Aggressive systemic mastocytosis with the co-occurrence of PRKG2::PDGFRB, KAT6A::NCOA2, and RXRA::NOTCH1 fusion transcripts and a heterozygous RUNX1 frameshift mutation.

Systemic mastocytosis (SM) is a myeloproliferative neoplasm displaying abnormal mast cell proliferation. It is subdivided into different forms, including aggressive systemic mastocytosis (ASM) and systemic mastocytosis with an associated hematologic neoplasm (SM-AHN). Oncogenic genetic alterations include point mutations, mainly the KIT D816V, conferring poor prognosis and therapy resistance, and fusion genes, with those involving PDGFRA/PDGFRB as the most recurrent events. We here describe an ASM case negative to the KIT D816V and JAK2 V617F alterations but showing a RUNX1 frameshift heterozygous mutation and the co-occurrence of three fusion transcripts. The first one, PRKG2::PDGFRB, was generated by a balanced t(4;5)(q24;q32) translocation as the sole abnormality. Other two novel chimeras, KAT6A::NCOA2 and RXRA::NOTCH1, originated from cryptic intra-chromosomal abnormalities. The patient rapidly evolved towards SM-AHN, characterized by the persistence of the PRKG2::PDGFRB chimera, due to the presence of an extra copy of the der(5)t(4;5)(q24;q34) chromosome and an increase in the RUNX1 mutation allelic frequency. The results indicated that the transcriptional landscape and the mutational profile of SM deserve attention to predict the evolution and prognosis of this complex disease, whose classification criteria are still a matter of debate.

Interleukin-1 blockade with RPH-104 in patients with acute ST-elevation myocardial infarction: study design and rationale.

BACKGROUND: Myocardial injury of ST-segment elevation myocardial infarction (STEMI) initiates an intense inflammatory response that contributes to further damage and is a predictor of increased risk of death or heart failure (HF). Interleukin-1 (IL-1) is a key mediator of local and systemic inflammatory response to myocardial damage. We postulate that the use of the drug RPH-104, which selectively binds and inactivates both α and ß isoforms of IL-1 will lead to a decrease in the severity of the inflammatory response which will be reflected by decrease in the concentration of hsCRP, as well as the rate of fatal outcomes, frequency of new cases of HF, changes in levels of brain natriuretic peptide (BNP) and changes in structural and functional echocardiographic parameters. METHODS: This is a double blind, randomized, placebo-controlled study in which 102 patients with STEMI will receive a single administration of RPH-104 80 mg, RPH-104 160 mg or placebo (1:1:1). The primary endpoint will be hsCRP area under curve (AUC) from day 1 until day 14. Secondary endpoints will include hsCRP AUC from day 1 until day 28, rate of fatal outcomes, hospitalizations due to HF and other cardiac and non-cardiac reasons during 12-month follow-up period, frequency of new cases of HF, changes in levels of brain natriuretic peptide (BNP, NT-pro-BNP), changes in structural and functional echocardiographic parameters during 12-month follow-up period compared to baseline. The study started in October 2020 and is anticipated to end in 2Q 2022. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04463251. Registered on July 9, 2020.

Concurrent chromothripsis events in a case of TP53 depleted acute myeloid leukemia with myelodysplasia-related changes.

Acute myeloid leukemia with myelodysplasia-related changes (AML-MRC) is a heterogeneous hematological disorder defined by morphological, genetic, and clinical features. Patients with AML-MRC often show cytogenetic changes, which are associated with poor prognosis. Straightforward criteria for AML-MRC diagnosis and a more rigorous characterization of the genetic abnormalities accompanying this disease are needed. Here we describe an informative AML-MRC case, showing two separate, but concurrent, chromothripsis events, occurred at the onset of the tumor, and originating an unbalanced t(5;7) translocation and a derivative chromosome 12 with a highly rearranged short arm. Conversely, despite chromothripsis has been often associated with genomic amplification in cancer, in this case a large marker chromosome harboring amplified sequences from chromosomes 19 and 22 arose from a stepwise mechanism. Notably, the patient also showed a TP53 mutated status, known to be associated with an increased susceptibility towards chromothripsis and a poor prognosis. Our results indicate that multiple chromothripsis events may occur early in neoplastic transformation and act in a synergistic way with progressive chromosomal alterations to determine a dramatic impact on disease outcome, as suggested by the gene expression profile analysis.

