Residents of Australia's most affluent city face the longest waits for emergency care, despite significant investments in hospitals. How bad is it? That depends on how sick you are, Markus Mannheim writes.

Animal rights activists have repeatedly called for college sports teams to stop using real animals as their mascots. Are these complaints fair or an overreaction?

#RelationshipGoals: what she said.

"New England nautical vintage cottage" is the soothing style we all need right now. READ MORE...

IT LOOKS CUTE.. but, it's from Australia...it will kill you!

No serious, I want one of these.

PRINCE WILLIAM followed the Queen's lead with a touching VE Day message yesterday, and archive footage has cast a light on the closeness of their bond over the years.

PRINCE WILLIAM followed the Queen's lead with a touching VE Day message yesterday, and archive footage has cast a light on the closeness of their bond over the years.

The Franklin Skeleton Crew is connecting small businesses with the community in an unconventional way.

Previous studies have shown that sphingosine kinase interacting protein (SKIP) inhibits sphingosine kinase (SK) function in fibroblasts. SK phosphorylates sphingosine producing the potent signaling molecule sphingosine-1-phosphate (S1P). SKIP gene (SPHKAP) expression is silenced by hypermethylation of its promoter in acute myeloid leukemia (AML). However, why SKIP activity is silenced in primary AML cells is unclear. Here, we investigated the consequences of SKIP down-regulation in AML primary cells and the effects of SKIP re-expression in leukemic cell lines. Using targeted ultra-HPLC-tandem MS (UPLC-MS/MS), we measured sphingolipids (including S1P and ceramides) in AML and control cells. Primary AML cells had significantly lower SK activity and intracellular S1P concentrations than control cells, and SKIP-transfected leukemia cell lines exhibited increased SK activity. These findings show that SKIP re-expression enhances SK activity in leukemia cells. Furthermore, other bioactive sphingolipids such as ceramide were also down-regulated in primary AML cells. Of note, SKIP re-expression in leukemia cells increased ceramide levels 2-fold, inactivated the key signaling protein extracellular signal-regulated kinase, and increased apoptosis following serum deprivation or chemotherapy. These results indicate that SKIP down-regulation in AML reduces SK activity and ceramide levels, an effect that ultimately inhibits apoptosis in leukemia cells. The findings of our study contrast with previous results indicating that SKIP inhibits SK function in fibroblasts and therefore challenge the notion that SKIP always inhibits SK activity.

Previous studies have shown that sphingosine kinase interacting protein (SKIP) inhibits sphingosine kinase (SK) function in fibroblasts. SK phosphorylates sphingosine producing the potent signaling molecule sphingosine-1-phosphate (S1P). SKIP gene (SPHKAP) expression is silenced by hypermethylation of its promoter in acute myeloid leukemia (AML). However, why SKIP activity is silenced in primary AML cells is unclear. Here, we investigated the consequences of SKIP down-regulation in AML primary cells and the effects of SKIP re-expression in leukemic cell lines. Using targeted ultra-HPLC-tandem MS (UPLC-MS/MS), we measured sphingolipids (including S1P and ceramides) in AML and control cells. Primary AML cells had significantly lower SK activity and intracellular S1P concentrations than control cells, and SKIP-transfected leukemia cell lines exhibited increased SK activity. These findings show that SKIP re-expression enhances SK activity in leukemia cells. Furthermore, other bioactive sphingolipids such as ceramide were also down-regulated in primary AML cells. Of note, SKIP re-expression in leukemia cells increased ceramide levels 2-fold, inactivated the key signaling protein extracellular signal-regulated kinase, and increased apoptosis following serum deprivation or chemotherapy. These results indicate that SKIP down-regulation in AML reduces SK activity and ceramide levels, an effect that ultimately inhibits apoptosis in leukemia cells. The findings of our study contrast with previous results indicating that SKIP inhibits SK function in fibroblasts and therefore challenge the notion that SKIP always inhibits SK activity.

