Vulnerable plaque: the challenge to identify and treat it

In order to understand, treat, and prevent acute coronary syndromes we need to improve our ability to identify the rupture-prone, vulnerable atherosclerotic coronary plaque. The diagnostic modalities that are currently available to clinical practice have not fulfilled this expectation, and newer diagnostic techniques based on the recently identified features of the vulnerable plaque are quite promising. Coronary angiography, intravascular ultrasound, and angioscopy have been used in the clinical arena of interventional cardiology with several limitations regarding the identification of the vulnerable plaque. Thermography, optical coherence tomography, elastography, Raman spectroscopy, and infrared spectroscopy are used in clinical trials and the results are encouraging. Ultrafast computed tomography and magnetic resonance imaging have the advantage of being noninvasive. With our progress in the identification of the rupture-prone vulnerable coronary plaque, we will be able to identify patients that are at high risk and will benefit from a more aggressive therapeutic approach.     

New insights into ice multiplication using remote-sensing observations of slightly supercooled mixed-phase clouds in the Arctic

Secondary ice production (SIP) can significantly enhance ice particle number concentrations in mixed-phase clouds, resulting in a substantial impact on ice mass flux and evolution of cold cloud systems. SIP is especially important at temperatures warmer than −10 ○C, for which primary ice nucleation lacks a significant number of efficient ice nucleating particles. However, determining the climatological significance of SIP has proved difficult using existing observational methods. Here we quantify the long-term occurrence of secondary ice events and their multiplication factors in slightly supercooled clouds using a multisensor, remote-sensing technique applied to 6 y of ground-based radar measurements in the Arctic. Further, we assess the potential contribution of the underlying mechanisms of rime splintering and freezing fragmentation. Our results show that the occurrence frequency of secondary ice events averages to <10% over the entire period. Although infrequent, the events can have a significant impact in a local region when they do occur, with up to a 1,000-fold enhancement in ice number concentration. We show that freezing fragmentation, which appears to be enhanced by updrafts, is more efficient for SIP than the better-known rime-splintering process. Our field observations are consistent with laboratory findings while shedding light on the phenomenon and its contributing factors in a natural environment. This study provides critical insights needed to advance parameterization of SIP in numerical simulations and to design future laboratory experiments.

