Therapy of diabetes mellitus. Pancreas transplantation, islet transplantation, stem cell and gene therapy

The long-term normalization of glucose metabolism - a prerequisite for the prevention of secondary complications in patients with diabetes mellitus - is only possible by transplantation of a whole pancreas or a reasonable number of islets. An absolute indication for pancreas grafting is given in type 1 diabetic patients with end-stage renal disease. The 1-year survival after simultaneous kidney/pancreas transplantation is, according to the international registry, 94-100% for patients, 89-92% for kidneys and 85-87% for the pancreas. The high success rate with long lasting normalization of glucose metabolism leads to a stabilization and/or amelioration of secondary complications, to an increase in quality of life and, most importantly, to a significant reduction in mortality when compared to diabetic kidney recipients. The indications for islet transplantation are similar to those for pancreatic grafting. Islet grafting is only a minor surgical procedure, but islet isolation is difficult. The 1-year survival for the recipients is 98%, for the islets 82% and for insulin-independency 42%. There is a significant decline of islet function to 10% 5 years after transplantation. Stem cell therapy would provide a definitive treatment solution not only for patients with type 1 diabetes. So far, this therapeutic option is still at an early stage of development.     

Therapie des Diabetes mellitus

The long-term normalization of glucose metabolism – a prerequisite for the prevention of secondary complications in patients with diabetes mellitus – is only possible by transplantation of a whole pancreas or a reasonable number of islets. An absolute indication for pancreas grafting is given in type 1 diabetic patients with end-stage renal disease. The 1-year survival after simultaneous kidney/pancreas transplantation is, according to the international registry, 94–100% for patients, 89–92% for kidneys and 85–87% for the pancreas. The high success rate with long lasting normalization of glucose metabolism leads to a stabilization and/or amelioration of secondary complications, to an increase in quality of life and, most importantly, to a significant reduction in mortality when compared to diabetic kidney recipients. The indications for islet transplantation are similar to those for pancreatic grafting. Islet grafting is only a minor surgical procedure, but islet isolation is difficult. The 1-year survival for the recipients is 98%, for the islets 82% and for insulin-independency 42%. There is a significant decline of islet function to 10% 5 years after transplantation. Stem cell therapy would provide a definitive treatment solution not only for patients with type 1 diabetes. So far, this therapeutic option is still at an early stage of development.     

Zufallsbefund Proteinurie

A positive signal when testing urine for proteinuria is a frequent finding, either in the context of a routine medical check-up or when searching for a specific renal disorder. This brief overview aims to provide assistance in the classification of proteinuria and to provide guidance to the next diagnostic and therapeutic steps. The normal urine protein loss of a healthy adult is less then 150 mg/day. Higher rates of proteinuria should be confirmed as this is often a sign of glomerular or tubular damage. In addition, proteinuria is a strong prognostic factor for cardiovascular and total mortality. Principally, proteinuria is 1) a symptom of renal diseases, 2) a progression factor for renal diseases and 3) a risk factor for cardiovascular diseases and total mortality. In this article proteinuria is defined, the correlation to various renal diseases is described and the relevance for progression of renal diseases and total mortality is shown. Finally, diagnostic procedures are described and a perspective on therapeutic measures is provided.     

Assessment of reperfusion after thrombolytic therapy for myocardial infarction.

The benefits of thrombolytic therapy in reducing the mortality associated with acute myocardial infarction are well documented. Presumably, this is on the basis of a patent IRA, although other mechanisms may be involved. Because there is a 25% to 30% failure rate for thrombolytic therapy that is associated with a significantly worse prognosis, it is crucial to document reperfusion in a timely fashion. In cases of failure to reperfuse, the patient could be considered a candidate for secondary mechanical intervention. While coronary arteriography is presently the "gold standard" to document reperfusion, this is an invasive procedure associated with small but defined risks for the patient. A noninvasive marker that is readily available and highly accurate is most desirable. There are a number of methods currently used to document coronary reperfusion noninvasively. This review discusses the advantages and disadvantages of each method, and the need for continued evaluation and refinement in noninvasive modalities to identify patients who are candidates for further intervention.     

