Indirect blood pressure monitoring in small mammals.
Direct blood pressure monitoring is the most accurate cardiovascular monitoring technique, but it is challenging in small mammals, as well as time-consuming and costly. Therefore, indirect blood pressure monitoring is most commonly used in clinic and laboratory settings. This column discusses indirect blood pressure monitoring in small mammals.


CBP/p300 double null cells reveal effect of coactivator level and diversity on CREB transactivation.
It remains uncertain how the DNA sequence of mammalian genes influences the transcriptional response to extracellular signals. Here, we show that the number of CREB-binding sites (CREs) affects whether the related histone acetyltransferases (HATs) CREB-binding protein (CBP) and p300 are required for endogenous gene transcription. Fibroblasts with both CBP and p300 knocked-out had strongly attenuated histone H4 acetylation at CREB-target genes in response to cyclic-AMP, yet transcription was not uniformly inhibited. Interestingly, dependence on CBP/p300 was often different between reporter plasmids and endogenous genes. Transcription in the absence of CBP/p300 correlated with endogenous genes having more CREs, more bound CREB, and more CRTC2 (a non-HAT coactivator of CREB). Indeed, CRTC2 rescued cAMP-inducible expression for certain genes in CBP/p300 null cells and contributed to the CBP/p300-independent expression of other targets. Thus, endogenous genes with a greater local concentration and diversity of coactivators tend to have more resilient-inducible expression. This model suggests how gene expression patterns could be tuned by altering coactivator availability rather than by changing signal input or transcription factor levels.


Association of Cesarean Delivery with Childhood Hospitalization for Infections Before 13 Years of Age.
To determine the association between cesarean delivery and childhood infections up to 13 years of age. We conducted a longitudinal cohort study of 731 803 children born between 2006 and 2016 at all hospitals in the province of Quebec, Canada. We followed children born by cesarean, operative vaginal, and nonoperative vaginal delivery up to 13 years of age. Outcomes included hospitalization for otitis media, respiratory, infectious enteritis, and other infections. We estimated hazard ratios with 95% CIs for the association between mode of delivery and childhood infections, adjusted for patient characteristics. At age 3-4 years, cesarean delivery was associated with a 1.07-fold greater risk of otitis media (95% CI, 1.03-1.11), a 1.15-fold greater risk of respiratory infection (95% CI, 1.09-1.22), and a 1.13-fold greater risk of infectious enteritis (95% CI, 1.03-1.25) compared with nonoperative vaginal delivery. However, operative vaginal delivery was associated with these same outcomes. Both cesarean and operative vaginal delivery were more strongly associated with infection hospitalization before age 1 year, but associations disappeared after 5 years. Cesarean delivery is associated with infection hospitalization before but not after age 5 years. However, associations were also present for operative vaginal delivery, which suggests that mechanisms other than exposure to maternal vaginal flora explain the relationship.


A case of malignant mastocytosis with near-haploid, near-diploid, and polyploid cells in the bone marrow.
Chromosome analysis in bone marrow cells of a 41-year-old woman with malignant mastocytosis (MM) revealed near-haploid (59%), near-diploid (36%), and polyploid (5%) cells. Near-haploid cells had a mode of 25 chromosomes with variable disomy and nullisomy of particular chromosomes. Disomy for chromosome 19 and chromosome 20 were most common. A 17p+ marker was observed in all cells. Other structural chromosomal changes were dicentrics, ring chromosomes, translocations, and double minutes. The modal chromosome number in near-diploid cells was 46 with a range of 41-52. The majority of cells with 46 chromosomes were pseudodiploid and only a few had a normal female karyotype. As in near-haploid cells, various structural chromosomal changes were found. The 17p+ marker was also present in occasional cells suggesting a relationship between the two tumor cell populations. Chromosome numbers in polyploid cells ranged from 70 to about 600. Identical copies of dicentrics or markers were identified in some cells.


Abnormal canine bone development associated with hypergravity exposure.
Chronic centrifugation of 85- to 92-day-old Beagles at 2.0 X g and 2.6 X g for 26 weeks during the time of active skeletal growth caused skeletal abnormalities in the radius and the ulna of ten of 11 dogs. The pattern of change mimicked that found in naturally occurring and experimentally induced premature distal ulnar physeal closure or delayed growth at this physis. Minimal changes in bone density were detected by sensitive photon absorptiometric techniques. Skeletal abnormalities also were found in five of the six cage-control dogs, although the run-control dogs were radiographically normal.


Population Pharmacokinetics of Oral Migalastat in Adolescents and Adults With and Without Renal Impairment.
Migalastat is approved for the treatment of Fabry disease (FD) with amenable variants. Objectives were to characterize effects of estimated glomerular filtration rate (eGFR) on oral clearance (CL), predict doses in mild to moderate renal impairment and in pediatric patients with FD, and to improve designs of FD studies. A 2-compartment model was fit to data from 260 subjects with/without FD and iteratively refined with evolving data. FD, eGFR, and weight affected CL, while weight and FD affected volume. Optimal sampling theory was used to choose pharmacokinetic sampling times for pediatric studies. Doses in patients with renal impairment and in pediatrics were determined by targeting exposure in adults receiving migalastat 123 mg every other day. A clinical study was conducted in 20 adolescent patients with FD ≥45 kg. eGFR had the largest effect on CL. Simulations showed that exposures in moderate renal impairment were within phase 2-3 exposures; patients aged 2-17 years require weight-based dosing; and predicted exposures in adolescent patients ≥45 kg receiving migalastat 123 mg every other day were similar to adults (data confirmed in a clinical study). Model-informed drug development optimized dosing and design of clinical studies and supported that no dose adjustments were needed in patients with mild to moderate renal impairment or in adolescent patients ≥45 kg.


Phylogenomics-based reclassifications in the genus Psychrobacter including emended descriptions of Psychrobacter pacificensis, Psychrobacter proteolyticus and Psychrobacter submarinus.
The taxonomic status of 43 Psychrobacter species was examined based upon the genome sequences of their type strains. Three groups of type strains were found to be conspecific, Psychrobacter salsus Shivaji et al. (Syst Appl Microbiol 27:628-635, 2004. 10.1078/0723202042369956) and Psychrobacter submarinus Romanenko et al. (Int J Syst Evol Microbiol 52:1291-1297, 2002. 10.1099/00207713-52-4-1291); Psychrobacter oceani Matsuyama et al. (Int J Syst Evol Microbiol 65:1450-1455, 2015. 10.1099/ijs.0.000118) and Psychrobacter pacificensis Maruyama et al. (Int J Syst Evol Microbiol 50:835-846, 2000. 10.1099/00207713-50-2-835); and Psychrobacter proteolyticus Denner et al. (Syst Appl Microbiol 24:44-53, 2001. 10.1078/0723-2020-00006), Psychrobacter marincola Romanenko et al. (Int J Syst Evol Microbiol 52:1291-1297, 2002. 10.1099/00207713-52-4-1291) and Psychrobacter adeliensis Shivaji et al. (Syst Appl Microbiol 27:628-635, 2004. 10.1078/0723202042369956). For all three groups, the average nucleotide identity (ANI) and digital DNA-DNA hybridization (dDDH) values are > 97.69% and > 80.2%, respectively. This conclusion is supported by similarities in morphology, growth properties, and fatty acid compositions. Based on this evidence, we propose the reclassification of Psychrobacter salsus Shivaji et al. (Syst Appl Microbiol 27:628-635, 2004. 10.1078/0723202042369956) as a later heterotypic synonym of Psychrobacter submarinus Romanenko et al. (Int J Syst Evol Microbiol 52:1291-1297, 2002. 10.1099/00207713-52-4-1291); Psychrobacter oceani Matsuyama et al. (Int J Syst Evol Microbiol 65:1450-1455, 2015. 10.1099/ijs.0.000118) as a later heterotypic synonym of Psychrobacter pacificensis Maruyama et al. (Int J Syst Evol Microbiol 50:835-846, 2000. 10.1099/00207713-50-2-835), and Psychrobacter marincola Romanenko et al. (Int J Syst Evol Microbiol 52:1291-1297, 2002. 10.1099/00207713-52-4-1291) and Psychrobacter adeliensis Shivaji et al. (Syst Appl Microbiol 27:628-635, 2004. 10.1078/0723202042369956) as later heterotypic synonyms of Psychrobacter proteolyticus Denner et al. (Syst Appl Microbiol 24:44-53, 2001. 10.1078/0723-2020-00006).


Rapid measurement of somatosensory evoked potential response to cerebral artery occlusion.
The aim of the paper is to determine the speed of the neurological response to cerebral artery occlusion by monitoring transient changes in somatosensory evoked potentials (SEPs). SEPs, continuously monitored during temporary clipping of the middle cerebral artery (MCA) in anaesthetised cats, are analysed. The SEP signals are modelled by a quasi-periodic Fourier series, the coefficients of which are estimated with the aid of two adaptive least squares estimation algorithms. The energy levels at various harmonics throughout the protocol are obtained directly from the filter weights. Noise covariance is estimated from pre-stimulus recording, and the adaptation rate of the algorithm is adjusted sweep-by-sweep to accommodate transient changes in the pre-stimulus noise level. After the occlusion, a significant decrease (p < 0.05) in SEP amplitude is observed. The change in latency is not statistically significant (p approximately equal to 0.5). The spectral trends show a sudden decline in energy at all harmonics immediately following occlusion, although when the amplifier bandwidth is changed to 5-1500 Hz (from an initial setting of 30-1500 Hz), the fundamental frequency component of the SEP signal shows the greatest responsiveness to injury. The average time constant of the decline in amplitude resulting from MCA occlusion is only 10.6 +/- 4.0 s. It is concluded that rapid detection of cerebral artery occlusion and ischaemia may be feasible by continuously monitoring SEP signals and analysing transient changes in time and frequency domains.


Weight reduction by Chinese medicinal herbs may be related to inhibition of fatty acid synthase.
Fatty acid synthase (EC 2. 3. 1. 85, abbr. FAS) is reported as a potential new therapeutic target for the treatment of obesity. Thirty one Chinese medicinal herbs used in weight reducing prescriptions of Traditional Chinese Medicine (TCM) were investigated for FAS inhibition. It was found that 17 of these herbs exhibited FAS inhibitor activity, and 9 were highly potent FAS inhibitors. The inhibitory potencies of the active components of tuber fleeceflower root, parasitic loranthus, green tea leaf and ginkgo leaf were similar to or greater than cerulenin and C75. The first three of these four herbs significantly reduced body weight of rats upon their oral incubation. Moreover, tuber fleeceflower root and parasitic loranthus significantly reduced food intake in rats. These results indicate that many of weight reducing herbs used in TCM do so by inhibiting FAS. They also hold promise for the development of new nontoxic and low cost weight reducing substances from these herbs.