Pharmacologic strategies to reduce cardiovascular disease in type 2 diabetes mellitus: focus on SGLT-2 inhibitors and GLP-1 receptor agonists.

Patients with type 2 diabetes mellitus (T2D) present an increased risk for cardiovascular (CV) complications. In addition to improvement in glycaemic control, glucose-lowering therapies, such as glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-dependent glucose cotransporter (SGLT)-2 inhibitors, have been shown to significantly reduce CV events. In 2008, the US Food and Drug Administration mandated that all new glucose-lowering drugs undergo CV outcomes trials (CVOTs) to determine their CV safety. These trials have largely demonstrated no major CV safety concerns. Most notably, the GLP-1RAs and SGLT-2 inhibitors have been found to be not only safe, but also cardioprotective compared to placebo. The SGLT-2 inhibitors have opened a new perspective for clinicians treating patients with T2D and established CV disease in light of their 'pleiotropic' effects, specifically on heart failure, while GLP-1RAs seem to present more favourable effects on atherosclerotic events. In this review, we discuss the role of GLP-1RAs and SGLT-2 inhibitors to reduce CV risk in T2D patients and suggest an individualized therapeutic approach in this population based on the presence of metabolic and CV comorbidities.

Assessment of hand superficial oxygenation during ischemia/reperfusion in healthy subjects versus systemic sclerosis patients by 2D near infrared spectroscopic imaging.

BACKGROUND AND OBJECTIVE: Patients affected by systemic sclerosis (SSc) develop functional and structural microcirculatory dysfunction, which progressively evolves towards systemic tissue fibrosis (sclerosis). Disease initially affects distal extremities, which become preferential sites of diagnostic scrutiny. This pilot investigation tested the hypothesis that peripheral microcirculatory dysfunction in SSc could be non-invasively assessed by 2D Near Infrared Spectroscopic (NIRS) imaging of the hand associated with Vascular Occlusion Testing (VOT). NIRS allows measurement of hemoglobin oxygen saturation (StO2) in the blood perfusing the volume tissue under scrutiny. METHODS: In five normal volunteers and five SSc patients we applied a multispectral oximetry imaging device (Kent camera, Kent Imaging, Calgary, Canada) to acquire StO2 2D maps of the whole hand palm during baseline, ischemia and reperfusion phase. RESULTS: We found significant differences between controls and SSc patients in basal StO2 (82.80 ±â€¯2.51 vs 65.44 ±â€¯7.96%, p = 0.0016), minimum StO2 (59.35 ±â€¯4.29 vs 40.73 ±â€¯6.47%, p = 0.0007), final StO2 (83.83 ±â€¯4.09 vs 68.84 ±â€¯11.41%, p = 0.02) and time to maximum StO2 (40 ±â€¯12.25 vs 62 ±â€¯4.47 s, p = 0.005). CONCLUSIONS: This is, to our knowledge, the first application of 2D NIRS imaging of the whole hand to the investigation of microvascular dysfunction in systemic sclerosis. The image processing presented here considered the StO2 in the entire hand allowing a comprehensive view of the spatial heterogeneity of microvascular dysfunction.

Interleukin-18 mediates cardiac dysfunction induced by western diet independent of obesity and hyperglycemia in the mouse.

Obesity and diabetes are independent risk factors for heart failure and are associated with the consumption of diet rich in saturated fat and sugar, Western diet (WD), known to induce cardiac dysfunction in the mouse through incompletely characterized inflammatory mechanisms. We hypothesized that the detrimental cardiac effects of WD are mediated by interleukin-18 (IL-18), pro-inflammatory cytokine linked to cardiac dysfunction. C57BL/6J wild-type male mice and IL-18 knockout male mice were fed high-saturated fat and high-sugar diet for 8 weeks. We measured food intake, body weight and fasting glycemia. We assessed left ventricular (LV) systolic and diastolic function by Doppler echocardiography and cardiac catheterization. In wild-type mice, WD induced a significant increase in isovolumetric relaxation time, myocardial performance index and left ventricular end-diastolic pressure, reflecting an impairment in diastolic function, paired with a mild reduction in LV ejection fraction. IL-18 KO mice had higher food intake and greater increase in body weight without significant differences in hyperglycemia. Despite displaying greater obesity, IL-18 knockout mice fed with WD for 8 weeks had preserved cardiac diastolic function and higher left ventricular ejection fraction. IL-18 mediates diet-induced cardiac dysfunction, independent of food intake and obesity, thus highlighting a disconnect between the metabolic and cardiac effects of IL-18.

