Increased levels of adenosine and ecto 5'-nucleotidase (CD73) activity precede renal alterations in experimental diabetic rats.

The pathogenesis of diabetic nephropathy (DN) has not been clearly established, making diagnosis and patient management difficult. Recent studies using experimental diabetic models have implicated adenosine signaling with renal cells dysfunction. Therefore, the study of the biochemical mechanisms that regulate extracellular adenosine availability during DN is of emerging interest. Using streptozotocin-induced diabetic rats we demonstrated that urinary levels of adenosine were early increased. Further analyses showed an increased expression of the ecto 5'-nucleotidase (CD73), which hydrolyzes AMP to adenosine, at the renal proximal tubules and a higher enzymatic activity in tubule extracts. These changes precede the signs of diabetic kidney injury recognized by significant proteinuria, morphological alterations and the presence of the renal fibrosis markers alpha smooth muscle actin and fibronectin, collagen deposits and thickening of the glomerular basement membrane. In the proximal tubule cell line HK2 we identified TGF-ß as a key modulator of CD73 activity. Importantly, the increased activity of CD73 could be screened in urinary sediments from diabetic rats. In conclusion, the increase of CD73 activity is a key component in the production of high levels of adenosine and emerges as a new tool for the early diagnosis of tubular injury in diabetic kidney disease.

[Psychomotor development in offspring of mothers with post partum depression]. / Alteración del desarrollo psicomotor en hijos de mujeres con depresión posparto de la ciudad de Valdivia-Chile.

BACKGROUND: Postpartum depression (PPD) has adverse effects on psychomotor development of the offspring. AIM: To evaluate the relationship between PPD and psychomotor development in children aged 18 months, consulting in primary care. MATERIAL AND METHODS: Cross-sectional study with 360 infants and their mothers. Children had their psychomotor evaluation at l8 months and mothers completed the Edinburgh Postnatal Depression Scale at 4 and 12 weeks postpartum. The prevalence of both PPD and psychomotor alteration was estimated. The association between PPD and psychomotor alteration, including confounding variables, was estimated through logistic multiple regression analysis. RESULTS: The prevalence of PPD and psychomotor alteration was 29 and 16%, respectively Mothers with PPD had twice the probability of having an offspring with psychomotor alteration (Odds ratio = 2.0, confidence intervals = 1.07-3.68). This probability was significantly higher among single mothers or those with an unstable partner. CONCLUSIONS: PPD has a detrimental impact on psychomotor development of children.

[Clinical and epidemiologic analysis of intestinal tract colonization with vancomycin-resistant enterococci in an intensive care unit]. / Análisis clínico-epidemiológico de la portación intestinal de enterococos resistentes a vancomicina en una unidad de terapia intensiva.

Intestinal tract colonization with vancomycin resistant enterococci (VRE) was studied during five months and 25 days. Out of 171 patients hospitalized in the intensive care unit, 124 (73%) were included in this study. Thirty five of them (28%) were recognized as colonized with VRE. VRE isolates (n = 35) were identified as Enterococcus faecium (n = 18), Enterococcus gallinarum (n = 16), and Enterococcus raffinosus (n = 1). All of them were resistant to vancomycin (MIC90 = 512 microg/ml) and to teicoplanin (MIC90 = 32 microg/ml), having the vanA gene. By means of molecular methods a high homology was found among E. faecium and E. gallinarum isolates, respectively, suggesting their spread as a kind of outbreak. No significant differences in age or sex were found among colonized and non-colonized patients (p > 0.05). On the other hand, the hospitalization time and the use of broad-spectrum antibiotics were associated with colonization. From this study we highlight the importance of enhancing all measures of control and prevention of hospital infections, carefully analyzing the empiric antimicrobial schemes, trying to reduce the hospital stage, and following the surveillance to evaluate the efficacy of such procedures.

Epstein-Barr virus infection in liver transplantation patients: correlation of histopathology and semiquantitative Epstein-Barr virus-DNA recovery using polymerase chain reaction.

