Constitutional and somatic rearrangement of chromosome 21 in acute lymphoblastic leukaemia.

Changes in gene dosage are a major driver of cancer, known to be caused by a finite, but increasingly well annotated, repertoire of mutational mechanisms. This can potentially generate correlated copy-number alterations across hundreds of linked genes, as exemplified by the 2% of childhood acute lymphoblastic leukaemia (ALL) with recurrent amplification of megabase regions of chromosome 21 (iAMP21). We used genomic, cytogenetic and transcriptional analysis, coupled with novel bioinformatic approaches, to reconstruct the evolution of iAMP21 ALL. Here we show that individuals born with the rare constitutional Robertsonian translocation between chromosomes 15 and 21, rob(15;21)(q10;q10)c, have approximately 2,700-fold increased risk of developing iAMP21 ALL compared to the general population. In such cases, amplification is initiated by a chromothripsis event involving both sister chromatids of the Robertsonian chromosome, a novel mechanism for cancer predisposition. In sporadic iAMP21, breakage-fusion-bridge cycles are typically the initiating event, often followed by chromothripsis. In both sporadic and rob(15;21)c-associated iAMP21, the final stages frequently involve duplications of the entire abnormal chromosome. The end-product is a derivative of chromosome 21 or the rob(15;21)c chromosome with gene dosage optimized for leukaemic potential, showing constrained copy-number levels over multiple linked genes. Thus, dicentric chromosomes may be an important precipitant of chromothripsis, as we show rob(15;21)c to be constitutionally dicentric and breakage-fusion-bridge cycles generate dicentric chromosomes somatically. Furthermore, our data illustrate that several cancer-specific mutational processes, applied sequentially, can coordinate to fashion copy-number profiles over large genomic scales, incrementally refining the fitness benefits of aggregated gene dosage changes.

Cytogenetic and genomic characterization of cell line ARH77.

The cell line ARH77 is derived from a patient with plasma cell leukemia and has a complex and continually evolving karyotype. It is frequently used in biological studies of myeloma and plasma cell leukemia, so accurate characterization of the genome is valuable. Here we present a detailed cytogenetic investigation using G-banding and multicolor fluorescence in situ hybridization (M-FISH) in association with assessment of copy number alterations (CNAs) throughout the genome using array-based comparative genomic hybridization (aCGH). In addition to providing an accurate description of the karyotype, this complementary approach highlighted the relative merits of the individual techniques. Conventional cytogenetics and M-FISH indicated the location and types of the major chromosomal changes, whether balanced or unbalanced, and at the same time demonstrated the level of karyotypic evolution between cells. The aCGH profiles reflected the unbalanced chromosomal abnormalities detected by cytogenetics, providing refinement of their genomic breakpoint locations as well as the identification of novel genomic changes. Three aCGH platforms, comprising bacterial artificial chromosome (BAC) or oligonucleotide templates, were available for evaluation. Sixteen CNAs were consistently detected by all three platforms. Novel submicroscopic CNAs ( approximately 0.4 Mb) were detected by the highest resolution platform only, whereas the clones from the BAC arrays provided locus-specific FISH probes for confirmation of CNA.

Intrachromosomal amplification of chromosome 21 (iAMP21) may arise from a breakage-fusion-bridge cycle.

Intrachromosomal amplification of chromosome 21 (iAMP21), involving amplification of the RUNX1 gene and duplication of chromosome 21, dup(21q), defines a new cytogenetic subgroup in B-lineage acute lymphoblastic leukemia (ALL) with a poor prognosis. Characterization of this abnormality has become vital to ensure that the most accurate detection method is used. We have previously defined common regions of amplification and deletion of chromosome 21 in these patients, although the level and extent of amplification within the amplicon was highly variable. This study, using interphase fluorescence in situ hybridization (FISH) with chromosome 21 locus specific probes, substantiated these findings in a large series of patients and confirmed that the amplicon always included RUNX1. Thus, FISH with probes directed to the RUNX1 gene remains the most reliable detection method. Metaphase FISH, supported by G- and multiple color chromosomal banding (mBAND) revealed the patient specific morphology and genetic profile of the dup(21q) chromosomes, as well as the complexity of the intrachromosomal changes giving rise to them. These findings suggested that iAMP21 had arisen from a breakage-fusion-bridge cycle: a mechanism previously described in tumors, which we report for the first time in ALL.

Prognosis of children with acute lymphoblastic leukemia (ALL) and intrachromosomal amplification of chromosome 21 (iAMP21).

