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1.  Altered Cortical Responsiveness to Pain Stimuli after High Frequency Electrical Stimulation of the Skin in Patients with Persistent Pain after Inguinal Hernia Repair 
PLoS ONE  2013;8(12):e82701.
Background
High Frequency electrical Stimulation (HFS) of the skin induces enhanced brain responsiveness expressed as enhanced Event-Related Potential (ERP) N1 amplitude to stimuli applied to the surrounding unconditioned skin in healthy volunteers. The aim of the present study was to investigate whether this enhanced ERP N1 amplitude could be a potential marker for altered cortical sensory processing in patients with persistent pain after surgery.
Materials and Methods
Nineteen male patients; 9 with and 10 without persistent pain after inguinal hernia repair received HFS. Before, directly after and thirty minutes after HFS evoked potentials and the subjective pain intensity were measured in response to electric pain stimuli applied to the surrounding unconditioned skin.
Results
The results show that, thirty minutes after HFS, the ERP N1 amplitude observed at the conditioned arm was statistically significantly larger than the amplitude at the control arm across all patients. No statistically significant differences were observed regarding ERP N1 amplitude between patients with and without persistent pain. However, thirty minutes after HFS we did observe statistically significant differences of P2 amplitude at the conditioned arm between the two groups. The P2 amplitude decreased in comparison to baseline in the group of patients with pain.
Conclusion
The ERP N1 effect, induced after HFS, was not different between patients with vs. without persistent pain. The decreasing P2 amplitude was not observed in the patients without pain and also not in the previous healthy volunteer study and thus might be a marker for altered cortical sensory processing in patients with persistent pain after surgery.
doi:10.1371/journal.pone.0082701
PMCID: PMC3871559  PMID: 24376568
2.  Altered resting state EEG in chronic pancreatitis patients: toward a marker for chronic pain 
Journal of Pain Research  2013;6:815-824.
Objectives
Electroencephalography (EEG) may be a promising source of physiological biomarkers accompanying chronic pain. Several studies in patients with chronic neuropathic pain have reported alterations in central pain processing, manifested as slowed EEG rhythmicity and increased EEG power in the brain’s resting state. We aimed to investigate novel potential markers of chronic pain in the resting state EEG of patients with chronic pancreatitis.
Participants
Resting state EEG data from 16 patients with persistent abdominal pain due to chronic pancreatitis (CP) were compared to data from healthy controls matched for age, sex and education.
Methods
The peak alpha frequency (PAF) and power amplitude in the alpha band (7.5–13 Hz) were compared between groups in four regions of interest (frontal, central, parietal, and occipital) and were correlated with pain duration.
Results
The average PAF was lowered in CP patients compared with that in healthy controls, observed as a statistically significant between-group effect (mean 9.9 versus 9.5 Hz; P=0.049). Exploratory post hoc analysis of average PAF per region of interest revealed a significant difference, particularly in the parietal and occipital regions. In addition, we observed a significant correlation between pain duration and PAF and showed increased shifts in PAF with longer pain durations. No significant group differences were found in peak power amplitudes.
Conclusion
CP pain is associated with alterations in spontaneous brain activity, observed as a shift toward lower PAF. This shift correlates with the duration of pain, which demonstrates that PAF has the potential to be a clinically feasible biomarker for chronic pain. These findings could be helpful for assisting diagnosis, establishing optimal treatment, and studying efficacy of new therapeutic agents in chronic pain patients.
doi:10.2147/JPR.S50919
PMCID: PMC3843642  PMID: 24379694
chronic pain; neuropathic pain; chronic pancreatitis; electroencephalography; EEG; alpha oscillations; peak frequency
3.  Renoprotective capacities of non-erythropoietic EPO derivative, ARA290, following renal ischemia/reperfusion injury 
Background
ARA290 is a non-erythropoietic EPO derivative which only binds to the cytoprotective receptor complex (EPOR2-βcR2) consisting of two EPO-receptors (EPOR) and two β common receptors (βcR). ARA290 is renoprotective in renal ischemia/reperfusion (I/R). In a renal I/R model we focussed on timing of post-reperfusional administration of ARA290. Furthermore, we investigated the anti-inflammatory properties of ARA290.
Methods
Twenty-six male Lewis/HanHsd rats were exposed to unilateral ischemia for 30 minutes, with subsequent removal of the contralateral kidney. Post-reperfusion, ARA290 was administered early (one hour), late (four hours) or repetitive (one and four hours). Saline was used as vehicle treatment. Rats were sacrificed after three days.
Results
Early ARA290 treatment improved renal function. Late- or repetitive treatment tended to improve clinical markers. Furthermore, early ARA290 treatment reduced renal inflammation and acute kidney injury at three days post-reperfusion. Late- or repetitive treatment did not affect inflammation or acute kidney injury.
Conclusions
ARA290 attenuated renal ischemia/reperfusion injury. This study showed the anti-inflammatory effect of ARA290 and suggests early administration in the post-reperfusional phase is most effective. ARA290 is a candidate drug for protection against ischemic injury following renal transplantation.
doi:10.1186/1479-5876-11-286
PMCID: PMC3842642  PMID: 24225194
Erythropoietin; Renoprotection; ARA290; Pyroglutamate helix B-surface peptide; Ischemia/reperfusion injury; Renal transplantation
4.  Early surgery versus optimal current step-up practice for chronic pancreatitis (ESCAPE): design and rationale of a randomized trial 
BMC Gastroenterology  2013;13:49.
Background
In current practice, patients with chronic pancreatitis undergo surgical intervention in a late stage of the disease, when conservative treatment and endoscopic interventions have failed. Recent evidence suggests that surgical intervention early on in the disease benefits patients in terms of better pain control and preservation of pancreatic function. Therefore, we designed a randomized controlled trial to evaluate the benefits, risks and costs of early surgical intervention compared to the current stepwise practice for chronic pancreatitis.
