The protective effect of COVID-19 vaccines on developing multisystem inflammatory syndrome in children (MIS-C): a systematic literature review and meta-analysis.
To review whether the current COVID-19 vaccines can prevent the occurrence of multisystem inflammatory syndrome in children (MIS-C) and adolescents. A systematic literature review and meta-analysis were performed. The data were abstracted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Primary outcome was the efficacy of COVID-19 vaccination in preventing MIS-C development. The search was performed in PubMed and Embase. The review yielded 13 studies, which were included for critical appraisal and data extraction. The available studies showed a reduced incidence of MIS-C after mRNA COVID-19 vaccination in children aged 12-18 years. Four studies were eligible for meta-analysis and the pooled odds ratio for MIS-C in vaccinated children compared to unvaccinated children was 0.04 (95% confidence interval: 0.03-0.06). Additionally, the risk of MIS-C as an adverse effect of vaccination was much lower compared to the risk of MIS-C post-infection. Our systematic review highlights the current available evidence on the efficacy of COVID-19 vaccination in preventing MIS-C. The published studies so far - mainly conducted during the Delta wave - indicate that (original strain) COVID-19 mRNA vaccines in children are safe and associated with significantly less development of MIS-C. These findings further reinforce the recommendation for COVID-19 vaccination in children, which should be promoted and largely supported.


Aiding empirical research on the commercial determinants of health: a scoping review of datasets and methods about lobbying.
To support public health researchers and advocates seeking to challenge the influence of powerful commercial actors on health, it is necessary to develop a deeper understanding of corporate political activities. This project explores political science scholarship analysing lobbying to identify new datasets and research methods that can be applied to public health and stimulate further research and advocacy. We undertook a systematic scoping review of peer-reviewed and grey literature reports analysing the practice of lobbying. Titles and abstracts of 4533 peer-reviewed and 285 grey literature reports were screened, with 233 peer-reviewed and 280 grey literature reports assessed for eligibility. We used a two-stage process for data extraction. In stage 1, we collected two pieces of information from all included studies: data sources and indicators used to measure lobbying. For the second stage, data extraction was limited to 15 studies that focused on meetings. The most common indicators used to measure lobbying activity were: registrations of active lobbyists; expenditure on lobbying; meetings; written comments and submissions made to government consultations; bills; and committee participation. A range of different data sources were used to analyse lobbying, including from governments, not-for-profits and commercial sources. All 15 studies analysing lobbyist meetings were from high-income contexts. The studies analysed three key variables: the types of government actors targeted by lobbying; the policies of interest; and the lobbyists and/or their clients. The studies used a range of taxonomies to classify policy issues and the types of actors engaged in lobbying. All studies discussed challenges with accessing and analysing lobbying data. There is enormous potential for public health research and advocacy concerned with commercial lobbying to learn from political science scholarship. This includes both conceptual frameworks and sources of empirical data. Moreover, the absence of good quality transparency internationally emphasises the importance of advocacy to support policy change to improve the quality of political transparency to make it easier to monitor commercial lobbying.


The Impact of Prehospital Transport Mode on Mortality of Penetrating Trauma Patients.
The optimal mode of transport of trauma patients from the scene to the hospital remains unknown. We aimed to study the impact of different prehospital modes of transport of penetrating trauma patients on hospital mortality. Using the Trauma Quality Improvement Program 2010 to 2016 database, we identified all adults with a penetrating injury. Univariate then multivariable logistic regression analyses were performed to study the correlation between the mode of transport and in-hospital mortality, adjusting for several covariates. A total of 92,427 subjects were included. The overall mean transport time for patients transported by a ground ambulance, helicopter, fixed wing ambulance, and police/private vehicle were 32.2, 61.2, 68.9, and 28.2 minutes, respectively. Multivariable analyses revealed that compared with ground ambulance, helicopter transport was associated with a 34% decrease in the odds of mortality (odds ratio = 0.66, P < .0001), whereas police transport and private vehicle transport were associated with a 52% decrease in the odds of mortality (odds ratio = 0.48, P < .0001). Helicopter, police, and private vehicle transports are associated with a decreased odds of mortality compared with ground ambulance. Further research should examine the variation in levels of care within different modes of prehospital transport.


Vitamin D and folate: A reciprocal environmental association based on seasonality and genetic disposition.
The purpose of this study was (1) to elucidate any reciprocal seasonal relationship that might exist between red cell folate (RCF) and serum vitamin D3 Levels; (2) to explore whether folate-related gene variants that influence/alter DNA-thymidylate and methyl group biosynthesis modify any associations detected in objective 1; and (3) to consider whether these processes might influence reproductive success consistent with the "folate-vitamin D-UV hypothesis of skin pigmentation" evolutionary model. A large (n = 649) Australian cross-sectional study population was examined. Polymerase chain reaction (PCR)/Restriction fragment length polymorphism (RFLP) analysis was used to genotype C677T-MTHFR, C1420T-SHMT, T401C-MTHFD and 2R > 3R-TS. RCF was measured by chemiluminescent immunoassay and vitamin D2 and D3 by HPLC. RCF and photosynthesized vitamin D3 , but not RCF and dietary vitamin D2 , exhibit a significant reciprocal association in spring and summer. Three folate genes (C677T-MTHFR, C1420T-SHMT, and 2R > 3R-TS) strengthen this effect in spring, and another (T401C-MTHFD) in summer. Effects are seasonal, and do not occur over the whole year. Findings are consistent with what might be required for the "folate-vitamin D-UV hypothesis of skin pigmentation" model. It suggests genetic influence in provision of one-carbon units by 5,10-methylene-H4 folate, may be an important factor in what appears to be a clear seasonal relationship between vitamin D3 and folate status.


Nebulized fentanyl citrate improves patients' perception of breathing, respiratory rate, and oxygen saturation in dyspnea.
Dyspnea, a subjective symptom of impaired breathing, occurs in 70% of terminally ill cancer patients. Current treatments are suboptimal and little is known about the patient's perception of effect. We tested nebulized inhaled fentanyl citrate on patient perceptions, respiratory rate, and oxygen saturation. The study was conducted using a convenience sample of 35 cancer patients on a dedicated oncology unit. We assessed patient perception (did breathing stay the same, worsen, or improve), respiratory rate, and oxygen saturation by pulse oximetry at baseline, 5 minutes, and 60 minutes. Twenty-six of 32 (81%) patients reported improvement in breathing, 3 (9%) were unsure, and 3 (9%) reported no improvement. Oxygen saturation improved from 94.6% at baseline to 96.8% at 5 minutes and 96.7% at 60 minutes (P = 0.0069 compared to baseline). Respiratory rates improved from a baseline of 28.4/min to 25.9/min at 5 minutes and 24.1/min at 60 minutes (P = 0.0251 compared to baseline). No side effects were observed. Inhaled nebulized fentanyl citrate significantly improved patient perception of breathing, respiratory rate, and oxygen saturation. This inexpensive and readily available treatment may offer substantial relief of end-of-life dyspnea. Randomized trials, dose, and length of effect trials are underway.


epg5 knockout leads to the impairment of reproductive success and courtship behaviour in a zebrafish model of autophagy-related diseases.
Dysregulation of the autophagic flux is linked to a wide array of human diseases, and recent findings highlighted the central role of autophagy in reproduction, as well as an association between impairment of autophagy and behavioural disorders. Here we deepened on the possible multilevel link between impairment of the autophagic processes and reproduction at both the physiological and the behavioural level in a zebrafish mutant model. Using a KO epg5 zebrafish line we analysed male breeding success, fertility rate, offspring survival, ejaculate quality, sperm and testes morphology, and courtship behaviour. To this aim physiological, histological, ultrastructural and behavioural analyses on epg5+/+ and mutant epg5-/- males coupled to WT females were applied. We observed an impairment of male reproductive performance in mutant epg5-/- males that showed a lower breeding success with a reduced mean number of eggs spawned by their WT female partners. The spermatogenesis and the ability to produce fertilising ejaculates were not drastically impaired in our mutant males, whereas we observed a reduction of their courtship behaviour that might contribute to explain their lower overall reproductive success. Collectively our findings corroborate the hypothesis of a multilevel link between the autophagic process and reproduction. Moreover, by giving a first glimpse on behavioural disorders associated to epg5 KO in model zebrafish, our results open the way to more extensive behavioural analyses, also beyond the reproductive events, that might serve as new tools for the molecular screening of autophagy-related multisystemic and neurodegenerative diseases.


Vascular response of the rabbit bladder to short term partial outlet obstruction.
Partial bladder outlet obstruction of the rabbit bladder results in a rapid increase in mass characterized by remodeling of the bladder wall. In this study we investigated the effect of partial outlet obstruction on microvessel density and distribution in the bladder wall immunohistochemically using CD31 as a marker for vascular endothelium, and on blood flow using a fluorescent microsphere technique. Transverse sections of bladder wall were examined after 0 (unobstructed), 1, 3, 5, 7, and 14 days of obstruction. The microvasculature of obstructed rabbit bladder mucosa and detrusor smooth muscle apparently increased relative to augmentation of these compartments, while new vessels appeared in the thickening serosa. These vascular changes correlated with results showing that, at 1 week after obstruction, blood flow (ml/min/g tissue) to the mucosa and detrusor was unchanged. Thickening of the serosa, apparent after 1 day of obstruction, began before its vascularization. Then, 1 week post-obstruction, there was significant microvessel formation in the transition region between the detrusor smooth muscle and the increasing serosa; after 2 weeks, the entire serosa was vascularized. The vascularization of the muscle-serosal transition region and then the remaining serosa apparently precedes fibroblast differentiation, providing blood supply and thus metabolic support for this process. All obstructed rabbit bladders in this study were in a state of compensated function based on their weights. Our working hypothesis is that blood flow per unit tissue mass is normal in compensated obstructed bladders, thus allowing for normal contractile function and cellular metabolism. The results of this study indicate the presence of an augmented microvasculature in compensated obstructed rabbit bladders that provides adequate blood perfusion for normal function.