Patients with acute lymphoblastic leukemia (ALL) and an intrachromosomal amplification of chromosome 21 (iAMP21) comprise a novel and distinct biological subgroup. We prospectively screened 1630 (84%) patients treated on the UK MRC ALL97 protocol for iAMP21 and herein present demographic, clinical, and survival data on the 28 (2%) children found to harbor this abnormality. They had a common or pre-B ALL immunophenotype, were significantly older (median 9 years vs 5 years), and had a lower white cell count (median 3.9 vs 12.4) compared with children without this abnormality. Notably, patients with iAMP21 had a significantly inferior event-free and overall survival at 5 years compared with other patients: 29% (95% confidence interval [CI], 13%-48%) versus 78% (95% CI, 76%-80%) and 71% (95% CI, 51%-84%) versus 87% (95% CI, 85%-88%), respectively. As a result of this 3-fold increase in relapse risk, newly diagnosed patients with iAMP21 recruited to the current UK MRC ALL2003 trial are being treated on the high-risk arm and are considered for bone marrow transplantation in first remission.

Complex genomic alterations and gene expression in acute lymphoblastic leukemia with intrachromosomal amplification of chromosome 21.

We have previously identified a unique subtype of acute lymphoblastic leukemia (ALL) associated with a poor outcome and characterized by intrachromosomal amplification of chromosome 21 including the RUNX1 gene (iAMP21). In this study, array-based comparative genomic hybridization (aCGH) (n = 10) detected a common region of amplification (CRA) between 33.192 and 39.796 Mb and a common region of deletion (CRD) between 43.7 and 47 Mb in 100% and 70% of iAMP21 patients, respectively. High-resolution genotypic analysis (n = 3) identified allelic imbalances in the CRA. Supervised gene expression analysis showed a distinct signature for eight patients with iAMP21, with 10% of overexpressed genes located within the CRA. The mean expression of these genes was significantly higher in iAMP21 when compared to other ALL samples (n = 45). Although genomic copy number correlated with overall gene expression levels within areas of loss or gain, there was considerable individual variation. A unique subset of differentially expressed genes, outside the CRA and CRD, were identified when gene expression signatures of iAMP21 were compared to ALL samples with ETV6-RUNX1 fusion (n = 21) or high hyperdiploidy with additional chromosomes 21 (n = 23). From this analysis, LGMN was shown to be overexpressed in patients with iAMP21 (P = 0.0012). Genomic and expression data has further characterized this ALL subtype, demonstrating high levels of 21q instability in these patients leading to proposals for mechanisms underlying this clinical phenotype and plausible alternative treatments.

ETV6/RUNX1 fusion at diagnosis and relapse: some prognostic indications.

This study was undertaken in order to compare the interphase and metaphase cytogenetics of 28 patients with ETV6/RUNX1 positive acute lymphoblastic leukemia, at diagnosis and relapse. The median time to relapse was 26 months. The significant fusion positive population heterogeneity revealed at interphase by a commercial probe for ETV6/RUNX1 fusion has not been described before. Six diagnostic samples had a single abnormal population; others had up to five each, which differed in the numbers of RUNX1 signals, and in the retention or loss of the second ETV6 signal. In contrast, the number of fusion signals was more constant. At relapse, there were fewer populations; the largest or unique clone was sometimes a re-emergence of a minor, diagnostic one, with a retained copy of ETV6 and the most RUNX1 signals. Abnormal, fusion negative clones were identified in bone marrow samples at extra-medullary relapse. Variant three or four-way translocations, which involved chromosomes 12 and 21, were prominent among the complex rearrangements revealed by metaphase FISH. The frequency of their occurrence at diagnosis and reappearance at relapse, sometimes accompanied by minor clonal evolution, was another new observation. Other recurrent cytogenetic features included a second copy of the fusion signal in six cases, partial duplication of the long arm of the X chromosome in two cases, and trisomy 10 in three cases. In comparing our data with previously reported cases, a picture is beginning to emerge of certain diagnostic features, which may provide circumstantial evidence of an increased risk of relapse.

Interphase molecular cytogenetic screening for chromosomal abnormalities of prognostic significance in childhood acute lymphoblastic leukaemia: a UK Cancer Cytogenetics Group Study.

