Differential adaptive response and survival of Salmonella enterica serovar enteritidis planktonic and biofilm cells exposed to benzalkonium chloride

This study examined the adaptive response and survival of planktonic and biofilm phenotypes of Salmonella enterica serovar Enteritidis adapted to benzalkonium chloride (BC). Planktonic cells and biofilms were continuously exposed to 1 μg ml⁻¹ of BC for 144 h. The proportion of BC-adapted biofilm cells able to survive a lethal BC treatment (30 μg ml⁻¹) was significantly higher (4.6-fold) than that of BC-adapted planktonic cells. Similarly, there were 18.3-fold more survivors among the BC-adapted biofilm cells than among their nonadapted (i.e., without prior BC exposure) cell counterparts at the lethal BC concentration, and this value was significantly higher than the value for BC-adapted planktonic cells versus nonadapted cells (3.2-fold). A significantly higher (P < 0.05) proportion of surviving cells was noticed among BC-adapted biofilm cells relative to BC-adapted planktonic cells following a 10-min heat shock at 55°C. Fatty acid composition was significantly influenced by phenotype (planktonic cells or biofilm) and BC adaptation. Cell surface roughness of biofilm cells was also significantly greater (P < 0.05) than that of planktonic cells. Key proteins upregulated in BC-adapted planktonic and biofilm cells included CspA, TrxA, Tsf, YjgF, and a probable peroxidase, STY0440. Nine and 17 unique proteins were upregulated in BC-adapted planktonic and biofilm cells, respectively. These results suggest that enhanced biofilm-specific upregulation of 17 unique proteins, along with the increased expression of CspA, TrxA, Tsf, YjgF, and a probable peroxidase, phenotype-specific alterations in cell surface roughness, and a shift in fatty acid composition conferred enhanced survival to the BC-adapted biofilm cell population relative to their BC-adapted planktonic cell counterparts.     

Relationship Between High Circulating Adiponectin With Bone Mineral Density and Bone Metabolism in Elderly Males With Chronic Heart Failure

BackgroundThe aim of the study was to investigate the associations of adiponectin and leptin to bone mass and bone specific surrogates in elderly males with chronic heart failure (CHF).Methods and ResultsSeventy-three males (mean age 68 ± 7 years) with stable mild to moderate CHF and 20 healthy individuals age- and body mass index–matching underwent dual energy x-ray absorptiometry measurements (bone mineral density (BMD) at hip and lumbar spine, total bone mineral content, and body composition); echocardiography; 6-minute walk test; grip strength; and biochemical assessment including adiponectin, leptin, bone specific surrogates (osteocalcin, β-CrossLaps, osteoprotegerin [OPG], receptor activator of nuclear factor κB ligand [RANKL]), parathyroid hormone, 25-hydroxy vitamin D, testosterone, sex hormone-binding globulin, and NT-pro-BNP. Serum adiponectin, osteocalcin, β-CrossLaps, OPG, RANKL, and parathyroid hormone were significantly increased in CHF patients, whereas 25-hydroxy vitamin D was significantly lower compared to healthy controls. The significant positive association was found between adiponectin level with osteocalcin, β-CrossLaps, OPG, and RANKL among CHF patients. In multivariate regression analysis, adiponectin was a significant determinant of total hip BMD, although the variance was small (r² = 0.239), whereas leptin was determinant for total bone mineral content (r² = 0.469) in patients with CHF.ConclusionsSerum adiponectin is an independent predictor of BMD in elderly males with mild to moderate CHF, and showed a positive correlation to bone specific surrogates. Adiponectin, as cardioprotective hormone, seems to be able to exert a negative effect on bone mass in chronic heart failure. Further research is needed to confirm the potential for adipokines in the crosstalk between bone and energy metabolism in CHF patients.     

Mental stress-induced ischemia in patients with coronary artery disease: echocardiographic characteristics and relation to exercise-induced ischemia

Objective The aims of this study were to investigate the incidence and parameters associated with myocardial ischemia during mental stress (MS) as measured by echocardiography and to evaluate the relation between MS-induced and exercise-induced myocardial ischemia. Methods Study participants were 79 patients (63 men; mean [M] [standard deviation {SD}] age = 52 [8] years) with angiographically confirmed coronary artery disease and previous positive exercise test result. The MS protocol consisted of mental arithmetic and anger recall task. The patients performed a treadmill exercise test 15 to 20 minutes after the MS task. Data of post-MS exercise were compared with previous exercise stress test results. Results The frequency of echocardiographic abnormalities was 35% in response to the mental arithmetic task, compared with 61% with anger recall and 96% with exercise (p < .001, exercise versus MS). Electrocardiogram abnormalities and chest pain were substantially less common during MS than were echocardiographic abnormalities. Independent predictors of MS-induced myocardial ischemia were: wall motion score index at rest (p = .02), peak systolic blood pressure (p = .005), and increase in rate-pressure product (p = .004) during MS. The duration of exercise stress test was significantly shorter (p < .001) when MS preceded the exercise and in the case of earlier exercise (M [SD] = 4.4 [1.9] versus 6.7 [2.2] minutes for patients positive on MS and 5.7 [1.9] versus 8.0 [2.3] minutes for patients negative on MS). Conclusions Echocardiography can be successfully used to document myocardial ischemia induced by MS. MS-induced ischemia was associated with an increase in hemodynamic parameters during MS and worse function of the left ventricle. MS may shorten the duration of subsequent exercise stress testing and can potentiate exercise-induced ischemia in susceptible patients with coronary artery disease.     

