Murine Stress-triggered Abortion is Mediated by Increase of CD8+ TNF-α+ Decidual Cells via Substance P

PROBLEM: Stress is known to induce abortions in mice and humans. Increased levels of abortogenic type 1 helper T-cell cytokines and decreased levels of pregnancy protective cytokines could be linked to stress-triggered embryonic loss. Stress promotes neurotransmitter substance P (SP) release in tissues. SP increases the production of decidual tumor necrosis factor (TNF)-alpha, whereby the phenotype of these TNF-alpha-producing cells is hypothetical. The objective of the present study was to identify decidual TNF-alpha-producing cell populations that are involved in stress-induced murine abortion. METHOD: DBA/2J-mated CBA/J female mice were exposed to ultrasonic sound stress on day 5.5 of pregnancy. The mice were randomized and half were treated with the SP NK1-receptor antagonist (SP-RA) RP 67580 (200 microg/mouse). Frequency and cytokine profile of CD8+ cells were evaluated by immunohistochemistry and flow cytometry. Degranulation of uterine mast cells was examined histologically. RESULTS: On day 13.5 of pregnancy, the uteri were removed and the resorption rate was calculated. A mean resorption rate of 38.4% was detected in stressed mice (n = 10) compared to 13.1% in non-stressed control mice (n = 11, P < 0.01). Injection of SP-RA decreased the abortion rate to 18.4% in stressed mice (n = 19, P < 0.01). Flow cytometry revealed a stress-related increase of TNF-alpha+/CD8+ decidual T cells, which could be abrogated by SP-RA (P < 0.05). No significant differences could be observed in numbers of mast cells and total CD8+ cells in situ. CONCLUSION: Our data suggest that stress-triggered abortion is mediated by SP, and SP receptor blockade abrogates stress-triggered abortion via reduced production of TNF-alpha by CD8+ T cells.     

Fat Content and Fatty Acid Composition of Infant Formulas

ABSTRACT. Fat content and fatty acid composition of 25 commercial infant formulas sold in the Federal Republic of Germany and of 3 home-made milk formulas were analysed, using gravimetry of extracted lipids and high-resolution capillary gaschromatography. Results were compared with the composition of human milk. Fat contents of all commercial formulas were similar to human milk values and met current recommendations, but 2 home-made preparations were at the upper and lower limits of the recommended range. Milk formulas tended to contain higher percentages of saturated and lower ones of cis-monounsaturated and trans-isomeric fatty acids than human milk. Linoleic acid (C18:2n-6) content was similar to human milk in most products but deviated clearly from recommended values in 2 home-made mixtures. Alpha-linolenic acid (C18:3n-3) values were often low in formulas, resulting a high n-6/n-3-ratios. In contrast to human milk, all formulas contained only minor amounts of the physiologically important long-chain polyunsaturated fatty acids with 20 and 22 carbon atoms. Some seasonal variation in the content of palmitic (C16:0), oleic (C18:ln-9), linoleic and trans-fatty acids was found when five arbitrarily selected adapted formulas were analysed repeatedly over one year. The composition of a home-made formula made from fresh cow's milk was markedly different in winter and in summer, when percentages of saturated and trans-fatty acids were higher and of linoleic acid were lower. We conclude that the composition of most commercial formulas is better suited to meet the lipid requirements of young infants than the home-made preparations investigated. However, the essential fatty acid composition of available milk formulas differs from that of human milk.     

