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Biomedical subjects

S Koren

Publications and source records attributed to S Koren.

At least 19 recordsLinked to original sources
PubMed1999

Manual laterality and hitting performance in major league baseball.

Asymmetrical hand function was examined in the context of expert sports performance: hitting in professional baseball. An archival study was conducted to examine the batting performance of all Major League Baseball players from 1871 to 1992, focusing on those who batted left (n = 1,059) to neutralize the game asymmetry. Among them, left-handers (n = 421) were more likely to hit with power and to strike out than right-handers (n = 638). One possible account, based on the idea of hand dominance and an analogy to tennis, is that batting left involves a double-handed forehand for left-handers and a weaker and more reliable double-handed backhand for right-handers. The results are also interpretable in the light of Y. Guiard's (1987) kinematic chain model of a between-hands asymmetrical division of labor, which provides a detailed account of why left batting is optimal for left-handers.

Baseball↗
PubMed1999

Tetracycline-controlled expression of glycosylated porcine interferon-gamma in mammalian cells.

Tetracycline-controlled expression plasmids that allow inducible expression of proteins in mammalian cells (Gossen & Bujard, 1992), have been used to express porcine interferon-gamma in the RK-13 rabbit kidney cell line. Following neomycin selection, stable clones produced recombinant, glycosylated porcine interferon-gamma (rGPoIFN-gamma) only after removal of tetracycline (Tc). Southern blot analysis of one clone showed that approximately 50 copies of IFN-gamma cDNA were present in the cell genome. In the absence of Tc, stable clones secreted large amounts of rGPoIFN-gamma (up to 16 microg/ml) into the medium supplemented with 10% FCS and high glucose concentration. Molecular weight comparison of 35S-Methionine, labelled rGPoIFN-gamma with natural leukocytic IFN-gamma after immunoprecipitation, revealed 4 major glycoforms with apparent Mr of 27,000; 25,000; 20,000 and 18,500, that are almost identical in both IFN-gamma species. In both cases, all 4 glycoforms resolved into 2 polypeptide monomers with apparent Mr of 16,500 and 14,500 upon deglycosylation with N-glycosydase F. The biological activity of rGPoIFN-gamma was in the same range as that of natural leukocytic PoIFN-gamma (2 x 10(6) U/mg). Eventually, this recombinant mammalian IFN-gamma should constitute a very useful substitute for leukocyte PoIFN-gamma in in vitro or in vivo experiments.

Animals↗
PubMed1999

Systemic effects of orally administered interferons and interleukin-2.

Orally administered interferons (IFN-alpha, IFN-beta, and IFN-gamma) have been shown to exert a number of systemic effects. Orally administered IFNs exert dose-dependent suppressive effects on the peripheral white blood cell (WBC) count. The suppression of the peripheral WBC count is mediated by a suppression of the function of the bone marrow, as measured in an in vitro bone marrow colony-forming assay. The peripheral WBC and bone marrow suppressive effects of orally administered IFNs are at least as potent as those occurring with parenterally administered IFNs. However, the mechanism by which orally administered IFNs exert these peripheral WBC suppressive and bone marrow suppressive effects differs significantly from that of parenterally administered IFNs: orally administered IFN is not detectable in the serum, the effect of orally administered IFN is not blocked by circulating antibody, the effect of orally administered IFN can be adoptively transferred by injection with peripheral white blood cells from donor mice, and the effect of orally administered IFN develops more slowly than that of parenterally administered interferon. Orally administered IFN-alpha employed alone and in synergistic combination with intraperitoneally administered IFN-gamma can exert an antitumor effect. Finally, orally administered interleukin-2 can exert a suppressive effect on both the peripheral white blood cell count and on the bone marrow. These observations suggest that the oral route may be an effective and novel mechanism for the efficacious administration of IFNs and other lymphokines/cytokines.

Administration, Oral↗
PubMed1997

Substrate autoregulation of glucose transport: hexose 6-phosphate mediates the cellular distribution of glucose transporters.

