Quantitative phase imaging unravels new insight into dynamics of mesenchymal and amoeboid cancer cell invasion.
Observation and analysis of cancer cell behaviour in 3D environment is essential for full understanding of the mechanisms of cancer cell invasion. However, label-free imaging of live cells in 3D conditions is optically more challenging than in 2D. Quantitative phase imaging provided by coherence controlled holographic microscopy produces images with enhanced information compared to ordinary light microscopy and, due to inherent coherence gate effect, enables observation of live cancer cells' activity even in scattering milieu such as the 3D collagen matrix. Exploiting the dynamic phase differences method, we for the first time describe dynamics of differences in cell mass distribution in 3D migrating mesenchymal and amoeboid cancer cells, and also demonstrate that certain features are shared by both invasion modes. We found that amoeboid fibrosarcoma cells' membrane blebbing is enhanced upon constriction and is also occasionally present in mesenchymally invading cells around constricted nuclei. Further, we demonstrate that both leading protrusions and leading pseudopods of invading fibrosarcoma cells are defined by higher cell mass density. In addition, we directly document bundling of collagen fibres by protrusions of mesenchymal fibrosarcoma cells. Thus, such a non-invasive microscopy offers a novel insight into cellular events during 3D invasion.


Sympathetic nervous system plays a role in postnatal eyeball enlargement in the rabbit.
To examine the role of ocular sympathetic activity in the enlargement of the rabbit eyeball during postnatal growth. Fourteen New Zealand albino rabbits aged 5 weeks underwent unilateral surgical transection of the cervical sympathetic trunk caudal to the superior cervical ganglion. Postoperative enlargement of both eyeballs was monitored by measuring the axial length and corneal diameters every 2 weeks for 22 weeks (7-27 weeks of age). Rabbits were housed under a 12-hour light/12-hour dark cycle, and the measurements were made in the middle of the light period. At a final age of 30 to 31 weeks, the refractive state of the whole eye was determined on both sides by measurement through the central cornea with a refractometer. Rabbits were then killed, eyeballs enucleated, and their ocular volumes determined. From 9 weeks of age the axial length and corneal diameters were significantly shorter (P < 0.05) in the decentralized eye (surgical side) compared with the intact eye. This reduction remained statistically significant throughout the study period. However, the final refractive states of the two eyes were found not to be different. The mean ocular volume determined after postmortem enucleation was 4.5% less in the decentralized eye than in the intact eye (P < 0.05). Sympathetic nervous system activity is involved in the normal enlargement of the rabbit eyeball during postnatal growth. However, removal of the ocular sympathetic tone at the age of 5 weeks does not significantly alter the refractive state of the eye when measured in young adulthood.


Global dietary calcium intake among adults: a systematic review.
Low calcium intake may adversely affect bone health in adults. Recognizing the presence of low calcium intake is necessary to develop national strategies to optimize intake. To highlight regions where calcium intake should be improved, we systematically searched for the most representative national dietary calcium intake data in adults from the general population in all countries. We searched 13 electronic databases and requested data from domain experts. Studies were double-screened for eligibility. Data were extracted into a standard form. We developed an interactive global map, categorizing countries based on average calcium intake and summarized differences in intake based on sex, age, and socioeconomic status. Searches yielded 9780 abstracts. Across the 74 countries with data, average national dietary calcium intake ranges from 175 to 1233 mg/day. Many countries in Asia have average dietary calcium intake less than 500 mg/day. Countries in Africa and South America mostly have low calcium intake between about 400 and 700 mg/day. Only Northern European countries have national calcium intake greater than 1000 mg/day. Survey data for three quarters of available countries were not nationally representative. Average calcium intake is generally lower in women than men, but there are no clear patterns across countries regarding relative calcium intake by age, sex, or socioeconomic status. The global calcium map reveals that many countries have low average calcium intake. But recent, nationally representative data are mostly lacking. This review draws attention to regions where measures to increase calcium intake are likely to have skeletal benefits.


Severe multisystem inflammatory syndrome (MIS-C/A) after confirmed SARS-CoV-2 infection: a report of four adult cases.
Multisystem inflammatory syndrome (MIS) triggered by a recent SARS-Cov-2 infection has been recognised worldwide. Although predominantly affecting children (MIS-C), similar presentations have been reported among adults (MIS-A). A retrospective case series describing four critically ill patients with MIS-C/A diagnosed between January and April 2021 at Sahlgrenska University Hospital, Gothenburg, Sweden. Clinical presentation, laboratory and radiological findings, treatment and outcome are reported. Cases occurred in previously healthy patients with a history of laboratory-confirmed mild SARS-CoV-2 infection four to seven weeks earlier. The median age was 24 years (range 19-43) and 3/4 were male. All fulfilled suggested MIS-C/A criteria according to the US Centre for Disease Control and all required care at an intensive care unit. Treatment was initiated with intravenous immunoglobulin, interleukin-1-receptor antagonists, and pulse steroids in 3/4 cases which resulted in rapid clinical improvement. No severe complications were noticed in any case during a three-month follow-up period. MIS-C/A should be considered, irrespective of age, in patients with fever, hyperinflammation and multiple organ system involvements emerging weeks after COVID-19. Previously suggested treatment regimens for MIS-C seem to be applicable also for MIS-A.


Association between serum leptin and anthropometric parameters at birth and at 15th day of life in infants born asymmetrically small for gestational age.
The aim of this study was to investigate changes in skinfold measurements taken at three sites, mid-arm circumference and umbilical circumference during the first 15 days of life; and to evaluate relationships between anthropometric measurements and umbilical cord blood serum leptin levels in infants born small for gestational age (SGA) and appropriate for gestational age (AGA) infants. Of 50 newborn infants, 25 were SGA and 25 were AGA. Neonates' weight, mid-arm circumference (MAC), umbilical circumference (UC), and triceps, subscapular and periumbilical skinfold thicknesses were measured (Holtain callipers) immediately after delivery. Anthropometric parameters were measured again at 15th days of age. At birth, mean birth weight, mean skinfold thickness, MAC and UC measurements in the AGA group were significantly higher than those of the SGA group. These differences were also found on the 15th day. Birth weight correlated with all skinfold thicknesses, MAC and UC at birth. Weight at 15th day of life correlated with skinfold thicknesses, MAC and UC at 15th day of life. Cord blood leptin level was significantly lower in the SGA than in the AGA infants. This difference continued on the 15th day. When cord blood leptin level was compared with that of the 15th day, we found that leptin levels in the cord blood were significantly higher. There were significantly positive correlations between leptin levels and birth weight and skinfold thicknesses when the infants were all grouped together. When the newborns were grouped according to birth weight, there were positive correlations between cord blood serum leptin levels and these parameters in the AGA group, but no correlation in the SGA group. At the 15th day of life serum leptin levels correlated with weight, subscapular and triceps skinfold thickness in the AGA group, but only with triceps skinfold thickness in the SGA group.


The Lower Limb Amputee Measurement Scale: reliability and predictive validity.
This study assesses the reliability and predictive validity of the Lower Limb Extremity Amputee Measurement Scale (LLAMS), which is an assessment tool designed to predict the length of stay (LOS) of patients with lower limb amputations in a rehabilitation program. In order to evaluate inter-rater reliability a prospective evaluation was completed by five independent evaluators (n = 10). Predictive validity was evaluated retrospectively by comparing the LLAMS predicted LOS to actual LOS (n = 147). The ability of the amputee team members to administer the LLAMS to patients was very high (ICC [2,1] = 0.98, CI 95% = 0.96 - 0.99, F[9, 36] = 78.71, p < 0.05). In addition, a moderate positive correlation was found between the LLAMS predicted LOS and the actual LOS (Pearson Correlation Coefficient, r = 0.465, p < 0.01), and the LLAMS was able to identify those patients who required short versus long rehabilitation stays. The incorporation of the LLAMS into the physiatrist's initial assessment of patients in the amputee clinic has enhanced the ability to manage better the LOS and the time patients wait to enter the rehabilitation program.


Smoothened translates Hedgehog levels into distinct responses.
In the Drosophila wing, Hedgehog is made by cells of the posterior compartment and acts as a morphogen to pattern cells of the anterior compartment. High Hedgehog levels instruct L3/4 intervein fate, whereas lower levels instruct L3 vein fate. Transcriptional responses to Hedgehog are mediated by the balance between repressor and activator forms of Cubitus interruptus, CiR and CiA. Hedgehog regulates this balance through its receptor, Patched, which acts through Smoothened and thence a regulatory complex that includes Fused, Costal, Suppressor of Fused and Cubitus interruptus. It is not known how the Hedgehog signal is relayed from Smoothened to the regulatory complex nor how responses to different levels of Hedgehog are implemented. We have used chimeric and deleted forms of Smoothened to explore the signaling functions of Smoothened. A Frizzled/Smoothened chimera containing the Smo cytoplasmic tail (FFS) can induce the full spectrum of Hedgehog responses but is regulated by Wingless rather than Hedgehog. Smoothened whose cytoplasmic tail is replaced with that of Frizzled (SSF) mimics fused mutants, interfering with high Hedgehog responses but with no effect on low Hedgehog responses. The cytoplasmic tail of Smoothened with no transmembrane or extracellular domains (SmoC) interferes with high Hedgehog responses and allows endogenous Smoothened to constitutively initiate low responses. SmoC mimics costal mutants. Genetic interactions suggest that SSF interferes with high signaling by titrating out Smoothened, whereas SmoC drives constitutive low signaling by titrating out Costal. These data suggest that low and high signaling (1) are qualitatively different, (2) are mediated by distinct configurations of the regulatory complex and (3) are initiated by distinct activities of Smoothened. We present a model where low signaling is initiated when a Costal inhibitory site on the Smoothened cytoplasmic tail shifts the regulatory complex to its low state. High signaling is initiated when cooperating Smoothened cytoplasmic tails activate Costal and Fused, driving the regulatory complex to its high state. Thus, two activities of Smoothened translate different levels of Hedgehog into distinct intracellular responses.