Mixed-phase clouds, where supercooled cloud droplets and ice particles coexist, are frequently observed in the Arctic (1). These clouds play a critical role in the hydrological cycle and radiative energy balance, and they have unignorable impacts on sea ice loss and warming in the Arctic (2, 3). Recent theoretical and modeling investigations suggest that the number concentration of ice particles in mixed-phase clouds has a significant influence on the evolution of the cloud microphysical properties (4). Improper representation of ice formation compromises simulation of Arctic mixed-phase clouds in climate and regional models, which can cause considerable errors in the simulated radiative budget (5). Extensive modeling and laboratory studies have been conducted in recent years to investigate ice formation by ice nucleation, especially for heterogeneous ice nucleation for which nucleation is catalyzed by ice-nucleating particles (6–9). The fundamental underlying mechanisms of heterogeneous ice nucleation are still not fully understood, and the parameterizations that are widely used in atmospheric models are generated by fitting the results from laboratory experiments for various types of ice-nucleating particles. However, observed ice number concentrations can be several orders of magnitude greater than in simulations, especially in supercooled clouds with the temperature warmer than −10 ○C (hereafter, “slightly supercooled clouds”). In this temperature range, some biological aerosols originating from soil, plants, and the ocean are found to be efficient ice-nucleating particles that can trigger ice nucleation above −10 ○C (10–13). However, these efficient ice-nucleating particles are rare, suggesting that secondary ice production (SIP) is important (14).The best-known mechanism of SIP in slightly supercooled clouds is the rime-splintering process, also known as the Hallett–Mossop (HM) process. The HM process occurs preferentially for a temperature range of −3 ○C ∼ −8 ○C in which small ice splinters are generated during riming. The HM process has been demonstrated in the laboratory using a riming rod rotating in a small chamber filled with supercooled liquid droplets (15). SIP can also be caused by other mechanisms, such as collision fragmentation (16), freezing fragmentation (17, 18), and sublimation fragmentation (19). Details regarding the current understanding of those mechanisms can be found in recent review articles by Field et al. (20) and Korolev and Leisner (21). Among those mechanisms, the HM process is argued to be the most important mechanism for SIP in slightly supercooled clouds (20, 22). However, recent in situ measurements show that substantial numbers of needles and columns (signs of splintering) are observed in mixed-phase clouds without the presence of rimers (i.e., fast falling ice particles). Instead, the presence of large cloud droplets suggests that those observed SIP events are likely due to freezing fragmentation rather than the HM process (23). Pitter and Pruppacher (24) also found in a laboratory wind tunnel study that a noticeable fraction of freezing drizzle drops developed pronounced knobs or spikes, with the spikes breaking off in many cases. The theory of freezing fragmentation is further supported by recent laboratory experiments in which SIP was observed during freezing of a levitated droplet (17, 18). However, conditions for the occurrence of SIP are still poorly known and which SIP mechanism is dominant in mixed-phase clouds is far from clear.Although laboratory experiments can demonstrate the existence of SIP under certain controlled conditions, the idealized mechanisms used for the studies (e.g., rotating rod or a levitated droplet in a calm environment) are not directly translatable to characterizing SIP processes in atmospheric clouds. Therefore, parameterizations of SIP in models using laboratory data are of debatable accuracy (25) because we still do not understand SIP mechanisms at a fundamental level. Aircraft in situ measurements of ice particles and ice-nucleating particles can help to identify the occurrence of SIP in atmospheric clouds; however, statistical studies using such measurements are severely restricted by the small sampling volumes and limited coverage of aircraft flights (23, 26).Remote-sensing techniques provide an alternative way to observe atmospheric clouds, offering larger sampling volumes and longer periods compared with in situ measurements. These features are beneficial for observing processes that are transient and/or infrequent, as may be true for SIP. The occurrence of a SIP event in mixed-phase clouds is indicated by the presence of a large concentration of small ice particles, especially at warmer temperatures where these concentrations are unlikely to be due solely to primary ice nucleation. A common foundation of existing radar-based remote-sensing techniques for identification of SIP events includes the detection of small, nonspherical ice particles using polarimetric variables, such as differential reflectivity (ZDR) (the ratio of the power returned from horizontally versus vertically transmitted and received pulses) and linear depolarization ratio (LDR) (the ratio of cross-polarized versus copolarized power returned with respect to the polarization of transmitted pulses) (27, 28). Close to the time of SIP initiation, radar methods and in situ measurements are challenged alike, as distinguishing small spherical ice particles from cloud droplets is extremely difficult (4). As newly formed small ice particles prefer growing into needle-like ice crystals within the HM temperature zone (between −3 ○C and −8 ○C), they can then alter the value of ZDR and LDR compared with spherical hydrometers, which makes detection of SIP events possible using remote-sensing techniques. Most previous remote-sensing studies of SIP focus on specific cases, for which the thermodynamic properties of the subject mixed-phase clouds are carefully chosen such that the detection of nonspherical ice particles is a readily apparent signal of a SIP event in a small dataset (29, 30).In this study, we obtain a statistical understanding of SIP events. A remote-sensing technique is used to identify SIP events occurring within 6 y (March 2013 to May 2019) of ground-based observations of slightly supercooled liquid clouds. As detailed later, the technique determines the presence of SIP events using joint thresholds of radar LDR and spectral reflectivity and, moreover, quantifies the enhancement of needle-like particle concentrations (i.e., multiplication) based on the spectral reflectivity with respect to a base threshold. We link the occurrence of SIP to the presence of rimers and drizzle, and we estimate the enhancement in ice number concentration with respect to rimer velocity and drizzle size. We show that SIP events can significantly impact ice number concentrations locally when they occur, and we are able to assess the relative importance of two SIP mechanisms, finding that freezing fragmentation is more productive at SIP than the rime splintering normally regarded as the leading process for SIP.     

Post‒cataract surgery endophthalmitis outbreak caused by multidrug-resistant Pseudomonas aeruginosa

In June 2010, a severe outbreak of 13 cases of post-cataract surgery endophthalmitis caused by multidrug-resistant Pseudomonas aeruginosa occurred. Pulse-field gel electrophoresis in eye isolates found 95% genetic similarity; however, extensive environmental and carriage investigation revealed no source of infection.     