Genetic and epigenetic variability in the gene for IGFBP-3 (IGFBP3): correlation with serum IGFBP-3 levels and growth in short children born small for gestational age.
IGF-I and IGFBP-3 play a central role in fetal and postnatal growth and levels are low in short SGA children. The -202 A/C and -185 C/T SNPs are located near elements involved in directing IGFBP3 promoter activity and expression. Changes in promoter CpG methylation status affect transcription factor binding and transcriptional activation of IGFBP3 in vitro. To assess the relationship between IGFBP3 promoter SNPs, IGFBP-3 levels, spontaneous growth and growth response to GH treatment in short prepubertal SGA children. To assess promoter methylation status in a subgroup of short SGA subjects and controls. 292 Short prepubertal SGA children, 39 short young SGA adults and 85 young adults with normal stature. Short prepubertal SGA children received GH 1mg/m(2)/day. Fasting levels of IGF-I and IGFBP-3, baseline and delta height SDS. At baseline, IGFBP-3 levels were highest in SGA children with -202 AA genotype and lower in children with 1 or 2 copies of the C-allele (P<0.001). Children with C(-202)/C(-185) haplotype, compared to children with A(-202)/C(-185) haplotype, had lower IGFBP-3 levels (P=0.003) and were shorter (P=0.03). During GH treatment, children with C(-202)/C(-185) haplotype showed a significantly greater increase in IGFBP-3 SDS and in height SDS than children with A(-202)/C(-185) haplotype, resulting in similar IGFBP-3 levels and similar height SDS after 12 months of GH treatment. CpG methylation patterns showed a trend towards more methylation of CpGs involved in transcription factor binding in short young SGA adults compared to controls. Polymorphic variation in the IGFBP3 promoter region is correlated with IGFBP-3 levels, spontaneous growth and response to GH treatment in short SGA children.


Heavy metals extraction from contaminated soil: recovery of the flushing solution.
The optimum conditions for the recovery of copper from a contaminated soil by using the soil flushing technique are evaluated. Tests on a soil artificially contaminated with copper chloride were carried out in order to evaluate the influence of the speed of percolation and of the chelating agent concentration (aqueous solution of an ethylendiaminotetraacetic acid di-sodium salt Na2-EDTA). At pH=7.3 an efficiency up to 93.9% for copper extraction was achieved by flushing 500 ml of Na2-EDTA 0.05 M solution and 100 ml of pure water at 0.792 cm/h. At these operating conditions the formation of EDTA complexes with other competitive cations (calcium and iron) was negligible. The experimental results were in agreement with the ones obtained using a model describing the chemistry of metal extraction. This model assessed that above pH=6 the formation of calcium and iron EDTA complexes was excluded and only the chelation of copper was allowed. The recovery of 91.6% of EDTA was also achieved by evaporating and acidifying the extracted solution: after filtration, solid EDTA was obtained, through the addition of sodium hydroxide Na2-EDTA. About 99.5% of the extracted copper was finally precipitated under alkaline conditions from the liquid phase.


Optical micro-elastography with magnetic excitation for high frequency rheological characterization of soft media.
The propagation of shear waves in elastography at high frequency (>3 kHz) in viscoelastic media has not been extensively studied due to the high attenuation and technical limitations of current techniques. An optical micro-elastography (OME) technique using magnetic excitation for generating and tracking high frequency shear waves with enough spatial and temporal resolution was proposed. Ultrasonics shear waves (above 20 kHz) were generated and observed in polyacrylamide samples. A cutoff frequency, from where the waves no longer propagate, was observed to vary depending on the mechanical properties of the samples. The ability of the Kelvin-Voigt (KV) model to explain the high cutoff frequency was investigated. Two alternative measurement techniques, Dynamic Mechanical Analysis (DMA) and Shear Wave Elastography (SWE), were used to complete the whole frequency range of the velocity dispersion curve while avoid capturing guided waves in the low frequency range (<3 kHz). The combination of the three measurement techniques provided rheology information from quasi-static to ultrasonic frequency range. A key observation was that the full frequency range of the dispersion curve was necessary if one wanted to infer accurate physical parameters from the rheological model. By comparing the low frequency range with the high frequency range, the relative errors for the viscosity parameter could reach 60 % and they could be higher with higher dispersive behavior. The high cutoff frequency may be predicted in materials that follow a KV model over their entire measurable frequency range. The mechanical characterization of cell culture media could benefit from the proposed OME technique.


Effects of selective H.E.L.P. LDL-apheresis on plasma inflammatory markers concentration in severe dyslipidemia: Implication for anti-inflammatory response.
Therapeutic plasmapheresis is a recognized medical procedure in which various techniques are used to separate and remove undesirable or excessively elevated plasma elements from blood. The main purpose of the procedure is to remove the substances responsible for the disease (autoantibodies, circulating immune complexes, lipoproteins and other molecules) from the patient's blood. Low-Density-Lipoproteins-apheresis (LDL_a) is the selective removal of all apolipoprotein-B100-containing lipoproteins: LDL, very low-density lipoprotein, and lipoprotein (a). They are lowered acutely by 65-75%. There is little effect on other plasma lipidic and non-lipidic components. LDL_a was reported to increase resistance of LDL to oxidation, counteract procoagulatory state and relief disturbances of hemorheology associated with atherosclerosis. These effects are likely to be regarded as to be pleiotropic effects. In the sense that they are not necessarily related to the apolipoprotein-B100-containing lipoproteins level in plasma. There is robust evidence that LDL_a can induce the stabilization of atherosclerotic plaques through its lipid-lowering action. However, other effects unrelated to the apolipoprotein-B100-containing lipoproteins extracorporeal removal, such as the decrease of cytokines and adhesion molecules induced by LDL_a were also reported. Altogether these actions are thought to favorably influence regression of florid, nonfibrous atherosclerotic lesions through a blockade of lipid deposition in the vessel wall, plaque stabilization, and ultimately, coronary and extracoronary artery disease progression. This brief review provides some indication on existing evidence of Heparin-induced Extracorporeal Low-density-lipoprotein Precipitation LDL_a effects on plasma mediators of inflammation.


Differential expression of TRAIL-R3 and TRAIL-R4 in human pancreatic cancer.
Pancreatic cancer is one of the most aggressive cancers, in part due to its insensitivity to most treatment modalities. This resistance towards cytotoxic therapy is thought to be caused--at least in part--by a general resistance of pancreatic cancer cells towards apoptosis. TRAIL-R3 and TRAIL-R4, which belong to the TRAIL receptor family, can inhibit TRAIL-induced apoptosis. Seven normal pancreatic tissues and 7 pancreatic cancer tissues were analyzed using Northern blotting, Western blotting and immunohistochemistry. TRAIL-R3 mRNA and protein expression were generally weak in pancreatic cancers and normal pancreatic tissues. In contrast, TRAIL-R4 mRNA and protein were expressed at moderate to high levels in human pancreatic cancer tissues, but demonstrated weak to negative expression in the normal pancreas. TRAIL-R4 but not TRAIL-R3 levels were significantly different in pancreatic cancer in comparison to the normal pancreas. These findings give new insight into the resistance mechanisms of pancreatic cancer towards TRAIL-mediated apoptosis.


Retrospective observational case-control study comparing prehospital thrombolytic therapy for ST-elevation myocardial infarction with in-hospital thrombolytic therapy for patients from same area.
To compare a system of prehospital thrombolytic therapy, delivered by paramedics under medical guidance, with in-hospital thrombolytic therapy in meeting National Service Framework (NSF) targets for treatment of acute myocardial infarction at a District General Hospital setting in England. Retrospective observational case-control study comparing patients with suspected acute myocardial infarction (AMI) treated with thrombolytic therapy in the prehospital environment with patients treated in hospital. Wyre Forest District and Worcestershire Royal Hospital, UK. (A) All patients who received prehospital thrombolytic therapy for suspected AMI accompanied by electrocardiographic features considered diagnostic.(B) Patients who received thrombolytic therapy after arrival at hospital for the same indication, matched with group A by age, gender and postcode. 1. Call to needle time. 2. Percentage of patients treated within one hour of calling for medical help. 3. Appropriateness of thrombolytic therapy. 4. Safety of thrombolytic therapy 1. The median call to needle time for patients treated before arriving in hospital (n = 27) was 40 minutes with an inter-quartile range 25-112 (mean 43 minutes). Patients from the same area who were treated in hospital (n = 27) had a median time of 106 minutes with an inter-quartile range 50-285 (mean 126 minutes). This represents a median time saved by prehospital treatment of 66 minutes. 2. 60 minutes after medical contact, 96 % of patients treated before arrival in hospital had received thrombolytic therapy; this compares with 4% of patients from similar areas treated in hospital. 3. Myocardial infarction was confirmed in 92% (25/27) of patients who received prehospital thrombolytic therapy and similarly 92% (25/27) of those given in-hospital thrombolytic therapy. 4. No major bleeding occurred in either group. Group A suffered fewer in-hospital deaths than group B (1 versus 4). Cardiogenic shock (3 patients) and ventricular arrhythmia (5 patients) were seen only in group B. Paramedic-delivered thrombolytic therapy can be delivered appropriately, safely, and effectively. Time gains are substantial and can meet the national targets for early thrombolytic therapy in the majority of patients.


Impact of pregnancy on progression of preclinical autoimmune disorders: a prospective cohort study.
The objective of this study was to evaluate the role of pregnancies in the progression from the preclinical phase of autoimmune disorder to a definite rheumatic disease. A cohort study of women with symptoms and laboratory findings suggestive for autoimmune disorder were enrolled during the first trimester of pregnancy and followed-up for 5 years with clinical and laboratory assessment. Multinomial logistic regression was used to compute the risk of progression to definite autoimmune disease correcting for confounders. At the end of follow-up, out of 208 subjects, 81 (38.9%) were considered negative, 53 (25.5%) had symptoms and abnormalities of autoantibody profile compatible with a non-criteria rheumatic status and 74 (35.6%) had a definite rheumatic disease (43 undifferentiated connective tissue disease, 5 systemic lupus erythematosus, 3 SS, 10 antiphospholipid syndrome, and 12 miscellaneous autoimmune disorders). The median time from enrolment to definite diagnosis was 28 months (interquartile range = 18-42). The rate of progression towards a definite autoimmune disease was 47.1% (48/102) among subjects with one or more subsequent viable pregnancies compared with 24.5% (26/106) of those with no subsequent pregnancies (adjusted odds ratio = 4.9, 95% CI: 2.4, 10). The occurrence of preeclampsia during the index pregnancy or subsequent pregnancy was an additional and independent risk factor for progression to a definite autoimmune disease (adjusted odds ratio = 4.3, 95% CI: 1.2, 14.8). Among women with suspected autoimmune disease during pregnancy, additional viable pregnancies and diagnosis of preeclampsia were independently associated with an increased rate of progression to definite rheumatic disorder. Hormonal modifications associated with pregnancy could worsen preclinical rheumatic disorders favouring their progression to a defined autoimmune disease.


