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Biomedical subjects

Y Altman

Publications and source records attributed to Y Altman.

At least 19 recordsLinked to original sources
PubMed2001

Cbl promotes ubiquitination of the T cell receptor zeta through an adaptor function of Zap-70.

Triggering of the T cell antigen receptor (TCR).CD3 complex induces its ubiquitination. However, the molecular events that lead to ubiquitin conjugation to these cell surface molecules have not been defined. Here we report that Cbl, a RING-type E3 ubiquitin-protein ligase, promotes ubiquitination of TCR zeta chain, which requires its functional variant Src homology 2 domain and an intact RING finger. The tyrosine kinase Zap-70, which binds to both TCR zeta and Cbl, plays an adaptor role in these events. Mutations in TCR zeta, Zap-70, or Cbl that disrupt the interaction between TCR zeta and Zap-70 or between Zap-70 and Cbl reduce ubiquitination of TCR zeta. Our results suggest a novel mechanism by which Cbl negatively regulates T cell development and activation by inducing ubiquitination of the TCR.CD3 components.

Cell Line↗
PubMed2001

Interrelationship between insulin, leptin and growth hormone in growth hormone-treated children.

OBJECTIVES: The aim of the study was to examine insulin homeostasis during growth hormone (GH) therapy, and to investigate the effect of GH treatment on insulin and leptin concentration in obese children. SUBJECTS: Nineteen obese children (8 with Prader-Willi Syndrome (PWS)) were treated with GH 0.1 IU/kg/day dose for 3 months and were compared with 29 non-treated age and sex matched obese children (9 PWS) and 49 GH treated non-obese short children. Mean age of the children was 10.3+/-1.8 (6.7-13.8) y, with body mass index of 23.6+/-10.4 (11.5-47) kg/m2. RESULTS: Leptin concentration decreased and was correlated inversely with initial leptin value (r2=-0.374, P<0.001) and decreased body mass (r2=0.338, P=0.001). Insulin sensitivity index was not significantly changed during therapy. Leptin decrease after 3 months of GH administration was correlated inversely with the increase in first phase insulin response to intravenous glucose tolerance test (IVGTT) (r2=-0.595, P<0.001). Results of long-term follow-up of treated patients demonstrated a decrease in insulin concentration after cessation of therapy. In GH-treated subjects, the glucose increase in response to glucose load appeared to be higher than in untreated subjects. CONCLUSION: The high insulin response to glucose load seen in GH-treated subjects was appropriate to their glucose concentration and the insulin sensitivity index was unchanged relative to the pretreatment period. Increased insulin dosage in our patients did not induce an increase in leptin concentrations as had been hypothesised.

Anthropometry↗
PubMed2000

Cbl-b, a RING-type E3 ubiquitin ligase, targets phosphatidylinositol 3-kinase for ubiquitination in T cells.

Cbl-b is implicated in setting the threshold of T lymphocyte activation. In Cbl-b-deficient T cells, the activation of Vav, a guanine nucleotide exchange factor, is significantly enhanced. The molecular mechanism underlying Cbl-b-regulated Vav activation was unclear. Here it is shown that Cbl-b interacts with and induces ubiquitin conjugation to the p85 regulatory subunit of phosphatidylinositol 3-kinase, an upstream regulator of Vav. A functional RING finger of Cbl-b was essential for p85 ubiquitination. However, a loss of function mutation at the well-conserved amino-terminal variant src homology (SH) 2 domain of Cbl-b did not affect its ligase activity. A distal carboxyl-terminal proline-rich region in Cbl-b was mapped to contain the primary binding sequences for the SH3 domain of p85. Deletion of either the distal proline-rich region in Cbl-b or the SH3 domain of p85 severely reduced ubiquitin conjugation to p85. The data suggest a molecular link for Cbl-b-mediated negative regulation of Vav, with phosphatidylinositol 3-kinase as a direct target for Cbl-b E3 ubiquitin ligase.

Adaptor Proteins, Signal Transducing↗
PubMed2000

Recognition and ubiquitination of Notch by Itch, a hect-type E3 ubiquitin ligase.

Genetic studies identified Itch, which is a homologous to the E6-associated protein carboxyl terminus (Hect) domain-containing E3 ubiquitin-protein ligase that is disrupted in non-agouti lethal mice or Itchy mice. Itch-deficiency results in abnormal immune responses and constant itching in the skin. Here, Itch was shown to associate with Notch, a protein involved in cell fate decision in many mammalian cell types, including cells in the immune system. Itch binds to the N-terminal portion of the Notch intracellular domain via its WW domains and promotes ubiquitination of Notch through its Hect ubiquitin ligase domain. Thus, Itch may participate in the regulation of immune responses by modifying Notch-mediated signaling.

