Epigenetic balance ensures mechanistic control of MLL amplification and rearrangement.

MLL/KMT2A amplifications and translocations are prevalent in infant, adult, and therapy-induced leukemia. However, the molecular contributor(s) to these alterations are unclear. Here, we demonstrate that histone H3 lysine 9 mono- and di-methylation (H3K9me1/2) balance at the MLL/KMT2A locus regulates these amplifications and rearrangements. This balance is controlled by the crosstalk between lysine demethylase KDM3B and methyltransferase G9a/EHMT2. KDM3B depletion increases H3K9me1/2 levels and reduces CTCF occupancy at the MLL/KMT2A locus, in turn promoting amplification and rearrangements. Depleting CTCF is also sufficient to generate these focal alterations. Furthermore, the chemotherapy doxorubicin (Dox), which associates with therapy-induced leukemia and promotes MLL/KMT2A amplifications and rearrangements, suppresses KDM3B and CTCF protein levels. KDM3B and CTCF overexpression rescues Dox-induced MLL/KMT2A alterations. G9a inhibition in human cells or mice also suppresses MLL/KMT2A events accompanying Dox treatment. Therefore, MLL/KMT2A amplifications and rearrangements are controlled by epigenetic regulators that are tractable drug targets, which has clinical implications.

Epigenetic modulators provide a path to understanding disease and therapeutic opportunity.

The discovery of epigenetic modulators (writers, erasers, readers, and remodelers) has shed light on previously underappreciated biological mechanisms that promote diseases. With these insights, novel biomarkers and innovative combination therapies can be used to address challenging and difficult to treat disease states. This review highlights key mechanisms that epigenetic writers, erasers, readers, and remodelers control, as well as their connection with disease states and recent advances in associated epigenetic therapies.

Elongin functions as a loading factor for Mediator at ATF6α-regulated ER stress response genes.

The bZIP transcription factor ATF6α is a master regulator of endoplasmic reticulum (ER) stress response genes. In this report, we identify the multifunctional RNA polymerase II transcription factor Elongin as a cofactor for ATF6α-dependent transcription activation. Biochemical studies reveal that Elongin functions at least in part by facilitating ATF6α-dependent loading of Mediator at the promoters and enhancers of ER stress response genes. Depletion of Elongin from cells leads to impaired transcription of ER stress response genes and to defects in the recruitment of Mediator and its CDK8 kinase subunit. Taken together, these findings bring to light a role for Elongin as a loading factor for Mediator during the ER stress response.

Neuroimmune proteins can differentiate between tauopathies.

BACKGROUND: Tauopathies are a group of neurodegenerative diseases where there is pathologic accumulation of hyperphosphorylated tau protein (ptau). The most common tauopathy is Alzheimer's disease (AD), but chronic traumatic encephalopathy (CTE), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and argyrophilic grain disease (AGD) are significant health risks as well. Currently, it is unclear what specific molecular factors might drive each distinct disease and represent therapeutic targets. Additionally, there is a lack of biomarkers that can differentiate each disease in life. Recent work has suggested that neuroinflammatory changes might be specific among distinct diseases and offers a novel resource for mechanistic targets and biomarker candidates. METHODS: To better examine each tauopathy, a 71 immune-related protein multiplex ELISA panel was utilized to analyze anterior cingulate grey matter from 127 individuals neuropathologically diagnosed with AD, CTE, PSP, CBD, and AGD. A partial least square regression analysis was carried out to perform unbiased clustering and identify proteins that are distinctly correlated with each tauopathy correcting for age and gender. Receiver operator characteristic and binary logistic regression analyses were then used to examine the ability of each candidate protein to distinguish diseases. Validation in postmortem cerebrospinal fluid (CSF) from 15 AD and 14 CTE cases was performed to determine if candidate proteins could act as possible novel biomarkers. RESULTS: Five clusters of immune proteins were identified and compared to each tauopathy to determine if clusters were specific to distinct disease. Each cluster was found to correlate with either CTE, AD, PSP, CBD, or AGD. When examining which proteins were the strongest driver of each cluster, it was observed the most distinctive protein for CTE was CCL21, AD was FLT3L, and PSP was IL13. Individual proteins that were specific to CBD and AGD were not observed. CCL21 was observed to be elevated in CTE CSF compared to AD cases (p = 0.02), further validating the use as possible biomarkers. Sub-analyses for male only cases confirmed the results were not skewed by gender differences. CONCLUSIONS: Overall, these results highlight that different neuroinflammatory responses might underlie unique mechanisms in related neurodegenerative pathologies. Additionally, the use of distinct neuroinflammatory signatures could help differentiate between tauopathies and act as novel biomarker candidate to increase specificity for in-life diagnoses.

