[Vascular Prosthesis Perforation Caused by a Stent Graft Inserted into the Innominate Artery after Total Aortic Arch Replacement].

The patient was a 60-year-old woman who underwent thoracoabdominal aorta replacement for type B aortic dissection three years ago and aortic root replacement and total aortic arch replacement due to asymptomatic type A aortic dissection two years previously. Her clinical course was uneventful until follow-up computed tomography (CT) disclosed anastomotic insufficiency in the innominate artery and left main coronary artery stenosis owing to hematoma. Emergent percutaneous coronary intervention and stent graft insertion into the innominate artery were performed successfully. Seven months later, however, CT scan revealed a perforation in the posterior wall of the artificial graft damaged by the edge of the implanted stent graft. The patient underwent open surgery and perforation of artificial graft was sutured and redundant stent graft edge was resected. Artificial graft damage by stent graft placement is rare to date, but may increase in the future in accordance with broader application of endovascular treatment.

[Recurrent High-grade Astroblastoma Treated with Stereotactic Radiotherapy:A Case Report].

INTRODUCTION: Astroblastoma is a rare, supratentorial glial tumor, occurring predominantly in children and young adults. However, treatment strategies have not yet been established for this rare disease. CASE PRESENTATION: A 6-year-old boy presented with headache and nausea. CT and MRI revealed a left frontal mass lesion with slight edema and macrocalcifications. Gross tumor resection was performed. Histological examination found neoplastic cells with astroblastic characteristics, and a striking perivascular array of pseudorosettes. The final diagnosis was high-grade astroblastoma. MRI 13 months after surgery suggested local recurrence, and an enlargement was found 3 months later. Stereotactic radiotherapy(SRT)was performed. MRI after SRT showed enhanced cyst formation around the tumor bed, suggesting tumor recurrence. However, 11C-methionine positron emission tomography(PET)revealed radiation necrosis. The last follow-up MRI 15 months after SRT showed no further recurrence. CONCLUSION: Astroblastoma is rare, therefore, no optimal management is known. SRT may be effective to treat recurrent astroblastomas. 11C-methionine PET/CT was useful to differentiate metastatic disease from radiation necrosis.

[Preliminary Experience of a Biplane Flat Panel and Tailor-made Operating Table-equipped Hybrid Operating Room].

A hybrid operating room(Hybrid OR), where operative equipment and flat panel angiography are both available, is becoming common for complex cerebrovascular surgery. However, the current Hybrid OR remains suboptimal as it is not cost-effective and contains uncomfortable operating beds, and a single-plane flat panel. Therefore, we introduced a novel Hybrid OR system, which has a biplane flat panel detector and three mutually exchangeable tailor-made operating beds. In this article, we report our preliminary experience of this novel Hybrid OR, focusing on improved cost-effectiveness by the availability of diagnostic angiography and standard endovascular surgery, optimal selection of three different types of operating beds, and procedural workflow in individual hybrid cerebrovascular surgery.

[Failed Surgical Clipping of a Posterior Communicating Artery Aneurysm with Oculomotor Nerve Palsy due to Ventricular Tachycardia:Validity of Endovascular Coiling in the Hybrid Operating Room].

Unruptured posterior communicating artery aneurysms with oculomotor nerve palsy are at high risk of rupture, and early intervention is recommended to prevent aneurysm bleeding and to improve oculomotor function. Both surgical clipping and endovascular coiling are available, and either of them is applied according to the anatomical condition and patient's comorbidity. In this article, we describe a case of an unruptured posterior communicating artery aneurysm with oculomotor nerve palsy, which was initially treated with surgical clipping. Owing to ventricular tachycardia during surgery, the craniotomy was discontinued and switched to endovascular coiling. In this operation, use of a hybrid operating room for coiling enabled adequate heparinization and immediate recraniotomy to prevent ischemic and hemorrhagic complications, respectively.

Abnormal distribution of GABAA receptors in brain of duchenne muscular dystrophy patients.