Animals↗
PubMed1998

Sertoli cell tumor causing precocious puberty in a girl with Peutz-Jeghers syndrome.

Distinctive ovarian and cervical tumors are associated with Peutz-Jeghers syndrome (PJS). The most common gynecological tumors in this syndrome are adenoma malignum of the uterine cervix and ovarian sex cord tumor, particularly sex cord tumor with annular tubules (SCTAT). Other kinds of ovarian tumors have been rarely reported in association of PJS, including Sertoli cell tumors. We report a case of a 4.5-year-old girl with PJS who presented with isosexual precocious puberty (IPP) due to ovarian lipid-rich Sertoli cell tumor. In addition to estrinizing effect of the tumor, the patient had decidual reaction secondary to tumor-derived progesterone secretion. The literature on gonadal tumors in PJS is reviewed, including one previous report of ovarian lipid-rich Sertoli cell tumor associated with this syndrome.

Child↗
PubMed1997

Extracorporeal losses of insulin-like growth factor-I and insulin-like growth factor binding protein-3 in adult patients on CAPD.

The effects of extracorporeal (urinary plus peritoneal) losses of insulin-like growth factor I (IGF-I) and insulin-like growth factor binding protein-3 (IGFBP-3) on their respective serum levels were studied in 10 adult patients (aged 42-74 years) with end-stage renal failure and residual renal function of 0-4.5 mL/min. All patients had been on continuous ambulatory peritoneal dialysis (CAPD) for a period of 2-27 months. Morning serum, 24-hour urine, and 8-hour overnight peritoneal concentrations of IGF-I and IGFBP-3 were measured by radioimmuno- (Incstar) and immunoradiometric (Active) assays. CAPD patients showed extracorporeal losses (mean +/- SEM) of 118.7 +/- 10.6 micrograms (urinary 6.4 +/- 2.8 and peritoneal 112.3 +/- 8.5 micrograms) of IGF-I/24 hour and 1.5 +/- 0.1 mg (urinary 0.2 +/- 0.1 mg and peritoneal 1.3 +/- 0.1 mg) of IGFBP-3/24 hour. Extracorporeal losses of IGF-I accounted for about 4% of the daily production rate of this polypeptide, and the peritoneal and urinary concentrations of IGFBP-3 did not exceed 4% and 14%, respectively, of their serum levels. Serum concentrations of IGF-I (227.7 +/- 64.2 micrograms/L) and IGFBP-3 (5.3 +/- 2.4 mg/L) were not significantly correlated with extracorporeal, peritoneal, or urinary losses of these proteins or with residual renal function. We suggest that extracorporeal losses of IGF-I and IGFBP-3 in adult patients on CAPD do not influence their serum levels and that IGF-I may therefore be used as a marker of malnutrition.

Adult↗
PubMed1996

Vitamin A levels and growth hormone axis.

Vitamin A (VA) is required for normal growth and development retinoic acid may be the active metabolite through binding to nuclear receptors. Recently a correlation between nocturnal growth hormone (GH) secretion and VA was was found in short slowly growing children. We determined the 24-hour integrated concentration of GH (IC-GH), GH response to provocative stimuli, IGF-I, IGF-binding protein-3 (IGF-BP3) and GH-binding protein (GH-BP) in 34 prepubertal children (25 m/9 f) 5-10 years of age, height -2.5 to 1.5 SDS and body mass index -1.5 to 1.5 SDS for age and sex. Since folic acid, vitamin B12, IGF-I, cholesterol, triglycerides and VA carrier proteins were normal we assumed that no major nutritional deficiency existed. The correlation matrix of the variates tested were p < 0.05 for VA and IC-GH and p < 0.006 for IGF-BP3. It is suggested that VA might have a direct affect on both ICGH and IGF-BP3.

Carrier Proteins↗
PubMed1995

Insulin-like growth factor-I in patients on CAPD and hemodialysis: relationship to body weight and albumin level.

