Laparoscopic correction of congenital portosystemic shunt in children

Congenital portosystemic shunt is a rare clinical entity that may progress to jaundice, severe encephalopathy, and pulmonary hypertension and require surgical correction or coil embolization. We present a novel approach to the management of children with congenital portosystemic shunt by means of a minimally invasive surgical technique. Congenital portosystemic shunts were identified between the superior mesenteric vein and inferior vena cava in case 1 and between the splenic vein and left renal vein in case 2. Both of them were successfully ligated by laparoscopic approach, and catheters were subsequently replaced to monitor portal venous pressure. The patients tolerated the procedure well, and short-term results were excellent. Laparoscopic ligation of congenital portosystemic shunt is technically feasible and less invasive to the management of patients with congenital portosystemic shunts, preventing late onset, life-threatening complications.     

Dysfunction of brain pericytes in chronic neuroinflammation

Brain pericytes are uniquely positioned within the neurovascular unit to provide support to blood brain barrier (BBB) maintenance. Neurologic conditions, such as HIV-1-associated neurocognitive disorder, are associated with BBB compromise due to chronic inflammation. Little is known about pericyte dysfunction during HIV-1 infection. We found decreased expression of pericyte markers in human brains from HIV-1-infected patients (even those on antiretroviral therapy). Using primary human brain pericytes, we assessed expression of pericyte markers (α1-integrin, α-smooth muscle actin, platelet-derived growth factor-B receptor β, CX-43) and found their downregulation after treatment with tumor necrosis factor-α (TNFα) or interleukin-1 β (IL-1β). Pericyte exposure to virus or cytokines resulted in decreased secretion of factors promoting BBB formation (angiopoietin-1, transforming growth factor-β1) and mRNA for basement membrane components. TNFα and IL-1β enhanced expression of adhesion molecules in pericytes paralleling increased monocyte adhesion to pericytes. Monocyte migration across BBB models composed of human brain endothelial cells and pericytes demonstrated a diminished rate in baseline migration compared to constructs composed only of brain endothelial cells. However, exposure to the relevant chemokine, CCL2, enhanced the magnitude of monocyte migration when compared to BBB models composed of brain endothelial cells only. These data suggest an important role of pericytes in BBB regulation in neuroinflammation.     

Inhibition of indoleamine 2,3-dioxygenase (IDO) enhances elimination of virus-infected macrophages in an animal model of HIV-1 encephalitis

Indoleamine 2,3-dioxygenase (IDO) is the rate-limiting enzyme in the kynurenine pathway of tryptophan metabolism. IDO activity is linked with immunosuppression by its ability to inhibit lymphocyte proliferation, and with neurotoxicity through the generation of quinolinic acid and other toxins. IDO is induced in macrophages by HIV-1 infection, and it is up regulated in macrophages in human brain tissue with HIV-1 encephalitis (HIVE). Using a model of HIVE, we investigated whether IDO inhibitor 1-methyl-d-tryptophan (1-MT) could affect the generation of cytotoxic T lymphocytes (CTLs) and clearance of virus-infected macrophages from the brain. Severe combined immunodeficient mice were reconstituted with human peripheral blood lymphocytes, and encephalitis was induced by intracranial injection of autologous HIV-1-infected monocyte-derived macrophages (MDMs). Animals treated with 1-MT demonstrated increased numbers of human CD3+, CD8+, CD8+/interferon-gamma+ T cells, and HIV-1(gag/pol)-specific CTLs in peripheral blood compared with controls. At week 2 after MDM injection in the basal ganglia, mice treated with 1-MT showed a 2-fold increase in CD8+ T lymphocytes in the areas of the brain containing HIV-1-infected MDMs compared with untreated controls. By week 3, 1-MT-treated mice showed 89% reduction in HIV-infected MDMs in brain as compared with controls. Thus, manipulation of immunosuppressive IDO activity in HIVE may enhance the generation of HIV-1-specific CTLs, leading to elimination of HIV-1-infected macrophages in brain.     

Impact of the etiology of acute kidney injury on outcomes following liver transplantation: acute tubular necrosis versus hepatorenal syndrome

Acute kidney injury (AKI) at the time of liver transplantation (LT) has been associated with increased morbidity and mortality. In patients with potentially reversible renal dysfunction, predicting whether there will be sufficient return of native kidney function is sometimes difficult. Previous studies have focused mainly on the effect of the severity of renal dysfunction or the duration of pretransplant dialysis on posttransplant outcomes. We performed a retrospective analysis of patients who underwent LT at our center after Model for End-Stage Liver Disease-based allocation so that we could determine the impact of the etiology of AKI [acute tubular necrosis (ATN) versus hepatorenal syndrome (HRS)] on post-LT outcomes. The patients were stratified according to the severity of AKI at the time of LT as described by the Risk, Injury, Failure, Loss, and End-Stage Kidney Disease (RIFLE) classification: risk, injury, or failure. The RIFLE failure group was further subdivided according to the etiology of AKI: HRS or ATN. The patient survival and renal outcomes 1 and 5 years after LT were significantly worse for those with ATN. At 5 years, the incidence of chronic kidney disease (stage 4 or 5) was statistically higher in the ATN group versus the HRS group (56% versus 16%, P < 0.001). A multivariate analysis revealed that the presence of ATN at the time of LT was the only variable associated with higher mortality 1 year after LT (P < 0.001). Our study is the first to demonstrate that the etiology of AKI has the greatest impact on patient and renal outcomes after LT.     