Molecular analysis of the gene encoding an antigenic polypeptide of Trichinella spiralis infective larvae.
The gene encoding an antigenic polypeptide of Trichinella spiralis infective larvae was studied using recombinant DNA techniques. cDNA synthesized from poly(A)-rich mRNA from T. spiralis infective larvae was ligated into phage vector lambda gt11 DNA and packaged in vitro. The phages were propagated on Escherichia coli and a lambda gt11 expression library was constructed. A cDNA clone encoding a 46 kDa antigenic polypeptide was selected by immunoscreening of the library and identified by the epitope selection method. A clone containing nearly full-length cDNA for a 46 kDa protein was isolated. The gene encoding this 46 kDa antigenic polypeptide was characterized by DNA and RNA blot analysis using the cDNA as a probe. The gene was transcribed to mRNA with approximately 1400 nucleotides and translated to 46 kDa polypeptide. The antigenic polypeptide was excreted/secreted as a 46 kDa native antigen. The antigenic beta-galactosidase fusion protein synthesized by bacteria had no cross-reactivity with other parasite-infected sera.


The exciting "bench to bedside" journey of cell therapies for acute kidney injury and renal transplantation.
Acute kidney injury (AKI) is characterized by an increasing incidence and poor outcomes in both developed and undeveloped countries. AKI is also acquiring importance in the setting of kidney transplantation (KT): besides all the classical forms of AKI that KT patients may undergo, several transplant-specific injuries can also lead to the loss of graft function. The mechanisms of tissue damage in native and grafted kidneys share several common pathogenic elements. Since appropriate therapeutic treatments are still lacking-probably due to the disease complexity-clinicians are forced to provide only supportive care. In this composite scenario, cell therapies represent an evolving frontier for AKI treatment in native and transplanted kidneys: ex-vivo manipulated stem or immune cells are able to counteract renal dysfunction by a wide range of biological mechanisms. In this review, we will discuss the potential applications of cell therapies in AKI and KT by analyzing the available clinical data and the most promising experimental prospects from a "bench to bedside" perspective.


Rate of increase and critical amount of nuclear polyhedrosis virus in lepidopterous larvae estimated from survival time assay data with a birth-death model.
A birth-death model developed for pathogens of vertebrates was used to estimate the in vivo rate of increase (alpha) and the doubling time (td) from survival time assay data. Host-pathogen combinations used in this study were two Autographa californica nuclear polyhedrosis virus isolates in Trichoplusia ni and Heliothis zea NPV in H. zea. The alpha's, estimated as he negative reciprocal of the slope of the linearly decreasing section of the plot of median survival times against the logarithm of inoculum concentration, were calculated in two ways. First, simple regression was used to fit a line through the linearly decreasing part using data points selected by eye; secondly, a three-phase segmented linear regression model was used and alpha was estimated from the slope of the middle segment. Estimates of alpha (and td) were 0.338 (2.05), 0.274 (2.53) and 0.243 h-1 (2.85 h) using the simple regression method, and 0.385 (1.80), 0.305 (2.27) and 0.223 h-1 (3.11 h) using the 3-phase segmented linear regression model for AcMNPV-1A, AcMNPV-HOB and HzSNPV, respectively. Although AcMNPV-HOB killed larvae faster (6 to 13 h) than AcMNPV-1A, it multiplied more slowly. Estimates for the critical number ranged from 4.8 x 10(9) to 4.5 x 10(14) genome copies for HzSNPV in H. zea larvae and AcMNPV-1A in T. ni larvae, respectively. The significance of the calculated critical numbers is discussed.


Early interactions between fully virulent Bacillus anthracis and macrophages that influence the balance between spore clearance and development of a lethal infection.
The role of macrophages in the pathogenesis of anthrax is unresolved. Macrophages are believed to support the initiation of infection by Bacillus anthracis spores, yet are also sporicidal. Furthermore, it is believed that the anthrax toxins suppress normal macrophage function. However, the significance of toxin effects on macrophages has not been addressed in an in vivo infection model. We used mutant derivatives of murine macrophage RAW264.7 cells that are toxin receptor-negative (R3D) to test the role of toxin-targeting of macrophages during a challenge with spores of the Ames strain of B. anthracis in both in vivo and in vitro models. We found that the R3D cells were able to control challenge with Ames when mice were inoculated with the cells prior to spore challenge. These findings were confirmed in vitro by high dose spore infection of macrophages. Interestingly, whereas the R3D cells provided a significantly greater survival advantage against spores than did the wild type RAW264.7 cells or R3D-complemented cells, the protection afforded the mutant and wild type cells was equivalent against a bacillus challenge. The findings appear to be the first specific test of the role of toxin targeting of macrophages during infection with B. anthracis spores.


Improving the quality of the evidence - The necessity to lead by example.
Published systematic reviews and meta-analyses should comply with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses, or PRISMA checklist. Variable reporting of systematic reviews has recently led to a number of publications demonstrating a lack of compliance with PRISMA. Poor reporting compliance can lower researchers' and clinicians' ability to detect bias in published research and can also lead to impaired clinical decision-making. The authors of this paper support the need for greater adherence to PRISMA standards when preparing systematic reviews and meta-analyses for publication and call on researchers who are drawing attention to this problem to lead by example.


Phenylephrine versus cafedrine/theodrenaline (Akrinor) for the treatment of spinal anaesthesia-induced maternal hypotension during caesarean section: a retrospective single-centre cohort study.
The main objective of this study was to assess the impact of phenylephrine and cafedrine/theodrenaline on the mother and newborn after spinal anaesthesia for caesarean section. University teaching hospital. A single-centre retrospective data cohort study. All obstetric patients who were scheduled for caesarean section in a 2-year period. Administration of either intravenous phenylephrine prophylactically or cafedrine/theodrenaline (Akrinor) reactively to maintain blood pressure after spinal anaesthesia. Maternal hypotension, heart rate during caesarean section and after admission to IMC, fetal arterial cord pH and base excess levels, maternal volume resuscitation and the use of rescue medication. 852 data sets could be included: n=440 Akrinor, n=412 in the phenylephrine cohort. During caesarean section blood pressure was slightly higher in the phenylephrine group compared with the Akrinor group, while hypotension <100 mm Hg systolic blood pressure (SBP) occurred significantly more often during arrival at the IMC after surgery when phenylephrine was used. Heart rate was lower and rescue medication was significantly more frequently given in the phenylephrine cohort. Irrespective of the medication used, women with baseline levels of <120 mm Hg SBP had a high risk to develop hypotension <100 mm Hg after spinal anaesthesia for caesarean section. While there was no statistical difference in mean umbilical arterial pH levels, the incidence of acidosis, defined as pH <7.2, was significantly higher with phenylephrine. Phenylephrine was not superior to Akrinor to treat spinal anaesthesia-induced maternal hypotension during caesarean section. DRKS00025795.


Relative heritage language and majority language use before school start explains variance in 2nd grade majority language but not reading skills.
The present study examined whether parents' and bilingual children's own relative use of the heritage language vs. the majority language in the homes of bilingual children in Denmark before school start explains variance in 2nd grade majority language skills and reading skills. The study included two groups of children: the Mixed bilinguals group (defined by having a native Danish and a nonnative parent, N = 376) and the Heritage bilinguals group (defined by having parents who were both speakers of a Heritage language, N = 276). Four-stage hierarchical regression analyses showed that, after accounting for type of bilingualism, socioeconomic status (SES) and home literacy environment quality, relative use of the heritage vs. the majority language explained variance in 2nd grade Danish language comprehension scores, but did not explain variance in two reading scores, namely decoding and reading comprehension. In addition, a home literacy factor denoting book exposure (number of books, frequency of reading, library visits, and age of beginning shared book reading) was a significant predictor of both 2nd grade language and reading outcomes, whereas SES became a nonsignificant predictor when adding home literacy and language use predictors. We interpret the results to mean that parents' and the child's own relative use of the heritage language vs. the majority language before school start does not influence bilingual children's early reading skills, whereas a supportive early home literacy environment is a positive predictor of reading skills independently of SES and parental majority language use and skill.


Ankle arthroscopy: neurovascular and arthroscopic anatomy of standard and trans-achilles tendon portal placement.
Ankle arthroscopy is an accepted method of evaluating ankle disorders. Accurate arthroscopic portal placement is essential because of the proximity of superficial and deep neurovascular and tendinous structures of the ankle. In order to define this anatomy as it pertains to safe portal placement, five fresh frozen cadaver ankles were dissected after standard arthroscopic portals were placed anteriorly and posteriorly. All structures were identified. The distances to these structures from the most lateral portals were recorded. Five other ankles were arthroscoped using standard portals and evaluated. In addition, a trans-achilles tendon (TAT) approach was evaluated for portal use. Ankle arthroscopy can be performed in a safe, reproducible manner when the following recommendations are followed: (a) outline tendinous structures, and remain parallel to them with the knife blade to avoid laceration of underlying structures; (b) penetrate only the skin with the knife to avoid laceration of superficial nerves in the subcutaneous tissue; (c) perform pre- and postneurovascular examination; and (d) understand that anterocentral and posteromedial portals are potentially hazardous to their respective neurovascular bundles. The TAT approach, based only on cadaver studies, appears anatomically safe and offers the potential advantage of an additional posterior portal.


Management of a dislocated intraocular lens with a suction-based grasping tool.
Spontaneous late subluxation of an intraocular lens (IOL) is a rare but serious complication of cataract surgery, often associated with poor zonular support. The management of this complication with a conventional forceps is difficult because the forceps often cannot adequately grasp the optic or haptic to fixate the IOL to the sclera or iris or remove it. The new suction-based grasping tool has a suction cup at the end. The combination of a suction vector and the use of a set of specially designed suction tips allow grasping and stabilization of the subluxated IOL. The properties of the suction-based grasping tool provide better control of the subluxated IOL, simplifying the management of these challenging cases. Drs. Olson and Mackenzie have a patent application pending for the disclosed device. No other author has a financial or proprietary interest in any material or method mentioned.