Patients' perceptions of a culturally targeted Hispanic Kidney Transplant Program: A mixed methods study.
Disproportionately fewer waitlisted Hispanics receive living donor kidney transplants (LDKTs) compared to non-Hispanic whites. Northwestern Medicine's® culturally targeted Hispanic Kidney Transplant Program (HKTP) is associated with a significant increase in LDKTs among Hispanics. This multisite study assessed potential kidney recipients' and donors' and/or family members' perceptions of the HKTP's cultural components through semi-structured interviews and validated surveys. Qualitative thematic analysis and descriptive statistics were performed. Thirty-six individuals participated (62% participation rate) comprising 21 potential recipients and 15 potential donors/family (mean age: 51 years, 50% female, 72% preferred Spanish). Participants felt confident about the educational information because a transplant physician delivered the education and viewed the group format as effective. Participants felt that education sessions addressed myths about transplantation shared by Hispanics. Primary use of Spanish enhanced participants' understanding of transplantation. While few knew about living donation before attending the HKTP, most were "more in favor of" kidney transplantation (97%) and living donation (97%) afterward. Few reported learning about the HKTP from outreach staff and suggested leveraging community leaders to promote HKTP awareness. Our findings suggest the HKTP's cultural components were viewed favorably and positively influenced perceptions of kidney transplantation and living donation, which may help reduce transplant disparities in Hispanics. (Clinicaltrial.gov registration # NCT03276390, date of registration: 9-7-17, retrospectively registered).


Outcomes of salvage therapy for steroid-refractory acute severe ulcerative colitis: ciclosporin vs. infliximab.
Up to 40% of patients who present with acute severe ulcerative colitis (UC) fail to make an adequate response to intravenous corticosteroids. Ciclosporin or infliximab are currently employed as salvage therapy in this clinical scenario. To compare clinical outcomes in patients treated with ciclosporin or infliximab in the setting of steroid-refractory acute severe UC. A prospective study of 83 consecutive presentations of steroid-refractory acute severe UC from 1999 to 2009 was conducted. All study participants satisfied the Truelove and Witts' criteria for acute severe UC. The primary outcome measures were rates of colectomy at discharge from hospital and at 3 months and 12 months following admission. Eighty-three steroid-refractory acute severe UC events were generated by 83 patients. Salvage therapy was instituted with ciclosporin in 45 patients and infliximab in the remaining 38 patients. Of those patients who received ≥72 h of ciclosporin (2-4 mg/kg), 56% (24/43) avoided colectomy at the time of discharge, while this figure was 84% (32/38) for those administered one dose of infliximab (5 mg/kg) (P = 0.006). At 3 months, the colectomy-free rate was 53% for ciclosporin (23/43) vs. 76% for infliximab (28/37) (P = 0.04), and 42% (18/43) vs. 65% (24/37) at 12 months (P = 0.04). There were no deaths and two serious adverse events, both occurring in the ciclosporin group. In this large cohort of patients presenting with acute severe UC, we have observed that infliximab salvage therapy is associated with lower rates of both severe adverse events and colectomy than ciclosporin in the short-term and medium-term.


The serological response of foals to vaccination against strangles.
A group of 100 foals was given either a commercial bacterin or an autogenous vaccine consisting of whole cells and an acid extract of Streptococcus equi. During the study, some of the foals developed clinical strangles. Various sets of sera were collected from these foals prevaccination, during vaccination, postvaccination and postinfection. The serological response of these foals was measured by passive haemagglutination and long chain tests. In foals which remained healthy, the highest titres were reached within one to two months postvaccination with a passive haemagglutination 10 x log2 mean titre of 6.78 and the long chain indices of 4.41. These levels persisted for 120 days postvaccination. Those foals which had clinical strangles exhibited lower passive haemagglutination titres (3.78) at one to two months postimmunization, but rose significantly after recovery. Four ponies immunized with formalinized Str. equi bacterin showed a partial protection against the challenge infection. The passive haemagglutination titres, long chain indices and serum bactericidal activity in these ponies were highest at 35 days postvaccination but did not increase after infection.


Relation of atrial fibrillation and right-sided cardiac thrombus to outcomes in patients with acute pulmonary embolism.
Atrial fibrillation (AF) can induce a hypercoagulable state in both the left and right atria. Thrombus in the right side of the heart (RHT) may lead to acute pulmonary embolism (APE). The aim of the study was to determine the prevalence of RHT and AF and to assess their impact on outcomes in patients with APE. The retrospective cohort included 1,006 patients (598 female), with a mean age of 66 ± 15 years. The primary end point was all-cause mortality. The secondary end point was incidence of complications (death, cardiogenic shock, cardiac arrest, vasopressor/inotrope treatment, or ventilatory support). Atrial fibrillation was detected in 231 patients (24%). RHT was observed in 50 patients (5%). The combination of AF and RHT was observed in 16 patients (2%). The overall mortality rate was significantly higher in patients with RHT compared with those without (32% vs 14%, respectively, odds ratio [OR] 3.0, 95% confidence interval [CI] 1.6 to 5.6, p = 0.001). The rate of complications was significantly higher in patients with RHT in comparison to those without (40% vs 22%, respectively, OR 2.4, 95% CI 1.3 to 4.4, p = 0.004). The mortality rate in patients with both AF and RHT was significantly higher in comparison to those with AF but without RHT (50% vs 20%, respectively, OR 3.86, 95% CI 1.3 to 11.2, p = 0.01). In multivariate analysis, RHT (p = 0.03) was an independent predictor of death. In conclusion, AF is a frequent co-morbidity in patients with APE, and the presence of RHT is not uncommon. Among patients with APE, the presence of RHT increases the mortality approximately threefold regardless of the presence of known AF.


A Rare Case of Misdiagnosed Silent Lung Cancer with Solitary Metastasis to the Temporomandibular Joint Condyle.
This article describes the case history of a 59-year-old female patient who sought advice for temporomandibular joint (TMJ) pain and sounds but who was actually diagnosed with a primary lung cancer with metastasis to the TMJ. The patient had a history of TMJ pain and deflection in jaw movement that progressively worsened over a few months and did not improve with the usual standard of care treatment provided by an orofacial pain practitioner. Magnetic resonance and computed tomography (CT) prescribed at a tertiary clinic showed an osteolytic bone mass within the right TMJ condyle. The neoformation was surgically removed and histologic assessment revealed it was a metastasis of a silent lung carcinoma. Thorax CT confirmed the presence of a formation within the apical segment of the right lung superior lobe. While this scenario of a silent lung cancer metastasis to the TMJ condyle mimicking classical symptoms of temporomandibular disorders (TMD) is rare, it does indicate that the path to differential diagnosis is often difficult in TMD and orofacial pain patients, and that practitioners managing such patients should be aware of the variegate spectrum of possible TMD-mimicking conditions to avoid dangerous diagnostic delays.


A review of cost measures for the economic impact of domestic violence.
Although economic analyses of domestic violence typically guide decisions concerning resource allocation, allowing policy makers to make better informed decisions on how to prioritize and allocate scarce resources, the methods adopted to calculate domestic violence costs have varied widely from study to study. In particular, only a few studies have reviewed the cost measures of the economic impact of domestic violence. This article reviews and compares these measures by covering approaches to categorizing costs, the cost components, and ways to estimate them and recommends an integrated framework that brings the various approaches together. Some issues still need to be addressed when further developing measures such as including omitted but significant measures and expanding the time horizons of others. The implications for future study of domestic violence costs are discussed.


Sex differences of human cortical blood flow and energy metabolism.
Brain energy metabolism is held to reflect energy demanding processes in neuropil related to the density and activity of synapses. There is recent evidence that men have higher density of synapses in temporal cortex than women. One consequence of these differences would be different rates of cortical energy turnover and blood flow in men and women. To test the hypotheses that rates of oxygen consumption (CMRO2) and cerebral blood flow are higher in men than in women in regions of cerebral cortex, and that the differences persist with aging, we used positron emission tomography to determine cerebral blood flow and cerebral metabolic rate of oxygen as functions of age in healthy volunteers of both sexes. Cerebral metabolic rate of oxygen did not change with age for either sex and there were no differences of mean values of cerebral metabolic rate of oxygen between men and women in cerebral cortex. Women had significant decreases of cerebral blood flow as function of age in frontal and parietal lobes. Young women had significantly higher cerebral blood flow than men in frontal and temporal lobes, but these differences had disappeared at age 65. The absent sex difference of cerebral energy turnover suggests that the known differences of synaptic density between the sexes are counteracted by opposite differences of individual synaptic activity.


Neuroticism and the Overlap Between Autistic and ADHD Traits: Findings From a Population Sample of Young Adult Australian Twins.
Neuroticism, a 'Big Five' personality trait, has been associated with sub-clinical traits of both autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD). The objective of the current study was to examine whether causal overlap between ASD and ADHD traits can be accounted for by genetic and environmental risk factors that are shared with neuroticism. We performed twin-based structural equation modeling using self-report data from 12 items of the Neo Five-Factor Inventory Neuroticism domain, 11 Social Responsiveness Scale items, and 12 Adult ADHD Self-Report Scale items obtained from 3,170 young adult Australian individual twins (1,081 complete pairs). Univariate analysis for neuroticism, ASD, and ADHD traits suggested that the most parsimonious models were those with additive genetic and unique environmental components, without sex limitation effects. Heritability of neuroticism, ASD, and ADHD traits, as measured by these methods, was moderate (between 40% and 45% for each respective trait). In a trivariate model, we observed moderate phenotypic (between 0.45 and 0.62), genetic (between 0.56 and 0.71), and unique environmental correlations (between 0.37and 0.55) among neuroticism, ASD, and ADHD traits, with the highest value for the shared genetic influence between neuroticism and self-reported ASD traits (r g = 0.71). Together, our results suggest that in young adults, genetic, and unique environmental risk factors indexed by neuroticism overlap with those that are shared by ASD and ADHD.


Gravimetric determination of urine volumes.
A procedure for estimating urine volumes from urine weights is presented. Regression analysis was used to assess correlation between weight-volume errors. The urine weight was divided by 1.016, the mean urine specific gravity in our patient population. It was found that the gravimetric method gave results lower than the volume method by one percent or less. We conclude that this difference is acceptable for clinical purposes. The gravimetric procedure has the advantages of rapidity, cost-effectiveness, and safety.


Psychoactive drug use and progression of HIV infection.
Early in the history of the AIDS epidemic there was clear evidence of differences in the outcomes of HIV infection between injecting drug users and men who have sex with men. There were also some indications that high levels of nonsterile drug injection may increase the progression of HIV infection. Recent epidemiologic studies indicate no differences in rates of progression to AIDS among drug injectors, men who have sex with men, or persons infected through heterosexual contact. In vitro and animal studies suggest that the effects of different psychoactive drugs on HIV infection may be negative, positive, or mixed, and that the effects of a psychoactive drug on immune functioning may differ among acute administration, chronic administration, or cessation of chronic administration. Although the current epidemiologic data do not provide support for the hypothesis that psychoactive drug use will have any important effects on the course of HIV infection, possible interactions between psychoactive drugs and antiviral medications and medication adherence issues among drug users are important areas for AIDS research. Relations between psychoactive drug use, the nervous system, and the immune system are a promising area for basic research.


