Biomedical subjects

I Nathan

Publications and source records attributed to I Nathan.

At least 19 recordsLinked to original sources

PubMed2005

The voltage-dependent anion channel-1 modulates apoptotic cell death.

The role of the voltage-dependent anion channel (VDAC) in cell death was investigated using the expression of native and mutated murine VDAC1 in U-937 cells and VDAC inhibitors. Glutamate 72 in VDAC1, shown previously to bind dicyclohexylcarbodiimide (DCCD), which inhibits hexokinase isoform I (HK-I) binding to mitochondria, was mutated to glutamine. Binding of HK-I to mitochondria expressing E72Q-mVDAC1, as compared to native VDAC1, was decreased by approximately 70% and rendered insensitive to DCCD. HK-I and ruthenium red (RuR) reduced the VDAC1 conductance but not that of E72Q-mVDAC1. Overexpression of native or E72Q-mVDAC1 in U-937 cells induced apoptotic cell death (80%). RuR or overexpression of HK-I prevented this apoptosis in cells expressing native but not E72Q-mVDAC1. Thus, a single amino-acid mutation in VDAC prevented HK-I- or RuR-mediated protection against apoptosis, suggesting the direct VDAC regulation of the mitochondria-mediated apoptotic pathway and that the protective effects of RuR and HK-I rely on their binding to VDAC.

Amino Acid Substitution↗

PubMed2003

Prognostic factors for patients with chronic myeloid leukaemia in chronic phase treated with imatinib mesylate after failure of interferon alfa.

We assessed clinical results in 145 patients with chronic myeloid leukaemia in chronic phase who satisfied criteria for interferon-alpha failure and were thus eligible for treatment with imatinib at the Hammersmith Hospital. We used univariate and multivariate analyses to develop a risk score based on features defined after treatment for 3 months. We identified a low neutrophil count and poor cytogenetic response (<35% Ph-negative marrow metaphases) at 3 months as principal independent predictive factors and incorporated them into a three-tier prognostic scoring system for individual patients. For patients in the low-, intermediate- and high-risk groups, the probabilities of survival at 24 months were 100, 82 and 40% (P<0.0001) and progression-free survival 100, 66 and 15% (P<0.0001), respectively. This Hammersmith prognostic scoring system was validated with an independent cohort of patients treated at another UK centre.

Adolescent↗

PubMed2001

A reassessment of the fat intake of children from meat and meat products and an estimate of haem iron intakes.

BACKGROUND: It is possible that fat intake from red meat has declined as a consequence of changes in animal husbandry and butchery practices. In particular, a study of the intake of vegetarian and meat-eating children concluded that their fat intakes were similar, but the most recent information on the fat content of meat was not available. In addition, iron availability is probably as important as the total amount of iron consumed but estimates of haem iron intake are rarely made. METHODS: The dietary intake of 50 omnivorous children was reanalysed to produce new estimates of fat and haem iron intakes. Fat intake from meat and meat products only was recalculated using supplements to the food tables not available to the initial survey. Haem iron intake was calculated by discriminating between the different types of meat consumed and estimates of the proportion of iron which is in the haem form. RESULTS: The recalculated diets had significantly lower energy (8.03-7.50 MJ), fat (79-73 g) and carbohydrate (257-237 g) levels. The proportions of energy from fat (36%) and carbohydrate (51%) were unaffected. Meat supplied 3.2 mg (33%) of the iron intake (9.6 mg) of which 1.3-1.5 mg (13-16% of the total) was estimated to be in the haem form. Children may be relatively unaffected by the changes in the composition of meat as such, if they consume highly processed foods which include, for example, rusk, pastry, breadcrumbs and batter. CONCLUSIONS: The original estimates of the intake of fat of these omnivorous children from meat and meat products do appear to have been overestimates, but only as the weight of fat consumed not as a percentage of energy. Haem iron was found to supply a substantial proportion of the iron intake of these children and may account for their higher haemoglobin values.

Animals↗

PubMed2000

Induction of oxidative DNA damage in u937 cells by TNF or anti-Fas stimulation.