On-admission serum uric acid predicts outcomes after acute myocardial infarction: systematic review and meta-analysis of prognostic studies

Aim

To evaluate the prognostic value of serum uric acid (SUA) in acute myocardial infarction (AMI) patients.

Methods

Systematic review and random-effects meta-analysis of prognostic studies assessing AMI outcomes (death, major adverse cardiac events, MACE) in relation to on-admission SUA.

Results

Nine studies (7655 patients) were identified, 6 in the ST-segment elevation AMI patients treated with invasive revascularization and three in mixed AMI type cohorts with variable reperfusion strategies. “High” SUA (vs “low,” different cut-offs) was univariately associated with higher short-term mortality (8 studies/6805 patients; odds ratio [OR], 3.24; 95% confidence interval [CI], 2.47-4.27) and incidence of MACE (7/6467; OR, 2.46; 95% CI, 1.84-3.27, moderate heterogeneity, mild bias), and with higher medium-term mortality (5/5194; OR, 2.69; 95% CI, 2.00-3.62, moderate heterogeneity, mild bias) and MACE (4/4299; OR, 1.93; 95% CI, 1.36-2.74, high heterogeneity, mild bias). It was independently associated with a higher short-term (4/3625; OR, 2.26, 95% CI, 1.85-2.77) and medium/long-term (3/2683; hazard ratio [HR], 1.30; 95% CI 1.01-1.68, moderate heterogeneity, mild bias) occurrence of poor outcomes (death/MACE). As a continuous variable (by 50 μmol/L), higher SUA was also independently associated with poorer medium/long-term outcomes (4/3533; HR, 1.19; 95% CI, 1.03-1.37, high heterogeneity, mild bias). All individual study effects (unadjusted or adjusted) were in the same direction, but differed in size. Heterogeneity was mainly due to the included AMI type and/or definition of MACE. All bias-corrected pooled effects remained significant.

Conclusion

Based on the available data, high(er) on-admission SUA independently predicts worse short-term and medium/long-term outcomes after AMI. However, the number of data are modest and additional prospective studies are warranted.In humans, uric acid is the end product of purine metabolism due to a genetically determined lack of uricase activity (1). It is generated by oxidation of xanthine, primarily in the liver, gut, kidneys, and apparently in the heart, but xanthine oxidase (XO) is a ubiquitous enzyme (2). Serum levels of uric acid (serum uric acid, SUA) are governed by its production and elimination rates (via the kidney). Concentrations >420 μmol/L in men and >360 μmol/L in women are conventionally considered to represent hyperuricemia, values <310 μmol/L and <250 μmol/L, respectively, are considered low-normal, whereas concentrations in-between these limits are considered high-normal (3). High purine intake (eg, animal foods, herring, anchovies, alcohol, fructose, sweetbreads) and a number of morbidity (reduced renal function, conditions with a high cellular turnover), pharmacological (eg, diuretics) and genetically determined factors (eg, urate transporter or organic anion transporter mutations) may contribute to development of high SUA (4).Uric acid has several effects of potential interest in cardiovascular diseases (CVD). It is a potent antioxidant but can also promote oxidative stress, particularly at high concentrations and/or in surroundings with a low pH and/or low levels of other antioxidants (3-5). Furthermore, in vitro, it has several effects on the vascular smooth muscle and mononuclear cells that are considered important in pathophysiology of CVD (5). Consequently, high(er) SUA has been extensively evaluated as a prognostic factor for different CVDs (3-5). However, increased SUA is linked to various conditions that per se are CVD risk factors (eg, hypertension, dyslipidemia, diabetes, metabolic syndrome, renal failure) and it has not been always possible to distinguish whether it is a cause or a consequence of such conditions (3-5). Next, in a failing heart or a hypoxic heart, activation of XO occurs (2,6). This inevitably results in increased SUA, but XO per se promotes oxidative stress and endothelial dysfunction (2). Inhibition of XO re-establishes endothelial function, whereas lowering of SUA by uricosuric agents does not seem to achieve this effect (2). Hence, the role of SUA in CVD has been accompanied by a controversy: should it be viewed as a “true” risk factor (ie, a “direct pathogen”) or as a mere marker of conditions that actually are the risk factors (6).Considering coronary artery disease, a recent meta-analysis of 26 large prospective cohort studies indicated an independent association between hyperuricemia and occurrence of the disease and related mortality (7). Less is known about SUA as a potential predictor of outcomes in patients affected by the acute myocardial infarction (AMI). By 2009, two studies indicated independent association between high(er) on-admission SUA and worse outcomes (8,9). The aim of the current study was to perform a systematic review and, if feasible, meta-analysis of observational studies in order to evaluate the prognostic value of SUA in this setting.     