INTRODUCTION: In this study we sought to: (1) determine the distribution of GABAA receptors (GABAA -Rs) in the brain of Duchenne muscular dystrophy (DMD) patients; and (2) ascertain if the distribution pattern correlates with cognitive dysfunction. METHODS: Fourteen DMD patients [young adult (n = 7, 18-25 years old) and older adult (n = 7, 30-37 years old) groups] and 16 age-matched normal volunteers participated. GABAA -R distribution was assessed using 123 I-IMZ-SPECT. Neuropsychological assessments were performed using 3 different test batteries, the WAIS-III, WMS-R, and Wisconsin Card Sorting Test (WCST). RESULTS: All DMD patients showed significant decline in 123 I-IMZ uptake in the prefrontal cortex (P < 0.05). Although no differences were detected in the WAIS-III and WMS-R, the WCST scores of DMD patients (2.8 ± 1.9) were significantly lower (P < 0.01) than those of normal volunteers (5.4 ± 0.7). Both abnormalities were more pronounced in older adult patients. CONCLUSION: The findings demonstrate that DMD is accompanied by a reduction in the prefrontal cortex distribution of GABAA -Rs. Muscle Nerve 55: 591-595, 2017.

Milk fat globule epidermal growth factor 8 attenuates acute lung injury in mice after intestinal ischemia and reperfusion.

RATIONALE: Milk fat globule epidermal growth factor 8 (MFG-E8) is a potent opsonin for the clearance of apoptotic cells and is produced by mononuclear cells of immune competent organs including the spleen and lungs. It attenuates chronic and acute inflammation such as autoimmune glomerulonephritis and bacterial sepsis by enhancing apoptotic cell clearance. Ischemia-reperfusion (I/R) injury of the gut results in severe inflammation, apoptosis, and remote organ damage, including acute lung injury (ALI). OBJECTIVES: To determine whether MFG-E8 attenuates intestinal and pulmonary inflammation after gut I/R. METHODS: Wild-type (WT) and MFG-E8(-/-) mice underwent superior mesenteric artery occlusion for 90 minutes, followed by reperfusion for 4 hours. A group of WT mice was treated with 0.4 microg/20 g recombinant murine MFG-E8 (rmMFG-E8) at the beginning of reperfusion. Four hours after reperfusion, MFG-E8, cytokines, myeloperoxidase activity, apoptosis, and histopathology were assessed. A 24-hour survival study was conducted in rmMFG-E8- and vehicle-treated WT mice. MEASUREMENTS AND MAIN RESULTS: Mesenteric I/R caused severe widespread injury and inflammation of the small intestines and remote organs, including the lungs. MFG-E8 levels decreased in the spleen and lungs by 50 to 60%, suggesting impaired apoptotic cell clearance. Treatment with rmMFG-E8 significantly suppressed inflammation (TNF-alpha, IL-6, IL-1beta, and myeloperoxidase) and injury of the lungs, liver, and kidneys. MFG-E8-deficient mice suffered from greatly increased inflammation and potentiated ALI, whereas treatment with rmMFG-E8 significantly improved the survival in WT mice. CONCLUSIONS: MFG-E8 attenuates inflammation and ALI after gut I/R and may represent a novel therapeutic agent.

[Total arch replacement through a mediansternotomy for an aortic arch aneurysm with an aberrant right subclavian artery].

The patient was a 77-year-old man. In 2004, he developed thrombosed aortic dissection extending from the distal aortic arch to the renal artery bifurcation. He was discharged after his condition improved with conservative treatment. He was followed up as an outpatient because there was an aneurysm, which measured 50 mm in diameter, at the aortic arch. Thereafter the aneurysm gradually enlarged. In May 2009, computed tomography (CT) showed that the aneurysm had increased to 10 cm in diameter and the patient began to have back pain. Thus, surgery was planned. CT revealed that the right subclavian artery originated distal to the left subclavian artery and coursed posterior to the esophagus and trachea. Surgery was performed using median sternotomy. Arch replacement and right subclavian artery reconstruction were performed under hypothermic circulatory arrest with selective cerebral perfusion. The right subclavian artery was controlled at the right border of the trachea, and cerebral perfusion was performed at this site. An end-to-side anastomosis to the reconstructed right common carotid artery was performed by an anterior tracheal approach. The patient had no cerebral complications and his postoperative course was uneventful.

