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

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.

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)

Bilateral acute otitis media (AOM) is considered more severe than unilateral AOM, and several guidelines recommend more active management of bilateral AOM. However, severity of symptoms and otoscopic signs of bilateral and unilateral AOM have previously not been comprehensively studied.

Bilateral AOM seems to be clinically only a slightly more severe illness than unilateral AOM. When assessing AOM severity, bilaterality should not be used as a determining criterion; instead, the child’s symptoms together with otoscopic signs should also be acknowledged. (Read the full article)

Children with acute liver failure due to a single-dose acetaminophen exposure have a characteristic liver biochemistry profile of low conjugated bilirubin and high alanine aminotransferase, which is associated with a favorable clinical outcome when treated with N-acetylcysteine.

Children with acute liver failure associated with chronic acetaminophen exposure also have a similar liver biochemistry profile, but for unknown reasons, they have a poorer clinical outcome than patients with single-dose acetaminophen exposure. (Read the full article)

Health care–associated infections cause considerable morbidity and mortality among hospitalized children. Simple barrier precautions such as universal gloving of health care workers’ hands may reduce transmission of infectious agents between patients.

Mandatory use of gloves during respiratory syncytial virus season in pediatric units prevented other health care–associated infections such as central line–associated bloodstream infections, particularly in intensive care settings. These secondary benefits suggest continuing mandatory gloving throughout the year. (Read the full article)

Prompt, high-quality diagnosis of acute pyelonephritis and later identification of children with scarring are important to prevent future complications. Examination by dimercaptosuccinic acid scan is the current clinical gold standard but is not routinely performed.

Procalcitonin demonstrated a more robust predictive ability, compared with C-reactive protein or white blood cell count, to selectively identify both children who had acute pyelonephritis during the early stage of urinary tract infections, as well as those with late scarring. (Read the full article)

Abdominal pain is a frequent complaint in pediatric emergency departments, with a broad differential diagnosis. The impact of demographic and clinical characteristics of patients on the evaluation and management of these children is not well known.

The most common cause of abdominal pain is constipation, which rarely requires hospital admission. Demographic factors, in particular race, do not seem to affect evaluation and management. (Read the full article)

Inconsistent results have been reported on the association between sleep duration and blood pressure (BP) in children, likely as a result of inadequate adjustment for confounders and the use of different time frames in assessing sleep duration.

Short sleep duration and poor sleep quality are associated with higher BP in normal-weight adolescents. One night of adequate sleep may partially ameliorate the risk of high BP but cannot completely reverse the effect of chronic sleep insufficiency. (Read the full article)

Hypertonic saline (3% and 5%), has been shown to improve clinical severity scores and reduce inpatient length of stay, and was associated with a trend toward lower admission rate in acute bronchiolitis.

We are not aware of any previous data using 7% hypertonic saline in bronchiolitis. Our results suggest that 7% saline does not lower clinical severity of illness, admission rate, or length of stay, when compared with normal saline. (Read the full article)

Bacille Calmette-Guerin (BCG) vaccination may provide benefits beyond protecting against pediatric tuberculosis. Evidence suggests links between cell-mediated immunity from tuberculosis and bacterial/viral-related pneumonia but the impact of BCG on acute lower respiratory infection is not fully known.

BCG-vaccinated children had a lower risk of suspected acute lower respiratory infection. Protection was amplified when children were vaccinated against diphtheria-tetanus-pertussis (DTP). Number of DTP doses did not modify this effect, but order in which vaccines were received did. (Read the full article)

Xylitol given as a gum or syrup 5 times daily has been shown to reduce the incidence of acute otitis media in children, but this dosing schedule is unlikely to be feasible for many families.

A regimen of viscous xylitol syrup in a dose of 5 g 3 times daily was ineffective in preventing recurrences of acute otitis media in otitis-prone children. (Read the full article)

Encephalitis in children can cause significant neurologic sequelae, such as motor and cognitive impairment. Previous reported data are based mostly on questionnaires and clinical assessments.

