Uri Amit

Prevalence of pharyngeal carriage of Kingella kingae in young children and risk factors for colonization.

The carriage rate of Kingella kingae among Jewish and Bedouin children living in southern Israel paralleled the age-related incidence of invasive infections. Age 6–29 months was a significant risk factor for K. kingae colonization in both ethnic groups; day-care attendance was a risk factor in Jewish children, whereas living in a shanty town was negatively associated with carriage in Bedouins.

Age-Dependent Carriage of Kingella kingae in Young Children and Turnover of Colonizing Strains

In a longitudinal study, Kingella kingae carriage rate was nil below 6 months of age, 1.5% at 6 months, 9.6% at 12 months, remained stable between 10.4% and 12.0% during the second year of life, and decreased significantly to 5.3% at 30 months. Replacement of carried strains occurred over time.

Epidemiology of invasive Kingella kingae infections in 2 distinct pediatric populations cohabiting in one geographic area.

The annual incidence of invasive Kingella kingae infection in children younger than 4 years of age was significantly higher in westernized Jews than in indigent Bedouins living side by side in southern Israel (12.21/100,000 and 5.83/100,000, respectively, (P , 0.05). One K. kingae clone was overrepresented among isolates from Jewish children, suggesting that differences in bacterial pathogenicity may contribute to the morbidity excess detected in this population group.

Left Ventricular Dysfunction Switches Mesenchymal Stromal Cells Toward an Inflammatory Phenotype and Impairs Their Reparative Properties Via Toll-Like Receptor-4

Background: Little is known about the potentially unfavorable effects of mesenchymal stromal cell (MSC) activation on the heart. MSCs can respond to tissue injury by anti- or proinflammatory activation. We aimed to study the potential negative interaction between left ventricular dysfunction (LVD) and MSC activation. Methods: We isolated MSCs from cardiac and subcutaneous fat tissues of mice with LVD 28 days after myocardial infarction or sham operation. To evaluate the effect of LVD on MSCs, we characterized cardiac MSCs and subcutaneous MSCs in vitro. Subsequently, we injected MSCs or saline into the infarcted myocardium of mice and evaluated LV remodeling and function 28 days after myocardial infarction. To test the hypothesis that toll-like receptor 4 (TLR4) mediates proinflammatory polarization of MSCs, we characterized cardiac MSCs from TLR4-/- and wild-type (WT) mice after inflammatory stimulation in vitro. Next, we transplanted cardiac MSCs from TLR4-/- and WT male mice into the infarcted myocardium of female WT mice and evaluated infarct size, MSC retention, inflammation, remodeling, and function after 7 days. Results: LVD switched cardiac MSCs toward an inflammatory phenotype, with increased secretion of inflammatory cytokines as well as chemokines. The effect of LVD on subcutaneous MSCs was less remarkable. Although transplantation of cardiac MSCs and subcutaneous MSCs from LVD and sham hearts did not improve LV remodeling and function, cardiac MSCs from LVD exacerbated anterior wall thinning 28 days after myocardial infarction. The inflammatory polarization of cardiac MSCs by LVD was mediated by TLR4, as we found less secretion of inflammatory cytokines and higher secretion of anti-inflammatory cytokines from activated cardiac MSCs of TLR4-deficient mice, compared with WT cardiac MSCs. Significantly, TLR4 deficiency preserved the expression of CD47 (don’t eat me signal) on cardiac MSCs after both TLR4 stimulation in vitro and transplantation into the infarcted heart. Compared with WT cardiac MSCs and saline, TLR4 -/- cardiac MSCs survived in the cardiac tissue and maintained their reparative properties, reduced infarct size, increased scar thickness, and attenuated LV dilatation 7 days after myocardial infarction. Conclusions: The environment of the failing and infarcted myocardium drives resident and transplanted MSCs toward a proinflammatory phenotype and restricts their survival and reparative effects in a mechanism mediated by TLR4.