Methods/design
The ESCAPE trial is a randomized controlled, parallel, superiority multicenter trial. Patients with chronic pancreatitis, a dilated pancreatic duct (≥ 5 mm) and moderate pain and/or frequent flare-ups will be registered and followed monthly as potential candidates for the trial. When a registered patient meets the randomization criteria (i.e. need for opioid analgesics) the patient will be randomized to either early surgical intervention (group A) or optimal current step-up practice (group B). An expert panel of chronic pancreatitis specialists will oversee the assessment of eligibility and ensure that allocation to either treatment arm is possible. Patients in group A will undergo pancreaticojejunostomy or a Frey-procedure in case of an enlarged pancreatic head (≥ 4 cm). Patients in group B will undergo a step-up practice of optimal medical treatment, if needed followed by endoscopic interventions, and if needed followed by surgery, according to predefined criteria. Primary outcome is pain assessed with the Izbicki pain score during a follow-up of 18 months. Secondary outcomes include complications, mortality, total direct and indirect costs, quality of life, pancreatic insufficiency, alternative pain scales, length of hospital admission, number of interventions and pancreatitis flare-ups. For the sample size calculation we defined a minimal clinically relevant difference in the primary endpoint as a difference of at least 15 points on the Izbicki pain score during follow-up. To detect this difference a total of 88 patients will be randomized (alpha 0.05, power 90%, drop-out 10%).
Discussion
The ESCAPE trial will investigate whether early surgery in chronic pancreatitis is beneficial in terms of pain relief, pancreatic function and quality of life, compared with current step-up practice.
Trial registration
ISRCTN: ISRCTN45877994
doi:10.1186/1471-230X-13-49
PMCID: PMC3610165  PMID: 23506415
Chronic pancreatitis; Pain; Surgical management; Surgery; Endoscopic treatment; Endoscopy; ERCP; Opioid; Pancreaticojejunostomy; Frey procedure
5.  Quantitative Sensory Testing Predicts Pregabalin Efficacy in Painful Chronic Pancreatitis 
PLoS ONE  2013;8(3):e57963.
Background
A major problem in pain medicine is the lack of knowledge about which treatment suits a specific patient. We tested the ability of quantitative sensory testing to predict the analgesic effect of pregabalin and placebo in patients with chronic pancreatitis.
Methods
Sixty-four patients with painful chronic pancreatitis received pregabalin (150–300 mg BID) or matching placebo for three consecutive weeks. Analgesic effect was documented in a pain diary based on a visual analogue scale. Responders were defined as patients with a reduction in clinical pain score of 30% or more after three weeks of study treatment compared to baseline recordings. Prior to study medication, pain thresholds to electric skin and pressure stimulation were measured in dermatomes T10 (pancreatic area) and C5 (control area). To eliminate inter-subject differences in absolute pain thresholds an index of sensitivity between stimulation areas was determined (ratio of pain detection thresholds in pancreatic versus control area, ePDT ratio). Pain modulation was recorded by a conditioned pain modulation paradigm. A support vector machine was used to screen sensory parameters for their predictive power of pregabalin efficacy.
Results
The pregabalin responders group was hypersensitive to electric tetanic stimulation of the pancreatic area (ePDT ratio 1.2 (0.9–1.3)) compared to non-responders group (ePDT ratio: 1.6 (1.5–2.0)) (P = 0.001). The electrical pain detection ratio was predictive for pregabalin effect with a classification accuracy of 83.9% (P = 0.007). The corresponding sensitivity was 87.5% and specificity was 80.0%. No other parameters were predictive of pregabalin or placebo efficacy.
Conclusions
The present study provides first evidence that quantitative sensory testing predicts the analgesic effect of pregabalin in patients with painful chronic pancreatitis. The method can be used to tailor pain medication based on patient’s individual sensory profile and thus comprises a significant step towards personalized pain medicine.
doi:10.1371/journal.pone.0057963
PMCID: PMC3585877  PMID: 23469256
6.  Is Altered Central Pain Processing Related to Disease Stage in Chronic Pancreatitis Patients with Pain? An Exploratory Study 
PLoS ONE  2013;8(2):e55460.
Background
The most dominant feature in chronic pancreatitis is intense abdominal pain. Changes in spinal and/or supraspinal central nervous system pain processing due to visceral nociceptive input play an important role in this pain. How altered pain processing is related to disease stage still needs study.
Methodology/Principal Findings
Sixty chronic pancreatitis patients were compared to 15 healthy controls. Two subgroups of pancreatitis patients were defined based on the M-ANNHEIM severity index of chronic pancreatitis; i.e. moderate and severe. Pain detection and tolerance thresholds for pressure and electric stimuli were measured in six selected dermatomes (C5, T4, T10, L1, L4 and T10BACK). In addition, the conditioned pain modulation response to cold pressor task was determined. These measures were compared between the healthy controls and chronic pancreatitis patients. Severe pancreatitis patients showed lower pain thresholds than moderate pancreatitis patients or healthy volunteers. Healthy controls showed a significantly larger conditioned pain modulation response compared to all chronic pancreatitis patients taken together.
Conclusions/Significance
The present study confirms that chronic pancreatitis patients show signs of altered central processing of nociception compared to healthy controls. The study further suggests that these changes, i.e. central sensitization, may be influenced by disease stage. These findings underline the need to take altered central pain processing into account when managing the pain of chronic pancreatitis.
doi:10.1371/journal.pone.0055460
PMCID: PMC3566206  PMID: 23405154
7.  ARA290, a non-erythropoietic EPO derivative, attenuates renal ischemia/reperfusion injury 
Background
In contrast with various pre-clinical studies, recent clinical trials suggest that high dose erythropoietin (EPO) treatment following kidney transplantation does not improve short-term outcome and that it even increases the risk of thrombotic events. ARA290 is a non-erythropoietic EPO derivative and does not increase the risk of cardiovascular events, but potentially has cytoprotective capacities in prevention of renal ischemia/reperfusion injury.
Methods
Eight female Dutch Landrace pigs were exposed to unilateral renal ischemia for 45 minutes with simultaneous cannulation of the ureter of the ischemic kidney. ARA290 or saline was administered by an intravenous injection at 0, 2, 4 and 6 hours post-reperfusion. The animals were sacrificed seven days post-reperfusion.