Summary Interphase fluorescence in situ hybridization (iFISH) was used independently to reveal chromosomal abnormalities of prognostic importance in a large, consecutive series of children (n = 2367) with acute lymphoblastic leukaemia (ALL). The fusions, TEL/AML1 and BCR/ABL, and rearrangements of the MLL gene occurred at frequencies of 22% (n = 447/2027) (25% in B-lineage ALL), 2% (n = 43/2027) and 2% (n = 47/2016) respectively. There was considerable variation in iFISH signal patterns both between and within patient samples. The TEL/AML1 probe showed the highest incidence of variation (59%, n = 524/884), which included 38 (2%) patients with clustered, multiple copies of AML1. We were thus able to define amplification of AML1 as a new recurrent abnormality in ALL, associated with a poor prognosis. Amplification involving the ABL gene, a rare recurrent abnormality confined to T ALL patients, was identified for the first time. The use of centromeric probes revealed significant hidden high hyperdiploidy of 33% and 59%, respectively, in patients with normal (n = 21/64) or failed (n = 32/54) cytogenetic results. The iFISH contributed significantly to the high success rate of 91% (n = 2114/2323) and the remarkable abnormality detection rate of 89% (n = 1879/2114). This study highlights the importance of iFISH as a complementary tool to cytogenetics in routine screening for significant chromosomal abnormalities in ALL.

t(14;19)(q32;q13): a recurrent translocation in B-cell precursor acute lymphoblastic leukemia.

The recurrent t(14;19)(q32;q13) translocation associated with chronic B-cell lymphoproliferative disorders, such as atypical chronic lymphocytic leukemia, results in the juxtaposition of the IGH@ and BCL3 genes and subsequent overexpression of BCL3. We report six patients with B-cell precursor acute lymphoblastic leukemia who have a cytogenetically identical translocation with different breakpoints at the molecular level. Fluorescence in situ hybridization with locus-specific probes confirmed the involvement of the IGH@ gene but showed that the breakpoint on 19q13 lay outside the region documented in t(14;19)(q32;q13)-positive chronic lymphocytic leukemia. This newly described translocation constitutes a distinct cytogenetic subgroup that is confined to older children and younger adults with B-cell precursor acute lymphoblastic leukemia.

Complex chromosomal abnormalities in utero, 5 years before leukaemia.

Prenatal acquisition of leukaemia-associated gene rearrangements is a well-established phenomenon. This is the first report of a complex cytogenetic clone, in association with an ETV6/AML1 fusion, developing in utero. Identical twin girls, aged 4 years, developed ETV6/AML1-positive acute lymphoblastic leukaemia (ALL) within 3 months of one another. Both demonstrated an identical four way, variant t(12;21). There was gain of an AML1 signal in twin 1 and loss of an ETV6 one in twin 2 at interphase. This unique case study demonstrates that ETV6/AML1 fusion and the associated complex chromosomal rearrangements occurred in utero. Clonal expansion of the abnormal cell in one twin was followed by metastasis to the other. There was a prolonged preleukaemic phase, which lasted well into childhood. The short time between the two diagnoses of ALL suggests a common precipitating event. The significance of the different secondary markers remains unclear.

Outcome heterogeneity in childhood high-hyperdiploid acute lymphoblastic leukemia.

High hyperdiploidy (HeH) (51 to 65 chromosomes) is found in one third of children with acute lymphoblastic leukemia and is associated with a good prognosis. Cytogenetic features may further refine this prognosis and identify patients with a poor outcome. We examined the effect of sex, age, individual trisomies, modal number, and structural abnormalities on survival among 700 children with HeH. Univariate analysis showed that age. sex, +4, +10, +18, and a high modal number were associated with survival. Multivariate analysis however, revealed that only age, sex, +4, and +18 were independent indicators. Hazard scores for predicting relapse and mortality were constructed. Three risk groups with 5-year event-free survival (EFS) rates of 86%, 75%, and 50% (P <.0001) were identified. The high-risk group comprised boys older than 9 years, boys aged 1 through 9 years without +18, and girls older than 9 years without +18, while girls aged 1 through 9 years with +18 had the best EFS. In terms of mortality, those younger than age 10 years with both +4 and +18 had an improved survival (96% vs 84% at 5 years, P <.0001). These findings confirm that the outcome of children with HeH is heterogeneous and that specific trisomies can identify patients with the greatest and least risk of treatment failure.

Three distinct subgroups of hypodiploidy in acute lymphoblastic leukaemia.

This study of children and adults with acute lymphoblastic leukaemia (ALL) is the largest series of patients with hypodiploidy (<46 chromosomes) yet reported. The incidence of 5% was independent of age. Patients were subdivided by the number of chromosomes; near-haploidy (23-29 chromosomes), low hypodiploidy (33-39 chromosomes) and high hypodiploidy (42-45 chromosomes). The near-haploid and low hypodiploid groups were characterized by their chromosomal gains and a doubled hyperdiploid population. Structural abnormalities were more frequent in the low hypodiploid group. Near-haploidy was restricted to children of median age 7 years (range 2-15) whereas low hypodiploidy occurred in an older group of median age 15 years (range 9-54). Patients with 42-45 chromosomes were characterized by complex karyotypes involving chromosomes 7, 9 and 12. The features shared by the few patients with 42-44 chromosomes and the large number with 45 justified their inclusion in the same group. Survival analysis showed a poor outcome for the near-haploid and low hypodiploid groups compared to those with 42-45 chromosomes. Thus cytogenetics, or at least a clear definition of the modal chromosome number, is essential at diagnosis in order to stratify patients with hypodiploidy into the appropriate risk group for treatment.