Effect of 80% ethanol or 10% formalin fixation, freezing at -20 °C and staining on Myxobolus (Myxosporea) spores to be deposited in parasitological collections.
The preparation of myxosporeans for the description of myxospores and their preservation as type material in parasitological collections show great variations. Most frequently, formalin and ethanol are used for fixation and Giemsa solution for staining spores. In this work, authors studied the effect of 80% ethanol and 10% formalin fixation, freezing at -20 °C and staining on the size and transparency of two Myxobolus species of cyprinid fishes, M. bramae and M. bliccae spore, and recommended a new method for the deposition of type material to parasitological collections in museums. The studies have commended that fresh spores from mature plasmodia are the best material for measuring the size and studying the inner structures, the number of polar tubules in polar capsules and the morphological characters of the intercapsular appendix. The obtained quantitative data suggest that cryo- and chemical preservation do not have a notable negative effect on spores compared to fresh samples but they decrease the transparency of spores. Staining the spores with Ziehl-Neelsen has proved to be a useful method for studying the fine structure without size reduction, while Giemsa staining induced a shrinkage of spores so it seems to be not ideal for description of a new species. When treating spores of Myxobolus spp. with Lugol's solution, iodinophilous vacuoles in the sporoplasm were not recognised but visualisation of the coils of polar tubules was enhanced. As a type material for newly described species, authors suggest phototypes and spores fixed in 80% ethanol to be deposited into collections, as this preservation method is suitable for subsequent research, such as re-measurements and molecular analysis.


The solution structure of EMILIN1 globular C1q domain reveals a disordered insertion necessary for interaction with the alpha4beta1 integrin.
The extracellular matrix protein EMILIN1 (elastin microfibril interface located protein 1) is implicated in maintaining blood pressure homeostasis via the N-terminal elastin microfibril interface domain and in trophoblast invasion of the uterine wall via the globular C1q (gC1q) domain. Here, we describe the first NMR-based homology model structure of the human 52-kDa homotrimer of the EMILIN1 gC1q domain. In contrast to all of the gC1q (crystal) structures solved to date, the 10-stranded beta-sandwich fold of the gC1q domain is reduced to nine beta strands with a consequent increase in the size of the central cavity lumen. An unstructured loop, resulting from an insertion unique to EMILIN1 and EMILIN2 family members and located at the trimer apex upstream of the missing strand, specifically engages the alpha4beta1 integrin. Using both Jurkat T and EA.hy926 endothelial cells as well as site-directed mutagenesis, we demonstrate that the ability of alpha4beta1 integrins to recognize the trimeric EMILIN1 gC1q domain mainly depends on a single glutamic acid residue (Glu(933)). Static and flow adhesion of T cells and haptotactic migration of endothelial cells on gC1q is fully dependent on this residue. Thus, EMILIN1 gC1q-alpha4beta1 represents a unique ligand/receptor system, with a requirement for a 3-fold arrangement of the interaction site.


How research ethics' protections can contribute to public policy: the case of community treatment orders.
Though community treatment orders (CTOs) were first used in 1986 in Australia, debate about their clinical and ethical merits continues even today. For some, the benefits of reduced frequency and duration of involuntary hospitalizations are believed to adequately outweigh the harms of restricted liberties in community living. For others, however, such benefits are believed to be achievable by simply arranging integrated, devoted community resources sans any threat of forced re-hospitalization. In response to this enduring controversy, this article examines the ethical merits of community orders using a novel approach. "Novel" because the examination is based on research ethics and its foundational principles. When hospital and community clinicians, family members, consumer/survivors, and advocacy groups discussed the idea of amending Ontario's mental health legislation to permit CTOs in the late 1990s, evidence of their effects and efficacy was very limited. Moreover, an order was characterized much like standard pharmacological or medical therapies because the person or an appropriate substitute decision maker's consent was necessary to authorize the order or make it valid. These two factors prompted this retrospective analysis: if CTOs--as a public policy initiative--had been treated like most other promising therapies, would any different ethics-related concerns have been raised that, in turn, would have benefited the public debate and the legislature's decisions? In other words, if respected safeguards that apply to new drugs and medical devices had applied to CTOs, would anything have changed?


Anticancer efficacy of monotherapy with antibodies to SIRPα/SIRPβ1 mediated by induction of antitumorigenic macrophages.
The interaction of signal regulatory protein α (SIRPα) on macrophages with CD47 on cancer cells is thought to prevent antibody (Ab)-dependent cellular phagocytosis (ADCP) of the latter cells by the former. Blockade of the CD47-SIRPα interaction by Abs to CD47 or to SIRPα, in combination with tumor-targeting Abs such as rituximab, thus inhibits tumor formation by promoting macrophage-mediated ADCP of cancer cells. Here we show that monotherapy with a monoclonal Ab (mAb) to SIRPα that also recognizes SIRPβ1 inhibited tumor formation by bladder and mammary cancer cells in mice, with this inhibitory effect being largely dependent on macrophages. The mAb to SIRPα promoted polarization of tumor-infiltrating macrophages toward an antitumorigenic phenotype, resulting in the killing and phagocytosis of cancer cells by the macrophages. Ablation of SIRPα in mice did not prevent the inhibitory effect of the anti-SIRPα mAb on tumor formation or its promotion of the cancer cell-killing activity of macrophages, however. Moreover, knockdown of SIRPβ1 in macrophages attenuated the stimulatory effect of the anti-SIRPα mAb on the killing of cancer cells, whereas an mAb specific for SIRPβ1 mimicked the effect of the anti-SIRPα mAb. Our results thus suggest that monotherapy with Abs to SIRPα/SIRPβ1 induces antitumorigenic macrophages and thereby inhibits tumor growth and that SIRPβ1 is a potential target for cancer immunotherapy.


The Nature and Meaning of Body Concepts in Everyday Language and Theoretical Discourse.
Within phenomenological philosophy four topics, (1) Body, (2) Time, (3) Others and the Social Order and (4) World serve as the major contexts in which human perception, action and reflection take place. At present only three of these domains have been studied from an empirical perspective, leaving Body as the one domain requiring further analysis. Given this state of affairs, the purpose of the present study is to determine the everyday and theoretical meanings of body. To accomplish this task participants coded randomly selected body- related words into groups on the basis of having similar meanings. Once these groupings were established they were then evaluated by statistical clustering and multidimensional scaling procedures. Results indicated that it was possible to define the everyday meaning of the human experience of the human body in terms of the following set of themes: (1) inside/outside, (2) visible/not visible, (3) vitality and activity, (4) instrument and object and (5) appearance and self-expression. Concerns about the representativeness of the words studied led to the development and use of individual word pools from which a set of 50 partially different words was randomly selected for each participant. Results indicated little difference between themes produced in the present study when compared with those of an earlier study. The specific themes derived from the present study were then related to embodiment issues as reflected in the philosophical writings of Merleau-Ponty, the psycholinguistic analyses of Lakoff and Johnson and experimental psychology.


Mental health of gatekeepers may influence their own attitudes toward suicide: A questionnaire survey from a suicide-prevention gatekeeper training program.
We aimed to investigate the association between general mental health and attitudes toward suicide of participants in suicide-prevention gatekeeper training programs. We conducted a number of half day training seminars within a suicide prevention program addressing gatekeepers. Participants filled in two questionnaires, one measuring general health (General Health Questionnaire, GHQ-12), and one measuring attitudes towards suicide (ATTS). The total sample size of participants was 230, of whom 115 completed questionnaires. There were no significant differences in demographic backgrounds between the good mental health (GHQ-12 ≤ 4) and the poor mental health (GHQ-12 ≥ 5) groups. The poor mental health group was more likely to think that people have the right to commit suicide. There was a difference in attitudes toward suicide between the good mental health and the poor mental health groups, indicating that attention should be paid to participants' mental health when conducting suicide-prevention gatekeeper training.


Regional cerebral blood flow for singers and nonsingers while speaking, singing, and humming a rote passage.
Two groups of singers (n = 12,13) and a group of nonsingers (n = 12) each produced the national anthem by (1) speaking and (2) singing the words and by (3) humming the melody. Regional cerebral blood flow (rCBF) was measured at rest and during each phonation task from seven areas in each hemisphere by the 133Xe-inhalation method. Intrahemisphere, interhemisphere, and global rCBF were generally similar across phonation tasks and did not yield appreciable differences among the nonsingers and the singers.


Changing epidemiology of intussusception in Australia.
Oral rotavirus vaccines are expected to become available in Australia within the next 2 years. In light of evidence for an association between a rotavirus vaccine and intussusception, it is important to define the baseline epidemiology of intussusception in Australia and establish a system for intussusception surveillance in the immediate post-licensure period. This study reports on incidence and epidemiology of intussusception in Australia. Data were obtained from the Australian Institute of Health and Welfare on all patients with a discharge diagnosis of intussusception from public and private hospitals in each state and territory of Australia from 1994 to 2000. We examined age at presentation, sex, month and year of presentation, indigenous status and clinical outcomes. The incidence of intussusception was calculated and annual trends examined. Surveillance data on rotavirus gastroenteritis hospitalizations over the same time period were also obtained to compare seasonal patterns. From 1994 to 2000, a 39% reduction in intussusception incidence in infants aged <1 year was observed in Australia (13.1/10,000 to 8.1/10,000; P < 0.001). The incidence of intussusception was lower in indigenous infants (3.3/10,000 <1 year) compared to non-indigenous infants (10.4/10,000 <1 year; P < 0.001). There was no association between the seasonality of rotavirus infection and intussusception. Only one of 12 deaths due to intussusception was reported in an infant <1 year. This study documents the epidemiology of intussusception in Australia from 1994 to 2000 and provides important baseline information for future rotavirus vaccines. A lower risk of intussusception was identified in indigenous compared to non-indigenous infants.


Lactobacillus plantarum-derived metabolites sensitize the tumor-suppressive effects of butyrate by regulating the functional expression of SMCT1 in 5-FU-resistant colorectal cancer cells.
A critical obstacle to the successful treatment of colorectal cancer (CRC) is chemoresistance. Chemoresistant CRC cells contribute to treatment failure by providing a mechanism of drug lethargy and modifying chemoresistance-associated molecules. The gut microbiota provide prophylactic and therapeutic effects by targeting CRC through anticancer mechanisms. Among them, Lactobacillus plantarum contributes to the health of the host and is clinically effective in treating CRC. This study confirmed that 5-fluorouracil (5-FU)-resistant CRC HCT116 (HCT116/5FUR) cells acquired butyrate-insensitive properties. To date, the relationship between 5-FU-resistant CRC and butyrate resistance has not been elucidated. Here, we demonstrated that the acquisition of butyrate resistance in HCT116/5FUR cells was strongly correlated with the inhibition of the expression and function of SMCT1, a major transporter of butyrate in colonocytes. L. plantarum-cultured cell-free supernatant (LP) restored the functional expression of SMCT1 in HCT116/5FUR cells, leading to butyrate-induced antiproliferative effect and apoptosis. These results suggest that LP has a synergistic effect on the SMCT1/butyrate-mediated tumor suppressor function and is a potential chemosensitizer to overcome dual 5-FU and butyrate resistance in HCT116 cells.