Results
ARA290 increased glomerular filtration rate during the observation period of seven days. Furthermore, ARA290 tended to reduce MCP-1 and IL-6 expression 15 minutes post-reperfusion. Seven days post-reperfusion ARA290 reduced interstitial fibrosis.
Conclusions
The improvement in renal function following renal ischemia/reperfusion and reduced structural damage observed in this study by ARA290 warrants further investigation towards clinical application.
doi:10.1186/1479-5876-11-9
PMCID: PMC3567997  PMID: 23302512
ARA290; Pyroglutamate helix B-surface peptide; Erythropoietin; Ischemia/reperfusion injury; Kidney transplantation
8.  Complicated intra-abdominal infections in Europe: a comprehensive review of the CIAO study 
Sartelli, Massimo | Catena, Fausto | Ansaloni, Luca | Leppaniemi, Ari | Taviloglu, Korhan | van Goor, Harry | Viale, Pierluigi | Lazzareschi, Daniel Vasco | Coccolini, Federico | Corbella, Davide | de Werra, Carlo | Marrelli, Daniele | Colizza, Sergio | Scibè, Rodolfo | Alis, Halil | Torer, Nurkan | Navarro, Salvador | Sakakushev, Boris | Massalou, Damien | Augustin, Goran | Catani, Marco | Kauhanen, Saila | Pletinckx, Pieter | Kenig, Jakub | Di Saverio, Salomone | Jovine, Elio | Guercioni, Gianluca | Skrovina, Matej | Diaz-Nieto, Rafael | Ferrero, Alessandro | Rausei, Stefano | Laine, Samipetteri | Major, Piotr | Angst, Eliane | Pittet, Olivier | Herych, Ihor | Agresta, Ferdinando | Vettoretto, Nereo | Poiasina, Elia | Tepp, Jaan | Weiss, Gunter | Vasquez, Giorgio | Vladov, Nikola | Tranà, Cristian | Delibegovic, Samir | Dziki, Adam | Giraudo, Giorgio | Pereira, Jorge | Tzerbinis, Helen | van Dellen, David | Hutan, Martin | Vereczkei, Andras | Krasniqi, Avdyl | Seretis, Charalampos | Mesina, Cristian | Rems, Miran | Campanile, Fabio Cesare | Coletta, Pietro | Uotila-Nieminen, Mirjami | Dente, Mario | Bouliaris, Konstantinos | Lasithiotakis, Konstantinos | Khokha, Vladimir | Zivanovic, Dragoljub | Smirnov, Dmitry | Marinis, Athanasios | Negoi, Ionut | Ney, Ludwig | Bini, Roberto | Leon, Miguel | Aloia, Sergio | Huchon, Cyrille | Moldovanu, Radu | de Melo, Renato Bessa | Giakoustidis, Dimitrios | Ioannidis, Orestis | Cucchi, Michele | Pintar, Tadeja | Krivokapic, Zoran | Petrovic, Jelena
The CIAO Study (“Complicated Intra-Abdominal infection Observational” Study) is a multicenter investigation performed in 68 medical institutions throughout Europe over the course of a 6-month observational period (January-June 2012).
Patients with either community-acquired or healthcare-associated complicated intra-abdominal infections (IAIs) were included in the study.
2,152 patients with a mean age of 53.8 years (range: 4–98 years) were enrolled in the study. 46.3% of the patients were women and 53.7% were men. Intraperitoneal specimens were collected from 62.2% of the enrolled patients, and from these samples, a variety of microorganisms were collectively identified.
The overall mortality rate was 7.5% (163/2.152).
According to multivariate analysis of the compiled data, several criteria were found to be independent variables predictive of patient mortality, including patient age, the presence of an intestinal non-appendicular source of infection (colonic non-diverticular perforation, complicated diverticulitis, small bowel perforation), a delayed initial intervention (a delay exceeding 24 hours), sepsis and septic shock in the immediate post-operative period, and ICU admission.
Given the sweeping geographical distribution of the participating medical centers, the CIAO Study gives an accurate description of the epidemiological, clinical, microbiological, and treatment profiles of complicated intra-abdominal infections (IAIs) throughout Europe.
doi:10.1186/1749-7922-7-36
PMCID: PMC3539964  PMID: 23190741
9.  Effects of Pregabalin on Central Sensitization in Patients with Chronic Pancreatitis in a Randomized, Controlled Trial 
PLoS ONE  2012;7(8):e42096.
Background
Intense abdominal pain is the dominant feature of chronic pancreatitis. During the disease changes in central pain processing, e.g. central sensitization manifest as spreading hyperalgesia, can result from ongoing nociceptive input. The aim of the present study is to evaluate the effect of pregabalin on pain processing in chronic pancreatitis as assessed by quantitative sensory testing (QST).
Methods
This randomized, double-blind, placebo-controlled trial evaluated effects of pregabalin on pain processing. QST was used to quantify pain processing by measuring thresholds to painful electrical and pressure stimulation in six body dermatomes. Descending endogenous pain modulation was quantified using the conditioned pain modulation (CPM) paradigm to elicit a DNIC (diffuse noxious inhibitory controls) response. The main effect parameter was the change in the sum of all body pain threshold values after three weeks of study treatment versus baseline values between both treatment groups.
Results
64 patients were analyzed. No differences in change in sum of pain thresholds were present for pregabalin vs. placebo after three weeks of treatment. For individual dermatomes, change vs. baseline pain thresholds was significantly greater in pregabalin vs. placebo patients for electric pain detection threshold in C5 (P = 0.005), electric pain tolerance threshold in C5 (P = 0.04) and L1 (P = 0.05), and pressure pain tolerance threshold in T4 (P = 0.004). No differences were observed between pregabalin and placebo regarding conditioned pain modulation.
Conclusion
Our study provides first evidence that pregabalin has moderate inhibitory effects on central sensitization manifest as spreading hyperalgesia in chronic pancreatitis patients. These findings suggest that QST can be of clinical use for monitoring pain treatments in the context of chronic pain.