Exposure of rat skeletal muscle and skeletal muscle cell lines to high glucose levels results in a time- and dose-dependent reduction of the rate of hexose uptake, paralleled by a reduction in the plasma membrane density of glucose transporters. The mechanism of this process was investigated in cultured L8 myocytes. Low concentrations (0.5-2.0 mmol/l) of deoxyglucose mimicked the downregulatory action of 20 mmol/l glucose both regarding the time-course and magnitude of the effect, but in an irreversible manner. A dose-dependent relationship between intracellular accumulation of deoxyglucose 6-phosphate and the magnitude of the downregulatory response was observed. Depletion of intracellular deoxyglucose 6-phosphate restored the rate of hexose transport to the control level. The reduction of hexose transport activity by deoxyglucose occurred independently of ATP depletion which by itself produced the opposite effect. The effects of deoxyglucose and high glucose on hexose transport were associated with reduced transport maximal velocity and GLUT1 transporter abundance in the plasma membranes of myocytes, as assessed by cell surface biotinylation. The reduction of myocyte GLUT1 mRNA content, observed after exposure to high glucose, did not accompany the transport down regulatory action of deoxyglucose. We suggest that hexose 6-phosphate is the mediator of the downregulatory signal for subcellular redistribution of GLUT1 in L8 myocytes. The signal responsible for reducing the GLUT1 mRNA level may be related to glucose metabolites downstream of the hexokinase reaction.

Adenosine Triphosphate↗
PubMed1997

Lack of effect of methylphenidate on serum growth hormone (GH), GH-binding protein, and insulin-like growth factor I.

The aim of this study was to assess the growth hormone (GH) axis in methylphenidate (MPH)-treated and untreated boys with attention-deficit and hyperactivity disorder (ADHD), by evaluating serum GH, GH-binding protein (GHBP) activity, and insulin-like growth factor I (IGF-I) levels as compared to age-matched normal controls. Blood samples were taken from 42 boys (aged 6-16 years) diagnosed as having ADHD according to DSM-III-R criteria and confirmed by using the Schedule for Affective Disorder and Schizophrenia for school-age children (K[Kiddle]-SADS). A total of 21 patients were treated with MPH (5-20 mg/day; 0.15-0.77 mg/kg/day), on a drug holiday protocol, for 1-36 months, and 21 were drug naive. A total of 46 age-matched normal boys at height and weight within normal range served as controls. No significant differences were detected between the MPH-treated ADHD children, the untreated ADHD children, and the control children on fasting serum GH levels, GHBP activity, or IGF-I levels. Active treatment with MPH, in ADHD children on a drug holiday protocol, does not cause changes in GH axis as manifested by normal values of GH, GHBP, and IGF-I.

Adolescent↗
PubMed1997

Evaluation of the automated COBAS AMPLICOR hepatitis C virus PCR system.

To evaluate the reliability and feasibility of the automated Roche COBAS AMPLICOR PCR system for routine detection of hepatitis C virus (HCV) RNA, a total of 405 serum samples previously tested by an in-house nested PCR and manual Roche AMPLICOR microwell plate HCV test were examined. Complete concordance was found between the results with the HCV COBAS AMPLICOR system and the previously determined HCV RNA status. The automated HCV COBAS AMPLICOR system provides the clinical microbiology laboratory with a specific and sensitive PCR method for rapid and reliable detection of HCV RNA.

Automation↗
PubMed1997

Molecular evidence for nosocomial spread of two different hepatitis C virus strains in one hemodialysis unit.

The highest prevalence of hepatitis C virus (HCV) infection among hemodialysis patients in Slovenia was found in a small dialysis unit with old equipment and room shortage, where the first anti-HCV-positive patient was detected in 1990. In 1992 and 1993, an additional 8 and 7 patients seroconverted, respectively. Genotyping analyses among 15 HCV RNA-positive patients showed quite unusual HCV genotype distribution for our country: genotypes 2 and 3 were determined in 9 and 6 patients, respectively. Sequence analysis of the 270-bp part of the NS-5 region was carried out in 12 patients. In 6 patients infected with subtype 2c and in 4 patients infected with subtype 3a, very similar sequences were obtained, forming two distinct clusters in the phylogenetic tree. In 2 patients infected with subtype 2c, viral strains were neither related to the main 2c strain nor to each other. Phylogenetic analysis unequivocally confirmed simultaneous nosocomial spread of two different HCV strains in one hemodialysis unit. The study confirmed that implementation of rigorous hygienic routines and introduction of separate rooms and machines for HCV-infected patients are important measures for effective control of HCV infection in a hemodialysis environment.

Cross Infection↗
PubMed1997

Distribution of hepatitis C virus genotypes in Slovenia.