Drugs for psychosis and mood: unique actions at D3, D2, and D1 dopamine receptor subtypes.
Drugs for psychosis and mood that bind dopamine D2 receptors can be classified not only by whether they also block serotonin 2A receptors, but by whether they also bind D3 or D1 receptors.


Familial carcinoma of ureters and other genitourinary organs.
We report on a woman, her mother and her mother's cousin who had papillary transitional cell carcinoma of the ureter associated with other cancers of the genitourinary tract. Neoplasms in these family members may be due to interactions between host susceptibility factors and exposure to environmental carcinogens. Studies of peripheral blood karyotype and urine mutagenic activity yielded normal results.


Two-step ligand binding and cooperativity. A model to describe the cooperative binding of myosin subfragment 1 to regulated actin.
The binding of actin to myosin subfragment 1 (S1) has been shown to occur as a two-step reaction. In the first step actin is weakly bound and then the complex isomerizes to the "rigor type" acto-S1 complex (Coates, J. H., A. H. Criddle, and M. A. Geeves, 1985 Biochem. J., 232:351-356). We propose here a model in which troponin/tropomyosin (Tn/Tm) controls the actin-S1 interaction by inhibiting the isomerization step. In this model the (actin)7 Tn/Tm unit is assumed to exist in two states: open and closed. S1 can bind to either of the two states but only the open form allows the isomerization reaction to take place. We demonstrate that this model can account for the cooperative binding of S1 and S1 nucleotide complexes to actin. The model provides a way of integrating both the effects of calcium and nucleotide on actin-S1 interactions.


An update on migraine: current understanding and future directions.
Migraine is a common brain disorder with high disability rates which involves a series of abnormal neuronal networks, interacting at different levels of the central and peripheral nervous system. An increase in the interest around migraine pathophysiology has allowed researchers to unravel certain neurophysiological mechanisms and neurotransmitter involvement culminating in the recent development of novel therapies, which might substantially change the clinical approach to migraine patients. The present review will highlight the current aspects of migraine pathophysiology, covering an understanding of the complex workings of the migraine state and the brain regions responsible for them. We will further discuss the therapeutic agents which have appeared in the most recent years for migraine care, from calcitonin gene-related peptide (CGRP) receptor antagonists, gepants; through serotonin 5-HT1F receptor agonists, ditans, and CGRP or CGRP receptor monoclonal antibodies to invasive and non-invasive neuromodulation techniques.


Tropical parabiotic ants: Highly unusual cuticular substances and low interspecific discrimination.
Associations between animal species require that at least one of the species recognizes its partner. Parabioses are associations of two ant species which co-inhabit the same nest. Ants usually possess an elaborate nestmate recognition system, which is based on cuticular hydrocarbons and allows them to distinguish nestmates from non-nestmates through quantitative or qualitative differences in the hydrocarbon composition. Hence, living in a parabiotic association probably necessitates changes of the nestmate recognition system in both species, since heterospecific ants have to be accepted as nestmates. In the present study we report highly unusual cuticular profiles in the parabiotic species Crematogaster modiglianii and Camponotus rufifemur from the tropical rainforest of Borneo. The cuticle of both species is covered by a set of steroids, which are highly unusual surface compounds. They also occur in the Dufour gland of Crematogaster modiglianii in high quantities. The composition of these steroids differed between colonies but was highly similar among the two species of a parabiotic nest. In contrast, hydrocarbon composition of Cr. modiglianii and Ca. rufifemur differed strongly and only overlapped in three regularly occurring and three trace compounds. The hydrocarbon profile of Camponotus rufifemur consisted almost exclusively of methyl-branched alkenes of unusually high chain lengths (up to C49). This species occurred in two sympatric, chemically distinct varieties with almost no hydrocarbons in common. Cr. modiglianii discriminated between these two varieties. It only tolerated workers of the Ca. rufifemur variety it was associated with, but attacked the respective others. However, Cr. modiglianii did not distinguish its own Ca. rufifemur partner from allocolonial Ca. rufifemur workers of the same variety. We conclude that there is a mutual substance transfer between Cr. modiglianii and Ca. rufifemur. Ca. rufifemur actively or passively acquires cuticular steroids from its Cr. modiglianii partner, while the latter acquires at least two cuticular hydrocarbons from Ca. rufifemur. The cuticular substances of both species are highly unusual regarding both substance classes and chain lengths, which may cause the apparent inability of Cr. modiglianii to discriminate Ca. rufifemur nestmates from allocolonial Ca. rufifemur workers of the same chemical variety.


Diuretics, beta-blockers, and the risk for sudden cardiac death in hypertensive patients.
To determine whether the use of non-potassium-sparing diuretics and beta-blockers is associated with an excess risk for sudden cardiac death in hypertensive patients. Case-control study. Rotterdam, the Netherlands. 257 case-patients who had died suddenly while receiving drug therapy for hypertension and 257 living controls also receiving drug therapy for hypertension. Detailed information on medication use and clinical characteristics of all case-patients and controls was collected from the files of general practitioners. Additional information on medication use was obtained from computerized pharmacy records. Patients receiving non-potassium-sparing diuretics had an increased risk for sudden cardiac death (relative risk, 1.8 [95% CI, 1.0 to 3.1]) compared with a reference group treated primarily with potassium-sparing diuretics. The corresponding relative risk for beta-blocker use was 1.7 (CI, 1.1 to 2.6). The use of non-potassium-sparing diuretics without beta-blockers was associated with a higher risk for sudden death (relative risk, 2.2 [CI, 1.1 to 4.6]) than was concomitant use of non-potassium-sparing diuretics and beta-blockers (relative risk, 1.4 [CI, 0.6 to 3.0]). The risk for sudden cardiac death among recipients of non-potassium-sparing diuretics was more pronounced in those who had been receiving the diuretic for less than 1 year and in those aged 75 years or younger. The use of non-potassium-sparing diuretics and beta-blockers is associated with an increased risk for sudden cardiac death. This association may offset part of the mortality benefit of these drugs in the treatment of hypertension.


Stachybotrys: An unusual mold associated with water-damaged buildings.
Chemical analyses of extracts of cultures ofS. chartarum show that this fungus has two chemotypes: producers of the potent cytotoxic macrocyclic trichothecenes (e. g. satratoxins) and those that produce the diterpenoid atranones and the simple trichothecenes, trichodermol and trichodermin. All isolates ofS. chartarum produce the immunosuppressant spirocyclic drimanes.


Mutational analysis of the Bacillus subtilis purA operator site.
The Bacillus subtilis purine repressor, PurR, regulates many genes involved in purine metabolism. These genes contain a conserved 14-nucleotide inverted repeat (PurBox). Both pur operon and purA, which are regulated by PurR, have this inverted repeat with a 16- or 17-nucleotide spacer, respectively. Mutational studies have earlier shown that PurR binding is dependent on the PurBox of pur operon. In contrast, these studies failed to establish the importance of purA PurBox to PurR binding. To examine this inconsistency, we studied the effects of PurBox mutations both in vivo and in vitro. The data presented here indicate that purA PurBox has a similar role as pur operon PurBox in PurR binding. In addition, our data suggest that the previously proposed classification of the two halves of the Purbox into weak and strong may need to be revised.


An MMP-degraded and cross-linked fragment of type III collagen as a non-invasive biomarker of hepatic fibrosis resolution.
Liver fibrosis results from a prolonged wound healing response to continued injury with excessive production of extracellular proteins. In patients with chronic liver disease, the monitoring of liver fibrosis dynamics is of high interest. Whilst markers of fibrogenesis exist, markers of hepatic fibrosis resolution remain an unmet clinical need. Thus, we sought to develop an assay quantifying a circulating proteolytic fragment of cross-linked type III collagen as a biomarker of fibrolysis, testing its utility in two clinical cohorts of liver fibrosis of distinct aetiology and regressing endotype METHODS: We used a monoclonal antibody targeting the C-telopeptide of type III collagen following C-proteinase cleavage to develop and validate a neo-epitope-specific enzyme-linked immunosorbent assay (CTX-III). A potential fibrosis resolution marker, CTX-III, was measured in two clinical cohorts of patients with obesity-associated non-alcoholic fatty liver disease undergoing bariatric surgery or hepatitis C virus infection from a clinical trial study evaluating the anti-fibrotic effect of farglitazar. CTX-III was robust and specific for the targeted neo-epitope with good reproducibility in EDTA plasma. We assessed type III collagen remodelling using a panel of biomarkers, including a type III collagen formation marker (PRO-C3), degradation (C3M), and CTX-III (fibrolysis). Net fibrolysis was increased in patients with non-alcoholic fatty liver disease following bariatric surgery (p < .001). Moreover, net fibrolysis identified spontaneous fibrotic regressors from stable and progressors (p < .05 and p < .001) among hepatitis C virus infection patients. Circulating CTX-III as a marker of fibrolysis indicates the biomarker's beneficial use in assessing hepatic fibrosis resolution.


Bioequivalence (bioavailability) of generic topical corticosteroids.
A new, quantitative modification of the vasoconstrictor assay was used to measure bioavailability of generic topical corticosteroid products in two categories: betamethasone valerate 0.1% cream and triamcinolone 0.1% cream. Betamethasone valerate products could be separated into two distinct categories, and triamcinolone acetonide products could be grouped into three categories of activity. A survey of local pharmacies showed that generic substitution would be made for the prescribed brand of betamethasone valerate in 58% of cases and for the prescribed triamcinolone acetonide 75% of the time. Because of the prevalence of generic substitution of products that may not have equivalent bioavailability, some standardization of the bioavailability of topical products is needed.


Histological discrimination of malignancy in mucinous ovarian tumours.
Eight histological features were measured quantitatively in a group of 77 ovarian mucinous carcinomas and a group of 28 benign mucinous cystomas. These were compared with the duration of survival of the patients and the clinical staging of the tumours. Using the method of discriminant function analysis it was possible to identify a group of tumours of 'borderline malignancy'. Although single histological features were inadequate indicators of prognosis a combination of three features proved fairly accurate.