Near infrared image processing to quantitate and visualize oxygen saturation during vascular occlusion.

The assessment of microcirculation spatial heterogeneity on the hand skin is the main objective of this work. Near-infrared spectroscopy based 2D imaging is a non-invasive technique for the assessment of tissue oxygenation. The haemoglobin oxygen saturation images were acquired by a dedicated camera (Kent Imaging) during baseline, ischaemia (brachial artery cuff occlusion) and reperfusion. Acquired images underwent a preliminary restoration process aimed at removing degradations occurring during signal capturing. Then, wavelet transform based multiscale analysis was applied to identify edges by detecting local maxima and minima across successive scales. Segmentation of test areas during different conditions was obtained by thresholding-based region growing approach. The method identifies the differences in microcirculatory control of blood flow in different regions of the hand skin. The obtained results demonstrate the potential use of NIRS images for the clinical evaluation of skin disease and microcirculatory dysfunction.

Network meta-analysis on the comparative effectiveness and safety of transcatheter aortic valve implantation with CoreValve or Sapien devices versus surgical replacement.

INTRODUCTION: Surgical replacement for aortic stenosis is fraught with complications in high-risk patients. Transcatheter techniques may offer a minimally invasive solution, but their comparative effectiveness and safety is uncertain. We performed a network meta-analysis on this topic. METHODS: Randomized trials on transcatheter aortic valve replacement vs surgery were searched. The primary outcome was all cause death. Risk estimates were obtained with Bayesian network meta-analytic methods. RESULTS: Four trials with 1,805 patients were included. After a median of 8 months, risk of death and myocardial infarction was not different when comparing surgery versus transcatheter procedures, irrespective of device or access. Conversely, surgery was associated with higher rates of major bleeding (odds ratio vs CoreValve=3.03 [95% credible interval: 2.23-4.17]; odds ratio vs transfemoral Sapien =1.82 [1.21-2.70]; odds ratio vs transapical Sapien =2.08 [1.20-3.70]), and acute kidney injury (odds ratio vs CoreValve =2.08 [1.33-3.32]; odds ratio vs transapical Sapien =2.78 [2.21-99.80]), but lower rates of pacemaker implantation (odds ratio vs CoreValve =0.41 [0.28-0.59]), and moderate or severe aortic regurgitation (odds ratio vs CoreValve =0.06 [0.02-0.27]; odds ratio vs Sapien=0.17 [0.02-0.76]). Strokes were less frequent with CoreValve than with transfemoral Sapien (odds ratio =0.32 [0.13-0.73]) or transapical Sapien (odds ratio =0.33 [0.10-0.93]), whereas pacemaker implantation was more common with CoreValve (odds ratio vs surgery =2.46 [1.69-3.61]; odds ratio vs transfemoral Sapien =2.22 [1.27-3.85]). CONCLUSIONS: Survival after transcatheter or surgical aortic valve replacement is similar, but there might be differences in the individual safety and effectiveness profile between the treatment strategies and the individual devices used in transcatheter aortic valve implantation.

An updated systematic review and meta-analysis on impedance threshold devices in patients undergoing cardiopulmonary resuscitation.

INTRODUCTION: Uncertainty persists on the clinical impact of impedance threshold devices in out-of-hospital cardiac arrest. We conducted an updated systematic review on impedance threshold devices. METHODS: Several databases were searched for studies testing the effectiveness of impedance threshold devices in patients with cardiac arrest. The primary endpoint was long-term survival. RESULTS: Seven trials (11,254 patients) were included. In 4 studies (2,284 patients) impedance threshold devices were used with active compression-decompression-cardiopulmonary resuscitation, and in the others alone. Overall, impedance threshold devices did not impact on the rate of return of spontaneous circulation (odds ratio=1.17 [0.96-1.43], p=0.114), favorable neurologic outcome (odds ratio=1.56 [0.97-2.50], p=0.065), or long-term survival (odds ratio=1.22 [0.94-1.58], p=0.127). These analyses were fraught with heterogeneity (respectively, p=0.055, p=0.236, and p=0.011) and inconsistency (respectively, I-squared=51% , I-squared=27% , and I-squared=67%). Exploratory analysis showed that combined use of impedance threshold devices with active compression-decompression significantly increased the likelihood of return of spontaneous circulation (odds ratio=1.19 [1.00-1.40], p=0.045), favorable neurologic outcome (odds ratio=1.60 [1.14-2.25], p=0.006), and long-term survival (odds ratio=1.52 [1.11-2.08], p=0.009). The favorable impact of the interaction between impedance threshold devices and active compression-decompression was also confirmed at meta-regression analysis (respectively, b=0.195 [0.004-0.387], p=0.045, b=0.500 [0.079-0.841], p=0.018, b=0.413 [0.063-0.764], p=0.021). CONCLUSIONS: The evidence base on impedance threshold devices is apparently inconclusive, with a neutral impact on clinically relevant outcomes. However, exploratory analysis focusing on the combined use of impedance threshold devices with active compression-decompression suggests that this combo treatment may be useful to improve patient prognosis.

