Knockdown of Glyoxalase 1 Mimics Diabetic Nephropathy in Nondiabetic Mice

Differences in susceptibility to diabetic nephropathy (DN) between mouse strains with identical levels of hyperglycemia correlate with renal levels of oxidative stress, shown previously to play a central role in the pathogenesis of DN. Susceptibility to DN appears to be genetically determined, but the critical genes have not yet been identified. Overexpression of the enzyme glyoxalase 1 (Glo1), which prevents posttranslational modification of proteins by the glycolysis-derived α-oxoaldehyde, methylglyoxal (MG), prevents hyperglycemia-induced oxidative stress in cultured cells and model organisms. In this study, we show that in nondiabetic mice, knockdown of Glo1 increases to diabetic levels both MG modification of glomerular proteins and oxidative stress, causing alterations in kidney morphology indistinguishable from those caused by diabetes. We also show that in diabetic mice, Glo1 overexpression completely prevents diabetes-induced increases in MG modification of glomerular proteins, increased oxidative stress, and the development of diabetic kidney pathology, despite unchanged levels of diabetic hyperglycemia. Together, these data indicate that Glo1 activity regulates the sensitivity of the kidney to hyperglycemic-induced renal pathology and that alterations in the rate of MG detoxification are sufficient to determine the glycemic set point at which DN occurs.     

Expression of Phosphofructokinase in Skeletal Muscle Is Influenced by Genetic Variation and Associated With Insulin Sensitivity

Using an integrative approach in which genetic variation, gene expression, and clinical phenotypes are assessed in relevant tissues may help functionally characterize the contribution of genetics to disease susceptibility. We sought to identify genetic variation influencing skeletal muscle gene expression (expression quantitative trait loci [eQTLs]) as well as expression associated with measures of insulin sensitivity. We investigated associations of 3,799,401 genetic variants in expression of >7,000 genes from three cohorts (n = 104). We identified 287 genes with cis-acting eQTLs (false discovery rate [FDR] <5%; P < 1.96 × 10⁻⁵) and 49 expression–insulin sensitivity phenotype associations (i.e., fasting insulin, homeostasis model assessment–insulin resistance, and BMI) (FDR <5%; P = 1.34 × 10⁻⁴). One of these associations, fasting insulin/phosphofructokinase (PFKM), overlaps with an eQTL. Furthermore, the expression of PFKM, a rate-limiting enzyme in glycolysis, was nominally associated with glucose uptake in skeletal muscle (P = 0.026; n = 42) and overexpressed (Bonferroni-corrected P = 0.03) in skeletal muscle of patients with T2D (n = 102) compared with normoglycemic controls (n = 87). The PFKM eQTL (rs4547172; P = 7.69 × 10⁻⁶) was nominally associated with glucose uptake, glucose oxidation rate, intramuscular triglyceride content, and metabolic flexibility (P = 0.016–0.048; n = 178). We explored eQTL results using published data from genome-wide association studies (DIAGRAM and MAGIC), and a proxy for the PFKM eQTL (rs11168327; r² = 0.75) was nominally associated with T2D (DIAGRAM P = 2.7 × 10⁻³). Taken together, our analysis highlights PFKM as a potential regulator of skeletal muscle insulin sensitivity.     

Contribution of Endogenous Glucagon-Like Peptide 1 to Glucose Metabolism After Roux-en-Y Gastric Bypass

The contribution of elevated glucagon-like peptide 1 (GLP-1) to postprandial glucose metabolism after Roux-en-Y gastric bypass (RYGB) has been the subject of uncertainty. We used exendin-9,39, a competitive antagonist of GLP-1, to examine glucose metabolism, islet hormone secretion, and gastrointestinal transit in subjects after RYGB and in matched control subjects. Subjects were studied in the presence or absence of exendin-9,39 infused at 300 pmol/kg/min. Exendin-9,39 resulted in an increase in integrated postprandial glucose concentrations post-RYGB (3.6 ± 0.5 vs. 2.0 ± 0.4 mol/6 h, P = 0.001). Exendin-9,39 decreased insulin concentrations (12.3 ± 2.2 vs. 18.1 ± 3.1 nmol/6 h, P = 0.002) and the β-cell response to glucose (ϕ_Total, 13 ± 1 vs. 11 ± 1 × 10⁻⁹ min⁻¹_, P = 0.01) but did not alter the disposition index (DI). In control subjects, exendin-9,39 also increased glucose (2.2 ± 0.4 vs. 1.7 ± 0.3 mol/6 h, P = 0.03) without accompanying changes in insulin concentrations, resulting in an impaired DI. Post-RYGB, acceleration of stomach emptying during the first 30 min by exendin-9,39 did not alter meal appearance, and similarly, suppression of glucose production and stimulation of glucose disappearance were unaltered in RYGB subjects. These data indicate that endogenous GLP-1 has effects on glucose metabolism and on gastrointestinal motility years after RYGB. However, it remains uncertain whether this explains all of the changes after RYGB.     

