, and the proportion of patients with an abnormal score and median change from baseline for PHQ-9 and MoCA using Fisher's exact test and Mann-Whitney U test. In the MMRM analysis, there was a positive test for interaction in the treatment arm by age for total FACT-P (p=0.048). FACT-P change from baseline over time was better for abiraterone than for enzalutamide in the ≥75-yr model (p=0.003), with no difference in the <75-yr model (p>0.9). A higher proportion of patients experienced clinically meaningful worsening with enzalutamide for the physical and functional well-being domains (37% vs 21%, p=0.013; 39% vs 23%, p=0.015). The distribution of change in PHQ-9 scores from baseline favored abiraterone at weeks 4, 8, and 12. These analyses were not prespecified, and results should be considered to be hypothesis generating. Patient-reported outcomes favored abiraterone compared with enzalutamide with differences in FACT-P HRQoL and PHQ-9 depression scores. Differences in the total FACT-P scores were seen only in the elderly patient subgroup. In this report, we examined the change in patient-reported quality-of-life scores from the start of treatment over time for patients treated with abiraterone versus enzalutamide for metastatic castration-resistant prostate cancer. We found that elderly patients treated with abiraterone had better quality of life over time, with no difference between treatments for the younger subgroup of patients.


A structural bio-chemo-mechanical model for vascular smooth muscle cell traction force microscopy.
Altered vascular smooth muscle cell (VSMC) contractility is both a response to and a driver for impaired arterial function, and the leading experimental technique for quantifying VSMC contraction is traction force microscopy (TFM). TFM involves the complex interaction among several chemical, biological, and mechanical mechanisms, making it difficult to translate TFM results into tissue-scale behavior. Here, a computational model capturing each of the major aspects of the cell traction process is presented. The model incorporates four interacting components: a biochemical signaling network, individual actomyosin fiber bundle contraction, a cytoskeletal network of interconnected fibers, and elastic substrate displacement due to cytoskeletal force. The synthesis of these four components leads to a broad, flexible framework for describing TFM and linking biochemical and biomechanical phenomena on the single-cell level. The model recapitulated available data on VSMCs following biochemical, geometric, and mechanical perturbations. The structural bio-chemo-mechanical model offers a tool to interpret TFM data in new, more mechanistic ways, providing a framework for the evaluation of new biological hypotheses, interpolation of new data, and potential translation from single-cell experiments to multi-scale tissue models.


Globalization, long memory, and real interest rate convergence: a historical perspective.
This paper investigates whether the real interest rate parity (RIRP) is valid during the three waves of globalizations that occurred in the last 150 years (1870-1914, 1944-1971, 1989 to the present). If any, these periods should favor RIRP, since globalization is a process where economies and financial markets become increasingly integrated into a global economic system. In contrast to the existing literature, we model the departures from RIRP as a long-term memory process and apply fractional integration methods on a sample of real interest rate differentials of seven developed countries: France, Germany, Holland, Italy, Japan, Spain, and the UK across the three globalization waves paired against the USA. We compute impulse response functions (IRF) to gain further insight into the memory characteristics of the RIRP differential processes and provide half-life estimates. We find that deviations from RIRP are mean reverting, providing robust evidence of real interest rate convergence during the three globalization waves. We shed further light on financial and commodity market integration during the three globalization waves by assessing the memory properties of uncovered interest rate parity (UIP) and relative purchasing power parity (PPP) differential processes. We find that deviations from relative PPP and UIP are not always mean-reverting processes. RIRP, relative PPP, and UIP hold simultaneously only in 7 out of 21 cases; RIRP and UIP hold in 11 out of 21 cases; RIRP hold without the support of relative PPP and UIP in 3 out of 21 cases. Thus, the evidence in favor of real interest rate convergence appears to be driven more by UIP than relative PPP. All these results are, to the authors knowledge, new to the literature.


Comparison of the volatile profile and sensory analysis of 'Golden Reinders' apples after the application of a cold air period after ultralow oxygen (ULO) storage.
All efforts to improve fruit quality are rewarded when consumers are satisfied after tasting the fruit. Apples are often stored under controlled atmosphere conditions to preserve them over time, but this frequently results in a loss of flavor. The aim of this work, which was based on two seasons, was to evaluate the influence of a period of short-term air storage (periods of 2 and 4 weeks) after removal from ultralow oxygen (ULO) storage (1 kPa of O(2)/1 kPa of CO(2)) with respect to increases in volatile compound emissions and the effect on standard and sensory quality in 'Golden Reinders' apples. The results showed that emissions of 26 volatile compounds increased as a result of ULO + 2 weeks or ULO + 4 weeks of storage. However, the results of tastings involving a panel of consumers and trained experts revealed that this increase was not matched by corresponding increases in either the degree of consumer preference or flavor attributes.