Comparative effectiveness of novel oral anticoagulants for atrial fibrillation: evidence from pair-wise and warfarin-controlled network meta-analyses.

INTRODUCTION: Novel oral anticoagulants have been tested against warfarin for atrial fibrillation, yet no direct comparison is available. We thus aimed to perform pair-wise (direct) and warfarin-adjusted network (i.e. indirect) meta-analyses of novel oral anticoagulants for atrial fibrillation. METHODS: Databases were searched for randomized warfarin-controlled trials of novel anticoagulants for non-valvular atrial fibrillation. The primary end-point was long-term stroke/systemic embolism. Odds ratios (95% intervals) were computed with RevMan and WinBUGS. RESULTS: Seven trials (52701 patients) were included, focusing on apixaban, dabigatran, edoxaban and rivaroxaban. Pair-wise meta-analysis showed that after a weighted average of 23 months these novel anticoagulants lead to significant reductions in the risk of stroke/systemic embolism (odds ratio=0.81 [0.71-0.92], I2=23%) and all cause death (odds ratio=0.88 [0.82-0.95], I2=0%) in comparison to warfarin. Network meta-analysis showed that apixaban and dabigatran proved similarly superior to warfarin in preventing stroke/systemic embolism (odds ratio=0.78 [0.62-0.96] for apixaban vs warfarin; odds ratio=0.66 [0.52-0.84] for high-dose dabigatran vs warfarin; odds ratio for apixaban vs high-dose dabigatran=1.17 [0.85-1.63]), but apixaban was associated with fewer major bleedings (odds ratio=0.73 [0.57-0.93]) and drug discontinuations (odds ratio=0.64 [0.52-0.78]) than dabigatran. Rivaroxaban did not reduce stroke/systemic embolism (odds ratio=0.87 [0.71-1.07]) or major bleedings in comparison to warfarin (odds ratio=0.87 [0.71-1.07]) and was associated with more major bleedings in comparison to apixaban (odds ratio=1.52 [1.19-1.92]). Data for edoxaban were inconclusive. CONCLUSIONS: Novel oral anticoagulants appear as a very promising treatment option for atrial fibrillation.

Minimal changes of thyroid axis activity influence brain functions in young females affected by subclinical hypothyroidism.

There is evidence of an association between thyroid hormones (TH) alterations and mental dysfunctions related to procedural and working memory functions, but the physiological link between these domains is still under debate, also for the presence of age as a confounding factor. Thus, we investigated the TH tuning of cerebral functions in young females affected by the borderline condition of subclinical hypothyroidism (SH) and in euthyroid females of the same age. The experiment consisted in the characterization of the affective state and cognitive abilities of the subjects by means of specific neuropsychological questionnaires, and of brain activity (EEG) in resting state and during the passive viewing of emotional video-clips. We found that SH had i) increased anxiety for Physical Danger; ii) better scores for both Mental Control and no-working-memory-related functions; iii) association between anxiety for Physical Danger and fT4 levels. Thus, in young adults, SH increases inward attention and paradoxically improves some cognitive functions. In addition, self-assessed questionnaires showed that SH had a greater susceptibility to unpleasant emotional stimulation. As for EEG data, SH compared to controls showed: i) reduction of alpha activity and of gamma left lateralization in resting state; ii) increased, and lateralized to the right, beta2 activity during stimulations. Both results indicated that SH have higher levels of arousal and greater susceptibility to negative emotion than controls. In conclusion, our study indicates that minimal changes in TH levels produce subtle but well-defined mental changes, thus encouraging further studies for the prediction of pathology evolution.

Cardiovascular changes during SCUBA diving: an underwater Doppler echocardiographic study.

