Children with hemoglobin SC (HbSC) disease suffer a significant incidence of silent cerebral infarcts but stroke is rare. A 2-year-old African American boy with HbSC disease presented with focal ...neurologic deficits associated with magnetic resonance imaging evidence of cerebral infarction with vascular abnormalities. After the acute episode he was treated with monthly transfusions and subsequently transitioned to hydroxyurea therapy. The benefits of hydroxyurea as a fetal hemoglobin inducer in HbSC disease, to ameliorate clinical symptoms are supported by retrospective studies. This case highlights the rare occurrence of stroke in a child with HbSC disease and the use of hydroxyurea therapy.
Membrane trafficking is essential to eukaryotic life and is controlled by a complex network of proteins that regulate movement of proteins and lipids between organelles. The GBF1/GEA family of ...Guanine nucleotide Exchange Factors (GEFs) regulates trafficking between the endoplasmic reticulum and Golgi by catalyzing the exchange of GDP for GTP on ADP Ribosylation Factors (Arfs). Activated Arfs recruit coat protein complex 1 (COP-I) to form vesicles that ferry cargo between these organelles. To further explore the function of the GBF1/GEA family, we have characterized a fission yeast mutant lacking one copy of the essential gene gea1 (gea1+/-), the Schizosaccharomyces pombe ortholog of GBF1. The haploinsufficient gea1+/- strain was shown to be sensitive to the GBF1 inhibitor brefeldin A (BFA) and was rescued from BFA sensitivity by gea1p overexpression. No overt defects in localization of arf1p or arf6p were observed in gea1+/- cells, but the fission yeast homolog of the COP-I cargo sac1 was mislocalized, consistent with impaired COP-I trafficking. Although Golgi morphology appeared normal, a slight increase in vacuolar size was observed in the gea1+/- mutant strain. Importantly, gea1+/- cells exhibited dramatic cytokinesis-related defects, including disorganized contractile rings, an increased septation index, and alterations in septum morphology. Septation defects appear to result from altered secretion of enzymes required for septum dynamics, as decreased secretion of eng1p, a β-glucanase required for septum breakdown, was observed in gea1+/- cells, and overexpression of eng1p suppressed the increased septation phenotype. These observations implicate gea1 in regulation of septum breakdown and establish S. pombe as a model system to explore GBF1/GEA function in cytokinesis.
•Higher miR-144 gene expression was observed in peripheral blood reticulocytes of sickle cell disease (SCD) patients with low fetal hemoglobin levels.•NRF2 protein levels are regulated by miR-144 as ...a mechanism of γ-globin gene silencing during erythropoiesis in SCD.
Inherited genetic modifiers and pharmacologic agents that enhance fetal hemoglobin (HbF) expression reverse the clinical severity of sickle cell disease (SCD). Recent efforts to develop novel strategies of HbF induction include discovery of molecular targets that regulate γ-globin gene transcription and translation. The purpose of this study was to perform genome-wide microRNA (miRNA) analysis to identify genes associated with HbF expression in patients with SCD. We isolated RNA from purified reticulocytes for microarray-based miRNA expression profiling. Using samples from patients with contrasting HbF levels, we observed an eightfold upregulation of miR-144-3p (miR-144) and miR-144-5p in the low-HbF group compared with those with high HbF. Additional analysis by reverse transcription quantitative polymerase chain reaction confirmed individual miR-144 expression levels of subjects in the two groups. Subsequent functional studies in normal and sickle erythroid progenitors showed NRF2 gene silencing by miR-144 and concomitant repression of γ-globin transcription; by contrast, treatment with miR-144 antagomir reversed its silencing effects in a dose-dependent manner. Because NRF2 regulates reactive oxygen species levels, additional studies investigated mechanisms of HbF regulation using a hemin-induced oxidative stress model. Treatment of KU812 cells with hemin produced an increase in NRF2 expression and HbF induction that reversed with miR-144 pretreatment. Chromatin immunoprecipitation assay confirmed NRF2 binding to the γ-globin antioxidant response element, which was inhibited by miR-144 mimic treatment. The genome-wide miRNA microarray and primary erythroid progenitor data support a miR-144/NRF2-mediated mechanism of γ-globin gene regulation in SCD.
