Current techniques for AB0-incompatible living donor liver transplantation

For a long time, it was considered medical malpractice to neglect the blood group system during transplantation. Because there are far more patients waiting for organs than organs available, a variety of attempts have been made to transplant AB0-incompatible (AB0i) grafts. Improvements in AB0i graft survival rates have been achieved with immunosuppression regimens and plasma treatment procedures. Nevertheless, some grafts are rejected early after AB0i living donor liver transplantation (LDLT) due to antibody mediated rejection or later biliary complications that affect the quality of life. Therefore, the AB0i LDLT is an option only for emergency situations, and it requires careful planning. This review compares the treatment possibilities and their effect on the patients’ graft outcome from 2010 to the present. We compared 11 transplant center regimens and their outcomes. The best improvement, next to plasma treatment procedures, has been reached with the prophylactic use of rituximab more than one week before AB0i LDLT. Unfortunately, no standardized treatment protocols are available. Each center treats its patients with its own scheme. Nevertheless, the transplant results are homogeneous. Due to refined treatment strategies, AB0i LDLT is a feasible option today and almost free of severe complications.     

Methods,units and quality requirements for the analysis of haemoglobin A1c in diabetes mellitus

The formation of glycohemoglobin, especially the hemoglobin A_1c (HbA_1c) fraction, occurs when glucose becomes coupled with the amino acid valine in the β-chain of Hb; this reaction is dependent on the plasma concentration of glucose. Since the early 1970s it has been known that diabetics display higher values OF HbA_1C because they have elevated blood glucose concentrations. Thus HbA_1c has acquired a very important role in the treatment and diagnosis of diabetes mellitus. After the introduction of the first quantitative measurement OF HbA_1C, numerous methods for glycohemoglobin have been introduced with different assay principles: From a simple mini-column technique to the very accurate automated high-pressure chromatography and lastly to many automated immunochemical or enzymatic assays. In early days, the results of the quality control reports for HbA_1c varied extensively between laboratories, therefore in United States and Canada working groups (WG) of the Diabetes Controls and Complications Trial (DCCT) were set up to standardize the HbA_1c assays against the DCCT/National Glycohemoglobin Standardization Program reference method based on liquid chromatography. In the 1990s, the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) appointed a new WG to plan a reference preparation and method for the HBA_1c measurement. When the reference procedures were established, in 2004 IFCC recommended that all manufacturers for equipment used in HbA_1c assays should calibrate their methods to their proposals. This led to an improvement in the coefficient of variation (CV%) associated with the assay. In this review, we describe the glycation of Hb, methods, standardization of the HbA_1c assays, analytical problems, problems with the units in which HbA_1c values are expressed, reference values, quality control aspects, target requirements for HbA_1c, and the relationship of the plasma glucose values to HbA_1c concentrations. We also note that the acceptance of the mmol/mol system for HbA_1c as recommended by IFCC, i.e., the new unit and reference ranges, are becoming only slowly accepted outside of Europe where it seems that expressing HbA_1c values either only in per cent units or with parallel reporting of percent and mmol/mol will continue. We believe that these issues should be resolved in the future and that it would avoid confusion if mmol/mol unit for HbA_1c were to gain worldwide acceptance.     

Decrease in the plasma von Willebrand factor concentration following glucose ingestion: The role of insulin sensitivity

Elevated plasma von Willebrand factor (vWF) concentration is thought to be associated with increased prevalence of cardiovascular events in the insulin resistance syndrome. We examined the effects of oral glucose challenge and accompanying metabolic and hemodynamic changes on vWF levels with respect to insulin sensitivity. Forty normotensive and hypertensive subjects (mean age +/- SD, 40 +/- 5 years) underwent a standard oral glucose tolerance test (OGTT). Plasma vWF antigen, glucose, insulin, catecholamines, and hemodynamics were measured at rest, and at 30, 60, 90, and 120 minutes after glucose intake. Insulin sensitivity was determined by the insulin sensitivity index (ISI(0,120)). Resting plasma vWF concentration was associated with screening systolic blood pressure (BP) (r =.43, P =.005). There were time effects for all variables of interest. While vWF antigen (P =.044), epinephrine (P =.003), and diastolic BP (P =.001) decreased after glucose challenge, norepinephrine (P =.009), systolic BP (P =.022), and heart rate (P <.001) increased. Decline in vWF (area under the curve) was associated with decrease in epinephrine (r =.46, P =.004) and with screening systolic BP (r =.45, P =.004). However, neither resting plasma vWF levels nor vWF decrease following glucose ingestion were significantly associated with the ISI(0,120.) The plasma vWF concentration decreases following glucose ingestion. While mechanisms underlying this phenomenon may relate to sympathetic nervous system function, they seem not related to insulin sensitivity. Endothelial dysfunction such as caused by hypertension rather than metabolic dysregulation per se may underlie the elevated plasma vWF concentration found with insulin resistance.     

