[Results of Surgical and Conservative Treatment for Enterocutaneous Fistulas. Is there an Indication for Conservative Treatment?]. / Therapieergebnisse von Operation und konservativer Therapie enterokutaner Fisteln. Gibt es eine Indikation zur konservativen Behandlung?

INTRODUCTION: The manifestation of enterocutaneous fistulas is varied. They can range from controlled secretion via the abdominal wall to septic disease. The disease is categorised into low-, moderate- and high-output fistulas. Often the only option is surgical treatment. Occasionally, there is spontaneous healing under conservative treatment. The aim of this study was to work out a possible subgroup of patients who benefit from conservative treatment. Material und Methods: Ninety-nine patients were treated for enterocutaneous fistulas from 1 January 1995 to 31 December 2005. Seventy patients underwent surgery, 29 patients were treated conservatively. All data was collected prospectively using an admission form and was analysed retrospectively. Conservative treatment consisted of fasting with parenteral nutrition, while fistulas in the surgical group were treated by suture repair or resection. Additive treatments such as vacuum dressings or TNF-α medication for patients with Crohn's disease were not performed. RESULTS: In our study we achieved a total cure rate of 69%, with an average hospital stay of 38 days. Surgical treatment led to significantly better results compared with conservative treatment (83 vs. 34%). Mortality in the surgical group was distinctly, but not significantly reduced at 7%, compared with 14% in the conservative group. The fistulas that healed after conservative treatment were low-output fistulas only. CONCLUSION: Enterocutaneous fistulas are diseases associated with long hospital stays and, therefore, expensive treatment. Low-output fistulas may heal spontaneously. The best results are achieved by surgical treatment. More recent treatments such as vacuum therapy and TNF-α medication for patients with Crohn's disease are promising approaches. In the future, many of these will have to be combined with surgical treatment.

[Colorectal Carcinoma in Young Patients - Is Age a Prognostic Factor?]. / Das kolorektale Karzinom (KRK) beim jungen Patienten - ist das Alter ein prognostischer Faktor?

INTRODUCTION: Concerning younger patients with colorectal carcinoma (CRC) controversies still exist regarding outcome. The aim of this study was to evaluate possible differences between patients suffering from CRC at a younger age (< 40 years) and at an age over 40 years. PATIENTS AND METHODS: Data of 51 younger patients (< 40 years) and 2122 older patients (≥ 40 years) were prospectively collected and retrospectively evaluated according to clinical parameters, treatment and prognosis. Patients with a CRC arising from familial adenomatous polyposis, ulcerative colitis or Crohn's disease have been excluded. RESULTS: The younger patients presented significantly more often with mucinous adenocarcinomas (p = 0.033). There were no differences between the groups concerning gender, localisation, elective and emergency surgery, UICC (Union internationale contre le cancer) stages and residual tumour classification. Postoperative therapy - in adjuvant, therapeutic or palliative intent - was applied significantly more often in younger patients, especially in those with colon carcinoma (p = 0.001). After curative resection of colon carcinoma a significantly better observed (5 year rate 94 vs. 76 %; p = 0.024) and disease-free (88 vs. 69 %; p = 0.013) survival were found. This trend was similar in patients with rectal carcinoma (84 vs. 75 % and 72 vs. 65 %) without reaching the level of significance (p = 0.155 and 0.269). Taking into account differences in life expectancy, just minor differences were detected in relative survival (colon carcinoma, 5 year rate 94 vs. 89 %; rectal carcinoma, 84 % both). CONCLUSIONS: The general assumption of a poorer prognosis in younger patients with CRC could not be confirmed. Younger patients have a poorer histological subtype of carcinoma. But this is compensated by the better overall condition, less comorbidities, faster postoperative recovery and an optimally organised post-operative (adjuvant, therapeutic or palliative) therapy. In summary, younger patients have a better observed survival but - considering differences in life expectancy - a similar relative survival.

Long-term outcome of liver transplantation as treatment modality in patients with hepatocellular carcinoma in cirrhosis: a single-center experience.