The yeast vacuole plays key roles in cellular stress responses. Here, we show that deletion of lvs1, the fission yeast homolog of the Chediak-Higashi Syndrome CHS1/LYST gene, increases vacuolar size, ...similar to deletion of the Rab4 homolog ypt4. Overexpression of lvs1-YFP rescued vacuolar size in ypt4Δ cells, but ypt4-YFP did not rescue lvs1Δ, suggesting that lvs1 may act downstream of ypt4. Vacuoles were capable of hypotonic shock-induced fusion and recovery in both ypt4Δ and lvs1Δ cells, although recovery may be slightly delayed in ypt4Δ. Endocytic and secretory trafficking were not affected, but ypt4Δ and lvs1Δ strains were sensitive to neutral pH and CaCl
2
, consistent with vacuolar dysfunction. In addition to changes in vacuolar size, deletion of ypt4 also dramatically increased cell size, similar to tor1 mutants. These results implicate ypt4 and lvs1 in maintenance of vacuolar size and suggest that ypt4 may link vacuolar homeostasis to cell cycle progression.
Background
Medication adherence (MA) is critical to successful chronic disease management. It is not clear how social determinants of health (SDH) impact MA. We conducted a systematic review and ...meta-analysis to summarize the evidence on the relationship between SDH and MA.
Methods
We conducted a systematic review of the literature using a Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) format. A literature search was performed using three databases: PubMed, Scopus, and Cochrane Clinical Trials Register in December of 2018. Included studies were completed in the USA, included adults aged 18 years and older, measured at least one social determinant of health, and medication adherence was the primary outcome measure. Data from included full texts were independently extracted using a standardized data extraction form. We then conducted a meta-analysis and pooled the odds ratios from the included studies for each social determinant as well as for all SDH factors collectively.
Results
A total of 3137 unduplicated abstracts were identified from our database searches. A total of 173 were selected for full text review after evaluating the abstract. A total of 29 articles were included for this systematic review. Economic-related SDH factors and MA were mostly commonly examined. The meta-analysis revealed a significant relationship between food insecurity (aOR = 0.56; 95% CI 0.42–0.7), housing instability (aOR = 0.64; 95% CI 0.44–0.93), and social determinants overall (aOR = 0.75; 95% CI 0.65–0.88) and medication adherence.
Discussion
Food insecurity and housing instability most consistently impacted medication adherence. Although included studies were heterogenous and varied widely in SDH and MA measurements, adverse social determinants overall were significantly associated with lower MA. The relationship between SDH and MA warrants more attention and research by health care providers and policymakers.
Matrix metalloproteinase (MMP)-8 and -9 released by degranulating polymorphonuclear cells (PMNs) promote pericellular proteolysis by binding to PMN surfaces in a catalytically active tissue inhibitor ...of metalloproteinases (TIMP)-resistant forms. The PMN receptor(s) to which MMP-8 and MMP-9 bind(s) is not known. Competitive binding experiments showed that Mmp-8 and Mmp-9 share binding sites on murine PMN surfaces. A novel form of TIMP-1 (an inhibitor of soluble MMPs) is rapidly expressed on PMN surfaces when human PMNs are activated. Membrane-bound TIMP-1 is the PMN receptor for pro- and active MMP-8 and -9 as shown by the following: 1) TIMP-1 is strikingly colocalized with MMP-8 and -9 on activated human PMN surfaces and in PMN extracellular traps; 2) minimal immunoreactive and active Mmp-8 or Mmp-9 are detected on the surface of activated
murine PMNs; and 3) binding of exogenous Timp-1 (but not Timp-2) to
murine PMNs reconstitutes the binding of exogenous pro-Mmp-8 and pro-Mmp-9 to the surface of
PMNs. Unlike full-length pro-Mmp-8 and pro-Mmp-9, mutant pro-Mmp proteins lacking the COOH-terminal hemopexin domain fail to bind to
murine PMNs. Soluble hemopexin inhibits the binding of pro-Mmp-8 and pro-Mmp-9 to
murine PMNs. Thus, the COOH-terminal hemopexin domains of pro-Mmp-8 and pro-Mmp-9 are required for their binding to membrane-bound Timp-1 on murine PMNs. Exposing nonhuman primates to cigarette smoke upregulates colocalized expression of TIMP-1 with MMP-8 and MMP-9 on peripheral blood PMN surfaces. By anchoring MMP-8 and MMP-9 to PMN surfaces, membrane-bound TIMP-1 plays a counterintuitive role in promoting PMN pericellular proteolysis occurring in chronic obstructive pulmonary disease and other diseases.