Regulation of ketogenesis and clinical aspects of the ketotic state

Recent studies of the regulation of ketogenesis are reviewed. Under circumstances of relative or absolute insulin deficiency there is a mobilization of free fatty acids from adipose tissue to the liver. While an increased delivery of fatty acids to this organ is important in providing substrate for ketone body formation, it is emphasized that enhanced uptake of fatty acids by the liver is not sufficient in itself to initiate maximal ketogenesis. It appears likely that a major determinant of the rate of ketogenesis is competition for the fatty acid substrate between the β-oxidative and triglyceride synthesizing pathways. While it is widely held that the rate of triglyceride synthesis is primary and that only those fatty acids not utilized for esterification become available for oxidation, evidence for the reverse sequence is presented. It is considered likely that fatty acids are utilized for triglyceride synthesis only insofar as they escape uptake and oxidation in the mitochondria. Regardless of the mechanism, fatty acid oxidation is increased in the ketotic state with the consequence that acetyl-CoA production is accelerated. Since the utilization of acetyl-CoA for fatty acid synthesis and, to a much lesser extent, its oxidation in the Krebs cycle is impaired, the synthesis of acetoacetate and β-hydroxybutyrate is stimulated to a remarkable degree. The hepatic overproduction of ketones appears to be coupled to a limited capacity for their utilization by peripheral tissues, the combined effect of which accounts for the life-threatening acidosis seen in diabetic coma. From a clinical standpoint, newer studies relating to the treatment of diabetic ketoacidosis have been covered, with particular attention paid to the problems of late cerebral edema, paradoxical acidification of the cerebrospinal fluid during treatment, shifts of the oxygen dissociation curve due to 2,3-diphosphoglycerate depletion and initial hypokalemia. Recommendations for therapy designed to minmize complications are presented.     

Semantics of insulin

The lack of a stringent terminology and a well-defined vocabulary for insulin and related subjects has been a deterrent to solving many of the problems encountered when using insulin in pumps. The same word is sometimes used to describe a number of different phenomena or the same phenomenon is referred to by different words. Thus the word 'insulin', meaning the substance, the protein hormone, is commonly used as a synonym for an 'insulin formulation' for the treatment of diabetes. The 'insulin dimer' can be the covalent or the non-covalent dimer, two very different substances. 'Isoelectric precipitation' is often mistaken for 'fibrillation' and both are referred to as 'aggregation' or 'polymerization'. The word 'crystal' is being used as a synonym for 'particle', and determination of 'the content of insulin' by HPLC is sometimes called a 'bioassay'. The nature and consequences of these pitfalls are discussed, and advice is given on how to avoid them.     

A New Stripline-Based Atmospheric Pressure Microwave Plasma Sheet Source Designed for Surface Modification of Materials

A new type of microwave plasma source is presented in which plasma at atmospheric pressure is generated inside a quartz rectangular flat box placed in a stripline supplied by a 2.45 GHz coaxial line. The plasma has a sheet shape and is designed for surface modification. Electric field and power flux distributions, tuning characteristics, and power characteristics (ratios of radiated, absorbed, and entering power) are numerically studied for three configurations: open, semi-closed, and closed. The calculations show that near-zero radiation reduction is possible only for the closed configuration, while the ratio of radiated power to entering power is always greater than 30% for the other configurations. The moving plunger is not sufficient for the ratio of reflected to incident power to fall below 20% for both the closed and open configurations. This is possible for the semi-closed configuration, but then the radiated power is the highest. The experiment shows that for the same entering power, the plasma volume is largest for the closed configuration and smallest for the open configuration, which we attribute to the difference in radiated power. The plasma generated using the closed stripline configuration has a larger volume than plasma generated using the rectangular waveguide.     