[Diagnostics of clinical and prodromal idiopathic Parkinson's disease : New criteria]. / Diagnostik des klinischen und prodromalen idiopathischen Parkinson-Syndroms : Neue Kriterien.

BACKGROUND: Recently, the Movement Disorder Society (MDS) published an adaptation of the previous United Kingdom Brain Bank Society (UKBBS) criteria for the diagnosis of idiopathic Parkinson's disease (iPD). OBJECTIVES: This article presents the changes in the current clinical diagnostic criteria for IPD. Furthermore, the new MDS criteria for prodromal iPD are discussed. RESULTS: The recently introduced MDS criteria for the clinical diagnosis of iPD include useful novel features (e.g. postural instability is no longer listed as a cardinal symptom, familiar history of iPD and intake of neuroleptics at the first visit no longer lead to exclusion of the diagnosis) and red flags do not lead to exclusion of the diagnosis; however, they must be counterbalanced by the presence of supportive criteria for iPD. The criteria for identification of persons in the prodromal stage are currently established only for scientific investigations. CONCLUSION: The new MDS criteria for the diagnostics of iPD should help to improve the sensitivity and specificity.

[Helpful instrumental examinations in idiopathic Parkinson's disease]. / Hilfreiche Zusatzuntersuchungen beim idiopathischen Parkinson-Syndrom.

BACKGROUND: The clinical diagnosis of idiopathic Parkinson's disease (iPD) can be challenging. In these cases, additional diagnostic methods are available that can help to improve diagnostic accuracy. OBJECTIVES, MATERIAL AND METHODS: This article provides an overview of currently available and promising novel ancillary methods for the early and differential diagnosis of iPD. RESULTS: Imaging tools, such as 1.5 Tesla magnetic resonance imaging (MRI) and computed tomography (CT) are mainly used for the differentiation between iPD and symptomatic parkinsonian syndromes (PS). High-resolution diffusion tensor imaging and iron and neuromelanin-sensitive high-field MRI sequences can become important in the future, particularly for earlier diagnosis. Transcranial B­mode sonography of the substantia nigra and basal ganglia is established for early and differential diagnostics, especially in the combination of diagnostic markers but necessitates an adequately trained investigator and the use of validated digital image analysis instruments. DATScan can discriminate iPD from essential tremor, medication-induced parkinsonism and psychogenic movement disorder but not iPD from atypical PS. For the latter differential diagnosis, fluorodeoxyglucose positron emission tomography and myocardial metaiodobenzylguanidine scintigraphy can be helpful. Olfactory testing should preferably be used in combination with other diagnostic tests. Genetic, biochemical and histopathological tests are currently not recommended for routine use. Novel sensor-based techniques have a high potential to support clinical diagnosis of iPD but have not yet reached a developmental stage that is sufficient for clinical use. Novel sensor-based techniques have high potential to support clinical diagnosis of iPD, but have not yet reached a development stage that is sufficient for clinical use. CONCLUSION: Ancillary diagnostic methods can support the early and differential diagnosis of iPD.

Weighted versus uniform dose of tranexamic acid in patients undergoing primary, elective knee arthroplasty: a prospective randomized controlled trial.

