Bradykinin receptors of cerebral microvessels stimulate phosphoinositide turnover.

We examined by ligand binding methods whether bradykinin (BK) receptors exist in rat and pig cerebral microvessels, and in the cerebral cortex from which the microvessels were isolated. We found a high-affinity and saturable BK receptor site in both rat and pig cerebral microvessels, but not in their cerebral cortex. The maximal density of binding and the dissociation constant were 8.0 +/- 4.1 and 6.8 +/- 1.5 fmol/mg of protein and 47 +/- 24 and 150 +/- 8 pM (mean +/- SD) in cerebral microvessels of the pig and rat, respectively. The high-affinity specific binding of BK was effectively displaced by des-Arg0[Hyp3-Thi5-8,D-Phe7]BK, a specific B2 receptor antagonist, but not by des-Arg9[Leu8]BK, a specific B1 antagonist. We also demonstrated that BK increases phosphatidylinositol hydrolysis in cerebral microvessels of the rat and pig. This effect was also blocked by the B2, but not by the B1, antagonist. Increased phosphatidylinositol hydrolysis was manifested by a rapid transient increase in inositol trisphosphate and the later slow accumulation of inositol bisphosphate and inositol monophosphate. Preincubation of microvessels with phorbol ester, stable GTP analogs, pertussis toxin, or in Ca(2+)-free buffer did not influence BK activation of phosphatidylinositol hydrolysis. These results demonstrate the existence of BK receptors of the B2 subtype in brain microvessels, which may play an important role in modulation of the brain microcirculation, probably via increased phosphoinositide turnover.     

Evaluating mechanism and severity of injuries among trauma patients admitted to Sina Hospital, the National Trauma Registry of Iran

Purpose: Injuries are one of the leading causes of death and lead to a high social and financial burden. Injury patterns can vary significantly among different age groups and body regions. This study aimed to evaluate the relationship between mechanism of injury, patient comorbidities and severity of injuries. Methods: The study included trauma patients from July 2016 to June 2018, who were admitted to Sina Hospital, Tehran, Iran. The inclusion criteria were all injured patients who had at least one of the following: hospital length of stay more than 24 h, death in hospital, and transfer from the intensive care unit of another hospital. Data collection was performed using the National Trauma Registry of Iran minimum dataset. Results: The most common injury mechanism was road traffic injuries (49.0%), followed by falls (25.5%). The mean age of those who fell was significantly higher in comparison with other mechanisms (p < 0.001). Severe extremity injuries occurred more often in the fall group than in the vehicle collision group (69.0% vs. 43.5%, p < 0.001). Moreover, cases of severe multiple trauma were higher amongst vehicle collisions than injuries caused by falls (27.8% vs. 12.9%, p = 0.003). Conclusion: Comparing falls with motor vehicle collisions, patients who fell were older and sustained more extremity injuries. Patients injured by motor vehicle collision were more likely to have sustained multiple trauma than those presenting with falls. Recognition of the relationship between mechanisms and consequences of injuries may lead to more effective interventions.     

N-nitro- -arginine methylester is protective against ethanol-induced gastric damage in cholestatic rats

In this study the effect of nitric oxide (NO) synthesis inhibition on ethanol-induced gastric damage was evaluated in bile duct-ligated, sham-operated and unoperated rats. The animals were injected intraperitoneally with saline, -arginine (200 mg/kg) or N^G-nitro- -arginine methylester ( -NAME) in doses of 5, 15 and 30 mg/kg, 30 min before ethanol administration. The animals were killed 1 h after ethanol administration and their stomachs were removed for measurement of gastric mucosal damage. The results showed that -NAME significantly enhanced the development of gastric mucosal lesions in sham-operated and unoperated rats, while in bile duct-ligated animals, -NAME decreased and -arginine enhanced the potentiation of ethanol-induced gastric mucosal damage. The plasma level of nitrite and nitrate was also measured and was significantly higher in bile duct-ligated rats than in control groups. The results suggest that inhibition of NO synthase with -NAME has different effects on ethanol-induced gastric damage in cholestatic groups and in normal rats and that these effects can be explained by overproduction of NO in bile duct-ligated animals.     

