Cancer of the rectum: comparison of two different surgical approaches

Surgical treatment of rectal cancer is still controversial as regards the type of operation and the extent of lymphadenectomy. Four hundred and fifty-eight patients with rectal cancer operated on at two different hospitals (206 patients, Surgical Department, S. Martino General Hospital and 252 patients, Surgical Department, Galliera General Hospital) in the decade 1980-1989 were studied. None of the patients were submitted to adjuvant or neoadjuvant therapy. The operations opted for were anterior resection for carcinoma of the upper rectum, anterior resection or abdominoperineal resection for carcinoma of the middle rectum, and abdominoperineal resection for lower rectal cancer. At the S. Martino General Hospital, anterior resection comprised ligation of the inferior mesenteric artery at its origin, with subsequent preaortic lymphadenectomy. In abdominoperineal resection, the pelvis was left open and was closed later. At the Galliera General Hospital, preaortic lymph node dissection was not performed, and abdominoperineal resection comprised a one-stage pelvic floor closure. Survival was no different in the two patient populations. Extended lymphadenectomy was of no benefit in terms of survival in operated rectal cancer patients. Abdominoperineal resection may still be useful for selected patients.     

The effect of ions at the surface of calcium oxalate monohydrate crystals on cell-crystal interactions

Magnesium is an abundant ion in biologic systems, including renal tubular fluid; however, the precise role of magnesium during the interaction of calcium oxalate crystals with cells has not been previously defined. In addition, the respective roles of calcium and hydrogen ions during the cell-crystal bonding interaction remain poorly defined. Here we report an atomic level three-dimensional study of a single crystal of calcium oxalate monohydrate (COM; whewellite) which was bathed in a solution of magnesium hexahydrate for 1 year. Magnesium was not incorporated into the structure of whewellite to any significant degree. Instead, COM accepted magnesium primarily as an adsorbate in a binding configuration which, as a surface phenomenon, is controlled by localized charge effects. The effect of magnesium and calcium on the efficiency of calcium oxalate crystal binding to renal cells was also investigated. When present in supraphysiologic concentrations (greater than 0.1 M), magnesium progressively inhibited adhesion of pre-formed COM crystals to cultured renal cells. Therefore, even though magnesium does not incorporate into the crystal structure of calcium oxalate, magnesium can exert important surface effects and change the interaction of pre-formed COM with molecules anchored on the cell surface. Similarly, binding was nearly blocked when the exogenous calcium concentration was > or =0.1 M (supraphysiologic range), although in lower concentrations (within the physiologic range) exogenous calcium promoted crystal adhesion. Finally, the ambient hydrogen ion concentration also influenced calcium oxalate crystal interactions with renal cells, with maximal binding occurring at a pH of 4. Therefore, hypercalciuria and/or an acidic urine could each promote renal stone formation via increased crystal adhesion to renal cells, a previously under-appreciated potential mechanism.     

Anastomotic Healing in a Small Bowel Transplantation Model in the Rat

Anastomotic healing is impaired after intestinal surgery because of ischemia and reperfusion injury (IRI), which can result in intestinal leaks leading to increased mortality. The objective of this study was to determine the effects of transplant IRI and immune mechanisms on intestinal graft anastomotic healing. Orthotopic intestinal transplantations (OIT) were performed in rats. The experimental design consisted of six groups A–F (n = 5/group): A, allogeneic OIT treated with tacrolimus (1mg/kg/day); B, syngeneic OIT treated with tacrolimus; C, syngeneic OIT; D, allogeneic OIT; E, proximal and distal anastomoses performed in nontransplanted animals; F, same as in group E but treated with tacrolimus. Anastomotic bursting pressure (ABP), hydroxyproline content (HPC), and mucosal inflammatory infiltrate (MII) were determined at the anastomotic sites (proximal and distal) and compared between groups. ABP was significantly (p < 0.001) reduced in OIT groups A, B, C, and D compared to control groups E and F at both the proximal and distal anastomotic sites. HPC was 1 g/mg of tissue in groups A, B, C, and D, and 5g/mg of tissue in groups E and F. This demonstrates a significant (p < 0.001) reduction in HPC after OIT. MII was significantly (p < 0.001) increased in OIT groups when compared to nontransplanted control groups. MII was also significantly (p < 0.05) increased in allogeneic OIT groups A and D compared to syngeneic OIT groups B and C. Generally, ABP and HPC were inversely proportional to MII in both nontransplanted control and OIT groups. Reduced anastomotic strength was demonstrated in both syngeneic and allogeneic OIT anastomotic sites irrespective of immunosuppressive therapy, and is probably related to IRI.     

D-amphetamine-induced hydrogen peroxide production in skeletal muscle is modulated by monoamine oxidase inhibition

The aim of this paper was to study the influence of d-amphetamine administration as a sympathomimetic drug on the synthesis of hydrogen peroxide (H2O2) in mouse soleus muscle and to investigate the modulating effects of pargyline, an inhibitor of monoamine oxidase (MAO) in this context. Charles River mice were assigned to four groups: Control, d-amphetamine treated, pargyline treated, and amphetamine + pargyline treated. Their soleus muscles were removed 0, 15, 30, 60, and 120 min after treatment. The amount of hydrogen peroxide formation within the muscles was estimated using an indirect method. The control data showed a continuous production of hydrogen peroxidase. Pargyline administration lead to an initial increase of H2O2 production that later faded below control levels. Administration of amphetamine finally stimulated H2O2 production much above control levels. When combining amphetamine and pargyline treatment, H2O2 production was accelerated in the initial phase but dropped to control levels at 30 min. It is concluded that in skeletal muscle MAO is an important source of hydrogen peroxide production triggered by amphetamine administration and that this tissue plays a hitherto not described role in oxidizing circulating biogenic monoamines.     