Impaired Efferocytosis Enables Apoptotic Osteoblasts to Escape Osteoimmune Surveillance During Aging.
Macrophage efferocytosis of apoptotic osteoblasts (apoOBs) is a key osteoimmune process for bone homeostasis. However, apoOBs frequently accumulate in aged bone marrow, where they may mount proinflammatory responses and progressive bone loss. The reason why apoOBs are not cleared during aging remains unclear. In this study, it is demonstrated that aged apoOBs upregulate the immune checkpoint molecule CD47, which is controlled by SIRT6-regulated transcriptional pausing, to evade clearance by macrophages. Using osteoblast- and myeloid-specific gene knockout mice, SIRT6 is further revealed to be a critical modulator for apoOBs clearance via targeting CD47-SIRPα checkpoint. Moreover, apoOBs activate SIRT6-mediated chemotaxis to recruit macrophages by releasing apoptotic vesicles. Two targeting delivery strategies are developed to enhance SIRT6 activity, resulting in rejuvenated apoOBs clearance and delayed age-related bone loss. Collectively, the findings reveal a previously unknown linkage between immune surveillance and bone homeostasis and targeting the SIRT6-regulated mechanism can be a promising therapeutic strategy for age-related bone diseases.


Factors affecting Sertoli cell function in the testis.
The Sertoli cell is the primary target for FSH action in the mammalian testis. These cells contain the majority of testicular plasma membrane receptors for this hormone. Receptor occupancy is directly correlated with a stimulation of adenylyl cyclase and a decrease in the activity of a cytoplasmic Ca++-sensitive cAMP phosphodiesterase. Regulation of these two enzymes allows increased intracellular accumulation of cAMP, activation of cAMP-dependent protein kinase and phosphorylation of a variety of protein substrates. All of these events occur within the first 30 min following exposure of isolated Sertoli cells to FSH. RNA and protein synthesis are also enhanced by FSH. Previous studies have suggested that this gonadotropin may augment the overall cellular synthesis of proteins. Our results reveal that protein kinase inhibitor (PKI) is selectively elevated by FSH both in vivo and in vitro. PKI thus becomes the initial intracellular protein whose synthesis is under FSH control. In addition to effects on protein synthesis, FSH also positively modulates the secretion of several specific proteins. One of the proteins in this latter category is androgen binding protein (ABP). Again, regulation can be observed both in vivo and in vitro. Elevated synthesis of PKI occurs prior to demonstrable secretion of ABP. Both of these events occur subsequent to the effects of FSH on cAMP metabolism. Indeed cAMP (or any of several nonhydrolyzable derivatives) can substitute for FSH in vitro. The temporal sequence of events subsequent to hormone binding and cAMP production are identical, but occur more rapidly. Together these data support the hypothesis that most of the biochemical steps leading to the synthesis and secretion of proteins by FSH are regulated by elevated levels of cAMP.


Idarubicin Dose Escalation During Consolidation Therapy for Adult Acute Myeloid Leukemia.
Purpose Higher doses of the anthracycline daunorubicin during induction therapy for acute myeloid leukemia (AML) have been shown to improve remission rates and survival. We hypothesized that improvements in outcomes in adult AML may be further achieved by increased anthracycline dose during consolidation therapy. Patients and Methods Patients with AML in complete remission after induction therapy were randomly assigned to receive two cycles of consolidation therapy with cytarabine 100 mg/m2 daily for 5 days, etoposide 75 mg/m2 daily for 5 days, and idarubicin 9 mg/m2 daily for either 2 or 3 days (standard and intensive arms, respectively). The primary end point was leukemia-free survival (LFS). Results Two hundred ninety-three patients 16 to 60 years of age, excluding those with core binding factor AML and acute promyelocytic leukemia, were randomly assigned to treatment groups (146 to the standard arm and 147 to the intensive arm). Both groups were balanced for age, karyotypic risk, and FLT3-internal tandem duplication and NPM1 gene mutations. One hundred twenty patients in the standard arm (82%) and 95 patients in the intensive arm (65%) completed planned consolidation ( P < .001). Durations of severe neutropenia and thrombocytopenia were prolonged in the intensive arm, but there were no differences in serious nonhematological toxicities. With a median follow-up of 5.3 years (range, 0.6 to 9.9 years), there was a statistically significant improvement in LFS in the intensive arm compared with the standard arm (3-year LFS, 47% [95% CI, 40% to 56%] v 35% [95% CI, 28% to 44%]; P = .045). At 5 years, the overall survival rate was 57% in the intensive arm and 47% in the standard arm ( P = .092). There was no evidence of selective benefit of intensive consolidation within the cytogenetic or FLT3-internal tandem duplication and NPM1 gene mutation subgroups. Conclusion An increased cumulative dose of idarubicin during consolidation therapy for adult AML resulted in improved LFS, without increased nonhematologic toxicity.


Pharmacogenetics of KCNQ channel activation in 2 potassium channelopathy mouse models of epilepsy.
Antiseizure drugs are the leading therapeutic choice for treatment of epilepsy, but their efficacy is limited by pharmacoresistance and the occurrence of unwanted side effects. Here, we examined the therapeutic efficacy of KCNQ channel activation by retigabine in preventing seizures and neurocardiac dysfunction in 2 potassium channelopathy mouse models of epilepsy with differing severity that have been associated with increased risk of sudden unexpected death in epilepsy (SUDEP): the Kcna1-/- model of severe epilepsy and the Kcnq1A340E/A340E model of mild epilepsy. A combination of behavioral, seizure threshold, electrophysiologic, and gene expression analyses was used to determine the effects of KCNQ activation in mice. Behaviorally, Kcna1-/- mice exhibited unexpected hyperexcitability instead of the expected sedative-like response. In flurothyl-induced seizure tests, KCNQ activation decreased seizure latency by ≥50% in Kcnq1 strain mice but had no effect in the Kcna1 strain, suggesting the influence of genetic background. However, in simultaneous electroencephalography and electrocardiography recordings, KCNQ activation significantly reduced spontaneous seizure frequency in Kcna1-/- mice by ~60%. In Kcnq1A340E/A340E mice, KCNQ activation produced adverse cardiac effects including profound bradycardia and abnormal increases in heart rate variability and atrioventricular conduction blocks. Analyses of Kcnq2 and Kcnq3 mRNA levels revealed significantly elevated Kcnq2 expression in Kcna1-/- brains, suggesting that drug target alterations may contribute to the altered drug responses. This study shows that treatment strategies in channelopathy may have unexpected outcomes and that effective rebalancing of channel defects requires improved understanding of channel interactions at the circuit and tissue levels. The efficacy of KCNQ channel activation and manifestation of adverse effects were greatly affected by genetic background, potentially limiting KCNQ modulation as a way to prevent neurocardiac dysfunction in epilepsy and thereby SUDEP risk. Our data also uncover a potential role for KCNQ2-5 channels in autonomic control of chronotropy.


Comparison of Oxidative and Hypoxic Stress Responsive Genes from Meta-Analysis of Public Transcriptomes.
Analysis of RNA-sequencing (RNA-seq) data is an effective means to analyze the gene expression levels under specific conditions and discover new biological knowledge. More than 74,000 experimental series with RNA-seq have been stored in public databases as of 20 October 2021. Since this huge amount of expression data accumulated from past studies is a promising source of new biological insights, we focused on a meta-analysis of 1783 runs of RNA-seq data under the conditions of two types of stressors: oxidative stress (OS) and hypoxia. The collected RNA-seq data of OS were organized as the OS dataset to retrieve and analyze differentially expressed genes (DEGs). The OS-induced DEGs were compared with the hypoxia-induced DEGs retrieved from a previous study. The results from the meta-analysis of OS transcriptomes revealed two genes, CRIP1 and CRIP3, which were particularly downregulated, suggesting a relationship between OS and zinc homeostasis. The comparison between meta-analysis of OS and hypoxia showed that several genes were differentially expressed under both stress conditions, and it was inferred that the downregulation of cell cycle-related genes is a mutual biological process in both OS and hypoxia.


Radiation in management of patients with dermatofibrosarcoma protuberans.
The preferred treatment of dermatofibrosarcoma protuberans (DFSP) is wide resection, namely, margins > or = 3 cm beyond the evident disease and histologically negative margins. We assess the success achieved by radiation combined with surgery for positive/close margins or by radiation alone for those tumors that are not resectable for technical/medical reasons. The literature on this point is virtually nonexistent. The outcome of treatment of 18 patients with DFSP by radiation alone (n = 3) and radiation and surgery (n = 15) at the Massachusetts General Hospital was assessed. All of the lesions at the time of the treatment by radiation alone or combined with surgery were less than 10 cm. This was the maximum dimension. The actual tumor volume was much less than indicated by this maximum dimension, as the tumors were usually relatively flat. The 10-year actuarial local control rate was determined to be 88%. Local control was realized in the three patients treated by radiation alone, with follow-up periods of > or = 9 years. Among 15 patients treated by radiation and surgery, there have been three local failures; the 10-year actuarial local control rate was 84%. The three local failures occurred in 12 patients whose surgical margins were positive. One of these three local failures developed in the group of two patients whose lesions were scored as grade II. Radiation in well-tolerated dose schedules is an effective option in the management of patients with DFSP. This appears to be true for radiation alone or postoperatively for margin-positive disease (primary or recurrent).


Palau's warmest reefs harbor thermally tolerant corals that thrive across different habitats.
Ocean warming is killing corals, but heat-tolerant populations exist; if protected, they could replenish affected reefs naturally or through restoration. Palau's Rock Islands experience consistently higher temperatures and extreme heatwaves, yet their diverse coral communities bleach less than those on Palau's cooler outer reefs. Here, we combined genetic analyses, bleaching histories and growth rates of Porites cf. lobata colonies to identify thermally tolerant genotypes, map their distribution, and investigate potential growth trade-offs. We identified four genetic lineages of P. cf. lobata. On Palau's outer reefs, a thermally sensitive lineage dominates. The Rock Islands harbor two lineages with enhanced thermal tolerance; one of which shows no consistent growth trade-off and also occurs on several outer reefs. This suggests that the Rock Islands provide naturally tolerant larvae to neighboring areas. Finding and protecting such sources of thermally-tolerant corals is key to reef survival under 21st century climate change.