In a prospective, randomized, double-blinded, controlled study (25 controls), TA was infused parenterally before tourniquet release in two study groups. Group 1 (n = 20) received a 1 g dose, and group 2 (n = 20) received a 20 mg/kg dose. There was no significant difference between groups 1 and 2 with intra-operative, post-operative and total blood loss. Both groups 1 and 2 exhibited significant improvements in intra-operative, post-operative, and total blood loss compared to the control group (P < 0.05). Two blood transfusions were given to one patient in the weighted group, compared to 19 transfusions (10 patients) in the control group. This study suggests that a single 1-g dose can be used with the same efficacy as a weighted 20 mg/kg dose.

Changes in landscape and climate in Mexico and Texas reveal small effects on migratory habitat of monarch butterflies (Danaus plexippus).

The decline of the iconic monarch butterfly (Danaus plexippus) in North America has motivated research on the impacts of land use and land cover (LULC) change and climate variability on monarch habitat and population dynamics. We investigated spring and fall trends in LULC, milkweed and nectar resources over a 20-year period, and ~ 30 years of climate variables in Mexico and Texas, U.S. This region supports spring breeding, and spring and fall migration during the annual life cycle of the monarch. We estimated a - 2.9% decline in milkweed in Texas, but little to no change in Mexico. Fall and spring nectar resources declined < 1% in both study extents. Vegetation greenness increased in the fall and spring in Mexico while the other climate variables did not change in both Mexico and Texas. Monarch habitat in Mexico and Texas appears relatively more intact than in the midwestern, agricultural landscapes of the U.S. Given the relatively modest observed changes in nectar and milkweed, the relatively stable climate conditions, and increased vegetation greenness in Mexico, it seems unlikely that habitat loss (quantity or quality) in Mexico and Texas has caused large declines in population size or survival during migration.

The effect of early prednisolone treatment on the generalization rate in ocular myasthenia gravis.

BACKGROUND AND PURPOSE: Several small retrospective studies have observed that patients with a purely ocular manifestation of myasthenia gravis (MG) are significantly less likely to convert to a generalized disease when treated early on with corticosteroids. However, given the limited number of reported patients in the literature these findings still remain controversial. METHODS: In order to increase the number of published cases, we performed a retrospective analysis on 44 patients with newly diagnosed ocular MG who were subsequently either treated with corticosteroids or received no immunosuppressive therapy at all. The generalization rate was assessed at the end of a 2-year follow-up period. RESULTS: Whereas none of 17 treated patients generalized, 11 of 27 (41%) untreated patients developed generalized symptoms. The difference between the groups was significant (P=0.003). CONCLUSIONS: Our results agree well with previous studies on this issue. Taken together, published data indicate risk ratios for generalization of below 0.32 under corticosteroid treatment in comparison to untreated patients.

Elimination of Postoperative Narcotics in Infant Robotic Pyeloplasty Using Caudal Anesthesia and a Non-Narcotic Pain Pathway.

Introduction: Research suggests that narcotic pain medications are dramatically overprescribed. We hypothesize that narcotics are unnecessary for postoperative pain control in most infants undergoing robotic pyeloplasty. In this series, we report our experience combining caudal blocks with a non-narcotic postoperative pathway as a means of eliminating postoperative narcotics after infant robotic pyeloplasty. Methods: We reviewed 24 consecutive patients who underwent robotic pyeloplasty by a single surgeon treated with an end-procedure caudal block followed by a non-narcotic postoperative pain pathway treated between May 2017 and May 2021. The standardized postoperative pathway consisted of an end-procedure caudal block followed by alternating intravenous acetaminophen and ketorolac. We reviewed demographics, outcomes, and unscheduled health care encounters within 30 postoperative days. Results: Sixty-three percent (15/24) of patients were male and average age was 12.1 months (range 4-34 months). Fifty-eight percent (9/15) underwent surgery on the left, and 16.7% (4/24) of patients received a single postoperative dose of narcotics in the postanesthesia care unit. No patient required narcotic prescriptions at discharge or anytime thereafter. The average length of stay was 1.13 days. There was no pain-related unscheduled visits or phone calls after discharge. Conclusions: This series shows that a non-narcotic standardized pain management strategy is a viable option for infants undergoing robotic pyeloplasty. Postprocedure caudal block is a good addition to a non-narcotic pathway. In the future, we intend to expand these findings to other pediatric urologic procedures in the hope of eliminating unnecessary narcotic use.

