•Treatment-naive and relapsed/refractory MDS patients receiving venetoclax and HMAs have an ORR of 59% with 63% of responders proceeding to transplant.•Allogeneic stem cell transplantation after ...treatment with venetoclax in combination with HMA is associated with prolonged survival.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Due to high rates of surgical site infections (SSIs) in damage control laparotomies (DCLs), many surgeons leave wounds to heal by secondary intention. We hypothesize that patients after DCL can have ...their wounds primarily closed with wicks/Penrose drains with low rates of superficial surgical site infections. A retrospective review of a prospectively maintained DCL database was performed for all patients who underwent DCL from January 2016 to June 2018. From January 2016 to June 2018, a total of 171 patients underwent DCL. After exclusions, 107 patients were reviewed to assess for SSI. 57 patients were closed with wicks/Penrose drains, 3 were closed with delayed primary closure, and 47 patients were closed completely at time of fascial closure. There were 4 (3.7%) superficial SSIs, 13 (12.1%) organ space infections, and 14 surgical site occurrences (3 of which required opening the skin). Primary closure of incisions after DCL has low superficial SSI rates.
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NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
As tissue-resident immune cells, mast cells are frequently found in close proximity to afferent neurons and are subjected to immunoactive mediators secreted by these neurons, including substance P ...(SP) and calcitonin gene-related peptide (CGRP). Neurogenic inflammation is thought to play an important role in the pathophysiology of many diseases. Unraveling the cellular mechanisms at the interface between the immune response and the peripheral nervous system is important for understanding how these diseases arise and progress. In this work, mast cell degranulation following direct exposure to CGRP and SP was studied both at the bulk and single-cell levels to characterize the mouse peritoneal mast cell response to neuropeptides and compare this response to well-studied mast cell activation pathways. Results show that mast cells secrete fewer chemical messenger-filled granules with increased IgE preincubation concentrations. The biophysical characteristics of mast cell degranulation in response to SP and CGRP is in many ways similar to calcium ionophore-induced mast cell degranulation; however, neuropeptide-stimulated mast cells secrete reduced chemical messenger content per secretion event, resulting in an overall relative decrease in secreted chemical messengers.
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IJS, KILJ, NUK, PNG, UL, UM, UPUK
Artemisinin combination therapies (ACTs) with broad efficacy are needed where multiple Plasmodium species are transmitted, especially in children, who bear the brunt of infection in endemic areas. In ...Papua New Guinea (PNG), artemether-lumefantrine is the first-line treatment for uncomplicated malaria, but it has limited efficacy against P. vivax. Artemisinin-naphthoquine should have greater activity in vivax malaria because the elimination of naphthoquine is slower than that of lumefantrine. In this study, the efficacy, tolerability, and safety of these ACTs were assessed in PNG children aged 0.5-5 y.
An open-label, randomized, parallel-group trial of artemether-lumefantrine (six doses over 3 d) and artemisinin-naphthoquine (three daily doses) was conducted between 28 March 2011 and 22 April 2013. Parasitologic outcomes were assessed without knowledge of treatment allocation. Primary endpoints were the 42-d P. falciparum PCR-corrected adequate clinical and parasitologic response (ACPR) and the P. vivax PCR-uncorrected 42-d ACPR. Non-inferiority and superiority designs were used for falciparum and vivax malaria, respectively. Because the artemisinin-naphthoquine regimen involved three doses rather than the manufacturer-specified single dose, the first 188 children underwent detailed safety monitoring. Of 2,542 febrile children screened, 267 were randomized, and 186 with falciparum and 47 with vivax malaria completed the 42-d follow-up. Both ACTs were safe and well tolerated. P. falciparum ACPRs were 97.8% and 100.0% in artemether-lumefantrine and artemisinin-naphthoquine-treated patients, respectively (difference 2.2% 95% CI -3.0% to 8.4% versus -5.0% non-inferiority margin, p = 0.24), and P. vivax ACPRs were 30.0% and 100.0%, respectively (difference 70.0% 95% CI 40.9%-87.2%, p<0.001). Limitations included the exclusion of 11% of randomized patients with sub-threshold parasitemias on confirmatory microscopy and direct observation of only morning artemether-lumefantrine dosing.
Artemisinin-naphthoquine is non-inferior to artemether-lumefantrine in PNG children with falciparum malaria but has greater efficacy against vivax malaria, findings with implications in similar geo-epidemiologic settings within and beyond Oceania.
Australian New Zealand Clinical Trials Registry ACTRN12610000913077. Please see later in the article for the Editors' Summary.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Asthma is a chronic inflammatory disease characterized by narrowed airways, bronchial hyper-responsiveness, mucus hyper-secretion, and airway remodeling. Mast cell (MC) infiltration into airway ...smooth muscle (ASM) is a defining feature of asthma, and ASM regulates the inflammatory response by secreting chemokines, including CXCL10 and CCL5. Single cell analysis offers a unique approach to study specific cellular signaling interactions within large and complex signaling networks such as the inflammatory microenvironment in asthma.