The effect of malnutrition on insulin binding to rat erythrocytes

Insulin binding to erythrocyte receptors was compared in malnourished and control rats. Percentage specific insulin binding to malnourished rat erythrocytes was significantly lower than to control erythrocytes (P<0.001). The low insulin binding in the malnourished rat erythrocytes was accompanied by low insulin receptor affinity (P=0.035).(AU)

The effect of the duration of malnutrition on erythrocyte insulin binding and carbohydrate tolerance in rats - abstract

To further investigate the effect of malnutrition on carbohydrate metabolism, we have examined the binding of insulin to its receptor in a rat model. The erythrocytes of malnourished animals bound less insulin than controls (6.4 percent vs 17 percent respectively, p<0.01, at 10 days post-weaning, pw). In the later stages of malnutrition (20 days pw), insulin-binding was significantly less than in the early stage (5 days pw) 2.7 percent vs 14.7 percent, p<0.01 respectively). The decreased in binding was also due to decreased receptor affinity in the malnourished compared to the control (0.54 Ke x 10(to 8 power)/M vs 1.4 Ke x 10(to 8 power/M, p<0.01, at 10 days pw). There was no significant difference between the number ob receptors in malnourished and control states. The malnourished animals became insulin-resistant, with a diminished glucose tolerance and a lowered insulin to glucose ratio. Insulin release was also presumably impaired as the malnourished animals had a lowered plasma insulin concentration compared to the controls of the same age (8 æU/ml vs 15.3 æU/ml, p0.05; 10 days pw). In the control animals, the plasma insulin levels increased with age from 8.1 æU/ml at weaning to 27.5 æU/ml (p<0.05): while increase in plasma insulin values shown by the malnourished was not statistically different (10.34æU/ml, 20 days pw). There was an inverse relationship between plasma insulin levels and insulin-binding as the control animals increased in age. The extent and the duration of manutrition adversely affects the binding of insulin to its receptor. This would contributed to the glucose intolerance characteristic of malnurtition (AU)

Erythrocyte insulin receptors in protein-energy malnutrition (PEM) - abstract

Impaired glucose tolerance, commonly observed in protein-energy malnutrition, may be attributed in part to abnormally low circulating insulin levels. However, low insulin/glucose ratios suggest that other factors related to defective uptake of glucose in the target organs may be involved. Evidence of insulin sensitivity in PEM is conflicting, and insulin receptor number and affinity are known to be altered in various nutritional states. Human erythrocytes are therefore most convenient for study when small volumes of blood are available, as in the 6-24 month-old infant with PEM. Our first studies were conducted on pooled blood from malnourished and control rats using monoiodinated A14 tyrosine 125I insulin (S. A. 270 æCi/æug), specially purified by High Performance Liquid Chromatography (HPLC). This insulin binds optimally to the insulin receptor. The animals were studied in the early of malnutrition (between 5 and 25 days after weaning, 10 experiments) and after prolonged malnutrition (40-60 days after weaning, 2 experiments). Erythrocyte suspensions (2-4 x 109/ml) were incubated in the presence of 30 pg of A 14 125I insulin and increasing concentrations of unlabelled insulin (Sigma porcine) for 2 hours at 15§C. The radioactivity in the separated and washed erythrocytes was determined by Gamma counter. During the early phases of malnutrition, erythrocytes from malnourished rats bound significantly less insulin (p<0.001) than controls. This decreased binding was shown to be related to reduced affinity of the hormone for the receptor rather than reduced numbers of receptors. The altered affinity was most clearly shown in the high affinity receptor sites, the K value in controls being 7.814 ñ 2.25 x 10-8(power)M (9) as compared with 2.808 ñ 1.09 x 10-8(power)M (5) in the malnourished (p<0.001). However, significantly increased insulin binding ("up-regulation") was demonstrated in malnourished animals after prolonged and severe malnutriton. Two experiments only were carried out in this phase, and further studies to clarifiy this phenomenon are in progress. Preliminary studies in malnourished children confirm the results shown in malnourished rats. Three children were studied, on kwashiorkor, one marasmic and one recovered. Erythrocyte-binding in the recovered child was significantly higher than in the malnourished. The reduction in binding of insulin to erythrocytes was 80 percent in the kwashiorkor child, and 20 percent in the marasmic child as compared with the recovered child. Our results indicate that in the early phase of protein-energy malnutrition, there is decreased insulin-binding in rat erythrocytes. This alteration in binding is caused by reduced affinity of the hormone for the receptor. Further studies are in progress to confirm the preliminary observation of "up-regulation" in severe and prolonged malnutrition. These results suggest that conflicting reports of insulin sensitivity in malnutrition may be related to the severity and duration of nutritional deprivation (AU)