Periodontitis, Helicobacter pylori infection, and gastrointestinal tract cancer mortality.
Periodontitis has been proposed to lead to Helicobacter pylori infection, which could cause many gastrointestinal tract cancers. This study aimed to determine the association or otherwise between periodontitis and survival outcomes in individuals with respect to H. pylori infection. The study population comprised 4955 subjects aged 20-90 who had received both periodontal examination and H. pylori serum test in the Third National Health and Nutrition Examination Survey (NHANES III) database. Logistic regression models were used to analyse the association between periodontitis and H. pylori seropositivity (H. pylori infection). Survival analysis was performed using the NHANES III linked to mortality data. Cox proportional hazard regression was carried out to investigate the association between periodontitis and gastrointestinal tract cancer mortality in individuals with/without H. pylori infection. Compared to periodontal health, periodontitis was significantly associated with increased odds of H. pylori infection (OR = 1.271, 95% CI = 1.177-1.372). Periodontitis significantly increased the mortality risk from all causes (HR = 1.574, 95% CI = 1.327-1.866) and all cancers (HR = 1.948, 95% CI = 1.701-2.232), including gastrointestinal (GI) tract cancer (HR = 4.140, 95% CI = 3.656-4.687), gastric cancer (HR = 4.288, 95% CI = 3.969-4.632), and colorectal cancer (HR = 4.814, 95% CI = 3.849-6.020) in subjects with H. pylori infection after adjusting for health-related factors. Periodontitis was significantly related to the decreased survival time in subjects with GI tract (p = .001) or colorectal cancer (p = .002) and H. pylori infection. Our study demonstrated that periodontitis was significantly associated with higher mortality risk of GI tract, gastric, and colorectal cancer in subjects with H. pylori infection. Owing to an interactive effect between periodontitis and H. pylori infection on cancer mortality, H. pylori infection has a significant moderating effect in regulating the association between periodontitis and mortality due to all cancers, including GI tract cancer and colorectal cancer.


Diagnostic Value of Vestibular Evoked Myogenic Potentials in Endolymphatic Hydrops: A Meta-Analysis.
In this study, we evaluated the clinical diagnostic value of vestibular evoked myogenic potentials (VEMPs) for endolymphatic hydrops (EH) by systematic review and Meta-analysis. The pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, diagnostic odds ratio and area under summary receiver operating characteristic curves (AUC) were calculated. Subgroup analysis and publication bias assessment were also conducted. The pooled sensitivity and the specificity were 49% (95% CI: 46% to 51%) and 95% (95% CI: 94% to 96%), respectively. The pooled positive likelihood ratio was 18.01 (95% CI: 9.45 to 34.29) and the pooled negative likelihood ratio was 0.54 (95% CI: 0.47 to 0.61). AUC was 0.78 and the pooled diagnostic odds ratio of VEMPs was 39.89 (95% CI: 20.13 to 79.03). In conclusion, our present meta-analysis has demonstrated that VEMPs test alone is not sufficient for Meniere's disease or delayed endolymphatic hydrops diagnosis, but that it might be an important component of a test battery for diagnosing Meniere's disease or delayed endolymphatic hydrops. Moreover, VEMPs, due to its high specificity and non-invasive nature, might be used as a screening tool for EH.


Molecular cloning of FKHRL1P2, a member of the developmentally regulated fork head domain transcription factor family.
Here we report the expression of a fork head domain protein in human T helper cells. We cloned and characterized a fork head cDNA from human T helper cell mRNA using differential display RT-PCR. The cDNA contains a 546-nucleotide (nt) open reading frame (ORF) that codes for the carboxyl-terminal 180 amino acids (aa) of the recently identified fkhrl1 gene. This ORF does not contain the characteristic DNA-binding domain found in members of the forkhead protein family. In-vitro transcription/translation of this cDNA expressed a protein of approximately 20 kDa. We have generated antibodies that specifically immunoprecipitated the in-vitro-translated 20-kDa protein. This antibody also recognizes in human T lymphocytes a 70-kDa protein corresponding in size to that predicted for the fkhrl1 gene product. The mRNA levels for fkhrl1 is elevated in T helper-induced lymphocytes in comparison to PHA-stimulated T lymphocytes. Further characterization of FKHRL1 and its related family members should shed light on the transcriptional mechanisms of this fork head gene subfamily and their role in T helper cell differentiation and regulation of cell growth.


Hodgkin's disease with lymphocytic predominance, nodular type (nodular paragranuloma) and progressively transformed germinal centres--a cytohistological study.
The histology, cytology, and enzyme cytochemistry of a nodular variant of Hodgkin's disease with lymphocytic predominance, called 'nodular paragranuloma', are presented. The histological features of nodular paragranuloma are compared with those of progressively transformed germinal centres, which are enlarged follicles showing a predominance of small lymphocytes and some residual germinal centre cells. Progressively transformed germinal centres are sometimes found in nonspecific lymphadenitis (reactive hyperplasia). The histological similarity and the association between lymph nodes with nodular paragranuloma and lymph nodes with progressively transformed germinal centres in the same patient at different moments or at the same time, suggest that progressively transformed germinal centres are the origin of nodular paragranuloma. Hence, it must be concluded that nodular paragranuloma takes place in B-cell areas of the lymph node, unlike the other, or at least most of the other, types of Hodgkin's disease.


Utilization of Endovascular and Surgical Treatments for Symptomatic Uterine Leiomyomas: A Population Health Perspective.
To conduct a population-level analysis of surgical and endovascular interventions for symptomatic uterine leiomyomata by using administrative data from outpatient medical encounters. By using administrative data from all outpatient hospital encounters in California (2005-2011) and Florida (2005-2014), all patients in the outpatient setting with symptomatic uterine leiomyomata were identified. Patients were categorized as undergoing hysterectomy, myomectomy, uterine artery embolization (UAE), or no intervention. Hospital stay durations and costs were recorded for each encounter. A total of 227,489 patients with uterine leiomyomata were included, among whom 39.9% (n = 90,800) underwent an intervention, including hysterectomy (73%), myomectomy (19%), or UAE (8%). The proportion of patients undergoing hysterectomy increased over time (2005, hysterectomy, 53.2%; myomectomy, 26.9%; UAE, 18.0%; vs 2013, hysterectomy, 80.1%; myomectomy, 14.4%; UAE, 4.0%). Hysterectomy was eventually performed in 3.5% of patients who underwent UAE and 4.1% who underwent myomectomy. Mean length of stay following hysterectomy was significantly longer (0.5 d) vs myomectomy (0.2 d) and UAE (0.3 d; P < .001 for both). The mean encounter cost for UAE ($3,772) was significantly less than those for hysterectomy ($5,409; P < .001) and myomectomy ($6,318; P < .001). Of the 7,189 patients who underwent UAE during the study period, 3.5% underwent subsequent hysterectomy. The proportion of women treated with hysterectomy in the outpatient setting has increased since 2005. As a lower-cost alternative with a low rate of conversion to hysterectomy, UAE may be an underutilized treatment option for patients with uterine leiomyomata.


An azine based sensor for selective detection of Cu2+ ions and its copper complex for sensing of phosphate ions in physiological conditions and in living cells.
A simple and cost effective unsymmetrical azine based Schiff base, 5-diethylamino-2-[(2-hydroxy-benzylidene)hydrazonomethyl]-phenol (1) was synthesized which selectively detect Cu2+ ions in the presence of other competitive ions through "naked eye" in physiological conditions (EtOH-buffer (1:1, v/v, HEPES 10mM, pH=7.4)). The presence of Cu2+ induce color change from light yellow green to yellow with the appearance of a new band at 450nm in UV-Vis spectra of Schiff base 1. The fluorescence of Schiff base 1 (10μM) was quenched completely in the presence of 2.7 equiv. of Cu2+ ions. Sub-micromolar limit of detection (LOD=3.4×10-7M), efficient Stern-Volmer quenching constant (KSV=1.8×105Lmol-1) and strong binding constant (log Kb=5.92) has been determined with the help of fluorescence titration profile. Further, 1-Cu2+ complex was employed for the detection of phosphate ions (PO43-, HPO42- and H2PO4-) at micromolar concentrations in EtOH-buffer of pH7.4 based on fluorescence recovery due to the binding of Cu2+ with phosphate ions. Solubility at low concentration in aqueous medium, longer excitation (406nm) and emission wavelength (537nm), and biocompatibility of Schiff base 1 formulates its use in live cell imaging.


COVID-19 pandemic impact on primary immunization uptake.
Pediatricians across the world are seeing a steep drop in the number of children coming in for appointments due to COVID-19 pandemic. To prevent outbreaks of serious diseases that pose an even greater threat to children than COVID-19, it is important that children not skip their routine vaccines. The aim of this study was to determine the impact of COVID-19 pandemic on primary immunization activities in Saudi Arabia. Cross-sectional design. The study was conducted at a community pediatric clinic. All parents of preschool-age children who visited the community pediatric clinics were asked to complete a self-administrated questionnaire on primary immunization uptake during the pandemic. The Chi-square and Fisher's exact test were performed to examine the demographic differences between participants who missed vaccination during the pandemic and reasons for missing the vaccination. Three hundred study participants completed our questionnaire. In total, 90.6% of respondents were up to date with their vaccinations prior to the pandemic, and most respondents believed that children should be immunized at an appropriate age, it is essential for children to be fully immunized, vaccination is effective in preventing serious disease, and childhood immunization is essential during the pandemic (98.3%, 98.7%, 97.3%, and 93.7%, respectively). In total, 72.4% of respondents did not miss their vaccinations during the pandemic, while 26.6% missed vaccinations. The most common reason for missing vaccinations during the pandemic was transportation difficulty and curfew, followed by fear of contracting COVID-19 infection (40.9% and 35.5%, respectively). Those who did not believe that childhood immunization was necessary during the pandemic were more likely to miss vaccinations during the pandemic (P < 0.001). In addition, those who did not have a family member with COVID-19 infection were more likely not to miss the vaccine (P < 0.001). Moreover, those who thought taking vaccinations in a primary care setting or hospital is safe were more likely not to miss the vaccination during the pandemic (P < 0.027) and (P < 0.001). Significant portion of the population was affected and missed immunizations during the pandemic. The perceptions on the importance of immunization and having a family member affected with COVID-19 during the pandemic were important factors in missing immunizations. Moreover, transportation and fear of contracting COVID-19 during the curfew were also common reasons for missing immunizations during the pandemic.