Reversing established sepsis in rats with human vasoactive hormone adrenomedullin and its binding protein.

We recently demonstrated that early administration of rat adrenomedullin (AM), a vasoactive peptide, in combination with its binding protein (human AMBP-1) produces various beneficial effects in sepsis. Human AM is a 52-amino acid peptide, but rat AM differs from human AM, having only 50 amino acid residues, with two amino acid deletions and six substitutions. It remains unknown whether a combination of human AM and human AMBP-1 (AM/AMBP-1) is also beneficial in sepsis and, if so, whether human AM/AMBP-1 reverses established sepsis in rats. To test the effects of human AM/AMBP-1, we induced sepsis in male adult rats by cecal ligation and puncture (CLP). At 10 h after CLP (i.e., severe sepsis), human AM (12-48 microg/kg body weight) was administered in combination with human AMBP-1 (40-160 microg/kg body weight). Vehicle-treated animals received a nonspecific human plasma protein (albumin). Blood and intestinal samples were collected at 20 h for various measurements. In additional groups of septic animals, the gangrenous cecum was surgically excised at 20 h after CLP. The 10-day survival was recorded. Our results showed that tissue injury, as evidenced by increased levels of transaminases and lactate, was present at 20 h after CLP. Proinflammatory cytokines tumor necrosis factor-alpha and interleukin-6 were significantly elevated. Gut barrier dysfunction, manifested by increased mucosal permeability to hydrophilic macromolecules and increased bacterial translocation to mesenteric lymph nodes, also occurred at 20 h after CLP. Administration of human AM/AMBP-1 in established sepsis markedly attenuated tissue injury, reduced proinflammatory cytokine levels, ameliorated intestinal-barrier dysfunction, and improved the survival rate from 47% to 67%-80%. Thus, human AM/AMBP-1 can be further developed as a safe and effective therapy for patients with established sepsis.

Unexpected intraabdominal hemorrhage due to segmental arterial mediolysis following subarachnoid hemorrhage: A case of ruptured intracranial and intraabdominal aneurysms.

BACKGROUND: Segmental arterial mediolysis (SAM) is an uncommon vascular disease, which manifests as catastrophic intraabdominal hemorrhage caused by rupture of visceral dissecting aneurysms in most cases. The etiology of SAM is still unclear, but SAM may be a vasospastic disorder and the responsible pressor agent is norepinephrine. Recently, abdominal SAM coexisting with intracranial dissecting aneurysms has been reported, but the relationship between intraabdominal and intracranial aneurysms in SAM remains unclear, as no cases of concomitant abdominal SAM and ruptured intracranial saccular aneurysm have been reported. CASE DESCRIPTION: A 49-year-old woman underwent emergent clipping for a ruptured saccular aneurysm at the left C1 portion of the internal carotid artery. Intraoperatively, norepinephrine was continuously administered intravenously under general anesthesia. Four days after the subarachnoid hemorrhage (SAH), the patient suddenly developed shock due to massive hematoma in the abdominal cavity. Imaging showed multiple aneurysms involving the splenic artery, gastroduodenal artery, common hepatic artery, and superior mesenteric artery. Coil embolization of the splenic artery was performed immediately to prevent bleeding. Subsequent treatment for cerebral vasospasm following SAH was performed with prevention of hypertension, and the patient recovered with left temporal lobe infarction. The diagnosis was abdominal SAM based on the clinical, imaging, and laboratory findings. CONCLUSION: Norepinephrine release induced by SAH and/or iatrogenic administration of norepinephrine may have promoted abdominal SAM in this case. Abdominal SAM may occur subsequent to rupture of ordinary saccular aneurysm, and may provoke catastrophic abdominal hemorrhage in the spasm stage after SAH.