The relationship between insulin-like growth factor-I (IGF-I), body weight, and serum albumin was studied in 17 patients on continuous ambulatory peritoneal dialysis (CAPD) and 17 patients on hemodialysis. Patients were matched for gender, age (33-83 years), body mass index (16.7-36.1 kg/m2), hematocrit, concentrations of serum growth hormone, and duration of dialysis (1-210 months). Serum IGF-I concentration was measured by radioimmunoassay (Incstar) and albumin by a standard laboratory technique. CAPD patients had significantly lower serum albumin concentrations than hemodialysis patients, whereas IGF-I levels in the two groups were similar and did not differ from those in 18 normal subjects. We did not find significant positive correlations between IGF-I and serum albumin levels in CAPD or in hemodialysis patients. On the other hand, IGF-I showed a strong positive correlation with body weight (for the CAPD group r = 0.523; for both groups together r = 0.493). Both groups (CAPD and hemodialysis) and CAPD patients who weighted less than 60 kg (44%) had significantly lower serum IGF-I levels (113.5 +/- 10.2 and 108.8 +/- 15.7 micrograms/l +/- SEM, respectively) than patients who weighed 60-80 kg (38.3%; 181.2 +/- 20.9 and 196.6 +/- 27.2 micrograms/L +/- SEM, respectively) or above 80 kg (17.6%; 205.2 +/- 37.7 and 229.5 +/- 43.5; micrograms/L +/- SEM, respectively). It therefore appears that a low serum IGF-I level is a better indicator of malnutrition in CAPD and hemodialysis patients than low serum albumin.

Adult↗
PubMed1993

Effect of timing of growth hormone administration on plasma growth-hormone-binding activity, insulin-like growth factor-I and growth in children with a subnormal spontaneous secretion of growth hormone.

Since normal pulsatile growth-hormone (GH) secretion displays a major and consistent surge during sleep, we studied the effect of timing of GH supplementation on plasma GH-binding protein activity (GH-BP), insulin-like growth factor-I (IGF-I) and growth. 34 prepubertal subjects (28 boys, 6 girls) aged 8-11 years, of short stature (< 2 SD for age), with a GH response to provocative test > 10 micrograms/l and a subnormal 24-hour GH secretion (< 3 micrograms/l), were randomly allocated to receive Bio-Tropin (recombinant GH, Bio-Technology, Israel) 0.81 IU/kg/week in 3 equally divided doses. GH was administered either at 8.00-10.00 h (M group), 14.00-16.00 h (AN group) or 19.00-21.00 h (NT group). Height velocity, IGF-I and GH-BP were determined prior to and after 6 and 12 months on GH therapy in the three groups. There was no significant difference between the three groups in the growth response, IGF-I and GH-BP increase, all of which increased significantly during GH therapy. Although GH levels after the injection decline to preinjection levels after 10 h, the changes induced by GH therapy, as reflected in IGF-I and GH-BP, last in the circulation long enough to prevent fluctuations in its action. The similarity of IGF-I and of GH-BP levels in the three treatment groups might explain the similar growth effects of the 3 protocols.

Carrier Proteins↗
PubMed1993

The effect of exogenous and endogenous growth hormone on plasma growth hormone binding activity in prepubertal children.

To investigate the relationship between plasma growth hormone (GH) and plasma GH-binding protein (GHBP) activity we studied the effects of exogenous and endogenous GH on GHBP in children with a normal response to GH stimulation. The effect of exogenous GH on plasma binding activity was studied for 12 h after the administration of a subcutaneous GH bolus of 0.1 IU/kg and during the first year of GH therapy. The effect of endogenous GH secretion on GHBP was studied by measuring the integrated concentration (IC) of GH and GHBP over 24 h by means of a continuous blood withdrawal procedure. We also measured the GH and GHBP response to GH provocative tests. One hundred and two prepubertal children, 69 males, 33 females, age 8.8 +/- 2.2 years (mean +/- SD), were studied. Eighty-one were short, < 2 SDS for age and gender, and 21 were of normal height for age and gender. There was no difference in IC-GHBP between boys and girls. It correlated positively with age and body mass index (r = 0.802, p < 0.001 and r = 0.340, p < 0.001, respectively) but correlated negatively with ICGH (r = -0.412, p < 0.001) and with height velocity standard deviation scores (SDS, r = -0.355, p = 0.001). No correlation of ICGHBP with maximal GH response to provocative tests, insulin-like growth factor 1 levels, height in SDS or growth velocity after 1 year of GH therapy was found. During a provocative test there is an abrupt increase in GH but not change in GHBP.(ABSTRACT TRUNCATED AT 250 WORDS)

Carrier Proteins↗
PubMed1992

Assessment of growth hormone (GH) axis in Turner's syndrome using 24-hour integrated concentrations of GH, insulin-like growth factor-I, plasma GH-binding activity, GH binding to IM9 cells, and GH response to pharmacological stimulation.