Alpha1B adrenoceptor expression is a marker of reduced survival and increased tumor recurrence in patients with endometrioid ovarian cancer

AIM: To investigate the expression patterns of different adrenoceptor isoforms in ovarian cancer and their association with survival and tumor recurrence. METHODS: The protein expression levels of α1B, α2C and β2 adrenoceptor were assessed in unselected ovarian cancer using immunohistochemistry on microarrayed archival tissue samples. A database containing clinical and pathology parameters and follow-up was used to investigate the association between adrenoceptor isoform expression with ovarian specific survival and tumor recurrence, using univariate and multivariate statistical analysis. RESULTS: Expression of α1B showed an association with reduced ovarian specific survival (P = 0.05; CI: 1.00-1.49) and increased tumor recurrence (P = 0.021, CI: 1.04-1.69) in the whole patient group. On sub-analysis the expression of α1B in endometrioid cancers (χ² = 5.867, P = 0.015) was found to predict reduced ovarian specific survival and increased tumor recurrence independently of tumor grade, clinical stage and chemotherapy. An association with clinical outcome was not seen for α2C or β2 AR. CONCLUSION: Alpha1B adrenoceptor protein was found to predict increased risk of tumor recurrence and reduced mortality in patients with endometrioid type ovarian cancer and should be investigated as a biomarker for identifying patients at increased risk of disease progression. Furthermore, α adrenergic receptor antagonists with α1B selectivity should be investigated as a possible adjuvant therapy for treating patients with endometrioid cancer. Proof of principle could be tested in a retrospective population study.     

Numerical Buoyancy-Wave Model for Wave Stress and Drag Simulations in the Atmosphere

Orographic drag formation is investigated using a numerical wave model (NWM), based on the pressure-coordinate dynamics of non-hydrostatic HIRLAM. The surface drag, wave stress (vertical flux of horizontal momentum), and wave drag are split to the longitudinal and transverse components and presented as Fourier sums of their spectral amplitudes weighted with the power spectrum of relative orographic height. The NWM is accomplished, enabling a spectral investigation of the buoyancy wave stress, and drag generation by orography and is then applied to a cold front, characterised by low static stability of the upper troposphere, large vertical and directional wind variations, and intensive trapped wave generation downstream of obstacles. Resonances are discovered in the stress and drag spectra in the form of high narrow peaks. The stress conservation problem is revisited. Longitudinal stress conserves in unidirectional flow, 2D orography conditions, but becomes convergent for rotating wind or 3D orography. Even in the convergent case the vertical momentum flux from the troposphere to stratosphere remains substantial. The transverse stress never conserves. Disappearing at the surface and on the top, it realises the main momentum exchange between lower an upper parts of the troposphere. Existence of stationary stratospheric quasi-turbulence (SQT) is established above wind minimum in the stratosphere.     

Dose-related effects of metoprolol on heart rate and pharmacokinetics in heart failure

BACKGROUND: The pharmacokinetics and pharmacodynamics of immediate-release (IR) metoprolol, 50 mg 3 times daily, were compared with those of different doses of controlled-release/extended-release metoprolol (CR/XL) given once daily. METHODS AND RESULTS: Fifteen patients with chronic heart failure were randomized to a 3-way crossover study to receive metoprolol IR 50 mg 3 times daily, CR/XL 100 mg once daily, and CR/XL 200 mg once daily for 7 days. On the seventh day of each treatment, serial plasma samples were drawn and standardized exercise tests and a 24-hour Holter recording were performed. Metoprolol IR 50 mg produced peak plasma levels comparable to those observed for CR/XL 200 mg (285 v 263 nmol/L). The difference in mean 24-hour heart rate between CR/XL 100 mg and IR 50 mg was 1.0 bpm (95% confidence interval [CI]), -2.9 to 4.9; NS) compared with -3.8 bpm (95% CI, -7.6 to -0.04; P = .048) between CR/XL 200 mg and IR 50 mg. Submaximal exercise heart rate was lower for patients receiving CR/XL 200 mg than those receiving IR 50 mg. No difference in tolerance or exercise performance was observed between treatment regimens. CONCLUSIONS: Peak plasma levels produced by metoprolol 200 mg CR/XL were similar to those of 50 mg IR. Metoprolol CR/XL 200 mg was associated with a more pronounced suppression of heart rate than metoprolol IR 50 mg. It is suggested that patients can safely be switched from multiple dosing of metoprolol IR 50 mg to a once-daily dose of metoprolol CR/XL.     

Risk aspects of dental restoratives: From amalgam to tooth-colored materials

Dental materials’ choice of patients has considerably changed. Whereas cast gold and amalgam have been the predominant biomaterials for decades, today tooth-colored materials like resin-based composites and ceramics are more and more successful. However, are we going to replace a good but biologically questionable material (amalgam) with an equal material (resin composite) being more esthetic but also biologically questionable For amalgam, long-term clinical studies reported some significant hints that in single cases amalgam may be a health hazard for patients, finally Norway banned amalgam completely. The main advantage of a resin-based composite over amalgam is its tooth-like appearance and more or less absence of extensive preparation rules. For many years it was believed that resin-based composites may cause pulpal injury. However, pulpal injury associated with the use of resin-based composites is not correlated with their cytotoxic properties. Nevertheless, resin-based composites and other dental materials require rigorous safety evaluation and continuous monitoring to prevent adverse events similar like with amalgam. Because of non-biocompatible pulp responses to resin-based composites and amalgam, they should not be placed in direct contact with the dental pulp. The less dentin remaining in the floor of preparations between resin-based composites or other dental materials is more likely to cause pulpitis. Percentage of patients and dental practitioners who display allergic reactions is between 0.7% and 2%. The release of cytotoxic monomers from resin-based materials is highest after polymerization and much lower after 1 wk. Substances released from resin-based composites have been shown to be toxic in cytotoxicity tests. Nevertheless, in vitro cytotoxicity assays have shown that amalgam has greater toxic effects than resin-based composites, sometime 100-700-fold higher. Altogether, the risk of side-effects is low, but not zero, especially for dental personnel.