Leaflet escape in an Edwards TEKNA mitral prosthesis.

In almost every type of artificial valve, structural failure has been described. We are reporting on a case of a sudden leaflet escape of an Edwards TEKNA mitral valve prosthesis 12 years after implantation. The patient had a sudden onset of dyspnea and severe pulmonary edema with subsequent cardiogenic shock. An emergency mitral replacement was successfully performed. A multi-detector computed tomography scanning and three-dimensional imaging showed two fragments that had embolized in the terminal aorta and the left common iliac artery. The patient presented visual field abnormality, and postoperative head computed tomography showed watershed cerebral infarction. The escaped leaflet that fractured transversely was removed, following the patient's recovery, during cardiac surgery.

Adrenomedullin and adrenomedullin binding protein-1 prevent acute lung injury after gut ischemia-reperfusion.

BACKGROUND: Ischemic bowel remains a critical problem, resulting in up to 80% mortality. Acute lung injury, a common complication after intestinal ischemia/reperfusion (I/R), might be responsible for such a high mortality rate. Our previous studies have shown that administration of a novel vasoactive peptide adrenomedullin (AM) and its binding protein (AMBP-1) reduces the systemic inflammatory response in rat models of both hemorrhage and sepsis. It remains unknown whether administration of AM/AMBP-1 has any protective effects on intestinal I/R-induced acute lung injury. We hypothesized that administration of AM/AMBP-1 after intestinal I/R prevents acute lung injury through downregulation of proinflammatory cytokines. STUDY DESIGN: Intestinal I/R was induced by placing a microvascular clip across superior mesenteric artery (SMA) for 90 minutes in adult male Sprague-Dawley rats (275 to 325 g). On release of the SMA clamp, the animals were treated with either AM (12 mug/kg body weight) in combination with AMBP-1 (40 microg/kg body weight) or vehicle (1 mL normal saline) during a period of 30 minutes through a femoral vein catheter. Lung samples were collected at 4 hours after treatment or sham operation. Lung injury was assessed by examining lung water content, morphologic changes, and granulocyte myeloperoxidase activity. Tumor necrosis factor-alpha and interleukin-6 gene expression and their protein levels in the lungs were measured by reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. In additional groups of animals, AM/AMBP-1 or vehicle was administered at 1 hour after onset of reperfusion. Lung histology was examined at 3 hours after treatment. RESULTS: Intestinal I/R induced considerable lung injury, as characterized by lung edema, histopathologic changes, increased myeloperoxidase activity, and proinflammatory cytokines (tumor necrosis factor-alpha and interleukin-6) levels in the lungs. Administration of AM/AMBP-1 after ischemia mitigated lung injury and dramatically downregulated proinflammatory cytokines. Lung injury was also ameliorated by delayed AM/AMBP-1 treatment as evidenced by improvement in lung histology. CONCLUSIONS: AM/AMBP-1 can be developed as a novel treatment to attenuate acute lung injury after an episode of gut ischemia. The protective effect of AM/AMBP-1 appears to be mediated through downregulation of proinflammatory cytokines.

Chronic contained rupture of aortic aneurysm with thoracic vertebral erosion.

A 66-year-old man was transferred to our hospital with the diagnosis of a large thoracoabdominal aneurysm. Computed tomography showed thoracic vertebral erosion, suggesting a chronic contained rupture. He was hemodynamically stable with no neurological complication preoperatively. He underwent successful surgical replacement of the descending aorta. During surgery, the 6th and 7th thoracic vertebral bones adjacent to the thoracic aneurysm were found to be eroded. The postoperative course was uneventful.

Spatial Change of Cruciate Ligaments in Rat Embryo Knee Joint by Three-Dimensional Reconstruction.