TNF and Fas signaling pathways are reported to induce mitochondrial damage associated with production of oxygen radicals. We examined whether such radical production elicited detectable nuclear DNA damage in U937 cells following treatment with TNF or with anti-Fas antibodies. Using GC-mass spectroscopy for analysing base oxidation, several oxidized species increased significantly following TNF treatment, whereas anti-Fas resulted in less detectable oxidative damage using this assay. Cytogenetic analysis showed that, in the presence of aphidicolin, which blocks several types of DNA repair, TNF induced extensive chromosomal damage. Aphidicolin also synergized with TNF and anti-Fas in inducing cell death which was prevented by reducing atmospheric oxygen or addition of n -acetyl cysteine, a scavenger of oxygen radicals. Thus, several lines of evidence point to the TNF and Fas pathways inducing extensive oxidative DNA damage and repair, and suggest potential roles for these pathways in mutagenesis and aging.

Adenosine↗

PubMed1999

Relationship of protamine dosing with postoperative complications of carotid endarterectomy.

Protamine sulfate (PS) neutralization of heparin (HEP) given during carotid endarterectomy (CEA) has been previously associated with an increased postoperative stroke rate. Dosing regimens of PS have varied in previous studies. The accuracy of PS dosing and its effect on postoperative complications was analyzed. The medical records of all patients undergoing elective CEAs from January 1993 to June 1996 in our institution were reviewed. A hematoma was defined as either an event requiring return to the operating room or when repeatedly identified in the medical record. The accuracy of dosing PS was determined utilizing a formula calculating the logarithmic exponential decay of HEP, which determined the residual HEP at the time of PS dosing. An ideal PS dose was then calculated and compared to the dose given. Statistical analyses was performed using a Fisher's exact test as well as the Student's t-test. Four hundred-seven CEAs were performed in 365 patients. There were 10/407 (2.5%) postoperative strokes (STROKE) and 11/407 (2.7%) hematomas, 3 of which required reoperation. Results indicate that (1) the administration of PS significantly reduced the incidence of postoperative hematoma; (2) there appears to be an association between the administration of PS and STROKE; (3) the inaccuracy in dosing PS appears to be based on a decision to dose PS to the total HEP given rather than the residual HEP on board at the time of neutralization. The effect of PS overdosing is unclear, but it may play a role in STROKE.

Aged↗

PubMed1998

Alterations in membrane lipid dynamics of leukemic cells undergoing growth arrest and differentiation: dependency on the inducing agent.

The effect of various differentiation inducers on membrane cell dynamics was studied using HL-60 and K562 leukemic cell lines. Membrane lipid dynamics was measured by the steady-state fluorescence polarization (P) method utilizing either 1,6-diphenyl-1,3,5-hexatriene (DPH) or the trimethyl ammonium derivative of DPH (TMA-DPH), which ascertains anchorage of the label to the membrane-water-lipid interface. Decrease in membrane microfluidity was observed in HL-60 cells undergoing differentiation into macrophages by 1,25-dihydroxyvitamin D3 and by K562 cells induced to differentiate by DMSO. Sodium butyrate caused an increase in membrane fluidity in K562 cells undergoing differentiation into erythroid-like cells while in HL-60 cells a dual effect was observed. At 0.4 mM concentration, in which the cells were induced to differentiate along the monocyte pathway, a decrease in membrane fluidity was observed, while at 1 mM concentration an increase in membrane fluidity occurred. Interferon-gamma (IFN-gamma) induced an increase in membrane fluidity in both cell lines. Using HL-60 cells fluorescently labeled by TMA-DPH, similar results indicating fluidization of the membrane following IFN-gamma treatment were obtained. Advanced fluorescence lifetime measurements, evaluated either by phase modulation spectrofluorometry or by single photon correlation fluorometry confirmed that the decrease in fluorescence polarization by IFN-gamma resulted from membrane fluidization and not from elongation of the probe's excited state lifetime. It is suggested that the inducer mode of action, and not the differentiation route, determine the outcome of changes in membrane microviscosity.

Butyrates↗

PubMed1998

Is a vegetarian diet adequate for children.