Epstein-Barr virus (EBV) infection may complicate orthotopic liver transplantation, and can lead to hepatitis with subsequent graft failure and to benign and malignant lymphoproliferative disorders. Early diagnosis allows for prevention or treatment of complications. Histopathologic features of EBV infection in the liver vary and may be difficult to recognize. To delineate the morphologic features that allow for recognition we studied 61 biopsy specimens from 37 patients, correlating the results of EBV-DNA demonstration after polymerase chain reaction with histopathology of formalin-fixed, hematoxylin-eosin-stained liver biopsy specimens. DNA was extracted from fresh liver biopsy samples, and polymerase chain reaction was carried out with EBV primers (capsid protein gp220) using standard techniques and 25-cycle amplification. Epstein-Barr virus-related sequences after polymerase chain reaction were detected by DNA blot assay. Histopathologic features were classified into three categories on the basis of the semiobjective determination of the number and distribution of immunoblasts and other immature lymphocytes in portal tracts and sinusoids: highly suggestive (three biopsy specimens), indeterminant (one biopsy specimen), and negative (57 biopsy specimens). Only the three highly suggestive biopsy specimens had high levels of EBV-DNA. We conclude that the histopathologic features of EBV infection after orthotopic liver transplantation can be relied on to establish the diagnosis.

Comparison of UW with other solutions for liver preservation in dogs.

The efficacy of the University of Wisconsin (UW) solution was compared with conventional Euro-Collins solution, as well as with 3 variants of a silica gel solution developed at the University of Minnesota (UM). Protection of the liver grafts with UW was superior after 24 hour preservation, although the results were inferior to those with immediate transplantation, as judged by animal survival, liver function tests, coagulation, and histopathologic parameters. The UM-III solution allowed similar animal survival as with the UW solution. Lactobionate and raffinose that are contained in both the UW and UM-III solutions were thought to be essential constituents for long-term preservation of liver grafts. The study not only establishes, under controlled circumstances, the superiority of the UW solution, but it also provides insight about the reasons for its effectiveness as well as a caution against its over exploitation.

Enhanced oral cyclosporine absorption with water-soluble vitamin E early after liver transplantation.

We evaluated the effect of Liqui-E, a water-soluble vitamin E preparation, on cyclosporin A (CyA) whole blood concentration in liver transplant recipients, and its impact on the cost of CyA. Patients were 26 liver transplant recipients (19 adults, 7 children) who were unable to achieve and maintain therapeutic CyA whole blood concentrations with the standard recommended oral daily dose in the early post-transplant period. Liqui-E 6.25 IU/kg orally was administered with CyA every 12 hours (median time of starting Liqui-E day 14.5). With Liqui-E, the daily oral CyA requirements (mean +/- SD) were decreased in adults from 22.6 +/- 8.9 to 16.2 +/- 7.3 mg/kg/day (p < 0.001) and in children from 78.6 +/- 34.1 to 53.7 +/- 35.0 mg/kg/day (p < 0.02); intravenous administration of CyA was unnecessary. The CyA trough concentrations (mean +/- SD) before and after Liqui-E were 670 +/- 186 and 1012 +/- 216 ng/ml, respectively, in adults (p < 0.001) and 732 +/- 187 and 1052 +/- 166 ng/ml, respectively, in children (p < 0.01). When given with Liqui-E, the daily cost of CyA decreased by 26% in both adults and children. No clinical or biochemical evidence of Liqui-E toxicity was observed. Thus its administration in the early post-transplantation period can enhance CyA absorption in adults and children who are unable to achieve adequate whole blood concentrations with the usual recommended oral dosages. In addition, a significant cost saving can be realized by coadministration.

Pediatric liver transplantation.

The excellent survival rates that have been achieved by pediatric liver transplantation today can be attributed to a multitude of factors. Refinements in immunosuppressive regimens, new immunosuppressive agents, improvements in surgical technique, and a better understanding of the unique issues that pertain to patient care have resulted in not only excellent survival rates, but also improvements in quality of life. The future promises even more progress in the directions of tolerance induction, expansion of the donor organ pool, and genetic manipulation allowing cellular transplantation for correction of inborn errors of metabolism.

Late surgical complications of choledochal cystoenterostomy.

Choledochal cyst is a rare congenital abnormality of the biliary tract characterized by dilatation and stasis. Cyst excision is now preferred to internal drainage because of the predilection for development of cancer in the unresected cyst wall. We report on four patients who required reoperations for complications of prior cystoenteric drainage from 14 to 21 years after the original operations. Gastrointestinal bleeding from cyst ulceration as occurred in one patient is heretofore unreported. This reoperative experience emphasizes the importance of cyst excision as primary therapy and underscores these principles: 1) The spectrum of complications, including infection, pancreatitis, cancer, and bleeding may occur with or without intracyst and ductal stones; 2) Radical operative procedures may be required for treatment of the complications; 3) Despite these, cholangiocarcinoma has a dismal prognosis; 4) Patients whose cysts remain unexcised require meticulous lifelong scrutiny and strong consideration for planned reoperation at the time of the first complication.