This study aimed to analyze the spatial developmental changes of rat cruciate ligaments by three-dimensional (3D) reconstruction using episcopic fluorescence image capture (EFIC). Cruciate ligaments of Wister rat embryos between embryonic day (E) 16 and E20 were analyzed. Samples were sectioned and visualized using EFIC. 3D reconstructions were generated using Amira software. The length of the cruciate ligaments, distances between attachment points to femur and tibia, angles of the cruciate ligaments and the cross angle of the cruciate ligaments were measured. The shape of cruciate ligaments was clearly visible at E17. The lengths of the anterior cruciate ligament (ACL) and posterior cruciate ligament (PCL) increased gradually from E17 to E19 and drastically at E20. Distances between attachment points to the femur and tibia gradually increased. The ACL angle and PCL angle gradually decreased. The cross angle of the cruciate ligaments changed in three planes. The primordium of the 3D structure of rat cruciate ligaments was constructed from the early stage, with the completion of the development of the structures occurring just before birth.

Distensibility of the pulmonary autograft under systemic pressure.

BACKGROUND AND AIMS OF THE STUDY: Although the Ross procedure has recently been recognized as one of the best replacements of the aortic valve, regurgitation has occasionally been observed with dilatation of the sinotubular junction (STJ) and/or basal ring (BR). This study was designed to evaluate the native distensibility of the free pulmonary root under systemic pressure. METHODS: Pulmonary arterial grafts (n = 7) were taken from pig hearts and pressurized (20-100 cmH2O) with crystal sensors attached around the STJ and BR. Dimensions of the STJ and BR were measured using a digital 3-D ultrasonic sonomicrometer at different pressures (20-100 cmH2O) with and without the STJ and/or BR plicated with felt-strip to prevent overdistension. Valve insufficiency was evaluated macroscopically and endoscopically. RESULTS: All grafts showed no obvious valve insufficiency at 20 cmH2O. Grafts pressurized at 100 cmH2O showed 125+/-6% and 113+/-5% enlargement of dimensions compared with baseline (20 cmH2O) data at the STJ and BR respectively, with recognizable insufficiency. When the STJ was plicated to prevent overdistension at 100 cmH2O with less dilated BR (106%), mild excentric insufficiency was observed. In case of the BR plicated at 100 cmH2O with a less dilated STJ (112%), central slight regurgitation was observed. Both the STJ and BR plications resulted in no recognizable regurgitation. CONCLUSION: Free pulmonary arterial grafts were remarkably enlarged under systemic pressure with recognizable valve insufficiency; this could be prevented by maintaining the original dimensions of the graft STJ and BR.

Coronary occlusion using bi-directionally stretched elastic sutures during off-pump coronary artery bypass grafting.

OBJECTIVE: Off-pump coronary artery bypass grafting may be partly invasive, particularly to the coronary endothelium that is snared. Efficacy of a simple technique to occlude a coronary artery with elastic sutures bi-directionally stretched just beneath the artery was evaluated. METHODS: Test subjects were eighteen adult mongrel dogs weighing 20-30 kg. After systemic heparinization (150 U/kg), the mid-left anterior descending artery (mid-LAD) was exposed with a stabilizer applied and snared using non-elastic sutures (n = 6) or elastic sutures (n = 6), or occluded with elastic sutures bi-directionally stretched (n = 6). The left internal thoracic artery (LITA) was anastomosed to the mid-LAD with humidified gas insufflation. After completion of the anastomosis, the mid-LAD was observed endoscopically through the LITA. The coronary endothelium was also observed by a scanning electron microscope (SEM) after perfusion fixation. RESULTS: Bleeding at the anastomotic site with the coronary artery occluded by bi-directionally stretched elastic sutures was observed. However, all anastomoses were done successfully with the aid of humidified gas insufflation. Coronary endoscope showed that the lumens snared with non-elastic sutures were collapsed with folds and often with clots. Coronary arteries snared with elastic sutures appeared similar to the arteries snared with non-elastic sutures endoscopically, but with less clots. In the case of coronary occlusion with bi-directionally stretched elastic sutures, the lumens were occluded in a flattened linear fashion without clots. SEM showed endothelial injuries with blood cells deposited when non-elastic sutures were used. When elastic sutures were used for snaring, endothelial injuries were ameliorated with less blood cells deposited, which were further decreased when elastic sutures were bi-directionally stretched. CONCLUSION: The coronary artery can be effectively occluded by bi-directionally stretched elastic sutures with minimal endothelial damage.