To determine the prevalence of HCV genotypes in Slovenia, 203 subjects infected with hepatitis C virus (HCV) were studied using the Inno-Lipa HCV II assay (Innogenetics, Belgium). Of 21 patients infected by blood transfusion 19% had HCV subtype 1a, 81% had subtype 1b, and none of them was infected with genotype 3. In chronic hepatitis C patients infected by unknown cause subtype 1b was the most prevalent (54.4%), followed by subtype 1a (24.6%), genotype 3 (15.8%) and genotype 2 (5.2%). Genotype 3 (45.9%) and subtype 1a (43.2%) predominated among 74 intravenous drug users. In 37 haemodialysis patients genotypes 1 and 2 were almost equally frequent (40.5% and 37.8%, respectively), followed by genotype 3 (21.6%). Significant differences in HCV genotype distribution among distinct epidemiological groups observed in Slovenia indicate a close relationship between certain HCV genotypes and particular routes of viral transmission.

Chi-Square Distribution↗
PubMed1997

Adrenal failure in systemic lupus erythematosus.

We describe a 39-year-old woman who developed Addison's disease 2 years after diagnosis of systemic lupus erythematosus (SLE). Examining her initial presentation, there is evidence to suggest that adrenal dysfunction may have commenced at the time of diagnosis of SLE. We suggest the need for considering adrenal dysfunction in patients with SLE with systemic complaints.

Addison Disease↗
PubMed1997

Comparative evaluation of four genotyping methods for hepatitis C virus.

Four most widely accepted genotyping methods for hepatitis C virus (HCV) were applied to 40 HCV RNA isolates obtained from Slovenian patients in order to determine the concordance and applicability of various genotyping systems. The four methods are: (i) amplification of the core region with genotype-specific primers; (ii) nested polymerase chain reaction (PCR) in the core region followed by hybridization to HCV type-specific probes; (iii) reverse hybridization with the line probe assay Inno LiPA (Innogenetics, Gent, Belgium) using type-specific probes for the 5' non-coding region (NCR); and (iv) restriction fragment length polymorphism analysis of DNA amplified from the 5' NCR. Additionally, in isolates with discordant results nucleotide sequence analysis of a part of the NS-5 region was performed. Both genotyping methods based on the analysis of the 5' NCR were found more sensitive than those methods based on the analysis of the HCV core region. None of the four genotyping methods correctly classified all Slovenian HCV RNA isolates. PCR with genotype-specific primers was identified as entirely unsuitable for genotyping of Slovenian HCV RNA isolates. The remaining genotyping methods could clearly differentiate between HCV genotypes, but were not entirely reliable for HCV subtyping. The specificity of genotyping methods, which are based on the 5' NCR or the core region, was occasionally hampered, due to a lack or excess of sequence variation in their respective target regions.

Genotype↗
PubMed1994

Modulation of peripheral leukocyte counts and bone marrow function in mice by oral administration of interleukin-2.

Interferons alpha, beta, and gamma have been shown to exert systemic effects following their oral administration to mice. It was of importance to determine whether oral administration of another biologic response modifier, interleukin-2 (IL-2), could also exert systemic effects in mice. Two systemic effects, peripheral WBC suppression and bone marrow suppression, were evaluated. Oral administration of IL-2 was found to suppress the peripheral WBC count in a dose-dependent manner. Oral administration of IL-2 was also found to suppress the bone marrow proliferative activity. The levels of suppression of both peripheral WBC and myelopoietic progenitor cell numbers observed with orally administered IL-2 were comparable to those seen with subcutaneously administered IL-2. The results demonstrate that orally administered IL-2 can exert systemic effects. Further, the results raise the possibility that oral administration of IL-2 may have therapeutic potential.

Administration, Oral↗
PubMed1993

Circadian dependence of interferon antitumor activity in mice.

BACKGROUND: Chronobiological studies with anticancer drugs have shown that their effectiveness and/or toxicity is significantly influenced by the time of their administration in the circadian cycle. Previous studies also have shown that the myelotoxicity of interferons is similarly influenced. PURPOSE: This study was undertaken to evaluate the antitumor activity of interferons as a function of their administration to animals at defined points in the circadian cycle with equal light and dark periods. METHODS: A murine tumor model was employed. Following adaptation to alternating cycles of 12 hours of light and 12 hours of dark for a period of 2-3 weeks, C57BL/6 mice were inoculated with B16 melanoma cells intraperitoneally at different hours after light onset. Exactly 24 hours after inoculation, each group received intraperitoneal injections of either recombinant human interferon alpha (rHuIFN-alpha A/D), recombinant murine IFN-gamma (rMuIFN-gamma), or interferon-carrier solution as control (once a day for 5 days) and were monitored for the length of their survival. RESULTS: The antitumor activity (calculated as percent increased life span) of both rHuIFN-alpha A/D and rMuIFN-gamma varied with the points at which they were administered in the circadian cycle. However, the points showing minimum and maximum activity for rHuIFN-alpha A/D (12-16 and 0-4 hours after light onset, respectively) did not correspond with the points for the rMuIFN-gamma (0-8 and 16 hours after light onset, respectively). To generate maximum antitumor activity, approximately fivefold higher amounts of rHuIFN-alpha A/D were required at 12 than at 4 hours after light onset (dose range, 3333-90,000 IU/d) (P < .0001). Similarly, for rMuIFN-gamma at least 8.5-fold greater amounts were required at 8 than at 16 hours after light onset (dose range, 667-6000 IU/d) (P < .01). CONCLUSIONS: In the murine tumor model, administration of rHuIFN-alpha A/D at 4 hours after light onset and rMuIFN-gamma at 16 hours after light onset may produce maximum antitumor activity.