SARS-CoV-2 disease severity and transmission efficiency is increased for airborne compared to fomite exposure in Syrian hamsters.
Transmission of SARS-CoV-2 is driven by contact, fomite, and airborne transmission. The relative contribution of different transmission routes remains subject to debate. Here, we show Syrian hamsters are susceptible to SARS-CoV-2 infection through intranasal, aerosol and fomite exposure. Different routes of exposure present with distinct disease manifestations. Intranasal and aerosol inoculation causes severe respiratory pathology, higher virus loads and increased weight loss. In contrast, fomite exposure leads to milder disease manifestation characterized by an anti-inflammatory immune state and delayed shedding pattern. Whereas the overall magnitude of respiratory virus shedding is not linked to disease severity, the onset of shedding is. Early shedding is linked to an increase in disease severity. Airborne transmission is more efficient than fomite transmission and dependent on the direction of the airflow. Carefully characterized SARS-CoV-2 transmission models will be crucial to assess potential changes in transmission and pathogenic potential in the light of the ongoing SARS-CoV-2 evolution.


Endogenous control of cell cycle progression by autocrine transforming growth factor beta in breast cancer cells.
Tumor progression due to loss of autocrine negative transforming growth factor-beta (TGF-beta) activity was reported in various cancers of epithelial origin. Estrogen receptor expressing (ER(+)) breast cancer cells are refractory to TGF-beta effects and exhibit malignant behavior due to loss or inadequate expression of TGF-beta receptor type II (RII). The exogenous TGF-beta effects on the modulation of cell cycle machinery were analyzed previously. However, very little is known regarding the endogenous control of cell cycle progression by autocrine TGF-beta. In this study, we have used a tetracycline regulatable RII cDNA expression vector to demonstrate that RII replacement reconstitutes autocrine negative TGF-beta activity in ER(+) breast cancer cells as evidenced by the delayed entry into S phase by the RII transfectants. Reversal of the delayed entry into S phase by the RII transfectants in the presence of tetracycline in addition to the decreased steady state transcription from a promoter containing the TGF-beta responsive element (p3TP-Lux) by TGF-beta neutralizing antibody treatment of the RII transfected cells confirmed that autocrine-negative TGF-beta activity was induced in the transfectants. Histone H1 kinase assays indicated that the delayed entry of RII transfectants into phase was associated with markedly reduced cyclin-dependent kinase (CDK)2 kinase activity. This reduction in kinase activity was due to the induction of CDK inhibitors p21/waf1/cip1 and p27/kip, and their association with CDK2. Tetracycline treatment of RII transfectants led to the suppression of p21/waf1/cip1and p27/kip expression, thus, directly demonstrating induction of CDK inhibitors by autocrine TGF-beta leading to growth control of ER(+) breast cancer cells.


High-Temporal-Resolution High-Spatial-Resolution Spaceborne SAR Based on Continuously Varying PRF.
Synthetic Aperture Radar (SAR) is a well-established and powerful imaging technique for acquiring high-spatial-resolution images of the Earth's surface. With the development of beam steering techniques, sliding spotlight and staring spotlight modes have been employed to support high-spatial-resolution applications. In addition to this strengthened high-spatial-resolution and wide-swath capability, high-temporal-resolution (short repeat-observation interval) represents a key capability for numerous applications. However, conventional SAR systems are limited in that the same patch can only be illuminated for several seconds within a single pass. This paper considers a novel high-squint-angle system intended to acquire high-spatial-resolution spaceborne SAR images with repeat-observation intervals varying from tens of seconds to several minutes within a single pass. However, an exponentially increased range cell migration would arise and lead to a conflict between the receive window and 'blind ranges'. An efficient data acquisition technique for high-temporal-resolution, high-spatial-resolution and high-squint-angle spaceborne SAR, in which the pulse repetition frequency (PRF) is continuously varied according to the changing slant range, is presented in this paper. This technique allows echo data to remain in the receive window instead of conflicting with the transmitted pulse or nadir echo. Considering the precision of hardware, a compromise and practical strategy is also proposed. Furthermore, a detailed performance analysis of range ambiguities is provided with respect to parameters of TerraSAR-X. For strong point-like targets, the range ambiguity of this technique would be better than that of uniform PRF technique. For this innovative technique, a resampling strategy and modified imaging algorithm have been developed to handle the non-uniformly sampled echo data. Simulations are performed to validate the efficiency of the proposed technique and the associated imaging algorithm.


Hepatitis C Virus Seroprevalence in Persons Who Inject Drugs in Korea, 2012-2022: A Multicenter, Retrospective Study.
Limited data are available on hepatitis C virus (HCV) infection in persons who inject drugs (PWID) in South Korea. The present study aimed to investigate the seroprevalence of HCV antibodies, risk factors for HCV seropositivity, and HCV treatment status in PWID between January 2012 and May 2022. We retrospectively reviewed the medical records of 418 drug users who underwent HCV antibody testing in three hospitals caring for 90% of known PWID in South Korea, of whom 373 were PWID. The HCV seroprevalence was 39.7% (148/373) in PWID vs. 6.7% (3/45) in non-injection drug users (P < 0.001). Age ≥ 40 years, hospital type (58.2% in the prison hospital vs. 34.0% in the private hospital), and enrollment year (68.2% in 2012-2014 vs. 30.0% in 2021-2022) were independently associated with HCV seropositivity. Among the HCV-seropositive PWID, 90.5% (134/148) were diagnosed with HCV infection; however, only 6.8% (10/148) received HCV treatment. The hepatitis B virus surface antigen and human immunodeficiency virus antibody positivity were 4.0% (14/352) and 1.9% (6/317) in tested PWID, respectively. The HCV seroprevalence in PWID was 39.7% with a very low treatment rate, which prompts active measures to test and treat PWID for HCV infection in South Korea.


[Cryptococcus neoformans var. gattii isolates from two Peruvian patients.].
The ecology of Cryptococcus neoformans var. gatti is restricted to tropical and subtropical areas whereas C. neoformans var. neoformans is cosmopolitan. Perú is a country with three different well defined geographic areas, some of them have the conditions for the presence of the variety gattii. In order to determine the presence of the two varieties of C. neoformans in Perú, we made the C. neoformans differentiation from the clinical isolates. C. neoformans var. gattii was identified by their ability to assimilate D-proline. We tested 68 strains; only two of them were recognized as the variety gattii and were recovered from two patients without any predisposing factor. We described the clinical spectrum of these two patients, who were diagnosed with disseminated cryptococcosis and cryptococcal meningitis. Neither the presence of Eucalyptus camaldulensis nor Eucalyptus tereticornis has been reported in Perú. So there should exist other ecologic niches for the presence of C. neoformans var. gattii in our country, different from those mentioned.


[Automatic analysis of electrocardiograph signals in the diagnosis of myocardial infarct].
At present the work of automatization of the processes of the ECG analysis for diagnosing myocardial infarction with the help of computer technique is going forward on an ever broader scale. For an automatic identification of the focal changes syndrome on the ECG, which in the clinical practice is considered to be tantanount to myocardial infarction, the use of a special diagnostic device (SDD) is proposed. The SDD are comparatively cheap and simple in operation. The process of diagnosing provides for utilization of medical experience, but, at the same time, eliminates shortcomings inherent in systems that reproduce the physicians' manipulations in establishing the diagnosis of myocardial infarction with the help of an electrocardiogram. The choice of the SDD was made by stimulating it with an all-purpose computer. The results of clinical trials of the SDD conducted at specialized clinics bear proof to great possibilities of the automatic electrocardiographic diagnostics.


Regulatory T cells in retroviral infections.
Tight regulation of immune responses is not only critical for preventing autoimmune diseases but also for preventing immunopathological damage during infections in which overactive immune responses may be more harmful for the host than the pathogen itself. Regulatory T cells (Tregs) play a critical role in this regulation, which was discovered using the Friend retrovirus (FV) mouse model. Subsequent FV studies revealed basic biological information about Tregs, including their suppressive activity on effector cells as well as the molecular mechanisms of virus-induced Treg expansion. Treg suppression not only limits immunopathology but also prevents complete elimination of pathogens contributing to chronic infections. Therefore, Tregs play a complex role in the pathogenesis of persistent retroviral infections. New therapeutic concepts to reactivate effector T-cell responses in chronic viral infections by manipulating Tregs also came from work with the FV model. This knowledge initiated many studies to characterize the role of Tregs in HIV pathogenesis in humans, where a complex picture is emerging. On one hand, Tregs suppress HIV-specific effector T-cell responses and are themselves targets of infection, but on the other hand, Tregs suppress HIV-induced immune hyperactivation and thus slow the infection of conventional CD4+ T cells and limit immunopathology. In this review, the basic findings from the FV mouse model are put into perspective with clinical and basic research from HIV studies. In addition, the few Treg studies performed in the simian immunodeficiency virus (SIV) monkey model will also be discussed. The review provides a comprehensive picture of the diverse role of Tregs in different retroviral infections and possible therapeutic approaches to treat retroviral chronicity and pathogenesis by manipulating Treg responses.


Contamination and washing of cloth masks and risk of infection among hospital health workers in Vietnam: a post hoc analysis of a randomised controlled trial.
In a previous randomised controlled trial (RCT) in hospital healthcare workers (HCWs), cloth masks resulted in a higher risk of respiratory infections compared with medical masks. This was the only published RCT of cloth masks at the time of the COVID-19 pandemic. To do a post hoc analysis of unpublished data on mask washing and mask contamination from the original RCT to further understand poor performance of the two-layered cotton cloth mask used by HCWs in that RCT. 14 secondary-level/tertiary-level hospitals in Hanoi, Vietnam. A subgroup of 607 HCWs aged ≥18 years working full time in selected high-risk wards, who used a two-layered cloth mask and were part of a randomised controlled clinical trial comparing medical masks and cloth masks. Washing method for cloth masks (self-washing or hospital laundry). A substudy of contamination of a sample of 15 cloth and medical masks was also conducted. Infection rate over 4 weeks of follow up and viral contamination of masks tested by multiplex PCR. Viral contamination with rhinovirus was identified on both used medical and cloth masks. Most HCW (77% of daily washing) self-washed their masks by hand. The risk of infection was more than double among HCW self-washing their masks compared with the hospital laundry (HR 2.04 (95% CI 1.03 to 4.00); p=0.04). There was no significant difference in infection between HCW who wore cloth masks washed in the hospital laundry compared with medical masks (p=0.5). Using self-reported method of washing, we showed double the risk of infection with seasonal respiratory viruses if masks were self-washed by hand by HCWs. The majority of HCWs in the study reported hand-washing their mask themselves. This could explain the poor performance of two layered cloth masks, if the self-washing was inadequate. Cloth masks washed in the hospital laundry were as protective as medical masks. Both cloth and medical masks were contaminated, but only cloth masks were reused in the study, reiterating the importance of daily washing of reusable cloth masks using proper method. A well-washed cloth mask can be as protective as a medical mask. ACTRN12610000887077.


