FIP1L1-PDGFRA molecular analysis in the differential diagnosis of eosinophilia

Background  

Primary eosinophlia associated with the FIP1L1-PDGFRA rearrangement represents a subset of chronic eosinophilic leukaemia (CEL) and affected patients are very sensitive to imatinib treatment. This study was undertaken in order to examine the prevalence and the associated clinicopathologic and genetic features of FIP1L1-PDGFRA rearrangement in a cohort of 15 adult patients presenting with profound eosinophilia (> 1.5 × 10⁹/L).     

Combined thirty-day exposure to thioacetamide and choline-deprivation alters serum antioxidant status and crucial brain enzyme activities in adult rats

Choline (Ch) is an essential nutrient that seems to be involved in a wide variety of metabolic reactions and functions that affect the nervous system, while thioacetamide (TAA) is a well-known hepatotoxic agent. The induction of prolonged Ch-deprivation (CD) in rats receiving TAA (through the drinking water) provides an experimental model of mild progressive hepatotoxicity that could simulate commonly-presented cases in clinical practice. In this respect, the aim of this study was to investigate the effects of a 30-day dietary CD and/or TAA administration (300 mg/L of drinking water) on the serum total antioxidant status (TAS) and the activities of brain acetylcholinesterase (AChE), Na⁺,K⁺-ATPase and Mg²⁺-ATPase of adult rats. Twenty male Wistar rats were divided into four groups: A (control), B (CD), C (TAA), D (CD+TAA). Dietary CD was provoked through the administration of Ch-deficient diet. Rats were sacrificed by decapitation at the end of the 30-day experimental period and whole brain enzymes were determined spectrophotometrically. Serum TAS was found significantly lowered by CD (−11% vs Control, p < 0.01) and CD+TAA administration (−19% vs Control, p < 0.001), but was not significantly altered due to TAA administration. The rat brain AChE activity was found significantly increased by TAA administration (+11% vs Control, p < 0.01), as well as by CD+TAA administration (+14% vs Control, p < 0.01). However, AChE was not found to be significantly altered by the 30-day dietary CD. On the other hand, CD caused a significant increase in brain Na⁺,K⁺-ATPase activity (+16% vs Control, p < 0.05) and had no significant effect on Mg²⁺-ATPase. Exposure to TAA had no significant effect on Na⁺,K⁺-ATPase, but inhibited Mg²⁺-ATPase (−20% vs Control, p < 0.05). When administered to CD rats, TAA caused a significant decrease in Na⁺,K⁺-ATPase activity (−41% vs Control, p < 0.001), but Mg²⁺-ATPase activity was maintained into control levels. Our data revealed that an adult-onset 30-day dietary-induced CD had no effect on AChE activity. Treatment with TAA not only reversed the stimulatory effect of CD on adult rat brain Na⁺,K⁺-ATPase, but caused a dramatic decrease in its activity (−41%). Previous studies have linked this inhibition with metabolic phenomena related to TAA-induced fulminant hepatic failure and encephalopathy. Our data suggest that CD (at least under the examined 30-day period) is an unfavorable background for the effect of TAA-induced hepatic damage on Na⁺,K⁺-ATPase activity (an enzyme involved in neuronal excitability, metabolic energy production and neurotransmission).     

Sleep-disordered breathing in a general heart failure population: relationships to neurohumoral activation and subjective symptoms