Comparison of markerless and marker-based motion capture of gait kinematics in individuals with cerebral palsy and chronic stroke: A case study series.
Three-dimensional (3D) motion analysis is an advanced tool used to quantify movement patterns in adults with chronic stroke and children with cerebral palsy. However, gold-standard marker-based systems have limitations for implementation in clinical settings. Markerless motion capture using Theia3D may provide a more accessible and clinically feasible alternative, but its accuracy is unknown in clinical populations. The purpose of this study was to quantify kinematic differences between marker-based and markerless motion capture systems in individuals with gait impairments. Three adults with chronic stroke and three children with cerebral palsy completed overground walking trials while marker-based and markerless motion capture data were synchronously recorded. Time-series waveforms of 3D ankle, knee, hip, and trunk angles were stride normalized and compared. Root mean squared error, maximum peak, minimum peak, and range of motion were used to assess discrete point differences. Pearson's correlation and coefficient of multiple correlation were computed to assess similarity between the time series joint angle waveforms from both systems. This study demonstrates that markerless motion capture using Theia3D produces good agreement with marker-based in the measurement of gait kinematics at most joints and anatomical planes in individuals with chronic stroke and cerebral palsy. This is the first investigation to study the feasibility of Theia3D markerless motion capture for use in chronic stroke and cerebral palsy gait analysis. Our results indicate that markerless motion capture may be an acceptable tool to measure gait kinematics in clinical populations to provide clinicians with objective movement assessment data.


Metal(loid) accumulation levels in submerged macrophytes and epiphytic biofilms and correlations with metal(loid) levels in the surrounding water and sediments.
The pollution of wetlands with metal(loid) s is a major ecological and environmental problem all over the world. However, the accumulation characteristics of metal(loid)s in submerged macrophytes and epiphytic biofilms in wetland systems where sediments are polluted by metal(loid)s are still unclear. In July (the wet season) and November (the dry season) 2018, surface water, sediments, submerged macrophytes (Potamogeton lucens L. and Myriophyllum verticillatum L.) and their epiphytic biofilms were collected to analyze the levels of Pb, Cd, Cu, Cr, Hg and As in Caohai wetland (China). Metal(loid) concentrations in sediments were ranked as follows: Cr > Pb > Cu > As > Cd > Hg. Although Pb, Cd and Hg levels exceeded the sediment background threshold levels of Guizhou Province, the water was not polluted by metal(loid)s. Except for Hg and Cr, most of the metal(loid) concentrations in epiphytic biofilms were higher than those in submerged macrophytes. No significant correlations were found between any of the metal(loid) concentrations in submerged macrophytes or biofilms and the metal(loid) concentrations in the surrounding water and sediments. Although the accumulation of As and Hg in submerged macrophytes had a very significant negative correlation with a few elements, the correlation between other elements was not significant. No co-accumulation phenomenon was found in submerged macrophytes; however, co-accumulation and competition among different metal(loid)s did occur in the epiphytic biofilms, which may be related to the different accumulation mechanisms of metal(loid)s in submerged macrophytes and epiphytic biofilms. This study enriches our understanding of the accumulation of metal(loid)s in submerged macrophytes and epiphytic biofilms in wetlands.


The impaired diaphragmatic function after bilateral lung transplantation: A multifactorial longitudinal study.
Lung transplantation is a complex but effective treatment of end-stage pulmonary disease. Among the post-operative complications, phrenic nerve injury, and consequent diaphragmatic dysfunction are known to occur but are hitherto poorly described. We aimed to investigate the effect of lung transplantation on diaphragmatic function with a multimodal approach. A total of 30 patients were studied at 4 time points: pre-operatively, at discharge after surgery, and after approximately 6 and subsequently 12 months post surgery. The diaphragmatic function was studied in terms of geometry (assessed by the radius of the diaphragmatic curvature delineated on chest X-ray), weakness (considering changes in forced vital capacity when the patient shifted from upright to supine position), force (maximal pressure during sniff), mobility (excursion of the dome of the diaphragm delineated by ultrasound), contractility (thickening fraction assessed by ultrasound), electrical activity (latency and area of compound muscle action potential during electrical stimulation of phrenic nerve), and kinematics (relative contribution of the abdominal compartment to tidal volume). Despite good clinical recovery (indicated by spirometry and 6 minutes walking test), a reduction of the diaphragmatic function was detected at discharge; it persisted 6 months later to recover fully 1 year after transplantation. Diaphragmatic dysfunction was demonstrated in terms of force, weakness, electrical activity, and kinematics. Our data suggest that the dysfunction was caused by phrenic nerve neurapraxia or moderate axonotmesis, potentially as a consequence of the surgical procedure (i.e., the use of ice and pericardium manipulation). The occurrence of diaphragmatic dysfunction in patients with a good clinical recovery indicates that the evaluation of diaphragmatic function should be included in the post-operative assessment after lung transplantation.


