The preoperative cardiology consultation: indications and risk modification.

BACKGROUND: The cardiologist is regularly consulted preoperatively by anaesthesiologists. However, insights into the efficiency and usefulness of these consultations are unclear. METHODS: This is a retrospective study of 24,174 preoperatively screened patients ≥18 years scheduled for elective non-cardiac surgery, which resulted in 273 (1%) referrals to the cardiologist for further preoperative evaluation. Medical charts were reviewed for patient characteristics, main reason for referring, requested diagnostic tests, interventions, adjustment in medical therapy, 30-day mortality and major adverse cardiac events. RESULTS: The most common reason for consultation was the evaluation of a cardiac murmur (95 patients, 35%). In 167 (61%) patients, no change in therapy was initiated by the cardiologist. Six consultations (2%) led to invasive interventions (electrical cardioversion, percutaneous coronary intervention or coronary artery bypass surgery). On average, consultation delayed clearance for surgery by two weeks. CONCLUSION: In most patients referred to the cardiologist after being screened at an outpatient anaesthesiology clinic, echocardiography is performed for ruling out specific conditions and to be sure that no further improvement can be made in the patient's health. In the majority, no change in therapy was initiated by the cardiologist. A more careful consideration about the potential benefits of consulting must be made for every patient.

[Extracorporeal life support in calcium antagonist intoxication]. / Extracorporele life support bij calciumblokkerintoxicatie.

BACKGROUND: Intoxication with calcium antagonists is associated with poor outcome. Even mild calcium antagonist overdose may be fatal. CASE DESCRIPTION: A 51-year-old woman and a 51-year-old man came to the Accident and Emergency Department in severe shock after they had taken a calcium antagonist overdose. After extensive medicinal therapy had failed, they both needed extracorporeal life support (ECLS) as a bridge to recovery. CONCLUSION: In severe calcium antagonist overdose, the combination of vasoplegia and cardiac failure leads to refractory shock. ECLS temporarily supports the circulation and maintains organ perfusion. In this way ECLS functions as a bridge to recovery and may possibly save lives. Timely consultation with and referral to an ECLS centre is recommended in patients with calcium antagonist overdose.

Neurotoxicity screening of (illicit) drugs using novel methods for analysis of microelectrode array (MEA) recordings.

Annual prevalence of the use of common illicit drugs and new psychoactive substances (NPS) is high, despite the often limited knowledge on the health risks of these substances. Recently, cortical cultures grown on multi-well microelectrode arrays (mwMEAs) have been used for neurotoxicity screening of chemicals, pharmaceuticals, and toxins with a high sensitivity and specificity. However, the use of mwMEAs to investigate the effects of illicit drugs on neuronal activity is largely unexplored. We therefore first characterised the cortical cultures using immunocytochemistry and show the presence of astrocytes, glutamatergic and GABAergic neurons. Neuronal activity is concentration-dependently affected following exposure to six neurotransmitters (glutamate, GABA, serotonin, dopamine, acetylcholine and nicotine). Most neurotransmitters inhibit neuronal activity, although glutamate and acetylcholine transiently increase activity at specific concentrations. These transient effects are not detected when activity is determined during the entire 30min exposure window, potentially resulting in false-negative results. As expected, exposure to the GABAA-receptor antagonist bicuculline increases neuronal activity. Exposure to a positive allosteric modulator of the GABAA-receptor (diazepam) or to glutamate receptor antagonists (CNQX and MK-801) reduces neuronal activity. Further, we demonstrate that exposure to common drugs (3,4-methylenedioxymethamphetamine (MDMA) and amphetamine) and NPS (1-(3-chlorophenyl)piperazine (mCPP), 4-fluoroamphetamine (4-FA) and methoxetamine (MXE)) decreases neuronal activity. MXE most potently inhibits neuronal activity with an IC50 of 0.5µM, whereas 4-FA is least potent with an IC50 of 113µM. Our data demonstrate the importance of analysing neuronal activity within different time windows during exposure to prevent false-negative results. We also show that cortical cultures grown on mwMEAs can successfully be applied to investigate the effects of different (illicit) drugs on neuronal activity. Compared to investigating multiple single endpoints for neurotoxicity or neuromodulation, such as receptor activation or calcium channel function, mwMEAs can provide information on integrated aspects of drug-induced neurotoxicity more rapidly. Therefore, this approach could contribute to a faster insight in possible health risks and shorten the regulation process.