Trial Registration
ClinicalTrials.gov NCT00755573
doi:10.1371/journal.pone.0042096
PMCID: PMC3412837  PMID: 22879908
10.  Patients with persistent pain after breast cancer surgery show both delayed and enhanced cortical stimulus processing 
Journal of Pain Research  2012;5:139-150.
Background
Women who undergo breast cancer surgery have a high risk of developing persistent pain. We investigated brain processing of painful stimuli using electroencephalograms (EEG) to identify event-related potentials (ERPs) in patients with persistent pain after breast cancer treatment.
Methods
Nineteen patients (eight women with persistent pain, eleven without persistent pain), who were surgically treated more than 1 year previously for breast cancer (mastectomy, lumpectomy, and axillary lymph node dissection) and/or had chemoradiotherapy, were recruited and compared with eleven healthy female volunteers. A block of 20 painful electrical stimuli was applied to the calf, somatopically remote from the initially injured or painful area. Simultaneously an EEG was recorded, and a visual analog scale (VAS) pain rating obtained.
Results
In comparison with healthy volunteers, breast cancer treatment without persistent pain is associated with accelerated stimulus processing (reduced P260 latency) and shows a tendency to be less intense (lower P260 amplitude). In comparison to patients without persistent pain, persistent pain after breast cancer treatment is associated with stimulus processing that is both delayed (ie, increased latency of the ERP positivity between 250–310 ms [P260]), and enhanced (ie, enhanced P260 amplitude).
Conclusion
These results show that treatment and persistent pain have opposite effects on cortical responsiveness.
doi:10.2147/JPR.S30487
PMCID: PMC3392843  PMID: 22792001
breast cancer surgery; persistent pain; nerve injury; event-related potentials; pain processing
11.  Rat Ace allele variation determines susceptibility to AngII induced renal damage 
INTRODUCTION
Ace b/l polymorphism in rat is associated to differential tissue ACE expression and activity, and susceptibility to renal damage. Same polymorphism was recently found in outbred Wistar rat strain with b allele accounting for higher renal ACE, and provided a model for studying RAAS response behind the innate high or low ACE conditions.
METHODS
We investigated the reaction of these alleles on chronic Angiotensin II (AngII) infusion. Wistar rats were selected to breed male homozygotes for the b (WU-B) or l allele (WU-L) (n=12). For each allele, one group (n=6) received AngII infusion via osmotic minipump (435 ng/kg/min) for three weeks. Other group (n=6) served as control.
RESULTS
WU-B had higher ACE activity at baseline then WU-L. Interestingly, baseline renal ACE2 expression and activity were higher in WU-L. AngII infusion induced same increase in blood pressure in both genotypes, no proteinuria, but caused tubulo-interstitial renal damage with increased α-SMA and monocyte/macrophage influx only in WU-B (p<0.05). Low ACE WU-L rats did not develop renal damage.
CONCLUSION
AngII infusion causes proteinuria independent renal damage only in rats with genetically predetermined high ACE while rats with low ACE seemed to be protected against the detrimental effect of AngII. Differences in renal ACE2, mirroring those in ACE, might be involved.
doi:10.1177/1470320311415886
PMCID: PMC3356861  PMID: 21788250
ACE; ACE2; WU-L and WU-B; Angiotensin II induced renal injury
12.  Complicated intra-abdominal infections in Europe: preliminary data from the first three months of the CIAO Study 
Sartelli, Massimo | Catena, Fausto | Ansaloni, Luca | Leppaniemi, Ari | Taviloglu, Korhan | van Goor, Harry | Viale, Pierluigi | Lazzareschi, Daniel Vasco | de Werra, Carlo | Marrelli, Daniele | Colizza, Sergio | Scibé, Rodolfo | Alis, Halil | Torer, Nurkan | Navarro, Salvador | Catani, Marco | Kauhanen, Saila | Augustin, Goran | Sakakushev, Boris | Massalou, Damien | Pletinckx, Pieter | Kenig, Jakub | Di Saverio, Salomone | Guercioni, Gianluca | Rausei, Stefano | Laine, Samipetteri | Major, Piotr | Skrovina, Matej | Angst, Eliane | Pittet, Olivier | Gerych, Ihor | Tepp, Jaan | Weiss, Guenter | Vasquez, Giorgio | Vladov, Nikola | Tranà, Cristian | Vettoretto, Nereo | Delibegovic, Samir | Dziki, Adam | Giraudo, Giorgio | Pereira, Jorge | Poiasina, Elia | Tzerbinis, Helen | Hutan, Martin | Vereczkei, Andras | Krasniqi, Avdyl | Seretis, Charalampos | Diaz-Nieto, Rafael | Mesina, Cristian | Rems, Miran | Campanile, Fabio Cesare | Agresta, Ferdinando | Coletta, Pietro | Uotila-Nieminen, Mirjami | Dente, Mario | Bouliaris, Konstantinos | Lasithiotakis, Konstantinos | Khokha, Vladimir | Zivanović, Dragoljub | Smirnov, Dmitry | Marinis, Athanasios | Negoi, Ionut | Ney, Ludwig | Bini, Roberto | Leon, Miguel | Aloia, Sergio | Huchon, Cyrille | Moldovanu, Radu | de Melo, Renato Bessa | Giakoustidis, Dimitrios | Ioannidis, Orestis | Cucchi, Michele | Pintar, Tadeja | Jovine, Elio
The CIAO Study is a multicenter observational study currently underway in 66 European medical institutions over the course of a six-month study period (January-June 2012).
This preliminary report overviews the findings of the first half of the study, which includes all data from the first three months of the six-month study period.
Patients with either community-acquired or healthcare-associated complicated intra-abdominal infections (IAIs) were included in the study.
912 patients with a mean age of 54.4 years (range 4–98) were enrolled in the study during the first three-month period. 47.7% of the patients were women and 52.3% were men. Among these patients, 83.3% were affected by community-acquired IAIs while the remaining 16.7% presented with healthcare-associated infections. Intraperitoneal specimens were collected from 64.2% of the enrolled patients, and from these samples, 825 microorganisms were collectively identified.