Hepatitis C virus is independently associated with increased insulin resistance after liver transplantation

BACKGROUND AND AIMS: There is a strong epidemiologic association between diabetes mellitus (DM) and hepatitis C virus (HCV) infection. However, the pathogenetic basis for this association has not been established. We sought to evaluate the association between insulin resistance (IR), beta-cell dysfunction, and HCV among orthotopic liver transplant (OLT) recipients. METHODS: We performed a cross sectional analysis comparing 39 HCV(+) with 60 HCV(-) OLT recipients. IR and beta-cell function were calculated using validated measures and were correlated with clinical variables. RESULTS: By multivariate analysis of the entire cohort, HCV infection and body mass index (BMI) were independent predictors of IR (P =0.04 and 0.0006, respectively). HCV infection was associated with 35% increase in IR. Because the model used to calculate IR was derived from nondiabetic subjects, we performed additional analysis of patients who did not meet criteria for diabetes at the time of their study evaluation. In this analysis, HCV(+) subjects had greater fasting insulin and homeostasis model assessment (HOMA) IR (15.3 mu U/mL and 3.8) compared with HCV(-) patients (10.7 mu U/mL and 2.5) (P =0.03, 0.03). There was no difference in beta-cell function or hepatic insulin extraction between the HCV (+) and (-) groups. HCV (P =0.0005), BMI (P <0.0001), and high high-density lipoprotein (P =0.039) were the only independent predictors of IR. The presence of HCV infection and a 10-fold increase in HCV RNA were associated with a 62% and 8% increase in IR, respectively. CONCLUSIONS: HCV is independently associated with increased IR after OLT. These findings provide a possible pathogenetic basis for the association of DM with HCV.     

Prophylactic gene therapy with human tissue kallikrein ameliorates limb ischemia recovery in type 1 diabetic mice

Diabetes macro- and microvascular disease causes tissue hypoperfusion. This deficit, together with a failure to mount an adequate angiogenic response, might explain why vascular occlusion evolves more severely among diabetic patients. The present study investigated whether prophylactic gene therapy with human tissue kallikrein (hTK) may protect diabetic limbs from the consequences of supervening ischemia. Vehicle (saline) or an adenovirus carrying the gene for either hTK (Ad.hTK) or luciferase (Ad.Luc) was injected into left adductor muscles of streptozotocin-induced type 1 diabetic mice 2 weeks before operative occlusion of the ipsilateral femoral artery. Saline-injected nondiabetic mice served as controls. Hindlimb blood flow recovery was analyzed sequentially over the 2 weeks after ischemia induction. At necroscopy, microvessel density and endothelial cell proliferation and apoptosis were quantified in skeletal muscles. We found that limb perfusion recovery of saline-injected type 1 diabetic mice is delayed because of insufficient reparative neovascularization and excessive activation of endothelial cell apoptosis. By contrast, prophylactic Ad.hTK renewed the ability to mount an appropriate neovascularization response to ischemia, suppressed apoptosis, and upregulated endothelial nitric oxide synthase expression. Ultimately, correction of diabetic endotheliopathy by Ad.hTK allowed proper perfusion recovery as seen in nondiabetic mice. These discoveries disclose new therapeutic options for the treatment of diabetic complications.     

Oxidative stress affects synaptosomal gamma-aminobutyric acid and glutamate transport in diabetic rats: the role of insulin

Evidence suggests that oxidative stress is involved in the pathophysiology of diabetic complications and that insulin has a neuroprotective role in oxidative stress conditions. In this study, we evaluated the in vitro effect of insulin in the susceptibility to oxidative stress and in the transport of the amino acid neurotransmitters gamma-aminobutyric acid (GABA) and glutamate in a synaptosomal fraction isolated from male type 2 diabetic Goto-Kakizaki (GK) rat brain cortex. The ascorbate/Fe(2+)-induced increase in thiobarbituric acid reactive substances (TBARSs) was similar in Wistar and GK rats and was not reverted by insulin (1 micromol/l), suggesting that other mechanisms, rather than a direct effect in membrane lipid peroxidation, may mediate insulin neuroprotection. Diabetes did not affect GABA and glutamate transport, despite the significant decrease in membrane potential and ATP/ADP ratio, and insulin increased the uptake of both GABA and glutamate in GK rats. Upon oxidation, there was a decrease in the uptake of both neurotransmitters and an increase in extrasynaptosomal glutamate levels and in ATP/ADP ratio in GK rats. Insulin treatment reverted the ascorbate/Fe(2+)-induced decrease in GABA accumulation, with a decrease in extrasynaptosomal GABA. These results suggest that insulin modulates synaptosomal GABA and/or glutamate transport, thus having a neuroprotective role under oxidizing and/or diabetic conditions.