Menstrual disturbances and fertility in chronic alcoholic women.
Data on menstrual pattern, gynecological disorders and infertility were obtained from 51 chronic alcoholic women aged 20--42 years attending an outpatient clinic for alcoholics, using 51 randomly drawn age-matched healthy women as controls. A higher variability (P less than 0.05) in the duration of both menstrual cycle and menstrual flow was recorded in the chronic alcoholic women during active alcoholism. A higher frequency (P less than 0.05) of menstrual disturbances (70% vs. 55%) and uterine curettages (38% vs. 16%) were found in the alcoholic women. The latter reported more abortions (63% vs. 28%, P less than 0.001) and miscarriages (23% vs. 8%, P less than 0.05) than controls, but due to a higher number of pregnancies in the alcoholic group the proportion of abortions and miscarriages did not differ significantly. No differences existed between the groups regarding frequency of difficult conception. Social classification had no independent influence on the results. The study shows that chronic alcoholic women are more prone to menstrual abnormalities and are at greater risk of gynecological interventions, while they do not seem to have reduced fertility.


Four Cases of Postoperative Pneumothorax Among 2814 Consecutive Laparoscopic Gynecologic Surgeries: A Possible Correlation Between Postoperative Pneumothorax and Endometriosis.
To evaluate the frequency of pneumothorax after laparoscopic surgery and to identify possible correlations to endometriosis. Retrospective review. Tokyo University Hospital between 2006 and 2013. Four patients among a total of 2814 patients with a postoperative pneumothorax. Laparoscopic surgery for gynecologic benign disease. The main outcome was the clinical frequency and characteristics of the patients with postoperative pneumothorax. We observed 4 (0.14%) cases of postoperative pneumothorax after laparoscopic surgery, all of whom were diagnosed with endometriomas and developed a right-sided pneumothorax. The incidence of postoperative pneumothorax in 1097 patients with endometriomas was 0.36%, which was significantly higher than those without endometriomas. The presence of endometrioma should be considered a risk factor for postoperative pneumothorax in gynecologic laparoscopic surgery.


Radiological features of late-onset multiple sclerosis: A systematic review and meta-analysis.
Late-onset multiple sclerosis (LOMS) is most commonly defined as the onset of the disease's presentations at age 50 or older. There is still much to discover about the radiological features of LOMS. The current study aims to assess the imaging features of LOMS, as well as the correlation between these findings and the clinical characteristics of these patients. This study was conducted following the PRISMA statement. A systematic search was conducted through PubMed, Scopus, and EMBASE databases to identify the studies that have applied magnetic-resonance imaging (MRI) or other imaging methods to investigate the radiological findings, as well as the relationship between them and clinical findings of LOMS patients. The risk of bias was assessed using the Joanna Briggs Institute (JBI) checklists. Meta-analysis was conducted using the third version of the compressive meta-analysis software (CMA3). Our search identified 753 unique titles. Among them, 15 studies, including seven case-control, five case-series, and three cross-sectional studies, met the eligibility criteria. According to the quantitative synthesis, brain lesions were detected among 72.2% of LOMS patients (4 studies; 95% CI: 67.0% - 93.1%). In the context of spinal lesions, overall spinal cord involvement was 64.0% (8 studies; 95% CI: 42.5% - 81.1%). Based on the available evidence, supratentorial involvement was found in 82.7% of cases (3 studies; 95% CI: 17.4% - 99.1%), juxtacortical involvement in 34.1% (3 studies; 95% CI: 26.4% - 42.7%), infratentorial involvement in 51.3% (4 studies; 95% CI: 32.1% - 70.1%), and cerebellar involvement in 18.5% (3 studies; 95% CI: 13.9% - 24.1%). Based on the neuroimaging findings, we found that, given the heterogeneity of MS, LOMS patients have a high rate of spinal cord lesions and supratentorial involvement. The limited available evidence suggests that Barkhof criteria are the best compromise for the diagnosis of LOMS. There is still a need for future studies.


Effect of beta-adrenergic blockade on blood pressure variation in patients with moderate hypertension.
The effect of beta-adrenergic blockade on blood pressure variation was studied in ten patients with moderate hypertension. Supine systolic and diastolic blood pressures were measured every 5 min during six hours sessions, using an ultrasonic method. Systolic and diastolic variation in each six hour session was defined as the standard deviation of the mean of systolic and diastolic readings made in that period. After 3 weeks of single-blind placebo, a 12 week double-blind randomized crossover study was initiated with placebo (6 weeks) and atenolol (100 mg b.i.d. for 3 weeks and 200 mg b.i.d. for 3 weeks). Systolic and diastolic blood pressure and heart rate decreased significantly (p less than 0.01) during atenolol treatment. Diastolic variation did not change significantly, whereas systolic variation decreased slightly but significantly (p less than 0.05) when expressed in absolute values, but not when expressed as a percentage of systolic blood pressure. It is concluded that beta-adrenergic blockade decreases blood pressure and heart rate without causing significant changes in spontaneous systolic or diastolic variation.


Single cell active force generation under dynamic loading - Part II: Active modelling insights.
In Part I of this two-part study a novel single cell AFM experimental investigation reveals a complex force-strain response of cells to cyclic loading. The biomechanisms underlying such complex behaviour cannot be fully understood without a detailed mechanistic analysis incorporating the key features of active stress generation and remodelling of the actin cytoskeleton. In order to simulate untreated contractile cells an active bio-chemo-mechanical model is developed, incorporating the key features of stress fibre (SF) remodelling and active tension generation. It is demonstrated that a fading memory SF contractility model accurately captures the transient response of cells to dynamic loading. Simulations reveal that high stretching forces during unloading half-cycles (probe retraction) occur due to tension actively generated by axially oriented SFs. On the other hand, hoop oriented SFs generate tension during loading half-cycles, providing a coherent explanation for the elevated compression resistance of contractile cells. Finally, it is also demonstrated that passive non-linear visco-hyperelastic material laws, traditionally used to simulate cell mechanical behaviour, are not appropriate for untreated contractile cells, and their use should be limited to the simulation of cells in which the active force generation machinery of the actin cytoskeleton has been chemically disrupted. In summary, our active modelling framework provides a coherent understanding of the biomechanisms underlying the complex patterns of experimentally observed single cell force generation presented in the first part of this study. A novel computational investigation into the active and passive response of cells to dynamic loading is performed. An active formulation that considers key features of actin cytoskeleton active contractility and remodelling throughout the cytoplasm is implemented. Simulations provide new insights into the sub-cellular biomechanical response, providing a coherent explanation for the complex patterns of cell force uncovered experimentally in the first part of this study. Our computational models also reveal that passive non-linear visco-hyperelastic material laws, traditionally used to simulate cell mechanical behaviour, are not appropriate for untreated contractile cells, and their use should be limited to the simulation of cells in which the active force generation machinery of the actin cytoskeleton has been chemically disrupted.


"Limited" double dorsal dartos flap coverage. An effective alternative to conventional flap coverage of the neourethra following Mathieu repair for subcoronal hypospadias.
Double dorsal dartos flap coverage of the neourethra has been reported to be superior to single flap coverage for the prevention of urethrocutaneous fistula following hypospadias surgery. Conventional flap coverage involves covering the entire neourethra with vascularised flap. We describe a "limited" double dorsal dartos flap coverage of the neourethra following Mathieu repair for subcoronal hypospadias. In a prospective study conducted between Feb 2003 and Feb 2007, 31 patients with primary subcoronal hypospadias who had a flat and narrow urethral plate with a healthy urethral meatus and minimal or no chordee underwent Mathieu hypospadias repair. A "limited" double dorsal dartos flap coverage of the neourethra was done in all patients. This involved covering only that portion of the neourethra which remained exposed after glans closure, i.e. the proximal neourethra. Primary surgical outcome assessed was the development of urethrocutaneous fistula following surgery. The mean age at the time of repair was seven years and mean follow up was eight months. There was no flap loss, urethrocutaneous fistula formation, or glanular dehiscence in any of the 31 patients. One patient developed meatal stenosis which was managed by dilatation. One patient developed superficial sloughing of the penile skin. Overall complication rate was 6.45%. "Limited" double dorsal dartos flap coverage of the neourethra seems to be an effective method to reduce the fistulous complication rate following Mathieu repair for subcoronal hypospadias. A larger comparative study needs to be done to evaluate conventional neourethral coverage with "limited" neourethral coverage.


Amlodipine-induced immune thrombocytopenia.
Drug-induced thrombocytopenia is a serious, but rare, side-effect of treatment with a number of drugs. In this report, we investigate the suspicion that amlodipine, a calcium-channel blocker, was responsible for immune thrombocytopenia in a 79-year-old patient. Our patient experienced two attacks of thrombocytopenic purpura after 10 years of treatment with amlodipine. Antibodies to platelets were tested by standard methods. Initially, the platelet count increased owing to treatment with prednisolone and intravenous immunoglobulin G, but decreased shortly after discontinuation of this treatment. The patient's serum was found to contain amlodipine-dependent antibodies to platelets, and he recovered after stopping the drug. Amlodipine can induce immune thrombocytopenia, which may strongly resemble autoimmune thrombocytopenia.


Pulse and steady-state labelled and actinomycin D chased 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole (DRB)-resistant hnRNA from uninfected HeLa cells.
The fraction of hnRNA synthesized in the presence of DRB in uninfected HeLa cells ranges in size from 4S to over 45S. High molecular weight DRB-resistant hnRNA has been demonstrated to decay after 2 h of actinomycin D chase. This fraction is composed of both poly(A)(+) and poly(A)(-) RNA molecules. The synthesis in the presence of DRB of short polyadenylated hnRNA was also observed. The nature of both hnRNA subfractions is discussed.


Science-based decision-making on complex issues: Marcellus shale gas hydrofracking and New York City water supply.
Complex scientific and non-scientific considerations are central to the pending decisions about "hydrofracking" or high volume hydraulic fracturing (HVHF) to exploit unconventional natural gas resources worldwide. While incipient plans are being made internationally for major shale reservoirs, production and technology are most advanced in the United States, particularly in Texas and Pennsylvania, with a pending decision in New York State whether to proceed. In contrast to the narrow scientific and technical debate to date, focused on either greenhouse gas emissions or water resources, toxicology and land use in the watersheds that supply drinking water to New York City (NYC), I review the scientific and technical aspects in combination with global climate change and other critical issues in energy tradeoffs, economics and political regulation to evaluate the major liabilities and benefits. Although potential benefits of Marcellus natural gas exploitation are large for transition to a clean energy economy, at present the regulatory framework in New York State is inadequate to prevent potentially irreversible threats to the local environment and New York City water supply. Major investments in state and federal regulatory enforcement will be required to avoid these environmental consequences, and a ban on drilling within the NYC water supply watersheds is appropriate, even if more highly regulated Marcellus gas production is eventually permitted elsewhere in New York State.