The overall mortality rate was 6.4% (58/912). According to univariate statistical analysis of the data, critical clinical condition of the patient upon hospital admission (defined by severe sepsis and septic shock) as well as healthcare-associated infections, non-appendicular origin, generalized peritonitis, and serious comorbidities such as malignancy and severe cardiovascular disease were all significant risk factors for patient mortality.
White Blood Cell counts (WBCs) greater than 12,000 or less than 4,000 and core body temperatures exceeding 38°C or less than 36°C by the third post-operative day were statistically significant indicators of patient mortality.
doi:10.1186/1749-7922-7-15
PMCID: PMC3444376  PMID: 22613202
13.  Glomerular and Tubular Damage Markers Are Elevated in Patients With Diabetes 
Diabetes Care  2011;34(4):975-981.
OBJECTIVE
We investigated in a cross-sectional study the levels of serum and urinary damage markers in diabetic patients (n = 94) and nondiabetic control subjects (n = 45) to study the association of glomerular (IgG), proximal tubular (kidney injury molecule [KIM]-1, N-acetyl-β-d-glucosaminidase [NAG], neutrophil gelatinase–associated lipocalin [NGAL], and cystatin C), and distal tubular (heart fatty acid–binding protein [H-FABP]) damage markers with kidney disease severity, as assessed by albuminuria and estimated glomerular filtration rate (eGFR).
RESEARCH DESIGN AND METHODS
Damage markers were measured in triplicate in fresh morning urine samples and in plasma.
RESULTS
Of the diabetic patients, 41 were normoalbuminuric, 41 were microalbuminuric, and 12 were macroalbuminuric. Urinary NAG (ninefold), NGAL (1.5-fold), and H-FABP (3.5-fold) were significantly elevated in normoalbuminuric diabetic patients compared with nondiabetic control subjects. Urinary concentrations of all markers increased per albuminuria stratum, except KIM-1. All urinary damage markers, except KIM-1, were significantly associated with albuminuria, independent of age, sex, and plasma concentrations of the corresponding biomarker (standard βs between 0.35 and 0.87; all P ≤ 0.001). All urinary damage markers, except KIM-1, were significantly associated with the eGFR in univariate models (standard βs between −0.38 and −0.21; all P < 0.04). After adjusting for age, sex, plasma concentration of the corresponding damage marker, and albuminuria, only the association of H-FABP with eGFR remained significant (standard β −0.26; P = 0.037).
CONCLUSIONS
Glomerular and tubular markers are associated with albuminuria, independently of eGFR, suggesting that albuminuria reflects both glomerular and tubulointerstitial damage. Only urinary H-FABP is associated with eGFR independently of albuminuria and, therefore, may be a promising urinary damage marker to assess diabetic kidney disease.
doi:10.2337/dc10-1545
PMCID: PMC3064060  PMID: 21307379
14.  Effect of Renin-Angiotensin-Aldosterone System Inhibition, Dietary Sodium Restriction, and/or Diuretics on Urinary Kidney Injury Molecule 1 Excretion in Nondiabetic Proteinuric Kidney Disease: A Post Hoc Analysis of a Randomized Controlled Trial 
Background
Tubulointerstitial damage plays an important role in chronic kidney disease (CKD) with proteinuria. Urinary kidney injury molecule 1 (KIM-1) reflects tubular KIM-1 and is considered a sensitive biomarker for early tubular damage. We hypothesized that a decrease in proteinuria by using therapeutic interventions is associated with decreased urinary KIM-1 levels.
Study Design
Post hoc analysis of a randomized, double-blind, placebo-controlled, crossover trial.
Setting & Participants
34 proteinuric patients without diabetes from our outpatient renal clinic.
Intervention
Stepwise 6-week interventions of losartan, sodium restriction (low-sodium [LS] diet), their combination, losartan plus hydrochlorothiazide (HCT), and the latter plus an LS diet.
Outcomes & Measurements
Urinary excretion of KIM-1, total protein, and N-acetyl-β-D-glucosaminidase (NAG) as a positive control for tubular injury.
Results
Mean baseline urine protein level was 3.8 ± 0.4 (SE) g/d, and KIM-1 level was 1,706 ± 498 ng/d (increased compared with healthy controls; 74 ng/d). KIM-1 level was decreased by using placebo/LS (1,201 ± 388 ng/d; P = 0.04), losartan/high sodium (1,184 ± 296 ng/d; P = 0.09), losartan/LS (921 ± 176 ng/d; P = 0.008), losartan/high sodium plus HCT (862 ± 151 ng/d; P = 0.008) and losartan/LS plus HCT (743 ± 170 ng/d; P = 0.001). The decrease in urinary KIM-1 levels paralleled the decrease in proteinuria (R = 0.523; P < 0.001), but not blood pressure or creatinine clearance. 16 patients reached target proteinuria with protein less than 1 g/d, whereas KIM-1 levels normalized in only 2 patients. Urinary NAG level was increased at baseline and significantly decreased during the treatment periods of combined losartan plus HCT only. The decrease in urinary NAG levels was not closely related to proteinuria.
Limitations
Post hoc analysis.
Conclusions
Urinary KIM-1 level was increased in patients with nondiabetic CKD with proteinuria and decreased in parallel with proteinuria by using losartan, sodium restriction, their combination, losartan plus HCT, and the latter plus sodium restriction. These results are consistent with the hypothesis of amelioration of proteinuria-induced tubular damage. Long-term studies are warranted to evaluate whether targeting treatment on KIM-1 can improve outcomes in patients with CKD with proteinuria.
doi:10.1053/j.ajkd.2008.07.021
PMCID: PMC3298772  PMID: 18823687
Renin-angiotensin-aldosterone system; losartan; angiotensin II type 1 receptor blockade; proteinuria; interstitial renal damage; kidney injury molecule 1; N-acetyl-β-D-glucosaminidase; tubular damage marker; biomarker
15.  Disparate effects of eplerenone, amlodipine and telmisartan on podocyte injury in aldosterone-infused rats 
Background. Several studies in patients with primary aldosteronism (PA) have suggested that aldosterone (ALD) is directly contributing to albuminuria. However, there are limited data pertaining to the direct role of ALD in in vivo models in regard to the induction of renal injury and the involved mechanisms. In the present study, we established a high-dose ALD-infused rat model to evaluate urinary albumin excretion rate (UAER) and podocyte damage. Moreover, we studied the effect of eplerenone (EPL), telmisartan (TEL) and amlodipine (AML) on ALD-induced renal structural and functional changes.