Effectiveness of naltrexone in the prevention of delayed respiratory arrest in opioid-naive methadone-intoxicated patients.
Acute methadone toxicity is a major public health concern in Iran. Methadone-intoxicated patients are in a great risk of recurrent or delayed respiratory arrest despite the prescription of initial doses of naloxone. This study aimed to evaluate the effectiveness of oral naltrexone in the management of acute methadone overdose in opioid-naive patients and check if it could be a substitute of continuous infusion of naloxone in maintaining adequate ventilation. In a randomized, double-blind, placebo-controlled study, a total of 54 opioid-naive patients with acute methadone toxicity were enrolled. The patients received either oral naltrexone or placebo capsules after awakening by naloxone. All patients underwent close monitoring of respiration. Frequency of respiratory depression or arrest, need for another dose of naloxone, duration of hospital stay, and adverse outcomes compared between the two groups. The incidence of respiratory depression was significantly less in those who had received naltrexone. Our results show that single oral dose of naltrexone is quite efficient in the prevention of recurrent or delayed respiratory arrest in opioid-naive methadone-intoxicated patients. It can shorten the duration of hospitalization and, as a consequence, decreased the risk of complications. Further studies are warranted before the generalization of this approach to other patient populations.


Has the Medicare prospective payment system led to increased nursing home efficiency?
To assess the impact of recent Medicare prospective payment system (PPS) changes on efficiency in skilled nursing homes. Medicare Cost Reports (MCR), On-line Survey Certification and Reporting System (OSCAR), Area Resource Files (ARF), a Centers for Medicare and Medicaid Services (CMS) hospital wage index website, a Consumer Price Index (CPI) database, and a survey of state Medicaid reimbursement rates. The sample was 8,361 nursing homes in the Medicare Cost Report databases from the years 1997 to 2003. Data-envelopment analyses (DEA) calculated efficiency scores for three separate DEA models: unadjusted, acuity-adjusted, and acuity-and-quality-adjusted efficiency. The efficiency scores from these models were regressed on the Medicare PPS changes (the Balanced Budget Act [BBA], the Balanced Budget Refinement Act [BBRA] and the Benefits Improvement and Protection Act) and other organizational and market explanatory variables using a panel-data truncated regression. Mean values for all efficiency measures decreased over time, the acuity-quality-adjusted efficiency measures decreasing the most. All policy variables were significantly negatively related to all efficiency measures. Higher nurse staffing was negatively related to efficiency in all but the acuity-quality-adjusted model. Other explanatory variables varied in their relationships to the efficiency variables. The results suggest that the reimbursement policy changes had a significantly negative impact on efficiency. Higher nurse staffing contributed to lower efficiency only when efficiency was not adjusted for quality. Various organizational and market factors also played significant roles in all efficiency models.


Production and functional properties of eosinophils from bone marrow cultures.
Bone marrow cultures have been established from mice infected with Mesocestoides corti and undergoing parasitic eosinophilia. In the absence of added conditioned medium, eosinophil differentiation ceases, and eosinophils are undetectable by 7 days, whereas neutrophil production continues over several weeks as with normal bone marrow. Eosinophil production can be induced by adding pokeweed mitogen-stimulated spleen supernatants (MSSS) or specific antigen-stimulated spleen supernatants (ASSS) produced from-spleen cells of M. corti-infected mice. In contrast to the continuous production of neutrophils, eosinophil production is transient, suggesting that there is no continued production of eosinophil progenitor cells in these cultures. More eosinophils are produced when MSSS is added at the initiation of cultures, compared to after a delay of 2 weeks, and establishing the cultures at 33 degrees C does not appear to enhance eosinophil production. The eosinophils produced are shown to express the eosinophil differentiation antigen defined by monoclonal antibody NIMP-R13, they produce eosinophil peroxidase in similar amounts to eosinophils taken from mice. They show normal phagocytic activity of antibody-coated erythrocytes and lyse red cells coated with antibodies of IgG1, IgG2a, IgG2b, but not IgM isotypes.


Serine protease homolog pairs CLIPA4-A6, A4-A7Δ, and A4-A12 act as cofactors for proteolytic activation of prophenoloxidase-2 and -7 in Anopheles gambiae.
Phenoloxidase (PO) catalyzed melanization and other insect immune responses are mediated by serine proteases (SPs) and their noncatalytic homologs (SPHs). Many of these SP-like proteins have a regulatory clip domain and are called CLIPs. In most insects studied so far, PO precursors are activated by a PAP (i.e., PPO activating protease) and its cofactor of clip-domain SPHs. Although melanotic encapsulation is a well-known refractory mechanism of mosquitoes against malaria parasites, it is unclear if a cofactor is required for PPO activation. In Anopheles gambiae, CLIPA4 is 1:1 orthologous to Manduca sexta SPH2; CLIPs A5-7, A12-14, A26, A31, A32, E6, and E7 are 11:4 orthologous to M. sexta SPH1a, 1b, 4, and 101, SPH2 partners in the cofactors. Here we produced proCLIPs A4, A6, A7Δ, A12, and activated them with CLIPB9 or M. sexta PAP3. A. gambiae PPO2 and PPO7 were expressed in Escherichia coli for use as PAP substrates. CLIPB9 was mutated to CLIPB9Xa by including a Factor Xa cleavage site. CLIPA7Δ was a deletion mutant with a low complexity region removed. After PAP3 or CLIPB9Xa processing, CLIPA4 formed a high Mr complex with CLIPA6, A7Δ or A12, which assisted PPO2 and PPO7 activation. High levels of specific PO activity (55-85 U/μg for PO2 and 1131-1630 U/μg for PO7) were detected in vitro, indicating that cofactor-assisted PPO activation also occurs in this species. The cleavage sites and mechanisms for complex formation and cofactor function are like those reported in M. sexta and Drosophila melanogaster. In conclusion, these data suggest that the three (and perhaps more) SPHI-II pairs may form cofactors for CLIPB9-mediated activation of PPOs for melanotic encapsulation in A. gambiae.


Insertion of a reamplification round into the ISSR-PCR protocol gives new flax fingerprinting patterns.
We expanded the basic ISSR-PCR protocol by an additional PCR reamplification round in order to detect whether increased PCR productivity would give new bands in ISSR patterns. We found that the reamplification step had a prominent impact on the quality of the inter-simple-sequence repeat (ISSR) PCR patterns of flax, depending on the particular primer used for PCR amplification. We could clearly distinguish between two types of reamplification effect. Most ISSR primers (16 out of 21) gave no reamplification effect as usual, but five primers (23.8%) provided a new ISSR fingerprinting pattern after the 2nd reamplification round, leaving the previous 1st round pattern completely blank. Therefore, we recommend the expansion of a basic ISSR-PCR protocol for another reamplification round in order to mine out full the fingerprinting potential from ISSR-PCR method.


Understanding the adsorption of ionic liquids onto zeolite ZSM-5 from aqueous solution: experimental and computational modelling.
Ionic liquids are considered as emergent pollutants as these compounds possess high persistence in aqueous solution and toxicity toward aquatic organisms. In this work, the adsorption equilibrium of 27 ionic liquids, with different cation head groups, alkyl chain lengths, and anions, onto ZSM-5 was measured experimentally at several compositions and at temperature 298.15 K and 0.1 MPa. The extensive number of ionic liquids studied allows a comprehensive study on the impact of adsorbate chemical structures toward their adsorption process. The gathered experimental results show that the anions have a dominant effect, when compared to the cation head group and the alkyl chain length, in ruling the adsorption of ionic liquids from aqueous solution onto ZSM-5. The adsorption isotherms reveal that the adsorption process is a combination between Langmuir and Freundlich behaviors, with the latter leading the general process. Moreover, computational modelling using COSMO-RS demonstrates the existence of several molecular forces that rule the adsorption process, reinforcing the idea that the ionic liquid anion rules the adsorption. The results collected in the present work provide new understanding on the molecular mechanism for the development of efficient adsorbents for removal and recovery of ionic liquids from aqueous solution.


Prolonged exposure of graphite oxide to soft X-ray irradiation during XPS measurements leads to alterations of the chemical composition.
X-ray photoelectron spectroscopy is an indispensable technique to analyse the structural and chemical features of graphene-based materials. Such detailed characterization is often imperative prior to the usage of these materials for various applications. In this work, the effects of the continuous irradiation with soft X-rays during the analysis of graphite oxide with X-ray photoelectron spectroscopy were investigated. Prolonged exposure to the X-ray source was observed to cause an overall decrease in the amount of oxygen-containing groups, which could consequently lead to the wrong interpretation of the XPS analysis result. Proper and careful consideration on the time span of XPS analysis of graphite oxide is, thus, highly advocated.


