Elevation of plasma viscosity induces sustained NO-mediated dilation in the hamster cremaster microcirculation in vivo

 We studied whether a flow-independent increase of luminal wall shear stress (WSS) could dilate hamster arterioles in vivo and which endothelial mediators are potentially involved. To this end the plasma viscosity was elevated by exchanging blood for dextran-erythrocyte solution thereby augmenting WSS. Diameters of small and large arterioles as well as red blood cell velocities were measured before and after exchange of blood for solutions of identical haematocrit containing either high- (HMWD) or low-molecular weight dextran (LMWD). The potential role of endothelial autacoids was investigated by local application of the NO-synthase inhibitor N ^G-nitro-L-arginine (L-NNA), the inhibitor of cyclooxygenase, indomethacin (3 μM), or the K⁺-channel blocker, tetrabutylammonium (TBA, 0.1 mM) to assess the potential effects of EDHF. HMWD (n = 11 animals) increased plasma viscosity by 64 ± 3% and dilated arterioles of all branching orders (A1–A4) significantly [by 24 ± 3% (A1–A2) and 32 ± 3% (A3–A4)]. This dilation compensated fully for the calculated initial increase of WSS. LMWD (n = 6) did not affect plasma viscosity or arteriolar diameters. Tissue treatment with L-NNA (30–300 μM, n = 12) substantially diminished the HMWD-induced dilation in small arterioles (A3–A4; to 13 ± 3%; P<0.05) and virtually abolished it in large ones (A1–A2). Consequently, the calculated WSS increased significantly in these arterioles (by 31 ± 5%). TBA combined with L-NNA (n = 4) did not reduce further the remaining dilation. Indomethacin (n = 6) had no effect on HMWD-induced dilation. We conclude that an increase of WSS induces a mainly NO-mediated arteriolar dilation. This dilation occurs in all arteriolar branching orders and is of sufficient magnitude to compensate for the initial WSS-increase. Thus, any elevations of WSS fulfil the requirement for a signal to change diameter along the arteriolar tree in a coordinated manner. The fully compensating dilation which we observed indicates that WSS is a controlled variable. It does, however, raise questions as to its role as a continuous endothelial stimulus. Received: 2 August 1996 / Received after revision: 24 February 1997 / Accepted: 14 April 1997     

1,3-Oxazoline intermediates in reactive processing applications, 1. Melt grafting of poly(ethene-co-methacrylic acid) with 2-substituted 1,3-oxazolines

A novel family of functional ethene copolymers with various side chains were prepared by melt grafting of poly(ethene-co-methacrylic acid), containing 3,00 and 4,25 mol-% of methacrylic acid, with 2-substituted 1,3-oxazolines such as 2-phenyl-1,3-oxazoline, 2-undecyl-1,3-oxazoline, 2-heptadecyl-1,3-oxazoline, and 4-(1,3-oxazolin-2-yl)phenyl 4-methoxybenzoate. ¹H NMR and FTIR studies of the polymer microstructures revealed that carboxylic acid groups reacted with 1,3-oxazolines within few minutes to form esteramide-coupled side chains in very high yields. Torque of the reaction mixture, mechanical and thermal properties of the graft copolymers were measured. In the case of 2-heptadecyl-esteramide-substituted polyethenes, the side-chain cocrystallization accounted for higher crystallinity of the resulting graft copolymers.     

Knowledge representation model for systems-level analysis of signal transduction networks

A Petri-net based model for knowledge representation has been developed to describe as explicitly and formally as possible the molecular mechanisms of cell signaling and their pathological implications. A conceptual framework has been established for reconstructing and analyzing signal transduction networks on the basis of the formal representation. Such a conceptual framework renders it possible to qualitatively understand the cell signaling behavior at systems-level. The mechanisms of the complex signaling network are explored by applying the established framework to the signal transduction induced by potent proinflammatory cytokines, IL-1beta and TNF-alpha The corresponding expert-knowledge network is constructed to evaluate its mechanisms in detail. This strategy should be useful in drug target discovery and its validation.     

Transgenic rat model of Huntington's disease

Huntington's disease (HD) is a late manifesting neurodegenerative disorder in humans caused by an expansion of a CAG trinucleotide repeat of more than 39 units in a gene of unknown function. Several mouse models have been reported which show rapid progression of a phenotype leading to death within 3-5 months (transgenic models) resembling the rare juvenile course of HD (Westphal variant) or which do not present with any symptoms (knock-in mice). Owing to the small size of the brain, mice are not suitable for repetitive in vivo imaging studies. Also, rapid progression of the disease in the transgenic models limits their usefulness for neurotransplantation. We therefore generated a rat model transgenic of HD, which carries a truncated huntingtin cDNA fragment with 51 CAG repeats under control of the native rat huntingtin promoter. This is the first transgenic rat model of a neurodegenerative disorder of the brain. These rats exhibit adult-onset neurological phenotypes with reduced anxiety, cognitive impairments, and slowly progressive motor dysfunction as well as typical histopathological alterations in the form of neuronal nuclear inclusions in the brain. As in HD patients, in vivo imaging demonstrates striatal shrinkage in magnetic resonance images and a reduced brain glucose metabolism in high-resolution fluor-deoxy-glucose positron emission tomography studies. This model allows longitudinal in vivo imaging studies and is therefore ideally suited for the evaluation of novel therapeutic approaches such as neurotransplantation.     