Comparison of six display modes for a multi-resolution foveated laparoscope.
To overcome the field of view and ergonomic limitations of standard laparoscopes, we are developing a multi-resolution foveated laparoscope that can simultaneously obtain both wide- and zoomed-in-view images through a single scope. To facilitate the effective access to the dual views of images with different resolution and field coverage acquired by our laparoscope, six different display modes have been developed. Each of the six display modes has inherent advantages and disadvantages. This study compares the six display modes through a human-subject experiment, which was conducted with an emulated laparoscope using a 4K camera. Twenty-four subjects without medicine background performed three evaluation trials of a touching task with each of the display modes. Various objective measurements including task completion time, the number of collisions, gaze position, and tooltip position, and subjective preference for the display modes were recorded. For all the measurements except for task completion time and moving speed of tooltip, there were statistically significant differences among the display modes. Although the focus plus warped context view mode was selected as one of the least preferred modes, it showed the best task performance. The unblocked wide context view was useful to provide a situational awareness even when it was severely distorted in some of the display modes, and information continuity played an important role in improving task performance. Moreover, the position change of viewing window coupled to the location of region of interest helped improve task performance, by providing an additional cue for spatial awareness.


[Prevention and management of dysfunction of prosthetic heart valves].
The ideal heart valve prosthesis has not been developed. The today available mechanical and biological prostheses are far from perfect concerning thrombogenesis, mechanical durability and hemodynamic performance. Failure of an implanted valve is possible due to inadequate indication, inadequate surgical technique and inadequate medical follow-up. The patient with a heart valve prosthesis must be seen as a life-long challenge for the cooperation between cardiologists and cardiac surgeons. This article describes the main causes of prosthetic heart valve dysfunction and the surgical treatment, including structural dysfunction, thrombosis, paravalvular leakage, tissue ingrowth and prosthetic valve endocarditis.


Gambogic acid induces apoptotic cell death in T98G glioma cells.
Gambogic acid (GA), a natural product with a xanthone structure, has a broad range of anti-proliferative effects on cancer cell lines. We evaluated GA for its cytotoxic effects on T98G glioblastoma cells. GA exhibited potent anti-proliferative activity and induced apoptosis in T98G glioblastoma cells in a dose-dependent manner. Incubation of cells with GA revealed apoptotic features including increased Bax and AIF expression, cytochrome c release, and cleavage of caspase-3, -8, -9, and PARP, while Bcl-2 expression was downregulated. Furthermore, GA induced reactive oxygen species (ROS) generation in T98G cells. Our results indicate that GA increases Bax- and AIF-associated apoptotic signaling in glioblastoma cells.


Fever and neutropenia in children with cancer: a therapeutic approach related to the underlying disease.
Antibiotic monotherapy is increasingly an option for the initial empiric treatment of febrile neutropenic cancer patients. We noted in a previous study that response to empiric therapy was related more to disease classification (solid tumors vs. leukemia) than to the regimen chosen. In the present study we based empiric monotherapy on the underlying disease in treating 240 episodes of fever and neutropenia in 145 children. Patients with leukemia or Stage III/IV non-Hodgkin's lymphoma (higher risk group) were treated with imipenem-cilastatin, whereas those with solid tumors or Stage I/II non-Hodgkin's lymphoma (lower risk group) received ceftriaxone. The regimens were modified in 15% of lower risk and 45% of higher risk episodes. Overall successful outcomes were obtained in 93.2% of the higher risk (n = 119) and 97.5% of the lower risk (n = 121) episodes. The two groups differed significantly in duration of neutropenia, frequency of positive blood cultures and superinfection and the need for modification of the monotherapy (P < 0.05). Empiric monotherapy based on primary disease appears to be safe and effective for febrile neutropenic children with cancer at our Brazilian institution. Further studies will be needed before these findings can be generalized to patient populations in other settings.


A rapid method combining immunofluorescence and flow cytometry for improved understanding of competitive interactions between lactic acid bacteria (LAB) and methicillin-resistant S. aureus (MRSA) in mixed culture.
The increasing frequency of methicillin-resistant Staphylococcus aureus (MRSA) infections in hospital and community settings highlights the need for effective anti-MRSA agents that will not contribute to the growing problem of antibiotic resistance. Lactic acid bacteria (LAB) are known to exclude various pathogens through multiple mechanisms. In vitro models studying interactions of pathogens and LAB in mixed cultures use selective agar plates to quantify changes in target populations. We applied commercially available S. aureus-specific polyclonal antibodies conjugated with fluorescein isothiocyanate (FITC) for this purpose, producing a bright green signal that clearly differentiates S. aureus from LAB species when mixed cultures are analyzed by flow cytometry and fluorescent microscopy. Flow cytometry of mixed cultures revealed a much larger population of MRSA cells than was detectable using selective agar plates. To our knowledge, this is the first time immunofluorescent flow cytometry has been applied to the study of competitive exclusion in mixed bacterial populations over time.


Protocol for evaluating antitumor activity of KIR3DL3 blockade in an NK cell-based xenogeneic lung tumor model.
Human killer cell immunoglobulin-like receptor, three Ig domains and long cytoplasmic tail (KIR3DL3) is expressed on natural killer (NK) cells and is a newly identified inhibitory receptor for B7 family member HERV-H LTR-associating protein 2 (HHLA2). Here, we summarize the isolation and expansion of KIR3DL3+ human NK cells, and in vitro functional characterization of in-house anti-KIR3DL3 monoclonal antibody (mAb). We also describe a human NK cell-based xenogeneic lung tumor model for testing the therapeutic activity of KIR3DL3 blockade in vivo. For complete details on the use and execution of this protocol, please refer to Wei et al. (2021).


Neighbourhood urban form and individual-level correlates of leisure-based screen time in Canadian adults.
Despite evidence for an association between the built environment and physical activity, less evidence exists regarding relations between the built environment and sedentary behaviour. This study investigated the extent to which objectively assessed and self-reported neighbourhood walkability, in addition to individual-level characteristics, were associated with leisure-based screen time in adults. We hypothesised that leisure-based screen time would be lower among adults residing in objectively assessed and self-reported 'high walkable' versus 'low walkable' neighbourhoods. The study was undertaken in Calgary, Alberta, Canada in 2007/2008. A random cross-section of adults who provided complete telephone interview and postal survey data (n=1906) was included. Captured information included leisure-based screen time, moderate-intensity and vigorous-intensity physical activity, perceived neighbourhood walkability, sociodemographic characteristics, self-reported health status, and self-reported height and weight. Based on objectively assessed built characteristics, participant's neighbourhoods were identified as being low, medium or high walkable. Using multiple linear regression, hours of leisure-based screen time per day was regressed on self-reported and objectively assessed walkability adjusting for sociodemographic and health-related covariates. Compared to others, residing in an objectively assessed high walkable neighbourhood, women, having a college education, at least one child at home, a household income ≥$120 000/year, and a registered motor vehicle at home, reporting very good-to-excellent health and healthy weight, and achieving 60 min/week of vigorous-intensity physical activity were associated (p<0.05) with less leisure-based screen time. Marital status, dog ownership, season, self-reported walkability and achieving 210 min of moderate-intensity physical activity were not significantly associated with leisure-based screen time. Improving neighbourhood walkability could decrease leisure-based television and computer screen time. Programmes aimed at reducing sedentary behaviour may want to consider an individual's sociodemographic characteristics, physical activity level, health status and weight status, in addition to the walkability of their neighbourhood as these factors were found to be important independent correlates of leisure-based screen time.


China special issue on gastrointestinal tumors-Cetuximab retreatment plus camrelizumab and liposomal irinotecan in patients with RAS wild-type metastatic colorectal cancer: Cohort B of the phase II CRACK study.
Patients with metastatic colorectal cancer (mCRC) have poor long-term survival. Rechallenge with anti-epidermal growth factor receptor (anti-EGFR) based therapy has shown certain activity as late-line therapy. To further improve clinical outcomes, we evaluated the antitumor efficacy and safety of cetuximab in combination with camrelizumab and liposomal irinotecan in patients with RASwt mCRC pretreated with anti-EGFR-based therapy. Patients with RASwt mCRC who had received at least two prior systemic therapies, including anti-EGFR-based treatment in the metastatic or unresectable disease setting, were enrolled in cohort B. Patients were treated with cetuximab (500 mg/m2 ) and camrelizumab (200 mg) plus liposomal irinotecan (HR070803, 60 mg/m2 ) intravenously once every 2 weeks. The primary endpoint was the objective response rate (ORR) by RECIST v1.1. The secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and safety. At the data cutoff (23 November 2022), 19 patients were enrolled in the two stages, and 16 were evaluable for efficacy analyses. The ORR was 25% (95% confidence interval [CI]: 10.2%-49.5%), and DCR was 75% (95% CI: 50.5%-89.8%). The median PFS and OS were 6.9 (95% CI: 2.6-11.2) and 15.1 (95% CI: 6.1-24.0) months, respectively. Grade 3 treatment-related adverse events (TRAEs) occurred in 15.8% (3/19) of patients. No grade ≥4 TRAEs were found in the safety population. Our study suggests that anti-EGFR retreatment therapy with cetuximab plus camrelizumab and liposomal irinotecan (HR070803) is a promising late-line treatment option with good antitumor activity and well-tolerated toxicity in RASwt mCRC patients.


HBV and HCV seroprevalence and their correlation with CD4 cells and liver enzymes among HIV positive individuals at University of Gondar Teaching Hospital, Northwest Ethiopia.
The co-existence of viral hepatitis caused by HBV and HCV become common causes of severe liver complication and immunological impairment among HIV infected individuals. The aim of this study was to assess the seroprevalence of HBV and HCV and their correlation with CD4 and liver enzyme levels among HAART naïve HIV positive individuals. A Cross-sectional study was conducted from March-May, 2011 at University of Gondar Teaching Hospital, Northwest Ethiopia. HBV and HCV serological tests and liver enzymes as well as CD4 T cell level determination were assessed following the standard procedures. Socio-demographic data was collected by using structured questionnaire. The data was entered and analyzed by using SPSS version 20.0 statistical software and p < 0.05 was considered as statistically significant. Among 400 study participants, the overall prevalence of HIV-viral hepatitis co-infection was 42(11.7%). The prevalence of HIV-HBV, HIV-HCV and HIV-HBV-HCV co-infections were 20(5.6%), 18(5.0%) and 4(1.1%) respectively. Study participants who had HIV-HBV, HIV-HCV and HIV-HBV-HCV co-infection have relatively raised mean liver enzyme levels (ALT, AST and ALP) than HIV mono-infected once. Individuals with HIV-HBV, HIV-HCV and HIV-HBV-HCV co-infection also had a lower mean CD4 levels than HIV mono-infected study participants. The mean CD4 value in males was lower than females. The prevalence of HBV and HCV was higher than reports from general population of the country. Raised levels of liver enzymes and lowered mean CD4 counts were seen in HIV-HBV, HIV-HCV and HIV-HBV-HCV co-infections. These findings underscore the importance of screening all HIV positive individuals before initiating antiretroviral treatment.