BACKGROUND: Hepatocellular carcinoma (HCC) is among the most frequent malignant diseases worldwide. In the vast majority of cases, it is associated with liver cirrhosis. Liver transplantation (OLT) is potentially the gold standard treatment for patients suffering HCC in cirrhosis, because of synchronous eradication of HCC and of the underlying hepatic disease. The aim of this study was to evaluate long-term outcomes of OLT in HCC patients. MATERIAL AND METHODS: Between January 2000 and December 2011, 43 patients who were diagnosed with HCC in liver cirrhosis and underwent OLT in our department, were identified from a prospective database. All patients received their grafts from deceased donors. We analyzed demographic data, laboratory values, number and size of lesions, primary liver disease, diagnostic methods, bridging therapy modalities, and postoperative outcomes, including complications, recurrences, and their treatment. RESULTS: Patient follow-up as of January 2012 or to death ranged from 0 to 138 months (median, 59; mean, 63). None of the patients were lost to follow-up. The gender bias was 85%:15% (male:female) and the median age, 57.8 years (range, 44-69). The most common underlying diseases for cirrhosis and HCC were alcoholic (n = 12) and hepatitis C (n = 16). Thirty-one subjects underwent bridging therapy through transarterial chemoembolization (TACE), and/or radiofrequency ablation. All patients underwent OLT within the Milan criteria according to the preoperative evaluation and histopathologic examination of the explanted liver. Twenty-one of them suffered postoperative complications (48.8%). HCC recurrence, which occurred in 5 (10.4%), was treated by surgery (n = 3), systemic chemotherapy with sorafenib (n = 1), or TACE (n = 1). CONCLUSIONS: OLT for HCC in cirrhosis, displays a relatively high complication rate. It shows good survivals with and low recurrence.

Expression of annexin AI in conventional renal cell carcinoma (CRCC) correlates with tumour stage, Fuhrman grade, amount of eosinophilic cells and clinical outcome.

There is increasing evidence that Annexin AI (ANX AI) expression is dysregulated in several carcinomas and tumour cell lines. In order to gain insight into the putative role of ANX AI in tumorigenesis, clinical outcome and metastatic potential of conventional renal cell carcinomas (CRCCs) we investigated the expression of ANX AI in CRCCs and metastases. Furthermore, it was elucidated whether ANX AI overexpression affects migratory potential in Caki-1 cells. ANX AI immunohistochemistry was performed on 33 samples of CRCCs and 10 metastases. ANX AI expression was assessed in 12 samples by 2-dimensional gelelectrophoresis (2-DE), subsequent mass spectrometry and RT-PCR. Immunohistochemical data were statistically correlated with pathological parameters, amount of eosinophilic cells and clinical outcome. Furthermore, a haptotactic migration assay was done on Caki-1 cells transfected with ANX AI. Immunostaining for ANX AI was found in 18 tumours and all metastases investigated. Intensity of immunohistochemical staining correlated to Fuhrman grade, amount of eosinophilic cells and clinical outcome. 2-DE and RT-PCR confirmed the presence of ANX AI in neoplastic tissue. Overexpression of ANX AI did not significantly influence cell migration. From these findings ANX AI expression seems to be related to Fuhrman grade, clinical outcome and metastatic potential of CRCCs. Thus ANX AI could serve as a prognostic marker for tumour progression.

Pharmacokinetic interaction of digoxin with an herbal extract from St John's wort (Hypericum perforatum).

