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.     

Effects of glucose in protected ischemic kidneys

Summary 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 mol/g_dw. While intrarenal pH decreased from 7.1 to 5.1 in Euro-Collins-kidneys during 420 min of ischemia at 25°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 detoriation. Mannitol seemed more appropriate than glucose in this respect, although other substances, which provide energy substrate and prevent structural damage, may exist.Supported by the Deutsche Forschungsgemeinschaft, SFB 89 —Kardiologie Göttingen     

Patterns of structural deterioration due to ischemia in Purkinje fibres and different layers of the working myocardium

Cellular and mitochondrial swelling are regarded as typical intra-ischemic alterations ("IIA"), contraction band lesions (CBL), in contrast, as products of post-ischemic reperfusion. The occurrence of both types of structural deterioration was investigated in Purkinje fibres and subendocardial and intramural working myocardium: initially after St. Thomas- or HTK cardioplegia, then during ensuing global ischemia up to the "practical limit of resuscitability", and following post-ischemic reperfusion. Generally, Purkinje fibres are not better preserved than neighbouring working myocardium. Comparing St. Thomas- and HTK cardioplegia, considerable quantitative, but not qualitative differences in the reaction patterns of different cell types or layers arise. Immediately after cardioplegia, CBL are completely lacking in both cell types. During ischemia, CBL occur occasionally in Purkinje fibres and seldom in subendocardial working myocardium, "IIA" predominate. During post-ischemic reperfusion "IIA" tend to reverse in all layers, whereas CBL are found to remain in the subendocardial cell types. In intramural layers, CBL occur only during reperfusion. Thus, we deduce that cardioplegia only modulates the severity of "IIA" and the frequency of CBL, but cannot abolish the particular sensitivity of subendocardial Purkinje fibres to global ischemia. Prerequisites for the development of irreversible CBL are on the one hand ischemic metabolic alterations and corresponding energy deficits, and, on the other hand, a supply of oxygen. The oxygen may be inadequately supplied via diffusion during ischemia or may be subsequently provided by reperfusion.     

Severe malabsorption in autoimmune polyendocrinopathy-candidosis-ectodermal dystrophy syndrome successfully treated with immunosuppression

A 15 year old boy with autoimmune polyendocrinopathy-candidosis-ectodermal dystrophy syndrome suffered recurrent episodes of severe intractable diarrhoea, steatorrhoea, and hypocalcaemia. The only treatment modality, which controlled the malabsorption syndrome, was immunosuppression with intravenous high dose methylprednisolone and oral methotrexate maintenance therapy.     

Toxic cardiogenic shock in a patient receiving weekly 24-h infusion of high-dose 5-fluorouracil and leucovorin

A 54-year-old man was treated with weekly 24-h infusion of high-dose 5-fluorouracil (2600 mg/m2) and leucovorin (100 mg/m2) for metastatic colon cancer. At first, he tolerated the treatment well and no significant toxicity was identified. After a total of eight courses of treatment, a stable disease was observed, but mild shortness of breath was found on occasion. The patient had no previous history of cardiac disease and the heart performance assessed by left ventricular ejection fraction before treatment was normal. Unfortunately, acute pulmonary edema with lethal cardiogenic shock occurred during the ninth course of treatment, in spite of intensive medical treatment. The chest X-ray showed extreme cardiomegaly. Repeated assessment of his heart function by echocardiogram and ventricular ejection fraction revealed a very poor cardiac performance. Toxic cardiogenic shock during weekly 24-h infusion of high-dose 5-fluorouracil and leucovorin is extremely rare. To the best of our knowledge, no case has been reported in the English literature. We report a case and the relevant literature about the incidence, clinical picture and possible pathophysiology on 5-fluorouracil-related cardioxicity is reviewed.      

Improvement of lipophilicity and membrane transport of cefuroxime using in vitro models.

Most beta-lactam antibiotics cannot be absorbed orally and, therefore, must be administered intravenously (i.v.) or intramuscularly (i.m.). Because of the obvious drawbacks of drug delivery by injection, the development of alternatives with enhanced oral bioavailability is receiving much attention in pharmaceutical research. Cefuroxime exhibiting significant advantages in the parental treatment of common infections, was used as model drug in the present study. The effect of the cationic absorption enhancers (four quaternary ammonium salts) on the lipophilicity of cefuroxime was investigated by means of the n-octanol/water system. The results on partitioning coefficients in the n-octanol/buffer system were confirmed using an in vitro transport model with artificial (dodecanol collodium membrane) and biological membranes (Charles-River guinea pig).     

Comparing Digital Therapeutic Intervention with an Intensive Obesity Management Program: Randomized Controlled Trial

In this study, we evaluated whether the digital program Vitadio achieves comparable results to those of an intensive in-person lifestyle intervention in obesity management. This is a 12-month prospective, randomized controlled trial. Obese patients with insulin resistance, prediabetes or type 2 diabetes were included. The intervention group (IG) used Vitadio. The control group (CG) received a series of in-person consultations. Body weight and various metabolic parameters were observed and analyzed with ANOVA. The trial is ongoing and the presented findings are preliminary. Among 100 participants (29% men; mean age, 43 years; mean BMI, 40.1 kg/m²), 78 completed 3-month follow-up, and 51 have completed the 6-month follow-up so far. Participants significantly (p < 0.01) reduced body weight at 3 months (IG: −5.9 ± 5.0%; CG: −4.2 ± 5.0%) and 6 months (IG: −6.6±6.1%; CG: −7.1 ± 7.1%), and the difference between groups was not significant. The IG achieved favorable change in body composition; significant improvement in TAG (−0.6 ± 0.9 mmol/l, p < 0.01), HDL (0.1 ± 0.1%, p < 0.05), HbA1c (−0.2 ± 0.5%, p < 0.05) and FG (−0.5 ± 1.5 mmol/l, p < 0.05); and a superior (p = 0.02) HOMA-IR reduction (−2.5 ± 5.2, p < 0.01). The digital intervention achieved comparable results to those of the intensive obesity management program. The results suggest that Vitadio is an effective tool for supporting patients in obesity management and diabetes prevention.