Phosphorylation-regulated axonal dependent transport of syntaxin 1 is mediated by a Kinesin-1 adapter

Presynaptic nerve terminals are formed from preassembled vesicles that are delivered to the prospective synapse by kinesin-mediated axonal transport. However, precisely how the various cargoes are linked to the motor proteins remains unclear. Here, we report a transport complex linking syntaxin 1a (Stx) and Munc18, two proteins functioning in synaptic vesicle exocytosis at the presynaptic plasma membrane, to the motor protein Kinesin-1 via the kinesin adaptor FEZ1. Mutation of the FEZ1 ortholog UNC-76 in Caenorhabditis elegans causes defects in the axonal transport of Stx. We also show that binding of FEZ1 to Kinesin-1 and Munc18 is regulated by phosphorylation, with a conserved site (serine 58) being essential for binding. When expressed in C. elegans, wild-type but not phosphorylation-deficient FEZ1 (S58A) restored axonal transport of Stx. We conclude that FEZ1 operates as a kinesin adaptor for the transport of Stx, with cargo loading and unloading being regulated by protein kinases.     

Central and peripheral serotonergic influences on viscerovisceral inhibitory reflex during duodenal distension in sheep

The effects of duodenal distension on forestomach and abomasal motility were investigated in conscious sheep chronically fitted with intraparietal electrodes, a duodenal cannula, and an intracerebroventricular cannula. Duodenal distensions with a balloon inflated with 40 ml (DD40) of water reduced the frequency of forestomach and abomasal contractions by 45 and 32%, respectively, while distension with 80 ml (DD80) induced a total inhibition. Methysergide, a mixed 5HT₁-5HT₂ antagonist administered intravenously (200 g/kg) or intracerebroventricularly (20 g/kg) suppressed the DD40-induced inhibition and reduced that induced by DD80. Sprioxatrine, a selective 5HT_1A antagonist, intravenously (100 g/kg) or intracerebroventricularly (10 g/kg), suppressed the DD40 and DD80-induced inhibition, which was also attenuated by the 5HT₂ antagonist ritanserin given intravenously (200 g/kg) or intracerebroventricularly (20 g/kg). Granisetron, a 5HT₃ antagonist, injected intravenously (150 g/kg), abolished the effects of DD40 and DD80 while it had no antagonistic action on DD40 and DD80 when given intracerebroventricularly (15 g/kg). It is concluded that in sheep, duodenal distension inhibits forestomach and abomasal motility through 5HT_1A and 5HT₂ receptors at the level of the central nervous system and 5HT₃ receptors located peripherally.This work was presented in part at the First United European Gastroenterology Week, September 25–30, 1992, Athens, Greece.     

Plasma level changes of fibrinopeptide a after uncomplicated coronary angioplasty

Fibrinopeptide A (FPA) is a small polypeptide cleaved from fibrinogen by thrombin, has a short half-life, and is considered a sensitive biochemical marker of thrombin activity, fibrin generation, and ongoing thrombosis. Increased plasma levels of FPA have been reported in various procoagulable and thrombotic medical and cardiovascular disorders, including acute myocardial infarction, unstable angina, and sudden cardiac death. However, activation of thrombosis by the arterial injury incurred during coronary angioplasty has not been systematically examined with use of plasma FPA measurements. To detect and monitor activation of thrombosis by coronary angioplasty, plasma levels of FPA were obtained by venipuncture and measured by radioimmunoassay before, immediately after, 24 to 48 h later, and 1 and 3 months after uncomplicated coronary angioplasty. From December 1990 through June 1991, FPA was measured in 30 patients (28 men and 2 women, aged 54 ± 9 years) with coronary artery disease who were undergoing coronary angioplasty. The mean left ventricular ejection fraction was 55 ± 7%. The dilated vessel was the left anterior descending coronary artery in 20 patients (together with a second vessel in 2), the right coronary artery in 9, and the left circumflex in 1. The procedure was successful and free of major complications in all patients. Before angioplasty the FPA levels averaged 6.50 ± 1.18 ng/ml. Shortly after angioplasty they rose to 20.20 ± 7.91 ng/ml (p = 0.08) despite intravenous heparin. At 24 to 48 h and after heparin had been discontinued for at least 4 h, the mean FPA levels were significantly higher (32.33 ± 10.86 ng/ml) compared with baseline values (p = 0.025 ). At 1 month after the procedure, the FPA levels measured in 22 patients were lower but still elevated (20.25 ± 9.29 ng/ml), albeit nonsignificantly, compared with baseline values, and at 3 months they had fallen to baseline values (4.84 ± 2.20 ng/ml, n = 11). No patient developed restenosis during the study period of 1 to 3 months, during which all patients were receiving aspirin. We conclude that, as reflected by increased FPA levels, angioplasty, most likely due to arterial injury incurred, activates thrombin and generates ongoing coronary thrombosis, which is not suppressed by heparin or aspirin and appears to extend at least through the first month after the procedure.     