AIM: Body immersion induces blood redistribution (from peripheral to intrathoracic vessels) and is a powerful autonomic stimulus (activating both parasympathetic and sympathetic systems). For these reasons, concerns have been raised about the safety of diving for subjects with previous heart disease. The aim of this study was to evaluate cardiovascular changes occurring during recreational SCUBA diving, as assessed by underwater Doppler echocardiography. METHODS: Eighteen healthy experienced divers underwent a 2D Doppler echocardiography basally, during two 15' steps of still SCUBA diving at different depths (10 m followed by 5 m) and shortly after the end of immersion. RESULTS: During dive, left ventricular (LV) diastolic volume and early left ventricular filling significantly increased (5 m vs. basal: P < 0.05 and P < 0.01, respectively), while both deceleration time of the early filling rate and late diastolic filling velocity significantly decreased (5 m and 10 m dive vs. basal: P < 0.01). LV volume increase and diastolic filling changes persisted at postdive evaluation, where a significant decrease in heart rate was also observed (P < 0.01 as compared to basal, 5-m and 10-m dive). CONCLUSION: This study documents that shallow-depth SCUBA diving induces LV enlargement and diastolic dysfunction. Direct underwater evaluation by Doppler echocardiography could be an appropriate tool for unmasking subjects at risk for underwater-related accidents.

Apolipoprotein A-I mimetic peptide L-4F prevents myocardial and coronary dysfunction in diabetic mice.

Diabetes is a major health problem associated with adverse cardiovascular outcomes. The apolipoprotein A-I mimetic peptide L-4F is a putative anti-diabetic drug, has antioxidant and anti-inflammatory proprieties and improves endothelial function. In obese mice L-4F increases adiponectin levels, improving insulin sensitivity, and reducing visceral adiposity. We hypothesized that the pleiotropic actions of L-4F can prevent heart and coronary dysfunction in a mouse model of genetically induced Type II diabetes. We treated db/db mice with either L-4F or vehicle for 8 weeks. Trans-thoracic echocardiography was performed; thereafter, isolated hearts were subjected to ischemia/reperfusion (IR). Glucose, insulin, adiponectin, and pro-inflammatory cytokines (IL-1ß, TNF-α, MCP-1) were measured in plasma and HO-1, pAMPK, peNOS, iNOS, adiponectin, and superoxide in cardiac tissue. In db/db mice L-4F decreased accumulation of subcutaneous and total fat, and increased insulin sensitivity and adiponectin levels while lowering inflammatory cytokines (P < 0.05). L-4F normalized in vivo left ventricular (LV) function of db/db mice, increasing (P < 0.05) fractional shortening and decreasing (P < 0.05) LV dimensions. In I/R experiments, L-4F prevented coronary microvascular resistance from increasing and LV function from deteriorating in the db/db mice. These changes were associated with increased cardiac expression of HO-1, pAMPK, peNOS, and adiponectin and decreased levels of superoxide and iNOS (P < 0.01). In the present study we showed that L-4F prevented myocardial and coronary functional abnormalities in db/db mice. These effects were associated with stimulation of HO-1 resulting in increased levels of anti-inflammatory, anti-oxidative, and vasodilatatory action through a mechanism involving increased levels of adiponectin, pAMPK, and peNOS.

Isolation, proliferation, cytogenetic, and molecular characterization and in vitro differentiation potency of canine stem cells from foetal adnexa: a comparative study of amniotic fluid, amnion, and umbilical cord matrix.

The possibility to isolate canine mesenchymal stem cells (MSCs) from foetal adnexa is interesting since several canine genetic disorders are reported to resemble similar dysfunctions in humans. In this study, we successfully isolated, cytogenetically and molecularly characterized, and followed the differentiation potency of canine MSCs from foetal adnexa, such as amniotic fluid (AF), amniotic membrane (AM), and umbilical cord matrix (UCM). In the three types of cell lines, the morphology of proliferating cells typically appeared fibroblast-like, and the population doubling time (DT) significantly increased with passage number. For AF- and AM-MSCs, cell viability did not change with passages. In UCM-MSCs, cell viability remained at approximately constant levels up to P6 and significantly decreased from P7 (P < 0.05). Amnion and UCM-MSCs expressed embryonic and MSC markers, such as Oct-4 CD44, CD184, and CD29, whereas AF-MSCs expressed Oct-4, CD44. Expression of the hematopoietic markers CD34 and CD45 was not found. Dog leucocyte antigens (DLA-DRA1 and DLA-79) were expressed only in AF-MSCs at P1. Isolated cells of the three cell lines at P3 showed multipotent capacity, and differentiated in vitro into neurocyte, adipocyte, osteocyte, and chondrocyte, as demonstrated by specific stains and expression of molecular markers. Cells at P4 showed normal chromosomal number, structure, and telomerase activity. These results demonstrate that, in dog, MSCs can be successfully isolated from foetal adnexa and grown in vitro. Their proven stemness and chromosomal stability indicated that MSCs could be used as a model to study stem cell biology and have an application in therapeutic programs.