The number of people who avoid eating meat is growing, especially among young people. Benefits to health from a vegetarian diet have been reported in adults but it is not clear to what extent these benefits are due to diet or to other aspects of lifestyles. In children concern has been expressed concerning the adequacy of vegetarian diets especially with regard to growth. The risks/benefits seem to be related to the degree of restriction of he diet; anaemia is probably both the main and the most serious risk but this also applies to omnivores. Vegan diets are more likely to be associated with malnutrition, especially if the diets are the result of authoritarian dogma. Overall, lacto-ovo-vegetarian children consume diets closer to recommendations than omnivores and their pre-pubertal growth is at least as good. The simplest strategy when becoming vegetarian may involve reliance on vegetarian convenience foods which are not necessarily superior in nutritional composition. The vegetarian sector of the food industry could do more to produce foods closer to recommendations. Vegetarian diets can be, but are not necessarily, adequate for children, providing vigilance is maintained, particularly to ensure variety. Identical comments apply to omnivorous diets. Three threats to the diet of children are too much reliance on convenience foods, lack of variety and lack of exercise.

Adolescent↗

PubMed1997

Distamycin-A derivatives potentiate tumor-necrosis-factor activity via the modulation of tyrosine phosphorylation.

The cytotoxic activities of 2 novel distamycin-A derivatives, FCE 24517 and FCE 25450A, alone and in combination with tumor-necrosis factor-alpha (TNF), were studied. Both drugs, especially FCE 25450A, analyzed extensively here, inhibited the growth of HL60 promyelocytic cells, and human SV80 and murine L929 transformed fibroblasts in a dose-dependent manner. The growth-inhibitory potential of sequential exposure to the distamycin-A analogs and TNF was determined. A 4-hr treatment of L929 fibroblasts with 100-1,000 ng/ml FCE 25450A, followed by 2 ng/ml TNF, resulted in a synergistic anti-proliferative effect. The synergism of FCE 24517 with TNF was less profound. Experiments to elucidate the mechanism underlying the cooperation revealed that FCE 25450A pre-treatment almost completely abolished the elevated tyrosine phosphorylation of a 137-kDa and other membranal proteins and prevented the de-phosphorylation of another protein band observed in L929 cells in the presence of TNF. FCE 25450A alone induced no changes in the phosphotyrosine profile of the cells. The effect of FCE 25450A was counteracted by the tyrosine-phosphatase inhibitor orthovanadate. In parallel, the inhibitor also diminished the antiproliferative action of the FCE 25450A/TNF combination. These findings suggest that, beyond their cytotoxic effects as single agents, the distamycin derivatives increase the sensitivity of cells to TNF. This effect is governed via the inhibition of TNF-induced tyrosine phosphorylation of specific proteins which are probably involved in the development of TNF resistance. Thus, protein de-phosphorylation might provide an additional mechanism of action of these novel distamycin-A-derived drugs.

Animals↗

PubMed1997

A longitudinal study of the growth of matched pairs of vegetarian and omnivorous children, aged 7-11 years, in the north-west of England.

OBJECTIVE: To assess the ability of a meat free diet to support normal growth of children. DESIGN: A one year longitudinal observational case--comparison study of growth. SETTING: Children were recruited mainly through schools from Merseyside and all measurements were taken in their homes. SUBJECTS: Fifty 'free-living' children following meat free diets, aged 7-11 y (expected to be pre-pubertal), were compared with a control group of 50 omnivores matched for age, sex and ethnic group. INTERVENTION: None. MAIN OUTCOME MEASURES: Height, weight, upper arm skinfold thicknesses and mid-upper arm circumference measurements were taken at baseline and one year later. The increments over one year were each analysed using a multiple stepwise regression model which derived predicted increments controlled for a variety of factors other than the diet factor. RESULTS: Of all the anthropometric measurements examined only the predicted height increment of the vegetarians was slightly greater than that of the omnivores (difference in predicted height increment = 0.47 cm, P = 0.05). This difference was only apparent after allowing for father's height, maternal smoking habit and number of siblings. A tendency for the vegetarians to be leaner than the omnivores was not significant at the 5% level and both the vegetarian and omnivorous groups lay close to the 50th percentiles for both height and weight (Child Growth Foundation, 1994). CONCLUSIONS: The results suggest that these children who followed a meat free diet and conventional lifestyles grew at least as well as children who ate meat.

Anthropometry↗

PubMed1996

A novel putative helicase produced in early murine lymphocytes.

