Biomedical subjects

S Koren

Publications and source records attributed to S Koren.

30 records · Page 2Linked to original sources

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↗

PubMed1986

Quantitation of in vivo potentiation resulting from combined interferon therapy: antitumor effect against B-16 melanoma in mice.

In this study, murine interferons (IFNs) were employed separately and in combination at subeffective and effective antitumor concentrations in a mouse B-16 melanoma system. Murine IFN-gamma (MuIFN-gamma) was demonstrated to be approximately 20 times more potent than MuIFN-alpha and MuIFN-beta in this system. Potentiation was observed with combinations of both subeffective and effective concentrations of MuIFN-gamma with MuIFN-alpha or MuIFN-beta. The level of potentiation was observed to increase from undetectable to two-fold to fourfold with three increasing IFN concentrations. Thirty percent of the mice treated for 14 days with 332 U/day MuIFN-gamma plus 7,500 U/day MuIFN-alpha survived apparently tumor-free for 100 days. Forty percent of the mice treated for 14 days with 332 U/day MuIFN-gamma plus 7,500 U/day MuIFN-beta survived apparently tumor-free for 100 days. All control mice died by day 41. The results are consistent with the suggestion that combination IFN therapy may have some use in the control of at least some tumors in humans.

Animals↗

PubMed1986

Macrophage colony stimulating factor (CSF-1) blocks the myeloid suppressive but not the antiviral or antiproliferative activities of murine alpha, beta, and gamma interferons in vitro.

Colony stimulating factors have been shown to antagonize the bone marrow suppressive effects of interferons in vitro. The effect of partially purified murine macrophage colony stimulating factor (CSF-1) was evaluated for its ability to antagonize interferon's bone marrow suppressive effect and was measured for its effect against two other interferon activities. The effect of CSF-1 against interferon's bone marrow suppressive effect was measured in a bone marrow colony growth assay. The effect of CSF-1 against interferon's antiviral activity was measured in single-cycle vesicular stomatitis virus growth experiments. The effect of CSF-1 against interferon's antiproliferative activity was measured in 3-day cell growth kinetics assays using B-16 melanoma cells and J-774 reticulum sarcoma cells of macrophage origin. Each of the three types of interferon (MuIFN-alpha, MuIFN-beta, and MuIFN-gamma) were employed and had common effects, though they differed in the levels of their effective concentrations. Concomitant treatment with CSF-1 and interferon blocked the interferon mediated bone marrow suppression in a dose dependent manner but had no effect on the antiviral or antiproliferative activities of the interferons. Importantly, CSF-1 did not affect interferon's antiproliferative activity against the growth of J-774 reticulum sarcoma cells, even though CSF-1 is a macrophage colony stimulating factor and J-774 cells are of macrophage origin. The results suggest that colony stimulating factors might be employed to specifically protect bone marrow function during interferon therapy while not interfering with interferon's antiviral and antitumor activities.

Animals↗

PubMed1986

Treatment of mice with macrophage colony stimulating factor (CSF-1) prevents the in vivo myelosuppression induced by murine alpha, beta, and gamma interferons.

Interferon (IFN) treatment has been shown to suppress the bone marrow in mice and humans, causing a leukopenia. In vitro studies with the mouse system have shown that colony stimulating factors (CSFs) antagonize the bone marrow suppressive, but not the antiviral or antiproliferative activities of IFNs. Partially purified murine macrophage colony stimulating factor (CSF-1) was evaluated for its ability to antagonize the myelosuppressive effect of murine (Mu) IFNs in vivo. All three interferon types (MuIFN-alpha, MuIFN-beta, and MuIFN-gamma) were used. IFNs and CSF-1 were administered subcutaneously for 3 successive days, blood was drawn by retro-ocular bleeding, and myelo-suppression was quantitated by subjecting the blood to total white blood cell (WBC) counts and to differential counts. The IFNs had similar effects, though MuIFN-gamma was a significantly more potent (50- to 100-fold) myelosuppressive agent than MuIFN-alpha or MuIFN-beta. Treatment with each of the three IFNs caused a reduction in the total WBC count (up to 40% reduction) and a generalized reduction of each of the three major leukocytes (lymphocytes, segmented polymorphonuclear leukocytes, and monocytes). Treatment with CSF-1 did not affect the total WBC count, but did cause a shift in the relative ratios of the leukocytes, decreasing the relative percentage of lymphocytes, and increasing the relative percentage of segmented polymorphonuclear leukocytes and monocytes. Combined treatment with CSF-1 and IFN inhibited the myelosuppressive activity of the IFNs, and restored the total WBC count to control levels. This restoration was largely due to increased levels of segmented polymorphonuclear leukocytes and monocytes.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMedDate not supplied

Thyroid function in attention deficit and hyperactivity disorder.

