Histocompatibility antigen studies in women with recurrent miscarriages and Müllerian uterine anomalies

The objective of the present study was to examine the effects of a long-acting angiotensin converting enzyme inhibitor, imidapril ((4S)-1-methyl-3-?(2S)-2-[N-(1S)-1-ethoxycarbonyl-3-phenylpropyl) amino] propionyl?-2-oxoimidazolidine-4-carboxylic acid hydrochloride), for 7 days on the cerebral blood flow autoregulatory response to hypotension in hypertensive rats. We measured the cerebral blood flow at rest and during hemorrhagic hypotension, using laser-Doppler flowmetry. At the same time, the absolute baseline cerebral blood flow values in the parietal cortex were quantified with the hydrogen clearance method. After administration of imidapril at a dose of 5 mg/kg/day for 7 days, the resting value of mean arterial blood pressure was significantly decreased by 25 mm Hg (P < 0.001), cerebral vascular resistance was lowered by 14.4% (P < 0.05) and the lower limit of cerebral blood flow autoregulation was shifted to a lower level, 106+/-11 mm Hg (mean +/- S.D.), from 137+/-8 mm Hg in the control group (P < 0.001), while resting cerebral blood flow remained unchanged. The present results demonstrated that imidapril preserves cerebral blood flow and significantly shifts the lower limit of cerebral autoregulation towards lower blood pressure levels.     

The use of sodium chloride baths in the treatment of diabetic patients with micro- and macroangiopathies

The morphological picture of different bacteria (Salmonella typhimurium, Proteus vulgaris, Klebsiella pneumoniae, Pseudomonas aeruginosa, Yersinia enterocolitica O3, Y.pseudotuberculosis 1, Y.frederiksenii, Y.intermedia, Y.kristensenii) on environmental objects was studied with the use of scanning electron microscopy (SEM). Bacteria adhered to the surface of pieces of fodder, egg shell, cabbage leaves and form microcolonies, whose morphology was similar to colonies, grown on nutrient media. The cells produced extracellular substances, seen in SEM as integuments. These integuments were gourd to protect the population from the action of unfavorable factors.     

Mechanism of maxi-K channel activation by dehydrosoyasaponin-I

Dehydrosoyasaponin-I (DHS-I) is a potent activator of high-conductance, calcium-activated potassium (maxi-K) channels. Interaction of DHS-I with maxi-K channels from bovine aortic smooth muscle was studied after incorporating single channels into planar lipid bilayers. Nanomolar amounts of intracellular DHS-I caused the appearance of discrete episodes of high channel open probability interrupted by periods of apparently normal activity. Statistical analysis of these periods revealed two clearly separable gating modes that likely reflect binding and unbinding of DHS-I. Kinetic analysis of durations of DHS-I-modified modes suggested DHS-I activates maxi-K channels through a high-order reaction. Average durations of DHS-I-modified modes increased with DHS-I concentration, and distributions of these mode durations contained two or more exponential components. In addition, dose-dependent increases in channel open probability from low initial values were high order with average Hill slopes of 2.4-2.9 under different conditions, suggesting at least three to four DHS-I molecules bind to maximally activate the channel. Changes in membrane potential over a 60-mV range appeared to have little effect on DHS-I binding. DHS-I modified calcium- and voltage-dependent channel gating. 100 nM DHS-I caused a threefold decrease in concentration of calcium required to half maximally open channels. DHS-I shifted the midpoint voltage for channel opening to more hyperpolarized potentials with a maximum shift of -105 mV. 100 nM DHS-I had a larger effect on voltage-dependent compared with calcium-dependent channel gating, suggesting DHS-I may differentiate these gating mechanisms. A model specifying four identical, noninteracting binding sites, where DHS-I binds to open conformations with 10-20-fold higher affinity than to closed conformations, explained changes in voltage-dependent gating and DHS-I-induced modes. This model of channel activation by DHS-I may provide a framework for understanding protein structures underlying maxi-K channel gating, and may provide a basis for understanding ligand activation of other ion channels.     

Is there a danger in delaying radiotherapy in childhood medulloblastoma?

Approximately 45-50% of children with medulloblastoma are cured by conventional surgery and radiotherapy, but survivors may face severe late neuropsychological toxicity. Studies showing good partial responses to platinum-based chemotherapy in relapsed patients and the theoretical possibility of a therapeutic window immediately after surgery have prompted neoadjuvant treatment studies which are ongoing. However, the absolute benefit of chemotherapy for the treatment of medulloblastoma in childhood is, as yet, not proven. There is a danger that chemotherapy may simply delay radiotherapy, and in so doing reduce the radiological impact of this known effective treatment. We report four children with medulloblastoma presenting consecutively to this unit over a 6-month period, whose management was problematic because of either failure to respond to neoadjuvant chemotherapy or their very young age. These cases are discussed in the light of the current literature and future treatment strategies that must seek to improve the therapeutic ratio of multimodality therapy.     

