Synthesis of N-(phosphonoacetyl)-dipeptide derivatives and evaluation of their antihypertensive activity

A series of N-(phosphonoacetyl)-dipeptide derivatives was synthesized for pharmacological testing as antihypertensive compounds. Several of these compounds demonstrated a moderate antihypertensive effect in Wistar spontaneous hypertensive rats (SHR) with p.o. dosing. ACE inhibition by the compounds was studied using ACE from rat plasma and lung. Inhibitors containing esterified C-termini are pro-drugs and showed activity only for plasma ACE.     

New phenotypic, functional and electrophysiological characteristics of KG-1 cells

Myeloid dendritic cells (DC) are representatives of a rare and phenotypically diverse population of professional antigen presenting cells possessing high functional heterogeneity and flexibility. Here we studied the phenotypic, functional and electrophysiological characteristics of KG-1 cells, an erythroleukemia model cell line, which shares morphological and physiological similarities with immature and mature myeloid DC. We compared the expression of internalizing receptors and other cell surface molecules, antigen uptake and migration of unstimulated and activated KG-1 cells with the characteristics of immature and mature DC. Unstimulated KG-1 cells were less potent in capturing extracellular materials than immature DC. In contrast to monocyte-derived DC KG-1 cells stimulated by PMA and ionomycin ceased to migrate along the MIP-3beta chemokine gradient despite their high expression of CCR7 chemokine receptor and MDR, a transporter implicated in DC migration. Moreover, we determined the ion channel repertoire of KG-1 cells before and after treatment with PMA and ionomycin by using the patch-clamp technique. We found that both unstimulated and activated KG-1 cells expressed time- and voltage-independent, ChTx sensitive intracellular Ca(2+)-gated potassium conductance suggesting the presence of K(Ca) channels in their membranes. Based on our results we propose that KG-1 cells resemble myeloid DC but also possess unique phenotypic, functional and electrophysiological characteristics.     

Analysis of the Equalization of Inverted Repeats and Neurovirulence Using a Pseudorabies Virus Mutant Strain Altered at the Ul/Ir Junction

A recombinant pseudorabies (Aujeszky’s disease) virus (PrV) designated as vE16lac was constructed by deleting a 3-kbp DNA segment spanning the junction of long and short components of the viral genome, and by replacing the deleted segment with a lacZ-expression cassette. The aim of constructing this mutant was (a) to determine whether the terminal repeat (Tr) can serve as a template for the regeneration of the internal repeat (Ir), and (b) whether this deletion causes a reduction in the neuroinvasiveness of the virus. To analyze the mechanism of equalization, revertant viruses were selected and structurally characterized from vE16lac infection of PK-15 cells, mice and pigs. Because all revertants acquired Ir sequences identical to that of the wild-type virus, the equalization process occurred using the Tr as a template to reconstitute the Ir. We also found that the recombinant virus vE16lac was virulent in both pigs and mice. The data are discussed in view of studies performed with similar PrV mutants by other authors (Rall et al., 1992, Dean and Cheung, 1995 and Dean et al., 1996). This revised version was published online in July 2006 with corrections to the Cover Date.     

Outcomes of gastrostomy placement with and without concomitant tracheostomy among ventilator dependent children

IntroductionSimultaneous gastrostomy tube (GT) and tracheostomy placement in young children offers potential benefit in limiting anesthetic exposure, but it is unknown whether combining these procedures introduces additional morbidity. This study compared outcomes after combined GT and tracheostomy placement versus GT placement alone among similar ventilator-dependent patients.MethodsVentilator-dependent children <2-years-old who underwent GT placement alone (MV-GT), simultaneous GT and tracheostomy placement (GT+T), and GT placement alone with a pre-existing tracheostomy (T-GT) were identified using 2012–2018 NSQIP-Pediatric Participant User Files. Multiple logistic regression models were used to compare outcomes while adjusting for other group differences.ResultsAmong 1100 children, 351 underwent MV-GT, 494 GT+T, and 255 T-GT. Major complications occurred in 23.6%, 17.0%, and 14.5% of the respective groups (p = 0.01). Major complications with GT+T were similar to T-GT (adjusted odds ratio [aOR]=1.19, 95%CI:0.78–1.83, p = 0.4) and lower than MV-GT (aOR=0.67, 95%CI:0.47–0.95, p = 0.02). Severe complications including mortality, cardiac arrest, and stroke were similar between the three groups (p = 0.8).ConclusionsChildren <2-years-old undergoing GT+T did not experience higher post-operative complications compared to children undergoing T-GT or MV-GT. Utilizing GT+T to limit anesthetic exposure may be reasonable within this high-risk population.Type of StudyTreatment StudyLevel of EvidenceLevel III     

Prognostic factors affecting survival in multiple myeloma

70 patients suffering from multiple myeloma were observed by authors in the last 15 years and three months. In the meantime fifty-two out of them have died, and 18 patients are under permanent care. 43 IgG, 17 IgA, 6 Bence-Jones, 2 IgD types were diagnosed according to the paraprotein distribution, one patient proved to be nonsecretory, and an other one to osteosclerotic form as well. The median survival time was 27 months in the group of deceased patients. In the group followed-up 50.8 months survival time was observed up to the closing of the study. Several prognostic factors were investigated. According to the classification by Durie and Salmon the survival time was 60 months in the patients with stage I, 33 months in stage II., and 9 months in stage III respectively. The prognosis is much poorer in patients into the "B" category: the survival time was 14 months. Classified in the basis of the type of the myeloma-cell, the cases with well matured cells have had the best prognosis with survival time of 46 months, while the most unfavourable prognosis was observed in patients with blast-cell type, with a median survival time of 10 months. The greatest number of patients suffered from multiple myeloma of IgG paraprotein type, in this group the serum IgA level was found to be significantly decreased in the patients died due to inevitable infections. The survival was injured significantly by the occurrence of concomitant severe diseases, to.(ABSTRACT TRUNCATED AT 250 WORDS)     