Achyranthes aspera ameliorates stress induced depression in mice by regulating neuroinflammatory cytokines.
Achyranthes aspera Linn. (A. aspera) (family: Amaranthaceae) is highly recognized in ethnomedicine and traditional systems of Indian medicine as a nervine restorative for several psychiatric disorders. Study presented here was designed to appraise the antidepressant-like effects of A. aspera in murine model of chronic unpredictable mild stress (CUMS) induced depression. Rodents were exposed to different stressor in unpredictive manner during CUMS protocol once a day for 4 weeks. Mice were intraperitoneally injected with A. aspera extract (2.5, 5 and 10 mg/kg) or fluoxetine (10 mg/kg) or betaine (20 mg/kg) once daily during day 15-28 of the CUMS protocol. Sucrose preference, motivation and self-care, immobility latency and plasma corticosterone were evaluated after 24 h of last stressor. After behavioral assessments TNF-α, Il-6 and BDNF immunocontent was determined in hippocampus and prefrontal cortex. A. aspera extract as well as betaine improved sucrose preference, increased grooming frequency and latency in splash test and ameliorated depression-like condition in CUMS mice in Porsolt test. A. aspera treatment decreased the elevated plasma corticosterone and reversed the effect of CUMS on TNF-α, Il-6 and BDNF immunocontent in mice. The results of the present study suggest A. aspera as a promising indigenous medicine for stress associated neurobehavioral and comorbid complications.


Impact of Sequential Culture Results on Diagnosis and De-Escalation of the Antibiotic Regimen in Joint and Bone Infections.
According to existing guidelines, orthopedic specimens collected in joint and bone infections (JBI) in our institution are cultured on several media sets and incubated for two, seven, and 14 days. The optimal timing for de-escalation of the first-line antibiotic combination according to the culture results needs to be defined. Single-center, retrospective analysis of all adult patients with a first documented episode of JBI between May 2012 and April 2013. Ninety patients were included, 51 males (57%), median age 58 y (range 18-87 y), with prosthesis infection in 62 cases (69%). Rapidly growing pathogens (Staphylococcus aureus [n = 36] and Enterobacteriaceae [n = 12]) usually were diagnosed within two days, whereas coagulase-negative staphylococci (n = 25) and Propionibacterium acnes (n = 13) generally were identified after seven days (p < 10-5). Positive culture results at day 2 fit with definitive microbiological diagnosis in 95% of cases, and prolonged incubation led to the identification of additional micro-organisms in only four of 76 patients (5%) with day-2-positive cultures. Conversely, for those with negative two-day culture (n = 14), the seven-day culture allowed identification of less virulent pathogens in eight cases (57%). Our results suggest that, in JBI, de-escalation of the empirical antibiotic regimen can be based on micro-organisms identified on the two-day culture set. The impact of such a strategy on clinical outcomes, antibiotic consumption, and costs needs to be assessed in larger studies.


Is pulseless electrical activity a reason to refuse cardiopulmonary resuscitation with ECMO support?
Cardiopulmonary resuscitation with ECMO support (ECPR) has shown to improve outcome in patients after cardiac arrest under resuscitation. Most current recommendations for ECPR do not include patients with a non-shockable rhythm such as PEA and asystole. The aim of this study was to investigate the outcome of 3 patient groups separated by initial rhythm at time of ECMO placement during CPR: asystole, PEA and shockable rhythm. We made a retrospective single-center study of adults who underwent ECPR for in-hospital cardiac arrest between June 2008 and January 2017. Outcome and survival were identified in 3 groups of patients regarding to the heart rhythm at the time decision for ECMO support was made: 1. patients with asystole, 2. patients with pulseless electrical activity, 3. patients with a shockable rhythm. 63 patients underwent ECPR in the mentioned time frame. Five patients were excluded due to incomplete data. Under the 58 included patients the number of cases for asystole, PEA, shockable rhythm was 7, 21 and 30 respectively. The means of CPR-time in these groups were 37, 41 and 37min. Survival to discharge was 0.0%, 23.8% and 40.0% respectively (p=0.09). All survivors to discharge had a good neurological outcome, defined as cerebral performance category 1or 2. Survival to discharge in patients with PEA as initial rhythm at the time of decision for ECPR is 23.8% while no patients with asystole as initial rhythm survived discharge. Patients with PEA should be carefully considered for ECPR.


COPD and Cardiovascular Disease: A Review of Association, Interrelationship, and Basic Principles for Integrated Management.
The presence of comorbid cardiovascular disease (CVD) in patients with chronic obstructive pulmonary disease (COPD) can result in unfavorable outcomes, ranging from deterioration in quality of life to increases in all-cause and cardiovascular mortality. Moreover, cardiovascular events are major cause of hospitalization in patients with COPD and contributing significantly to the economic burden of the disease. Despite the acknowledgment of the prognostic significance of CVD comorbidity in COPD patients, CVD remains underrecognized and undertreated in this patient population. In this article, we address the current knowledge about the estimated prevalence, pathophysiologic association, as well as important considerations in the diagnosis and management of CVD in COPD patients.


The effect of geopolitical risk on environmental stress: evidence from a panel analysis.
The current paper concentrates on whether geopolitical risk can create environmental stress or not. It empirically explores the geopolitical risk effect on energy and carbon intensities of human well-being. Our paper postulates that geopolitical risk's impacts change over time because of the continuous amendments in the decision process through the geopolitical events' reoccurrence and the interaction with unobserved variables or the time-specific disturbances. Thus, our paper uses the two-way fixed Prais-Winsten regression approach to measure this dynamic relationship period yearly. It extracts evidence from 18 countries worldwide during the period (1992-2018). It finds that the effect of geopolitical risk on environmental stress is changing between positive and negative signs. The results show that geopolitical risk is biased toward reducing environmental stress or supporting environmental sustainability. From a policy implication side, policymakers and scholars should pay more attention to understand how geopolitical risk effects evolve on the country and the international levels and how to manage the geopolitical events to encourage their positive impacts on the environment.


NUDT5-Determines the fate of head and neck squamous cell carcinoma cells under endoplasmic reticulum stress by catalyzing nuclear ATP production to promote DNA repair.
NUDT5 is the only discovered enzyme that catalyses ATP production in cell nuclei. In this study, we investigate the character of NUDT5 in head and neck squamous cell carcinoma (HNSCC) cells under endoplasmic reticulum (ER) stress. The formation of ER stress was confirmed in HNSCC cells using Real-time PCR and Western blot techniques. The expression of NUDT5 was modified by transfecting HNSCC cells with siRNA and plasmids, respectively. The effects of NUDT5 manipulation were assessed using various methods including cell counting kit-8 assay, western blotting, RNA sequencing, Immunofluorescence Microscopy analysis, cell cycle analysis and nucleic ATP measurement, and a xenograft mouse model. In this study, we found that the expression of NUDT5 proteins was upregulated under ER stress conditions in HNSCC cells. Knocking down NUDT5 under ER stress could hinder nuclear ATP generation and thus induce more DNA damage and apoptosis of HNSCC cells. Only the wild-type NUDT5 or ATP catalysis active mutant T45A-NUDT5, rather than the ATP catalysis null mutant T45D-NUDT5, could directly rescue nuclear ATP depletion caused by NUDT5 inhibition and protect HNSCC cells from DNA damage and cell apoptosis. Finally, in vivo studies showed that knocking down NUDT5 in ER-stressed conditions could significantly inhibit tumour growth. Our study demonstrated for the first time that NUDT5 guaranteed the integrity of DNA under ER stress-triggered DNA damage by catalysing nuclear ATP production. Our findings offer new insights into how the energy supply in cell nuclei fuels cancer cell survival in stressful microenvironment.


Simple and fast colorimetric detection of lipopolysaccharide based on aptamer and SYBR Green I mediated aggregation of gold nanoparticles.
Lipopolysaccharide (LPS) poses a considerable threat to food safety and human health. A colorimetric assay for LPS detection based on LPS binding aptamer (LBA) and SYBR Green I (SG) mediated aggregation of gold nanoparticles (AuNPs) was established. In the absence of LPS, the LBA was absorbed onto the AuNPs surface which prevented SG-induced aggregation of AuNPs, and the sensing system exhibited red color. When LPS was added, it interacted with the LBA, forming a complex. At higher LPS concentration, many LBAs were exhausted resulting in SG-induced aggregation of AuNPs, and color change from red to blue. The range of colorimetric detection of LPS was linear in 0-12 EU/mL, with a limit of detection of 0.1698 EU/mL. Spiked LPS in real samples and interfering substances were also identified. This assay ingeniously using the fluorescent dye SG as an effective trigger of AuNPs aggregation, is rapid and facile than most of those earlier reported LBA-based LPS assays, and there is potential to be modified to construct assays for other targets.


Targeting matrix metallopeptidase 2 by hydroxyurea selectively kills acute myeloid mixed-lineage leukemia.
Oncogene-induced tumorigenesis results in the variation of epigenetic modifications, and in addition to promoting cell immortalization, cancer cells undergo more intense cellular stress than normal cells and depend on other support genes for survival. Chromosomal translocations of mixed-lineage leukemia (MLL) induce aggressive leukemias with an inferior prognosis. Unfortunately, most MLL-rearranged (MLL-r) leukemias are resistant to conventional chemotherapies. Here, we showed that hydroxyurea (HU) could kill MLL-r acute myeloid leukemia (AML) cells through the necroptosis process. HU target these cells by matrix metallopeptidase 2 (MMP2) deficiency rather than subordinate ribonucleotide reductase regulatory subunit M2 (RRM2) inhibition, where MLL directly regulates MMP2 expression and is decreased in most MLL-r AMLs. Moreover, iron chelation of HU is also indispensable for inducing cell stress, and MMP2 is the support factor to protect cells from death. Our preliminary study indicates that MMP2 might play a role in the nonsense-mediated mRNA decay pathway that prevents activation of unfolding protein response under innocuous endoplasmic reticulum stress. Hence, these results reveal a possible strategy of HU application in MLL-r AML treatment and shed new light upon HU repurposing.