Macrophages dictate the progression and manifestation of hypertensive heart disease

BACKGROUND Inflammation has been implicated in the initiation, progression and manifestation of hypertensive heart disease. We sought to determine the role of monocytes/macrophages in hypertension and pressure overload induced left ventricular (LV) remodeling. METHODS AND RESULTS We used two models of LV hypertrophy (LVH). First, to induce hypertension and LVH, we fed Sabra salt-sensitive rats with a high-salt diet. The number of macrophages increased in the hypertensive hearts, peaking at 10 weeks after a high-salt diet. Surprisingly, macrophage depletion, by IV clodronate (CL) liposomes, inhibited the development of hypertension. Moreover, macrophage depletion reduced LVH by 17% (p<0.05), and reduced cardiac fibrosis by 75%, compared with controls (p=0.001). Second, to determine the role of macrophages in the development and progression of LVH, independent of high-salt diet, we depleted macrophages in mice subjected to transverse aortic constriction and pressure overload. Significantly, macrophage depletion, for 3 weeks, attenuated LVH: a 12% decrease in diastolic and 20% in systolic wall thickness (p<0.05), and a 13% in LV mass (p=0.04), compared with controls. Additionally, macrophage depletion reduced cardiac fibrosis by 80% (p=0.006). Finally, macrophage depletion down-regulated the expression of genes associated with cardiac remodeling and fibrosis: transforming growth factor beta-1 (by 80%) collagen type III alpha-1 (by 71%) and atrial natriuretic factor (by 86%). CONCLUSIONS Macrophages mediate the development of hypertension, LVH, adverse cardiac remodeling, and fibrosis. Macrophages, therefore, should be considered as a therapeutic target to reduce the adverse consequences of hypertensive heart disease.

Comparison of Statin Alone Versus Bezafibrate and Statin Combination in Patients With Diabetes Mellitus and Acute Coronary Syndrome

Acute coronary syndromes (ACS) in patients with diabetes mellitus (DM) are associated with a high risk for major adverse cardiovascular events (MACEs) despite statin treatment. The impact of combined bezafibrate and statin therapy in patients with DM and ACS has not been specifically investigated. The aim of this study was to evaluate the association of combined therapy with 30-day MACEs in patients with DM participating in the nationwide Acute Coronary Syndrome Israeli Surveys (ACSIS). The study population comprised 3,063 patients with DM from the ACSIS 2000, 2002, 2004, 2006, 2008, and 2010 enrollment waves who were alive at discharge and received statins. Of these, 225 (7.3%) received on discharge combined bezafibrate and statin therapy, and 2,838 (92.7%) were treated with statins alone. MACEs were defined as a composite measure of death, recurrent myocardial infarction, recurrent ischemia, stent thrombosis, ischemic stroke, and urgent revascularization. The development of 30-day MACEs was recorded in 8% patients receiving combination therapy and 14.2% of those receiving statins alone (p = 0.01). Crude 1-year mortality and 30-day rehospitalization rates were also significantly lower in patients receiving combination therapy: 4.0% versus 8.1% (p = 0.03) and 13.3% versus 21.6% (p = 0.003), respectively. Multivariate analysis identified combined therapy as an independent predictor of reduced risk for 30-day MACEs, with an odds ratio of 0.56 (95% confidence interval 0.34 to 0.92), corresponding to a 44% relative risk reduction. In conclusion, a significantly lower risk for 30-day MACEs was observed in statin-treated patients with DM who also received bezafibrate after ACS. Signals regarding improvement of 30-day rehospitalization and 1-year mortality rates emerged as well.

Macrophages and regeneration: Lessons from the heart

One of the most ambitious goals in modern cardiology is to regenerate the injured myocardium. The human myocardium has poor regenerative power. Thus, significant myocardial injury results in irreversible damage, scar formation, remodeling, and dysfunction. The search for therapies that will improve myocardial regeneration needs a better understanding of the mechanisms of repair and regeneration. While the role of macrophages in inflammation, scar formation, and fibrosis are well defined, their role in myocardial regeneration is less clear. Recent reports have suggested that cardiac macrophages regulate myocardial regeneration in neonatal mice. The present review aims to describe the latest discoveries about the possible role of macrophages in myocardial regeneration. We discuss the promises and difficulties to translate the latest findings into new therapies.

Kingella kingae Expresses Four Structurally Distinct Polysaccharide Capsules That Differ in Their Correlation with Invasive Disease.