Hepatic resection for malignancy in the elderly.

Although elderly patients are accounted for in all large series of major hepatic resections, the role of age as a determinant of outcome remains unclear. At Cedars-Sinai Medical Center, we review a series of 20 major hepatectomies for neoplasia performed in patients older than 66 years of age (4 of them > or = 80 years old) over a 5-year period. A retrospective comparison was conducted with a group of 22 hepatectomies for malignancy performed in 20 patients younger than 59 years of age during the same time period. The younger group had a significantly greater degree of liver resected (12 trisegmentectomies vs 3). Although one operative death (5% mortality) was observed in the elderly group, no statistically significant difference was noted, when compared to the younger group (Chi-square, P = 0.48). Likewise, no significant difference in the complication rate (20% vs 33%) was noticed (Chi-square, P = 0.8). Severe postoperative liver dysfunction was present in 2 cases (10%) in the elderly group and one (4%) in the younger group. These patients underwent a right trisegmentectomy (TS). Nine patients from each group were resected without red blood cell transfusion. We conclude that major hepatic resection in elderly patients without severe comorbid disease is a safe procedure that is not associated with an increased perioperative morbidity or mortality rate.

Bilateral simultaneous rupture of the infrapatellar tendon in a recreational athlete. A case report.

Bilateral rupture of the infrapatellar tendons is a rare event in an otherwise healthy athletic individual. The event is usually quite severe and diagnosis can be readily made on a clinical examination. In the case presented here, predisposing factors consisted of an underlying patella alta and a long history of repetitive trauma to the knee. Prompt diagnosis and surgical repair will lead to a good functional result.

The long-term followup of primary anterior cruciate ligament repair. Defining a rationale for augmentation.

Fifty primary ACL repairs using the Marshall multiple suture technique were analyzed. The average age at surgery was 23 years (range, 15 to 56), with 76% under the age of 30. The average followup was 61.3 months (range, 48 to 86). The average time from injury to surgery was 7 days (range, 1 to 18). Eighty percent of the injuries were sports-related with football and skiing predominating. Thirty-eight percent were "isolated" ACL tears, and 62% had associated injuries. There was a 46% incidence of meniscal tear with 59% of the meniscal tears being repaired. The postoperative evaluation included a multifactorial analysis correlating 43 variables including subjective, objective, radiographic, and KT-1000 data. The Hospital for Special Surgery Knee Diagnostic Score, a clinical objective score based on the postoperative Lachman and pivot shift examination, a KT-1000 arthrometer data score, and an overall combined assessment score were determined. The results showed 59% excellent, 18% good, 14% fair, and 8% poor. The Lachman test was diagnostic in all cases. The quality of ACL tissue at repair was rated excellent or good in 62% of the cases. Four patterns of ACL tears were distinguished by the location of the tear. Football injury, younger age, increased peroperative pivot shift, midsubstance Type IV tear, and return of full motion correlated with poor postoperative results. Increasing age, tight jointedness, Type I tears, and a 5 degrees flexion contracture correlated with good postoperative results.

Hepatocellular adenoma in glycogen storage disease type IV.

The development of hepatocellular adenoma has been recognized in association with glycogen storage disease type I and, less often, with glycogen storage disease type III, but, to our knowledge, it has not been reported in glycogen storage disease type IV. We had the opportunity to study an 11-month-old male infant who underwent orthotopic liver transplantation for cirrhosis that developed in the setting of glycogen storage disease type IV. A clinically unsuspected hepatocellular adenoma was present in the explanted liver. Glycogen storage disease type IV should be considered as a potential precursor to the development of hepatocellular adenoma. Recognition of this association is important, both in terms of the differential diagnosis of tumors that occur in this setting and also to anticipate potential complications of this benign neoplasm.

Improved method of porcine renal allografting for transplantation research.

This study presents a refined, reproducible, and clinically appropriate animal model of renal transplantation. A pair of kidneys are harvested from a donor pig and preserved in Euro-Collins' solution (4 degrees C). After a set period of preservation, the allografts are transplanted to two recipient pigs. The abdomen is entered through a midline incision. The right common iliac artery and vein are dissected and bilateral native nephrectomy is performed. Each allograft is then randomly assigned and transplanted to the recipients. Three minutes before unclamping, 100 mg of furosemide and 10 g of mannitol are given IV. Immediately after reperfusion, urine output is measured for 1 h. The allograft is biopsied and ureteroneocystostomy is created. Cystostomy is then placed using a 16F Foley catheter. The bladder neck is ligated to secure complete diversion of urine, and the abdomen is closed in layers. This kidney transplant model allows an absolutely paired study of the kidney allograft function from the same donor and also collection of pure urine at any time postoperatively, obviating the need for metabolic cages or sedation for urinary collection. This model and its unique modifications allow various transplant studies, including organ preservation, immunosuppressive protocol, and the prevention of reperfusion injury from oxygen free radicals.