Incorporation of second‐tier tests and secondary biomarkers to improve positive predictive value (PPV) rate in newborn metabolic screening program

BackgroundNowadays, neonatal screening has become an essential part of routine newborn care in the world. This is a non‐invasive evaluation that evaluated inborn errors of metabolisms (IEMs) using tandem mass spectrometry (LC‐MS/MS) for the evaluation of the baby''s risk of certain metabolic disorders.MethodsThis retrospective study was conducted on 39987 Iranian newborns who were referred to Nilou Medical Laboratory, Tehran, Iran, for newborn screening programs of IEMs. We incorporated second‐tier tests and secondary biomarkers to improve positive predictive value (PPV).ResultsStatistical data were recorded via call interviewing in 6–8 months after their screening tests. The overall prevalence of IEM was 1:975. The mean age of all participants was 3.9 ± 1.1 days; 5.1% of participants were over 13 days and 7.7% were preterm or underweight. A total of 11384 (29.4%) of the cases were born in a consanguineous family. The type of delivery was the cesarean section in 8332 (51.3%) valid cases. The neonatal screening results had an overall negative predictive value (NPV) of 100% and the overall PPV of 40.2%. The false‐positive rate was 0.15%.ConclusionThis study showed a high incidence of metabolic disease due to a high rate of consanguineous marriages in Iran and indicated that incorporation of second‐tier tests and secondary biomarkers improves PPV of neonatal screening programs.     

Premature Ticagrelor Discontinuation in Secondary Prevention of Atherosclerotic CVD: JACC Review Topic of the Week

Ticagrelor is a cornerstone of modern antithrombotic therapy alongside aspirin in patients with acute coronary syndrome and after percutaneous coronary intervention. Adverse effects such as bleeding and dyspnea have been associated with premature ticagrelor discontinuation, which may limit any potential advantage of ticagrelor over clopidogrel. The randomized trials of ticagrelor captured adverse events, offering the opportunity to more precisely quantify these effects across studies. Therefore, a meta-analysis of 4 randomized clinical trials of ticagrelor conducted between January 2007 and June 2017 was performed to quantify the incidence and causes of premature ticagrelor discontinuation. Among 66,870 patients followed for a median 18 months, premature ticagrelor discontinuation was seen in 25%; bleeding was the most common cause of discontinuation followed by dyspnea. Versus the comparators, the relative risk of dyspnea-related discontinuation during follow-up was 6.4-fold higher, the relative risk of bleeding was 3.2-fold higher, and the relative risk of discontinuation due to any adverse event was 59% higher for patients receiving ticagrelor. Understanding these potential barriers to adherence to ticagrelor is crucial for informed patient-physician decision making and can inform future efforts to improve ticagrelor adherence. This review discusses the incidence, causes, and biological mechanisms of ticagrelor-related adverse effects and offers strategies to improve adherence to ticagrelor.     

Trisomy 3q25.1-qter and monosomy 8p23.1-pter in a patient: cytogenetic and molecular analysis with delineation of the phenotype

We describe a 4-year-old boy with partial 3q trisomy and distal 8p monosomy. The patient presented with mental retardation, dysmorphic face, congenital heart defect, brain and genital anomalies, and behavioral problems. The conventional cytogenetic analysis showed a 46,XY,add(8p) karyotype. Reverse painting and microsatellite analysis demonstrated a partial monosomy of 8p23.1 --> pter and a partial trisomy of 3q25.1 --> qter. The data suggest that the chromosomal rearrangement originated from a de novo translocation in a paternal germinal cell. The phenotype observed in our patient resulted from the combination of those defects described in the isolated dup(3q) and distal del(8p) syndromes.     

Levels of IL-15 in serum and cerebrospinal fluid of patients with Behçet's disease

Interleukin‐15 (IL‐15) is a novel proinflammatory cytokine, involved in the pathogenesis of inflammatory/autoimmune disease. The objective of our study was to measure serum and cerebrospinal fluid (CSF) IL‐15 levels in patients with Behçet's disease (BD). CSF/serum IL‐15 ratio was introduced to assess the origin of elevated IL‐15 levels. We measured serum and CSF‐IL‐15 levels in 40 patients with BD (20 patients in active stage). Inflammatory and non‐inflammatory neurological disease patients acted as controls. Active BD patients have significantly higher serum IL‐15 levels (median 10.4 pg/ml; range 5.3–17.4) compared with BD in remission (6.05 pg/ml; 4–10.4) and healthy controls (4.65 pg/ml; 3.9–6.2). Similar serum IL‐15 levels were found in active neuro‐BD and inflammatory neurological disease (9.5 pg/ml; 5–13). Elevated levels of IL‐15 were observed in CSF samples from neuro‐BD patients (11 pg/ml; 8.5–15) and inflammatory neurological disease patients (10 pg/ml; 6.5–14) compared with patients with non‐inflammatory neurological disease (4 pg/ml; 4–5.5; P < 0.001). Vascular cerebral BD lesions were associated with high CSF/serum IL‐15 ratio. Our findings suggest that IL‐15 is involved in BD inflammatory process, particularly in vasculitis foci, as an elevated CSF/serum IL‐15 ratio characterizes vascular cerebral lesions.     