Prognostic impact of left ventricular noncompaction in patients with Duchenne/Becker muscular dystrophy--prospective multicenter cohort study.

BACKGROUND: The reported prevalence of left ventricular noncompaction (LVNC) varies widely and its prognostic impact remains controversial. We sought to clarify the prevalence and prognostic impact of LVNC in patients with Duchenne/Becker muscular dystrophy (DMD/BMD). METHODS: We evaluated the presence of LNVC in patients with DMD/BMD aged 4-64 years old at the study entry (from July 2007 to December 2008) and prospectively followed-up their subsequent courses (n=186). The study endpoint was all-cause death and the presence of LVNC was blinded until the end of the study (median follow-up: 46 months; interquartile range: 41-48 months). RESULTS: There were no significant differences in baseline characteristics between patients with LVNC (n=35) and control patients without LVNC (n=151), with the exception of LV function. Patients with LVNC showed, in comparison with patients without LVNC, a significant negative correlation between age and LVEF (R=-0.7 vs. R=-0.4) at baseline; and showed a significantly greater decrease in absolute LVEF (-8.6 ± 4.6 vs. -4.3 ± 4.5, p<0.001) during the follow-up. A worse prognosis was observed in patients with LVNC (13/35 died) than in patients without LVNC (22/151 died, Log-rank p<0.001). Multivariate Cox analysis revealed that LVNC is an independent prognostic factor (relative hazard 2.67 [95% CI: 1.19-5.96]). CONCLUSION: LVNC was prevalent in patients with DMD/BMD. The presence of LVNC is significantly associated with a rapid deterioration in LV function and higher mortality. Neurologists and cardiologists should pay more careful attention to the presence of LVNC.

Gut hyperpermiability after ischemia and reperfusion: attenuation with adrenomedullin and its binding protein treatment.

Ischemia bowel remains a critical problem resulting in up to 80% mortality. The loss of gut barrier function plays an important role. Our previous studies have shown that administration of adrenomedullin (AM), a novel vasoactive peptide, and its binding protein (AMBP-1), reduces the systemic inflammatory response and organ injury after systemic ischemia induced by hemorrhagic shock. However, it remains unknown whether administration of AM/AMBP-1 preserves gut barrier function after gut ischemia reperfusion (I/R). We therefore hypothesized that AM/AMBP-1 prevents structural and functional damages to the intestinal mucosa after gut I/R. To test this, gut ischemia was induced by placing a microvascular clip across the superior mesenteric artery (SMA) for 90 min in male adult rats. After release of the SMA clamp, AM (12 mug/kg BW) and AMBP-1 (40 mug/kg BW) in combination or vehicle (1-ml normal saline) were administered intravenously over a period of 30 min. The mucosal barrier function in the small intestine was assessed in an isolated everted ileum sac using fluorescein-isothiocyanate dextran (FD4) at 4 h after AM/AMBP-1 treatment. FD4 clearance was used as a measure of gut permeability. In additional groups of animals, blood and small intestine samples were collected at 4 h after the treatment. Morphological changes in the small intestine were assessed by H-E staining. Serum concentrations of alanine aminotransferase, aspartate aminotransferase, total bilirubin, direct bilirubin, lactate and lactate dehydrogenase were also assessed. The gene expression and protein levels of TNF-alpha in the small intestine were determined by RT-PCR and ELISA, respectively. Our results showed that administration of AM/AMBP-1 significantly attenuated the development of intestinal mucosal hyperpermeability during the reperfusion. Treatment with AM/AMBP-1 dramatically improved I/R-induced intestinal mucosal damages, attenuated remote organ injury, and downregulated gene expression and protein levels of TNF-alpha in the small intestine. In conclusion, AM/AMBP-1 attenuates structural and functional damages to the intestinal mucosa, and it appears to be a novel treatment for reperfusion injury after gut ischemia. The beneficial effect of AM/AMBP-1 on gut barrier function after I/R is associated with downregulation of TNF-alpha.