Kingella kingae is an encapsulated gram-negative organism that is a common cause of osteoarticular infections in young children. In earlier work, we identified a glycosyltransferase gene called csaA that is necessary for synthesis of the [3)-β-GalpNAc-(1→5)-β-Kdop-(2→] polysaccharide capsule (type a) in K. kingae strain 269–492. In the current study, we analyzed a large collection of invasive and carrier isolates from Israel and found that csaA was present in only 47% of the isolates. Further examination of this collection using primers based on the sequence that flanks csaA revealed three additional gene clusters (designated the csb, csc, and csd loci), all encoding predicted glycosyltransferases. The csb locus contains the csbA, csbB, and csbC genes and is associated with a capsule that is a polymer of [6)-α-GlcpNAc-(1→5)-β-(8-OAc)Kdop-(2→] (type b). The csc locus contains the cscA, cscB, and cscC genes and is associated with a capsule that is a polymer of [3)-β-Ribf-(1→2)-β-Ribf-(1→2)-β-Ribf-(1→4)-β-Kdop-(2→] (type c). The csd locus contains the csdA, csdB, and csdC genes and is associated with a capsule that is a polymer of [P-(O→3)[β-Galp-(1→4)]-β-GlcpNAc-(1→3)-α-GlcpNAc-1-] (type d). Introduction of the csa, csb, csc, and csd loci into strain KK01Δcsa, a strain 269–492 derivative that lacks the native csaA gene, was sufficient to produce the type a capsule, type b capsule, type c capsule, and type d capsule, respectively, indicating that these loci are solely responsible for determining capsule type in K. kingae. Further analysis demonstrated that 96% of the invasive isolates express either the type a or type b capsule and that a disproportionate percentage of carrier isolates express the type c or type d capsule. These results establish that there are at least four structurally distinct K. kingae capsule types and suggest that capsule type plays an important role in promoting K. kingae invasive disease.

SIRT6 Overexpression Improves Various Aspects of Mouse Healthspan.

The extension in human lifespan in the last century results in a significant increase in incidence of age related diseases. It is therefore crucial to identify key factors that control elderly healthspan. Similar to dietary restriction, mice overexpressing the NAD+ dependent protein deacylase SIRT6 (MOSES) live longer and have reduced IGF-1 levels. However, it is as yet unknown whether SIRT6 also affects various healthspan parameters. Here, a range of age related phenotypes was evaluated in MOSES mice. In comparison to their wild-type (WT) littermates, old MOSES mice showed amelioration of a variety of age-related disorders, including: improved glucose tolerance, younger hormonal profile, reduced age-related adipose inflammation and increased physical activity. The increased activity was accompanied with increased muscle AMP-activated protein kinase (AMPK) activity. Altogether, these results indicate that overexpression of SIRT6 in mice retards important aspects of the aging process and suggest SIRT6 to be a potential therapeutic target for the treatment of a set of age-related disorders.

Short- and Long-Term Survival in Metastatic Pancreatic Adenocarcinoma, 1993–2013

Background: During the past 2 decades, numerous clinical trials have focused on improving outcomes in patients with metastatic pancreatic cancer (mPDAC). The efficacy of new treatments has been demonstrated among highly selected patients in randomized phase III trials; hence, it is not clear to what extent these advances are reflected within the broader mPDAC population. Materials and Methods: Survival statistics were extracted from the SEER database for patients diagnosed with mPDAC between 1993 and 2013. Survival was analyzed using the Kaplan-Meier method and proportional hazard models. Results: The study population consisted of 57,263 patients diagnosed with mPDAC between 1993 and 2013; 52% were male, with a median age of 69 years (range, 15-104). Superior prognosis correlated with younger age, being married, tumor located within the head of the pancreas, lower grade disease, and more recent year of diagnosis. Median overall survival (OS) remained stable at 2 months between 1993 and 2013. Improvements in OS were seen for younger patients (age <50 years) and those with a more recent year of diagnosis (2009-2013). The percentage of patients who died within 2 months of initial diagnosis decreased between 1993 and 2013 (from 63.5% to 50.6%; P<.0001). The percentage of patients surviving ≥12 months improved from 4.9% in 1993 to 12.7% in 2013 (P<.0001). Conclusions: In recent years a modest improvement in OS has been seen among younger patients with mPDAC. The percentage of patients living beyond 1 year has significantly increased over time; however, the percentage of those dying within 2 months remains substantial.