OBJECTIVE: Extracts of St John's wort (Hypericum perforatum) are widely used in the treatment of depression, often as an over-the-counter drug. In contrast to its frequent use, knowledge about the pharmacokinetics of ingredients and drug interactions of St John's wort is poor. We studied the interaction between hypericum extract LI160 and digoxin. METHODS: The pharmacokinetics of digoxin were investigated in a single-blind, placebo-controlled parallel study. After the achievement of steady state for digoxin on day 5, healthy volunteers received digoxin (0.25 mg/d) either with placebo (n = 12) or with 900 mg/d LI160 (n = 13) for another 10 days. Digoxin concentration profiles on day 5 were compared with day 6 (single-dose interaction) and day 15 (tenth day of co-medication). RESULTS: There was a highly significant combined-day-and-group effect for digoxin area under the plasma concentration-time curve [AUC(0-24); P = .0001], peak concentration in plasma (Cmax; P = .0001), and plasma drug concentration at the end of a dosing interval (P = .0003) by two-way ANOVA. No statistically significant change was observed after the first dose of hypericum extract [AUC(0-24) at day 6 of 18.1+/-2.9 microg x h/L and 17.7+/-3.0 microg x h/L, mean +/- SD for placebo and hypericum group, respectively]. However, 10 days of treatment with hypericum extract resulted in a decrease of digoxin AUC(0-24) by 25% (day 15, 17.2+/-4.0 microg x h/L and 12.9+/-2.3 microg x h/L; P = .0035). Furthermore, comparison with the parallel placebo group after multiple dosing showed a reduction in trough concentrations and Cmax of 33% (P = .0023) and 26% (P = .0095), respectively. The effect became increasingly pronounced until the tenth day of co-medication. CONCLUSION: As with grapefruit juice, a food product, physicians should also be aware of potential drug-herb interactions. The interaction of St John's wort extract with digoxin kinetics was time dependent. The mechanism involved may be induction of the P-glycoprotein drug transporter.

Hypericin levels in human serum and interstitial skin blister fluid after oral single-dose and steady-state administration of Hypericum perforatum extract (St. John's wort).

The photodynamically active plant pigment hypericin, a characteristic metabolite of Hypericum perforatum (St. John's wort), is widely used as an antidepressant. When administered orally, phototoxic symptoms may limit the therapeutic use of hypericin-containing drugs. Here we describe the high-performance liquid chromatographic (HPLC) detection of hypericin and semiquantitative detection of pseudohypericin in human serum and skin blister fluid after oral single-dose (1 x 6 tablets) or steady-state (3 x 1 tablet/day, for 7 days) administration of the Hypericum extract LI 160 in healthy volunteers (n = 12). Serum levels of hypericin and pseudohypericin were always significantly higher than skin levels (p 100 ng/ml).

The hypertensive Ren-2 transgenic rat TGR (mREN2)27 in hypertension research. Characteristics and functional aspects.

Primary human hypertension is a polygenic disorder. It is the prevalent cause of cardiovascular disease leading to cardiac failure, stroke, chronic renal failure and, ultimately to death. Several genes are involved in cardiovascular control mechanisms and their genetics are complex. Experimental models which are well defined are needed to clarify the role of individual genes. The generation of the hypertensive transgenic rat line TGR (mREN2)27 bearing the murine Ren-2 gene cloned from the DBA/2J mouse strain provides a monogenic model of hypertension in which the genetic basis (the additional renin gene) is known. These rats develop severe hypertension, which reaches 200 mm Hg and higher at 8 weeks of age in the heterozygous animal. Homozygous rats develop even higher blood pressures than heterozygous animals, which is paralleled by a higher mortality rate in homozygous rats. Animals develop pathomorphologic alterations which are characteristic for systemic hypertension. The transgenic rats are characterized by unchanged or even suppressed concentrations of active renin, angiotensin I (ANG I), ANG II, and angiotensinogen compared to transgene-negative littermates. In contrast, plasma levels of inactive renin (prorenin) are much higher in TGR (mREN)27 rats than in control animals. In the kidneys, renin is suppressed, probably mediated through negative feedback inhibition, in other tissues, especially in the adrenal gland, murine Ren-2 mRNA is expressed at very high levels. The cascade of pathophysiologic events which finally lead to hypertension is not fully understood in this rat model. Treatment with ACE inhibitors or angiotensin II receptor antagonists such as losartan is extremely efficient, which could mean that hypertension in this model is mediated through ANG II. Since the the renin-angiotensin system (RAS) in the kidneys is suppressed, other ANG II generating sites must be considered. This favors the concept of extrarenal RASs in this model.

Role of the cardiac renin-angiotensin system in human heart failure.