Significant cognitive impairment, attention-deficit/hyperactivity disorder, and learning disabilities are common after childhood encephalitis. Even children who were considered fully recovered may be significantly affected. Identifiable pathogens, abnormal neuroimaging, and abnormal neurologic examination on discharge are risk factors of poor outcome. (Read the full article)

Quantitative real-time polymerase chain reaction allows sensitive detection of respiratory viruses. The clinical significance of detection of specific viruses is not fully understood, however, and several viruses have been detected in the respiratory tract of asymptomatic children.

Our results indicate that quantitative real-time polymerase chain reaction is limited at distinguishing acute infection from detection in asymptomatic children for rhinovirus, bocavirus, adenovirus, enterovirus, and coronavirus. (Read the full article)

Concussions in youth are a common injury evaluated in the emergency department (ED). Early recognition and active management of this mild traumatic brain injury are important to safe recovery. Tools to assess and manage concussion in the ED are lacking.

Acute Concussion Evaluation tools, modified for ED use, improved reported follow-up with primary care or concussion specialists and adherence to recommendations. Barriers to follow-up remain and the importance of ongoing outpatient management should be stressed. (Read the full article)

Ceftriaxone at therapeutic doses can lead to renal stone formation.

Renal stone formation with ceftriaxone therapy can result in postrenal acute renal failure in children. The condition can be treated effectively by timely pharmacotherapy or retrograde ureteral catheterization with good prognosis. (Read the full article)

Children are often evaluated in the emergency department after a concussion. Although prolonged symptoms are associated with higher initial symptom severity when measured 2 to 3 weeks after injury, a similar association with acute symptom severity has not been demonstrated.

Higher acute symptom severity is not associated with development of persistent post-concussion symptoms 1 month after injury, but persistent post-concussive symptoms affect a significant number of children after concussion. Outpatient follow-up is essential to identify children who develop persistent symptoms. (Read the full article)

Many pediatric acute respiratory tract infections (ARTI) are viral and do not require antimicrobial treatment. Recent estimates of antimicrobial overprescribing for these infections, defined based on the published bacterial disease prevalence among all ARTI, are not available.

Based on the published bacterial prevalence rates for pediatric ARTI, antimicrobial agents are prescribed almost twice as often as expected to outpatients nationally, amounting to an estimated 11.4 million potentially preventable antimicrobial prescriptions annually. (Read the full article)

Expert consensus recommends rest after concussion with stepwise return to activity. Animal and retrospective human data suggest that early mental and physical activity may worsen outcome. There are no pediatric studies testing the efficacy of recommending strict rest after concussion.

Recommending strict rest postinjury did not improve outcome and may have contributed to increased symptom reporting. Usual care (rest for 1–2 days with stepwise return to activity) is currently the best discharge strategy for pediatric mild traumatic brain injury/concussion. (Read the full article)

Migraine headaches are a common presenting complaint in emergency departments. Abortive treatment in this setting is not well studied, leading to considerable variation in treatment. The relationship between acute medications and emergency department revisits has not been studied.

Eighty-five percent of children with migraine are successfully discharged from the emergency department; only 1 in 18 children require a return visit. Prochlorperazine is associated with less revisits than metoclopramide, and diphenhydramine use is associated with increased risk of return visits. (Read the full article)

Acute kidney injury (AKI) occurs in up to 50% of children after cardiopulmonary bypass and is associated with adverse outcomes. Renal biomarkers have been shown to predict postoperative AKI, but few studies have examined cardiac biomarkers for risk classification.

Preoperative levels of creatine kinase-MB and heart-type fatty acid binding protein are strongly associated with the development of postoperative AKI after pediatric cardiac surgery and can be used to improve preoperative clinical risk prediction. (Read the full article)

Otorrhea is common in children with tympanostomy tubes: annually, 2 of 3 children develop 1 or more episodes. Antibiotic-glucocorticoid eardrops are the most effective treatment in both the short- and long-term.

Treatment with antibiotic-glucocorticoid eardrops costs less than oral antibiotics and initial observation in children with tympanostomy tubes who develop otorrhea. Non–health care costs constitute a substantial proportion of the total costs of this condition. (Read the full article)

Most prospective cohort studies of acquired demyelinating syndromes in children have focused on the genetic, environmental, and neuroimaging predictors of multiple sclerosis. Less is known regarding the severity of the incident demyelinating event and predictors of residual attack–related physical disability.