Prostaglandin D2-induced eosinophilic airway inflammation is mediated by CRTH2 receptor.
Mast cell-derived prostaglandin D(2) (PGD(2)) is one of the essential modulators of eosinophilic airway inflammation in asthma and allergic rhinitis. Two G protein-coupled receptors for PGD(2), prostaglandin D(2) receptor (DP) and chemoattractant receptor-homologous molecule expressed on Th(2) cells (CRTH2), are both expressed on the surface of eosinophils, and CRTH2 has been demonstrated to mediate PGD(2)-induced eosinophil mobilization in vitro. However, it has not yet been determined whether PGD(2) and its receptors mediate in vivo eosinophil trafficking into the airways or other organs. We demonstrated that intratracheal administration of PGD(2) in rats pretreated with systemic interleukin-5 (IL-5) injection induced marked airway eosinophilia, determined by the differential counts of cells in bronchoalveolar lavage (BAL) fluid and lung histology, within 2 h. Systemic IL-5 alone significantly increased the number of eosinophils in the peripheral blood but showed no effect on airway eosinophilia. Three CRTH2-specific agonists (13,14-dihydro-15-keto-PGD(2), 11-deoxy-11-methylene-15-keto-PGD(2), and indomethacin) demonstrated equivalent induction of BAL eosinophilia to that of PGD(2), but a DP agonist (BW 245C [5-(6-carboxyhexyl)-1-(3-cyclohexyl-3-hydroxypropyl)-hydantoin]) or a thromboxane A(2) receptor (TP) agonist ([1S-1alpha,2beta(5Z), 3alpha(1E,3R*),4alpha)]-7-[3-(3-hydroxy-4-(4'-iodophenoxy)-1-butenyl)-7-oxabicyclo-[2.2.1]heptan-2-yl]-5-heptenoic acid) showed no effect. PGD(2) or CRTH2 agonist-induced BAL eosinophilia was almost completely inhibited by pretreatment with a CRTH2/TP antagonist, ramatroban [BAY-u3405; (+)-(3R)-3-(4-fluorobenzenesulfonamido)-1,2,3,4-tetra-hydrocarbazole-9-propionic acid], whereas a TP-specific antagonist, SQ29,548 (5-heptenoic, 7-[3-[[2-[(phenylamino)carbonyl]hydrazino]methyl]-7-oxabicyclo[2.2.1]-hept-2-yl]-[1S-[1alpha,2alpha(Z),3alpha,4alpha]]), or a DP-specific antagonist, BW A868C [3-benzyl-5-(6-carboxyhexyl)-1-(2-cyclohexy-2-hydroxyethylamino)-hydantoin], did not inhibit the effects of PGD(2). These results suggest that CRTH2 plays a significant role in the eosinophil trafficking from the bloodstream into the airways in PGD(2)-related airway inflammation.


Laparoscopic splenectomy with interferon therapy in 100 hepatitis-C-virus-cirrhotic patients with hypersplenism and thrombocytopenia.
We intended to determine whether laparoscopic splenectomy (Lap-Sp) contributes to treatment with interferon therapy in hepatitis C virus (HCV)-cirrhotic patients with thrombocytopenia caused by hypersplenism. From December 2004 to August 2008, 100 cirrhotic patients (54 men and 46 women) underwent Lap-Sp for a clinical application of interferon therapy. All the patients were Child-Pugh class A or B with thrombocytopenia (average platelet count, 56 × 10(3) /mm(3)). The HCV genotype was type 1 in 80 patients and type 2 in 20 patients. Pure laparoscopic or hand-assisted laparoscopy was performed in 78 and 22 patients, respectively, without mortality. Conversion to open surgery was not required in any of the patients. The platelet counts improved (mean platelet count 172 × 10(3) /mm(3) 1 month after surgery) and interferon (IFN) therapy was started in 97 patients. In this study period, 36 patients obtained a sustained virologic response. Eight patients discontinued IFN therapy because of depression, neutropenia or other reasons. Lap-Sp permits most patients with HCV cirrhosis and hypersplenism to receive sufficient IFN therapy. Therefore, Lap-Sp can become a strong supportive surgery for cirrhotic patients who require antiviral therapy.