The aim of this study was to determine the prevalence of sleep-related breathing disorders (SDB) in a UK general heart failure (HF) population, and assess its impact on neurohumoral markers and symptoms of sleepiness and quality of life. Eighty-four ambulatory patients (72 male, mean (SD) age 68.6 (10) yrs) attending UK HF clinics underwent an overnight recording of respiratory impedance, SaO2 and heart rate using a portable monitor (Nexan). Brain natriuretic peptide (BNP) and urinary catecholamines were measured. Subjective sleepiness and the impairment in quality of life were assessed (Epworth Sleepiness Scale (ESS), SF-36 Health Performance Score). SDB was classified using the Apnoea/Hypopnoea Index (AHI). The prevalence of SDB (AHI > 15 events h(-1)) was 24%, increasing from 15% in mild-to-moderate HF to 39% in severe HF. Patients with SDB had significantly higher levels of BNP and noradrenaline than those without SDB (mean (SD) BNP: 187 (119) versus 73 (98) pg mL(-1), P = 0.02; noradrenaline: 309 (183) versus 225 (148) nmol/24 h, P = 0.05). There was no significant difference in reported sleepiness or in any domain of SF-36, between groups with and without SDB (ESS: 7.8 (4.7) versus 7.5 (3.6), P = 0.87). In summary, in a general HF clinic population, the prevalence of SDB increased with the severity of HF. Patients with SDB had higher activation of a neurohumoral marker and more severe HF. Unlike obstructive sleep apnoea, SDB in HF had little discernible effect on sleepiness or quality of life as measured by standard subjective scales.     

Intermediate postchallenge hyperglycemia in overweight and obese subjects: a new marker of impaired glucose regulation?

The objective of this study was to compare subjects with intermediate postchallenge hyperglycemia (INPH) to those with normal glycemic status, impaired fasting glucose (IFG), and/or impaired glucose tolerance (IGT), as well as type 2 diabetes mellitus. Furthermore, the authors evaluated the impact of INPH on target organ damage. In total, 487 overweight and obese adults (BMI > or =27 kg/m(2)), 252 men and 235 women, mean age 52.9 +/-10.2 years, were studied. All participants underwent a clinical and laboratory evaluation, as well as an oral glucose tolerance test (OGTT). They were also investigated by echocardiography, carotid ultrasonography, and pulse wave analysis. Overall, 302 (62%) subjects had normal glycemic status, 64 (13.1%) had IFG and/or IGT, 95 (19.5%) had type 2 diabetes mellitus, and 26 (5.4%) had INPH. Individuals with INPH had an increased index of insulin resistance (higher homeostasis model assessment-insulinogenic index [HOMA-IR], p<0.0001), impaired insulin secretion (lower insulinogenic index, p<0.0001), and higher glycosylated hemoglobin (HbA(1c)) levels (p<0.0001) in comparison with the normoglycemic subjects, but not to those with IFG and/or IGT or diabetes (p = 0.6). No difference was observed concerning the risk factors studied, left ventricular mass and vascular remodeling, among subjects with INPH, IFG and/or IGT, and diabetes. However, individuals with INPH had a higher proportion of echolucent carotid artery plaques in comparison with the normoglycemic subjects (p = 0.04) and those with IFG and/or IGT (p = 0.01). Intermediate postchallenge hyperglycemia seems to represent a new category of glucose metabolism disturbances with increased atherogenic impact. Therefore, evaluating intermediate glucose levels in an OGTT could contribute to better identify overweight individuals at risk of developing diabetes mellitus and cardiovascular events.     

High homocysteine and low folate concentrations in acute aortic dissection

Background

Biomarkers for monitoring progression and prognosis of thoracic aneurysm are of great interest. Homocysteine (Hcy) induces elastolysis in arterial media and may directly affect fibrillin-1 or collagen whereas lipoprotein (Lp) (a) inhibits elastolysis by reducing activation of matrix metallopeptidase-9.

Methods

We studied 31 consecutive patients with acute aortic dissection (AAD) admitted for emergency surgery (group I, 60 ± 13 years old, 25 men), 30 consecutive patients with chronic aneurysms of the ascending aorta (group II, 67 ± 12 years old, 24 men) and 20 healthy controls (group III, 58 ± 15 years old, 14 men). We evaluated Hcy, folate, B12, Lp(a) and methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism at baseline.