In a national, prospective longitudinal study, incident acquired demyelinating syndromes in children were characterized in terms of physical deficits and acuity at onset, and recovery over the first 12 months. Follow-up evaluations up to 10 years’ postonset were analyzed. (Read the full article)

Strictly-defined pediatric bipolar I disorder (BP-I) is a serious condition. Although lithium is a benchmark treatment and has shown effectiveness in adults for decades, no definitive efficacy or long-term safety studies had been performed in pediatric patients with BP-I.

This study provides evidence to support the efficacy of lithium in the acute treatment of youths with BP-I who are currently in a manic or mixed state. Lithium had an adverse effect profile that was acceptable for most patients. (Read the full article)

Ya paso otro año así que le daremos otro vistazo a nuestra busca perpetua por el ISP mas veloz en México

Gepotidacin, a triazaacenaphthylene bacterial type II topoisomerase inhibitor, is in development for treatment of uncomplicated urinary tract infection (uUTI). This Phase 2a study in female participants with uUTI evaluated the pharmacokinetics (primary objective), safety, and exploratory efficacy of gepotidacin. Eligible participants (N = 22) were confined to the clinic at baseline, received oral gepotidacin 1,500 mg twice daily for 5 days (on-therapy; Days 1 to 5), and returned to the clinic for test-of-cure (Days 10 to 13) and follow-up (Day 28±3). Pharmacokinetic, safety, clinical, and microbiological assessments were performed. Maximum plasma concentrations were observed approximately 1.5 to 2 hours postdose. Steady state was attained by Day 3. Urinary exposure over the dosing interval increased from 3,742 μg.h/ml (Day 1) to 5,973 μg.h/ml (Day 4), with trough concentrations of 322 to 352 μg/ml from Day 3 onward. Gepotidacin had an acceptable safety-risk profile with no treatment-limiting adverse events and no clinically relevant safety trends. Clinical success was achieved in 19 (86%) and 18 (82%) of 22 participants at test-of-cure and follow-up, respectively. Eight participants had a qualifying baseline uropathogen (growth; ≥10⁵ CFU/ml). A therapeutic (combined clinical and microbiological [no growth; <10³ CFU/ml]) successful response was achieved in 6 (75%) and 5 (63%) of 8 participants at test-of-cure and follow-up, respectively. Plasma area under the free-drug concentration-time curve over 24 hours at steady state divided by the MIC (fAUC_0-24/MIC) and urine AUC_0-24/MIC ranged from 6.99 to 90.5 and 1,292 to 121,698, respectively. Further evaluation of gepotidacin in uUTI is warranted. (NCT03568942)

Chagas disease, caused by the protozoan Trypanosoma cruzi, is one of the main causes of death due to cardiomyopathy and heart failure in Latin American countries. The treatment of Chagas disease is directed at eliminating the parasite, decreasing the probability of cardiomyopathy, and disrupting the disease transmission cycle. Benznidazole (BZ) and nifurtimox (NFX) are recognized as effective drugs for the treatment of Chagas disease by the World Health Organization, but both have high toxicity and limited efficacy, especially in the chronic disease phase. At low doses, aspirin (ASA) has been reported to protect against T. cruzi infection. We evaluated the effectiveness of BZ in combination with ASA at low doses during the acute disease phase and evaluated cardiovascular aspects and cardiac lesions in the chronic phase. ASA treatment prevented the cardiovascular dysfunction (hypertension and tachycardia) and typical cardiac lesions. Moreover, BZ+ASA-treated mice had a smaller cardiac fibrotic area than that in BZ-treated mice. These results were associated with an increase in the number of eosinophils and reticulocytes and level of nitric oxide in the plasma and cardiac tissue of ASA-treated mice relative to respective controls. These effects of ASA and BZ+ASA in chronically infected mice were inhibited by pretreatment with the LXA₄ receptor antagonist, Boc-2, indicating that the protective effects of ASA are mediated by ASA-triggered lipoxin. These results emphasize the importance of exploring new drug combinations for treatments of acute phase of Chagas disease that are beneficial for chronic patients.