A continental-scale survey of Wolbachia infections in blue butterflies reveals evidence of interspecific transfer and invasion dynamics.

Infections by maternally inherited bacterial endosymbionts, especially Wolbachia, are common in insects and other invertebrates but infection dynamics across species ranges are largely under studied. Specifically, we lack a broad understanding of the origin of Wolbachia infections in novel hosts, and the historical and geographical dynamics of infections that are critical for identifying the factors governing their spread. We used Genotype-by-Sequencing data from previous population genomics studies for range-wide surveys of Wolbachia presence and genetic diversity in North American butterflies of the genus Lycaeides. As few as one sequence read identified by assembly to a Wolbachia reference genome provided high accuracy in detecting infections in host butterflies as determined by confirmatory PCR tests, and maximum accuracy was achieved with a threshold of only 5 sequence reads per host individual. Using this threshold, we detected Wolbachia in all but 2 of the 107 sampling localities spanning the continent, with infection frequencies within populations ranging from 0% to 100% of individuals, but with most localities having high infection frequencies (mean = 91% infection rate). Three major lineages of Wolbachia were identified as separate strains that appear to represent 3 separate invasions of Lycaeides butterflies by Wolbachia. Overall, we found extensive evidence for acquisition of Wolbachia through interspecific transfer between host lineages. Strain wLycC was confined to a single butterfly taxon, hybrid lineages derived from it, and closely adjacent populations in other taxa. While the other 2 strains were detected throughout the rest of the continent, strain wLycB almost always co-occurred with wLycA. Our demographic modeling suggests wLycB is a recent invasion. Within strain wLycA, the 2 most frequent haplotypes are confined almost exclusively to separate butterfly taxa with haplotype A1 observed largely in Lycaeides melissa and haplotype A2 observed most often in Lycaeides idas localities, consistent with either cladogenic mode of infection acquisition from a common ancestor or by hybridization and accompanying mutation. More than 1 major Wolbachia strain was observed in 15 localities. These results demonstrate the utility of using resequencing data from hosts to quantify Wolbachia genetic variation and infection frequency and provide evidence of multiple colonizations of novel hosts through hybridization between butterfly lineages and complex dynamics between Wolbachia strains.

A Role for FACT in RNA Polymerase II Promoter-Proximal Pausing.

FACT (facilitates chromatin transcription) is an evolutionarily conserved histone chaperone that was initially identified as an activity capable of promoting RNA polymerase II (Pol II) transcription through nucleosomes in vitro. In this report, we describe a global analysis of FACT function in Pol II transcription in Drosophila. We present evidence that loss of FACT has a dramatic impact on Pol II elongation-coupled processes including histone H3 lysine 4 (H3K4) and H3K36 methylation, consistent with a role for FACT in coordinating histone modification and chromatin architecture during Pol II transcription. Importantly, we identify a role for FACT in the maintenance of promoter-proximal Pol II pausing, a key step in transcription activation in higher eukaryotes. These findings bring to light a broader role for FACT in the regulation of Pol II transcription.

Extended interhuman transmission of monkeypox in a hospital community in the Republic of the Congo, 2003.

This report describes the first reported outbreak of human monkeypox in the Republic of Congo. Eleven confirmed and probable monkeypox cases were observed during this outbreak, all were less than 18 years old, and most resided on the grounds of the Government Hospital in Impfondo. Molecular, virologic, and serologic, and diagnostic assays were used to detect evidence of monkeypox (or orthopox) virus infection in individuals with striking dermatologic and other clinical manifestations. The majority of cases in this outbreak experienced significant, symptomatic illnesses; there was one death, possibly involving secondary complications, and one instance of profound sequelae. Up to six sequential transmissions of monkeypox virus from person to person are hypothesized to have occurred, making this the longest uninterrupted chain of human monkeypox fully documented to date. The pattern of sustained human-to-human transmission observed during this outbreak may influence our current perception of the capacity for this zoonotic virus to adapt to humans.

