Enzymic and nonenzymic release of NO accounts for the vasodilator activity of the metabolites of CAS 936, a novel long-acting sydnonimine derivative

Summary The molecular mechanism(s) underlying the vasodilator activity of CAS 936 (3-(cis-2,6-dimethylpiperidino)-N-(4-methoxybenzoyl)-sydnonimine) and its metabolites 3-(cis-2,6-dimethylpiperidino)-sydnonimine (C87 3754) and N-(cis-2,6-dimethylpiperidino)-N-nitroso-2-aminoacetonitril (C873786) was investigated. These compounds were tested for their relaxant activity in isolated rabbit arterial segments, activation of purified soluble guanylyl cyclase and release of nitric oxide (NO) in vitro and in vivo. C873754 and C873786 inhibited the noradrenalin-induced contraction and increased the cyclic GMP content of endothelium-denuded rabbit aortic and femoral segments, whereas CAS 936 was without effect. Similarly, both metabolites, but not CAS 936, activated purified soluble guanylyl cyclase (EC₅₀ about 30 M) and released NO in buffered aqueous solutions, as detected by electron spin resonance (esr) spectrometry. Both in vitro and in vivo an accumulation of NO was detected by esr spectrometry in vascular tissues exposed to the metabolites of CAS 936, whereas a significant release of NO from CAS 936 was only detected in the isolated rabbit liver, but not in vascular tissue. It is conceivable, therefore, that the metabolites of CAS 936 appearing in the systemic circulation after hepatic biotransformation induce vasodilatation by release of NO and activation of soluble guanylyl cyclase in vascular smooth muscle. Moreover, the activation of soluble guanylyl cyclase in vitro by the metabolites of CAS 936 was significantly enhanced by co-incubation with certain particulate fractions from bovine aortic endothelial and smooth muscle cells. Thus, an enzymic release of NO from these metabolites in addition to their spontaneous decomposition may play a significant role for their vasodilator activity in vivo.Correspondence to A. Mülsch at the above address     

Poly (triethylenglycol monomethacrylate) and poly(glycerol monomethacrylate) cross-linked gel as potential viscoelastics for intraoperative use

Background: The highly swelling poly(glycerol monomethacrylate) gel (polyGLYMA) and hydrophilic polymer poly(triethylenglycol monomethacrylate (polyTEGMA) were tested as potential viscoelastics for intraopertive use in anterior segment surgery. Methods: PolyGLYMA was implanted into the anterior chamber in 5 rabbits, and 40% polyTEGMA in 16 rabbits. The eyes were enucleated 1 week to 3 months after the operation. The corneal endothelium was examined with specular microscopy, and then the whole eye histopathologically. Results: In all eyes of the polyGLYMA group, the clinical findings were characterized by a marked ciliary injection and severe secondary glaucoma, and the histologic ones by a marked inflammatory infiltration and thickening of Descemet's membrane in the anterior chamber angle. Specular microscopy revealed a decrease in the endothelial cell density and polymorphism of the endothelial cells. In the polyTEGMA group, the anterior segment and the fundus were physiologic all the time, and specular microscopy and histologic findings showed no degenerative and/or inflammatory changes. Conclusions: PolyGLYMA proved unsuitable for intracameral application in rabbits. The new polymer polyTEGMA is characterized by high biologic tolerance after its implantation into the anterior chamber of rabbits. PolyTEGMA 40% might be considered as a potential viscoelastic material in humans.     

Morphological parameters of breast cancers detected by mammography with and without organized screening; a comparative study]

Some pathological findings and prognostic indices recorded in breast cancer cases, detected, on one hand, by a provider-initiated mammography screening program (Group 1), and, opportunistically, in self-referred symptomatic women (Group 2) on the other, are compared. In 8877 symptom-free women, aged 50-65 years, individually invited to attend the screening offered for the residents of the III., XII. and XIII. districts of Budapest, 67 cancer cases were detected (7.5 in 1000 screenees), in accordance with the cancer detection rate of the first, "prevalence" round of organised screening programmes. In the other group of 1593 symptomatic, self-referred women of the same age, 113 cancer cases were diagnosed by mammography. As far as the pathological parameters are concerned, the number of cases with invasive cancer less than 15 mm in diameter, and those with axillary nodes present was found to be significantly higher in the screened group as compared to the self-referred one (p < 0.01). In "small" cancers (i.e. less than 15 mm in diameter), no significant difference was found in the proportion of histologic grade III tumours among the two groups. In screen-detected cancers both the morphometric prognostic index (as calculated by Baak et al.) and the Nottingham Prognostic Index (NPI) proved to be more favourable, as compared to those in the self-referred group. The p-value as determined by Mann-Whithey test was 0.000003 in the screened group, and 0.000015 in the other one. These findings provide convincing evidence in support of the public health importance of provider-initiated, organised mammography screening for breast cancer, therefore, the introduction on service basis of organised breast screening into the health care system in Hungary is strongly recommended by the authors.     