Physical violence and violent threats reported by Aboriginal and Torres Strait Islander people with a disability: cross sectional evidence from a nationally representative survey.
A recent Royal Commission into the treatment of Australians living with disabilities has underscored the considerable exposure to violence and harm in this population. Yet, little is known about exposure to violence among Aboriginal and Torres Strait Islander people living with disabilities. The objective of this paper was to examine the prevalence, disability correlates and aspects of violence and threats reported by Aboriginal and Torres Strait Islander people living with disabilities. Data from the 2014-15 National Aboriginal and Torres Strait Islander Social Survey were used to measure physical violence, violent threats and disability. Multivariable logistic and ordinal logistic regression models adjusted for complex survey design were used to examine the association between measures of disability and exposure to violence and violent threats. In 2014-15, 17% of Aboriginal and Torres Strait Islander people aged 15-64 with disability experienced an instance of physical violence compared with 13% of those with no disability. Approximately 22% of those with a profound or severe disability reported experiencing the threat of physical violence. After adjusting for a comprehensive set of confounding factors and accounting for complex survey design, presence of a disability was associated with a 1.5 odds increase in exposure to physical violence (OR = 1.54 p < 0.001), violence with harm (OR = 1.55 p < 0.001), more frequent experience of violence (OR = 1.55 p < 0.001) and a 2.1 odds increase (OR = 2.13 p < 0.001) in exposure to violent threats. Severity of disability, higher numbers of disabling conditions as well as specific disability types (e.g., psychological or intellectual) were associated with increased odds of both physical violence and threats beyond this level. Independent of these effects, removal from one's natural family was strongly associated with experiences of physical violence and violent threats. Aboriginal and Torres Strait Islander women, regardless of disability status, were more likely to report partner or family violence, whereas men were more likely to report violence from other known individuals. Aboriginal and Torres Strait Islander people with disability are at heightened risk of physical violence and threats compared to Aboriginal and Torres Strait Islander people without disability, with increased exposure for people with multiple, severe or specific disabilities.


Antibacterial prophylaxis in pediatric patients with leukemia.
Bacterial infections in pediatric patients with leukemia are associated with increased risks for morbidity and mortality. Few Recommendations have been made on the use of antibacterial prophylaxis in pediatrics with acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML). To determine the role of antibacterial prophylaxis in pediatric patients with leukemia and the most appropriate regimen that can be safely and effectively used. Literature search was conducted independently by 3 reviewers to find studies on the safety and effectiveness of antibacterial prophylactic regimens. The search strategy resulted in 13 studies; most of them were observational studies. The available evidence recommends use of antibiotics with Gram-positive bacterial coverage in AML patients. In ALL patients, prophylaxis was used during the intensive phases of chemotherapy with ciprofloxacin being recommended most commonly. Antibacterial prophylaxis mainly with coverage against Gram-positive bacteria is recommended in pediatric patients with AML. For ALL patients, prophylaxis may be considered for patients who are undergoing intensive chemotherapy phases and are at high risk for infections with ciprofloxacin being the most commonly used agent. In general more studies are needed to determine the role of antibacterial prophylaxis in pediatric patients with leukemia.


Chronic respiratory failure due to bilateral vocal cord paralysis managed with nocturnal nasal positive pressure ventilation.
A patient with bilateral vocal cord paralysis developed chronic respiratory failure. Treatment with nocturnal inspiratory positive airway pressure via nasal mask improved symptoms and reduced hypercapnia.


Preliminary evaluation of the production of non-carrier added 111Ag as core of a therapeutic radiopharmaceutical in the framework of ISOLPHARM_Ag experiment.
Research in the field of radiopharmaceuticals is increasingly promoted by the widespread and growing interest in applying nuclear medicine procedures in both disease diagnosis and treatment. The production of radionuclides of medical interest is however a challenging issue. Along with the conventional techniques other innovative approaches are being investigated and, among those, the ISOLPHARM project is being developed at INFN-LNL (Istituto Nazionale di Fisica Nucleare - Laboratori Nazionali di Legnaro). Such technique foresees the employment of the SPES ISOL facility to produce isobarically pure Radioactive Ion Beams (RIBs), obtained thanks to electromagnetic mass separation and collected on appropriate substrates. The latter are successively recovered and dissolved, allowing thus the chemical separation and harvesting of the nuclides of interest, free from any isotopic contaminant. Although ISOLPHARM can be potentially employed for most of the routinely used medical radioisotopes, its innovation potential is better expressed considering its capability to provide carrier free unconventional nuclides, difficult to produce with state-of-art techniques, such as 111Ag, a β- emitter potentially interesting for therapeutic applications. Thus, in the framework of ISOLPHARM, INFN supported a two-years experiment, called ISOLPHARM_Ag, aimed at evaluating the feasibility of the production of a111Ag labelled radiopharmaceutical. The ISOL production yields are estimated by computing intensive Monte Carlo codes, that require an appropriate custom Information Technology infrastructure. The presented work is focused on the first part of the production chain including the capability to extract, ionize, and collect stable Ag beams with SPES technologies. MC calculations were used to estimate the expected 111Ag in-target yields, whereas experiments with stable Ag were performed to test the ionization, transport and collection of Ag beams.


Optimizing Outcomes with Radiofrequency Ablation of Barrett's Esophagus: Candidates, Efficacy and Durability.
The treatment of early Barrett's esophagus (BE) has undergone a paradigm shift from surgical subtotal esophagectomy to organ-saving endoluminal treatment. Over the past 15 years, several high-quality studies were conducted to assess safe oncological outcome of endoscopic resection of mucosal adenocarcinoma and high-grade dysplasia. It became clear that add-on ablative therapy with radiofrequency ablation (RFA) significantly reduces recurrence risk of neoplasia after resection. In this review, we highlight the most essential elements to optimize outcomes of RFA of BE, addressing the correct indication and patient selection in combination with the most efficient and safest treatment protocols to obtain long-term durability.


Laparoscopic distal pancreatectomy. Three cases of insulinoma.
Surgery for benign pancreatic disease has traditionally required a major laparotomy however the minimal-access approach is now being applied to a wide variety of procedures, and surgery of the pancreas need not be excluded. Laparoscopic distal pancreatectomy was performed on three patients presenting with insulinomas found on preoperative investigation to lie within the tail of the pancreas. All three patients had an excellent clinical outcome and returned to a state of normoglycemia. All of them made a rapid recovery with no major complications. Laparoscopic distal pancreatectomy is a viable technique for removing insulinoma of the tail of the pancreas.


Active immunisation with RAMA does not provide protective immunity against Plasmodium yoelii challenge despite its association with protective responses in endemic populations.
The rhoptry associated membrane antigen (RAMA) of Plasmodium falciparum has been proposed as a potential candidate for inclusion in a multivalent subunit vaccine against malaria. Previous studies have found that the RAMA gene is refractory to genetic deletion in vitro and is conserved in a range of clinical isolates. Importantly, two independent studies demonstrated that antibodies against the C-terminal region of RAMA are associated with immunity in endemic populations of both Asia and Africa. However, there is presently no direct evidence that anti-RAMA immune responses have a demonstrable anti-parasitic effect either in vitro or in vivo. In this study we used an in vitro invasion inhibition assay and the Plasmodium yoelii mouse model of infection to evaluate the potential of RAMA as a vaccine candidate. Our results demonstrate that anti-PfRAMA antibodies have only a weak inhibitory effect on P. falciparum invasion in vitro. Immunisation with recombinant PyRAMA protein did not protect mice against a lethal P. yoelii infection and did not boost the level of protection induced by a known protective antigen, merozoite surface protein 4/5. Taken together, these data do not support RAMA as a priority vaccine candidate.


ccm2-like is required for cardiovascular development as a novel component of the Heg-CCM pathway.
The Heart of Glass-Cerebral Cavernous Malformation (Heg-CCM) pathway is essential for normal cardiovascular development in zebrafish and mouse. In zebrafish, the Heg-CCM pathway mutants santa(ccm1/san), valentine (ccm2/vtn), and heart of glass (heg) exhibit severely dilated hearts and inflow tracts and a complete absence of blood circulation. We identified a novel gene based on its sequence identity with ccm2, which we have named ccm2-like (ccm2l), and characterized its role in cardiovascular development. Disruption of ccm2l by morpholino injection causes dilation of the atrium and inflow tract and compromised blood circulation. Morpholino co-injection experiments identify ccm2l as an enhancer of the characteristic Heg-CCM dilated heart phenotype, and we find that ccm2 overexpression can partially rescue ccm2l morphant defects. Finally, we show that Ccm2l binds Ccm1 and perform deletion and mutational analyses to define the regions of Ccm1 that mediate its binding to Ccm2l and its previously established interactors Ccm2 and Heg. These genetic and biochemical data argue that ccm2l is a necessary component of the Heg-CCM pathway.


Overexpression of the Tibetan Plateau annual wild barley (Hordeum spontaneum) HsCIPKs enhances rice tolerance to heavy metal toxicities and other abiotic stresses.
The calcineurin B-like protein (CBL) and CBL-interacting protein kinase (CIPK) signaling system plays a key regulatory role in plant stress signaling. The roles of plant-specific CIPKs, essential for CBL-CIPK functions, in the response to various abiotic stresses have been extensively studied so far. However, until now, the possible roles of the CIPKs in the plant response to heavy metal toxicities are largely unknown. In this study, we used bioinformatic and molecular strategies to isolate 12 HsCIPK genes in Tibetan Plateau annual wild barley (Hordeum spontaneum C. Koch) and subsequently identified their functional roles in the response to heavy metal toxicities. The results showed that multiple HsCIPKs were transcriptionally regulated by heavy metal toxicities (e.g., Hg, Cd, Cr, Pb, and Cu) and other abiotic stresses (e.g., salt, drought, aluminum, low and high temperature, and abscisic acid). Furthermore, the ectopic overexpression of each HsCIPK in rice (Oryza sativa L. cv Nipponbare) showed that transgenic plants of multiple HsCIPKs displayed enhanced tolerance of root growth to heavy metal toxicities (Hg, Cd, Cr, and Cu), salt and drought stresses. These results suggest that HsCIPKs are involved in the response to heavy metal toxicities and other abiotic stresses. Tibetan Plateau annual wild barley HsCIPKs possess broad applications in genetically engineering of rice with tolerance to heavy metal toxicities and other abiotic stresses.


Hazard identification and exposure assessment for microbial food safety risk assessment.
The four cornerstones of microbial food safety risk assessment are hazard identification, exposure assessment, hazard characterization, and risk characterization. These steps represent a systematic process for identifying adverse consequences and their associated probabilities arising from consumption of foods that may be contaminated with microbial pathogens and/or microbial toxins. This paper presents a discussion of the first two steps: hazard identification and exposure assessment, and considerations for different approaches that can be used to analyze the relevant information.