Superimposed Whole-Body Electrostimulation Augments Strength Adaptations and Type II Myofiber Growth in Soccer Players During a Competitive Season.
The improvement of strength and athletic performance during a competitive season in elite soccer players is a demanding task for the coach. As whole-body electrostimulation (WB-EMS) training provides a time efficient stimulation potentially capable in exerting skeletal muscle adaptations we aimed to test this approach over 7 weeks in trained male soccer players during a competitive season. We hypothesized that a superimposed WB-EMS will increase maximal strength and type I and type II myofiber hypertrophy. Twenty-eight male field soccer players were assigned in either a WB-EMS group (EG, n = 10), a training group (TG, n = 10), or a control group (CG, n = 8). The regular soccer training consists of two to four sessions and one match per week. In concurrent, the EG performed 3 × 10 squat jumps superimposed with WB-EMS twice per week, TG performed 3 × 10 squat jumps without EMS twice per week, and the CG only performed the regular soccer training. Muscle biopsies were collected and strength tests were performed under resting conditions before (Baseline) and after the intervention period (Posttest). Muscle biopsies were analyzed via western blotting and immunohistochemistry for skeletal muscle adaptive responses. To determine the effect of the training interventions a 2 × 3 (time ∗ group) mixed ANOVA with repeated measures was conducted. Maximal strength in leg press (p = 0.009) and leg curl (p = 0.026) was significantly increased in EG along with a small but significant increase in type II myofiber diameter (p = 0.023). All of these adaptations were not observed in TG and CG. WB-EMS can serve as a time efficient training method to augment strength capacities and type II fiber myofiber growth in soccer players when combined with specific resistance training. This combination may therefore be a promising training modification compared to traditional strength training for performance enhancement.


Contraction delay of the RV outflow tract in patients with Brugada syndrome is dependent on the spontaneous ST-segment elevation pattern.
A growing body of evidence suggests that the arrhythmogenic substrate underlying Brugada syndrome (BrS) is located in the right ventricular outflow tract (RVOT), and electrophysiological abnormalities recently evidenced most commonly concur in conduction slowing. Also, imaging studies reported wall motion abnormalities of the RVOT in patients with BrS, with a various extent of RV remodeling. However, there are no data regarding a potential relationship between electrophysiological alterations and contraction abnormalities in BrS. We aimed to assess (1) the potential relationship between contraction delays of the RV quantified by phase analysis of equilibrium radionuclide angiography (ERNA), and the spontaneous ST-segment elevation pattern; and (2) to evidence RV remodeling in patients with BrS. Seventy patients with BrS and 18 control subjects were included in the study. For the purpose of the study, the spontaneous ST-segment elevation pattern was graded simultaneously to ERNA acquisition. RV contraction delays and amplitude were assessed using multiharmonic phase analysis of ERNA, and ventricular volumes and ejection fraction were assessed using gated blood-pool single photon emission computed tomography. RVOT contraction was delayed in patients with BrS, and RV contraction heterogeneity increased according to the pattern of ST-segment elevation, without impairment of the amplitude of contraction. RV volumes were greater in patients with BrS compared with control subjects, without impairment of the ejection fraction, whatever the ST-segment elevation pattern or the magnitude of contraction heterogeneity. In patients with BrS, we found a relationship between RV contraction heterogeneity and ST-segment pattern, providing evidence of a functional modulation of the arrhythmogenic substrate.


Wet-spun bi-component alginate based hydrogel fibers: Development and in-vitro evaluation as a potential moist wound care dressing.
In this study, bi-component alginate-hyaluronic acid (AHA) fibers were developed by using two different routes. In the first method, sodium alginate dope solution was extruded into a coagulation bath containing CaCl2 and subsequently dip-coated with hyaluronic acid (HA) whereas, in the second method, hyaluronic acid-containing sodium alginate dope solution was directly extruded into CaCl2 bath. The resulting AHA fibers were then dehydrated in 25-100% v/v acetone solutions and dried in air. The fibers were characterized by surface morphology, physicochemical analysis, mechanical performance, swelling percentage, and total liquid absorption (g/g), cell viability, and release behavior. The results showed that AHA fibers produced by the second method have better mechanical performance, high liquid absorption, and swelling percentage with a more controlled release of hyaluronic acid. The AHA fibers showed high biocompatibility toward nHDF cell line in in-vitro testing, and the MVTR values (650-800 g/m2/day) are in a suitable range for maintaining a moist wound surface proving to be appropriate for promoting wound healing.


Radiofrequency Ablation of Barrett's Esophagus: Patient Selection, Preparation, and Performance.
Radiofrequency ablation (RFA) is a safe and effective thermal ablative therapy for dysplastic Barrett's esophagus (BE) and, to a lesser extent, nondysplastic BE. Before the utilization of RFA, there must be an appropriate indication, assessment of potential contraindications, discussion of risks and benefits with patients, and careful endoscopic planning. The ease of performance of the procedure along with its efficacy and low rate of adverse events have established RFA as a reliable technique for endoscopic management of dysplastic BE.