Defibrillation Energy Requirements with Single Endocardial (Endotak™) Lead

The need for thoracotomy in usually high risk patients has limited the use of the implantable cardioverter defibrillator. Initial clinical results with endocardial and subcutanous patch electrodes (SQPs) are en couraging. Using a single endocardial lead in the absence of a SQP for chronic implantation of the cardioverter defibrillator, the goal of the study was to obtain defibrillation thresholds (DFTs) of 15 Joules (J) or less and to investigate changes in DFT over time. We tested 19 consecutive patients (15 men, 4 women] age 62 ± 8.5 years with malignant ventricular arrhythmias (14 VT/5 VF). The underlying heart disease was coronary artery disease in 15 pafients, dilative cardiomyopathy in two patients, and primary electricaJ disease in two patients. Four patients had undergone previous cardiac surgery. Left ventricular ejection fraction ranged between 14% and 66% (39%± 12.6%). Pacing thresholds (0.54 ± 0.17 Vat 0.5 msec), R wave amplitude for pacemaker sensing (14.2 ± 7.0 mV), slew rate (2.12 ± 1.4 V/sec), and resistance (500.3 ± 73.9 W) were sufficient in all patients. Eighteen patients met our endocardial impiant criteria with a DFT ≤ 15 J (10.05 ± 4.03 J) using monophasic (14 patients) or biphasic (four patients) pulse wave forms. In the one remaining patient, with a DFT of 20 J, we implanted a SQP but there was no reduction of the DFT. All patients tested showed successful defibrillation prior to discharge. During follow-up of 88 patient-months (1–9 months), 114 spontaneous VT/VF episodes occurred in five patients and were all successfully terminated. Eleven patients with a minimum follow-up of 2 months were reassessed. In seven out of 11 patients, termination of VF was achieved with the same minimal energy requirements obtained intraoperatively. In three patients, DFT increased by 5 J (one patient) and 10 J (two patients). In a further patient, X ray revealed dislocation of the endocardial lead. Our data suggest that effective defibrillation is feasible with a single endocardial lead for implantation of cardioverter defibrillator. In addition, we strongly recommend repetitive x-ray control to detect asymptomatic lead dislocation. Despite stable DFTs in most of our patients, an energy difference of ≤ 15 J between acute DFT and cardioverter defibrillator energy rating seems to be currently desirable to ensure successful postoperative defibrillation.     

Cyclic disulfide analogues of the complement component C3a Synthesis and conformational investigations

The flexible C-terminal region of the anaphylatoxic peptide C3a was reported to contain the receptor binding site. To elucidate the receptor binding conformation of the C-terminus, as well as to examine a synthetic approach to potential C3a-antagonists, 26 cyclic disulfide bridged C3a analogues were synthesized. Solid phase peptide synthesis was performed on different polymeric supports by individual peptide synthesis, with Fmoc strategy, and simultaneous multiple peptide synthesis, using Boc and Fmoc strategies. Both strategies gave open-chain peptides in comparable yields. Syntheses using the Boc strategy employed the HF-labile 4(methoxy)benzyl group (Mob) for β-thiol protection of cysteine; in contrast, the TFA-stable protecting groups, acetamidomethyl (Acm) and trityl (Trt), were chosen for syntheses employing Fmoc strategy. Ring closure reactions by iodine oxidation were carried out starting from protected (Acm/Acm, Trt/Acm) or unprotected dithiols. The resulting cyclic C3a analogues were characterized by HPLC, amino acid analysis, and FAB-MS. Conformational investigations using CD spectroscopy and theoretical structural investigations by means of molecular dynamics calculations revealed that slight variations in sequence result in pronounced conformational consequences. The potential of cyclic C3a analogues to activate or to desensitize guinea pig platelets, a standard test system for biological activities of anaphylatoxic peptides like C3a, revealed relatively low activities for cyclic peptides (<0.1% C3a activity). N-terminal acylation with cationic, arginine-rich sequences like YRRGR- led to amplified biological effects. Three of the synthesized peptides, namely CAALCLAR (P1), YRRGR°CGGLCLAR (P5) and YRRGRAhx°CGGLCLAR (P8), point in the direction of C3a antagonists.     

Recovery of left ventricular function after myocardial infarction can be predicted immediately after thrombolysis by semiquantitative intracoronary thallium and technetium pyrophosphate scintigraphy

The accuracy with which intracoronary thallium and technetiumpyrophosphate scintigraphy during intra-coronary thrombolysispredicts myocardial salvage was studied in 58 patients withacute myocardial infarction by comparing the acute scintigraphicfindings with subsequent left ventricular function. Scintigramsobtained before and immediately after thrombolysis were interpretedby three independent observers using a scoring system. Regionalwall motion in the infarct area was determined from left ventricular(LV) cine angiograms using the center-line method. Patients with mild hypokinesis (hypokinesis –2 SD fromnormal) could be distinguished from those with severe hypokinesis(hypokinesis > – 2SD) using the prethrombolysis thalliumscore with an accuracy of 83%. Accuracy using the post-thrombolysisscore was 76%. When the post-thrombolysis thallium and technetiumpyrophosphate scores were combined, differentiation was possiblein 91% of all patients studied, and in 100% of patients withanterior myocardial infarction. Thus, analysis of combined thallium and technetium phyrophosphatescintigraphy accurately predicts recovery of LV function afterthrombolysis and may be helpful in deciding whether acute percutaneoustransluminal coronary angioplasty or bypass surgery should beperformed after thrombolysis.     