The chloride transport induced by triaklyl-tin compound across erythrocyte membrane.
The effect of tripropyl-tin chloride on anion permeability was studied using red cells previously treated with a covalent binding inhibitor 4-acetamido-4'-isothiocyanostilbene-2,2'-disulfonic acid (SITS) to inhibit completely and irreversibly the natural anion transport system. It was demonstrated that the tin compound can mediate chloride-hydroxide and chloride-chloride exchanges across the "impermeabilised" erythrocyte membrane. In the non hemolytic range, the rate of exchange increased with the concentration of the tin compound in a non linear fashion, and no saturation effect was seen. The temperature profile of the chloride self exchange induced by tripropyl-tin was studied and the apparent activation energy found was 29 Kcal/mol. The tripropyl-tin chloride cannot mediate a chloride-bicarbonate exchange. Because of this discriminatory effect between hydroxide and bicarbonate, the tin compound can be useful in certain experimental conditions as seen for the study of the anion "carrier" of the red cell membrane ("cousin, J.L., Motais, R. and Sola, F. (1975) J. Physiol. Lond. 253, 385-399).


Practical considerations for rapid and quantitative NMR-based metabolomics.
NMR is a key technology for metabolomics because of its robustness and reproducibility. Herein we discuss practical considerations that extend the utility of NMR spectroscopy. First, the long T1 spin relaxation times of small molecules limits high-throughput data acquisition because most experimental time is lost while waiting for signal recovery. In principle, the addition of a small amount of commercially-available paramagnetic gadolinium chelate allows cost-effective and efficient high-throughput mixture analysis with correct concentration determination. However, idle time caused by slow temperature regulation during sample exchanges, poses a next constraint. We show how, with proper care, NMR sample scanning times can be reduced additionally by a factor of two. Lastly, we describe how equidistant bucketing is a simple and fast procedure for metabolomic fingerprinting. The combination of these advancements help to make NMR metabolomics more versatile than it is today.


The seasonal variation in a population of house dust mites in a North American city.
Mattress dust collected at monthly intervals for 2 1/2 yr was examined for mites. Both Dermatophagoides pteronyssinus and D. farinae were found. There was a significant association between the presence of live mites and the relative humidity (RH): Live mites were seen only when the RH had been greater than or equal to 50% for at least part of every day during the month of collection. There was a seasonal variation in that live mites were found only in the warmer months and not in the winter. However, the peak in the mite population was consistent neither for month nor for numbers: In 1977 a slight peak in mite numbers occurred in October, while in 1978 the peak was higher and occurred in July. Use of data from previously published studies to preduct mite levels may therefore be misleading.


Metabolic and thermogenic response to continuous and cyclic total parenteral nutrition in traumatised and infected patients.
16 traumatised or infected patients on mechanical ventilation were randomised to continuous TPN or to cyclic TPN after a 24-h period of glucose infusion (1.25 kJ x kg BW(-1) x h(-1)). Energy supply was equivalent to 1.3 x baseline energy expenditure. Glucose, fat and amino acids were administered at a constant rate over 24 h in the continuous TPN group and over 12 h, followed by glucose (1.25 kJ x kg BW(-1) x h(-1)), in the cyclic TPN group. Nutrient-induced thermogenesis was lower during continuous than during cyclic TPN (5 +/- 4 vs. 12 +/- 7%, mean +/- SD, p < 0.05), as was the increase in CO(2) elimination (13 +/- 11 vs. 30 +/- 7%, respectively, p < 0.01). Energy balance was more positive during continuous TPN. In both groups, energy expenditure reached a plateau during the first 12 h of TPN infusion. The lower nutrient-induced thermogenesis and more positive energy balance, indicates a more efficient utilisation of nutrients during continuous than during cyclic TPN. The lower CO(2) production during continuous TPN, may be advantageous when respiratory function is compromised. The plateau in energy expenditure in response to TPN infusion may be useful as a guideline for nutritional therapy.


Prevalence and correlates of antipsychotic polypharmacy: a systematic review and meta-regression of global and regional trends from the 1970s to 2009.
To assess the prevalence and correlates of antipsychotic polypharmacy (APP) across decades and regions. Electronic PubMed/Google Scholar search for studies reporting on APP, published from 1970 to 05/2009. Median rates and interquartile ranges (IQR) were calculated and compared using non-parametric tests. Demographic and clinical variables were tested as correlates of APP in bivariate and meta-regression analyses. Across 147 studies (1,418,163 participants, 82.9% diagnosed with schizophrenia [IQR=42-100%]), the median APP rate was 19.6% (IQR=12.9-35.0%). Most common combinations included first-generation antipsychotics (FGAs)+second-generation antipsychotics (SGAs) (42.4%, IQR=0.0-71.4%) followed by FGAs+FGAs (19.6%, IQR=0.0-100%) and SGAs+SGAs (1.8%, IQR=0.0-28%). APP rates were not different between decades (1970-1979:28.8%, IQR=7.5-44%; 1980-1989:17.6%, IQR=10.8-38.2; 1990-1999:22.0%, IQR=11-40; 2000-2009:19.2% IQR=14.4-29.9, p=0.78), but between regions, being higher in Asia and Europe than North America, and in Asia than Oceania (p<0.001). APP increased numerically by 34% in North America from the 1980s 12.7%) to 2000s (17.0%) (p=0.94) and decreased significantly by 65% from 1980 (55.5%) to 2000 (19.2%) in Asia (p=0.03), with non-significant changes in Europe. APP was associated with inpatient status (p<0.001), use of FGAs (p<0.0001) and anticholinergics (<0.001), schizophrenia (p=0.01), less antidepressant use (p=0.02), greater LAIs use (p=0.04), shorter follow-up (p=0.001) and cross-sectional vs. longitudinal study design (p=0.03). In a meta-regression, inpatient status (p<0.0001), FGA use (0.046), and schizophrenia diagnosis (p=0.004) independently predicted APP (N=66, R(2)=0.44, p<0.0001). APP is common with different rates and time trends by region over the last four decades. APP is associated with greater anticholinergic requirement, shorter observation time, greater illness severity and lower antidepressant use.


New antiepileptic medications.
Several new compounds are undergoing extensive investigation in the United States and Europe. The available animal and human studies suggest that these new antiepileptic drugs are very promising. Some or all of them will be approved for clinical use during the next decade. New antiepileptic drugs offer new options in the treatment of epilepsy. Although there already has been considerable testing of these drugs, additional studies that incorporate traditional medical outcome measures and quality of life measures remain to be done to establish the ultimate role of the new antiepileptic drugs in the treatment hierarchy for epilepsy.


Does sodium nitroprusside improve tissue oxygenation during cardiopulmonary bypass?
Eight patients undergoing cardiopulmonary bypass with hypothermia received, during part of the hypothermic phase, an infusion of sodium nitroprusside (SNP). Oxygen consumption was measured during the infusion and during control periods. Despite causing a marked reduction of arterial pressure, SNP was not shown to have any significant effect upon whole-body oxygen consumption or lactate concentration in the blood.


Chronic type I interferon signaling promotes lipid-peroxidation-driven terminal CD8+ T cell exhaustion and curtails anti-PD-1 efficacy.
Identifying signals that govern the differentiation of tumor-infiltrating CD8+ T cells (CD8+ TILs) toward exhaustion can improve current therapeutic approaches for cancer. Here, we show that type I interferons (IFN-Is) act as environmental cues, enhancing terminal CD8+ T cell exhaustion in tumors. We find enrichment of IFN-I-stimulated genes (ISGs) within exhausted CD8+ T cells (Tex cells) in patients across various cancer types, with heightened ISG levels correlating with poor response to immune checkpoint blockade (ICB) therapy. In preclinical models, CD8+ TILs devoid of IFN-I signaling develop less exhaustion features, provide better tumor control, and show greater response to ICB-mediated rejuvenation. Mechanistically, chronic IFN-I stimulation perturbs lipid metabolism and redox balance in Tex cells, leading to aberrant lipid accumulation and elevated oxidative stress. Collectively, these defects promote lipid peroxidation, which potentiates metabolic and functional exhaustion of Tex cells. Thus, cell-intrinsic IFN-I signaling regulates the extent of CD8+ TIL exhaustion and has important implications for immunotherapy.


Comparative pharmacokinetic profiles of a novel isotretinoin formulation (isotretinoin-Lidose) and the innovator isotretinoin formulation: a randomized, 4-treatment, crossover study.
A high-fat meal is needed for optimal absorption of isotretinoin. A new formulation of isotretinoin, which enhances absorption of isotretinoin in the absence of dietary fat, has recently been approved by the Food and Drug Administration (FDA). We sought to compare the pharmacokinetic profiles of a new formulation of isotretinoin (isotretinoin-Lidose) with the innovator isotretinoin formulation. This study was an open-label, single-dose, randomized, 4-treatment, crossover comparative trial between a new and innovator formulation of isotretinoin in the fasting and fed states. Both formulations were bioequivalent under fed conditions. As expected in a fasting state, absorption of both formulations was reduced. A considerable difference between the 2 drugs occurred under fasted conditions-there was a marked improvement in overall bioavailability of the isotretinoin-Lidose formulation. Mean plasma levels of the isotretinoin-Lidose formulation during fasting reached 66.8% of that observed with a fatty meal, and those of the isotretinoin formulation only reached 39.6% of that observed with a fatty meal. Only the FDA-stipulated standard high-fat, high-calorie meal of 50-g fat was studied in the fed state. Isotretinoin-Lidose formulation is bioequivalent to the innovator formulation under fed conditions with regard to its pharmacokinetic profile but delivers twice as much isotretinoin and 4-oxo-isotretinoin when administered after an overnight fast.


Selective enhancement of optical nonlinearity in two-dimensional organic-inorganic lead iodide perovskites.
Reducing the dimensionality of three-dimensional hybrid metal halide perovskites can improve their optoelectronic properties. Here, we show that the third-order optical nonlinearity, n 2, of hybrid lead iodide perovskites is enhanced in the two-dimensional Ruddlesden-Popper series, (CH3(CH2)3NH3)2(CH3NH3) n-1Pb n I3n+1 (n = 1-4), where the layer number (n) is engineered for bandgap tuning from E g = 1.60 eV (n = ∞; bulk) to 2.40 eV (n = 1). Despite the unfavorable relation, [Formula: see text], strong quantum confinement causes these two-dimensional perovskites to exhibit four times stronger third harmonic generation at mid-infrared when compared with the three-dimensional counterpart, (CH3NH3)PbI3. Surprisingly, however, the impact of dimensional reduction on two-photon absorption, which is the Kramers-Kronig conjugate of n 2, is rather insignificant as demonstrated by broadband two-photon spectroscopy. The concomitant increase of bandgap and optical nonlinearity is truly remarkable in these novel perovskites, where the former increases the laser-induced damage threshold for high-power nonlinear optical applications.Hybrid metal halide perovskites can exhibit improved optoelectronic properties when their dimensionality is reduced. Here, Saouma et al. study the enhancement of third-order nonlinearities in two-dimensional lead iodide perovskites in the Ruddlesden-Popper series.