Acute myocardial infarction (MI) triggers a local and systemic inflammatory response. We recently showed microglia involvement using TSPO imaging. Here, we evaluate whether ¹¹C-methionine provides further insights into heart-brain inflammation networking. Methods: Male Bl6N mice underwent permanent coronary artery ligation followed by ¹¹C-methionine PET at 3 and 7 days (n = 3). In subgroups, leukocyte homing was blocked by integrin antibodies (n = 5). The cellular substrate for PET signal was identified using brain section immunostaining. Results: ¹¹C-methionine uptake peaked in the MI region at d3 (5.9±0.9vs 2.4±0.5 %ID/cc), decreasing to control level by d7 (4.3±0.6 %ID/cc). Brain uptake was proportional to cardiac uptake (r=0.47,p<0.05), peaking also at d3 (2.9±0.4vs 2.4±0.3 %ID/cc) and returning to baseline at d7 (2.3±0.4 %ID/cc). Integrin blockade reduced uptake at every time point. Immunostaining at d3 revealed co-localization of the L-type amino acid transporter with GFAP-positive astrocytes but not CD68-positive microglia. Conclusion: PET imaging with ¹¹C-methionine specifically identifies an astrocyte component, enabling further dissection of the heart-brain axis in post MI inflammation.

Previous studies have shown that sphingosine kinase interacting protein (SKIP) inhibits sphingosine kinase (SK) function in fibroblasts. SK phosphorylates sphingosine producing the potent signaling molecule sphingosine-1-phosphate (S1P). SKIP gene (SPHKAP) expression is silenced by hypermethylation of its promoter in acute myeloid leukemia (AML). However, why SKIP activity is silenced in primary AML cells is unclear. Here, we investigated the consequences of SKIP down-regulation in AML primary cells and the effects of SKIP re-expression in leukemic cell lines. Using targeted ultra-HPLC-tandem MS (UPLC-MS/MS), we measured sphingolipids (including S1P and ceramides) in AML and control cells. Primary AML cells had significantly lower SK activity and intracellular S1P concentrations than control cells, and SKIP-transfected leukemia cell lines exhibited increased SK activity. These findings show that SKIP re-expression enhances SK activity in leukemia cells. Furthermore, other bioactive sphingolipids such as ceramide were also down-regulated in primary AML cells. Of note, SKIP re-expression in leukemia cells increased ceramide levels 2-fold, inactivated the key signaling protein extracellular signal-regulated kinase, and increased apoptosis following serum deprivation or chemotherapy. These results indicate that SKIP down-regulation in AML reduces SK activity and ceramide levels, an effect that ultimately inhibits apoptosis in leukemia cells. The findings of our study contrast with previous results indicating that SKIP inhibits SK function in fibroblasts and therefore challenge the notion that SKIP always inhibits SK activity.

Naoko Sawada
Apr 14, 2020; 0:jlr.RA119000312v1-jlr.RA119000312
Research Articles

Oxidized low-density lipoprotein (oxLDL) is a known risk factor for atherogenesis. This study aimed to reveal structural features of oxLDL present in human circulation related to atherosclerosis. When LDL was fractionated on an anion-exchange column, in vivo-oxLDL, detected by the anti-oxidized phosphatidylcholine (oxPC) monoclonal antibody, was recovered in flow-through and electronegative LDL (LDL(-)) fractions. The amount of the electronegative in vivo-oxLDL, namely oxLDL in LDL(-) fraction, present in patients with acute myocardial infarction (AMI) was three-fold higher than that observed in healthy subjects. Surprisingly, LDL(-) fraction contained apoA1 in addition to apoB, and HDL-sized particles were observed with transmission electron microscopy. In LDL(-) fractions, acrolein adducts were identified at all lysine residues in apoA1, with only a small number of acrolein-modified residues were identified in apoB. The amount of oxPC adducts of apoB was higher in LDL(-) than in L1 fraction as determined using western blotting. The electronegative in vivo-oxLDL was immunologically purified from the LDL(-) fraction with an anti-oxPC monoclonal antibody. Majority of PC species was not oxidized, whereas oxPC and lysoPC did not accumulate. Here, we propose that there are two types of in vivo-oxLDL in human circulating plasma and the electronegative in vivo-oxLDL accompanies oxidized HDL.