Follow-up treatment effects of contingency management and motivational interviewing on substance use: A meta-analysis.
Motivation is an integral factor in substance use treatment and long-term recovery. However, it is unclear what role intrinsic and extrinsic motivation play across different treatment modalities. A meta-analysis (N = 84) was performed to estimate the pooled effect size of Motivational Interviewing (MI; primarily targeting intrinsic motivation) and contingency management (CM; primarily targeting extrinsic motivation) at different follow-up periods. Collapsed across all substance types, CM had a significant effect at 3-month follow-up, only. In contrast, MI had a significant effect at 6-month follow-up, only. CM had small and medium effects on multiple substances at 3-month follow-up (i.e., tobacco, marijuana, stimulants, polysubstances), but not at 6-month follow-up. MI had 1 significant medium effect at 3-month follow-up (i.e., marijuana), but several significant small effects at 6-month follow-up (i.e., alcohol, tobacco, polysubstances). This meta-analysis suggests that both CM and MI promote reductions in a range of substances, even several months after the intervention concludes. Further, these results provide some evidence that extrinsically focused CM may produce medium follow-up effects in the short run, but intrinsically focused MI may produce small but durable follow-up effects. However, this interpretation is complicated by the differences between the MI and CM studies that preclude statistical tests comparing effect sizes, and few studies assessed motivation itself. Future researchers should investigate how motivational dynamics impact lasting outcomes in substance use treatment. (PsycINFO Database Record


Study on Bhasma Kalpana with special reference to the preparation of Kasisa Bhasma.
Bhasma means ash but according to Ayurveda, Bhasma means conversion of a metal into a form which is irreversible in the sense that one cannot derive the metal back from it again (Apunarbhava). It should be so light so that it must float on the surface of water after sprinkling, called Varitara. Its particle should be so small that it can enter in to the creases of fingers called Rekha-purnatva. The preparative procedure of Bhasma is a bit complicated. Many texts are available regarding the identification, acceptable qualities of metals and minerals, their purification, uses and method of preparation of their Bhasma. But in many texts, the method of Bhasma preparation of some metals and minerals is mentioned very briefly, i.e. their references are available in Sutrarupa. This leads to many practical difficulties in the preparation of Bhasma. Kasisa Bhasma is one of them. The present work was aimed to study the basic concept of Bhasma Kalpana by means preparing Kasisa Bhasma. This study suggests some modifications and ways for standardization of Bhasma procedure.


Estimating incidence trends in regular heroin use in 26 regions of Switzerland using methadone treatment data.
Regional incidence trends in regular heroin use are important for assessing the effectiveness of drug policies and for forecasting potential future epidemics. To estimate incidence trends we applied both the more traditional Reporting Delay Adjustment (RDA) method as well as the new and less data demanding General Inclusion Function (GIF) method. The latter describes the probability of an individual being in substitution treatment depending on time since the onset of heroin use. Data on year of birth, age at first regular heroin use and date of admission to and cessation of substitution treatment was available from 1997 to 2006 for 11 of the 26 regions (cantons) of Switzerland. For the remaining cantons, we used the number of patients in 5-year age group categories published in annual statistics between 1999 and 2006. Application of the RDA and GIF methods on data from the whole of Switzerland produced equivalent incidence trends. The GIF method revealed similar incidence trends in all of the Swiss cantons. Imputing a constant age of onset of 21 years resulted in almost equal trends to those obtained when real age of onset was used. The cantonal incidence estimates revealed that in the mid 80s there were high incidence rates in various regions distributed throughout all of the linguistic areas in Switzerland. During the following years these regional differences disappeared and the incidence of regular heroin use stabilized at a low level throughout the country. It has been demonstrated that even with incomplete data the GIF method allows to calculate accurate regional incidence trends.


Longitudinal Impact of Two Universal Preventive Interventions in First Grade on Educational Outcomes in High School.
This study examined the longitudinal effects of 2 first-grade universal preventive interventions on academic outcomes (e.g., achievement, special education service use, graduation, postsecondary education) through age 19 in a sample of 678 urban, primarily African American children. The classroom-centered intervention combined the Good Behavior Game (H. H. Barrish, Saunders, & Wolfe, 1969) with an enhanced academic curriculum, whereas a second intervention, the Family-School Partnership, focused on promoting parental involvement in educational activities and bolstering parents' behavior management strategies. Both programs aimed to address the proximal targets of aggressive behavior and poor academic achievement. Although the effects varied by gender, the classroom-centered intervention was associated with higher scores on standardized achievement tests, greater odds of high school graduation and college attendance, and reduced odds of special education service use. The intervention effects of the Family-School Partnership were in the expected direction; however, only 1 effect reached statistical significance. The findings of this randomized controlled trial illustrate the long-term educational impact of preventive interventions in early elementary school.


Effects of short-term endurance exercise training on acute doxorubicin-induced FoxO transcription in cardiac and skeletal muscle.
Doxorubicin (DOX) is a potent antitumor agent used in cancer treatment. Unfortunately, DOX can induce myopathy in both cardiac and skeletal muscle, which limits its clinical use. Importantly, exercise training has been shown to protect against DOX-mediated cardiac and skeletal muscle myopathy. However, the mechanisms responsible for this exercise-induced muscle protection remain elusive. These experiments tested the hypothesis that short-term exercise training protects against acute DOX-induced muscle toxicity, in part, due to decreased forkhead-box O (FoxO) transcription of atrophy genes. Rats (n = 6 per group) were assigned to sedentary or endurance exercise-trained groups and paired with either placebo or DOX treatment. Gene expression and protein abundance were measured in both cardiac and skeletal muscles to determine the impact of DOX and exercise on FoxO gene targets. Our data demonstrate that DOX administration amplified FoxO1 and FoxO3 mRNA expression and increased transcription of FoxO target genes [i.e., atrogin-1/muscle atrophy F-box (MaFbx), muscle ring finger-1 (MuRF-1), and BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3)] in heart and soleus muscles. Importantly, exercise training protected against DOX-induced increases of FoxO1 and MuRF-1 in cardiac muscle and also prevented the rise of FoxO3, MuRF-1, and BNIP3 in soleus muscle. Furthermore, our results indicate that exercise increased peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1α) in both the heart and soleus muscles. This is important because increased PGC-1α expression is known to suppress FoxO activity resulting in reduced expression of FoxO target genes. Together, these results are consistent with the hypothesis that exercise training protects against DOX-induced myopathy in both heart (FoxO1 and MuRF-1) and skeletal muscles (FoxO3, MuRF-1, and BNIP3).


On equal footing: Trends in ankle/foot injuries for men vs. women.
The objective of the current study was to examine trends in ankle/foot (A/F) injuries during the period 2001-2014, in order to determine whether the incidence of these injuries has changed and whether a previously identified difference in risk by gender still existed. In addition, other driver and crash-related risk factors were examined separately for men and women. Passenger vehicle drivers aged 16+ were identified from NASS-CDS; weighted data were analyzed for model years 2001-2014. Model years (MY) were grouped as 2001-2004 (older) vs. 2005-2014 (newer), and drivers in frontal crashes were included. Ankle injuries included fractures and dislocations to the malleolus and distal tibia/fibula. Foot injuries included fractures and dislocations of the talus, calcaneus, and tarsal/metatarsal bones. Logistic regression models were constructed to identify risk factors, including MY, age, belt use, toepan/instrument panel intrusion, and body mass index (BMI) separately for each gender using odds ratios. The incidence of A/F injuries declined significantly between older and newer MY, especially for women. Whereas before MY 2005, ankle and foot injury risk was significantly higher for women than men, risks for ankle injury are now virtually the same for both genders, and women are only 1.2 times more likely than men to sustain a foot injury in a frontal crash. From multivariable regression models, however, it is apparent that there are different risk factors for A/F injuries for men vs. women. Body weight was a significant factor for both groups, but for men it was a risk only for those extremely obese, whereas for women those who were categorized as overweight were also at increased risk. Age greater than 55 was also found to be a risk factor for foot injuries among women but not men. For men and women, toepan intrusion remained the most important factor for both foot and ankle injuries, with significantly higher odds ratios noted for men. Foot pedals were a more likely injury source for women, whereas the toepan was more likely for men. In addition, belt use was protective for ankle injuries in women but not men. Significant declines in A/F injuries have been noted in recent years, especially for women, whose risks are now similar to those for men. However, significant risk factors remain for each gender, primarily related to body habitus (BMI) and toepan intrusion. Age was a risk factor for foot injuries among women, for whom the foot pedals were more likely to be an injury source. Toepan intrusion remains a major factor for both men and women, but, with the exception of 30+ cm of intrusion, odds ratios were primarily much higher for men in each category of intrusion.


Limited hyperoxia-induced proliferative retinopathy: A model of persistent retinal vascular dysfunction, preretinal fibrosis and hyaloidal vascular reprogramming for retinal rescue.
Retinopathy of prematurity (ROP) remains the leading cause for blindness in children. Limited hyperoxia induced proliferative retinopathy (L-HIPR) was recently introduced as a potential animal model for ROP and persistent fetal vasculature; however, the detailed pathological changes remain unclear. To model L-HIPR, we placed C57BL/6J mice in 65% oxygen from birth to post-natal day 7 (P7). We examined eyes at intervals between P12 and P30. Retinal morphometry, thickness, and preretinal fibrosis were quantified at different time points on histological sections stained with hematoxylin and eosin (H&E) and Masson Trichrome, respectively. Vascular development, angiogenesis, inflammation, and pericyte coverage were analyzed using immunohistochemistry staining in retinal flat mounts and cross sections. In L-HIPR, the hyaloidal vessels persisted until the latest time point in this study, P30 and began to invaginate the peripheral then central retina starting at P12. Central retinal distortion was noted beginning at P17, while the peripheral retina demonstrated a trend of thinning from P12 to P30. We found that L-HIPR was associated with delayed and abnormal retinal vascular development with subsequent retinal inflammation, pericyte loss and preretinal fibrosis. Our study presents a detailed analysis of the L-HIPR animal model demonstrating vitreoretinal pathologic changes, preretinal fibrosis and persistent hyaloidal vessels into adulthood. Based on our findings, we suggest that the persistence and peculiar stepwise migration of the hyaloidal vessels into the retina may provide a potential rescue mechanism for inner retinal development that deserves further study.


The Macedo-Malone antegrade continence enema procedure: early experience.
The successful treatment of fecal incontinence can dramatically improve the quality of life of affected children. The introduction of the Malone antegrade continence enema provides the opportunity to manage previously resistant cases. However, using the to create this catheterizable channel is not always possible, and the duration of these antegrade enemas is a source of concern for the patients. We describe a new approach to create left continent colonic access to shorten the duration of these enemas, and report the experience gained from the first 9 cases managed at our institution. During a 5-year period 9 patients underwent a Macedo-Malone antegrade continence enema at our institution. Incontinence was associated with myelomeningocele in 7 patients and anorectal malformation in 2. The antegrade continence enema procedure is begun by isolating a 2 cm flap in a tenia on the left colon (spleen flexure). A 12Fr silicone Foley catheter is placed on the mucosal surface of the flap to allow tubularization of the plate with interrupted polyglycolic acid 3-zero transverse sutures, creating an efferent tubular conduit. Antegrade colonic washouts were started 2 weeks after surgery with saline solution or tap water in all patients. Followup of our 9 cases ranged from 8 to 33 months (average 20.7). Enema volume varied from 250 to 800 ml, with administration taking from 45 to 60 minutes, and colonic evacuation occurred within 30 to 60 minutes of enema administration. Of the 9 patients 8 were completely continent and 1 was partially continent. Four patients experienced difficulty with catheterization initially because of stenosis of the stomal track. The affected stomas were dilated, which was successful in 1 case. Three patients subsequently required stomal revision. The Macedo-Malone procedure is a relatively straightforward operative approach providing an effective washout technique that is acceptable to parents and children.