Analysis of Variance↗
PubMed1993

Optimal circadian timing reduces the myelosuppressive activity of recombinant murine interferon-gamma administered to mice.

There is a marked, reproducible circadian variation in the toxicity of a number of antineoplastic drugs. A recent study has employed a murine model to show that recombinant human interferon-alpha A/D (rHuIFN-alpha A/D) exhibited a differential potency in its peripheral white blood cell (WBC)-suppressive and bone marrow-suppressive activities according to the time in the circadian cycle at which it was administered. It was of interest to determine whether another biological response modifier such as IFN-gamma would also exhibit a differential potency during the circadian cycle. A mouse model was used to study peripheral WBC suppression, a toxicity associated with IFN-gamma therapy. Recombinant murine (rMu)IFN-gamma was employed to induce peripheral WBC suppression and was evaluated for its ability to induce peripheral WBC suppression as a function of the time of rMuIFN-gamma administration. Mice were maintained on cycles of 12 h of light and 12 h of darkness. The rMuIFN-gamma was administered at various hours after light onset (HALO). The rMuIFN-gamma-induced peripheral WBC-suppressive effect varied in its intensity in a cyclical manner. Administration of rMuIFN-gamma at 4 HALO caused the greatest suppressive effect, whereas administration of rMuIFN-gamma at 14 HALO caused the least suppressive effect. Mice treated at 14 HALO were found to be about 20-fold less sensitive to the peripheral WBC-suppressive effects of rMuIFN-gamma than mice treated at 4 HALO. This differential sensitivity to the peripheral WBC-suppressive effects of rMuIFN-gamma was examined at six different times in the circadian cycle and was found to be a general effect, occurring throughout the circadian cycle.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Orally administered interferons suppress bone marrow function.

The accepted routes of interferon (IFN) administration in clinical applications are intramuscular, subcutaneous, intraperitoneal, intratumor, and intravenous. Recently, oral administration of interferons has been shown to cause a suppression of peripheral white blood cell (WBC) counts. Moreover, orally administered interferons mediate their peripheral WBC suppression via a different mechanism than that of intraperitoneally administered interferons. This study extends the previous studies to show that the peripheral WBC suppression induced by oral interferon treatment reflects an actual bone marrow suppression. The bone marrow-suppressive effects of orally and subcutaneously administered recombinant human IFN-alpha A/D (rHuIFN-alpha A/D) have been partially characterized in kinetics studies and compared with the peripheral WBC-suppressive effects of orally and subcutaneously administered rHuIFN-alpha A/D. Oral and subcutaneous administrations of rHuIFN-alpha A/D cause a significant suppression of peripheral WBC counts with 1 day of rHuIFN-alpha A/D administration. This suppression reaches its maximum level with 3 days of rHuIFN-alpha A/D administration and plateaus over a 12-day treatment time. Similarly, oral and subcutaneous administrations of rHuIFN-alpha A/D cause a significant suppression of bone marrow function with 1 day of rHuIFN-alpha A/D administration. This suppression reaches its maximum level with 3 days of rHuIFN-alpha A/D administration and plateaus over a 12-day treatment time. Thus, the WBC-suppressive and bone marrow-suppressive effects of rHuIFN-alpha A/D administered either orally or subcutaneously parallel each other. The peripheral WBC-suppressive activities of orally and subcutaneously administered rHuIFN-alpha A/D diminish at the same rate, after cessation of rHuIFN-alpha A/D treatment. Peripheral WBC suppression is lost by 5 days after cessation of rHuIFN-alpha A/D treatment. The mechanisms by which orally and subcutaneously administered interferons exert their bone marrow-suppressive effects differ, however. Bone marrow suppression mediated by subcutaneous administration of murine IFN-alpha/beta (MuIFN-alpha/beta) is blocked by the presence of circulating antibodies to MuIFN-alpha/beta. In contrast, the bone marrow suppression mediated by oral administration of MuIFN-alpha/beta occurs even in the presence of circulating antibodies to MuIFN-alpha/beta. These results continue to support a potential clinical role for oral administration of interferons, particularly for the control of diseases of myelogenous origin.