Methods. Immunohistochemical and real-time PCR analyses, and TUNEL assays were performed to evaluate nephrin expression and podocyte injury.
Results. ALD-receiving rats (ARR) showed a progressive increase in BP, UAER and proteinuria when compared with control rats (CR). Conversely, BP was significantly reduced in ALD + EPL (A/ERR)-, ALD + AML (A/ARR)- and ALD + TEL (A/TRR)-treated rats. However, UAER and proteinuria were decreased only in A/ERR and A/TRR, but not in A/ARR. Only EPL administration provided protection against ALD-induced podocyte apoptosis. Renal tissue of ARR revealed enhanced expression of nephrin protein and mRNA. This effect of ALD was inhibited by EPL, but not by TEL or AML.
Conclusions. ALD induces direct glomerular injury independent of its haemodynamic effects; this effect of ALD is, at least in part, mediated through activation of the mineralocorticoid receptor.
doi:10.1093/ndt/gfq514
PMCID: PMC3108348  PMID: 20729265
aldosterone; amlodipine; eplerenone; podocyte; telmisartan
16.  Complicated Intra-Abdominal Infections Observational European study (CIAO Study) 
Complicated intra-abdominal infections are frequently associated with poor prognoses and high morbidity and mortality rates.
Despite advances in diagnosis, surgery, and antimicrobial therapy, mortality rates associated with complicated intra-abdominal infections remain exceedingly high.
In order to describe the clinical, microbiological, and management-related profiles of both community-acquired and healthcare-acquired complicated intra-abdominal infections (IAIs), the World Society of Emergency Surgery (WSES), in collaboration with the Surgical Infections Society of Europe (SIS-E) and other prominent European surgical societies, has designed the CIAO study.
The CIAO study is a multicenter, observational study and will be carried out in various surgical departments throughout Europe. The study will include patients undergoing surgery or interventional drainage for complicated IAI.
doi:10.1186/1749-7922-6-40
PMCID: PMC3251528  PMID: 22152549
17.  Long-Term Type 1 Diabetes Enhances In-Stent Restenosis after Aortic Stenting in Diabetes-Prone BB Rats 
Type 1 diabetic patients have increased risk of developing in-stent restenosis following endovascular stenting. Underlying pathogenetic mechanisms are not fully understood partly due to the lack of a relevant animal model to study the effect(s) of long-term autoimmune diabetes on development of in-stent restenosis. We here describe the development of in-stent restenosis in long-term (~7 months) spontaneously diabetic and age-matched, thymectomized, nondiabetic Diabetes Prone BioBreeding (BBDP) rats (n = 6-7 in each group). Diabetes was suboptimally treated with insulin and was characterized by significant hyperglycaemia, polyuria, proteinuria, and increased HbA1c levels. Stented abdominal aortas were harvested 28 days after stenting. Computerized morphometric analysis revealed significantly increased neointima formation in long-term diabetic rats compared with nondiabetic controls. In conclusion, long-term autoimmune diabetes in BBDP rats enhances in-stent restenosis. This model can be used to study the underlying pathogenetic mechanisms of diabetes-enhanced in-stent restenosis as well as to test new therapeutic modalities.
doi:10.1155/2011/396734
PMCID: PMC3038840  PMID: 21331346
18.  WSES consensus conference: Guidelines for first-line management of intra-abdominal infections 
Intra-abdominal infections are still associated with high rate of morbidity and mortality.
A multidisciplinary approach to the management of patients with intra-abdominal infections may be an important factor in the quality of care. The presence of a team of health professionals from various disciplines, working in concert, may improve efficiency, outcome, and the cost of care.
A World Society of Emergency Surgery (WSES) Consensus Conference was held in Bologna on July 2010, during the 1st congress of the WSES, involving surgeons, infectious disease specialists, pharmacologists, radiologists and intensivists with the goal of defining recommendations for the early management of intra-abdominal infections.
This document represents the executive summary of the final guidelines approved by the consensus conference.
doi:10.1186/1749-7922-6-2
PMCID: PMC3031281  PMID: 21232143
19.  Heart failure-associated anemia: bone marrow dysfunction and response to erythropoietin 
Heart failure (HF)-associated anemia is common and has a poor outcome. Because bone marrow (BM) dysfunction may contribute to HF-associated anemia, we first investigated mechanisms of BM dysfunction in an established model of HF, the transgenic REN2 rat, which is characterized by severe hypertrophy and ventricular dilatation and SD rats as controls. Secondly, we investigated whether stimulation of hematopoiesis with erythropoietin (EPO) could restore anemia and BM dysfunction. After sacrifice, erythropoietic precursors (BFU-E) were isolated from the BM and cultured for 10 days. BFU-E were quantified and transcript abundance of genes involved in erythropoiesis were assayed. Number of BFU-E were severely decreased in BM of REN2 rats compared to SD rats (50 ± 6.2 vs. 6.4 ± 1.7, p < 0.01). EPO treatment increased hematocrit in the SD-EPO group (after 6 weeks, 49 ± 1 vs. 58 ± 1%, p < 0.01); however, in the mildly anemic REN2 rats, there was no effect (43 ± 1 vs. 44 ± 1%). This was paralleled by a 67% decrease in BFU-E in BM of REN2 rats compared to SD (p < 0.01). EPO significantly improved BFU-E in both SD and REN2 but could not restore this to control levels in the REN2 rats. Expression of several genes involved in differentiation (LMO2), mobilization (SDF-1), and iron incorporation (transferrin receptor) of the BM were differentially expressed in REN2 rats compared to SD rats, and EPO did not normalize this. Altogether, these results suggest that BM dysfunction is an important contributor to HF-associated anemia and that EPO is not an effective agent to treat HF-associated anemia.
