Continuous quantitative monitoring of cerebral oxygen metabolism in neonates by ventilator-gated analysis of NIRS recordings

Oxidative stress during fetal development, delivery, or early postnatal life is a major cause of neuropathology, as both hypoxic and hyperoxic insults can significantly damage the developing brain. Despite the obvious need for reliable cerebral oxygenation monitoring, no technology currently exists to monitor cerebral oxygen metabolism continuously and noninvasively in infants at high risk for developing brain injury. Consequently, a rational approach to titrating oxygen supply to cerebral oxygen demand – and thus avoiding hyperoxic or hypoxic insults – is currently lacking. We present a promising method to close this crucial technology gap in the important case of neonates on conventional ventilators. By using cerebral near-infrared spectroscopy and signals from conventional ventilators, along with arterial oxygen saturation, we derive continuous (breath-by-breath) estimates of cerebral venous oxygen saturation, cerebral oxygen extraction fraction, cerebral blood flow, and cerebral metabolic rate of oxygen. The resultant estimates compare very favorably to previously reported data obtained by non-continuous and invasive means from preterm infants in neonatal critical care.National Institutes of Health (U.S.) (Grant R01EB001659)National Institutes of Health (U.S.) (Grant K24NS057568)National Institutes of Health (U.S.) (Grant R21HD056009

Utility of CRISPR/Cas9 systems in hematology research

Since the end of the 20th century, the development of novel approaches have emerged to manipulate experimental models of hematological disorders, so they would more accurately mirror what is observed in the clinic. Despite these technological advances, the characterization of crucial genes for benign or malignant hematological disorders remains challenging, mainly because of the dynamic nature of the hematopoietic system and the genetic heterogeneity of these disorders. To overcome this limitation, genome editing technologies have been developed to specifically manipulate the genome via deletion, insertion or modification of targeted loci. These technologies have swiftly progressed, allowing their common use to investigate genetic function in experimental hematology. Amongst them, homologous recombination (HR)-mediated targeting technologies have facilitated the manipulation of specific loci by generating knockout and knock-in models. Despite promoting significant advances in the understanding of the molecular mechanisms involved in hematology, these inefficient, time-consuming and labor-intensive approaches did not permit the development of cellular or animal models recapitulating the complexity of hematological disorders. In October 2016, Dr. Ben Ebert and Dr. Chad Cowan shared their knowledge and experiences with the utilization of CRISPR for models of myeloid malignancy, disease, and novel therapeutics. Here we provide an overview of the topics they covered including insights into the novel applications of the technique as well as its strengths and limitations

"Viva Bacco e viva Amore": Bacchic Imagery in the Renaissance

The fifteenth century in Italy is often studied for its revival of antiquity, but looking at this revival through the particular lens of Bacchus and his band of ecstatic followers reveals a unique view of the complex texture of the intellectual, cultural, and artistic fabric of the Renaissance. Although Bacchus, as a god of wine and revelry, was not an obvious role model for Renaissance patrons, he appeared nonetheless in drawings, paintings, engravings, plaquettes, and sculpture, and in marriage parades, banquet entertainments, plays, and songs. This dissertation examines how and why such a god and his wild cohort could acquire such a broad appeal and what they signified to their contemporary audiences. Stepping off from Aby Warburg's insight that emotionality is a third vector of historical measurement in addition to form and content, we first explore what it was in ancient Bacchic art that appealed to Renaissance artists striving to reinvigorate their work, finding that they were drawn to its expressive realism, shown with vigorous movement and figural variety, as well as its portrayal of lassitude and voluptuous pleasure. We look also at shifts in ideas about invention, imagination, composition, and imitation, and their impact on how artists viewed this antique inheritance and found inspiration in the Bacchic figures. Philosophical concepts, especially Neoplatonic ideas of inspiration and Aristotelian notions of Necessity, are considered for their impact on the meanings gleaned from Bacchic imagery. Each member of the Bacchic retinue is then explored to determine how his or her gestural vocabulary was employed, and what meanings he or she was made to bear in new settings. The frenzied maenad, with her hints of madness and untamed eroticism, was transformed into grieving Mary Magdalenes, heroic Judiths, and dancing Salomes, or was prettified into all'antica serving girls, nymphs, and personifications. The discovery of a sleeping Ariadne, unveiled by a satyr, contributed to one of the more popular motifs of the Renaissance, which even in new contexts retained associations with the epiphany and resurrection experienced by Ariadne when she was rescued by Bacchus. Revived epithalamic traditions employed the Triumph of Bacchus and Ariadne as a metaphor for both the taming forces of marriage and the bittersweet aura of youth and love. The frolicking, ithyphallic satyr embodied visions not only of a lost Arcadia, but also of the balancing forces of nature that require sexuality to sustain life. Tales of Silenus' wisdom inflected Renaissance depictions of the dissipated old satyr with contemporary notions of the morosoph, or wise fool. And as a symbol of the cosmos, Pan became the leader of a revived pastoral mode, a noble prince for a restored Golden Age. As a fecund, frenzied god, Bacchus came to embody the newly awakened Neoplatonic notion of divine furor: the inspiration that fueled all transcendent thought and creative imagination. At a moment when visual artists were striving to attain the status of their poetic counterparts, Bacchus epitomized the nature of artistic frenzy as a complement to the poet's Apollonian furor. The Bacchanalian paintings commissioned for Alfonso d'Este's Camerino d'Alabastro in Ferrara were a final flourish to this revival of Bacchus (before the archaeological and mythographical rigor of the mid-sixteenth century reduced him to a stereotype). The god's associations with love and fertility enhanced the duke's self-presentation as a magnanimous, liberal, and prolific ruler. The presentation of Epicurean delights signified a true understanding of an elevated voluptas, which saw the greatest good attained through the metaphor of sensual pleasures. Titian's paintings fully materialized the energy and pathos that first attracted the early Renaissance artists to Bacchic imagery