Pediatric post-transplant lymphoproliferative disorder after cardiac transplantation

Post-transplant lymphoproliferative disorder (PTLD) is a well recognized and potentially fatal complication after pediatric cardiac transplantation. PTLD encompasses a wide spectrum, ranging from benign hyperplasia to more aggressive lymphoma. Most cases are Epstein-Barr virus (EBV)-related B-cell tumors resulting from impaired immunity due to immunosuppressive therapy. Pediatric recipients, often seronegative for EBV at transplantation, have a greater risk for PTLD than adults. The clinical presentation of PTLD varies from isolated lymphadenopathy to systemic disease; common sites involved are gastrointestinal tract, lung or airway, and cervical lesions. Timely and accurate diagnosis based on histological examination of biopsy tissue is essential for early intervention. Immunostaining for EBV and evaluation for clonality are needed. For prophylaxis when EBV viral loads are increasing or for initial treatment of early lesions or polymorphic PTLD, a reduction in immunosuppressive treatment is a key component of therapy, but caution is needed for possible rebound allograft rejection. Chemotherapy is indicated for patients with poor response to reduced immunosuppression and for highly aggressive monomorphic PTLD. The use of rituximab in combination with chemotherapy is effective. For the time being, avoiding excessive immunosuppression is the most effective strategy for reducing the incidence of PTLD. Calcineurin inhibitor (CNI) minimization with proliferation signal inhibitors (PSIs) or conversion from a CNI to a PSI might be useful for preventing both development of PTLD and allograft rejection.     

Radiofrequency treatment of lung tumours

Formal surgical resection is the standard treatment for patients with an operable non-small cell lung tumour and for selected patients with limited lung metastases, even if only a small number of patients are suitable for formal surgical resection due to comorbidities. CT-guided radiofrequency treatment is a minimally invasive therapeutic option that has been successfully applied to different organs, and for the lung is considered to be an alternative to surgery for patients who are not candidates for surgery. The procedure is well-tolerated and the complication rate is acceptable.     

Algorithm for the coproscopic diagnosis of human intestinal parasites

The purpose of the study was to elaborate a detection algorithm for human intestinal helminth eggs. There is a broad spectrum ofcoproscopic methods recommended for the detection of Opisthorchis eggs in man and animals; these include Fulleborn's method, formalin-ether method, Goryachev's, Katoh's, Kalantaryan's, Shcherbovich's, and Kotelnikov-Varenichev methods. Combined coproscopic methods are significantly more effective in detecting the causative agents of enteric parasitoses than is Katoh's method. Among the considered coproscopic techniques for the diagnosis of human ascariasis, it is most rational to use a combined method for fecal examination, the basis for which is a multicomponent flotation system (such as the author's one). The Kotelnikov-Varenichev method is optimal for diagnosing opisthorchiasis. It is optimal to use 2-3 methods of different groups simultaneously for the screening diagnosis of intestinal parasitoses.     

Routine ultrasound-guided liver biopsy: a time whose idea has come?

Percutaneous liver biopsy is a commonly performed procedure in modern hepatology. Although it is a safe procedure and performed in most cases on an outpatient basis, complications including mortality have been reported. It is widely perceived that the use of ultrasound guiding for the biopsy produces a decrease in complications and is safer. There is now a trend for more centers to adopt a policy of ultrasound-guided biopsies only. There are, however, no official guidelines that recommend such a policy. This trend for ultrasound guidance of invasive procedures is also becoming apparent in other areas such as the insertion of a central venous line in children. The literature in support of such a position is far from conclusive. Because there are medicolegal and economic implications for the policy of routine ultrasound guiding of biopsies, we suggest that there is a need for the major professional organizations to make a clear declaration on this issue.     

T.I.A. revisited: new wine--old bottle

TIA has been accepted as a concept of transient cerebral ischemia. There is an ever enlarging body of literature sparking controversies considering its natural history, prognosis, outcomes of clinical trials and usefulness of the concept. Much of the controversy is related to the diverse pathophysiology of TIAs, the selection of patients for clinical trials and the associated risk factor in the studied population. The advantages of the concept are a warning of the possibility of future irreversible pathology an opportunity to treat and/or remove risk factors an opportunity to establish a basis for monitoring the patient and making interim decisions concerning intervention. The risks of the concept are: administering a specific therapy to all patients, failure to fully evaluate the patient once the diagnosis is made, tendency to rely on "experts" for guidance. TIA is a useful concept if one recognizes: the pathophysiology is polymorphous and multiplex, the concept is a signal for diligent search for the underlying cause or causes, it is more important to treat the risk factors than to give a specific therapy.     