Administration, Oral↗
PubMed1993

Circadian variations in myelosuppressive activity of interferon-alpha in mice: identification of an optimal treatment time associated with reduced myelosuppressive activity.

A number of antitumor drugs have been shown to vary in their toxicity and in their antitumor potency according to the time in the circadian cycle at which they are administered. It was of interest to determine whether other agents, such as a biological response modifier, would also exhibit differential potency during the circadian cycle. Interferons (IFNs) are biological response modifiers which have antitumor and antiviral activity and which also have toxic side effects. A mouse model was used to study one of these toxic side effects, peripheral white blood cell (WBC) suppression. Interferon-induced peripheral WBC suppression was evaluated as a function of the time of recombinant human (rh) IFN-alpha A/D administration. Mice were maintained on cycles of 12 hours of light and 12 hours of darkness. The rhIFN-alpha A/D was administered at various hours after light onset (HALO). The rhIFN-alpha A/D-induced peripheral WBC suppressive effect varied in its intensity in a cyclical manner. Administration of rhIFN-alpha A/D at 0 HALO caused the greatest suppressive effect, while administration of rhIFN-alpha A/D at 8 HALO caused the least suppressive effect. Mice treated at 8 HALO were found to be about 10-fold less sensitive to the peripheral WBC suppressive effects of rhIFN-alpha A/D than mice treated at 0 HALO. This differential sensitivity to the peripheral WBC suppressive effects of rhIFN-alpha A/D was examined for 6 different times in the circadian cycle and was found to be a general effect, occurring throughout the circadian cycle. Using a granulocyte/macrophage colony-forming unit (GM-CFU) assay, bone marrow function was also shown to be differentially affected by treatment with rhIFN-alpha A/D at 0 HALO and 8 HALO in a manner parallel to that seen with peripheral WBC. Thus, rhIFN-alpha A/D exerts a differential effect on peripheral WBC counts and on bone marrow function according to the time in the circadian cycle at which it is administered to the mouse. Such temporal variation in the myelosuppressive activity of interferons could be important in designing future clinical trials with these antiviral and antitumor agents. Administration of interferons at empirically determined times in the circadian cycle could be used to reduce the myelotoxic side effects of interferons in humans.

Animals↗
PubMed1992

Orally administered interferons exert their white blood cell suppressive effects via a novel mechanism.

Interferons (IFN) have been approved for a number of clinical uses. The accepted routes of administration are intramuscular, subcutaneous, and intravenous. Recently, interferons administered by the oral route have been shown to exert a systemic effect. Oral administrations of IFN-alpha, IFN-beta, and IFN-gamma have been shown to cause a suppression of the peripheral white blood cell (WBC) count in mice. This study investigates the mechanism by which this suppression occurs. The results show that, in contrast to their intraperitoneal administration, oral administration of rHuIFN-alpha A/D or rMuIFN-gamma does not result in the presence of detectable levels of interferons in the blood. In addition, although the presence of circulating specific antibody to interferon blocks the peripheral WBC suppressive effects of intraperitoneally administered MuIFN-beta or rMuIFN-gamma, the presence of those antibodies does not block the peripheral WBC suppressive effects of the orally administered interferons. The peripheral WBC suppressive effect of orally administered rHuIFN-alpha A/D and rMuIFN-gamma can be transferred by injection of blood from oral interferon-treated donor mice to recipient mice. Recipient mice receiving plasma from donor mice showed no peripheral WBC suppression. Recipient mice receiving blood cells from donor mice showed significant peripheral WBC suppression. No effect of orally administered rHuIFN-alpha A/D on the relative percentages of lymphocytes, neutrophils, and monocytes was noted. These results indicate that the mechanism by which orally administered interferons exert their WBC suppressive effect differs from that of intraperitoneally administered interferons. WBC suppression resulting from orally administered interferons may involve cell to cell transfer of the interferons' effects, rather than the systemic distribution of the interferons in the blood. These studies further suggest that there may be a role for oral administration as a new route of interferon administration and provide a glimpse into the mechanism by which the orally administered interferons exert their systemic effects.

Administration, Oral↗