Early detection of Psa infection in kiwifruit by means of infrared thermography at leaf and orchard scale.
Pseudomonas syringae pv. actinidiae (Psa), the causal agent of bacterial canker of kiwifruit, has become a worldwide threat for the kiwifruit industry. In this work, the potential of infrared thermography for early detection of physiological symptoms related to Psa-infection at leaf and at orchard block scale was assessed. At the leaf level, thermal cold spots appeared shortly after Psa-infection, well before any visual symptoms. A few weeks after infection, thermal hot spots were observed, associated with, but not limited to, spots of visible leaf necrosis. At orchard block level, Psa-infected canes were significantly warmer in both blocks and on all measurement days. A novel wet reference surface, existing of a cluster of cotton imitation leaves with similar dimensions and orientation as real leaves and remaining wet through sucking up water from a small container, was used to estimate the crop water stress index (CWSI). CWSI showed stable values of infected and uninfected areas during the day and between following days. Crop temperature and CWSI were closely correlated with leaf stomatal conductance, which was lower in infected canes. A Psa-infection map based on canopy temperature revealed that Psa infects the outer canes rather than the central part of the canopy.


The Roles of Parent-and-Child Mental Health and Parental Internet Addiction in Adolescent Internet Addiction: Does a Parent-and-Child Gender Match Matter?
Objective: This study aimed to investigate the relationship between parental mental health, particularly depression, and Internet addiction (IA) among adolescents taking into consideration adolescent mental health and parental IA as possible mediating factors. Of particular interest was the effect of parent-and-child gender match on these relationships. Materials and Methods: This was a population-based parent-and-child dyad health survey utilizing a random sampling technique. Adolescent IA was measured by the Internet Addiction Test (IAT) designed by Young. The mental health status of the parents was assessed using the Depression, Anxiety, Stress Scale (DASS). Data were analyzed using Structural Equation Model (SEM) techniques with stratification by parent-and-child gender match. Results: One thousand ninety-eight (n = 1,098) parent-and-child dyads were recruited, and useful information was obtained. The mean IAT score was 28.6 (SD = 9.9) for parents and 41.7 (SD = 12.4) for adolescents. Results of the SEM suggested that the effect of parental depression on adolescent IA was mediated through adolescent mental health mainly through adolescent stress (regression weight = 0.33, p < 0.001) and less so through adolescent depression (regression weight = 0.19, p < 0.001) or parental IA (regression weight = 0.13, p < 0.001). Further analysis revealed that these mediating relationships are more significantly manifested in the father-and-son and mother-and-daughter dyads. Conclusions: Result suggested that the relationship between parental mental health and adolescent IA is complex and that adolescent mental health and parental IA also play important roles as mediating factors. These results have direct implications on the treatment and prevention of IA among young people.


A 14-3-3 Family Protein from Wild Soybean (Glycine Soja) Regulates ABA Sensitivity in Arabidopsis.
It is widely accepted that the 14-3-3 family proteins are key regulators of multiple stress signal transduction cascades. By conducting genome-wide analysis, researchers have identified the soybean 14-3-3 family proteins; however, until now, there is still no direct genetic evidence showing the involvement of soybean 14-3-3s in ABA responses. Hence, in this study, based on the latest Glycine max genome on Phytozome v10.3, we initially analyzed the evolutionary relationship, genome organization, gene structure and duplication, and three-dimensional structure of soybean 14-3-3 family proteins systematically. Our results suggested that soybean 14-3-3 family was highly evolutionary conserved and possessed segmental duplication in evolution. Then, based on our previous functional characterization of a Glycine soja 14-3-3 protein GsGF14o in drought stress responses, we further investigated the expression characteristics of GsGF14o in detail, and demonstrated its positive roles in ABA sensitivity. Quantitative real-time PCR analyses in Glycine soja seedlings and GUS activity assays in PGsGF14O:GUS transgenic Arabidopsis showed that GsGF14o expression was moderately and rapidly induced by ABA treatment. As expected, GsGF14o overexpression in Arabidopsis augmented the ABA inhibition of seed germination and seedling growth, promoted the ABA induced stomata closure, and up-regulated the expression levels of ABA induced genes. Moreover, through yeast two hybrid analyses, we further demonstrated that GsGF14o physically interacted with the AREB/ABF transcription factors in yeast cells. Taken together, results presented in this study strongly suggested that GsGF14o played an important role in regulation of ABA sensitivity in Arabidopsis.


Nanoscale mineralization of cell-laden methacrylated gelatin hydrogels using calcium carbonate-calcium citrate core-shell microparticles.
Conventional biomaterials developed for bone regeneration fail to fully recapitulate the nanoscale structural organization and complex composition of the native bone microenvironment. Therefore, despite promoting osteogenic differentiation of stem cells, they fall short of providing the structural, biochemical, and mechanical stimuli necessary to drive osteogenesis for bone regeneration and function. To address this, we have recently developed a novel strategy to engineer bone-like tissue using a biomimetic approach to achieve rapid and controlled nanoscale mineralization of a cell-laden matrix in the presence of osteopontin, a non-collagenous protein, and a supersaturated solution of calcium and phosphate medium. Here, we build on this approach to engineer bone regeneration scaffolds comprising methacrylated gelatin (GelMA) hydrogels incorporated with calcium citrate core-shell microparticles as a sustained and reliable source of calcium ions for in situ mineralization. We demonstrate successful biomineralization of GelMA hydrogels by embedded calcium carbonate-calcium citrate core-shell microparticles with the resultant mineral chemistry, structure, and organization reminiscent of that of native bone. The biomimetic mineralization was further shown to promote osteogenic differentiation of encapsulated human mesenchymal stem cells even in the absence of other exogenous osteogenic induction factors. Ultimately, by combining the superior biological response engendered by biomimetic mineralization with the intrinsic tissue engineering advantages offered by GelMA, such as biocompatibility, biodegradability, and printability, we envision that our system offers great potential for bone regeneration efforts.


Functional neuroanatomy of the noradrenergic locus coeruleus: its roles in the regulation of arousal and autonomic function part I: principles of functional organisation.
The locus coeruleus (LC) is the major noradrenergic nucleus of the brain, giving rise to fibres innervating extensive areas throughout the neuraxis. Recent advances in neuroscience have resulted in the unravelling of the neuronal circuits controlling a number of physiological functions in which the LC plays a central role. Two such functions are the regulation of arousal and autonomic activity, which are inseparably linked largely via the involvement of the LC. The LC is a major wakefulness-promoting nucleus, resulting from dense excitatory projections to the majority of the cerebral cortex, cholinergic neurones of the basal forebrain, cortically-projecting neurones of the thalamus, serotoninergic neurones of the dorsal raphe and cholinergic neurones of the pedunculopontine and laterodorsal tegmental nucleus, and substantial inhibitory projections to sleep-promoting GABAergic neurones of the basal forebrain and ventrolateral preoptic area. Activation of the LC thus results in the enhancement of alertness through the innervation of these varied nuclei. The importance of the LC in controlling autonomic function results from both direct projections to the spinal cord and projections to autonomic nuclei including the dorsal motor nucleus of the vagus, the nucleus ambiguus, the rostroventrolateral medulla, the Edinger-Westphal nucleus, the caudal raphe, the salivatory nuclei, the paraventricular nucleus, and the amygdala. LC activation produces an increase in sympathetic activity and a decrease in parasympathetic activity via these projections. Alterations in LC activity therefore result in complex patterns of neuronal activity throughout the brain, observed as changes in measures of arousal and autonomic function.


The light at the end of the tunnel: an unusual case of acute kidney injury in a pediatric patient: Answers.
Monoclonal gammopathies are a rare diagnosis in pediatric patients. A 19-year-old female patient with past medical history of hypogammaglobulinemia and natural killer cell deficiency and stage III follicular lymphoma, in remission, presented with a right-sided pneumonia, noted to have acute kidney injury and proteinuria. Complement C3 and C4 levels were normal. Anti-double-stranded DNA antibodies, antinuclear antibodies, anti-extractable nuclear antigen antibodies, and antineutrophil cytoplasmic antibodies were negative. A renal biopsy showed numerous fractured tubular casts that were periodic acid-Schiff and silver-stain negative and fuchsinophilic on trichrome stain, with associated giant cells, tubulitis, acute tubular injury, and tubular rupture. The tubular casts had 3+ staining for lambda light chains and 0-1+ staining for kappa light chains. These findings were consistent with light chain cast nephropathy (LCCN). Serum free light chains, serum immunofixation, urine protein electrophoresis, and urine immunofixation studies supported the renal biopsy diagnosis of LCCN. A bone marrow biopsy showed normal trilineage hematopoiesis and also revealed an atypical B cell population detected by flow cytometry. Pathology specimens from lesions in the distal small bowel were characteristic of diffuse large B cell lymphoma (DLBCL). Chemoreduction therapy followed by chemotherapy was initiated for the DLBCL. Three months after initiation of chemotherapy, the patient's creatinine has improved by > 50%. The likely cause of her LCCN was the new diagnosis of a DLBCL. Other risk factors include her history of hypogammaglobulinemia, natural killer (NK) cell deficiency, community-acquired pneumonia, and prior follicular lymphoma. Our patient may be the youngest reported case of LCCN. Treatment of LCCN is based on treating the underlying clonal plasma cell or B cell proliferation, typically with chemotherapy.


Phylogenetic evidence against evolutionary stasis and natural abiotic reservoirs of influenza A virus.
Zhang et al. (G. Zhang, D. Shoham, D. Gilichinsky, S. Davydov, J. D. Castello, and S. O. Rogers, J. Virol. 80:12229-12235, 2006) have claimed to have recovered influenza A virus RNA from Siberian lake ice, postulating that ice might represent an important abiotic reservoir for the persistence and reemergence of this medically important pathogen. A rigorous phylogenetic analysis of these influenza A virus hemagglutinin gene sequences, however, indicates that they originated from a laboratory reference strain derived from the earliest human influenza A virus isolate, WS/33. Contrary to Zhang et al.'s assertions that the Siberian "ice viruses" are most closely related either to avian influenza virus or to human influenza virus strains from Asia from the 1960s (Zhang et al., J. Virol. 81:2538 [erratum], 2007), they are clearly contaminants from the WS/33 positive control used in their laboratory. There is thus no credible evidence that environmental ice acts as a biologically relevant reservoir for influenza viruses. Several additional cases with findings that seem at odds with the biology of influenza virus, including modern-looking avian influenza virus RNA sequences from an archival goose specimen collected in 1917 (T. G. Fanning, R. D. Slemons, A. H. Reid, T. A. Janczewski, J. Dean, and J. K. Taubenberger, J. Virol. 76:7860-7862, 2002), can also be explained by laboratory contamination or other experimental errors. Many putative examples of evolutionary stasis in influenza A virus appear to be due to laboratory artifacts.


