Immunological and virological effects of long term IL-2 therapy in HIV-1-infected patients.

We report the long-term outcome of 27 HIV-infected patients treated for over 3 years with IL-2 and binucleoside analogues. These patients experienced a sustained increase in CD4 cells and a decrease of proviral DNA with infrequent IL-2 cycles. In three cases, virus could not be isolated from activated peripheral cells. A high frequency of HIV-1-specific memory CD4 T cells was found in the patients studied. IL-2 maintains specific effector cells and reduces the pool of infected cells in patients, albeit treated only with binucleosides.

Mechanism of action of 1-beta-D-2,6-diaminopurine dioxolane, a prodrug of the human immunodeficiency virus type 1 inhibitor 1-beta-D-dioxolane guanosine.

(-)-beta-D-2,6-Diaminopurine dioxolane (DAPD), is a nucleoside reverse transcriptase (RT) inhibitor with activity against human immunodeficiency virus type 1 (HIV-1). DAPD, which was designed as a water-soluble prodrug, is deaminated by adenosine deaminase to give (-)-beta-D-dioxolane guanine (DXG). By using calf adenosine deaminase a K(m) value of 15 +/- 0.7 microM was determined for DAPD, which was similar to the K(m) value for adenosine. However, the k(cat) for DAPD was 540-fold slower than the k(cat) for adenosine. In CEM cells and peripheral blood mononuclear cells exposed to DAPD or DXG, only the 5'-triphosphate of DXG (DXG-TP) was detected. DXG-TP is a potent alternative substrate inhibitor of HIV-1 RT. Rapid transient kinetic studies show the efficiency of incorporation for DXG-TP to be lower than that measured for the natural substrate, 2'-deoxyguanosine 5'-triphosphate. DXG-TP is a weak inhibitor of human DNA polymerases alpha and beta. Against the large subunit of human DNA polymerase gamma a K(i) value of 4.3 +/- 0.4 microM was determined for DXG-TP. DXG showed little or no cytotoxicity and no mitochondrial toxicity at the concentrations tested.

Treatment of isografted 9L rat brain tumors with beta-5-o-carboranyl-2'-deoxyuridine neutron capture therapy.

beta-5-o-Carboranyl-2'-deoxyuridine (D-CDU) is a nontoxic pyrimidine nucleoside analogue designed for boron neutron capture therapy of brain tumors. In vitro studies indicated that D-CDU accumulates to levels 92- and 117-fold higher than the extracellular concentration in rat 9L and human U-251 glioma cells, respectively, and persists for several hours at levels 5-fold higher than the extracellular concentration. Furthermore, D-CDU was not toxic to rats injected i.p. with up to 150 mg/kg. On the basis of these studies, D-CDU was evaluated as a neutron capture therapy agent using rats bearing stereotactically implanted intracranial 9L tumors at single i.p. doses of 30 mg/kg and 150 mg/kg of D-CDU (20% 10B enriched), given 2 h before irradiation with thermal neutrons. Boron concentrations in tumors 2 h after dosing were 2.3 +/- 1.6 and 7.4 +/- 1.3 micrograms boron/g tissue (mean +/- SD), corresponding to tumor/brain ratios of 11.5 +/- 3.6 and 6.8 +/- 2.0 micrograms boron/g tissue for the low and high doses, respectively. All untreated animals died within 28 days, whereas half survived at days 32, 55, and 38 for groups receiving neutrons only, 30 mg/kg D-CDU, and 150 mg/kg D-CDU, respectively. Odds ratios of all treatment groups differed significantly from the untreated group (P < 0.002; logrank test). The median survival time for the 30 mg/kg-treated group but not for the 150 mg/kg-treated group was significantly longer than for rats treated with neutrons only (P = 0.036), which may correlate with the decreased tumor selectivity for D-CDU observed at the higher dose. Additional pharmacodynamic studies are warranted to determine optimal dosing strategies for D-CDU.

[Comparative study of peripheral circulation, lipid metabolism and hemocoagulation in families with atherosclerosis and diabetes mellitus]. / Sravnitel'noe issledovanie sostoianiia perifericheskogo krovoobrashcheniia, lipidnogo obmena i gemokoaguliatsii v sem'iakh bol'nykh aterosklerozom i sakharnym diabetom.

AIM: The study of peripheral circulation (PC) in patients with atherosclerosis (AS), diabetes mellitus (DM) type I and II as well as their close relatives to clarify correlations between circulatory disorders, disturbances of lipid metabolism (LM) and hemocoagulation. MATERIALS AND METHODS: The patients and their relatives were divided into 3 groups: with AS, DM type I and II. Individuals without relevant hereditary predisposition served control. A total of 564 subjects were examined. Thermography (TG), TV capillaroscopy of the nail bed (TVCNB), measurements of total blood cholesterol (TBC), high density lipoproteins (HDLP) cholesterol, triglycerides, coagulation time, plasma recalcification, free heparin, fibrinogen concentration, calculation of the atherogenic and prothrombin indices were conducted. RESULTS: Microcirculation suffered most of all, especially in patients and their relatives with AS and DM type I. TVCNB detected morphological changes of the capillaries confirmed by TG. DM patients and their relatives, especially those with DM type I had most distinct morphological shifts. CONCLUSION: The above PC disorders result from lipid metabolism and hemocoagulation abnormalities affecting blood rheology. In DM patients and their relatives especially in those with DM type I specific alterations of the capillary structure in DM and hereditary predisposition to DM are a contributing factor.