Clinical and electrophysiological findings and long-term outcomes in paediatric patients with critical illness polyneuromyopathy.

BACKGROUND: Neuromuscular weakness in paediatric patients with sepsis and multiple organ dysfunction is increasingly reported. However, many aspects of neuromuscular involvement in critically ill children are not completely understood. As more patients survive the critical illness, an understanding of the long-term outcomes of this condition is needed. AIMS: To describe clinical and electrophysiological features and evaluate the long-term outcomes in critically ill paediatric patients with neuromuscular complications. METHODS: A case series of five critically ill children was observed prospectively for a 1-month period. Selected clinical and laboratory parameters were evaluated. Electrophysiological studies were performed during the first week and then 1 month later in order to detect signs of critical illness polyneuromyopathy (CIPM). Patients with neuromuscular involvement completed a 1-year follow-up. RESULTS: Electrophysiological abnormalities were detected in two patients. Flaccid quadriplegia was a clinical presentation. Both children had electromyographic evidence of chronic partial denervation at follow-up, findings indicative of a preceding axonal neuropathy. Marked but incomplete recovery within 1 year after the onset of the disease occured in both patients. With a mild residual functional handicap the health-related quality of life was not significantly impaired (Barthel Index > 80). CONCLUSIONS: In both our patients with CIPM, the long-term clinical outcome is markedly better than we expected when electromyography in the 1-year follow-up demonstrated a persistent severe chronic partial denervation. These findings can have important implications for the management and rehabilitation of paediatric intensive care survivors.     

Artificial Anisotropy in Ge2Sb2Te5 Thin Films after Femtosecond Laser Irradiation

Ge₂Sb₂Te₅ (GST225) looks to be a promising material for rewritable memory devices due to its relatively easy processing and high optical and electrophysical contrast for the crystalline and amorphous phases. In the present work, we combined the possibilities of crystallization and anisotropic structures fabrication using femtosecond laser treatment at the 1250 nm wavelength of 200 nm thin amorphous GST225 films on silicon oxide/silicon substrates. A raster treatment mode and photoexcited surface plasmon polariton generation allowed us to produce mutually orthogonal periodic structures, such as scanline tracks (the period is 120 ± 10 μm) and laser-induced gratings (the period is 1100 ± 50 nm), respectively. Alternating crystalline and amorphous phases at the irradiated surfaces were revealed according to Raman spectroscopy and optical microscopy studies for both types of structures. Such periodic modulation leads to artificial optical and electrophysical anisotropy. Reflectance spectra in the near infrared range differ for various polarizations of probing light, and this mainly results from the presence of laser-induced periodic surface structures. On the other hand, the scanline tracks cause strong conductivity anisotropy for dc measurements in the temperature range of 200–400 K. The obtained results are promising for designing new GST225-based memory devices in which anisotropy may promote increasing the information recording density.     

Optimization of the High-Shear Wet Granulation Wetting Process Using Fuzzy Logic Modeling

A fuzzy model has been developed for the optimization of high-shear wet granulation wetting on a plant scale depending on the characteristics of pharmaceutical active substance particles. The model optimized on the basis of experimental data involves a set of rules obtained from expert knowledge and full-scale process data. The skewness coefficient of particle size distribution and the tapped density of the granulated mixture were chosen as the model input variables. The output of the fuzzy ruled system is the optimal quantity of wetting liquid. In comparison to manufacturing practice, a very strong sensitivity of the optimal quantity of the added wetting liquid to the size and shape of the active substance particles has been identified by fuzzy modeling.     

Blastocyst development after sperm selection at high magnification is associated with size and number of nuclear vacuoles

Spermatozoa selection at high magnification before intracytoplasmic sperm injection seems to be positively associated with pregnancy rates after day 3 embryo transfers. The aim was to demonstrate an association between the presence of vacuoles in sperm nuclei and the competence of embryos to develop to day 5. Grading of spermatozoa at x 6000-x 12,500 magnification: grade I, no vacuoles; grade II, or=1 large vacuole; grade IV, large vacuoles with other abnormalities. The outcome of embryo development in a group of 25 patients after sibling oocyte injection with the four different grades of spermatozoa showed no significant difference in embryo quality up to day 3. However, the occurrence of blastocyst formation was 56.3 and 61.4% with grade I and II spermatozoa respectively, compared with 5.1% with grade III and 0% with grade IV respectively (P < 0.001). Spermatozoa selection at high magnification using Nomarski interference contrast is useful to identify more precisely the size and the number of nuclear vacuoles that greatly exert a negative effect on embryo development to the blastocyst stage. These observations confirm previous studies pointing to possible 'early and late paternal effects', both of which may have an impact on early embryonic development.