Ganglioneuroma of the adrenal gland]

149 patients with adrenal incidentalomas were examined. Sixty-eight cases were histologically confirmed, five of them had ganglioneuromas. On the basis of these patients history current knowledge of this benign tumour was summarized. Histological and pathological characteristics of one tumour suggest that ganglioneuromas may develop by maturing of malignant neuroblastic tumours. The clinical symptoms (abdominal pain, meteorism) were local. In 2 of 5 cases mildly elevated levels of urinary vanillylmandelic acid and catecholamine could be measured. One patient had persisting hypertension after surgery. In an other patient previous diarrhoea stopped after the removal of tumour. On the basis of ultrasound and computertomographic features, the size and origin of a tumour and its relation to the surrounding organs can be well characterized. One patient was inoperable because of an infiltratively spreading tumour, but during five years of follow-up no tumour progression could be observed with computertomography. After surgery we could follow only 2 of 4 patients. Until now no recurrence of tumour were detected.     

Thermoanalytic determination of the enantiomeric purity of selegiline]

The thermal behaviour of Selegiline (a chiral, non racemic pharmaceutical used in the therapy of Parkinson disease) was studied by differential scanning calorimetry (DSC) for determining the enantiomeric purity (e.p.) of the bulk substance. It has been found, that (i) the binary phase diagram (melting point phase diagram) of the R/S enantiomer mixtures is characteristic to that of the true racemic compounds; (ii) the melting behaviour of the R/S binary mixtures follows the thermodynamic laws (i.e. the Schr?der-Van Laar and the Prigogine-Defay equations); (iii) the e.p. of the highly purified bulk substance can be expressed as "DSC purity" (this latter is obtained from the Van't Hoff equation) and the microcalorimetric method as above gives good reproducibility; (iv) due to the minor impurities (other than the S(-) enantiomer) the obtained e.p. (expressed as DSC purity) can be higher but not lower than the actual e.p. of the investigated substance.     

Quality control of radiographic imaging of the lumbar spine]

The qualitative control of the roentgenographic findings was performed independently by the assessment of five x-ray specialists on 40 two-directional lumbosacral roentgenograms. The findings were based on questioners including all details and a table of the internationally used "Radiological Diagnosis". In earlier publications the anatomical and structural changes were considered the risk factors of the waist. (Osteoporosis, changes in the position of the vertebral body, change in the shape of the spine, restriction of the intervertebral cleft and deformation of the small articulations). The views of the research workers were compared by means of statistical analysis. Compared with other authors the methods of these findings are in agreement with the international norms. These findings drew attention to the necessity of an objective assessment of the subjective findings.     

Parlodel treatment of patients with pathospermia

The response to bromoergocryptine (Parlodel, Sandoz) was examined in 42 pathospermic patients. The authors conclude that Parlodel did not influence the spermiogram considerably. Serum prolactin levels were lowered significantly, while the FSH, LH, testosterone, 17--hydroxyprogesterone and 17--oestradiol concentrations did not change. Improvement was reported in potentia coeundi in one third of the patients.Supported by the Scientific Research Council, Ministry of Health, Hungary (4-29-0302-01-2/S).     

GABAA receptor mediated elevation of Ca2+ and modulation of gonadotrophin-releasing hormone action in alphaT3-1 gonadotropes

gamma-amino butyric acid (GABA) is the major inhibitory neurotransmitter in the CNS, mediating fast inhibitory synaptic transmission, by activating GABAA receptors. However, these GABA-gated Cl- channels can also be excitatory, causing depolarization, and increasing Ca2+ entry via voltage-operated Ca2+ channels (VOCCs). Evidence exists for excitatory ionotropic GABA receptors in anterior pituitary cells, including gonadotropes, but these have not been directly characterized and their pharmacology remains controversial. Here we have measured the cytosolic Ca2+ concentration ([Ca2+]i) in alphaT3-1 gonadotropes, to test for expression of excitatory GABA receptors. The GABAA agonists, GABA and muscimol, both caused rapid, robust and dose-dependent increases in [Ca2+]i (EC50 values 2.7 and 1 microM), whereas the GABAB agonist, baclofen, did not. The GABAA antagonist, bicuculline, inhibited muscimol's effect, whereas the GABAB antagonist, phaclofen, did not. The neuroactive steroid 5alpha-pregnan-3alpha-ol-11,20-dione (an allosteric activator of GABAA receptors) increased [Ca2+]i, and this effect, like that of muscimol, was inhibited by picrotoxin. The muscimol effect on [Ca2+]i was blocked by the VOCC antagonist, nifedipine, or by Ca2+-free medium. When cells were pretreated with muscimol this increased the spike phase of the [Ca2+]i response to subsequent stimulation with gonadotropin-releasing hormone (GnRH). Similar amplification was seen in muscimol-pretreated cells stimulated with GnRH in Ca2+-free medium, but not when cells were pretreated with muscimol in Ca2+-free medium. The amplification was not, however, GnRH receptor-specific, because the spike response to ionomycin was also increased by muscimol pretreatment. These data provide the first direct evidence for expression of excitatory GABAA receptors, and the first demonstration of acute steroid effects, on GnRH-responsive pituitary cells. They also reveal a novel mechanism by which GABAA activation modulates GnRH action, raising the possibility that this may also influence gonadotrophin secretion from non-immortalized gonadotropes.