Contrast-enhanced computed tomographic evaluation of the deep digital flexor tendon in the equine foot compared to macroscopic and histological findings in 23 limbs.

REASONS FOR PERFORMING THE STUDY: Distal deep digital flexor tendinopathy is an important cause of foot lameness in horses that is difficult to diagnose with radiography and ultrasonography. Magnetic resonance imaging is a well-accepted and validated technique for the identification of deep digital flexor tendon (DDFT) lesions, but has some practical and financial drawbacks. Contrast-enhanced computed tomography (CECT) has been proposed as a suitable alternative, but validation studies are currently lacking. OBJECTIVE: To assess the accuracy of CECT for the identification and characterisation of deep digital flexor tendinopathy. STUDY DESIGN: Descriptive study of CT, macroscopic and histological findings of the DDFT. METHODS: Plain and CECT scans were acquired of 23 limbs of 16 horses with clinical lameness localised to the foot. All horses had lesions of the DDFT that were identified and characterised with CT and CECT with respect to their anatomic location and extent. All horses underwent post mortem examination and gross abnormalities were described. Samples of the DDFT were taken at specific sites (lesion and nonlesion) for histological evaluation. Macroscopic and histological outcomes were compared with CECT findings. RESULTS: Of 67 sites in 23 DDFTs that were evaluated, 42 sites in 18 tendons had lesions on CECT images. These 42 sites also had lesions on macroscopic evaluation. There were 3 false negative and 3 false positive results identified on CECT. The sensitivity of CECT for diagnosing lesions of the DDFT in the equine foot was 93%. CONCLUSION: CECT is an effective adjunct to the more commonly used diagnostic techniques in equine foot pain.

p38 inhibition and not MK2 inhibition enhances the secretion of chemokines from TNF-α activated rheumatoid arthritis fibroblast-like synoviocytes.

OBJECTIVES: For many years the p38 MAP kinase (MAPK) has been a major anti-inflammatory target for the development of an oral therapy for rheumatoid arthritis (RA). However, disappointing results from Phase II clinical studies suggest that adaptations may occur, which allow escape from blockade of the p38 pathway. In this study we investigated whether p38 inhibition mediated JNK activation represents such an escape mechanism. METHODS: Interaction between the JNK and p38 pathways was studied in TNF-α stimulated THP-1 monocytes, primary macrophages and fibroblast-like synoviocytes from OA and RA patients using pharmacological inhibitors and siRNAs. RESULTS: TNF-α induced phosphorylation of JNK and c-Jun was sustained by p38 inhibitors in monocytes, primary macrophages and FLS. Upregulation of Mip1α, Mip1ß and IL-8 mRNAs and protein were observed upon p38 inhibition. More importantly, inhibition of MK2, the substrate of p38 did not sustain JNK activation upon TNF-α activation and did not elevate Mip1α, Mip1ß and IL-8 chemokines as compared to TNF-α alone. In this study, TNF-α or IL-1ß induced JNK activation is sustained by p38 inhibition, resulting in enhanced chemokine secretion. CONCLUSIONS: Based on the suggested role of these chemokines in RA pathogenesis, the upregulation of these chemokines may provide an explanation for the lack of efficacy of p38 inhibitors in Phase II. The absence of any effect of MK2 inhibition in our models on this mechanism, while coming with similar efficacy on blocking p38, provides support for further investigations to reveal the potential of MK2 inhibition as a novel treatment of RA.

Coronary revascularization in diabetic patients. A focus on the 3-year SYNTAX trial outcomes.