Analgesic synergy between topical morphine and butamben in mice

Studies have revealed that lidocaine is an effective analgesic when applied topically to the tail of a mouse in the radiant heat tail-flick assay. In addition, the topical combination of lidocaine with morphine revealed synergistic interactions between the two drugs. In the current studies, we demonstrate that topical butamben, benzocaine, and bupivacaine are active in the radiant heat tail-flick assay. In this assay, topical lidocaine has a ceiling effect and displays a biphasic curve, with large doses markedly decreasing the responses almost to baseline levels. In contrast, butamben has an S-shape dose-dependent response in the assay and did not display a biphasic curve as seen with lidocaine, suggesting that topical butamben may have advantages over lidocaine. Both benzocaine and bupivacaine also showed dose-dependent analgesic activity in this model. Like lidocaine, butamben/morphine combinations displayed synergistic interactions. Indeed, the synergy appeared more prominent with a butamben/morphine combination. We also observed synergy between topical benzocaine and morphine. Although the bupivacaine/morphine combination was suggestive of synergy on isobolographic analysis, it did not achieve statistical significance. These studies indicate that a series of local anesthetics are all active topically in the radiant heat tail-flick assay in mice and that several interact synergistically with morphine. Of the local anesthetics tested, butamben seemed to have several pharmacological characteristics, alone and in combination with morphine, which suggest that it may be superior to the other local anesthetics. Together, these observations suggest that topical combinations of opioids and local anesthetics may prove clinically valuable. IMPLICATIONS: Topical administration of the opioid micro -agonist morphine and the sodium channel inhibitors butamben and benzocaine results in a synergistic interaction for antinociception in radiant heat tail-flick assay in mice, suggesting that the combination of these drugs will enhance rather than detract from the analgesia of either alone.     

Laparoscopic curative resection of pheochromocytomas

PURPOSE: Pheochromocytomas are relatively uncommon tumors whose operative resection has clear medical and technical challenges. While the safety and efficacy of laparoscopic adrenalectomy are relatively well documented, few studies with extended follow-up have been conducted to measure the success of the procedure for the most challenging of the adrenal tumors. In addition, several reports question the applicability of a minimally invasive approach for sizeable pheochromocytomas. The purpose of our investigation was to assess the outcomes of laparoscopic adrenalectomy for pheochromocytomas in the largest study to date when performed by experienced laparoscopic surgeons. METHODS: All pheochromocytomas removed by the authors from January 1995 to October 2004 were reviewed under an Institutional Review Board approved protocol. Eighty-five percent were documented in a prospective fashion. RESULTS: Eighty consecutive patients underwent laparoscopic resection of 81 pheochromocytomas. Seventy-nine were found in the adrenal (42 left, 35 right, 1 bilateral); 2 were extra-adrenal paragangliomas. Eight patients had multiple endocrine neoplasia syndrome. Two lesions were malignant. There were 48 females and 32 males with a mean age of 45 years (range, 15-79 years). Mean tumor size was 5.0 cm (range, 2-12.1 cm); 41 of these lesions were 5 cm in size or larger. Average operative time and blood loss were 169 minutes (range, 69-375 minutes) and 97 mL (range, 20-500 mL), respectively. Intraoperative hypertension (systolic blood pressure, >170 mm Hg) was reported in 53% of patients and hypotension (systolic blood pressure, <90 mm Hg) in 28% of patients. There were no conversions to open surgery. Mean length of stay was 2.3 days (range, 1-10 days). There were 6 perioperative morbidities (7.5%) and no mortalities. No patient required a blood transfusion. No recurrence of endocrinopathy has been documented at a mean follow-up of 21.4 months. CONCLUSION: Laparoscopic resection of pheochromocytomas, including large lesions, can be accomplished safely by experienced surgeons. A short hospital stay with minimal operative morbidity and eradication of endocrinopathy support the minimally invasive approach for adrenalectomy in the setting of pheochromocytoma.     

Role of ERK1/2 and p38 mitogen-activated protein kinases in the regulation of thrombospondin-1 by TGF-beta1 in rat proximal tubular cells and mouse fibroblasts

Thrombospondin-1 (TSP-1) inhibits angiogenesis and activates latent TGF-beta1, both of which are strongly associated with progression of renal disease. Recently, it was reported that Smad2 but not Smad3 regulates TSP-1 expression in response to TGF-beta1 in rat tubular epithelial cells as well as in mouse fibroblasts. This study investigated the role of ERK1/2 and p38 mitogen-activated protein kinases (MAPK). TGF-beta1 activated both ERK1/2 and p38 in the rat proximal tubular cell line NRK52E. Blocking ERK1/2 and p38 inhibited TGF-beta1-induced TSP-1 mRNA and protein expression. Next, the cross-talk between Smad2 and ERK1/2 or p38 was examined. Whereas blocking of ERK1/2 or p38 failed to inhibit TGF-beta1-induced Smad2 activation, inhibition of Smad2 by Smad7 overexpression inhibited the phosphorylation of ERK1/2 but not p38 in response to TGF-beta1. Similar results were observed using mouse fibroblasts from Smad2 knockout embryos, in that TGF-beta1 was able to activate p38 but not ERK1/2 in this cell line. In conclusion, TSP-1 expression is regulated by both ERK1/2 and p38 MAPK in rat proximal tubular cells and mouse fibroblasts in response to TGF-beta1. The ERK1/2 activation is dependent on Smad2 activation, whereas the p38 activation occurs independent of Smad2. Because TSP-1 is a major antiangiogenic molecule and an activator of TGF-beta1, this provides an important insight to the mechanism by which TGF-beta1 may mediate interstitial fibrosis and progressive renal disease.