The brain mechanisms underlying the association of hyperglycemia with depressive symptoms are unknown. We hypothesized that disrupted glutamate metabolism in pregenual anterior cingulate cortex (ACC) in type 1 diabetes (T1D) without depression affects emotional processing. Using proton magnetic resonance spectroscopy (MRS), we measured glutamate concentrations in ACC and occipital cortex (OCC) in 13 T1D without major depression (HbA1c=7.1±0.7% [54±7mmol/mol]) and 11 healthy non-diabetic controls (HbA1c=5.5±0.2% [37±3mmol/mol]) during fasting euglycemia (EU) followed by a 60-minute +5.5mmol/l hyperglycemic clamp (HG). Intrinsic neuronal activity was assessed using resting-state blood oxygen level dependent functional MRI to measure the fractional amplitude of low frequency fluctuations in slow-band 4 (fALFF4). Emotional processing and depressive symptoms were assessed using emotional tasks (Emotional-Stroop, Self-Referent-Encoding-Task SRET) and clinical ratings (HAM-D, SCL-90-R), respectively. During HG, ACC glutamate increased (1.2mmol/kg, +10%, p=0.014) while ACC fALFF4 was unchanged (-0.007, -2%, p=0.449) in T1D; in contrast, glutamate was unchanged (-0.2mmol/kg, -2%, p=0.578) while fALFF4 decreased (-0.05, -13%, p=0.002) in controls. OCC glutamate and fALFF4 were unchanged in both groups. T1D had longer SRET negative-word response-times (p=0.017) and higher depression-rating scores (HAM-D p=0.020; SCL-90-R-depression p=0.008). Higher glutamate change tended to associate with longer Emotional-Stroop response-times in T1D only. Brain glutamate must be tightly controlled during hyperglycemia due to the risk for neurotoxicity with excessive levels. Results suggest that ACC glutamate control mechanisms are disrupted in T1D, which affects glutamatergic neurotransmission related to emotional or cognitive processing. Increased prefrontal glutamate during acute hyperglycemic episodes could explain our previous findings of associations between chronic hyperglycemia, cortical thinning and depressive symptoms in T1D.

Type 2 diabetes mellitus predicts outcome following acute myocardial infarction (AMI). Since underlying mechanics are incompletely understood, we investigated left ventricular (LV) and atrial (LA) pathophysiological changes and their prognostic implications using cardiovascular magnetic resonance (CMR). Consecutive patients (n=1147, n=265 diabetic; n=882 non-diabetic) underwent CMR 3 days after AMI. Analyses included LV ejection fraction (LVEF), global longitudinal, circumferential and radial strains (GLS, GCS and GRS), LA reservoir, conduit and booster pump strains, as well as infarct size, edema and microvascular obstruction. Predefined endpoints were major adverse cardiovascular events (MACE) within 12 months. Diabetic patients had impaired LA reservoir (19.8 vs. 21.2%, p<0.01) and conduit strains (7.6 vs. 9.0%, p<0.01) but not ventricular function or myocardial damage. They were at higher risk of MACE than non-diabetic patients (10.2% vs. 5.8%, p<0.01) with most MACE occurring in patients with LVEF≥35%. Whilst LVEF (p=0.045) and atrial reservoir strain (p=0.024) were independent predictors of MACE in non-diabetic patients, GLS was in diabetic patients (p=0.010). Considering patients with diabetes and LVEF≥35% (n=237), GLS and LA reservoir strain below median were significantly associated with MACE. In conclusion, in patients with diabetes, LA and LV longitudinal strain permit optimized risk assessment early after reperfused AMI with incremental prognostic value over and above LVEF.

In the US the licence, or marketing authorisation, for alteplase is limited to 0-3 hours after onset of stroke, but some other countries - including the UK and Australia - have extended the licence to 4.5 hours. In an analysis article on thebmj.com Brian Alper, vice president of evidence based medicine research and development at Dynamed, and...

Acute respiratory distress syndrome was first described in 1967 and has become a defining condition in critical care. Around 40% of patients with ARDS will die, and survivors experience long term sequelae. No drug treatments exist for ARDS, however good supportive management reduces harm and improves outcome. In this podcast, John Laffey,...