Histone deacetylases are dysregulated in rheumatoid arthritis and a novel histone deacetylase 3–selective inhibitor reduces interleukin‐6 production by peripheral blood mononuclear cells from rheumatoid arthritis patients

Objective

To characterize the role of histone deacetylase (HDAC) activity in rheumatoid arthritis (RA) and to evaluate the effects of MI192, a novel HDAC‐3–selective inhibitor, compared with the established nonselective HDAC inhibitor trichostatin A (TSA), on proinflammatory cytokine production.

Methods

Activity of HDAC and histone acetyltransferase was measured in peripheral blood mononuclear cells (PBMCs) from RA patients by spectrophotometric assay, prior to and after 12 weeks of etanercept therapy. The effects of HDAC inhibitor treatment on cytokine production in both RA and healthy PBMCs were assessed by enzyme‐linked immunosorbent assay.

Results

RA PBMCs exhibited significantly increased HDAC activity (P = 0.007) compared to PBMCs from healthy individuals, and the increase was unaltered after 12 weeks of etanercept therapy. TSA was a potent inhibitor of tumor necrosis factor (TNF) and interleukin‐6 (IL‐6) production in both RA and healthy PBMCs and of interferon‐γ (IFNγ) production in healthy PBMCs; IFNγ was not produced by RA PBMCs. MI192 inhibited TNF production at high concentrations and dose‐dependently inhibited IL‐6 in RA PBMCs but not healthy PBMCs, across a dose range of 10 μM–5 nM.

Conclusion

HDAC activity is dysregulated in RA PBMCs and is a potential target for therapeutic intervention, as it is not affected by conventional anti‐TNF treatment with etanercept. Both the selective and the nonselective HDAC inhibitors (MI192 and TSA, respectively) were found to regulate cytokine production from PBMCs, but their effects were cell type and compound specific. HDAC inhibitors have potential in the treatment of RA, and HDAC‐selective inhibition may improve the therapeutic margin of safety; however, further clinical characterization and evaluation for adverse effects is needed.

     

Appearance of Hürthle cell carcinoma soon after surgical extirpation of Hürthle cell adenoma and follicular adenoma of the thyroid gland

Background

Hürthle cell neoplasms could be benign (Hürthle cell adenoma) or malignant (Hürthle cell carcinoma). Hürthle cell carcinoma is a rare tumour, representing 5% of all differentiated thyroid carcinomas. The cytological evaluation of Hürthle cell neoplasms by fine needle aspiration biopsy (FNAB) is complicated because of the presence of Hürthle cells in both Hürthle cell adenoma and Hürthle cell carcinoma. Thus, the preoperative distinction between these two entities is very difficult and possible only with pathohistological findings of the removed tumour.

Case report

A 57-year old female patient was admitted at our Department, for investigation of nodular thyroid gland. She was euthyroid and FNAB of the nodules in both thyroid lobes were consistent of Hürthle cell adenoma with cellular atypias. After thyroidectomy the histopathology revealed Hürthle cell adenoma with high cellular content and discrete cellular atypias in the left lobe and follicular thyroid adenoma without cellular atypias in the right lobe. One year after substitution therapy, a palpable tumour on the left side of the remnant tissue was found, significantly growing with time, presented as hot nodule on ^99mTc-sestamibi scan and conclusive with Hürthle cell adenoma with marked cellularity on FNAB. Tumorectomy was performed and well-differentiated Hürthle cell carcinoma detected. The patient received ablative dose of 100 mCi ¹³¹I. No signs of metastatic disease are present up to date.

Conclusions

The differences between Hürthle cell adenomas and Hürthle cell carcinomas could be clearly made only by histopathological evaluation. Patients with cytological diagnosis of Hürthle cell neoplasms should proceed to total thyroidectomy, especially if tumour size is > 1cm, FNAB findings comprise cellular atypias and/or multiple bilateral nodules are detected in the thyroid gland.