Long non-coding RNA KRT8P41/miR-193a-3p/FUBP1 axis modulates the proliferation and invasion of chordoma cells.
Chordomas are low-grade malignancies accounting for 1-4% of primary bone malignancies. Moreover, local recurrences increase the rate of metastasis. Our previous study identified the far upstream element (FUSE)-binding protein 1 (FUBP1) as a biomarker and potential therapeutic target for chordoma. In this study, lncRNA KRT8P41 was identified as a lncRNA positively correlated with FUBP1. In chordoma patients, higher lncRNA KRT8P41 expression was correlated with a poorer prognosis. LncRNA KRT8P41 silencing significantly inhibited chordoma cell proliferation and invasion. miR-193a was negatively correlated with lncRNA KRT8P41 and FUBP1; lncRNA KRT8P41 inhibited miR-193a expression, and miR-193a inhibited FUBP1 expression. Furthermore, miR-193a directly bound to lncRNA KRT8P41 and FUBP1 and lncRNA KRT8P41 competed with FUBP1 for miR-193a binding and relieved miR-193a-mediated FUBP1 inhibition. LncRNA KRT8P41 silencing inhibited, whereas miR-193a inhibition promoted chordoma cell proliferation and invasion; the inhibition of miR-193a attenuated the roles of lncRNA KRT8P41. Within chordoma tissues, the expression of miR-193a was decreased, and the expression of FUBP1 increased compared to normal control tissues. LncRNA KRT8P41 exhibited a positive correlation with FUBP1 and a negative correlation with miR-193a in vivo. Therefore, it was concluded that lncRNA KRT8P41, miR-193a-3p, and FUBP1 form a lncRNA-miRNA-mRNA axis, modulating the proliferation and invasion of chordoma cells.


Computed tomography and intracranial aspergillosis.
A case of aspergillosis of the central nervous system with multiple granulomas examined by computed tomography is reported. The findings are those of chronic mass lesions with and without calcium deposits. An associated cystic configuration probably is not specific for aspergillomas.


Emotions generated by meat and other food products in women.
Eating behaviour depends partly on food preference, which is itself determined by different types of emotions. Among the emotions generated by food, disgust with red meat is common in women and can lead to reduced meat consumption. We tested the hypothesis that low meat intake is related to different negative emotions towards meat but does not affect the emotions expressed towards other food categories. Food intake of sixty women was followed throughout each day for 1 week and allowed us to assign women to two groups (low v. high meat-eating women). They were then invited to assess the intensity of twenty-six emotions described by words and induced by thirty food pictures. We determined the number of necessary dimensions to describe the space created by the twenty-six words. The results showed differences in emotions between the low and high meat-eating women. As expected, there were overall differences in the emotions generated by the thirty food pictures. Six clusters of emotions were necessary and sufficient to summarise the emotional space. These dimensions were described by 'disappointment', 'satisfaction', 'guilt', 'doubt', 'amused' and 'indifference'. As expected, the low meat-eating women felt more 'disappointment', 'indifference' and less 'satisfaction' towards meat than did the high meat-eating women. However, the low meat-eating women also stated other negative emotions such as 'doubt' towards some starchy foods. The only foods that they liked more than high meat-eating women were pears and French beans. In conclusion, low meat consumption was associated with specific negative emotions regarding meat and other foods.


Modeling COVID-19 infection risks for a single hand-to-fomite scenario and potential risk reductions offered by surface disinfection.
We used a quantitative microbial risk assessment approach to relate log10 disinfection reductions of SARS-CoV-2 bioburden to COVID-19 infection risks. Under low viral bioburden, minimal log10 reductions may be needed to reduce infection risks for a single hand-to-fomite touch to levels lower than 1:1,000,000, as a risk comparison point. For higher viral bioburden conditions, log10 reductions of more than 2 may be needed to achieve median infection risks of less than 1:1,000,000.


Genomic structure of chromosome 17 deletions in BRCA1-associated ovarian cancers.
The aim of this study was to determine the genomic structure of the deletions on chromosome 17 in ovarian carcinomas from women with inherited BRCA1 mutations. Normal and tumor DNA from 14 ovarian tumors associated with inherited BRCA1 mutations were extracted and tested for loss of heterozygosity (LOH) at microsatellite markers along chromosome 17. Finer mapping using more microsatellite markers and single nucleotide polymorphisms helped further define the LOH margins. The genomic repeated elements within the LOH breakpoint regions were identified using the University of California Santa Cruz Genome Database, and the frequencies were compared to regions of equal GC percentages across the genome. Of the 14 ovarian tumors, 12 showed LOH of the entire chromosome 17. The other two tumors lost the distal end of the 17q arm. The breakpoints of these two tumors occurred in regions with significantly high frequencies of short interspersed nuclear elements (SINE), specifically Alu elements. Ovarian tumors of high grade and stage have large regions of LOH along chromosome 17, with most tumors showing loss of the entire chromosome. In those tumors with retention of part of chromosome 17, LOH margins suggest that a high Alu content may have a role in the deletions.


Cause of apical thinning on attenuation-corrected myocardial perfusion SPECT.
Decreases in apical and apex activities - namely, 'apical thinning' - are a well-known phenomenon in attenuation-corrected (AC) myocardial perfusion. The aim of this study was to compare actual myocardial thickness derived from a multidetector-row computed tomography with AC myocardial perfusion count from a hybrid single-photon emission computed tomography/computed tomography to investigate the cause of apical thinning. We enrolled 21 participants with a low likelihood of coronary artery disease (mean age 65 ± 21 years, 13 men) from 185 consecutive patients and 11 healthy volunteers, who independently underwent ⁹⁹mTc-sestamibi single-photon emission computed tomography/computed tomography and 64-slice multidetector-row computed tomography scans. AC and non-AC myocardial perfusion counts and thickness were measured on the basis of a 17-segment model and averaged at the apex, apical, mid, and basal walls. Myocardial thickness at the apex was significantly thinner than that at the apical and mid walls (5.1 ± 1.3, 7.3 ± 1.3, and 9.9 ± 2.4 mm, respectively; P<0.005). AC count at the apex was significantly lower than that at the apical and mid regions (76.0 ± 5.5, 82.8 ± 4.7, and 85.6 ± 3.8, respectively; P<0.002). Moderate relationship was observed between myocardial thickness and AC count (y=-10.5 + 0.22x, r=0.54, P<0.0001. No relationship was found between thickness and non-AC count (r=0.16, P=0.263). The low apex and apical counts were caused by anatomical thinning of the myocardium in AC myocardial perfusion imaging. Attenuation correction provided an accurate relationship between myocardial count and thickness because of the partial volume effect.


How to kill a mandate. Hospital lobby persuades Scully, CMS to scuttle proposal that would have required hospitals to measure patient satisfaction.
The Centers for Medicare and Medicaid Services has backed off its plan to require all Medicare-certified hospitals to publicly report mandatory patient surveys, Modern Healthcare has learned. Instead, no regulations will be written and hospitals will be asked to voluntarily use surveys. American Hospital Association President Richard Davidson, left, co-authored a letter urging hospitals to participate.


Successful nonoperative management of acute intraperitoneal hemorrhage due to undiagnosed polyarteritis nodosa.
We present a rare case of polyarteritis nodosa (PAN), where the initial presentation was intraperitoneal hemorrhage. The diagnosis was confirmed on angiography, and the patient was managed medically without laparotomy. PAN is an extremely rare cause of spontaneous intraperitoneal bleeding but must be carefully considered in the differential diagnosis in order to insure appropriate management of this group of patients.


The shared epitope and severity of rheumatoid arthritis.
After two decades of research involving thousands of RA patients, it is still not possible to precisely define the relation of HLA-DRB1 SE alleles to RA severity. Improvements in our understanding require more careful consideration of several factors such as ethnicity, gender, and the specific SE allele and genotype inherited. Large studies of heterogeneous groups of patients are required and indicate the need for collaborative efforts among researchers. In the interim, meta-analysis of the existing literature may provide some insight, because it allows utilization of the tremendous amount of research already completed. A preliminary meta-analysis highlighted the significant heterogeneity among the existing literature, and a more ambitious meta-analysis that uses individual patient-level data is currently ongoing. Profound implications exist for determination of the precise relationship between the SE and RA severity. This information could be valuable in identifying patients at greater risk of severe complications or as a stratification variable for clinical trials. Moreover, patients genetically predisposed to severe disease may benefit from early initiation of more aggressive therapy. Ultimately, clarification of the role of the SE may be valuable for the development of specific therapies directed toward DRB1 and related targets.


Idiopathic posterior papillary muscle rupture; a case report.
Papillary muscle rupture is a rare condition. Its clinical presentation, diagnosis and management can be very challenging for the clinician. A 73-year-old woman with hypertension presented with chest pain, ST-segment changes, and elevated serum troponin levels. Coronary angiography was normal. Echocardiography revealed normal ventricular function, flail posterior mitral leaflet, and severe mitral regurgitation. She underwent emergent mitral valve replacement. The diagnostic and management strategies of this uncommon presentation are discussed.


Myoglobinuria.
Myoglobinuria has a variety of causes, ranging from trauma to heavy exercise. Symptoms usually consist of myalgia and muscle weakness; dark, bloody-looking urine may be noted. Myoglobin can be identified by readily available laboratory techniques. Acute renal failure can be a dangerous consequence of myoglobinuria but, with rapid recognition and strict monitoring, the prognosis in most cases is good.


A dynamic family practice information system for enhanced financial management.
The definition of the fiscal unit/family structure has enabled users of the FMIS, or family practices in Colorado and Wyoming, to maintain accurate, ongoing financial information on their patients. In turn, this structure has been a major incentive for maintaining accurate family information, and a distinct benefit to FMIS users. This article has presented the rationale, design, and method of implementation of the fiscal unit structure, with the intention of presenting this concept to others for use in other information systems used in maintaining family-oriented financial and medical information for medical practices.


Interventional ultrasound in the musculoskeletal system.
This article highlights the multiple applications of ultrasound as a guidance modality for interventional procedures in the musculoskeletal system. The percutaneous aspiration, drainage, and biopsy of musculoskeletal abscesses, masses, and focal muscular pathology in the extremities, trunk, and neck using ultrasound as the guidance system is described. Techniques for biopsy, fluid aspiration, catheter insertion, and needle visualization by ultrasound are discussed.


Herniation of calcified cervical intervertebral disc causes dissociated motor loss in a child.
Herniation of the calcified nucleus pulposus is a rare complication of intervertebral disc calcification in children. Surgical intervention is rarely indicated in the majority of such cases. This paper reports a 12-year-old boy with a calcified nucleus pulposus at C7-T1 which had ruptured into the spinal canal, causing dissociated motor loss. Anterior discectomy and fusion were performed and the patient's muscle weakness markedly improved after surgery.