Neurotrophins Regulate Bone Marrow Stromal Cell IL-6 Expression through the MAPK Pathway

The host's response to infection is characterized by altered levels of neurotrophins and an influx of inflammatory cells to sites of injured tissue. Progenitor cells that give rise to the differentiated cellular mediators of inflammation are derived from bone marrow progenitor cells where their development is regulated, in part, by cues from bone marrow stromal cells (BMSC). As such, alteration of BMSC function in response to elevated systemic mediators has the potential to alter their function in biologically relevant ways, including downstream alteration of cytokine production that influences hematopoietic development.In the current study we investigated BMSC neurotrophin receptor expression by flow cytometric analysis to determine differences in expression as well as potential to respond to NGF or BDNF. Intracellular signaling subsequent to neurotrophin stimulation of BMSC was analyzed by western blot, microarray analysis, confocal microscopy and real-time PCR. Analysis of BMSC Interleukin-6 (IL-6) expression was completed using ELISA and real-time PCR.BMSC established from different individuals had distinct expression profiles of the neurotrophin receptors, TrkA, TrkB, TrkC, and p75(NTR). These receptors were functional, demonstrated by an increase in Akt-phosphorylation following BMSC exposure to recombinant NGF or BDNF. Neurotrophin stimulation of BMSC resulted in increased IL-6 gene and protein expression which required activation of ERK and p38 MAPK signaling, but was not mediated by the NFkappaB pathway. BMSC response to neurotrophins, including the up-regulation of IL-6, may alter their support of hematopoiesis and regulate the availability of inflammatory cells for migration to sites of injury or infection. As such, these studies are relevant to the growing appreciation of the interplay between neurotropic mediators and the regulation of hematopoiesis

Reframing Academic Productivity, Promotion and Tenure As a Result of the COVID-19 Pandemic

Faculty members have been impacted in a multitude of ways by the COVID-19 pandemic. In particular, faculty seeking promotion and tenure have been impacted by the disruption and inconsistent levels of productivity. In this article, we consider academic productivity in the context of clinical, research, education and service missions within higher education and the academic medicine professoriate. We offer a series of recommendations to faculty members, to institutions, and to professional societies in hopes we can challenge pre-existing deficits in promotion and tenure processes, and academic worth

Biallelic PI4KA variants cause a novel neurodevelopmental syndrome with hypomyelinating leukodystrophy

Phosphoinositides are lipids that play a critical role in processes such as cellular signalling, ion channel activity and membrane trafficking. When mutated, several genes that encode proteins that participate in the metabolism of these lipids give rise to neurological or developmental phenotypes. PI4KA is a phosphoinositide kinase that is highly expressed in the brain and is essential for life. Here we used whole exome or genome sequencing to identify 10 unrelated patients harbouring biallelic variants in PI4KA that caused a spectrum of conditions ranging from severe global neurodevelopmental delay with hypomyelination and developmental brain abnormalities to pure spastic paraplegia. Some patients presented immunological deficits or genito-urinary abnormalities. Functional analyses by western blotting and immunofluorescence showed decreased PI4KA levels in the patients' fibroblasts. Immunofluorescence and targeted lipidomics indicated that PI4KA activity was diminished in fibroblasts and peripheral blood mononuclear cells. In conclusion, we report a novel severe metabolic disorder caused by PI4KA malfunction, highlighting the importance of phosphoinositide signalling in human brain development and the myelin sheath

Women's knowledge and attitudes regarding alcohol consumption in pregnancy: a national survey