A rare case of solitary colonic fibromatosis mimicking a cystic tumour

Mesenteric fibromatosis or intrabdominal desmoid tumour is a rare proliferative disease that frequently involves the gastrointestinal tract. These tumours account for less than 3% of all tumours among soft tissue neoplasms. Most such lesions are large (10cm or more in diameter) at the time of the excision. Although grossly well-circumscribed, they lesions typically infiltrate the surrounding soft tissues including the bowel wall. The case described here concerns a 62-year-old woman with a partly cystic mesenteric fibromatosis incorporating the large bowel wall, which degenerated into an abscess. A right colectomy was undertaken, and the sample was sent for histological examination. Based on the morphological and immunohistochemical findings, a diagnosis of abdominal fibromatosis was established. The surgical margins were free of disease, and the examined lymph nodes showed cortical hyperplasia and histiocytosis of the lymph sinuses. The patient recovered from surgery with no complications; her fever subsided, and she was discharged from hospital 12 days later. Surgery is the primary therapy for extra-abdominal and intra-abdominal desmoid tumours. Considering the unique biology of desmoid tumours, conservative treatment strategies merit further investigation in both unresectable primary disease and resectable disease. The optimal criteria for choosing surgical or non-surgical treatment still need further evaluation with randomized controlled studies.     

Incarcerated transmesosigmoid hernia presenting in a 28-year-old female

We report the case of a transmesosigmoid hernia in a 28-year-old female who presented to the emergency room complaining of abdominal pain. History, clinical and radiographic examination revealed small bowel ileus, but without being able to diagnose the cause. We decided to perform laparoscopy, which showed herniation of a small intestine loop through a small defect of the mesosigmoid. Due to the inability to reduce the internal hernia laparoscopically, we converted to mini-laparotomy; we reduced the hernia and performed segmental small bowel resection and anastomosis. It is essential to suspect the presence of an internal hernia as soon as possible, because if the operation is delayed, it will often eventually lead to bowel necrosis.     

Effect of renal angioembolization on post-traumatic acute kidney injury after high-grade renal trauma: A comparative study of 52 consecutive cases

Background

Acute kidney injury (AKI) is associated with unfavourable outcomes and higher mortality after trauma. Renal angioembolization (RAE) has proved efficiency in the management of high-grade renal trauma (HGRT), but inevitably expose to unavoidable ischaemic areas or contrast medium nephrotoxicity which may impair renal function in the following hours. The aim of this study was to assess the potential acute impact of RAE on renal function in a consecutive series of HGRTs treated nonoperatively.

Materials and methods

Of 101 cases of renal trauma admitted to our Regional Trauma Center between January 2005 and January 2010, 52 cases of HGRT were treated nonoperatively; they were retrospectively classified into 2 groups according to whether RAE was used. Incidence and progression of AKI (RIFLE classification), maximum increase in serum creatinine (SCr), level since admission and recovery of renal function at discharge were compared between the groups. Multivariable analysis was performed to determine the role of RAE as an independent risk factor of AKI.

Results

RAE was performed in 10 patients within the first 48 h. The RAE and no RAE groups were comparable in terms of severity score, renal injury grade, and level of SCr on admission. AKI incidence (RIFLE score Risk or worse) after 48 and 96 h was 33% and 10%, respectively and did not differ significantly between groups at 48 h (p = 1.00) or 96 h (p = 1.00). The median maximum increase in SCr was significantly higher in no RAE than RAE group (30.4% vs. 6.9%, p = 0.04). RAE was not found to be a significant variable in a multiple linear regression analysis predicting maximum SCr rise (p = 0.34). SCr at discharge was >120% of baseline in only 5 patients, with no difference according to RAE (p = 0.24).

Conclusion

In a population of nonoperatively treated HGRT, the incidence of AKI decreased from almost 30% to 10% at 48 h and 96 h. RAE proceeding did not seem to affect significantly the occurrence and course of AKI or renal recovery. The decision to use RAE should probably not be restricted by fear of worsening renal function.     

Tissue Management With Tri-Staple Technology in Major and Minor Laparoscopic Liver Resections