The local effects of angiotensin II (ANG II) on the heart may play an important role for the pathophysiology of cardiovascular disease. Numerous in vitro studies have demonstrated that angiotensin II has distinctive cellular effects in the cardiovascular system which are independent from its effects on blood pressure. These have led to the hypothesis that activation of the angiotensin system in the heart could be of functional relevance for the adaptive processes in several cardiovascular disorders such as cardiac hypertrophy heart failure. This concept has been further supported by clinical studies showing the beneficial effects of angiotensin-converting enzyme inhibitors in these circumstances. In order to study the gene regulation of renin-angiotensin system components in cardiac disorders we investigated the gene expression of angiotensin converting enzyme in human heart failure. Results showed that the enzyme is activated locally in this condition, supporting previous studies in animals. Taken together with recent evidence from genetic studies linking the enzyme to myocardial infarction and cardiac hypertrophy, our findings are in support of the notion that angiotensin converting enzyme plays a central role in cardiovascular physiology and pathophysiology.

PCR analysis of human renal biopsies--renin gene regulation in glomerulonephritis.

Animal studies show that the renin-angiotensin system contributes to hypertension, glomerulosclerosis and progressive chronic renal failure in renal disease. Direct data on the activity of the renal renin-angiotensin system (RAS) in human renal disease are scarce, however. The small amount of tissue in renal biopsies and insufficient sensitivity of analytical methods have precluded reliable measurements of the tissue components of the RAS in the past. Due to its highly sensitivity the quantitative polymerase chain reaction (QPCR) assay today allows the quantitation of gene transcription products in small tissue samples, for example, renal biopsies. The clinical applicability of the PCR has raised the interest in this methodology. We adopted quantitative PCR to study expression and regulation of the renin gene in patients with different forms of glomerulonephritis. For PCR a deletion mutant of the renin gene was used as an internal standard exhibiting the same primer binding sites as the human gene. The number of glomeruli per biopsy sample was counted by microscopic transillumination immediately after biopsy and was used as a reference base. Renin mRNA was expressed as fg per glomerulus. Compared to nonaffected tissue of tumor nephrectomy samples, renin gene expression was significantly lower in glomerulonephritic patients without converting enzyme inhibitor (CEI) treatment, that is, 63 +/- 20 (6) versus 250 +/- 50 (7) (P < 0.02), although plasma renin concentration was in the normal range. Significantly higher renin mRNA expression was found in patients with glomerulonephritis treated with CEI, that is, 210 +/- 50 (8) versus 63 +/- 20 (6) in patients not treated.(ABSTRACT TRUNCATED AT 250 WORDS)

Glucose content and efficiency of glycolysis in protected ischemic kidneys of different species.

In ischemic canine kidneys protected by Bretschneider's HTK solution the glycolytic lactate production is limited by a low renal substrate content. However, for anaerobic energy supply ischemic organs depend on glycolysis. To evaluate the role of glycolysis in renal protection, the relationship between lactate production and anaerobic energy supply was examined in protected kidneys of dogs, sheep, and swine. Additionally, in canine kidneys an attempt was made to improve anaerobic energy provision by adding glucose to the protective solution. The results were as follows: (1) According to increasing lactate production from swine to dog to sheep, intraischemic ATP decay was delayed least in swine and most in sheep. (2) Glucose addition (10 mM) to the HTK solution roughly doubled the time for ATP to fall to 1 mumol/g dry wt (tATP) in dogs. (3) The greater the lactate production in all three species, the lower the decrease in SAN (ATP + ADP + AMP) from 5 to 120 min of ischemia. (4) A glucose additive in the protective solution led to a significant (p less than .005) increase of SAN in dogs at 120 min of ischemia. A sufficient substrate supply seems to be an essential component of a reliable renal protection.

Postischaemic interrelations between energy metabolism and functional recovery of protected canine kidneys.