Faculty and programmatic influences on the percentage of graduates of color from professional physical therapy programs in the United States.
The physical therapy profession in the United States suffers from a shortage of providers of color. This is unlikely to change with newly graduating students, as 2.6% of 2017 graduates were African American and 5.7% were Hispanic or Latino. Faculty mentorship has a more profound influence on the retention of underrepresented minority students as compared with students from privileged backgrounds, according to undergraduate literature. The influences of faculty characteristics on physical therapy graduates of color are unknown. The purpose of this study was to determine faculty and programmatic characteristics that could influence the percentage of physical therapy graduates of color. This study implemented the theory of academic capitalism to inform the results of a retrospective panel analysis, which used accreditation data from 2008 to 2017. Data from 231 programs was used to create fixed effects and random effects models to estimate the effects that faculty and program characteristics had on the percentage of graduates of color that a program produced. There was a statistically significant positive relationship between faculty of color and graduates of color (p < 0.001), but faculty must be sufficiently diverse before a program can expect a meaningful change in their percentage of graduates of color. Academic capitalist principles suggest that competition between programs for resources could negatively influence the proportion of graduates of color. Cause and effect associations between variables cannot be established. The authors concluded that professional physical therapy programs appeared to have increases in the percentages of graduates of color when they had more core faculty members of color.


Effect of volume expansion on pressor response to angiotensin II in pregnant ewes.
Vascular refractoriness to infused angiotensin II (AII) characterizes normal human and ovine pregnancy. To ascertain whether the refractoriness in the gravid ewe is mediated by either endogenous plasma concentrations of renin and AII or vasomotor reflexes, effects of acute volume expansion (VE) on the pressor response to AII were studied in chronically instrumented nonpregnant and near-term pregnant sheep. Dose-response curves describing the pressor response (delta BP) were determined before and after infusions of 1.0 1 of isotonic saline (NS) or 0.5 1 of 10% dextran (D). In nonpregnant sheep, hematocrit (Hct) and plasma renin activity (PRA) fell in all animals after NS (n = 7) and D (n = 6) (P less than 0.005). After VE with NS and D, delta BP increased at each dose of AII (P less than 0.05). The pressor response to AII in pregnant sheep was not altered by NS although decreases in Hct and PRA were comparable to those in nonpregnant sheep. Baroreceptor responses were not altered. Vascular refractoriness to infused AII in pregnant sheep is not due primarily to changes in plasma concentrations of renin-AII but more likely to another factor, vessel wall refractoriness. In this respect, the ewe is similar to the human.


H3K4me3 demethylation by the histone demethylase KDM5C/JARID1C promotes DNA replication origin firing.
DNA replication is a tightly regulated process that initiates from multiple replication origins and leads to the faithful transmission of the genetic material. For proper DNA replication, the chromatin surrounding origins needs to be remodeled. However, remarkably little is known on which epigenetic changes are required to allow the firing of replication origins. Here, we show that the histone demethylase KDM5C/JARID1C is required for proper DNA replication at early origins. JARID1C dictates the assembly of the pre-initiation complex, driving the binding to chromatin of the pre-initiation proteins CDC45 and PCNA, through the demethylation of the histone mark H3K4me3. Fork activation and histone H4 acetylation, additional early events involved in DNA replication, are not affected by JARID1C downregulation. All together, these data point to a prominent role for JARID1C in a specific phase of DNA replication in mammalian cells, through its demethylase activity on H3K4me3.


Establishment of human induced pluripotent stem cell line (SDQLCHi060-A) from a patient with AUTS2 syndrome carrying a heterozygous mutation in AUTS2 gene.
AUTS2 syndrome is a neurodevelopmental disorder caused by pathogenic variants and deletions of the AUTS2 gene, resulting in intellectual disability, microcephaly, and other phenotypes. Here, we generated a human induced pluripotent stem cell (iPSC) line from a 21-month-old boy with AUTS2 syndrome caused by a heterozygous mutation (c.1486C > T, p.Q496X) in the AUTS2 gene. The iPSCs had normal morphology and karyotype, expressed pluripotency markers, showed differentiation potential in vitro, and carried the AUTS2 gene mutation.


The triumvirate of beta-cell regeneration: solutions and bottlenecks to curing diabetes.
On 11 January 1922 insulin injection was used for the first time in the treatment of diabetes. Even today, daily insulin injections are the life-saving treatment for patients with Type 1 diabetes and advanced Type 2 diabetes. However, insulin injections often fail to achieve full glucose control, which in the long-term leads to multiple complications and mortality. Beta-cells, the natural producers and secretors of insulin, remain the gold-standard in regulating blood glucose levels. In this review, we focus on three strategies aiming at counteracting beta-cell loss in order to gain insulin independence: replacement, replication and protection. The three approaches, together termed as the triumvirate of beta-cell regeneration, may constitute the basis for a future cure for diabetes.


Homologies, analogies, synapomorphies and homoplasies: problems and considerations.
The author discusses, on the evidence of some typical examples, some problems in the assessment of homologies which have surfaced by the integration of ultrastructural and genetic evidences in the assessment of the morphologic and evolutionary significance of structures. He thence considers problems of correct assessment of homologies as true apomorphic rather than homoplastic traits and which are often overlooked in the construction of cladistic matrixes. His conclusions are that a more comprehensive approach in morphological research should be stressed and that a strong effort is badly needed for the development of classical comparative anatomy versus the present trend towards ultra specialized studies; moreover, at the present stage of research, the available evidence is generally quite insufficient for the development of reliable matrixes of data, so that a more empirical and pragmatic approach is much safer.


Physical therapy enhances functions and quality of life in older patients with breast cancer-related lymphedema: A prospective experimental study.
Lymphedema of the arm is one of the most common complications following breast cancer surgery. The primary aim of this study was to evaluate the effects of complex decongestive physical therapy (CDPt) on upper extremity functions, activities of daily living (ADL), and quality of life (QoL), and secondly the effects of the degree of lymphedema on post-treatment differences in older patients with breast cancer-related lymphedema (BCRL). Sixty-eight patients who had BCRL were included between 2015 and 2017. Arm function was evaluated with the Constant-Murley scale, while ADL was measured with the Lawton Instrumental Activities of Daily Living Scale, and QoL was measured with the Lymphedema Functioning, Disability and Health Questionnaire as pre- and post-treatment tests. The patients underwent a CDPt program for 6 weeks. There were statistically significant improvements for all outcome measurements in older patients with Grade 1 and 2 lymphedemas after the treatment (P < 0.001). The Grade 1 patients had a greater difference at mobility, participation in the life and social activities, and their total scores of quality of life had a significance level of P < 0.001. Older patients with Grade 1 BCRL had better mobility, participation in the life, and social activities. CDPt provides enhancement of arm functions, ADL, and QoL in older patients with breast cancer-related lymphedema.


Gas-Solid Phase Transition in Laser Multiple Filamentation.
While propagating in transparent media, near-infrared multiterawatt (TW) laser beams break up in a multitude of filaments of typically 100-200 um diameter with peak intensities as high as 10 to 100 TW/cm^{2}. We observe a phase transition at incident beam intensities of 0.4 TW/cm^{2}, where the interaction between filaments induce solidlike two-dimensional crystals with a 2.7 mm lattice constant, independent of the initial beam diameter. Below 0.4 TW/cm^{2}, we evidence a mixed phase state in which some filaments are closely packed in localized clusters, nucleated on inhomogeneities (seeds) in the transverse intensity profile of the beam, and other are sparse with almost no interaction with their neighbors, similar to a gas. This analogy with a thermodynamic gas-solid phase transition is confirmed by calculating the interaction Hamiltonian between neighboring filaments, which takes into account the effect of diffraction, Kerr self-focusing, and plasma generation. The shape of the effective potential is close to a Morse potential with an equilibrium bond length close to the observed value.


Sleep-Disordered Breathing, Hypoxia, and Pulmonary Physiologic Influences in Atrial Fibrillation.
Background We leverage a large clinical cohort to elucidate sleep-disordered breathing and sleep-related hypoxia in incident atrial fibrillation (AF) development given the yet unclear contributions of sleep-related hypoxia and pulmonary physiology in sleep-disordered breathing and AF. Methods and Results Patients who underwent sleep studies at Cleveland Clinic January 2, 2000, to December 30, 2015, comprised this retrospective cohort. Cox proportional hazards models were used to examine apnea hypopnea index, percentage time oxygen saturation <90%, minimum and mean oxygen saturation, and maximum end-tidal carbon dioxide on incident AF adjusted for age, sex, race, body mass index, cardiopulmonary disease and risk factors, antiarrhythmic medications, and positive airway pressure. Those with spirometry were additionally adjusted for forced expiratory volume in 1 second, forced vital capacity, and forced expiratory volume in 1 second/forced vital capacity. This cohort (n=42 057) was 50.7±14.1 years, 51.3% men, 74.1% White individuals, had median body mass index 33.2 kg/m2, and 1947 (4.6%) developed AF over 5 years. A 10-unit apnea hypopnea index increase was associated with 2% higher AF risk (hazard ratio [HR], 1.02 [95% CI, 1.00-1.03]). A 10-unit increase in percentage time oxygen saturation <90% and 10-unit decreases in mean and minimum oxygen saturation were associated with 6% (HR, 1.06 [95% CI, 1.04-1.08]), 30% (HR, 1.30 [95% CI, 1.18-1.42]), and 9% (HR, 1.09 [95% CI, 1.03-1.15]) higher AF risk, respectively. After adjustment for spirometry (n=9683 with available data), only hypoxia remained significantly associated with incident AF, although all coefficients were stable. Conclusions Sleep-related hypoxia was associated with incident AF in this clinical cohort, consistent across 3 measures of hypoxia, persistent after adjustment for pulmonary physiologic impairment. Findings identify a strong role for sleep-related hypoxia in AF development without pulmonary physiologic interdependence.