DNA helicases (Hel) play a role in a number of processes involving DNA strand separation, including replication, repair, recombination and transcription. Rearrangement of receptor genes, which occurs in immature lymphocytes, could also be mediated by Hel. We report here the cloning from murine fetal thymus tissue of a novel putative Hel containing seven conserved Hel domains and belonging to the DEGH subclass of DNA Hel. We term the encoding gene lsh (lymphoid-specific Hel), since the gene is expressed in early thymocytes, but not in heart, liver, lung, muscle, brain or kidney, as judged by Northern analysis. Spleen cells expressed lsh following activation. T- and B-cell lines, at both the immature and mature stage, expressed lsh. To examine the earliest stages of lymphopoiesis, mouse embryonic tissues were examined; lsh was not detected in the yolk sac of day 12 of gestation, but was expressed in fetal liver and at high levels in fetal thymus at day 15 of gestation.

Amino Acid Sequence↗

PubMed1996

The dietary intake of a group of vegetarian children aged 7-11 years compared with matched omnivores.

There is a lack of information concerning the diet of vegetarian children. The present study compared the dietary intake of fifty vegetarian children, aged 7-11 years, with fifty matched omnivores. Three 3 d food records were completed by each child at intervals of 6 months. The day after completing the record each child was interviewed to clarify food items and assess portion sizes. Food records were analysed using Microdiet (University of Salford). Finger-prick cholesterol and haemoglobin measurements were taken from a subsample of the group. Only one child's family was a member of the Vegetarian Society and almost one-third of vegetarian children had omnivorous parents (seventeen of fifty subjects). The energy intake (MJ) of the vegetarians was significantly lower than that of the omnivores, 7.6 (SD 1.05) and 8.0 (SD 1.36) respectively; there were no significant differences in Fe or fat intakes. For the vegetarians polyunsaturated:saturated fat ratio (P:S 0.7 (SD 0.04)) and NSP intake (13.8 (SD 0.7) g/d) were significantly higher than those of the omnivores (P:S 0.5 (SD 0.02), NSP 10.3 (SD 0.4) g/d). There was no significant difference in cholesterol measurements (mmol/l) between the two groups: vegetarian 3.5 (SD 0.12), omnivores 3.7 (SD 0.15). The haemoglobin level (g/l) of the vegetarians (11.8 (SD 0.2)) was significantly below that of the omnivores (12.4 (SD 0.2)); 47.5% of the vegetarian children fell below the third percentile of the Dallman reference curves (Dallman & Siimes, 1979). The intake of the vegetarians more closely resembled current recommendations (Department of Health, 1991), although they need to be as aware as omnivores of the need to reduce fat intake. The haemoglobin levels of vegetarian children suggest that they need dietary advice to ensure optimal absorption of Fe.

Child↗

PubMed1996

The roles of protein phosphorylation/dephosphorylation in tumor necrosis factor antitumor effects.

The roles of protein phosphorylation and dephosphorylation in the tumor necrosis factor (TNF) cytotoxic and antiproliferative effects on L-929-transformed fibroblasts were explored. Genistein and erbstatin, specific inhibitors of tyrosine kinase, had antiproliferative but not cytotoxic effects on the cells by themselves and synergistically enhanced the cytotoxic and antiproliferative effects of TNF-alpha. Immunoblot analysis with a monoclonal antiphosphotyrosine antibody revealed that TNF, administered for 5-180 min, induced tyrosine dephosphorylation of two pairs of membranal proteins, 34-36 kDa and 50-52 kDa, and potentiated tyrosine phosphorylation of a 115-kDa protein in both the cytosolic and membranal fractions of the cells. A very brief exposure (30 sec) to TNF induced rapid phosphorylation of several proteins, whereas genistein, but not inhibitors of other protein kinases, enhanced this effect of TNF. The results suggest that TNF activity could be potentiated by the inhibition of tyrosine phosphorylation and point to specific proteins that are dephosphorylated on tyrosine in response to TNF.

Animals↗

PubMed1996

The role of endoscopic retrograde cholangiopancreatography and cholangiography in the laparoscopic era.