Orbitofrontal cortex neurons as a common target for classic and glutamatergic antipsychotic drugs

Until recently, all known antipsychotic drugs were thought to block the dopamine D2 receptor. New evidence that agonists of the metabotropic glutamate 2/3 (mGlu2/3) receptors ameliorate psychotic and affective symptoms of schizophrenia suggests that compounds with different molecular targets may act on a common cellular target to treat schizophrenia. We hypothesized that normalizing the activity of neurons in the orbitofrontal cortex (OFC), a region that is increasingly implicated in the pathophysiology of schizophrenia, presents such a target. We disrupted OFC activity in behaving rats with a use-dependent NMDA antagonist to model the NMDA hypofunction state that may occur in schizophrenia. This systemic treatment increased the activity of most pyramidal cells while inhibiting the activity of putative inhibitory GABA interneurons and increasing behavioral stereotypy. A similar pattern of OFC firing disruption was observed after amphetamine, which models a dopamine hyperactivity state in schizophrenia and which produces a pattern of firing disruption different from those of NMDA antagonists in other prefrontal cortex regions. Antipsychotic drugs haloperidol and clozapine, which target monoamine receptors, as well as an mGlu2/3 agonist and an mGlu5 receptor modulator proposed to have antipsychotic efficacy, reversed the impact of NMDA hypofunction on OFC cells and on behavior. A similar pattern of normalization of OFC activity was observed when treatments were given after amphetamine. Thus, proven or putative antipsychotic drugs with different mechanisms of action similarly reduced the impact of NMDA hypofunction and dopamine hyperfunction on OFC neurons, suggesting that these neurons are a candidate target for the therapeutic effects of antipsychotic medications.     

The interplay between metabolic alterations,diastolic strain rate and exercise capacity in mild heart failure with preserved ejection fraction: a cardiovascular magnetic resonance study

Background

Heart failure (HF) is characterized by altered myocardial substrate metabolism which can lead to myocardial triglyceride accumulation (steatosis) and lipotoxicity. However its role in mild HF with preserved ejection fraction (HFpEF) is uncertain. We measured myocardial triglyceride content (MTG) in HFpEF and assessed its relationships with diastolic function and exercise capacity.

Methods

Twenty seven HFpEF (clinical features of HF, left ventricular EF >50%, evidence of mild diastolic dysfunction and evidence of exercise limitation as assessed by cardiopulmonary exercise test) and 14 controls underwent ¹H-cardiovascular magnetic resonance spectroscopy (¹H-CMRS) to measure MTG (lipid/water, %), ³¹P-CMRS to measure myocardial energetics (phosphocreatine-to-adenosine triphosphate - PCr/ATP) and feature-tracking cardiovascular magnetic resonance (CMR) imaging for diastolic strain rate.

Results

When compared to controls, HFpEF had 2.3 fold higher in MTG (1.45?±?0.25% vs. 0.64?±?0.16%, p?=?0.009) and reduced PCr/ATP (1.60?±?0.09 vs. 2.00?±?0.10, p?=?0.005). HFpEF had significantly reduced diastolic strain rate and maximal oxygen consumption (VO₂ max), which both correlated significantly with elevated MTG and reduced PCr/ATP. On multivariate analyses, MTG was independently associated with diastolic strain rate while diastolic strain rate was independently associated with VO₂ max.

Conclusions

Myocardial steatosis is pronounced in mild HFpEF, and is independently associated with impaired diastolic strain rate which is itself related to exercise capacity. Steatosis may adversely affect exercise capacity by indirect effect occurring via impairment in diastolic function. As such, myocardial triglyceride may become a potential therapeutic target to treat the increasing number of patients with HFpEF.