Mesenteric and renal oxygen transport during hemorrhage and reperfusion: evaluation of optimal goals for resuscitation

BACKGROUND: Changes in flow to the gut and the kidney during hemorrhage and resuscitation contribute to organ dysfunction and outcome. We evaluated regional and splanchnic oxygen (O2) flow distribution and calculated oxygen supply distribution during hemorrhage and reperfusion and compared them with global measures. METHODS: Seven anesthetized pigs were instrumented to evaluate global hemodynamics, visceral blood flow, and oxygen transport. Tonometric pH probes were positioned in the stomach and jejunum. Animals were bled to 45 mm Hg for 1 hour. Crystalloids and blood were infused during the following 2 hours to normalize blood pressure, heart rate, urine output, and hemo- globin. RESULTS: During hemorrhage, mesenteric flow and O2 consumption were significantly decreased, whereas systemic consumption remained normal. Renal flow was reduced, but renal O2 consumption remained normal. After resuscitation, despite normal hemodynamics, neither systemic, mesenteric, nor renal O2 delivery returned to baseline. Lactate remained significantly increased. Arterial pH, base excess, and gastric and jejunal pH were all decreased. CONCLUSION: During hemorrhage, the gut is more prone than other regions to O2 consumption supply dependency. After resuscitation, standard clinical parameters do not detect residual O2 debt. Lactate, arterial pH, base excess, and intramucosal gut pH are all markers of residual tissue hypoperfusion.     

Biologic therapy for psoriasis: an update on the tumor necrosis factor inhibitors infliximab, etanercept, and adalimumab, and the T-cell-targeted therapies efalizumab and alefacept

Psoriasis is a chronic skin disorder that affects approximately 2% of the US and European population. Over the last several years, one of the major focuses in psoriasis research has been the development of biologic therapies for this disease. The aim of these therapies is to provide selective, immunologically directed intervention with fewer side effects than traditional therapies. The goal of this article is to update the progress of the tumor necrosis inhibitors which are available, or under investigation, for clinical use in psoriasis: infliximab, etanercept, and adalimumab, as well as the T-cell-targeted therapies efalizumab and alefacept (Table 1).     

Prevalence of fasting hypercalciuria associated with increased citraturia in the ambulatory evaluation of nephrolithiasis

BACKGROUND: Nephrolithiasis is a common, high costing pathology of the urinary tract. The most common urinary abnormalities are fasting hypercalciuria, hypercalciuria and hypocitraturia. This study aimed to identify the principal urinary abnormalities in our patients. METHODS: Ninety-eight patients (pts) (43 females, 55 males) with recurrent calcium nephrolithiasis underwent metabolic evaluation. In two 24-hr urine collections the following parameters were evaluated: calcium, phosphate, sodium, potassium, chloride, magnesium, citrate, oxalate, uric acid, creatinine (Cr), urea, ammonium and pH; blood measurement of calcium, phosphate, sodium, potassium, chloride, magnesium, uric acid, Cr, urea, acid-base balance ionized calcium and intact parathyroid hormone (iPTH) were also performed. A first morning voided urine sample was collected for measuring the urinary cross-links and fasting calciuria. The tubular threshold of phosphate (TmP) was calculated according to Walton and Bijovet. Metabolic evaluation was repeated in 63/98 pts after 7 days on a low calcium diet. RESULTS: The most common urinary abnormalities were fasting hypercalciuria in 51/96 pts (53.1%), hypercalciuria in 33/97 pts (34%) and hypocitraturia in 29/98 pts (29%); 24/33 pts (73%) with hypercalciuria had fasting hypercalciuria. Hypercalciuria was partially corrected on the calcium-restricted diet, while fasting hypercalciuria was not. Urine citrate levels were significantly higher in patients with fasting hypercalciuria. CONCLUSIONS: Fasting hypercalciuria was the most frequent urinary abnormality and it was not corrected with a calcium-restricted diet. In fasting hypercalciuric patients, increased bone resorption activity could be responsible for higher citraturia levels.     