The GH axis was studied in Turner's syndrome (TS) patients. Thirty-seven prepubertal TS patients and 42 normally growing girls (NGG; 5.5-16.3 yr old), of whom 13 were prepubertal, were studied by 24-h continuous blood withdrawal and provocative tests. The 24-h integrated concentrations of GH (IC-GH), FSH (IC-FSH), and insulin-like growth factor-I (IC-IGF-I) as well as the IC-IGF-I/IC-GH ratio were determined. An increase in IC-GH with age and progression of puberty was found in NGG, but not in TS. IC-GH in the NGG was significantly higher than that in age-matched TS patients. Estrogen replacement therapy normalized IC-GH levels in 6 TS patients in whom these levels were subnormal for age. A positive correlation between IC-GH and IC-FSH or IC-estradiol was found in NGG (r = 0.462; P less than 0.01), but not in TS patients. The IC-IGF-I/IC-GH ratio was significantly higher in the TS than in the NGG group. Serum GH-binding activity and serum GH binding to IM9 cells in the TS group did not differ from those in the normal group. We hypothesize that the growth retardation of TS results from a combination of insufficient GH secretion, mainly due to sex steroid deficiency, and an end-organ resistance to IGF-I. IGF-I receptor studies are needed to test this speculation about IGF-I resistance.

Adolescent↗
PubMed1985

Activated interferon system in healthy homosexual men.

More than 50% of a group of healthy homosexuals in Israel were found to have an activated interferon (IFN) system as evidenced by markedly elevated blood IFN levels, increased in vitro production of IFN by unstimulated peripheral blood mononuclear cells and HuIFN-alpha and HuIFN-gamma production by appropriately stimulated cells, and a surprisingly high incidence of an antiviral state of cells. This pattern resembles that found in persons with acute viral illness, and is unlike that found in normal healthy controls. The type of IFN in the blood was found to be unusual in that it was mainly HuIFN-alpha, pH 2-labile, a type of IFN found in certain collagen diseases as well as in homosexual men suffering from Kaposi's sarcoma or lymphadenopathy. Natural killer (NK) cytotoxic activity was found to be somewhat lower than that found in normal controls, although no correlation was found between blood IFN levels and NK activity. Mean (2'-5')-oligoisoadenylate synthetase levels in cell extracts were intermediate between normal controls and patients with viral illness. Likewise no correlation was found between enzyme levels and blood IFN levels. The highly activated IFN system found in certain homosexuals, as well as the increased spontaneous production of IFN by unstimulated mononuclear cells, suggest the possibility of the presence of a virus, active or latent, in these individuals. This virus could be a retrovirus such as HTLV-III or LAV which have recently been isolated from AIDS patients. The special type of IFN present could be the response to a novel virus in an unusual situation. On the basis of recent reports, we speculate that homosexuals with highly activated IFN systems who produce pH 2-labile HuIFN-alpha could be at increased risk for developing AIDS.

Acquired Immunodeficiency Syndrome↗
PubMed1984

Suppressor T-cell activity in newborns and mothers.

We studied autologous and allogeneic concanavalin A (Con A)-induced suppression of proliferative responses to phytohemagglutinin (PHA) and Con A in peripheral blood mononuclear cells in 24 normal newborns and compared the results with those obtained from 20 normal older children. Three concentrations of PHA and one of Con A were used to stimulate responder cells. Suppressor activity, elicited in the stimulated cell population after 48 h pre-incubation with Con A, was expressed as percentage inhibition of the proliferative response to PHA. There was an inverse relationship between PHA concentration and suppressor activity, and autologous suppression was greater than allogeneic suppression within each group of patients and at each mitogen concentration. In both the autologous and allogeneic systems, older children showed more suppressor activity than newborns. Feto-maternal pairing showed that newborns efficiently suppress their mother's mitogenic responses, but the mothers do not suppress their own or other newborn's lymphocytes, despite having normal autologous suppressor capability. We suggest that suppressor activity by the fetus and it's inhibition in the mother may play a part in the mechanism for controlling maternal-fetal immune rejection.

Adult↗
PubMed1983

Effect of colchicine on immunoregulatory abnormalities in familial Mediterranean fever.