Results

Hcy, folate and B12 differed significantly among the 3 studied groups (P = 0.016, P = 0.004 and P = 0.001, respectively). The levels of Hcy and B12 were significantly higher in group I compared to both groups II and III (P = 0.05 and P = 0.002, P < 0.001 and P = 0.017, respectively) and without significant differences between groups II and III (P = 0.083 and P = 0.124). Folate was significantly lower in group I compared to both groups II and III (P = 0.001 and P = 0.006, respectively) and without marked difference between groups II and III (P = 0.409). No significant difference was found in serum levels of Lp (a) (P = 0.074) or among the frequency of MTHFR C677T genotypes.

Conclusions

Patients with AAD present with higher Hcy and lower folate compared to both chronic aneurysms and controls.     

Design of a multi-classifier system for discriminating benign from malignant thyroid nodules using routinely H&E-stained cytological images

A multi-classifier diagnostic system was designed for distinguishing between benign and malignant thyroid nodules from routinely taken (FNA, H&E-stained) cytological images. To construct the multi-classifier system, several combination rules and different mixtures of ensemble classifier members, employing morphological and textural nuclear features, were comparatively evaluated. Experimental results illustrated that the classifier combination k-NN/PNN/Bayesian and the majority vote rule enhanced significantly classification accuracy (95.7%) as compared to best single classifier (PNN: 89.6%). The proposed system was designed with purpose to be utilized in daily clinical practice as a second opinion tool to support cytopathologists' decisions, when a definite diagnosis is difficult to be obtained.     

Interleukin-1beta modulates proinflammatory cytokine production in human epithelial cells

Periodontitis is a chronic human inflammatory disease initiated and sustained by dental plaque microorganisms. A major contributing pathogen is Porphyromonas gingivalis, a gram-negative bacterium recognized by Toll-like receptor 2 (TLR2) and TLR4, which are expressed by human gingival epithelial cells (HGECs). However, it is still unclear how these cells respond to P. gingivalis and initiate inflammatory and immune responses. We have reported previously that HGECs produce a wide range of proinflammatory cytokines, including interleukin-6 (IL-6), IL-8, granulocyte-macrophage colony-stimulating factor, tumor necrosis factor alpha (TNF-alpha), and IL-1beta. In this study, we show that IL-1beta has a special role in the modulation of other inflammatory cytokines in HGECs challenged with P. gingivalis. Our results show that the increased production of IL-1beta correlates with the cell surface expression of TLR4, and more specifically, TLR4-normal HGECs produce fourfold more IL-1beta than do TLR4-deficient HGECs after challenge. Moreover, blocking the IL-1beta receptor greatly reduces the production of "secondary" proinflammatory cytokines such as IL-8 or IL-6. Our data indicate that the induction of IL-1beta plays an important role in mediating the release of other proinflammatory cytokines from primary human epithelial cells following challenge with P. gingivalis, and this process may be an inflammatory enhancement mechanism adopted by epithelial cells.     

Significant peri-operative reduction in plasma osteopontin levels after coronary artery by-pass grafting

ObjectivesOsteopontin (OPN) is a multifunctional protein associated with vascular injury and has been linked to atherosclerosis and inflammation. We sought to investigate whether OPN changes in relation to coronary artery by-pass grafting (CABG) surgery.Design and methodsWe studied 50 consecutive patients (63 ± 10 years old, 6 women and 44 men) undergoing elective CABG. Plasma OPN levels were determined by an enzyme-linked immunosorbent assay at baseline and in 24 and 72 h, post-operatively. Cardiac enzymes — creatine kinase, the MB isoenzyme of creatine kinase, troponin-I- and C-reactive protein (CRP) were also determined at all three time points.ResultsOPN levels 72 h post-op decreased significantly compared to pre-op and 24 h post-op levels (p < 0.001) whereas there was no difference between the pre-op and first post-op values (p = 0.57). The relative change in OPN levels between pre-op and 72 h post-op correlated negatively with absolute troponin-I levels at 72 h post-op (? 0.51, p = 0.005). OPN levels 72 h post-op correlated significantly with CRP at baseline (r = 0.73, p = 0.002).ConclusionsOPN plasma concentrations decreased after CABG surgery in the early post-operative period. The significance of this observation needs further investigation.