Diagnosis of pulmonary embolism.

The patient with suspected pulmonary embolism presents a challenging diagnostic problem. The symptoms and signs are nonspecific, and objective testing is required to establish or exclude the presence of pulmonary embolism. Lung scanning continues to be a first-line test, but in 40% to 70% of all patients, the results do not definitively provide indication for either giving or withholding anticoagulant treatment even when combined with the clinical assessment. Pulmonary angiography is the reference standard, but it is invasive and may not be available in all clinical settings. Pulmonary embolism is strongly associated with proximal deep-vein thrombosis of the legs (popliteal, femoral, or iliac vein thrombosis). Objective testing for proximal deep-vein thrombosis is useful in patients with suspected pulmonary embolism. A positive result from such testing provides an indication for anticoagulant treatment. Serial testing for proximal deep-vein thrombosis is a safe and effective alternative to pulmonary angiography in patients with adequate cardiorespiratory reserve. The assay for plasma D-dimer using either a rapid enzyme-linked immunospecific assay technique or a bedside whole-blood agglutination technique is promising as a test for excluding venous thromboembolism. A positive result by spiral CT imaging is useful for ruling in a diagnosis of pulmonary embolism, but the safety of withholding treatment in patients with negative spiral CT results remains uncertain. Pulmonary angiography continues to have an important role in selected patients in whom it is critical to definitively confirm or exclude the presence of pulmonary embolism.     

Stationary spiral flow in polytropic stellar models

It is shown that, in addition to the static Emden solution, a self-gravitating polytropic gas has a dynamic option in which there is stationary flow along spiral trajectories wound around the surfaces of concentric tori. The motion is obtained as a solution of a partial differential equation which is satisfied by the meridional stream function, coupled with Poisson's equation and a Bernoulli-type equation for the pressure (density). The pressure is affected by the whole of the Bernoulli term rather than by the centrifugal part only, which acts for a rotating model, and it may be reduced down to zero at the center. The spiral type of flow is illustrated for an incompressible fluid (n = 0), for which an exact solution is obtained. The features of the dynamic constant-density model are discussed as a basis for future comparison with the solution for compressible models.     

Preoperative testing and medication management

The preoperative evaluation of the geriatric patient is an important time to make a series of assessments. Careful attention is paid to cardiac and pulmonary readiness for the physiologic stress of surgery. It is also a time to focus on the patient's mental capacities and social support system, and nutritional state. Because so many patients take multiple medications and supplements, the preoperative assessment is also a time to carefully review exactly what it being taken. It is a time to assess for drug interactions, and also to adjust medications to prepare the patient for the stress of surgery.     

Personalized Medicine for Diabetes: Detecting Undiagnosed Type 2 Diabetes: Family History as a Risk Factor and Screening Tool

A family history of diabetes is a major risk factor for the disease. As such, it is often included in a variety of tools designed to detect either people at risk of diabetes or people with undiagnosed diabetes. One of the reasons to screen for diabetes is that it has a prolonged asymptomatic phase, which includes impaired fasting glucose, impaired glucose tolerance, and the early stages of diabetes. In terms of prevalence, diabetes is a major public health problem. Evidence shows that the detection of impaired glucose metabolism in its early stages (prediabetes) could lead to the delay or prevention of the disease and its complications. However, the issue of using family history to screen for diabetes must be discussed within the context of screening for diabetes in general. Screening for a disease among asymptomatic people must meet a series of stringent requirements to ensure the best possible outcomes. Screening for diabetes meets most of these requirements but the ones it does not meet are still important. Therefore, based on systematically collected evidence or simply by consensus among scientists, influential organizations recommend screening only among high-risk individuals. As a result, researchers have developed a variety of simple tools to identify high-risk individuals for diabetes in populations. Family history is included as a key variable in the vast majority of them. This article is a brief overview of the reasons to screen for diabetes in general, the tools available for conducting this screening, and the role of family history in these tools.     