Multifaceted therapeutic approaches for a multigenic disease

Diabetes is a severe chronic disease that affects approximately 200 million individuals worldwide, with extremely debilitating effects and considerably high health care costs. The two major classes of diabetes, known as type 1 (previously known as insulin-dependent or juvenile-onset diabetes) and type 2 (non-insulin-dependent diabetes), share common symptoms such as hyperglycemia and the development of long-term complications, but they differ in many aspects, including their etiopathogenesis. New insights suggest that overlapping factors, formerly considered typical hallmarks of each specific type, can coexist in the same diabetic patient, making it difficult to support a sharp distinction between the two classes and, more importantly, to adopt appropriate therapeutic solutions. In type 1 and type 2 diabetic subjects, but even more in patients with combined types, multiple genetic factors play a role in determining susceptibility or resistance to the disease, and perhaps also the time of onset, the severity of the symptoms, the possibility of developing complications and, ultimately, the response to therapy. In this review, the therapeutic treatments currently under investigation, as well as the curative strategies envisioned for future applications, are reanalyzed considering the multifaceted and complex aspects of a continuum that can be just defined as "diabetes."     

Gene transfer of constitutively active Akt markedly improves human islet transplant outcomes in diabetic severe combined immunodeficient mice

Akt is an important intracellular mediator of beta-cell growth and survival in rodents. However, whether constitutive activation of Akt in human beta-cells enhances the survival and function of transplanted islets is unknown. In the current study, we examined the efficacy of constitutive activation of Akt in improving human islet transplant outcomes using a marginal mass model in diabetic severe combined immunodeficient (SCID) mice. Human islets transduced with adenoviruses encoding constitutively active Akt1 (Adv-CA-Akt) displayed increased total and phosphorylated Akt and Akt kinase activity compared with control islets. Expression of CA-Akt in human islets induced a significant increase in beta-cell replication and a significant decrease in beta-cell death induced by serum and glucose deprivation or chronic hyperglycemia. Two control groups of islets (1,500 uninfected or adenovirus LacZ [Adv-LacZ]-transduced human islet equivalents [IEQs]) transplanted under the kidney capsule of streptozotocin-induced diabetic SCID mice were insufficient to correct hyperglycemia. Importantly and in marked contrast to these controls, 1,500 Adv-CA-Akt-transduced IEQs were capable of restoring euglycemia in diabetic SCID mice. Moreover, blood glucose normalization persisted for at least 6 months. Human plasma insulin at day 54 after transplant was 10-fold higher in Adv-CA-Akt islet recipients (2.4 +/- 0.4 ng/ml) compared with those receiving Adv-LacZ islets (0.25 +/- 0.08 ng/ml) (P < 0.05). In summary, expression of CA-Akt in human islets improves islet transplant outcomes in a subcapsular renal graft model in SCID mice. Akt is an attractive target for future strategies aimed at reducing the number of islets required for successful islet transplantation in humans.     

Proton spectroscopy in Alzheimer's disease and cognitive impairment not dementia: a community study

OBJECTIVE: To describe the proton magnetic resonance spectroscopy (1H-ERM) data in Alzheimer's disease (AD) and Cognitive Impairment Not Dementia (CIND) in a community sample. METHOD: We investigated subjects with AD (n=6), CIND (n=7) and normal control (n=7). 1H-ERM was performed with single voxel (8 cm3) placed in temporal, parietal and occipital regions and studied metabolites were: N-acetylaspartate (NAA), creatine (Cr), choline (Cho) and myo-inositol (mI). RESULTS: NAA concentration was higher in control subjects than AD and intermediated in CIND patients. Cho parietal plus occipital and Cr parietal plus Cho occipital classified correctly 92.3% of subjects Control vs AD. Temporal mI classified 78.6% of subjects between Control vs CIND. CONCLUSION: Spectroscopy can be used in the diagnosis and follow-up of individuals with cognitive impairment; evaluation of community subjects may show different patterns of brain metabolites distribution.     