Carbon-fiber microelectrode amperometry was used to study the effects of ASM-secreted chemokines on mouse peritoneal MC degranulation.
MC degranulation in response to CXCL10 and CCL5 was monitored at the single cell level. Relative to IgE-mediated degranulation, CXCL10- and CCL5-stimulated MCs released a decreased amount of serotonin per granule with fewer release events per cell. Decreased serotonin release per granule was correlated with increased spike half-width and rise-time values.
MCs are directly activated by ASM-associated chemokines. CXCL10 and CCL5 induce less robust MC degranulation compared to IgE- and A23187-stimulation. The kinetics of MC degranulation are signaling pathway-dependent, suggesting a biophysical mechanism of regulated degranulation that incorporates control over granule trafficking, transport, and docking machinery.
The biophysical mechanisms, including variations in number of exocytotic release events, serotonin released per granule, and the membrane kinetics of exocytosis that underlie MC degranulation in response to CXCL10 and CCL5 were characterized at the single cell level. These findings clarify the function of ASM-derived chemokines as instigators of MC degranulation relative to classical mechanisms of MC stimulation.
•CFMA allows direct observation of single cell mast cell degranulation in real time.•Both CXCL10 and RANTES, airway smooth muscle-relevant cytokines, are capable of directly inducing mast cell degranulation.•Mast cells are capable of stimulation pathway-dependent regulation of exocytosis.
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IJS, KILJ, NUK, OILJ, SAZU, SBCE, UL, UM, UPCLJ, UPUK
Following intubation, the patient developed hypotension that responded well to a transfusion of two units of packed red blood cells. Other findings on imaging may include a prominent pulmonary artery ...and lung tissue situated between the aorta and pulmonary artery.3 Treatment of pericardial defects is dependent on the degree of the defect and symptomatology. Some experts have pointed to an increased risk of aortic dissections among individuals with a complete defect.4 These patients, however, have a similar life expectancy and cardiac function with normal ejection fractions.1 Partial pericardial defects can prove to be more problematic.
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NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
This article reviews measurement of single cell exocytosis with microelectrodes, covering history, basic instrumentation, cell types investigated, and fundamental insight gained.
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IJS, KILJ, NUK, PNG, UL, UM
The role of endoscopic retrograde cholangiopancreatography (ERCP) in the trauma patient is limited. Therefore, reporting of outcomes is sparse in the literature. The purpose of this study was to ...review outcomes of patients who underwent ERCP for traumatic biliopancreatic injury. We retrospectively reviewed 1550 ERCPs, from a prospectively maintained database, performed by a single surgical endoscopist consulted by the trauma surgical service for the management of traumatic fistulae. Referral was made for patients with high output (greater than 200 mL/d) and/or persistent (failure to resolve within 30 days) fistulae and traumatic biliary stricture. Primary end point was postprocedural complications. Secondary end points included patient characteristics, stents placed, and duration of stenting. Seventeen patients underwent a total of 31 ERCPs for biliary and/or pancreatic injury resulting from abdominal trauma (eight penetrating, nine blunt). Fourteen patients had ERCP after laparotomy, with a mean interval to ERCP of 74 days. In three patients, ERCP was the only intervention required. Fourteen biliary stents were placed, seven of which were metallic. Ten pancreatic stents were placed; one proximally migrated but was successfully retrieved. Four patients had both ducts simultaneously stented. The mean duration of stenting was 158 days. All fistulae resolved after stenting. There were no serious complications.
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Sickle cell disease, caused by a mutation of hemoglobin, is characterized by a complex pathophysiology including an important inflammatory component. Mast cells are tissue-resident leukocytes known ...to influence a range of immune functions in a variety of different ways, largely through the secretion of biologically active mediators from preformed granules. However, it is not understood how mast cells influence the inflammatory environment in sickle cell disease. A notable consequence of sickle cell disease is severe pain. Therefore, morphine is often used to treat this disease. Because mast cells express opioid receptors, it is pertinent to understand how chronic morphine exposure influences mast cell function and inflammation in sickle cell disease. Herein, carbon-fiber microelectrode amperometry (CFMA) was used to monitor the secretion of immunoactive mediators from single mast cells. CFMA enabled the detection and quantification of discrete exocytotic events from single mast cells. Mast cells from two transgenic mouse models expressing human sickle hemoglobin (hBERK1 and BERK) and a control mouse expressing normal human hemoglobin (HbA-BERK) were monitored using CFMA to explore the impact of sickle-cell-induced inflammation and chronic morphine exposure on mast cell function. This work, utilizing the unique mechanistic perspective provided by CFMA, describes how mast cell function is significantly altered in hBERK1 and BERK mice, including decreased serotonin released compared to HbA-BERK controls. Furthermore, morphine was shown to significantly increase the serotonin released from HbA-BERK mast cells and demonstrated the capacity to reverse the observed sickle-cell-induced changes in mast cell function.
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IJS, KILJ, NUK, PNG, UL, UM, UPUK
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