Annotation: travel and thrombosis

Travel appears to be a weak risk factor for venous thromboembolism (VTE) and is more relevant for passengers with additional VTE risk factors. The association is not limited to air travel and is related to duration of travel. Life-threatening pulmonary embolism (PE) is rare. There is limited evidence to support interventions, including ‘sensible measures’, graduated compression stockings (GCS) and low-molecular-weight heparin (LMWH). It is difficult to confidently define a population who would benefit from thromboprophylaxis and no validated risk assessment exists for this purpose. LMWH has traditionally been used for flight thromboprophylaxis but a direct oral anticoagulant (DOAC) would be a more appealing oral option.     

Blood group genotyping: from patient to high-throughput donor screening

Blood group antigens, present on the cell membrane of red blood cells and platelets, can be defined either serologically or predicted based on the genotypes of genes encoding for blood group antigens. At present, the molecular basis of many antigens of the 30 blood group systems and 17 human platelet antigens is known. In many laboratories, blood group genotyping assays are routinely used for diagnostics in cases where patient red cells cannot be used for serological typing due to the presence of auto-antibodies or after recent transfusions. In addition, DNA genotyping is used to support (un)-expected serological findings. Fetal genotyping is routinely performed when there is a risk of alloimmune-mediated red cell or platelet destruction. In case of patient blood group antigen typing, it is important that a genotyping result is quickly available to support the selection of donor blood, and high-throughput of the genotyping method is not a prerequisite. In addition, genotyping of blood donors will be extremely useful to obtain donor blood with rare phenotypes, for example lacking a high-frequency antigen, and to obtain a fully typed donor database to be used for a better matching between recipient and donor to prevent adverse transfusion reactions. Serological typing of large cohorts of donors is a labour-intensive and expensive exercise and hampered by the lack of sufficient amounts of approved typing reagents for all blood group systems of interest. Currently, high-throughput genotyping based on DNA micro-arrays is a very feasible method to obtain a large pool of well-typed blood donors. Several systems for high-throughput blood group genotyping are developed and will be discussed in this review.     

A Combined FEM/Genetic Algorithm for Vascular Soft tissue Elasticity Estimation

Tissue elasticity reconstruction is a parameter estimation effort combining imaging, elastography, and computational modeling to build maps of soft tissue mechanical properties. One application is in the characterization of atherosclerotic plaques in diseased arteries, wherein the distribution of elastic properties is required for stress analysis and plaque stability assessment. In this paper, a computational scheme is proposed for elasticity reconstruction in soft tissues, combining finite element modeling (FEM) for mechanical analysis of soft tissues and a genetic algorithm (GA) for parameter estimation. With a model reduction of the discrete elasticity values into lumped material regions, namely the plaque constituents, a robust, adaptive strategy can be used to solve inverse elasticity problems involving complex and inhomogeneous solution spaces. An advantage of utilizing a GA is its insistence on global convergence. The algorithm is easily implemented and adaptable to more complex material models and geometries. It is meant to provide either accurate initial guesses of low-resolution elasticity values in a multi-resolution scheme or as a replacement for failing traditional elasticity estimation efforts.     

Long-term prophylaxis in venous thromboembolism: LMWH or oral anticoagulation?

Warfarin remains the standard drug for secondary prophylaxis following venous thromboembolism, however this treatment is not ideal. In patients for whom monitoring is problematic or who have a high risk of bleeding complications, other possible solutions have been explored. Unfractionated heparin has been used to a limited extent in these situations and requires dose adjustment in order to achieve an acceptable efficacy. Low-molecular-weight heparin (LMWH) is a valuable alternative to warfarin for these patients and for thromboprophylaxis during pregnancy. In several subgroups of patients with venous thromboembolism the use of a LMWH instead of warfarin could offer specific advantages. The combination of warfarin and LMWH is warranted in patients for whom it is predicted that warfarin treatment alone may fail. The optimal dose of LMWH in long-term prophylaxis has not been evaluated in a properly designed study and the optimal duration of prophylaxis with LMWH is thought to be similar to that for warfarin.