Electronic supplementary material
The online version of this article (doi:10.1007/s00109-010-0710-6) contains supplementary material, which is available to authorized users.
doi:10.1007/s00109-010-0710-6
PMCID: PMC3056002  PMID: 21191566
Anemia; Heart failure; Bone marrow dysfunction; REN2; Erythropoietin; Renin; Renin-angiotensin system
20.  Electrocautery causes more ischemic peritoneal tissue damage than ultrasonic dissection 
Surgical Endoscopy  2010;25(6):1827-1834.
Background
Minimizing peritoneal tissue injury during abdominal surgery has the benefit of reducing postoperative inflammatory response, pain, and adhesion formation. Ultrasonic dissection seems to reduce tissue damage. This study aimed to compare electrocautery and ultrasonic dissection in terms of peritoneal tissue ischemia measured by microdialysis.
Methods
In this study, 18 Wistar rats underwent a median laparotomy and had a peritoneal microdialysis catheter implanted in the left lateral sidewall. The animals were randomly assigned to receive two standard peritoneal incisions parallel to the catheter by either ultrasonic dissection or electrocautery. After the operation, samples of microdialysis dialysate were taken every 2 h until 72 h postoperatively for measurements of pyruvate, lactate, glucose, and glycerol, and ratios were calculated.
Results
The mean lactate–pyruvate ratio (LPR), lactate–glucose ratio (LGR), and glycerol concentration were significantly higher in the electrocautery group than in the ultrasonic dissection group until respectively 34, 48, and 48 h after surgery. The mean areas under the curve (AUC) of LPR, LGR, and glycerol concentration also were higher in the electrocautery group than in the ultrasonic dissection group (4,387 vs. 1,639, P = 0.011; 59 vs. 21, P = 0.008; 7,438 vs. 4,169, P = 0.008, respectively).
Conclusion
Electrosurgery causes more ischemic peritoneal tissue damage than ultrasonic dissection.
doi:10.1007/s00464-010-1474-3
PMCID: PMC3109994  PMID: 21140171
Adhesions; Electrocautery; Ischemia; Microdialysis; Ultrasonic dissection
21.  Adhesion Awareness: A National Survey of Surgeons 
World Journal of Surgery  2010;34(12):2805-2812.
Background
Postoperative adhesions are the most frequent complication of abdominal surgery, leading to high morbidity, mortality, and costs. However, the problem seems to be neglected by surgeons for largely unknown reasons.
Methods
A survey assessing knowledge and personal opinion about the extent and impact of adhesions was sent to all Dutch surgeons and surgical trainees. The informed-consent process and application of antiadhesive agents were questioned in addition.
Results
The response rate was 34.4%. Two thirds of all respondents (67.7%) agreed that adhesions exert a clinically relevant, negative effect. A negative perception of adhesions correlated with a positive attitude regarding adhesion prevention (ρ = 0.182, p < 0.001). However, underestimation of the extent and impact of adhesions resulted in low knowledge scores (mean test score 37.6%). Lower scores correlated with more uncertainty about indications for antiadhesive agents which, in turn, correlated with never having used any of these agents (ρ = 0.140, p = 0.002; ρ = 0.095, p = 0.035; respectively). Four in 10 respondents (40.9%) indicated that they never inform patients on adhesions and only 9.8% informed patients routinely. A majority of surgeons (55.9%) used antiadhesive agents in the past, but only a minority (13.4%) did in the previous year. Of trainees, 82.1% foresaw an increase in the use of antiadhesive agents compared to 64.5% of surgeons (p < 0.001).
Conclusions
The magnitude of the problem of postoperative adhesions is underestimated and informed consent is provided inadequately by Dutch surgeons. Exerting adhesion prevention is related to the perception of and knowledge about adhesions.
doi:10.1007/s00268-010-0778-8
PMCID: PMC2982960  PMID: 20814678
22.  Intra-arterial tert-Butyl-Hydroperoxide Infusion Induces an Exacerbated Sensory Response in the Rat Hind Limb and is Associated with an Impaired Tissue Oxygen Uptake 
Inflammation  2010;34(1):49-57.
The objective of this study was to investigate oxidative stress and oxygen extraction mechanisms in an animal model of continuous intra-arterial infusion of a free radical donor and in an in vitro model using isolated mitochondria. tert-Butyl-hydroperoxide (tert-BuOOH, 25 mM) was infused for 24 h in the left hind limb of rats to induce soft tissue damage (n = 8). After 7 days, we assessed local sensory response, tissue oxygen consumption, oxygen radicals, and antioxidant levels. In vitro mitochondrial function was measured after stimulation of isolated mitochondria of skeletal muscle cells with increasing doses of tert-BuOOH. tert-BuOOH infusion resulted in an increased skin temperature (p = 0.04), impaired function, and a significantly increased pain sensation (p = 0.03). Venous oxygen saturation levels (p = 0.01) and the antioxidant ceruloplasmin (p = 0.04) were increased. tert-BuOOH inhibited mitochondrial function in vitro. Induction of free radical formation in the rat hind limb results in an exacerbated sensory response and is associated with impaired oxygen extraction, which likely results from mitochondrial dysfunction caused by free radicals.
doi:10.1007/s10753-010-9207-2
PMCID: PMC3021700  PMID: 20386971
rat model; oxygen radicals; oxygen extraction; mitochondrial dysfunction; complex regional pain syndrome
23.  Differential Expression of Proteoglycans in Tissue Remodeling and Lymphangiogenesis after Experimental Renal Transplantation in Rats 
PLoS ONE  2010;5(2):e9095.
Background
Chronic transplant dysfunction explains the majority of late renal allograft loss and is accompanied by extensive tissue remodeling leading to transplant vasculopathy, glomerulosclerosis and interstitial fibrosis. Matrix proteoglycans mediate cell-cell and cell-matrix interactions and play key roles in tissue remodeling. The aim of this study was to characterize differential heparan sulfate proteoglycan and chondroitin sulfate proteoglycan expression in transplant vasculopathy, glomerulosclerosis and interstitial fibrosis in renal allografts with chronic transplant dysfunction.