Onshore industrial wind turbine locations for the United States up to March 2014.

Wind energy is a rapidly growing form of renewable energy in the United States. While summary information on the total amounts of installed capacity are available by state, a free, centralized, national, turbine-level, geospatial dataset useful for scientific research, land and resource management, and other uses did not exist. Available in multiple formats and in a web application, these public domain data provide industrial-scale onshore wind turbine locations in the United States up to March 2014, corresponding facility information, and turbine technical specifications. Wind turbine records have been collected and compiled from various public sources, digitized or position verified from aerial imagery, and quality assured and quality controlled. Technical specifications for turbines were assigned based on the wind turbine make and model as described in public literature. In some cases, turbines were not seen in imagery or turbine information did not exist or was difficult to obtain. Uncertainty associated with these is recorded in a confidence rating.

Orthopoxvirus variola infection of Cynomys ludovicianus (North American black tailed prairie dog).

Since the eradication of Smallpox, researchers have attempted to study Orthopoxvirus pathogenesis and immunity in animal models in order to correlate results human smallpox. A solely human pathogen, Orthopoxvirus variola fails to produce authentic smallpox illness in any other animal species tested to date. In 2003, an outbreak in the USA of Orthopoxvirus monkeypox, revealed the susceptibility of the North American black-tailed prairie dog (Cynomys ludovicianus) to infection and fulminate disease. Prairie dogs infected with Orthopoxvirus monkeypox present with a clinical scenario similar to ordinary smallpox, including prodrome, rash, and high mortality. This study examines if Black-tailed prairie dogs can become infected with O. variola and serve as a surrogate model for the study of human smallpox disease. Substantive evidence of infection is found in immunological seroconversion of animals to either intranasal or intradermal challenges with O. variola, but in the absence of overt illness.

[Comparative high rising dose study of oral 17-alpha-ethinylestradiol (EE2), estriol (E3), and parenteral 16-alpha-17-beta-estrioldihemisuccinate (E3-suc) in their effects on serum levels of glutamate transaminase (GOT), pyruvate transaminase (GPT), leucine amino peptidase (LAP), alkaline phosphatase (AP), and bilirubin in 30 hysterectomized and ovarectomized women (author's transl)]. / Vergleich von Enzymen und Bilirubin im Serum nach kurzer, hochdosierter Einnahme von Ostriol, 17alpha-Athinylöstradiol und intramuskulärer Gabe von Ostriol-16-alpha-17-beta-Dihemisuccinat.

UNLABELLED: 30 hysterectomized and ovarectomized women were treated with three different estrogens: EE2 orally, E3 orally, and E3-suc intramuscularly. Each patient received one substance over 5 days doubling the dose every consecutive day, and switching to another estrogen after a treatment free interval of 2 days, rising the dosage of the second preparation twofold every consecutive day over another 5 days. Thus, each patient served as her own control with respect to 2 of the 3 tested estrogens. Six groups were required to test all sequences possible. The patients were allocated by random. GOT, GPT, LAP, AP and bilirubin were estimated daily over 2 weeks. The starting dose of EE2 was 0.25 mg, of E3 2 mg, and of E3-suc 2.5 mg. RESULTS: There were marked elevations of all serum enzymes during the week of EE2 treatment. If EE2 was given in the first week, and either E3 or E3-suc in the second one there was a prompt fall of all enzyme levels in spite of the approximately tenfold higher dose of the latter two estrogens. There were only minor elevations of the enzymes after oral E3 and parenteral E3-suc in some subjects and no differences of response between these two estrogens. Bilirubin reacted with an overall rise in the majority of patients irrespective of the type of estrogen.