Impaired clearance of apoptotic cells leads to HMGB1 release in the bone marrow of patients with myelodysplastic syndromes and induces TLR4-mediated cytokine production

Excessive pro-inflammatory cytokine production in the bone marrow has been associated with the pathogenesis of myelodysplastic syndromes. We herein investigated the involvement of toll-like receptors and their endogenous ligands in the induction/maintenance of the inflammatory process in the marrow of patients with myelodysplastic syndromes. We evaluated the expression of toll-like receptors in marrow monocytes of patients (n=27) and healthy controls (n=25) by flow-cytometry and also assessed the activation of the respective signaling using a real-time polymerase chain reaction-based array. We measured the high mobility group box-1 protein, a toll-like receptor-4 ligand, in marrow plasma and long-term bone marrow culture supernatants by an enzyme-linked immunosorbent assay and we performed cross-over experiments using marrow plasma from patients and controls in the presence/absence of a toll-like receptor-4 inhibitor to evaluate the pro-inflammatory cytokine production by chemiluminescence. We assessed the apoptotic cell clearance capacity of patients’ macrophages using a fluorescence microscopy-based assay. We found over-expression of toll-like receptor-4 in patients’ marrow monocytes compared to that in controls; this over-expression was associated with up-modulation of 53 genes related to the respective signaling. Incubation of patients’ monocytes with autologous, but not with normal, marrow plasma resulted in over-production of pro-inflammatory cytokines, an effect that was abrogated by the toll-like receptor-4 inhibitor suggesting that the pro-inflammatory cytokine production in myelodysplastic syndromes is largely mediated through toll-like receptor-4. The levels of high mobility group box-1 protein were increased in patients’ marrow plasma and culture supernatants compared to the levels in controls. Patients’ macrophages displayed an impaired capacity to engulf apoptotic cells and this defect was associated with excessive release of high mobility group box-1 protein by dying cells. A primary apoptotic cell clearance defect of marrow macrophages in myelodysplastic syndromes may contribute to the induction/maintenance of the inflammatory process through aberrant release of molecules inducing toll-like receptor-4 such as high mobility group box-1 protein.     

Temperature differences are associated with malignancy on lung lesions: a clinical study

Background  

Although new endoscopic techniques can enhance the ability to detect a suspicious lung lesion, the primary diagnosis still depends on subjective visual assessment. We evaluated whether thermal heterogeneity of solid tumors, in bronchial epithelium, constitutes an additional marker for the diagnosis of benign and malignant lesions.     

Differences in the morphology and duration between premature P waves and the preceding sinus complexes in patients with a history of paroxysmal atrial fibrillation

BACKGROUND: Atrial fibrillation (AF) is the most common arrhythmia encountered in clinical practice. Experimental and human mapping studies have demonstrated that perpetuation of AF is due to the presence of multiple reentrant wavelets with various sizes in the right and left atria. HYPOTHESIS: Atrial fibrillation may be induced by atrial ectopic beats originating in the pulmonary veins, and premature P-wave (PPW) patterns may help to identify the source of firing. METHODS: To evaluate the morphology and duration of PPWs, 12-lead digital electrocardiogram (ECG) strips containing clearly definable PPWs not merging with the preceding T waves were obtained in 25 patients with AF history (9 men, mean age 59.5 +/- 2.2 years) and 25 subjects without any previous AF history (11 men, mean age 53.6 +/- 25 years). The polarity of PPWs was evaluated in all 12 ECG leads. Previously described indices, such as P maximum, P dispersion (= P maximum-P minimum), P mean, and P standard deviation were also calculated. RESULTS: Premature P-wave patterns were characterized by more positive P waves in lead V1. All P-wave analysis indices were significantly higher in patients with AF than in controls when calculated in the sinus beat, whereas they did not differ between the two groups when calculated in the PPW. P-wave indices did not differ between the PPW and the sinus either patients with AF or controls, except for P mean, which was significantly higher in the sinus (110.1 +/- 1.7 ms) than in the PPW (100 +/- 2 ms) only in patients with AF (p = 0.001). CONCLUSION: The evaluation of PPW patterns is only feasible in a small percentage of short-lasting digital 12-lead ECG recordings containing ectopic atrial beats. Premature P wave patterns characterized by more positive P waves in lead V1, which indicates a left atrial origin in the ectopic foci. The observed differences in P-wave analysis indices between patients with AF and controls and between sinus beats and PPWs may be attributed to the presence of electrophysiologic changes in the atrial substrate.