The pulmonary absorption of aerosolized and intratracheally instilled rhG-CSF and monoPEGylated rhG-CSF

PURPOSE: The objective of this study was to highlight differences in the pulmonary absorption of a monoPEGylated rhG-CSF and rhG-CSF after intratracheal instillation and aerosol delivery. METHODS: Male Sprague Dawley rats (250 g) were anesthetized and intratracheally instilled (IT) with protein solution or were endotracheally intubated and administered aerosol for 20 min via a Harvard small animal ventilator. A DeVilbiss "Aerosonic" nebulizer containing 5 ml of protein solution at approximately 3 mg/ml was used to generate aerosol. The volume of protein solution deposited in the lung lobes was estimated to be approximately 13 microliters after delivery of Tc-99m HSA solutions. The PEGylated proteins consisted of a 6 kDa (P6) or 12 kDa PEG (P12) linked to the N-terminus of rhG-CSF. rhG-CSF also was administered IT in buffers at pH 4 and pH 7 and in dosing volumes ranging from 100 to 400 microliters. Blood samples were removed at intervals after dosing and the total white blood cell counts (WBC) were determined. Plasma was assayed for proteins by an enzyme immuno assay. RESULTS: The plasma protein concentration v. time profiles were strikingly different for aerosol v. IT delivery. The Cmax values for rhG-CSF and P12 after aerosol delivery were greater than found after IT (Aerosol: 598 +/- 135 (ng/ml) rhG-CSF; 182 +/- 14 P12 v. IT: 105 +/- 12 rhG-CSF; 65.9 +/- 5 P12). Similarly, Tmax was reached much earlier after aerosol administration (Aerosol: 21.7 +/- 4.8 (min) rhG-CSF; 168 +/- 31 P12 v. IT: 100 +/- 17 rhG-CSF; 310 +/- 121 P12). Estimated bioavailabilities (F(lung)%) were significantly greater via aerosol delivery than those obtained after IT (Aerosol: 66 +/- 14 rhG-CSF; 12.3 +/- 1.9 P12 v. IT: 11.9 +/- 1.5 rhG-CSF; 1.6 +/- 0.1 P12). An increase in circulating WBC counts was induced by all proteins delivered to the lungs. The rate and extent of absorption of rhG-CSF was not influenced by the pH employed nor the instilled volume. CONCLUSIONS: Estimates of bioavailability are dependent upon the technique employed to administer drug to the lungs. Aerosol administration provides a better estimate of the systemic absorption of macromolecules.     

Communication with parents of children with cancer

The authors summarize the results of recent work evidencing the existence of latent merozoites during the course of the erythrocytic cycle of the rodent Plasmodia. These merozoites, unlike the majority of merozoites released at schizogony, do not penetrate immediately into the erythrocytes and remain latent for a variable length of time. The merozoites of each of the species or subspecies show marked peculiarities which are responsible for the characteristics of their cycle. The presence of latent merozoites free in the blood, the asynchronous development, and the resistance to chloroquine, are three closely related factors. Knowing that the merozoite is so far drug resistant, and that latent merozoites can maintain the infection for any length of time, it appears important to take into account these purely biological data, when studying the drug resistance of the human falciparum malaria.     

Functional state of the supraepithelial mucous layer of the digestive tract in mice in the postnatal period after irradiation

It was studied the condition of mucous layer of intestine in mice model experiments after ionizing radiation. It were found out the differences in reaction of intestine on radiation in mice at the age of 55 and 95 days. In mice at the age of 55 days at the whole stretch of intestine was marked increased secretion of the polymeric glycoproteins, whereas in mice at the age of 95 days such alterations were marked at smaller degree. In both groups mice was marked increased secretion of bicarbonate after radiation, that is possible to count as characteristic compensative mechanism.     

Arrestin/clathrin interaction. Localization of the arrestin binding locus to the clathrin terminal domain

Previously we demonstrated that nonvisual arrestins exhibit a high affinity interaction with clathrin, consistent with an adaptor function in the internalization of G protein-coupled receptors (Goodman, O. B., Jr., Krupnick, J. G., Santini, F., Gurevich, V. V., Penn, R. B., Gagnon, A. W., Keen, J. H., and Benovic, J. L. (1996) Nature 383, 447-450). In this report we show that a short sequence of highly conserved residues within the globular clathrin terminal domain is responsible for arrestin binding. Limited proteolysis of clathrin cages results in the release of terminal domains and concomitant abrogation of arrestin binding. The nonvisual arrestins, beta-arrestin and arrestin3, but not visual arrestin, bind specifically to a glutathione S-transferase-clathrin terminal domain fusion protein. Deletion analysis and alanine scanning mutagenesis localize the binding site to residues 89-100 of the clathrin heavy chain and indicate that residues 1-100 can function as an independent arrestin binding domain. Site-directed mutagenesis identifies an invariant glutamine (Glu-89) and two highly conserved lysines (Lys-96 and Lys-98) as residues critical for arrestin binding, complementing hydrophobic and acidic residues in arrestin3 which have been implicated in clathrin binding (Krupnick, J. G., Goodman, O. B., Jr., Keen, J. H., and Benovic, J. L. (1997) J. Biol. Chem. 272, 15011-15016). Despite exhibiting high affinity clathrin binding, arrestins do not induce coat assembly. The terminal domain is oriented toward the plasma membrane in coated pits, and its binding of both arrestins and AP-2 suggests that this domain is the anchor responsible for adaptor-receptor recruitment to the coated pit.     

SPECT and PET in neurobiology

PET (positron emission tomography) and SPECT (single photon emission computed tomography) are isotopic methods in which the distribution is registered of radiolabelled tracers given in such small amounts that they are without effect on the organism or the organism's disposal of them. Thus, a series of important biological processes in the intact organism can be studied. The methods have been used in many disciplines but in particular for neurobiological research on the brain--e.g., the brain's regional blood circulation and mapping of the brain's functional structure. The methods have also been used in the investigation of glucose and amino acid metabolism in the brain and receptor conditions.