Nicorandil attenuates reperfusion injury after long cardioplegic arrest.

The cardioprotective efficacy of nicorandil in cardiac surgery was determined using a surgically relevant 4-hr cardioplegic arrest model. Each isolated rabbit heart was parabiotically blood-perfused using a modified Langendorff column. The magnitude of left ventricular developed pressure and rate of change of developed pressure over time were measured before (baseline) and after ischemia. Nicorandil was administered either pre-ischemia, post-ischemia, pre/post-ischemia, or continuously (before, during, and after ischemia). The endothelium of the coronary artery was observed by scanning electron microscopy. Serum myeloperoxidase activities were also measured. Although pretreatment with nicorandil did not affect recovery of developed pressure, administration of nicorandil after ischemia, or before and after ischemia, enhanced the recovery of developed pressure. Serum myeloperoxidase activity was decreased in the pre/post-ischemia and continuous groups. Endothelial reperfusion injury decreased in all nicorandil-treated groups. Administration of nicorandil attenuated ischemia-reperfusion injury of the myocardium and coronary endothelium while ameliorating leukocyte activation. In the event of unexpected prolonged cardioplegic arrest, administration of nicorandil, even just after declamping, may improve cardiac function. However, pre-ischemia administration alone was not helpful in the heart subjected to prolonged cardioplegic arrest.

Downregulation of hepatic cytochrome P-450 isoforms and PPAR-gamma: their role in hepatic injury and proinflammatory responses in a double-hit model of hemorrhage and sepsis.

BACKGROUND: The "double-hit" model of hemorrhage and sepsis mimics the critically ill patient admitted to the surgical intensive care unit. Although the protein expression of a cytochrome (CYP) P-450 isoform CYP1A2 is reduced in the late stage of sepsis, the effect of hemorrhage on CYP isoforms and the anti-inflammatory nuclear receptor peroxisome proliferator-activated receptor-gamma (PPAR-gamma) has not been investigated. We hypothesized that hemorrhage down-regulates CYP isoforms and PPAR-gamma in the liver, which plays an important role in producing tissue injury and proinflammatory responses after the subsequent sepsis (i.e., double-hit). MATERIALS AND METHODS: Male Sprague Dawley rats were divided into four groups. Animals in the double-hit group underwent hemorrhage (40 +/- 2 mmHg for 90 min) followed by fluid resuscitation. Polymicrobial sepsis was induced by cecal ligation and puncture (CLP) 20 h after hemorrhage, and the animals were sacrificed 4 h after CLP. Rats in the hemorrhage-alone group were sacrificed 20 h after the insult. Rats in the CLP-alone group were sacrificed 4 h after the onset of sepsis. Animals in the sham-operated group underwent neither hemorrhage nor CLP. The gene expression of P-450 isoforms (i.e., CYP1A2 and 2C11) and PPAR-gamma in the liver was determined using RT-PCR. Serum concentrations of alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate, and proinflammatory cytokines (i.e., IL-6, TNF-alpha) were also assessed. RESULTS: In the hemorrhage-alone group, hepatic mRNA expression of CYP1A2, CYP2C11, and PPAR-gamma was significantly down-regulated 20 h after the initial stress compared with sham-operated rats. Double-hit did not appear to further decrease CYP and PPAR-gamma gene expression. In contrast, serum levels of AST, ALT, lactate, IL-6, and TNF-alpha did not change significantly in either hemorrhaged or septic animals. Those organ injury indicators and cytokines, however, were significantly elevated after the double-hit of hemorrhage and sepsis. CONCLUSIONS: Hepatic CYP1A2, CYP2C11, and PPAR-gamma were down-regulated after the initial stress (hemorrhage). These down-regulated CYPs and PPAR-gamma seem to work as important factors contributing to the progression of organ injury and proinflammatory responses after the second stress (CLP).