One of the most relevant technologic advancements in laparoscopic liver resection (LLR) is owing to the improved ability to safely secure and divide vascular and biliary structures and the liver parenchyma by the use of endostaplers. We compared, retrospectively, 35 LLRs with the Tri-Staple technology versus 57 LLRs without, during a 14-month period. Colorectal liver metastases were overall the main indication for LLR. Neither major hepatectomy nor left lateral sectionectomy was done in the nonstapled group. Mean surgical time and blood loss were similar, whereas the tumor number and size were significantly larger in the stapled group (P ≤ 0.01). The conversion rate was 0% and 3.5% (n = 2); and the morbidity rate was 9% (n = 3) and 12% (n = 7), respectively, in the stapled and nonstapled group (P = 0.8). No overall 3-month mortality was recorded. Endo GIA Reloads with Tri-Staple technology allow a proper division of the intrahepatic vessels and biliary structure. These devices in LLRs are safe and feasible, allowing major hepatectomy and complex cases as 2-staged procedures and laparoscopic living donor liver resections.Key words: Laparoscopic liver resection, Minimally invasive liver surgery, Endo-staplers, Tri-Staple technology, Laparoscopic living donor liver resectionThere has been exponential growth of reported experiences of laparoscopic liver resection (LLR) since the first procedure was performed in 1992, with more than 3000 published procedures available worldwide today.^1–7 Meticulous knowledge of surgical anatomy of the liver, improvements in perioperative care, development of newer instruments, enhanced diagnostic imaging, and advancement in laparoscopic skills are considered the major advances that have been achieved in this field.The indications for laparoscopic hepatic resection are usually the same as the standard approach, as previously advised by the Louisville Statement Consensus Conference.⁸ Although LLR was initially indicated for benign lesions, the recurrence pattern has been shown to be similar to that described for open resection of colorectal liver metastases (CRLM) and/or hepatocellular carcinoma, reporting outcomes at least as good as those reported for open surgery.^9–14In addition, laparoscopic living liver donor hepatectomy has demonstrated its potential role especially in left lateral sectionectomy procurement, where it looks to be more appropriate compared with laparoscopic-assisted techniques in right-lobe living liver donation.^15,16One of the most relevant technologic advancements in minimally invasive liver surgery is owing to the improved ability to safely secure and divide vascular and biliary structures and eventually the liver parenchyma. For this, endostaplers are playing a very important role.The Endo GIA Reloads with Tri-Staple technology (Covidien Europa, Dublin, Ireland) were introduced in 2010 and have been utilized for LLR at Ghent University Hospital since April 2011 as part of standard of care.The Department of General, Hepatobiliary, and Pancreatic Surgery at the Ghent University Hospital started a systematic program of laparoscopic liver surgery in 2004. Today, more than 60% of all resectional procedures are done by laparoscopy.The purpose of this study is to analyze the personal experience and overall results in major and minor LLR comparing stapled versus nonstapled groups.     

In utero repair of myelomeningocele with autologous amniotic membrane in the fetal lamb model

Background

Despite advances in prenatal repair, myelomeningocele (MMC) still produces devastating neurologic deficits. The amniotic membranes (AM) are a biologically active tissue that has been used anecdotally for human fetal MMC repair. This study evaluated the use of autologous AM compared to skin closure in an established fetal MMC model.

Methods

Seven fetal lambs underwent surgical creation of MMC at gestational age of 75 days followed by in utero repair at gestational age of 100 days. Lambs were repaired with an autologous AM patch followed by skin closure (n = 4) or skin closure alone (n = 3). Gross necropsy and histopathology of the spinal cords were performed at term to assess neuronal preservation at the lesion.

Results

An increase in preserved motor neurons and a larger area of spinal cord tissue were seen in AM-repaired lambs, as was decreased wound healing of the overlying skin. Loss of nearly all spinal cord tissue with limited motor neuron preservation was seen in skin only-repaired lambs.

Conclusions

AM-repaired lambs showed increased protection of spinal cord tissue compared to skin only-repaired lambs, but the overlying skin failed to close in AM-repaired lambs. These results suggest a potential role for AM in fetal MMC repair that warrants further study.     

Bone graft gel: autologous growth factors used with autograft bone for lumbar spine fusions

A method to combine autologous growth factors (AGF) with autologous bone graft in a bone graft gel for spine fusions is described. The bone graft gel can be inserted into cages for interbody fusions or used directly for posterolateral intertransverse fusions. Sixty patients have undergone spinal fusion surgery under this technique. No equipment problems have been encountered and no adverse effects observed that could be attributed to AGF. Early clinical outcomes indicated solid or maturing fusions in 58 of 60 patients. AGFs to enhance bone healing represent an economical and readily available autologous source of growth factors.     

Caudal anesthesia with sedation for inguinal hernia repair in high risk neonates

Background/Purpose

The use of caudal anesthesia with sedation (CAS) has theoretical benefits over general anesthesia (GA) in high risk neonates undergoing inguinal hernia repair. This benefit has not been established in clinical studies. We compare outcomes of these two approaches at a single institution.

Methods

A retrospective review was performed of all neonates and preterm infants undergoing inguinal hernia over an 8 year period.

Results

Of 71 infants meeting inclusion criteria, 50 underwent repair with caudal block and systemic sedation, and 21 with general anesthesia. Minor incidents of respiratory depression requiring non invasive interventions were common in the first 24 h post operatively (24% for CAS, 14% with GA), 4% of patients receiving CAS had a respiratory complication which prolonged their hospital stay beyond 24 h post operation. Both required conversion to general anesthesia. Statistically significant differences between the two groups were lacking in terms of preoperative risk and post operative outcome.

Conclusions

CAS is a safe, effective anesthetic option for high risk neonates undergoing inguinal hernia repair. Patients requiring conversion to GA from CAS may be at increased risk for complications. Large, randomized trials are needed to determine any benefit over GA.