Following renal ischaemia under effective protection glomerular filtration starts at a time when renal high-energy phosphates are resynthesized. The present investigation was carried out to examine the interdependence of the two processes. Therefore, canine kidneys were protected with sodium poor and nominally Ca2+ free buffered solutions. After different times of ischaemia and reperfusion the glomerular filtration rates (GFR) were determined and afterwards tissue specimens were excised for the determination of high-energy phosphates. Both the GFR and the renal energy content were higher with shorter ischaemia periods or longer reperfusion. As a rule there was a correlation between GFR and ATP, both probably mainly signifying the degree of preservation of proximal nephron sites, as the interrelation between the GFR and the renal SAN (ATP + ADP + AMP) content also signifies. However, with the addition of aspartate to the protective solution it could be demonstrated that the GFR also can rise without a concomitant increase of ATP. Under certain conditions an increase of GFR can even be associated with a lowering of the renal ATP content.

Contribution of amino acids in protective solutions to postischemic functional recovery of canine kidneys.

Amino acids are known to increase glomerular filtration rate (GFR). There is also an early resumption of filtration following 2-h renal ischemic stress under protection by histidine-buffered histidine-tryptophan-ketoglutarate solution (HTK), possibly due in part to an amino acid effect. Hence, we have examined the possibility of further enhancing the postischemic GFR by adding 32 (ASP I; 4 mM Mg2+) or 36 (ASP II; 6 mM Mg2+) mM L-aspartate (asp) or 32 mM DL-aspartate (ASP III) to the HTK solution in place of chloride. After infusion of 500 ml 5% glucose, canine kidneys were protected by an 8-min perfusion with HTK (n = 5), ASP I (n = 4), ASP II (n = 5) or ASP III-solution (n = 3). The subsequent ischemia lasted for 2 h at 27-31 degrees C. During reperfusion, both GFR and filtration fraction (FF) were higher in kidneys protected by L-aspartate-containing solutions. ASP III showed no improvement against HTK. An additional preischemic intra-aortal application of HTK or ASP I solution just above the exit of the renal arteries prior to the intrinsic protective perfusion further raised the postischemic GFR. The present results suggest that L-aspartate but also histidine may have favorable amino acid effects in renal protective solutions in addition to known positive effects of histidine.

Metabolic, energetic and structural changes in protected and unprotected kidneys at temperatures of 1 degree C and 25 degrees C.

In 110 canine kidneys, we examined the time course of energy rich phosphates, lactate, intrarenal ph and renal morphology with Euro-Collins- or with HTK-protection of Bretschneider and compared these findings with unprotected kidneys during complete ischemia at 1 degree C and at 25 degrees C. Both kidney protective solutions prolonged energy-rich phosphate-decline by a factor of 3-4 compared with that of unprotected kidneys. The lactate increase was greater in Euro-Collins-protected kidneys than in HTK-protected and in unprotected kidneys, leading to pH values of 6.5 in Euro-Collins and to 6.4 in unprotected kidneys after 24 hours, in contrast to a pH-value of 7.3 with HTK-protection. This may be the reason for structural deterioration seen in unprotected and in Euro-Collins-protected kidneys after 12, and 48 h of ischemia at 1 degree C, whereas in HTK-protected kidneys a sufficient preservation of structure can be seen. In one human kidney, protected with Euro-Collins-solution, we were able to show that at 1 degree C intrarenal pH and lactate accumulation is similar to the levels in canine kidneys. In Euro-Collins preserved kidneys lactate accumulation at 25 degrees C is even greater than at 1 degree C, leading to inhibition of energy metabolism and to structural deterioration, whereas HTK-solution, because of its high buffer concentration, is able to maintain ischemic metabolism leading to sufficient protection of intrarenal pH and of adenine nucleotides as well as structural protection at 1 degree C and at 25 degrees C.

[Kidney function parameters following ischemia stress using the Euro-Collins solution or the Bretschneider cardioplegic HTK solution]. / Nierenfunktionsparameter nach Ischämiebelastung unter der Euro-Collins-Lösung oder unter der kardioplegischen Lösung HTK nach Bretschneider.