Thyroid hormone, amiodarone therapy, and prognosis in left ventricular systolic dysfunction.

BACKGROUND: Amiodarone protects patients with left ventricular systolic dysfunction (LVSD) against serious arrhythmias, but it also has numerous side effects on non-cardiac organs, such as the thyroid. Indeed, amiodarone may inhibit the peripheral conversion of T4 into T3. Pathologically reduced serum levels of T3 - the so-called "low T3 syndrome" (LOWT3) - increase mortality in patients with LVSD and not on amiodarone. AIM: The aim of the study was to examine the relationship between thyroid hormone status, amiodarone therapy, and outcome in a population with LVSD. MATERIAL/ SUBJECTS AND METHODS: A total of 2344 patients with LVSD and free of overt hyper- and hypothyroidism were enrolled. The population was divided into 4 groups: group 1 (LOWT3 and amiodarone therapy, no.=126), group 2 (isolated amiodarone therapy, no.=74), group 3 (isolated LOWT3, no.=682), group 4 (controls, no.=1462). RESULTS: Kaplan-Meier curves showed, after a mean follow-up of 31 months, increased total and cardiac mortality in groups 1 (30% and 20%, respectively), 2 (23%, 11%), and 3 (22%, 12%) compared to group 4 (total mortality log-rank 82.8, p<0.0001; cardiac mortality log-rank 63.1, p<0.0001). At Cox analysis, adjusted for several clinical variables, survival was reduced in groups 1 and 3 compared to group 4. Group 2 had a similar mortality to group 4, although the number of patients was too limited to accurately assess the effect of amiodarone on long-term prognosis. CONCLUSIONS: LOWT3 exerts an adverse impact on prognosis in LVSD, which is not influenced by concomitant amiodarone therapy.

Iron deficiency anemia and cardiac mortality in patients with left ventricular systolic dysfunction undergoing coronary stenting.

AIM: The aim of this study was to assess cardiac mortality in patients with reduced ejection fraction (EF< or =45%) and anemia (Hb< or =12 g/dL) undergoing coronary stenting and to investigate whether iron-deficiency anemia influenced outcome when compared to non-anemic patients or patients with other types of anemia. METHODS: One hundred twenty consecutive patients undergoing percutaneous coronary intervention (PCI) between April 2003 and December 2005 were identified and followed for a median of 30 months. Patients were divided into 2 groups, anemic (Hb< or =12 g/dL) and non-anemic. Anemic patients were then divided into 3 sub-groups based on laboratory analysis and anemia work-up: iron-deficiency, malignancy-associated, and anemia of chronic disease (including chronic kidney disease). Mortality rates and cause of death were retrieved using both the Social Security database and the hospital records. RESULTS: Thirty-one percent of patients had iron deficiency, 24% had a malignancy-associated anemia and 45% had anemia of chronic disease. Overall mortality was 12% of which 29% was cardiac death. All-cause and cardiac mortality were significantly higher in anemic vs. non-anemic patients, (31% vs. 6%, P<0.001, and 10% vs. 1%, P=0.016, respectively). Iron-deficiency anemia strongly predicted cardiac mortality (33% vs. 1% in non-anemic patients, P<0.001), while malignancy-associated anemia was the strongest predictor of non-cardiac death (57% vs. 4% in non-anemic patients, P<0.001). Anemia of chronic disease neither predicted cardiac nor non-cardiac death. CONCLUSIONS: To the authors' knowledge, this is the first study to show that iron-deficiency anemia is a strong predictor of cardiac death when compared to patients with other types of anemia or to non-anemic patients.

Time course of carbon monoxide transfer factor after breath-hold diving.