The use of infrared thermography has not been used previously to assist sheep reproduction. The aim of this study was evaluate the viability of infrared thermography to identify body surface ...temperature patterns during ewes' estrous cycle. The estrous cycles of 20 Santa Ines ewes were synchronized through hormone treatment (progesterone implant). The ewes were submitted to measurements of body temperature (rectal and vaginal) with a digital thermometer and surface temperature of the anus, vulva, muzzle, left ear and left eye by infrared thermography. Temperature and humidity of the environment and wet-bulb globe temperature (WBGT) were measured. After the progesterone implant's removal, the follicular dynamic was evaluated daily during five days with ultrasound. The estrous cycle was separated into six phases to facilitate interpretation of the differences in body temperatures in each period. Phase 1 was the period before estrous synchronization, phase 2 was the beginning of estrous synchronization, phase 3 was the intermediate period and end of synchronization, phase 4 was the period of estrus manifestations, phase 5 was the ovulation period, and phase 6 was the post-ovulatory period. There was a difference among phases for all body regions evaluated (P < 0.05). All temperatures were higher in the ovulation phase. The rectal and vaginal temperatures measured by digital thermometer were lower during the diestrus period and increased during and after ovulation. The surface temperature of the vulva, measured by thermography, was higher from the estrus phase (4) to the ovulation and post-ovulation phases (5 and 6). The surface temperature of the muzzle was higher from the ovulation phase (5) to the post-ovulation phase (6), showing potential to detect ovulation. The thermography was efficient to detect small temperature variations during different phases of the estrous cycle, allowing the identification of different phases of the cycle in Santa Ines ewes.
•The surface temperature of ewes varies during the estrous cycle.•Thermography can identify temperature variation during estrus.•IRT is a promising tool for reproductive management in ewes.•Vulva and muzzle are good anatomical regions for temperature evaluation of estrous cycle.
Environmental pollution of pharmaceuticals arises during drug development, production, use and disposal and can damage ecosystems, increase antimicrobial resistance and generate substantial ...greenhouse gas emissions. As a result, environmental sustainability of pharmaceuticals is an expanding theme in today's society. Several sustainability assessment methods have been developed for pharmaceuticals, however, most assessments typically consider only parts of the pharmaceutical chain and focus on the burdens of resource use and emissions, defined as the ‘footprint’. On the other hand, these assessments usually do not simultaneously consider the societal benefits of pharmaceuticals, called the ‘handprint’, in addition to the benefit/risk assessment for the patient. Existing sustainability assessments are often limited to traditional impact categories, neglecting other dimensions of sustainability. A comprehensive sustainability assessment should capture more than just the environmental dimension and could thus holistically capture the three pillars of sustainability, i.e., environment, social, and economic. Currently, holistic methods that cover all impacts over the entire life cycle of pharmaceuticals are lacking. The objective of this study is to conceptualise and propose a holistic framework for integrated sustainability assessment of pharmaceuticals, based on the three pillars of sustainability and taking into account both footprint and handprint outcomes. The framework was developed using both top-down (literature search) and bottom-up approaches (stakeholder involvement). Gaps, barriers and opportunities to achieve sustainability are identified. As a result, this holistic framework can be helpful in decision making.
•Today, focus is mainly on environmental burden of pharmaceuticals' production.•We propose a holistic framework for integrated sustainability assessment.•All pharmaceutical life cycle stages are part of this assessment framework.•The framework considers both footprint and handprint of pharmaceuticals.•A selection of impact categories to measure overall sustainability is proposed.
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