Fast decline of hematopoiesis and uncoupling protein 2 content in human liver after birth: location of the protein in Kupffer cells

Hepatic hematopoiesis is prominent during fetal life and ceases around birth. In rodent liver, the decline of the hepatic hematopoiesis starts abruptly at birth being accompanied by a decrease of mitochondrial uncoupling protein 2 (UCP2) expression in monocytes/macrophages, whereas hepatocytes may express UCP2 only under pathologic situations. The goals of this study were to characterize hepatic hematopoiesis in humans around birth, and to identify cells expressing UCP2. Hematopoiesis was evaluated histologically in the liver of 22 newborns (mostly very premature neonates), who died between 45 min and 140 d after birth, and one fetus. UCP2 expression was characterized by Northern blots, immunoblotting, immunohistochemistry, and by in situ hybridization. The number of hematopoietic cells started to decrease rapidly at birth, irrespectively of the gestational age (23-40 wk) of neonates. A similar decline was observed for UCP2 expression, which was relatively high in fetal liver. UCP2 was detected only in myeloid cells (mainly in Kupffer cells), but not in hepatocytes, although sepsis or other pathologies occurred in the critically ill newborns. Kupffer cells represent the major site of mitochondrial UCP2 expression in the human newborn. UCP2 may be essential for the differentiation and function of macrophages and serve as a marker for these cells in human liver during the perinatal period.     

Brain metastases after stereotactic radiosurgery using the Leksell gamma knife: can FDG PET help to differentiate radionecrosis from tumour progression?

Stereotactic radiosurgery (SRS) using the Leksell gamma knife promotes acute and chronic local changes in glucose metabolism. We have been able to find very few papers on Medline on the subject of assessment of metastases by 2-[(18)F]fluoro-2-deoxy- D-glucose positron emission tomography (FDG PET) after SRS. The aim of this work was to specify the additional value of FDG PET, in comparison with magnetic resonance imaging (MRI), in differentiating SRS-induced radionecrosis from viable brain metastasis in a clinical setting. Fifty-seven metastases in 25 patients were treated by SRS. An average of 33 weeks later, all the patients underwent FDG PET. At the same time (SD=2 weeks) all the patients underwent MRI. The sensitivity, specificity and accuracy of both FDG PET and MRI examinations were calculated with reference to clinical and radiological follow-up or biopsies. The additional value derived from use of FDG PET after MRI was assessed and progression-free survival rates were compared. The difference in progression-free survival rates between the negative and positive subgroups was significant ( P=0.0005) for MRI and even more so ( P<0.00001) for FDG PET. Sensitivity, specificity and accuracy were 75% (6/8), 93.9% (46/49) and 91.2% (52/57) for FDG PET, and 100% (8/8), 65.3% (32/49) and 70.2% (40/57) for MRI. In the subgroup of patients with positive or non-diagnostic MRI, the probability of presence of a viable tumour was only 32% (8/25). This probability increased to 100% (5/5) when subsequent FDG PET was positive and decreased to 11.1% (2/18) when FDG PET was negative. The frequency of a viable neoplasm was significantly different ( P=0.001) in the FDG PET negative and positive subgroups. MRI and FDG PET both have an important predictive value for persistent viable metastases after treatment by SRS. Neither sensitive but non-specific MRI nor specific but insensitive FDG PET is reliable on its own. While FDG PET significantly improved the diagnostic accuracy in the subgroup of patients with positive and non-diagnostic MRI, it provided no additional value in the MRI-negative subgroup.     

Antimycobacterial and antifungal isosters of salicylamides

A set of 40 derivatives of 3-hydroxypicolinic acid and 2-sulfanylbenzoic acid, isosteric to salicylanilides was synthesized. The compounds were evaluated for in vitro activity against Mycobacterium tuberculosis, Mycobacterium kansasii and Mycobacterium avium, Candida albicans, Candida tropicalis, Candida krusei, Candida glabrata, Trichosporon beigelii, Aspergillus fumigatus, Absidia corymbifera, Trichophyton mentagrophytes and Microsporum gypseum. Structure-activity relationships of antimycobacterial activity and antifungal activity against T. mentagrophytes and M. gypseum were analyzed by the Free-Wilson method. An increase in antimycobacterial activity was observed only for the sulfanylbenzoic acid derivatives, especially those with the benzyl moiety. The antifungal activity was not significant.     

TABLE OF AMINO ACID REPLACEMENTS IN PROTEINS POSSIBLE AS A RESULT OF ONE-POINT MUTATIONS

A Table of amino acid replacements based on one-point mutations is presented. For each amino acid replacement the number of mutations of various codons resulting in this mutation is recorded.     