The effect of colchicine on immunoregulatory T lymphocytes in children with familial Mediterranean fever (FMF) was studied. Concanavalin A (Con A)-induced suppressor cell function was significantly (P less than 0.0001) decreased in five untreated FMF patients (15 +/- 3%, mean +/- s.e.) as compared to six age matched paediatric controls (46 +/- 3%) and eight healthy adults (49 +/- 4%). When the five untreated FMF patients' mononuclear cells were pre-incubated in vitro with Con A plus 10(-5) M colchicine, their suppressor cell function was significantly increased (52 +/- 10%, P less than 0.01). Similarly, oral colchicine treatment (0.5 mg twice daily) significantly (P = 0.02) increased the five FMF patients' Con A-induced suppressor cell function to levels (34 +/- 6%) that were not significantly (P greater than 0.05) different than the paediatric controls or the healthy adults. The percentage of OKT8+ cells (but not OKT3+ or OKT4+ cells) was significantly (P less than 0.0001) decreased in 10 untreated FMF patients (16.0 +/- 0.9) as compared to 10 paediatric controls (27.6 +/- 2) or 10 healthy adults (25.7 +/- 0.6). The 10 untreated FMF patients had a significant (P less than 0.002) increase in the OKT4/OKT8 ratio (2.41 +/- 0.13) as compared to 10 FMF patients treated with 0.5 mg twice daily of colchicine (1.81 +/- 0.08), 10 pediatric controls (1.47 +/- 0.2), or 10 healthy adults (1.78 +/- 0.11). Colchicine appears to have corrected the FMF patients' elevated OKT4/OKT8 ratio by both decreasing the percentage of OKT4+ cells and increasing (but only partially correcting) the percentage of OKT8+ cells. Thus FMF patients have a suppressor cell deficiency in which colchicine treatment corrects their deficiency of Con A-induced suppressor cell function and their elevated OKT4/OKT8 ratio. This raises the possibility that colchicine might be potentially useful as an immunomodulating drug in treating patients with autoimmune or allergic diseases associated with a suppressor cell deficiency.

Adolescent↗
PubMed1982

Cellular immunity in children with coeliac disease.

The experimental evidence implicating defective cell-mediated immunity in coeliac disease, a condition where symptomatology is believed to be due to immunological reaction to wheat gluten, is often inconsistent and sometimes controversial. Studies of certain parameters of cellular immunity in four groups of pediatric patients were performed: coeliac patients on normal diet; coeliac patients consuming gluten-free diet; children with cow's milk sensitivity. In all these assays no significant differences were found between treated or untreated coeliac children, infants with milk allergy or the gastro-intestinal control groups. On the basis of this study we could find no evidence of impairment of cell-mediated immunity in coeliac children. This conclusion is compatible with the hypothesis that intestinal damage may be due to a subpopulation of lymphocytes sensitive to gluten in persons with normal immune systems. In adults where abnormalities of cell-mediated immunity have sometimes been noted, the reason could be a loss of lymphocytes from the damaged mucosa of the gastrointestinal tract following prolonged antigenic stimulation. This indicated the need for strict adherence to a gluten-free-diet.

Adolescent↗
PubMed1979

Effect of thymic humoral factor on cellular immune factors of normal children and of pediatric patients with ataxia telangiectasia and Down's syndrome.

Cellular immune functions of nine Down's syndrome patients and of nine was Ataxia telangiectasia vs. nine normal children and nine cord bloods, were evaluated using in vitro assays of peripheral blood lymphocytes. The in vitro assays included E rosette formation, antilymphocytic cytotoxicity by an antithymic antiserum and leukocyte migration inhibition factor (LIF) production. The mitogens and antigens used were phytohemagglutinin, purified protein derivative, and monilia antigen. The effect of a thymic hormone (THF) on these parameters was evaluated and it was administered therapeutically to three Down's syndrome patients and to two patients with Ataxia telangiectasia. Most deficient T-cell functions were reversed to normal after incubation of the lymphocytes with THF, or after THF therapeutic administration. In two Down's syndrome cases, the clinical course was not altered by THF administration, while one seemed to benefit from it markedly. One of the Atactic patients recovered from a severe viral infection, while the other died from intractable bronchopneumonia.

Ataxia Telangiectasia↗
PubMed1979

Thymic deficiency in Down's syndrome.

Children with Down's syndrome (DS) often have small and abnormal thymuses, with lymphocyte depletion, diminution of the cortex, and loss of corticomedullary demarcation--a picture resembling thymic involution. Besides this, they have markedly enlarged Hassall's corpuscles, some surrounded by a sheath of lymphocytes. Patients with DS are known to have increased numbers of respiratory infections; they also have a higher incidence of lymphatic leukemia than do individuals who do not have DS. Studies of cell-mediated (thymic-dependent) immunity demonstrate that children with DS have both diminished numbers of T cells as well as functional deficiency of these cells.

Child↗