Combined administration of membrane-permeable and impermeable iron-chelating drugs attenuates ischemia/reperfusion-induced hepatic injury.

BACKGROUND: The underlying pathophysiological mechanisms of hepatic ischemia-reperfusion (I/R) injury have not been completely elucidated. However, it is well known that oxidative stress, caused by a burst of reactive oxygen species (ROS) production during the reperfusion phase, plays a crucial role. A growing body of evidence indicates that the intracellular availability of free iron represents a requirement for ROS-induced adverse effects, as iron catalyzes the generation of highly reactive free radicals. The aim of this study was to examine whether a combination of iron chelators with varying lipophilicity could offer enhanced protection against I/R by diminishing the conversion of weak oxidants, like H2O2, to extremely reactive ones such as hydroxyl radicals (HO.). METHODS: HepG2 cells (hepatocellular carcinoma cell line) were exposed to oxidative stress conditions after pre-treatment with the iron chelators desferrioxamine (DFO) and deferiprone (DFP) alone or in combination. Labile iron pool was estimated using the calcein-acetoxymethyl ester (calcein-AM) method and DNA damage with the comet assay. We subsequently used a rabbit model (male New Zealand white rabbits) of hepatic I/R-induced injury to investigate, by measuring biochemical (ALT, ALT, ALP, γGT) and histological parameters, whether this may be true for in vivo conditions. RESULTS: The combination of a membrane-permeable iron chelator (DFP) with a strong membrane-impermeable one (DFO) raises the level of protection in both hepatic cell lines exposed to oxidative stress conditions and hepatic I/R rabbit model. CONCLUSIONS: Our results show that combinations of iron chelators with selected lipophilicity and iron-binding properties may represent a valuable strategy to protect against tissue damage during reperfusion after a period of ischemia.

Microcirculatory alterations during continuous renal replacement therapy in ICU: A novel view on the 'dialysis trauma' concept.

OBJECTIVE: The purpose of this study was to evaluate microcirculation over 24 h renal replacement therapy (CRRT) in critically ill patients. METHODS: We conducted a single-center, prospective, observational study, measuring microcirculation parameters, monitored by near infrared spectroscopy (NIRS) before hemodiafiltration onset (H0), and at six (H6) and 24 h (H24) during CRRT in critically ill patients. Serum Cystatin C (sCysC) and soluble (s)E-selectin levels were measured at the same time points. Twenty-eight patients [19 men (68%)] were included in the study. RESULTS: Tissue oxygen saturation (StO2, %) [76.5 ± 12.5 (H0) vs 75 ± 11 (H6) vs 70 ± 16 (H24), p = 0.04], reperfusion rate, indicating endothelial function (EF, %/sec) [2.25 ± 1.44 (H0) vs 2.1 ± 1.8 (H6) vs 1.6 ± 1.4 (H24), p = 0.02] and sCysC (mg/L) [2.7 ± 0.8 (H0) vs 2.2 ± 0.6 (H6) vs 1.8 ± 0.8 (H24), p < 0.0001] significantly decreased within the 24 h CRRT. Change of EF positively correlated with changes of sCysC within 24 h CRRT (r = 0.464, p = 0.013) while in patients with diabetes the change of StO2 correlated with dose (r = − 0.8, p = 0.01). No correlation existed between hemoglobin and temperature changes with the deteriorated microcirculation indices. sE-Selectin levels in serum were elevated; no difference was established over the 24 h CRRT period. A strong correlation existed between the sE-Selectin concentration change at H6 and H24 and the mean arterial pressure change in the same period (r = 0.77, p < 0.001). CONCLUSIONS: During the first 24 h of CRRT implementation in critically ill patients, deterioration of microcirculation parameters was noted. Microcirculatory alterations correlated with sCysC changes and with dose in patients with diabetes.

Serum S100B protein is increased and correlates with interleukin 6, hypoperfusion indices, and outcome in patients admitted for surgical control of hemorrhage.

S100B protein, an acknowledged biomarker of brain injury, has been reported to be increased in hemorrhagic shock. Also, acute hemorrhage is associated with inflammatory response. The aim of this study was to investigate the concentrations of serum S100B and the potential relationships with interleukin 6 (IL-6), severity of tissue hypoperfusion, and prognosis in patients admitted for surgical control of severe hemorrhage. Patients undergoing elective abdominal aortic aneurysm surgery participated as control subjects. Serum samples were drawn before, at the end of surgery, and after 6 and 24 h. Sixty-four patients with severe hemorrhage (23 trauma and 41 nontrauma) and 17 control subjects were included. Increased preoperative concentrations of S100B protein (1.70 ± 2.13 and 0.81 ± 1.23 µg/L) and IL-6 (241 ± 291 and 226 ± 238 pg/mL) were found in patients with traumatic and nontraumatic reason, respectively, and remained elevated throughout 24 h. Compared with nontrauma, trauma patients exhibited higher preoperative S100B levels (P < 0.05). Overall mortality was 47%. In control subjects, preoperative S100B and IL-6 levels were within normal limits and increased at the end of surgery (P < 0.001 and P < 0.01, respectively). Preoperative S100B correlated with IL-6 (r = 0.78, P < 0.01), arterial lactate (r = 0.50, P < 0.01), pH (r = -0.45, P < 0.01), and bicarbonate (r = -0.40, P < 0.01). Multiple analysis revealed that preoperative S100B in trauma and lactate in nontrauma patients were independently associated with outcome. In predicting death, preoperative S100B yielded receiver operator characteristics curve areas of 0.75 for all patients and 0.86 for those with trauma. These results indicate that severe hemorrhage in patients without brain injury is associated with increased serum levels of S100B, which correlates with IL-6 and tissue hypoperfusion. Moreover, the predictive ability of S100B for mortality, suggests that it could be a marker of potential clinical value in identifying, among patients with severe hemorrhage, those at greater risk for adverse outcome.