In view of the recent conflicting findings regarding the causative role of thyroid abnormalities in attention deficit hyperactivity disorder (ADHD), we performed a replication study to clarify the issue and establish clinical guidelines. Thyroid tests were performed in 43 ADHD children and 28 age- and gender-matched controls. Sixteen ADHD children showed total triiodothyronine (TT3) levels which were slightly above the upper limit of normal, but no significant difference in TT3 values was noted between the ADHD and the control groups. Moreover, none of the ADHD subjects had abnormal levels of total thyroxine, free thyroxine, thyroid stimulating hormone or total triiodothyronine reuptake. The present study supplies additional evidence for the lack of an association between thyroid function and ADHD, and counters the suggestion that thyroid function be routinely screened for in ADHD children.

Adolescent↗

PubMedDate not supplied

The prevalence of mitral valve prolapse in children with anxiety disorders.

Studies in adults have suggested a comorbidity of mitral valve prolapse and anxiety disorders, especially panic disorder. The nature of the association between these disorders is yet unclear. In the last years, case studies have appeared, reporting on the comorbidity of anxiety disorders and mitral valve prolapse in children. The present study evaluated the prevalence of mitral valve prolapse in children with anxiety disorders as compared to normal controls. The study group consisted of 52 children, 6-18 years old, with a diagnosis of panic disorder (9.6%), separation anxiety disorder (65.4%) and/or overanxious disorder (61.5%). Fifty-one normal age- and gender-matched healthy children served as controls. All participants were evaluated for the presence of mitral valve prolapse by cardiac auscultation and echocardiography. None of the 52 children with anxiety disorder and one of the 51 control children (1.96%) had mitral valve prolapse. There appears to be no association between childhood anxiety disorders and mitral valve prolapse. Whether children with panic disorder proper show a greater prevalence of mitral valve prolapse remains an open question. Implications to the association of mitral valve prolapse and panic disorder are discussed.

Adolescent↗

PubMedDate not supplied

Trophoblastic interferons: do they modulate uterine cellular markers at the time of conceptus attachment in the pig?

Between days 12 and 20 of pregnancy, the trophectoderm of the porcine conceptus secretes two species of interferons (IFN): IFN-gamma (Type II), which is produced in substantial amounts, and IFN-delta (type I), for which secretion peaks at days 15-16 of gestation. The role of these embryonic IFNs is not known. We made the assumption that, in the pig, one possible role of these IFNs may be the remodelling and/or depolarization of the uterine endometrial epithelium, as a prerequisite for implantation and establishment of a functional placenta. A comparative analysis by immunohistochemistry of several cell membrane markers and ECM components of the cyclic and pregnant uterus was performed at day 15 post-oestrus. The markers were those likely to differ between a pregnant and cyclic uterus, or between different stages of pregnancy. A highly specific marker of IFN-gamma activity, namely MHC class II antigens in the uterine mucosa, was also examined. This study provides so far unreported data: in the endometrial epithelium of the pregnant uterus, we observed a partial relocalization of ZO-1, a marker of epithelial tight junctions, thus suggesting significant changes to the endometrial polarity. Heparan-Sulphate Proteoglycan (HSPG) expression did not differ significantly between cyclic and pregnant uteri. In contrast with the accepted rodent model of trophoblast-uterus adhesion, the porcine trophoblast and luminal epithelium were negative for HSPG. Finally, MHC class II antigens were absent from the cyclic uterus, but markedly induced in the day 15 pregnant uterus, particularly in endothelial cells, suggesting that IFN-gamma may indeed cross the maternal epithelium. This hypothesis was supported by the observation of IFN-gamma immunoreactivity associated with clusters of endometrial cells in the pregnant uterus.

Animals↗

PubMedDate not supplied

Neurocognitive correlates of anxiety disorders in children: a preliminary report.

Children with anxiety disorders have been suggested to possess a specific cognitive scheme that underscores negative information and leads to the formation of a negative view of themselves and of the world. The aim of the present study was to assess the neuropsychological processes of children and adolescents with anxiety disorders, as compared to healthy matched controls. Nineteen children (6-18 years) with anxiety disorders and 14 age-matched healthy controls participated in the study. Both groups scored within normal range on the Wechsler Intelligence Scale for Children-Revised (WISC-R). All children underwent neuropsychological assessment with the California Verbal Learning Test (CVLT) (Verbal Processing), the Rey-Osterrieth Complex Figure test (ROCF) (Nonverbal Processing), and the Wisconsin Card Sorting Test (WCST) (Executive Functions). The anxiety group scored lower than the control group on all measures of the CVLT and had a significantly greater number of errors, perseverative responses, and incorrect answers after negative feedback on the WCST. No differences were detected for the ROCF. We conclude that in children and adolescents, anxiety disorders may be associated with lowered linguistic abilities and cognitive flexibility, as measured by neuropsychological paradigms. Anxiety does not appear to be associated with nonverbal processes.

Adolescent↗