The prevalence of diabetes is growing worldwide. Diabetics are predisposed to coronary artery disease due to an increased rate of atherosclerosis. The optimal treatment for these patients remains uncertain. Randomized trials compared percutaneous coronary intervention (PCI) to coronary artery bypass surgery (CABG) to determine the most suitable revascularization strategy. Meta-analyses suggest a survival advantage in favor of surgery over angioplasty or stenting with bare-metal stents (BMS). New evidence was needed since advances in medical therapy, PCI technology, and surgical techniques have emerged. The Synergy between PCI with Taxus and Cardiac Surgery (SYNTAX) trial was the first to compare a drug-eluting stent to CABG and showed an increased rate of major adverse cardiac or cerebrovascular events after PCI. Results are mainly driven by the increased rates in patients with high lesion complexity; therefore, the current evidence suggests that diabetic patients with complex coronary disease have better outcomes with CABG.

Cervical ripening and parturition in cows are driven by a cascade of pro-inflammatory cytokines.

The final stages of cervical ripening and parturition resemble an inflammatory process. Although the role of cytokines in both spontaneous and experimentally induced parturitions has been described in several small laboratory animals and humans, the involvement of pro-inflammatory and regulatory cytokines in physiologic parturition in cows has not been determined. In this study, the cytokine expression profiles were assessed in bovine cervical tissue at several stages of pregnancy and at parturition. Serial biopsy samples of the cervix were obtained from 10 cows on day 185 and day 275 of pregnancy (which was on average 5.4 days before parturition) and at parturition. Messenger RNA expression levels of interleukin (IL)-1beta, IL-6, IL-8, IL-10 and tumour necrosis factor (TNF)alpha were determined using real-time polymerase chain reaction and the number of neutrophils and eosinophils was estimated by Luna and Sirius Red staining. At parturition, IL-8 expression had increased 430-fold (p < 0.001) when compared with that of the day 185 of pregnancy, large numbers of neutrophils had invaded the cervix while eosinophils remained scarce, IL-1beta had increased eightfold (p < 0.05) and IL-6 had not changed significantly. Additionally, IL-10 was increased by 10-fold (p < 0.001) and TNFalpha decreased by 57% (p < 0.05) when compared with that of the day 185 of pregnancy. The large increase in expression of IL-8, enabling the influx of neutrophils, is indicative of its important role in the final stage of cervical ripening and at parturition. As previous studies have shown that neutrophils excrete matrix metalloproteinases (MMP), this might contribute to softening of the cervix. In contrast, the only slightly increased levels of IL-1, steady concentrations of IL-6 and decreased TNFalpha, the potential consequences of increased IL-10 expression, indicate that final cervical of cows in ripening at term parturition is an inflammatory process influenced by regulatory cytokines.

Acute fasting in heifers as a model for assessing the relationship between plasma and follicular fluid NEFA concentrations.

It is known from epidemiological studies that negative energy balance in early lactating dairy cows is related to a depression in reproductive performance. Elevated plasma concentrations of non-esterified fatty acids (NEFA) are a typical metabolic characteristic of these animals and are proposed as the possible link. The suggestion is that NEFA might have a direct effect on the ovary, by affecting development of the oocyte or the granulosa cells. However, no data is available concerning the relationship between the concentration of NEFA in follicular fluid and plasma. Therefore, a cross-over study with 10 heifers around 15 months of age was conducted to analyze this relationship and examine the suggested effects of the negative energy balance on follicular growth. Investigation of these effects was performed on fasted heifers. The experimental treatment consisted of feeding hay with a subsequent period of fasting, to induce elevated plasma NEFA concentrations. Sampling of follicular fluid was performed using transvaginal aspiration of follicles, which were standardized using a synchronization protocol. In addition, concentrations of glucose, insulin, NEFA, and estradiol were measured in plasma. Follicular estradiol and progesterone concentrations were also measured to assess the quality of the dominant follicle. Fasting resulted in significantly lower plasma glucose (P=0.0006) and plasma insulin (P<0.0001) concentrations, higher plasma estradiol (P=0.008) and higher NEFA (P<0.001) concentrations, and smaller follicles (P=0.04) with lower estradiol:progesterone (E/P) ratios (P=0.05). Concentrations of NEFA in follicular fluid and plasma were closely related. Given this close relationship, we concluded that the presence of high plasma NEFA concentrations might link energy metabolism in early lactation with fertility.