Combination of renal biomarkers predicts acute kidney injury in critically ill adults.

OBJECTIVE: Most studies so far have focused on the performance of individual biomarkers to detect early acute kidney injury (AKI) in the adult intensive care unit (ICU) patients; however, they have not determined the predictive ability of their combinations. The aim of this study was to compare the predictive abilities of plasma neutrophil gelatinase-associated lipocalin (pNGAL), urine neutrophil gelatinase-associated lipocalin (uNGAL), plasma cystatin C (pCysC), serum creatinine (sCr), and their combinations in detecting AKI in an adult general ICU population. METHODS: A total of 100 consecutive ICU patients were included in the analysis. AKI was defined according to RIFLE criteria. Biomarker predictive abilities were evaluated by area under the curve (AUC), net reclassification improvement (NRI), and integrated discrimination improvement (IDI). RESULTS: AKI occurred in 36% of patients 7 days post-admission. All three novel biomarkers as well as sCr had moderate predictive abilities for AKI occurrence. The most efficient combinations (pNGAL + sCr and pNGAL + uNGAL + sCr) were selected to participate in the subsequent analyses. Both combinations, when added to a reference clinical model, increased its AUC significantly (0.858, p = 0.04). Their NRI (0.78, p = 0.0002) was equal to that of pNGAL, but higher than that of the other three biomarkers, whereas their IDI was higher than that of any individual biomarker (0.23, p = 0.0001). Both combinations had better specificities, positive likelihood ratios, and positive predictive values than those of any individual biomarker. CONCLUSION: The biomarker combinations had better predictive characteristics compared with those of each biomarker alone.

Comparison of high-frequency oscillation and tracheal gas insufflation versus standard high-frequency oscillation at two levels of tracheal pressure.

PURPOSE: In acute respiratory distress syndrome (ARDS), combined high-frequency oscillation (HFO) and tracheal gas insufflation (TGI) may improve oxygenation through a TGI-induced increase in mean tracheal pressure (P(tr)). We compared standard HFO and HFO-TGI matched for P(tr), in order to determine whether TGI affects gas exchange independently from P (tr). METHODS: We conducted a prospective, randomized, crossover, physiological study in a 37-bed intensive care unit. Twenty-two patients with early acute lung injury (ALI) or ARDS were enrolled. On day 1, patients were ventilated with HFO, without (60 min) and combined with TGI (60 min) in random order. HFO/HFO-TGI sessions were repeated in inverse order within 7 h. HFO/HFO-TGI mean airway pressure (P(aw)) was titrated to a P(tr) that was either equal to (low P(aw)) or 3 cmH(2)O higher than (high P(aw)) the P(tr) of the preceding conventional mechanical ventilation. On day 2, the protocol was repeated at the alternative P(tr) level relative to day 1. RESULTS: Gas exchange and hemodynamics were determined before, during, and after HFO/HFO-TGI sessions. HFO-TGI-high P(aw) versus HFO-high P(aw) resulted in significantly higher PaO(2)/inspired O(2) fraction (FiO(2)) [mean +/- standard error of the mean (SEM): 281.6 +/- 15.1 versus 199.0 +/- 15.0 mmHg; mean increase: 42%; P < 0.001]. HFO-TGI-low P(aw), versus HFO-low P(aw), resulted in significantly higher PaO(2)/FiO(2) (222.8 +/- 14.6 versus 141.3 +/- 8.7 mmHg; mean increase: 58%; P < 0.001). PaCO(2) was significantly lower during HFO-TGI-high P(aw) versus HFO-high P(aw) (45.3 +/- 1.6 versus 53.7 +/- 1.9 mmHg; mean decrease: 16%; P = 0.037). CONCLUSIONS: At the same P(tr) level, HFO-TGI results in superior gas exchange compared with HFO.

Systemic sclerosis associated with generalized vasculitis and hypopituitarism.