Protection-methods, for an improvement of ischemic tolerance of the kidney, can be investigated by intraischemic analysis of metabolism and structure. A definite proof for the effectiveness of a protection method is only postischemic function in combination with postischemic structure-regeneration. For this reason postischemic function was chosen for examination of the protective ability of the Euro-Collins-solution and the HTK-solution during a two-hour reperfusion period. We perfused 57 dog kidneys either with the Euro-Collins- or with the HTK-solution prior to ischemia. Ischemia was 7, 60, 90 and 120 min after Euro-Collins-perfusion and 7, 120, 150 and 180 min after HTK-protection. The protected and ischemic kidneys were left in-situ; the mean ischemic temperature was therefore 20-25 degrees C for the shorter ischemic times and 30-34 degrees C for the longer ischemic times. We compared the protected and ischemic kidneys with 14 untreated kidneys (control). Postischemic renal blood flow (RBF) was measured by an electromagnetic flow probe; renal oxygen consumption (V02/min) was calculated by arterio-venous oxygen content difference and the renal blood flow. If urine could be collected, the glomerular filtration rate (GFR) was measured by an endogenous creatinine clearance. In Euro-Collins-protected kidneys after 60-120 min ischemia the RBF was after 15 min of reperfusion between 20 and 100 ml/min/100 g. After 30 min we got values of 100-200 ml/min/100 g. The V02/min, which was in the control kidneys between 5-6 ml/min/100 g, was about 2 ml/min/100 g.(ABSTRACT TRUNCATED AT 250 WORDS)

Short-term perfusion and "equilibration" of canine kidneys with protective solutions.

Kidneys were perfused either with Euro-Collins-solution or with HTK-solution of Bretschneider. The perfusion pressure as well as the perfusion flow were measured during a six-minute perfusion. The perfusion resistance was higher in Euro-Collins-kidneys than during HTK-perfusion. The venous outflow of the kidney as well as the ureteral outflow was measured during each minute of the perfusion and has analysed for osmolality, and for sodium and potassium concentrations. In Euro-Collins-kidneys a complete "equilibration" of the extracellular space was not achieved, while during HTK-perfusion concentrations in the venous as in the tubular outflow, similar to those in the HTK-solution itself, could be reached. At the end of the different perfusions, tissue was analysed for biochemical parameters such as ATP, ADP, AMP and lactate as well as for morphological features. Lactate had increased and ATP had decreased during perfusion with Euro-Collins-solution, while ATP had not changed and lactate had decreased during perfusion with HTK-solution. Normal glomerular, tubular and dilated vascular structures can be seen after HTK-perfusion, while a glomerular and vascular contraction takes place during Euro-Collins-perfusion.

Effects of glucose in protected ischemic kidneys.

Energy reserves (TAN) and anaerobic substrates (glucose, glycogen) are lower in renal than in myocardial tissue. Euro-Collins-solution contains nearly 200 mmol/l glucose, while the HTK-solution of Bretschneider contains none. Therefore the influence of glucose on kidney lactate production, on energy reserves (TAN), intrarenal pH and on morphology during the protection of ischemic kidneys was analysed using either Euro-Collins-solution, or modified "Euro-Collins-solution", containing mannitol instead of glucose, or HTK-solution with and without the addition of 5, 10 and 20 mmol/l glucose. Glucose content changed during kidney perfusion with Euro-Collins-solution from about 60 to 800 mumol/gdw. While intrarenal pH decreased from 7.1 to 5.1 in Euro-Collins-kidneys during 420 min of ischemia at 25 degrees C, pH decreased to 6.7 with the modified, mannitol containing "Euro-Collins-solution". In HTK-protected kidneys intrarenal pH decreased with increasing glucose addition to the solution. Although Total Adenine Nucleotides are highest at the end of ischemia with Euro-Collins-solution, structural protection after the same ischemic stress was best in HTK-protected kidneys without glucose addition. We conclude that glucose stimulated lactate production, reduced interstitial pH in the kidney even in combination with a highly buffered solution and that it might cause greater membrane permeability leading to a structural deterioration. Mannitol seemed more appropriate than glucose in this respect, although other substances, which provide energy substrate and prevent structural damage, may exist.