Inefficient protection of human TAP-deficient fibroblasts from autologous NK cell-mediated lysis by cytokines inducing HLA class I expression

We studied HLA class I expression and susceptibility to lysis of activated autologous NK cells in normal and TAP-deficient fibroblasts. These cells were cultured in the presence or absence of cytokines known to increase the surface expression of HLA class I molecules. All the cytokines tested (IFN-alpha, IFN-gamma, TNF-alpha and IFN-gamma + TNF-alpha) increased the expression of HLA class I molecules on fibroblasts after 48-h culture, but on TAP-deficient cells this expression remained very low as compared to that of normal cells. In the presence of IFN-alpha, IFN-gamma or IFN-gamma + TNF-alpha, normal target cells became resistant to lysis by autologous NK cells, whereas this effect was much less pronounced in the case of TAP-deficient fibroblasts. Addition of an anti-HLA class I mAb to fibroblasts treated with cytokines increased lysis of normal but not of TAP-deficient cells. These results suggest that activated TAP-deficient NK cells are strongly cytotoxic to normal autologous cells and that these cells cannot be efficiently protected by cytokines inducing HLA class I expression. Thus, in human TAP deficiency, activated NK cells may contribute to the progressive lung degradation which characterizes the clinical course of these patients.     

Experimental evaluation of eye-blink parameters as a drowsiness measure

Drowsiness and increased tendency to fall asleep during daytime is still a generally underestimated problem. An increased tendency to fall asleep limits the efficiency at work and substantially increases the risk of accidents. Reduced alertness is difficult to assess, particularly under real life settings. Most of the available measuring procedures are laboratory-oriented and their applicability under field conditions is limited; their validity and sensitivity are often a matter of controversy. The spontaneous eye blink is considered to be a suitable ocular indicator for fatigue diagnostics. To evaluate eye blink parameters as a drowsiness indicator, a contact-free method for the measurement of spontaneous eye blinks was developed. An infrared sensor clipped to an eyeglass frame records eyelid movements continuously. In a series of sessions with 60 healthy adult participants, the validity of spontaneous blink parameters was investigated. The subjective state was determined by means of questionnaires immediately before the recording of eye blinks. The results show that several parameters of the spontaneous eye blink can be used as indicators in fatigue diagnostics. The parameters blink duration and reopening time in particular change reliably with increasing drowsiness. Furthermore, the proportion of long closure duration blinks proves to be an informative parameter. The results demonstrate that the measurement of eye blink parameters provides reliable information about drowsiness/sleepiness, which may also be applied to the continuous monitoring of the tendency to fall asleep. Electronic Publication     

Sleep deprivation as a probe in the elderly

Decreased slow-wave sleep (SWS) and sleep continuity are major effects of healthy aging and of associated psychopathological states. Using sleep deprivation, we studied the extent to which age- and psychopathology-related sleep "decay" is reversible in aged normal, depressed, and demented subjects. Depression or probable Alzheimer's dementia compromised the augmentation of sleep continuity and SWS seen in healthy elderly following sleep deprivation. Rapid eye movement (REM) latency decreased during recovery sleep in the controls but increased in both patient groups. Compared with demented patients, depressed elderly had greater severity of sleep continuity disturbance both before and after sleep deprivation, a more protracted course of recovery sleep, and increased slow-wave density in the second non-REM (NREM) sleep period (during recovery). The REM sleep time was diminished in dementia compared with depression both at baseline and during recovery sleep. These differential effects of age, health, and neuropsychiatric disease on recovery from sleep loss are relevant to recovery or reversal theories of sleep and have implications for daytime well-being in the elderly.     

The relevance of categorical and dimensional classification systems for the comparability of patient samples in psychopharmacological research of depression

Operational diagnoses of endogenous depression have gained special importance for psychopharmacological research. The high reliability of operationally defined diagnoses is a prerequisite for sampling comparable patient group. The simultaneous application of competing categorical diagnostic system ("polydiagnosis") allows us to determine whether differences in research findings are due to differences in patient samplings. Furthermore, a dimensional classification of patients by means of a newly developed polydiagnostic scale (so called OPD scale) allows us to compare the diagnostic homogeneity of patient groups diagnosed as endogenous depression cases and to select extreme groups with high diagnostic homogeneity for comparing the distribution of variables under research in patients with endogenous and nonendogenous depression.     

Deciphering the molecular effects of non-ablative Er:YAG laser treatment in an in vitro model of the non-keratinized mucous membrane

Lasers in Medical Science -     

Liver transplantation in a patient after COVID-19 – Rapid loss of antibodies and prolonged viral RNA shedding

To date, little is known about the duration and effectiveness of immunity as well as possible adverse late effects after an infection with SARS-CoV-2. Thus it is unclear, when and if liver transplantation can be safely offered to patients who suffered from COVID-19. Here, we report on a successful liver transplantation shortly after convalescence from COVID-19 with subsequent partial seroreversion as well as recurrence and prolonged shedding of viral RNA.