[The effect of heredity and environmental conditions on the development of atherogenic metabolic shifts]. / Vliianie nasledstvennosti i uslovii sredy na razvitie aterogennykh sdvigov obmena.

Lipid metabolism and lipid peroxidation (LPO) were studied in residents of St. Petersburg (healthy subjects without atherosclerosis history, healthy relatives of atherosclerotic patients, postmyocardial infarction patients, post-apoplectic patients and coronary heart disease sufferers) versus matched subjects living in rural area. Altogether 215 patients were examined. Besides genotype factors, lipid metabolism and LPO were found responsive to environmental factors. These were especially potent in changing the activity of superoxide dismutase, glutathione peroxidase, catalase. In those living in the country myeloperoxidase, superoxide dismutase and catalase activity was higher than in city population. The latter exhibited, though, higher activity of glutathione peroxidase. It is evident that more advantageous ecological conditions have distinct antiatherogenic action on lipid metabolism and LPO, especially, suggesting possible treatment of atherosclerosis by moving to more healthy locality as regards environmental pollution.

Expression and biological activity of interleukin-1 receptors in mouse gamma/delta thymocytes during ontogeny.

We have recently shown that the response of mouse thymocytes to interleukin (IL)-1 + IL-2 was maximal at birth and that the responding cells displayed a CD4-CD8- T cell receptor (TcR) gamma/delta + phenotype. Unexpectedly, despite their high proportion of gamma/delta + cells, fetal thymocyte populations responded only weakly to IL-1 + IL-2. In this report, we demonstrate that the discrepancy between the day 17.5 fetal and newborn sensitivities to the combined action of IL-1 and IL-2 is a consequence of the different patterns of high-affinity IL-1 receptor (IL-1R) expression displayed by these two cell subsets. Actually, high- and low-affinity IL-1R are found in TcR gamma/delta + newborn cells and, in contrast, only low-affinity IL-1R are detectable in day 17.5 fetal cells. Our binding and functional studies strongly support the hypothesis that high-affinity IL-1R on the one hand, and low-affinity ones on the other hand, are involved in the response to IL-1 + IL-2 of newborn and day 17.5 fetal thymocytes, respectively. In addition, the high-affinity IL-1R appear to be far more efficient than the low-affinity receptors in promoting IL-2 responsiveness of thymocytes.

[Indicators of lipid metabolism and lipid peroxidation system in patients with different types of lesions of the vessels of the lower limbs]. / Pokazateli lipidnogo obmena i sistemy perekisnogo okisleniia lipidov u lits s razlichnymi tipami porazhenii sosudov nizhnikh konechnostei.

A total of 66 patients were investigated with IR imager and television capillaroscopy for the blood circulation in the vessels of low extremities as well as for the values of lipid metabolism and the system of lipid peroxidation. According to the status of the vascular system in the low extremities the examinees were divided into the groups with the normal status of the vascular system, the groups with the signs of venous insufficiency, microcirculatory disorders and atherosclerosis of major vessels. With the disorders of microcirculation in low extremities staged increments in the atherogenic shifts in the exchange were demonstrated. It was suggested that atherosclerotic changes in the arteries could be preceded with the hemodynamic changes in the venous and capillary systems due to rheological disorders due to the development of hypercoagulation which accompanied dyslipoproteinemias and other atherogenic shifts in the metabolism.

[Indicators of lipid metabolism and the blood lipid peroxidation system in men with regard to hereditary predisposition to atherosclerotic vascular pathology]. / Pokazateli lipidnogo obmena i sistemy perekisnogo okisleniia lipidov krovi u muzhchin s uchetom nasledstvennoi predraspolozhennosti k ateroskleroticheskoi sosudistoi patologii.

Lipid metabolism and the blood lipid peroxidation system were examined in 56 military males living in rather similar conditions. The parameters in question were compared in the following groups: (1) control subjects, including healthy individuals without a family history of atherosclerotic vascular abnormalities; (2) healthy subjects with a family history of atherosclerosis; (3) patients with coronary heart diseases. There were significant differences only in single cases between the groups. The application of a system of grids setting upright the distribution curves for the parameters under study proved to be effective in finding significant differences between the groups, showing the value of the hereditary factors in the development of atherogenic lipid changes.

Cellular basis of the resistance of newborn mice to the pathogenic effects of anti-CD3 treatment.