Extreme oxygen isotope ratios in the early Solar System.
The origins of the building blocks of the Solar System can be studied using the isotopic composition of early planetary and meteoritic material. Oxygen isotopes in planetary materials show variations at the per cent level that are not related to the mass of the isotopes; rather, they result from the mixture of components having different nucleosynthetic or chemical origins. Isotopic variations reaching orders of magnitude in minute meteoritic grains are usually attributed to stellar nucleosynthesis before the birth of the Solar System, whereby different grains were contributed by different stars. Here we report the discovery of abundant silica-rich grains embedded in meteoritic organic matter, having the most extreme 18O/16O and 17O/16O ratios observed (both approximately 10(-1)) together with a solar silicon isotopic composition. Both O and Si isotopes indicate a single nucleosynthetic process. These compositions can be accounted for by one of two processes: a single exotic evolved star seeding the young Solar System, or irradiation of the circumsolar gas by high energy particles accelerated during an active phase of the young Sun. We favour the latter interpretation, because the observed compositions are usually not expected from nucleosynthetic processes in evolved stars, whereas they are predicted by the selective trapping of irradiation products.


Pregnant women with mild COVID-19 followed in community setting by telemedicine, and factors associated with unfavorable outcome.
Few is known on pregnant women with mild COVID-19 managed in a community setting with a telemedicine solution, including their outcomes. The objective of this study is to evaluate the adverse fetal outcomes and hospitalization rates of pregnant COVID-19 outpatients who were monitored with the Covidom© telemedicine solution. A nested study was conducted on pregnant outpatients with confirmed COVID-19, who were managed with Covidom© between March and November 2020. The patients were required to complete a standard medical questionnaire on co-morbidities and symptoms at inclusion, and were then monitored daily for 30 days after symptom onset. Adverse fetal outcome was defined as a composite of preterm birth, low birthweight, or stillbirth, and was collected retrospectively through phone contact with a standardized questionnaire. The study included 714 pregnant women, with a median age of 32.0 [29.0-35.0] and a median BMI of 23.8 [21.3-27.0]. The main comorbidities observed were smoking (53%), hypertension (19%). The most common symptoms were asthenia (45.6%), cough (40.3%) and headache (25.7%), as well as anosmia (28.4%) and agueusia (32.3%). Adverse fetal outcomes occurred in 64 (9%) cases, including 38 (5%) preterm births, 33 (5%) low birthweights, and 6 (1%) stillbirths. Hospitalization occurred in 102 (14%) cases and was associated with adverse fetal outcomes (OR 2.4, 95% CI 1.3-4.4). Our study suggests that adverse fetal outcomes are rare in pregnant women with mild COVID-19 who are monitored at home with telemedicine. However, hospitalization for COVID-19 and pregnancy-induced hypertension are associated with a higher risk of adverse fetal outcome.


Postoperative analgesia after circumcision. A randomized comparison between caudal analgesia and intramuscular morphine in boys.
A randomised blind comparison between caudal analgesia (1.5 mg/kg bupivacaine) and intramuscular morphine (0.15 mg/kg) is reported. Forty boys were studied. Caudal analgesia is shown to be significantly better than morphine by means of a linear analogue scale designed to quantify behaviour immediately after operation.


Neurological improvement predicts clinical outcome after acute basilar artery stroke thrombectomy.
Mechanical thrombectomy (MT) is the standard of care for patients with anterior circulation large vessel occlusion. Early neurological improvement (ENI), defined as a reduction of ≥ 8 on the National Institutes of Health Stroke Scale (NIHSS) compared with baseline score, or an NIHSS score of 0 or 1 at 24 h after MT, is a strong predictor of 3-month favorable outcome in such patients. The impact of ENI after MT in stroke patients with basilar artery occlusion (BAO) on 3-month outcome is not clear. We aimed to study the effects of ENI in patients with BAO. We performed a retrospective analysis of a multicenter prospective cohort of all consecutive stroke patients with BAO who underwent MT. We compared clinical outcomes between BAO patient groups according to ENI status. Multivariate analyses were performed to determine the impact of ENI on favorable 90-day outcome (modified Rankin scale score 0-3) and to report factors contributing to ENI. A total of 237 patients were included. ENI was observed in 70 patients (30%). Outcomes were significantly better in ENI-positive patients, with 84% achieving favorable outcome (mRS score 0-3) at 3 months versus 30% for ENI-negative patients (P < 0.0001). In multivariate analysis, ENI was an independent predictive factor associated with higher rates of favorable outcome {odds ratio (OR) 18.12 [95% confidence interval (CI) 3.95-83.10]; P = 0.0001}. Higher number of passes [OR 0.62 (95% CI 0.43-0.89); P = 0.010] and need for stenting [OR 0.27 (95% CI 0.07-0.95); P = 0.041] were negatively associated with ENI. Early neurological improvement on day 1 following MT for BAO is a strong independent predictor of a favorable 3-month clinical outcome.


The Impact of Therapeutic Exercises on the Quality of Life and Shoulder Range of Motion in Women After a Mastectomy, an RCT.
Breast cancer ranks highest in incidence and mortality among females and second among both genders. Lebanon has the second highest rate of breast cancer worldwide for those 35-39 years old and the highest for those 40-49. Mastectomy often results in deceased shoulder and arm mobility and decreased quality of life. The objective of this study was to assess the effect of an educational program of therapeutic exercises on the quality of life and functional ability in women after a mastectomy. Sixty women undergoing a mastectomy were randomly assigned to either an intervention or control group. The intervention group received extensive pre-surgery education as well as training on therapeutic exercises. Follow-up phone calls to the intervention group were made to ensure that the exercises were being done. Both groups were visited at home at two and four weeks to obtain the outcome variables. The Breast Cancer Patient Version was used to assess quality of life, and the "Goniometer" was used to assess the range of motion of the affected shoulder. At two and four weeks after surgery, women in the intervention group had significant improvements in their shoulder range of motion: flexion, extension, and abduction were significantly different between the control and intervention group at p = 0.04-0.00. For quality of life, physical, psychological, psychological, social, and spiritual well-being were significantly higher for the intervention group at both two and four weeks after surgery, p < 0.001. In a middle-income country, one-to-one education provided by a nurse, which included demonstrations, back demonstrations, and weekly phone calls had a positive impact on women's shoulder range of motion and quality of life. NCT04184102.


Sigma binding site ligands inhibit cell proliferation in mammary and colon carcinoma cell lines and melanoma cells in culture.
Recent evidence suggests a role for sigma (sigma) binding sites in maintenance of cell growth and/or proliferation. The present study examines, for the first time, the effect of sigma binding site ligands on in vitro growth of tumour cells derived from human mammary adenocarcinoma (MCF-7, MDA) and colon carcinoma (LIM 1215, WIDr), and melanoma (Chinnery). Addition of the sigma ligands haloperidol, reduced haloperidol, 1,3-di(2-tolyl)guanidine (DTG), (+)- and (-)-N-allylnormetazocine (SKF 10,047), (+)- and (-)-pentazocine and rimcazole at 6.25, 12.5, 25, 50, 100 microM at the beginning of culture or 24 h later, inhibited cell proliferation in a dose-dependent manner. Light microscopy revealed cell detachment, rounding and cell death. The potency of sigma ligands on melanoma cells was rimcazole > reduced haloperidol > haloperidol = (+)-pentazocine, whereas DTG and (+)- and (-)-SKF 10,047 and (-)-pentazocine had no effect even at 100 microM. In contrast, in MCF-7 cells, rimcazole > reduced haloperidol > haloperidol > (-)-pentazocine > DTG > (+)-pentazocine > (+)-SKF 10,047 > (-)-SKF 10,047. For colon cancer cells, reduced haloperidol > DTG > haloperidol = (-)-pentazocine = (+)-pentazocine = (+)-SKF 10,047. Of all the ligands tested, rimcazole and reduced haloperidol were the most potent inhibitors of cell proliferation. With the exception of one slow-growing colon cancer cell line (LIM 1215), the order of sensitivity of various cell lines to reduced haloperidol, SFK 10,047, DTG, haloperidol and (+)- and (-)-pentazocine was colon carcinoma > mammary adenocarcinoma > melanoma, whereas to rimcazole, the sensitivities of mammary adenocarcinoma and melanoma cells were comparable. The effect of sigma ligands in MCF-7 and melanoma cells was not due to blockade of dopamine D1 and D2 receptors, serotonin (5-HT2) receptors, N-methyl-D-aspartate (NMDA)/phencyclidine receptors, beta-adrenoceptors or opioid receptors, since 100 microM SCH 23390, raclopride, mianserin, (+)-MK-801, propranolol and 1 microM naloxone respectively, were ineffective. However, mianserin and raclopride were inhibitory to melanoma cells and one colon carcinoma cell line, respectively. Taken together, the results are consistent with the recent observation that sigma binding sites may play a role in cell growth and/or cell proliferation.


Piperazine analog of vesamicol: in vitro and in vivo characterization for vesicular acetylcholine transporter.
The probes to detect vesicular acetylcholine transporter (VAChT) in vivo are important to evaluate the mapping and function in cholinergic system. To develop high-specific and high-affinity radiotracer for single photon emission computed tomography, we investigated piperazine analogs which replaced the piperidine ring of (-)-vesamicol with a piperazine ring. We found that the piperazine analog of iodobenzovesamicol, trans-5-iodo-2-hydroxy-3-[4-phenylpiperazinyl] tetralin (DRC140), had high affinity for VAChT in rat brain. We carried out binding assay in subcellular fraction of the rat brain. The highest B(max) for [(125)I]-DRC140 binding was observed in the synaptic vesicle fraction (1,751 fmol/mg protein), followed by the crude vesicle (821 fmol/mg protein) and the P2 fraction (187 fmol/mg protein). These K(d) values were similar to the affinity of highly purified synaptic vesicular fraction (K(d) = 0.3 nM) with a one-site model. The possibility that [(125)I]-DRC140 recognizes sigma receptor was excluded by our finding large inhibition constants (K(i) = 849 nM for haloperidol, K(i) = 3,052 nM for 1,3-di(2-tolyl)guanidine). In vivo distribution studies with the [(123)I]-DRC140 in rats showed a rapid brain uptake. The highest brain area was in striatum, followed by frontal cortex, occipital cortex, and hippocampus. The lowest brain area was cerebellum. The radioactivity of high-accumulated areas in ex vivo autoradiography was reduced by a preinjection of (-)-vesamicol and these levels were reduced to the radioactivity in cerebellum. These results show that [(125)I]-DRC140 can provide extremely high specific tracer with excellent brain permeability as a ligand for single photon emission computed tomography.