Clinical Significance of Sleep-Related Breathing Disorders in Patients with Implantable Cardioverter Defibrillators

The prevalence and clinical significance of sleep-related breathing disorders (SRBDs) in patients with cardiac disease and a history of life-threatening ventricular tachyarrhythmias is unclear. Forty consecutive recipients of implantable cardioverter defibrillators (ICDs) with cardiac disease and a documented history of spontaneous, life-threatening, ventricular tachyarrhythmias underwent full night polysomnography. SRBDs were diagnosed if the apnea/hypopnea index was > 10. SRBD were diagnosed in 16 of 40 patients (40%): central sleep apnea (CSA) was present in 9 of these 16 patients (56%), 8 of whom had associated Cheyne-Stoke respiration. Seven of the 16 patients with SRBD (44%) had obstructive sleep apnea (OSA). Patients with and without SRBDs were comparable with respect to left ventricular ejection fraction, NYHA classification, underlying heart disease, ICD indications, and concomitant antiarrhythmic drug and beta-blocker therapy. Patients were followed prospectively for 2 years. ICD-treated ventricular tachyarrhythmias occurred in 10 of 24 patients (42%) without SRBD, in 4 of 9 patients (44%) with CSA, and in 3 of 7 patients (44%) with OSA (NS). The numbers and circadian distributions of episodes recorded during follow-up in patients without SRBD versus with CSA or OSA were not significantly different (14 ± 25, median = 4 vs 4 ± 5, median = 2.5 vs 15 ± 15, median = 7, respectively). The 2-year mortality, which was entirely attributable to nonsudden cardiac events, was highest in patients with CSA (4/9 [44%], vs 0/7 [0%] with OSA, vs 3/24 patients (12.5%) without SRBD; P < 0.05).     

Dose reduction of asparaginase under pharmacokinetic and pharmacodynamic control during induction therapy in children with acute lymphoblastic leukaemia

The enzyme asparaginase is an important element in the therapy of acute lymphoblastic leukaemia (ALL). The usual asparaginase dose as prescribed in the ALL-BFM-86/90 treatment protocol for the therapy of ALL is 10 000 IU/m² at 3 d intervals and had been developed on the basis of the E. coli asparaginase preparation Crasnitin^TM from the Bayer company. Using the described schedule the E. coli asparaginase preparation from the Medac company shows significantly higher biological activity than the Bayer preparation. These findings prompted an attempt to reduce the dose of the Asparaginase medac^TM under careful pharmacokinetic and pharmacodynamic monitoring. At the first step of dose reduction in ALL treatment protocol I, 11 children received 5000 IU/m² of Asparaginase medac^TM. Another 15 children were given 2500 IU/m² of the enzyme at the second step of dose reduction. Prior to each asparaginase dose, blood samples were taken to determine amino acids and trough enzyme activity. Concurrent with the asparaginase monitoring, the coagulation parameters were measured. 96% of samples from the first step of dose reduction (5000 IU/m² every third day) showed complete L-asparagine depletion (<0.1 μM ), the median trough enzyme acitivity was 265 IU/l. At the second step of dose reduction (2500 IU/m²) complete L-asparagine depletion was seen in 97% of samples, and the median trough enzyme acitivity was 102 IU/l. Cerebrospinal fluid (CSF) depletion was complete in all samples tested (11/11). We concluded that an Asparaginase medac^TM dose reduced from the usual 10000 IU/m² down to 5000 IU/m² or 2500 IU/m², applied at 3 d intervals, was sufficient to achieve complete L-asparagine depletion in serum. Changes of the fibrinogen levels was significantly less pronounced in the group on 2500 IU.     