OBJECTIVE: The authors reviewed the results of endoscopic retrograde cholangiopancreatography (ERCP) and intraoperative cholangiography in a series of patients who underwent laparoscopic cholecystectomy. SUMMARY BACKGROUND DATA: The indications for preoperative and postoperative ERCP and intraoperative cholangiography as adjuncts to laparoscopic cholecystectomy are evolving. The debate regarding the use of selective or routine intraoperative cholangiography has intensified with the advent of laparoscopic cholecystectomy. METHODS: The authors reviewed the records of 343 consecutive patients who underwent laparoscopic cholecystectomy during a 1-year period. Historical, biochemical, and radiologic findings for the patients who underwent ERCP and intraoperative cholangiography were analyzed. RESULTS: Three hundred forty- three patients underwent laparoscopic cholecystectomy during the period reviewed. Preoperative ERCP was performed in 42 patients. Twenty-seven of these patients (64%) had common bile duct (CBD) stones, which were cleared with a sphincterotomy. Intraoperative cholangiography was performed for 101 patients (29%). Three cholangiograms had false- positive results (3%), leading to two CBD explorations, in which no CBD stones were found, and one normal ERCP. Six patients underwent postoperative ERCP, three for the removal of retained CBD stones (0.9%), all of which were cleared with a sphincterotomy. Fifteen patients had gallstone pancreatitis, six of whom had CBD stones (40%) that were cleared by ERCP. There were 33 complications (10%) and no CBD injuries. CONCLUSION: The use of routine intraoperative cholangiography is discouraged in view of its low yield and the significant rate of false positive cholangiogram results.

Acute Disease↗

PubMed1994

Rapid interferon-gamma-stimulated tyrosine phosphorylation of cytosolic and membranal proteins in HL-60 promyelocytic cells.

The involvement of tyrosine phosphorylation in the early stages of interferon-gamma (IFN gamma)-induced monocytic differentiation of HL-60 cells was studied. Immunoblotting analysis demonstrated that IFN gamma induced rapid changes in the tyrosine phosphorylation of several endogenous cytosolic and membranal proteins. The most prominent of these polypeptides was a 84 kDa protein. In membranes, the IFN gamma-induced phosphorylation of this protein was detectable in 5 min, remained elevated for 3 h and declined thereafter, while a gradual decrease in the phosphotyrosine content was observed in cytosols. In parallel, a 40% increase in the phosphotyrosine phosphatase activity was detected in the later stages of IFN gamma treatment. Rapid changes in tyrosine phosphorylation were detected also in a 64 kDa protein. In contrast, 2-day exposure to IFN gamma was needed to potentiate significantly the tyrosine phosphorylation of a 36 kDa membranal polypeptide. These data support the involvement of tyrosine phosphorylation in the early stages of IFN gamma-induced monocytic differentiation of HL-60 cells.

Cell Differentiation↗

PubMed1994

A biomechanical study of the aponeurotic inguinal hernia repair.

The aponeurotic inguinal hernia repair is essentially a union of the aponeuroses of the external oblique and transversus abdominis muscles in the groin. Its tension-free status and resistance to intra-abdominal stress were measured in a biomechanical study. Comparative studies were made with the American Bassini procedure. Suture tensions were measured at three sites in six aponeurotic repairs and the mean tension was 3.9 +/- 2.9 grams, which was within the accuracy of the combined transducer and recorder measurement. Similar measurements in six American Bassini operations registered 633 +/- 230 grams mean tension. A relaxing incision in the Bassini repair reduced but did not eliminate tension. Mean tension figures remained at 401 +/- 198 grams. Specimens of external oblique aponeuroses in six random patients were tested, counter to their parallel fibers, in a tensiometer. The thickness of the specimens varied from 0.21 to 1.2 millimeters. The tissue mean stress capacity under tension was 4.1 +/- 1.9 x 10(6) pascals with a range of 2.5 to 6.5 x 10(6) pascals. An analysis was made of the impact of intra-abdominal pressure at five possible sites of failure in the aponeurotic repair. Established values of suture bite tissue tear resistance and our values of external oblique aponeurosis stress tension were used to calculate the resistance of the aponeurotic repair to established values of intra-abdominal pressure. The maximum reported intra-abdominal pressure is 26.6 kilopascals. In this series, the largest reconstructed inguinal floor was 5 square centimeters and supported a load of 1,360 grams force. There was a safety margin of 2.4 against a failure of tissue of minimal thickness (0.2 millimeter) in the aponeurotic repairs when subjected to maximum intra-abdominal pressure. With average thickness of specimen (0.45 millimeter) there was a safety margin of 5.4. The 2-0 polypropylene suture had a requirement of 1,590 grams force maximum knot pull strength, which was much greater than our measured tensions. The added suture-line tension created by the assumed intra-abdominal pressure with sutures spaced one-half centimeter apart was calculated to be 65 grams force. This figure is well below the reported tensions of 5,300 and 9,100 grams force resisting tissue pull through failure in the external oblique and transversus aponeurosis, respectively. The transversalis aponeurosis component of the repair had shown in the proceeding study a tensile strength greater than the external oblique aponeurosis, and by analogy, a competence to resist intra-abdominal pressure.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗

PubMed1994

Dynamic cardiomyoplasty: left ventricular diastolic compliance at different skeletal muscle tensions.

The possible limitation of left ventricular (LV) relaxation during diastole is a concern for clinicians and researchers utilizing dynamic cardiomyoplasty. This study was designed to evaluate the LV compliance at three different skeletal muscle tensions, in a normal heart and in a failing heart, created by propranolol infusion (11.6 mg/kg). A biventricular latissimus dorsi muscle (LDM) wrap was performed in 10 dogs. The LV pressure (Millar) and two minor axis dimensions (endocardial crystals) were measured. LV pressure-volume loops were constructed, and LV diastolic compliance was calculated. The measurements were obtained before wrap and after wrap at different LDM tensions with 0, 5, and 10 volts stimulation each time. These measurements were repeated after propranolol treatment. The results showed that LV diastolic compliance (dV/dP) was 1.79 before wrap and about 0.7 after wrap, and after propranolol, at various tensions and stimulations. LDM wrap decreased LV compliance significantly. LV compliance was not significantly affected by changing tension or voltage of stimulation in either the failing or the non-failing heart. The reduction in compliance may be an indication that LDM wrap causes a limitation of LV relaxation, which is one of wrap's deleterious effects.

Animals↗

PubMed1993

Increased platelet thromboxane A2/prostaglandin H2 receptors in patients with pregnancy induced hypertension.

Pregnancy induced hypertension (PIH) is associated with a variety of disturbances in the hemostatic system including alterations in platelet function, thrombocytopenia, and an increase in platelet turnover. The density of platelet Thromboxane A2 (TXA2)/Prostaglandin H2 (PGH2) receptors was determined in patients with PIH and normal pregnant women, using [125I]-PTA-OH, a TXA2/PGH2 receptor antagonist. The number of platelet TXA2/PGH2 receptors significantly increased (p < 0.008) from 1734 +/- 370 sites/platelet (n = 8) in normal pregnant women to 3703 +/- 846 sites/platelet (n = 9) in patients with severe PIH. The sensitivity of platelets to the TXA2 mimetic U46619 was significantly (p < 0.0005) increased in platelets obtained from severe PIH patients (EC50 = 150 +/- 10nM, n = 3) compared to controls (EC50 = 290 +/- 60 nM, n = 5). These results indicate that an increased number of TXA2/PGH2 receptors as well as increased sensitivity to TXA2/PGH2 mimetics occurs in PIH. Collectively, these results provide further support for the notion that TXA2 and its receptor may play an important role in the pathophysiology of PIH.

Blood Platelets↗

PubMed1993

Synergistic effect of interferon-gamma and phorbol myristate acetate on superoxide production by human monocytes.

This study demonstrates a synergistic effect of IFN gamma and PMA on superoxide generation by human monocytes. A strict correlation was observed between the induction of superoxide production and PK-C activation by PMA alone. No such correlation was evident for IFN gamma. However, exposure of the cells to IFN gamma for 10 to 15 hr prior to PMA treatment enhanced both superoxide production and PK-C activation. Using protein kinase inhibitors, we noticed that while PMA exerted its effect by activating PK-C, IFN gamma operated via activation of calcium/calmodulin-dependent or some other calcium-dependent protein kinases. These kinases appeared to be involved in the effect of IFN gamma on superoxide production, as well as in its potentiation of PMA activity.

Cells, Cultured↗