Systemic sclerosis (SSc) is a progressively evolving multisystemic disorder of unknown etiology. Beyond skin, several other organs can also be affected with a severity of involvement that is often heterogeneous. We describe a 53-year-old female patient who was admitted urgently to the hospital almost collapsed, because of numerous bleeding deep skin ulcers, located all over the body. Clinical findings and autoantibody screening were typical of SSc. Moreover, both histopathology and immunofluorescence findings were compatible with scleroderma and vasculitis as well. In addition, pituitary hormone investigation revealed severely damaged function of the gland. We assume that severe skin ulceration and serious hypopituitarism were both implications of underlying SSc-associated vasculitis. To the best of our knowledge, these peculiar clinical manifestations have not been described in the international literature to date.

Isolated primary cardiac amyloidosis associated with porokeratosis of Mibelli.

In this report we briefly describe a 54-year-old woman who was referred to our institution for evaluation and management of newly diagnosed congestive heart failure associated with a skin rash. Detailed investigations revealed the presence of restrictive cardiomyopathy due to isolated primary cardiac amyloidosis as well as the presence of a skin disease named 'porokeratosis of Mibellli'. Interestingly, porokeratotic lesions rarely have been associated with localized cutaneous amyloidosis. Presumably, porokeratosis induces secondary dermal amyloid deposition by a yet unknown mechanism. This is the first case of primary amyloidosis associated with porokeratosis reported in the literature.

Correlation between increased serum sFas levels and microalbuminuria in type 1 diabetic patients.

OBJECTIVE: The aim of this study was to elucidate if apoptosis dysregulation is present in type 1 diabetic patients with microalbuminuria. SUBJECTS AND METHODS: The following variables were determined in 29 type 1 diabetic patients: the duration of diabetes, soluble Fas (sFas), Bcl-2, hemoglobin A(1c) levels, glomerular filtration rate (GFR) and microalbuminuria, using the urine albumin to urine creatinine ratio (ACR). Age and gender were assessed and patients were categorized into two groups, according to their ACR: the microalbuminuric (MA) group with an ACR > or =30 mg/g, and the normoalbuminuric (NA) group with an ACR <30 mg/g. RESULTS: The differences between the two groups regarding sFas, Bcl-2 and GFR were not statistically significant. However, in the MA group, a significant positive relationship between sFas and ACR was observed (r = 0.736, p = 0.015). Dividing patients into two subgroups--mild versus severe (ACR > or =150 mg/g) microalbuminuric patients--significant differences in sFas (60.4 vs. 87.2 pg/ml; p = 0.047) and GFR (113 vs. 69.5 ml min(-1) 1.73 m(-2); p = 0.021) were observed, whereas in Bcl-2, the difference was not significant (77.96 vs. 71.13 ng/ml). CONCLUSIONS: At the early stages of diabetic nephropathy in type 1 diabetic patients, there seems to be a dysregulation of apoptosis, as expressed by enhanced sFas levels, leading to the speculation that the prevalence of antiapoptotic mechanisms (sFas) may promote mesangial proliferation.

High prevalence of subclinical peripheral artery disease in Greek hospitalized patients.

BACKGROUND: Peripheral artery disease (PAD) represents a common manifestation of systemic atherosclerosis that is associated with an increased risk of cardiovascular death and ischemic events but one that may be underdiagnosed in clinical practice. The purpose of this study was to identify PAD using the ankle-brachial index (ABI) in hospitalized patients from a Department of Internal Medicine and to further investigate the association of this index with traditional cardiovascular risk factors. METHODS: We measured ABI in 990 consecutive patients (400 men and 590 women) aged 50 years or older (71.2+/-9.1) without a history or symptoms suggestive of PAD. ABI values below 0.90 were considered abnormal. RESULTS: PAD was detected in 356 patients (36%), and men had a higher prevalence than women (p<0.001). Hypertension (p<0.001), smoking (p<0.001), diabetes (p<0.05), male sex (p<0.001), and dyslipidemia (p<0.05) were statistically more frequent in patients with PAD, whereas obesity had no significant relation to PAD in our series. In a stepwise, logistic regression analysis, hypertension, male sex, diabetes mellitus, smoking, and dyslipidemia were found to be independent risk factors with odds ratios (95% confidence intervals) of 2.46 (1.85-3.27), 2.25 (1.66-3.05), 1.80 (1.32-2.47), 1.78 (1.31-2.42), and 1.64 (1.22-2.19), respectively. CONCLUSIONS: A simple ABI measurement revealed a large number of patients with unrecognized PAD. It is, therefore, recommended that ABI measurement should be included in the evaluation of cardiovascular risk in hospitalized patients aged 50 years or older.

Coxsackievirus infection associated with acute pancreatitis.

CONTEXT: A variety of infectious agents have been reported as rare causes of acute pancreatitis. CASE REPORT: We briefly describe a 36-year-old man who presented with acute pancreatitis and a maculopapular rash. The marked elevation in antibody titer against coxsackievirus B, as well as the skin biopsy, was compatible with acute coxsackievirus B viral infection. CONCLUSION: This case highlights the fact that an appropriate investigation for viral infections should be performed in patients having acute pancreatitis and no classical risk factors.