Enantioselective Friedel-Crafts reactions between phenols and N-tosylaldimines catalyzed by a leucine-derived bifunctional catalyst.
Enantioselective Friedel-Crafts reactions between phenols and N-tosylaldimines were developed using a bifunctional catalyst readily prepared from L-leucine. The chiral benzylic amine products were obtained in high yields (up to 96% yield) and good to high enantiomeric excesses (up to 95% ee).


Real-world gaseous emission characteristics of natural gas heavy-duty sanitation trucks.
As compared to conventional diesel heavy-duty vehicles, natural gas vehicles have been proved to be more eco-friendly due to their lower production of greenhouse gas and pollutant emissions, which are causing enormous adverse effects on global warming and air pollution. However, natural gas vehicles were rarely studied before, especially through on-road measurements. In this study, a portable emission measurement system (PEMS) was employed to investigate the real-world emissions of nitrogen oxides (NOx) (nitrogen monoxide (NO), nitrogen dioxide (NO2)), total hydrocarbons (THC), carbon monoxide (CO), and carbon dioxide (CO2) from two liquified natural gas (LNG) China V heavy-duty cleaning sanitation trucks with different weight. Associated with the more aggressive driving behaviors, the vehicle with lower weight exhibited higher CO2 (3%) but lower NOx (48.3%) (NO2 (78.2%) and NO (29.4%)), CO (44.8%), and THC (3.7%) emission factors. Aggressive driving behaviors were also favorable to the production of THC, especially those in the medium-speed range but significantly negative to the production of CO and NO2, especially those in the low-speed range with high engine load. In particular, the emission rate ratio of NO2/NO decreased with the increase of speed/scaled tractive power in different speed ranges.


Effects of sacubitril/valsartan on life quality in chronic heart failure: A systematic review and meta-analysis of randomized controlled trials.
Sacubitril/valsartan has been demonstrated to have cardiovascular benefits in patients with chronic heart failure (CHF). We aimed to conduct a meta-analysis of its effects on life quality in patients with CHF, in comparison with the angiotensin-converting enzyme inhibitor/angiotensin receptor blocker (ACEI/ARB). PubMed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov were searched from inception through March 2022 for all relevant randomized controlled trials assessing the impact of sacubitril/valsartan and ACEI/ARB on health-related quality of life (HRQoL) in patients with CHF. Two reviewers independently conducted study selection, data extraction, and assessment of bias and quality of evidence. Review Manager 5.3 software was used for meta-analysis. We included 10 clinical studies involving 10,426 patients with heart failure with reduced ejection fraction (HFrEF) and 7,689 patients with heart failure with preserved ejection fraction (HFpEF). Meta-analysis results showed that, in terms of the primary outcome, the sacubitril/valsartan group was superior than the ACEI/ARB group in improving HRQoL of HFrEF, and the difference was statistically significant (SMD 1.26; 95% CI: 0.14, 2.37; p = 0.03), while there was no significant difference between the two groups in HFpEF (SMD 0.37; 95% CI: -0.35, 1.09; p = 0.32). The effect of sacubitril/valsartan on the secondary outcome of the minimal important improvement rate of HRQoL in HFrEF was consistent with the primary outcome, while the effect in HFpEF was not clear. The descriptive analysis of individual studies indicated no significant difference in the improvement of 6-min walk distance between the two groups. Sacubitril/valsartan is beneficial to improve HRQoL outcome in patients with HFrEF with high quality of evidence. Compared with ACEI/ARB, sacubitril/valsartan was more effective. While in patients with HFpEF, this improvement was similar between the two groups.


The dichloroacetamide safener benoxacor is enantioselectively metabolized by monkey liver microsomes and cytosol.
The metabolism and toxicity of current-use herbicide safeners remain understudied. We investigated the enantioselective metabolism of the safener benoxacor in Rhesus monkey subcellular fractions. Benoxacor was incubated with liver microsomes and cytosol from female and male monkeys (≤30 min). Benoxacor levels and enantiomeric fractions were determined with gas chromatography. Benoxacor was metabolized by microsomal cytochrome P450 enzymes (CYPs), cytosolic glutathione-S-transferases (GSTs), and microsomal and cytosolic carboxylesterase (CESs). CES-mediated microsomal metabolism followed the order males > females, whereas the CYP-mediated clearance followed the order females > males. CYP-mediated metabolism initially resulted in an enrichment of the second eluting benoxacor enantiomer (E2-benoxacor), whereas the first eluting benoxacor enantiomer (E1-benoxacor) was enriched after 10 or 30 min in female or male microsomal incubations. Benoxacor metabolism by GSTs was enantiospecific, with a total depletion of E1-benoxacor after approximately 20 min. Thus, the enantioselective metabolism of benoxacor by GSTs and CYPs may affect its toxicity.


Application of Nanozymes and its Progress in the Treatment of Ischemic Stroke.
Nanozymes are a new kind of material which has been applied since the beginning of this century, and its birth has promoted the development of chemistry, materials science, and biology. Nanozymes can be used as a substitute for natural enzyme and has a wide range of applications; therefore, it has attracted extensive attention from all sectors of the community, and the number of studies has constantly increasing. In this paper, we introduced the outstanding achievements in the field of nanozymes in recent years from the main function, the construction of nanozyme-based biosensors, and the treatment of ischemic stroke, and we also illustrated the internal mechanism and the catalytic principle. In the end, the obstacles and challenges in the future development of nanozymes were proposed.


BMI-1 expression is inversely correlated with the grading of renal clear cell carcinoma.
BMI-1 regulates cell proliferation and differentiation, is involved in stem cell maintenance and can act as an oncogene. We investigated BMI-1 expression in healthy normal kidney and in 77 renal tumours by immunohistochemistry, and correlated it with tumour differentiation. BMI-1 could regularly be demonstrated in distal tubules and in Bowman's capsule, whereas it was mostly lacking in proximal tubules, indicating that it may rather be a differentiation marker of different renal cell populations than a stem cell marker. In contrast to previous studies demonstrating a correlation between BMI-1 expression and malignancy, we showed that its expression was inversely correlated with the differentiation grade of clear cell carcinoma. Furthermore, despite their different biologies, BMI-1 was strongly expressed in both papillary carcinomas and oncocytomas. Thus, in renal clear cell carcinomas BMI-1 is rather a differentiation marker lost in carcinomas with high malignancy than an oncogene involved in tumour progression.


Commonly Used Screening Instruments to Identify Frailty Among Community-Dwelling Older People in a General Practice (Primary Care) Setting: A Study of Diagnostic Test Accuracy.
Rapid frailty screening remains problematic in primary care. The diagnostic test accuracy (DTA) of several screening instruments has not been sufficiently established. We evaluated the DTA of several screening instruments against two reference standards: Fried's Frailty Phenotype [FP] and the Adelaide Frailty Index [AFI]), a self-reported questionnaire. DTA study within three general practices in South Australia. We randomly recruited 243 general practice patients aged 75+ years. Eligible participants were 75+ years, proficient in English and community-dwelling. We excluded those who were receiving palliative care, hospitalized or living in a residential care facility.We calculated sensitivity, specificity, predictive values, likelihood ratios, Youden Index and area under the curve (AUC) for: Edmonton Frail Scale [EFS], FRAIL Scale Questionnaire [FQ], Gait Speed Test [GST], Groningen Frailty Indicator [GFI], Kihon Checklist [KC], Polypharmacy [POLY], PRISMA-7 [P7], Reported Edmonton Frail Scale [REFS], Self-Rated Health [SRH] and Timed Up and Go [TUG]) against FP [3+ criteria] and AFI [>0.21]. We obtained valid data for 228 participants, with missing scores for index tests multiply imputed. Frailty prevalence was 17.5% frail, 56.6% prefrail [FP], and 48.7% frail, 29.0% prefrail [AFI]. Of the index tests KC (Se: 85.0% [70.2-94.3]; Sp: 73.4% [66.5-79.6]) and REFS (Se: 87.5% [73.2-95.8]; Sp: 75.5% [68.8-81.5]), both against FP, showed sufficient diagnostic accuracy according to our prespecified criteria. Two screening instruments-the KC and REFS, show the most promise for wider implementation within general practice, enabling a personalized approach to care for older people with frailty.


Clinical applications of BMP-7: the UK perspective.
Treatment of fracture non-union is a challenging situation in skeletal surgery. Since the discovery of bone morphogenetic proteins (BMPs) by Urist preclinical research as well as clinical trials has shown the efficacy of these molecules in bone healing enhancement. Recombinant bone morphogenetic protein became available in UK during August 2001. We evaluated the type of indications and the efficacy of BMP-7 in a variety of clinical conditions including persistent fracture non-unions, augmentation of periprosthetic fracture treatment and osteotomies, enhancement of fracture healing following acetalular reconstruction, distraction osteogenesis, free fibular graft and arthrodesis of joints. Out of 653 cases, the overall success rate was 82% (535 cases). No local or systemic adverse effects were encountered. The role of BMP's as a bone stimulating agent is safe, well established and could be considered as a power adjunct in the surgeon's armamentarium for the treatment of these challenging clinical conditions.


Synthesis and assessment of sodium alginate-modified silk fibroin microspheres as potential hepatic arterial embolization agent.
Transcatheter arterial chemoembolization (TACE) is well known as an effective treatment for hepatocellular carcinoma (HCC). In the present study, a novel embolic agent of sodium alginate (SA)-modified silk fibroin (SF) microspheres was successfully prepared by emulsifying cross-linking method. The SA-modified SF microspheres were evaluated for the ability of embolization by investigating the morphology, particle size, swelling ratio, degradation, cytotoxicity, blood compatibility, and in vivo embolization. The results found that SA-modified SF microspheres had smooth surfaces and good sphericity. Swelling ratio of the microspheres can meet the requirements of arterial embolic agent and have pH and temperature sensitivity. Furthermore, hemolytic and anticoagulant studies have proved that the microspheres have good blood compatibility. Cytotoxicity tests indicated that the microspheres could promote the proliferation of fibroblasts and HUVEC. In vivo embolization evaluation of microspheres revealed that the arteries could be embolized by SA-modified SF microspheres in 3 weeks. The ability of drug loading and releasing of microspheres was proved by the controlled release profile of Adriamycin hydrochloride. The findings indicated that the SA-modified SF microspheres can be used as a potentially biodegradable arterial embolic agent for liver cancer therapy.