We have analysed the mechanisms underlying the differences in the susceptibilities of adult and newborn mice to the pathogenic effects of anti-CD3 mAbs. Our data show that the thymus cell number in adults is reduced by 93% 48 h after one single injection of 5 mg/kg of Ab whereas the same dose in newborns induces only a 30% decrease. In the adult, this effect is associated with a marked depletion of CD4+ CD8+ double positive (DP) cells and with the appearance of important areas of cell necrosis in the thymic cortex. In newborns, the DP cells are less affected and the thymic cortex does not present any cell necrosis even after an injection of 45 mg/kg of mAbs. Pre-treatment of adults with anti-CD4 and anti-CD8 Abs, while completely abolishing the toxic side-effects induced by anti-CD3 mAbs, does not protect the thymus from the depletion of DP cells. In vitro, anti-CD3 mAbs induce the proliferation of thymocytes and spleen cells from adults but not from newborns. Tumour necrosis factor-alpha (TNF alpha) is found in the serum of adults 90 min after injection of anti-CD3 but is never detected in the serum of anti-CD3 treated newborns. Taken together our data support the view that anti-CD3 mAbs act by two different mechanisms. The first one results from the binding of anti-CD3 on the CD3+ thymocytes which induces a direct toxicity for only the CD4+ CD8+ cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Ontogeny of the response of mouse thymocytes to interleukin 1 and interleukin 2.

In the present report we demonstrate that the in vitro proliferative response of the newborn thymocytes to interleukin (IL) 1 and IL 2, which is remarkably stronger than the adult thymocyte response, is associated with a considerable increase of CD4-CD8- cells expressing a gamma/delta T cell receptor (TcR). By polymerase chain reaction analysis we show that the V gamma gene segment usage in the adult and newborn responding cells reflects the developmentally regulated expression of the V gamma gene segments, suggesting that the increase in TcR gamma/delta+ cells results from the polyclonal expansion of pre-existing clones. Surprisingly, although the fetal thymocyte populations contain higher numbers of TcR gamma/delta+ cells than the adult and newborn ones, the highest proliferative response to IL 1 and IL 2 is obtained with the newborn thymocytes. Non mutually exclusive hypotheses are discussed to explain these results.

Syntactic competence and reading ability in children.

The effect of syntactic context on auditory word identification and on the ability to detect and correct syntactic errors in speech was examined in severely reading disabled children and in good and poor readers selected from the normal distribution of fourth graders. The poor readers were handicapped when correct reading required analysis of the sentence context. However, their phonological decoding ability was intact. Identification of words was less affected by syntactic context in the severely disabled readers than in either the good or poor readers. Moreover, the disabled readers were inferior to good readers in judging the syntactical integrity of spoken sentences and in their ability to correct the syntactically aberrant sentences. Poor readers were similar to good readers in the identification and judgment tasks, but inferior in the correction task. The results suggest that the severely disabled readers were inferior to both good and poor readers in syntactic awareness, and in ability to use syntactic rules, while poor readers were equal to good readers in syntactic awareness but were relatively impaired in using syntactic knowledge productively.

Whole Language vs. Code Emphasis: Underlying assumptions and their implications for reading instruction.

Promoters of Whole Language hew to the belief that learning to read and write can be as natural and effortless as learning to perceive and produce speech. From this it follows that there is no special key to reading and writing, no explicit principle to be taught that, once learned, makes the written language transparent to a child who can speak. Lacking such a principle, Whole Language falls back on a method that encourages children to get from print just enough information to provide a basis for guessing at the gist. A very different method, called Code Emphasis, presupposes that learning the spoken language is, indeed, perfectly natural and seemingly effortless, but only because speech is managed, as reading and writing are not, by a biological specialization that automatically spells or parses all the words the child commands. Hence, a child normally learns to use words without ever becoming explicitly aware that each one is formed by the consonants and vowels that an alphabet represents. Yet it is exactly this awareness that must be taught if the child is to grasp the alphabetic principle and so understand how the artifacts of an alphabet transcribe the natural units of language. There is evidene that preliterate children do not, in fact, have much of this awareness; that the amount they do have predicts their reading achievement; that the awareness can be taught; and that the relative difficulty of learning it that some childen have may be a reflection of a weakness in the phonological component of their natural capacity for language.

[Serotonin concentration and transport in the blood platelets of ischemic stroke patients and their relatives]. / O soderzhanii serotonina i ego transporte v trombotsitakh krovi bol'nykh s ishemicheskim insul'tom i ikh rodstvennikov.

Serotonin levels and transport were studied in patients with ischemic stroke (n = 31), their relatives (n = 50) and clinically healthy subjects (n = 45). A statistically significant difference was found in the absorption of exogenic serotonin in the patients and relatives. It has been shown that if judged by serotonin levels, the distribution curves in the control subjects patients with ischemic stroke and their relatives correspond to a model of the polygenic type of the heredity of the traits studied.