Failure of ergotamine to act as an amplifier of sulfonylurea-stimulated insulin secretion

Summary Normal dogs were injected i.v. with 0.25 mg/kg sodium salt of HB 419 (gliben-clamide) and plasma insulin concentrations were measured over a period of 2 hrs. When the animals were given a single i.v. injection of 0.2 mg/kg dihydroergotamine tartrate (DHE) 30 min prior to the administration of HB 419, the insulinogenic effect of the sulfonylurea was considerably amplified (192 μU/mlvs 34 μU/mI at 45 min). No augmentation of the insulinogenic effect of HB 419 was observed when the same experiments were conducted with 0.05, 0.025 or 0.01 mg/kg ergotamine tartrate. At the dose level of 0.1 mg/kg the insulinogenic effect of HB 419 was suppressed. Since the structural difference between these two ergor alkaloids consists of the presence or absence of the double bond at C₉ and C₁₀ of the lysergic acid moiety, it appears that saturation of this double bond is an essential structural requirement for DHE to function as an amplifier of sulfonylurea-stimulated insulin release. Supported by the Karel Ančerl Fund of the University of Toronto.     

Radioprotective effects of amifostine (WR-2721) or cystamine on radiation damage and its repair in rats whole body exposed to fission neutrons

Sulphur containing radioprotective drugs amifostine (gammaphos, WR-2721) or cystamine (disulfide of meracaptoethylamine) of Czechoslovak production were examined in whole body fission neutrons irradiated rats in the thermal column of reactor VVR-S. Using the split-dose technic the first sublethal neutron dose in the range 1-2 Gy was followed by second lethal exposures in the two time intervals (3 or 6 days) using whole body fission neutrons irradiations (3 days interval) or whole body gamma-irradiations (6 days interval) for LD50/30 evaluation within next 30 days survival observation. In other experiments the mean survival time (MST) in days was estimated in different rats group, when animals were whole body fission neutrons irradiated twice with 3-days interval using the total lethal doses of 4 or 5 Gy. Protected rats received amifostine (160 mg.kg(-1) i.p. and 200 mg.kg(-1) i.m.) or cystamine (40 mg.kg(-1) i.p. and 50 mg.kg(-1) i.m.), control rats obtained saline 20 min before beginning of irradiation in the amount of 0.5 ml.100 g(-1) of the rat's body weight. Non-significant DRF value 1.13 for WR-2721 i.p. was calculated in survival studies in rats twice neutron irradiated with 3 days interval (DRF 1.04 for cystamine). Chemical protectors were administered before each neutron exposure. MST of twice neutron lethal iradiated rats was prolonged not regularly by radioprotectors tested. WR-2721 and cystamine i.m. were not able to increase 6 days reparation processes after sublethal 2 Gy fission neutrons whole body irradiated rats.     

Rapid subtyping of tick-borne encephalitis virus isolates using multiplex RT-PCR

Tick-borne encephalitis virus, an emerging pathogen in several countries in Europe and Asia, has been divided into three subtypes (European, Siberian and Far Eastern). These subtypes are associated with different severities of the disease. For that reason, early determination of the subtype in a clinical sample or in ticks removed from a patient in areas of co-circulation of two or three subtypes is of high importance. The development of a simple method of multiplex RT-PCR for rapid and easy subtyping of tick-borne encephalitis virus isolates is reported to fill this requirement. The method is based on the unique combination of oligonucleotide primers hybridizing with subtype-specific "signature" positions of the sequence encoding the viral envelope protein. The developed multiplex RT-PCR also appears to be a useful method in studies focused on the molecular-epidemiology of tick-borne encephalitis virus.     

Detection of feto-maternal infection/inflammation by the soluble receptor for advanced glycation end products (sRAGE): results of a pilot study

Abstract Objective: The receptor for advanced glycation end products, RAGE, plays an important role in the pathogenesis of several diseases. sRAGE, soluble receptor for advanced glycation end products, is an inhibitor of the pathological effect mediated via RAGE. The aim of this study was to assess the usefulness of measuring sRAGE concentration in pregnant women with threatening preterm labor. Methods: Serum levels of sRAGE, interleukin-6 (IL-6) and routine markers of inflammation were determined in 46 pregnant women with threatening preterm labor, 35 healthy pregnant women and 15 non-pregnant controls. Results: Serum levels of sRAGE in healthy pregnant women were significantly lower than in non-pregnant controls (669+/-296 vs. 1929+/-727 pg/mL, P<0.05). Women with threatening preterm birth had a significantly higher concentration of serum sRAGE in comparison with healthy pregnant women (819+/-329 pg/mL vs. 669+/-296 pg/mL, P<0.05). Conversely, patients with PPROM had significantly lower levels of sRAGE compared with patients with threatening premature labor (600+/-324 pg/mL, P<0.05). sRAGE correlated negatively with leukocyte counts (r=-0.325, P<0.05). Conclusions: sRAGE might be a new and promising marker of premature labor, especially with the symptoms of PPROM.