Background. Alcohol exposure in pregnancy is a common and modifiable risk factor for poor pregnancy and child outcomes. Alcohol exposure in pregnancy can cause a range of physical and neurodevelopmental problems in the child including the Fetal Alcohol Spectrum Disorders (FASD). In order to improve prevention strategies, we sought to describe the knowledge and attitudes of women of childbearing age regarding alcohol consumption during pregnancy and its effects on the fetus.Methods. We conducted a national cross-sectional survey via computer assisted telephone interview of 1103 Australian women aged 18 to 45 years. Participants were randomly selected from the Electronic White Pages. Pregnant women were not eligible to participate. Quotas were set for age groups and a minimum of 100 participants per state to ensure a national sample reflecting the population. The questionnaire was based on a Health Canada survey with additional questions constructed by the investigators. Descriptive statistics were calculated and logistic regression analyses were used to assess associations with participants' knowledge and attitudes.Results. Of women surveyed, 61.5% had heard about effects of alcohol on the fetus and 55.3% had heard of Fetal Alcohol Syndrome. Although 92.7% agreed alcohol can affect the unborn child, 16.2% did not agree that the disabilities could be lifelong. Most women agreed that pregnant women should not drink alcohol (80.2%) and 79.2% reported having negative feelings towards pregnant women drinking alcohol. Women with higher education levels were more likely to know the effects of alcohol consumption in pregnancy (adjusted OR 5.62; 95% CI 3.20 to 9.87) but education level and knowledge were not associated with attitude.Conclusions. There was a disjunction between knowledge and attitudes towards alcohol consumption in pregnancy. These findings will assist in developing effective health promotion campaigns to reduce fetal alcohol exposure and subsequent fetal damage

Banff 2022 liver group meeting report: monitoring long term allograft health.

The Banff Working Group on Liver Allograft Pathology met in September 2022. Participantsincluded hepatologists, surgeons, pathologists, immunologists and histocompatibility specialists.Presentations and discussions focused on the evaluation of long-term allograft health, including noninvasive and tissue monitoring, immunosuppression optimisation and long-term structural changes.Potential revision of the rejection classification scheme to better accommodate and communicate lateT cell-mediated rejection patterns and related structural changes, such as nodular regenerativehyperplasia, were discussed. Improved stratification of long-term maintenance immunosuppression tomatch the heterogeneity of patient settings will be central to improving long-term patient survival.Such personalised therapeutics are in turn contingent on better understanding and monitoring ofallograft status within a rational decision-making approach, likely to be facilitated in implementationwith emerging decision support tools. Proposed revisions to rejection classification emerging fromthe meeting include incorporation of interface hepatitis and fibrosis staging. These will be opened toonline testing, modified accordingly and subject to consensus discussion leading up to the next Banffconference

Attitudes and behaviour predict women's intention to drink alcohol during pregnancy: the challenge for health professionals

Background. To explore women's alcohol consumption in pregnancy, and potential predictors of alcohol consumption in pregnancy including: demographic characteristics; and women's knowledge and attitudes regarding alcohol consumption in pregnancy and its effects on the fetus. Methods. We conducted a national cross-sectional survey via computer assisted telephone interview of 1103 Australian women aged 18 to 45 years. Participants were randomly selected from the Electronic White Pages. Pregnant women were not eligible to participate. Quotas were set for age groups and a minimum of 100 participants per state to ensure a national sample reflecting the population. The questionnaire was based on a Health Canada survey with additional questions constructed by the investigators. Descriptive statistics were calculated and logistic regression analyses were used to assess associations of alcohol consumption in pregnancy with participants' characteristics, knowledge and attitudes.Results. The majority of women (89.4%) had consumed alcohol in the last 12 months. During their last pregnancy (n = 700), 34.1% drank alcohol. When asked what they would do if planning a pregnancy (n = 1103), 31.6% said they would consume alcohol and 4.8% would smoke. Intention to consume alcohol in a future pregnancy was associated with: alcohol use in the last pregnancy (adjusted OR (aOR) 43.9; 95% Confidence Interval (CI) 27.0 to 71.4); neutral or positive attitudes towards alcohol use in pregnancy (aOR 5.1; 95% CI 3.6 to 7.1); intention to smoke in a future pregnancy (aOR 4.7; 95% CI 2.5 to 9.0); and more frequent and higher current alcohol consumption. Conclusions. Women's past pregnancy and current drinking behaviour, and attitudes to alcohol use in pregnancy were the strongest predictors of alcohol consumption in pregnancy. Targeted interventions for women at higher risk of alcohol consumption in pregnancy are needed to change women's risk perception and behaviour

Bone Marrow Osteoblast Damage by Chemotherapeutic Agents

Hematopoietic reconstitution, following bone marrow or stem cell transplantation, requires a microenvironment niche capable of supporting both immature progenitors and stem cells with the capacity to differentiate and expand. Osteoblasts comprise one important component of this niche. We determined that treatment of human primary osteoblasts (HOB) with melphalan or VP-16 resulted in increased phospho-Smad2, consistent with increased TGF-β1 activity. This increase was coincident with reduced HOB capacity to support immature B lineage cell chemotaxis and adherence. The supportive deficit was not limited to committed progenitor cells, as human embryonic stem cells (hESC) or human CD34+ bone marrow cells co-cultured with HOB pre-exposed to melphalan, VP-16 or rTGF-β1 had profiles distinct from the same populations co-cultured with untreated HOB. Functional support deficits were downstream of changes in HOB gene expression profiles following chemotherapy exposure. Melphalan and VP-16 induced damage of HOB suggests vulnerability of this critical niche to therapeutic agents frequently utilized in pre-transplant regimens and suggests that dose escalated chemotherapy may contribute to post-transplantation hematopoietic deficits by damaging structural components of this supportive niche