PIP: Serum enzyme and bilirubin levels were measured in 30 hysterectomized and ovarectomized women, 42-58 years of age, after using various estrogen preparations. Each of 3 preparations (estriol (E), 17 alpha-ethinyl estradiol (17AEE), and estriol dihemisucconate (ED)) was administered for 5 days of 3 consecutive weeks, with the dosage of the preparation being doubled daily. The initial dosage was 2 mg E and 25 mg 17AEE, which were administered orally, and 2.5 mg ED, which was administered intravenously. In the cases where E and ED treatment followed one another, regardless of order, no regular tendencies in changes of enzyme or bilirubin levels were observed. In cases where 17AEE was administered before or after E or ED, serum enzyme levels were markedly elevated during the week of 17AEE use. Bilirubin levels tended to rise slightly in spite of the order of medicative treatment.

[On the feto-maternal transfusion of red blood cells during transplacental and para-placental genetic amniocenteses (author's transl)]. / Uber die Einschwemmung fetaler Erythrozyten bei para- und transplazentarer Amniozentese in der Frühschwangerschaft.

The concentrations of fetal hemoglobin (HbF) containing red blood cells in the peripheral blood of the mothers was studied in 113 cases by the method of Kleihauer & Betke prior and following trans-abdominal amniocenteses for genetic reasons between 15 and 18 weeks of pregnancy. Prior to the amniocentesis, 25% of the patients had HbF positive cells. Following the amniocentesis 36% of the patients showed HbF positive cells. In one out of six amniocenteses a measurable increase of the concentration of HbF containing red blood cells by approximately 0.22% was detected. These increases are within the limits found prior to amniocentesis and are not significant. There was no difference in the incidence and level of microtransfusions between paraplacental and transplacental amniocenteses. Because of the possibility of Rh sensitization Rh negative mothers should receive Rh immunoglobulin. None of the 112 patients had an abortion within two weeks following the amniocentesis.

[Inhibition of uterine contraction in emergencies (author's transl)]. / Notfalltokolyse

During the first stage of labour 48 parturients were treated with the tocolytic agent TH 1165 a (Fenoterol-hydrobromide) because of danger to the foetus. The product was slowly injected i.v. in doses of 50 mcg (35 pat.) and 25 mcg (9 pat.) and on 4 patients in doses of 35 mcg. We investigated the effects of this therapy on labour, on the mother's and the child's circulation and on the foetal acid-base balance and foetal gas partial pressure. Whilst the different TH 1165a doses were not markedly different in their tocolytic effect, we discovered that side-effects occurred considerably more often and more intensively when higher doses of TH 116A WERE ADMINISTERED. We therefore recommend one i.v. injection of 25 mcg TH 1165a for clinical uterine relaxation in emergencies during labour. To guard against a vena cava compression syndrome, the injection should always be given with the patient in a lateral position. In emergency uterine relaxation the cardiac tocography (supplemented if necessary by micro blood gas analysis) should be monitored. In order tnce-only syringe containing 25 mcg TH1165a.

[Applications and limits of prenatal diagnosis (author's transl)]. / Möglichkeiten und Grenzen der Pränataldiagnose.

By means of antenatal diagnosis mainly chromosome aberrations, malformations and inborn errors of metabolism may be recorded. At present there exist four ways for gaining information on the fetus in a pregnant woman: analysis of the amniotic fluid after amniocentesis, fetoscopy, ultrasound diagnosis and analysis of the maternal serum. Prenatal diagnosis becomes necessary in pregnancies where a child suffering from a severe illness or malformation is to be expected. Only if the disorder can be diagnosed by antenatal diagnosis and its severity justifies abortion prenatal diagnosis is to be carried out. Most cases transferred to antenatal diagnosis are pregnancies of women in advanced age because of the increasing risk of carrying a child with Down's syndrome. Another important group is formed by pregnant women with a previous child with Down's syndrome or another chromosomal disorder.