Response of human islets to isolation stress and the effect of antioxidant treatment

The process of human islet isolation triggers a cascade of stressful events in the islets of Langerhans involving activation of apoptosis and necrosis and the production of proinflammatory molecules that negatively influence islet yield and function and may produce detrimental effects after islet transplantation. In this study, we showed that activation of nuclear factor-kappaB (NF-kappaB) and poly(ADP-ribose) polymerase (PARP), two of the major pathways responsible for cellular responses to stress, already occurs in pancreatic cells during the isolation procedure. NF-kappaB-dependent reactions, such as production and release of interleukin-6 and -8 and macrophage chemoattractant protein 1, were observed days after the isolation procedure in isolated purified islets. Under culture conditions specially designed to mimic isolation stress, islet proinflammatory responses were even more pronounced and correlated with higher islet cell loss and impaired secretory function. Here we present novel evidence that early interventions aimed at reducing oxidative stress of pancreatic cells and islets through the use of the catalytic antioxidant probe AEOL10150 (manganese [III] 5,10,15,20-tetrakis [1,3,-diethyl-2imidazoyl] manganese-porphyrin pentachloride [TDE-2,5-IP]) effectively reduces NF-kappaB binding to DNA, the release of cytokines and chemokines, and PARP activation in islet cells, resulting in higher survival and better insulin release. These findings support the concept that the isolation process predisposes islets to subsequent damage and functional impairment. Blocking oxidative stress can be beneficial in reducing islet vulnerability and can potentially have a significant impact on transplantation outcome.     

Simultaneous liver-kidney transplantation for glycogen storage disease type IA (von Gierke's disease)

INTRODUCTION: Glycogen storage disease type Ia (GSDIa) is due to the deficiency of glucose-6-phosphatase activity in the liver, kidney, and intestine. Although significant progress has been achieved in the management of patients with GSDIa, complications still emerge. The potential for development of liver adenomatosis and kidney failure makes these patients candidates for simultaneous liver-kidney transplantation (SLKT). Herein, we describe such a transplantation in a patient affected by this rare storage disease. METHODS: A 25-year-old female patient with GSDIa developed hepatic adenoma and kidney failure despite dietary therapy. The patient underwent an SLKT from a cadaveric donor. RESULTS: The operative time was 8 hours without hemotransfusion. Only a transitory lactic acidosis was observed. Laboratory results normalized on postoperative day 7. The patient was discharged on postoperative day 9. After 4 months, the patient is in good condition with well-functioning kidney and liver allografts. CONCLUSION: Patients with end-stage renal disease secondary to GSDIa should be considered for SLKT, especially when the disease is in an early stage.     

Potential predictive value of the MELD score for short-term mortality after liver transplantation

In the last years, a model for end-stage liver disease (MELD) was suggested as a disease severity score for patients with end-stage liver disease awaiting liver transplantation. In the early 2002, United Network for Organ Sharing (UNOS) has proposed to replace the current status 2A, 2B, and 3 by a modified version of the original MELD score based upon patient risk for 3-month mortality on the waiting list. In this study UNOS status and MELD score were evaluated retrospectively for postoperative 3-month mortality in patients who underwent liver transplantation from 2000 to 2001. Liver recipients were stratified for UNOS status 2A, 2B, and 3, and the corresponding MELD score was calculated for each patient. A receiver operating characteristic (ROC) analysis was performed for both conventional UNOS status and MELD score by fitting patient deaths within 3 months after liver transplantation. The MELD score revealed a better prediction rate for 3-month mortality after the first LT than conventional UNOS status, although no statistical significance was evident by ROC curve comparison. This preliminary study seems to suggest a potentially better predictive rate for the MELD score than conventional UNOS status concerning short-term mortality after liver transplantation.     

Liver transplantation with monosegment from a living donor

The shortage of organ donors for low-weight liver transplant recipients, especially for small children, has led to the development of new surgical techniques to increase the donor pool. Almost all of these techniques use the left lateral segment (Couinaud's segments II and III), but even this graft could be too large for children under 10 kg. We report here the case of an 8-month-old boy, weighing 6.1 kg, who received a monosegmental graft (segment III) from his grandmother weighing 68 kg. The graft was reduced at the donor surgery, before clamping of the vessels. The donor was discharged on the fourth post-operative day; the recipient had an uneventful post-operative period and was discharged after 22 days.