Characterization of dynamical changes in vital signs during allogeneic human umbilical cord-derived mesenchymal stem cells infusion.
Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs), a kind of adult stem cell, were studied for clinical applications in regenerative medicine. To date, the safety evaluations of intravenous infusion of allogeneic hUC-MSCs were focused on fever, infection, malignancy, and death. However, the characteristics of dynamical changes in vital signs during hUC-MSCs infusion are largely unknown. In this study, twenty participants with allogeneic hUC-MSCs transplanted (MSC group) and twenty sex- and age-matched individuals with cardiovascular disease who treated with the equal volume of 0.9% normal saline were recruited (NS group). Heart rate, respiratory rate, oxygen saturation, systolic and diastolic blood pressure, and temperature were monitored at intervals of 15 min during infusion. Adverse events were recorded during infusion and within seven days after infusion. No adverse events were observed during and after infusion in both groups. Compared with the baseline, the mean systolic blood pressure (SBP) levels were significantly decreased at 15 min, 30 min, 45 min and 60 min in the MSC group (all P < 0.05) during infusion. In addition, SBP changed significantly from baseline during hUC-MSCs infusion when compared with that of NS group (P < 0.05). Repeated measures analysis of variance confirmed difference over time on the SBP levels (P < 0.05). Our results showed that the process of allogeneic hUC-MSCs intravenous infusion was safe and the vital signs were stable, whereas a slight decrease in SBP was observed.


Stepwise phosphorylation of leukotriene B4 receptor 1 defines cellular responses to leukotriene B4.
Leukotriene B4 (LTB4) receptor type 1 (BLT1) is abundant in phagocytic and immune cells and plays crucial roles in various inflammatory diseases. BLT1 is phosphorylated at several serine and threonine residues upon stimulation with the inflammatory lipid LTB4 Using Phos-tag gel electrophoresis to separate differentially phosphorylated forms of BLT1, we identified two distinct types of phosphorylation, basal and ligand-induced, in the carboxyl terminus of human BLT1. In the absence of LTB4, the basal phosphorylation sites were modified to various degrees, giving rise to many different phosphorylated forms of BLT1. Different concentrations of LTB4 induced distinct phosphorylation events, and these ligand-induced modifications facilitated additional phosphorylation events at the basal phosphorylation sites. Because neutrophils migrate toward inflammatory sites along a gradient of LTB4, the degree of BLT1 phosphorylation likely increases in parallel with the increase in LTB4 concentration as the cells migrate. At high concentrations of LTB4, deficiencies in these two types of phosphorylation events impaired chemotaxis and β-hexosaminidase release, a proxy for degranulation, in Chinese hamster ovary (CHO-K1) and rat basophilic leukemia (RBL-2H3) cells, respectively. These results suggest that an LTB4 gradient around inflammatory sites enhances BLT1 phosphorylation in a stepwise manner to facilitate the precise migration of phagocytic and immune cells and the initiation of local responses, including degranulation.


Long-term outcome of a proximal humerus fracture predicted after 1 year: a 13-year prospective population-based follow-up study of 47 patients.
Earlier reports of results after proximal humerus fractures have often been short- or medium-term studies. The aim of this investigation was to follow an unselected group of patients prospectively and assess the long-term results in relation to fracture type and health, and to evaluate the possibility of predicting the long-term results after 1 year. 258 consecutive urban patients who sustained a proximal humerus fracture in 1987 were followed prospectively and examined after 1 and 13 years. 158 patients had died by the year 2000 and 47 of the surviving patients were available for clinical and radiographic evaluation. The Constant-Murley score (CM-score) was used in the clinical assessment. In the final follow-up group, all patients except 1 were treated nonoperatively. 21 patients had asymptomatic, pain-free shoulders. In 26 patients with shoulder symptoms, 11 had severe pain and 10 had moderate pain, and only 2 of these 21 patients had normal shoulder function. The remaining 5 patients in the symptomatic group had no shoulder pain but had reduced shoulder function. Shoulders with a displaced fracture and also injured shoulders of patients with a chronic disease were significantly worse at the long-term follow-up. The 1-year examination had been able to predict the long-term results with 71% sensitivity for protracted pain and 88% sensitivity for persistent shoulder dysfunction. Our results suggest that there is a substantial mortality in patients with a proximal humerus fracture, as we have previously reported, and that surviving patients frequently have persistent symptoms that can be predicted as early as after 1 year.


Establishment of baseline profiles of 50 bile acids in preclinical toxicity species: A comprehensive assessment of translational differences and study design considerations for biomarker development.
The use of bile acids as functional biomarkers for hepatobiliary injury and disease has been proposed for decades, but the utility has been generally limited due to lack of sensitivity in diagnosis and assay availability. However, recent advances in liquid chromatography and mass spectrometry have allowed for highly sensitive profiling of individual bile acids across several different matrices. In the current work, a panel of 54 bile acids were quantified in plasma by high resolution mass spectrometry in the common species used for preclinical toxicity studies, including rat (both Wistar and Sprague-Dawley strains), Beagle dog, Cynomolgus macaque monkey, and New Zealand White rabbit. In each species, blood draws were collected across three days in such a way to derive overall interpretations of: 1) biological variability across species, 2) sex differences, 3) diurnal fluctuations in the bile acid pool (including over light/dark cycles), and 4) changes due to fed or fasting state. Various methods of normalization were applied to the dataset to overcome notable inter-individual variability in bile acid concentrations to allow for better data derivations and interpretation. As such, the current work elucidates not only key differences in the bile acid pool across species, but also informs best practices in protocol design and analytical methods for interpreting large sets of bile acid data. When taken together, these data facilitate better species translation and application of bile acids as biomarkers for hepatobiliary injury and disease.


Cobbler's Technique for Iridodialysis Repair.
We describe a novel "Cobbler's technique" for iridodialysis repair in the right eye of a patient aged 18 years, with a traumatic iridodialysis secondary to open globe injury with an iron rod. Our technique is simple with easy surgical maneuvers, that is, effective for repairing iridodialysis. The "Cobbler's technique" allows a maximally functional and cosmetic result for iridodialysis.


Low-latitude glaciation and rapid changes in the Earth's obliquity explained by obliquity-oblateness feedback.
Palaeomagnetic data suggest that the Earth was glaciated at low latitudes during the Palaeoproterozoic (about 2.4-2.2 Gyr ago) and Neoproterozoic (about 820-550 Myr ago) eras, although some of the Neoproterozoic data are disputed. If the Earth's magnetic field was aligned more or less with its spin axis, as it is today, then either the polar ice caps must have extended well down into the tropics-the 'snowball Earth' hypothesis-or the present zonation of climate with respect to latitude must have been reversed. Williams has suggested that the Earth's obliquity may have been greater than 54 degrees during most of its history, which would have made the Equator the coldest part of the planet. But this would require a mechanism to bring the obliquity down to its present value of 23.5 degrees. Here we propose that obliquity-oblateness feedback could have reduced the Earth's obliquity by tens of degrees in less than 100 Myr if the continents were situated so as to promote the formation of large polar ice sheets. A high obliquity for the early Earth may also provide a natural explanation for the present inclination of the lunar orbit with respect to the ecliptic (5 degrees), which is otherwise difficult to explain.


Dynamics of populations with changing rates: generalization of the stable population theory.
A general and complete exposition of the dynamics of populations with changing vital rates is given in the discrete time formulation. Results obtained are stronger than Lopez's or Hajnal's. In addition to the proof of existence of limits, an explicit expression for the age distribution is obtained by considering forward products of population projection matrices, while an explicit expression for the generalized reproductive values is obtained by considering backward products. The forward and backward characteristic equations respectively determine the forward and backward growth rates. The relative age distribution is compared to the alternative expression of Y.J. Kim (1986, Demography 23 (3), 451-461), which is the discrete version of S.H. Preston and A.J. Coale (1982, Pop. Index 48 (2), 217-259).


p38 Kinase rescues failing myocardium after myocardial infarction: evidence for angiogenic and anti-apoptotic mechanisms.
As a leading cause of heart failure, postinfarction left ventricular remodeling represents an important target for therapeutic interventions. Mitogen-activated protein kinases regulate critical cellular processes including stress response and survival, but their role in left ventricular remodeling is unknown. In the present study, rats were subjected to myocardial infarction by ligating the left anterior descending coronary artery. Western blot and kinase assay analysis revealed an inactivation of p38 kinase after myocardial infarction. Local adenovirus-mediated cotransfection of wild-type (WT) p38 kinase and constitutively active MKK3b reduced infarct size (26+/-3% vs. 47+/-4%, P<0.05 vs. LacZ-treated control) associated with improved ejection fraction (66.9+/-5.5% vs. 44.4+/-4.0%, P<0.001), fractional shortening (30.2+/-2.1% vs. 19.7+/-2.2%, P<0.001), and decreased left ventricular diastolic diameter (8.5+/-0.4 mm vs. 9.5+/-0.2 mm, P<0.01). p38 kinase gene transfer increased capillary density (2423+/-107/mm(2) vs. 1934+/-86/mm(2), P<0.001) and resulted in microvessel enlargement in the ischemic border zone. Apoptosis (35+/-7 vs. 69+/-13 cells, P<0.01) and fibrosis (16+/-3% vs. 34+/-8%, P<0.05) were reduced, while the number of c-kit positive cardiac stem-like cells remained unchanged. These results indicate that reduced p38 signaling predisposes to adverse postinfarction remodeling. The rescue of failing myocardium with p38 kinase may be a potential new therapy for heart failure after myocardial infarction.


A biomechanics dataset of healthy human walking at various speeds, step lengths and step widths.
The biomechanics of human walking are well documented for standard conditions such as for self-selected step length and preferred speed. However, humans can and do walk with a variety of other step lengths and speeds during daily living. The variation of biomechanics across gait conditions may be important for describing and determining the mechanics of locomotion. To address this, we present an open biomechanics dataset of steady walking at a broad range of conditions, including 33 experimentally-controlled combinations of speed (0.7-2.0 m·s-1), step length (0.5-1.1 m), and step width (0-0.4 m). The dataset contains ground reaction forces and motions from healthy young adults (N = 10), collected using split-belt instrumented treadmill and motion capture systems respectively. Most trials also include pre-computed inverse dynamics, including 3D joint positions, angles, torques and powers, as well as intersegmental forces. Apart from raw data, we also provide five strides of good quality data without artifacts for each trial, and sample software for visualization and analysis.