Silent Cerebral Events/Lesions Related to Atrial Fibrillation Ablation: A Clinical Review

Brain magnetic resonance imaging (MRI) has identified a high incidence of cerebral ischemia in asymptomatic patients after atrial fibrillation (AF) ablation (silent). Detection of cerebral ischemic events on MRI is based on acute hyperintense lesions on diffusion‐weighted imaging. In the literature, the incidence is related to specifications of MRI and depends on the definition applied. In comparative studies, silent cerebral events (SCE, diffusion‐weighted MRI [DWI] positive only) appear to be approximately 3 times more common compared to using a definition of silent cerebral lesions (SCL; without fluid attenuated inverse recovery sequence [FLAIR] positivity). Whereas the FLAIR sequence may turn positive within days after the ischemic event, SCE definition is highly sensitive for early phases of ischemic brain damage. SCE/SCL appear to represent cerebral ischemic infarcts and determine the “embolic fingerprint” of a specific ablation technology and strategy used. The optimum time point for detecting SCE is early after AF ablation (24–72 hours), whereas detection of SCL can only be performed within the first 2–7 days (due to delay of FLAIR positivity). Different technology‐, procedure‐, and patient‐related parameters have been identified to play a role in the multifactorial genesis of SCE/SCL. In recent years, evidence has been gathered that there may be differences of SCE/SCL rates depending upon the ablation technology used, but small patient numbers and a large number of potential confounders hamper all studies. As major findings of recent studies, mode of periprocedural and intraprocedural anticoagulation has been identified as a major predictor for incidences of SCE/SCL. Whereas procedural characteristics related to higher SCE/SCL‐rates may be modified, unchangeable patient‐related factors should be taken into account for future individualized risk assessment. Novel ablation devices introduced into the market should be tested for their potential embolic fingerprint and refinements of ablation procedures to reduce their embolic potential should be prompted. The knowledge of “best practice” in terms of low SCE/SCL rates has prompted changes in work‐flow, which have been implemented into ablation procedures using novel ablation devices. So far, no study has linked SCE/SCL to neuropsychological decline and the low number of AF‐ablation‐associated events needs to be weighted against the multitude of preexisting asymptomatic MRI‐detected brain lesions related to the course of AF itself. Future studies are needed to evaluate if more white matter hyperintensities due to AF may be prevented by AF ablation (producing only a small number of SCE/SCL).     

The Use of Impella 2.5 in Severe Refractory Cardiogenic Shock Complicating an Acute Myocardial Infarction

Objectives

To investigate the outcome of patients with acute myocardial infarction (AMI) complicated by refractory cardiogenic shock (CS) who underwent mechanical circulatory support with Impella 2.5.

Background

AMI complicated by CS remains a highly fatal condition. A potent and minimally invasive left ventricular assist device might improve patient outcomes.

Methods

We analyzed the procedural characteristics and outcomes of 22 consecutive patients who underwent, between July 2008 and December 2012, a percutaneous coronary intervention and Impella 2.5 support for AMI complicated by CS refractory to first‐line therapy with inotropes and/or Intra‐aortic balloon pump.

Results

In this analysis, patients were relatively young with a mean age of 57.9 ± 11.6 year old and 59.1% were male. The majority of patients (77.3%) were admitted in CS and 40.9% sustained cardiac arrest prior to admission. Hemodynamics improved significantly upon initiation of support, end‐organ and tissue perfusion improved subsequently demonstrated by a significant decrease in lactate levels from 6.37 ± 5.3 mmol/L to 2.41 ± 2.1 mmo/L, (P = 0.008) after 2 days of support. Thirteen (59.1%) patients were successfully weaned‐off Impella 2.5 and 4 (18.2%) were transitioned to another device. We observed a functional recovery of the left ventricle when compared to baseline (43 ± 10% vs. 27 ± 9%, P < 0.0001). The survival rate at 6 months and 1 year was 59.1% and 54.5%, respectively.

Conclusion

Impella 2.5 was initiated as a last resort therapy to support very sick patients with refractory CS after failed conventional therapy. The use of the device yielded favorable short and mid‐term survival results with recovery being the most frequently observed outcome. (J Interven Cardiol 2015;28:41–50)