It can be difficult to know what to do when a person in severe psychological distress presents to a general practice or community clinic, particularly if they are behaving aggressively, or if they are refusing help. Most patients who are acutely disturbed present no danger to others, however situations can evolve rapidly. Frontline staff need to...

As we cover the covid-19 outbreak, we want to hear some of the stories from the frontline - And who better to heart of what this pandemic is doing to the profession in the UK, than some of the people who write regularly for The BMJ? In this first one, we wanted to look specifically at acute care - those at the sharp end of the response, so we're...

Andreas Festa
Apr 1, 2002; 51:1131-1137
Complications

Candace D. McNaughton
Apr 1, 2011; 29:51-59
Feature Articles

Joseph Henson
Jan 1, 2016; 39:130-138
IDF-ADA Translational Symposium

Gary F Lewis
Apr 1, 1996; 19:390-393
Symposium On Insulin Resistance

Closing the U.S.-Mexico border and cutting off aid to Central America would only feed the crisis unfolding at key points along the U.S.-Mexico border. This commentary outlines a range of immediate and long-term policy responses that would more effectively address the complex mix of factors fueling rising Central American migration to the United States.

India is the world's largest source for immigrant physicians, and for Indian-trained doctors and nurses the allure of working abroad is strong despite an acute domestic shortage of health-care workers. Against this pull, the Indian government has enacted a number of policies to limit and regulate the emigration of health-care professionals, though these have been more ad hoc in nature and not part of a fully realized strategy.

Breslau : E. Morgenstern, 1882.

Berlin : A. Hirschwald, 1865.

Erlangen : F. Enke, 1850.

Berlin : T.C.F. Enslin, 1830.

Wien : Kaulfuss Witwe, Prandel, 1844.

Officials say a high school baseball coach and his wife were electrocuted while installing a new scoreboard at a Florida baseball field to replace one that had been destroyed by Hurricane Michael.

French translation of press release - the Basel Committee on Banking Supervision is finalising stress-testing principles, reviews ways to stop regulatory arbitrage behaviour, agrees on annual G-SIB list, discusses leverage ratio, crypto-assets, market risk framework and implementation, 20 September 2018.

Sugar gliders — cute little marsupials from Australia and Indonesia — are an up-and-coming exotic pet in Atlantic Canada. But are they as sweet as they look?

A young lady in a small Laotian village is pressured to recant her faith or jeopardize her educational future.

A search warrant executed by Hamilton police vice and drugs officers at an address in the city’s east end has resulted in the arrest of a couple and multiple charges, police said in a Friday release.

The standard initial management for infants and children with acute pyelonephritis is intravenous antibiotic treatment.

Our results support the use of an oral cefixime treatment of initial episodes of acute pyelonephritis involving a gram-negative bacteria strain in children aged 1 month to 3 years who are without urological abnormalities and without clinical hemodynamic impairment. (Read the full article)

Most acute wheezing episodes in preschool children are associated with rhinovirus, which decreases extracellular adenosine triphosphate levels, leading to airway surface liquid dehydration and submucosal edema, which cause failure of mucus clearance. These children respond poorly to available treatments.

Hypertonic saline inhalation, a pro–airway surface liquid hydration therapy, significantly decreases both length of stay by 33% (1 day) and the absolute risk of hospitalization by 30% in preschool children presenting with acute wheezing episode to the emergency department. (Read the full article)

A growing number of epidemiologic studies suggest that individuals with lower vitamin D levels are at higher risk of acute respiratory tract infection. Randomized controlled trials are needed to determine if vitamin D supplementation would decrease this risk.

In a randomized controlled trial of 247 Mongolian children with vitamin D deficiency in winter, with double-blinding and 99% follow-up, vitamin D supplementation significantly reduced the risk of acute respiratory tract infections. (Read the full article)

Pediatric osteoarticular infections can be treated with successful microbiologic and clinical outcomes with a transition from parenteral to oral therapy. The best way to determine the timing of this transition is neither well studied nor standardized.

A total of 193 (99.5%) of 194 pediatric patients with acute bacterial osteoarticular infections were successfully transitioned to oral therapy, determined by using a combination of clinical findings and C-reactive protein levels, representing the largest single-center data set analyzed. (Read the full article)