Breath-hold divers may experience haemoptysis during diving. Central pooling of blood as well as compression of pulmonary gas content can damage the integrity of the blood-gas barrier, resulting in alveolar hemorrhage. The single-breath carbon monoxide test (DL,CO) was used to investigate the blood-gas barrier following diving. The study population consisted of 30 divers recruited from a training course. DL,CO levels were measured before diving and at 2, 10 and 25 min after the last of a series of four dives to depths of 10, 15, 20 and 30 m. When compared to pre-diving values, DL,CO values increased significantly at 2 min following diving in all subjects except one. Thereafter values progressively decreased toward baseline at 10 and 25 min in all subjects but one, while in four divers DL,CO values decreased below baseline. The early but transient increase in DL,CO levels shortly after diving supports the persistence of capillary pooling of red blood cells following emersion. Persistence at 25 min of high DL,CO values in one subject could be attributed by lung CT to extravasation of blood into the alveoli. Early or late DL,CO values >10% below baseline values suggest the presence of pulmonary edema. The relatively high prevalence of DL,CO alterations found suggests caution on the safety of breath-hold diving activities.

Computer simulation of coronary flow waveforms during caval occlusion.

OBJECTIVES: Mathematical modeling of the cardiovascular system is a powerful tool to extract physiologically relevant information from multi-parametric experiments. The purpose of the present work was to reproduce by means of a computer simulator, systemic and coronary measurements obtained by in vivo experiments in the pig. METHODS: We monitored in anesthetized open-chest pig the phasic blood flow of the left descending coronary artery, aortic pressure, left ventricular pressure and volume. Data were acquired before, during, and after caval occlusion. Inside the software simulator (CARDIOSIM) of the cardiovascular system, coronary circulation was modeled in three parallel branching sections. Both systemic and pulmonary circulations were simulated using a lumped parameter mathematical model. Variable elastance model reproduced Starling's law of the heart. RESULTS: Different left ventricular pressure-volume loops during experimental caval occlusion and simulated cardiac loops are presented. The sequence of coronary flow-aortic pressure loops obtained in vivo during caval occlusion together with the simulated loops reproduced by the software simulator are reported. Finally experimental and simulated instantaneous coronary blood flow waveforms are shown. CONCLUSIONS: The lumped parameter model of the coronary circulation, together with the cardiovascular system model, is capable of reproducing the changes during caval occlusion, with the profound shape deformation of the flow signal observed during the in vivo experiment. In perspectives, the results of the present model could offer new tool for studying the role of the different determinants of myocardial perfusion, by using the coronary loop shape as a "sensor" of ventricular mechanics in various physiological and pathophysiological conditions.

Pexelizumab in ischemic heart disease: a systematic review and meta-analysis on 15,196 patients.

OBJECT: Pexelizumab is a humanized monoclonal antibody inhibiting C5 complement. It has been postulated to improve outcomes in patients undergoing coronary artery bypass surgery and urgent reperfusion therapy for ST elevation myocardial infarction. We aimed at evaluating the risk/benefit profile of pexelizumab (bolus + infusion) versus placebo on top of current approaches in the management of patients with ST elevation myocardial infarction or undergoing coronary artery bypass. METHODS: We conducted a search of BioMedCentral, CENTRAL, mRCT, and PubMed without language restrictions (updated October 2007) for randomized controlled trials. Outcomes of interest were the risk of major adverse events (the composite of all-cause death, myocardial infarction, and thromboembolic stroke), the risk of single end points, and heart failure. RESULTS: Seven trials were included (15,196 patients: 7019 patients with ST elevation myocardial infarction and 8177 undergoing coronary bypass surgery). No benefit of adding pexelizumab was found in the overall analysis for major adverse events (OR 0.91 [0.76-1.09]; P = .29], death (OR 0.79 [0.61-1.03], P = .11], myocardial infarction (OR 1.04 [0.89-1.22]; P = .14), stroke (OR 0.95 [0.66-1.38]; P = .8), heart failure (OR1.0 [0.82-1.22]; P = .99), nor in the settings of patients with ST elevation myocardial infarction treated with mechanical or pharmacologic reperfusion therapy. Pexelizumab was associated with a 26% reduction of the risk of death in the setting of coronary artery bypass (OR 0.74 [0.58-0.94]; P = .01). The number needed to treat was 100. CONCLUSION: Our data ruled out the hypothesis of any benefit of adding pexelizumab on top of currently available therapies for ST elevation myocardial infarction. However, pexelizumab reduces the risk of death in patients undergoing coronary artery bypass grafting.