Methods
Renal allografts were transplanted in the Dark Agouti-to-Wistar Furth rat strain combination. Dark Agouti-to-Dark Agouti isografts and non-transplanted Dark Agouti kidneys served as controls. Allograft and isograft recipients were sacrificed 66 and 81 days (mean) after transplantation, respectively. Heparan sulfate proteoglycan (collXVIII, perlecan and agrin) and chondroitin sulfate proteoglycan (versican) expression, as well as CD31 and LYVE-1 (vascular and lymphatic endothelium, respectively) expression were (semi-) quantitatively analyzed using immunofluorescence.
Findings
Arteries with transplant vasculopathy and sclerotic glomeruli in allografts displayed pronounced neo-expression of collXVIII and perlecan. In contrast, in interstitial fibrosis expression of the chondroitin sulfate proteoglycan versican dominated. In the cortical tubular basement membranes in both iso- and allografts, induction of collXVIII was detected. Allografts presented extensive lymphangiogenesis (p<0.01 compared to isografts and non-transplanted controls), which was associated with induced perlecan expression underneath the lymphatic endothelium (p<0.05 and p<0.01 compared to isografts and non-transplanted controls, respectively). Both the magnitude of lymphangiogenesis and perlecan expression correlated with severity of interstitial fibrosis and impaired graft function.
Interpretation
Our results reveal that changes in the extent of expression and the type of proteoglycans being expressed are tightly associated with tissue remodeling after renal transplantation. Therefore, proteoglycans might be potential targets for clinical intervention in renal chronic transplant dysfunction.
doi:10.1371/journal.pone.0009095
PMCID: PMC2816722  PMID: 20140097
24.  High Urinary Excretion of Kidney Injury Molecule-1 Is an Independent Predictor of Graft Loss in Renal Transplant Recipients 
Transplantation  2007;84(12):1625-1630.
Background
Chronic transplant dysfunction is characterized by renal function decline and proteinuria. Kidney injury molecule (KIM)-1, a transmembrane tubular protein with unknown function, is undetectable in normal kidneys, but markedly induced after injury. Urinary KIM-1 excretion has been quantified as biomarker of renal damage. We prospectively studied whether urinary KIM-1 predicts graft loss, independent of renal function and proteinuria.
Methods
Renal transplant recipients (n=145) visiting our outpatient clinic between August 2001 and July 2003 collected 24-hour urine samples for assessment of baseline urinary KIM-1 excretion (microsphere-based Luminex technology), and were followed for graft loss.
Results
Recipients participated at a median (interquartile range) of 6.0 (2.5–12.0) years posttransplant in baseline measurements. Follow-up beyond baseline was 4.0 (3.2–4.5) years. Urinary KIM-1 excretion was 0.72 (0.42–1.37) ng per 24 hours. Occurrence of graft loss increased over tertiles of KIM-1 excretion: 3 (6.3%), 11 (22.4%), and 17 cases (35.4%; P=0.001), respectively. High KIM-1 excretion was associated with proteinuria, low creatinine clearance, and high donor age (all P<0.01). In multivariate Cox regression analyses, prediction of graft loss by KIM-1 appeared independent of creatinine clearance, proteinuria, and donorage. Hazard ratios (95% CI) for the second and third tertile of KIM-1 excretion were 3.6 (0.9–13.5) and 5.1 (1.5–17.8) in the final model.
Conclusions
Urinary excretion of KIM-1 is an independent predictor of long-term graft loss and therefore a promising new biomarker in early prediction of graft loss.
doi:10.1097/01.tp.0000295982.78039.ef
PMCID: PMC2745062  PMID: 18165774
Chronic transplant dysfunction; Renal transplantation; Kidney injury molecule-1; Biomarker
25.  Aldosterone Induces Apoptosis in Rat Podocytes: Role of PI3-K/Akt and p38MAPK Signaling Pathways 
Nephron. Experimental nephrology  2009;113(1):e26-e34.
Background
Podocytes play a critical role in the pathogenesis of glomerulosclerosis. Increasing evidence suggests that aldosterone (ALD) is involved in the initiation and progression of glomerular damage. It is, however, unknown whether there is a direct injurious effect of ALD on podocytes. Therefore, in the present study, we evaluated the effect of ALD on podocyte apoptosis and studied the role of phosphatidylinositol 3-kinase/Akt (PI3-K/Akt) and p38 mitogen-activated protein kinase (p38MAPK) signaling pathways in this process.
Methods
Podocytes were incubated in media containing either buffer or increasing concentrations of ALD (10–9∼10–5M) for variable time periods. The cells were also treated with either wortmannin (inhibitor of PI3-K, 100 nM), SB202190 (SB20, inhibitor of p38MAPK, 10 μM) or buffer. All treatments were performed with or without ALD (10–7M) for 24 h. At the end of the incubation period, apoptosis was evaluated by cell nucleus staining and flow cytometric analyses. Activation of PI3-K/Akt and p38MAPK phosphorylation of cultured rat podocytes was evaluated by performing Akt kinase assay and Western blot, respectively.
Results
Apoptosis of cultured rat podocytes was induced by ALD in a dose- and time-dependent manner. ALD inhibited the activity of PI3-K/Akt and increased the activation of p38MAPK. PI3-K/Akt activity was further inhibited by the addition of wortmannin to the cells in the presence of ALD. This was accompanied by a significant increase in apoptosis. ALD-induced p38MAPK phosphorylation and apoptosis were inhibited when the cells were pretreated with SB20. Furthermore, treatment with spironolactone not only attenuated the proapoptotic effect of ALD, but also significantly reversed its effects on PI3-K/Akt and p38MAPK signaling pathways.
Conclusion
ALD induces apoptosis in rat podocytes through inhibition of PI3-K/Akt and stimulation of p38 MAPK signaling pathways. Spironolactone attenuates ALD-induced podocyte apoptosis, thereby positioning this compound as a potential promising target of intervention in human renal damage.
doi:10.1159/000228080
PMCID: PMC2790761  PMID: 19590239
Aldosterone; Podocyte; Phosphatidylinositol 3-kinase/Akt; p38 mitogen-activated protein kinase; Apoptosis

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