Immunodepletion in xenotransplantation.

Xenograft transplantation is perhaps the most immunologically difficult problem in transplantation today. An overwhelming hyperacute rejection reaction (HAR) occurs within minutes of organ implantation. Preformed antibodies are thought to initiate this process. We used a pig-to-dog renal xenograft transplant model and investigated methods of decreasing the severity of hyperacute rejection. Female pigs weighing 15-20 kg were used as donors. Recipients were mongrel dogs weighing 15-25 kg. Experimental dogs were all given a number of treatments of IgG depletion using an antibody removal system (Dupont-Excorim). This machine immunoadsorbs plasma against a column containing immobilized staphylococcal protein A, which is known to bind the IgG Fc receptor. An 84% reduction in the IgG levels and a 71% reduction in IgM levels was achieved. Postoperative assessment was made of urine output, time to onset of HAR, and histopathological examination of the rejected kidneys. Although cross-matches between donor lymphocytes and recipient sera remained strongly positive in the treated dogs, there was a two- to fourfold reduction in the titers. The time to onset of HAR was prolonged in the experimental group, and the urine output was increased slightly. The histopathologic changes in the experimental group generally showed signs of HAR, but of less intensity than in the nonimmunodepleted control group.

Liver regeneration in rats treated with the antiandrogen flutamide.

Previous studies have shown that male rat liver undergoes demasculinization during hepatic regeneration after partial hepatectomy. In the present study the effect of the antiandrogen flutamide on liver regeneration was assessed. Adult male Wistar rats were treated with flutamide (2 mg/rat/day or 5 mg/rat/day subcutaneously) or vehicle for 3 days prior to and daily after partial hepatectomy. Rates of DNA and polyamine synthesis were assessed by measuring thymidine kinase and ornithine decarboxylase activities, respectively. The rate of liver growth after partial hepatectomy in the three groups was similar at all time points examined. The increases in thymidine kinase activity and ornithine decarboxylase activity after partial hepatectomy were comparable throughout the study. Thus, administration of flutamide did not influence the regenerative response after partial hepatectomy.

Orthotopic liver transplantation in dogs receiving FK-506.

Ten dogs that survived the perioperative events of liver transplantation were treated with 1 mg/kg/d oral FK. Eight of the recipients lived for at least 1 month postoperatively, and seven are still alive with normal hepatic function after 35 to 65 days. The consistency and good quality of results with this difficult transplant preparation using FK, in spite of its rumored great toxicity in dogs, have highlighted the importance of further developing the drug.

Effect of FK506 in experimental organ transplantation.

FK506 is the most potent immunosuppressive agent known. Its toxicity is substantial in dogs, minor in rats, and unknown in subhuman primates. In small doses that are nontoxic even in dogs, it can be used in synergistic combination with cyclosporine, steroids, and presumably in other drugs.

Liver transplantation: an unfinished product.

Liver transplantation has become an extraordinarily valuable and useful operation, but one that is not perfect and that has not been exploited to anything like its full potential. Better immunosuppression may become available soon as exemplified by developments with the Japanese drug, FK506. Improved preservation with the UW solution is already here. With these advantages, liver transplantation is certain to become far more widely used than at any time in the past. Examples were cited of innovative approaches using liver transplantation for the treatment of hepatic malignancies.

Amelioration of normothermic canine liver ischemia with prostacyclin.

A model of hepatic ischemia was developed in dogs using a pump-driven splanchnic-to-jugular vein bypass during crossclamping of the portal triad. An LD50 was established with three hours of ischemia. PGI2 given for one hour before the ischemic insult ameliorated the ischemic injury and increased survival.

Knee bracing.

Bracing the knee is a controversial, complex, and often confusing subject. Knee braces are categorized as either prophylactic, rehabilitative, or functional. Bracing goals are to prevent, assist, restrict, align, or simulate function of the knee. A working knowledge of the capabilities and limitations of specific braces in these different categories is required of the physician to properly prescribe these orthotics.