The metabolic effects of fenfluramine (ponderax) on obese diabetics - abstract

A trial of Ponderax in the management of refractory obesity in diabetic patients was conducted at the University Hospital of the West Indies over a 14-month period. The duration of the exhibition of the drug was six to fourteen months. Sixty-one patients were selected for the trial. They consisted of patients more than 25 percent in excess of ideal body weight in whom all methods of weight reduction had failed. Of the 61 patients 48 completed the trial, 13 defaulted or did not attend regularly enough to make assessment meaningful. There were 42 women and 6 men with an age range of 17-71 years. At the onset of the trial the drug therapy of the 48 patients was as follows: Diet alone - 8 patients, Diet + Diabinese - 15 patients, Diet + Metformin - 5 patients, Diet + Diabinese + Metformin - 12 patients, Diet + Insulin - 6 patients, Diet + Insulin +Metformin - 2 patients. All the patients had difficulty in the control of their diabetes and had 2-hour post prandial blood sugar levels in excess of 251 mgm percent on no treatment, and 153 mgm percent on their standard therapy. The dose of Ponderax given to the patients was as follows: 60 mgm/day - 5 patients, 80 mgm/day 10 patients, 100 mgm/day - 2 patients, 120 mgm/day - 22 patients, 140 mgm/day - 2 patients, 160 mgm/day - 8 patients. Of the 48 patients who completed the trail, the mean blood sugar level fell to 92 mgm percent on Ponderax and their usual therapy. Interestingly, in ten patients the dose of Diabinese had to be either reduced or stopped. In two patients taking insulin, there was a fall in the insulin requirements. Six patients taking metformin alone or metformin and diabinese had to habe a reduction in their dosage. 5 patient lost no weight, although blood sugar control improved, 10 patients lost less than 5 pounds, 9 patients lost less than 10 pounds, 9 patients lost less than 15 pounds, 4 patients loss less than 20 pounds and 11 patients loss more than 25 pounds. 25 percent of patients lost more than 10 pounds in weight. Weight loss lagged behind blood sugar and diabetic control by a mean of six to eight weeks. Serum Insulin levels were measured in 16 patients. In 11 of these patients there was a mean rise in the 2-hr. p.p. Insulin levels of 35u Units/ml. In 4 patients serum insulin levels fell by 24 units and in 1 patient there was no change. There was a considerable fall in blood pressure in all patients. The fall was greatest in the hypertensive and least in the normotensive patients. Side effects seen postural hypotension (36 patients), diarrhea (24), drowsiness (42), skin rash (1), depression (3). The 3 patients who suffered depression had a previous history of psychiatric disturbances and had stopped taking the Ponderax abruptly (AU)

Insulin and growth hormone inter-relationships in vitro and in vivo - abstract

The effect of growth hormone on insulin release was observed in rabbit pancreas in vitro. Isolated islets and pancreas slices were incubated with varying concentrations of human growth hormone. Insulin released in the medium was measured by double antibody immunoassay. Human growth harmone stimulated insulin release in both pancreas preparations (p=.01). However the response was concentration dependent in that insulin release was inhibited at high concentrations of growth hormone. These observations support the concept that growth hormone plays a physiological role in the control of insulin release. Correlation between insulin and growth hormone levels in vivo was investigated in infants recovering from malnutrition. Plasma immunoreactive insulin was measured by a specially modified assay which descriminated between 0, 3, 6 and 12 uu/ml (P=.01). Growth hormone assay was equally sensitive, detecting 0.16 uu/ml. Fasting hormone levels were observed during acute malnutrition, rapid catch-up growth and recovery. In 19 acutely malnourished children insulin levels were low (2.3ñ0.3 uu/ml) (mean ñ SEM) while growth hormone levels were high (32.5 ñ 7.1). During the phase of rapid growth, insulin levels were significantly increased (4.5 ñ 0.6) (p = 0.025) while growth hormone level was 21.7 ñ 4.1. When growth curves plateaued with recovery, mean insulin level was 2.8 ñ 0.3 while growth hormone was 17.6 ñ 3.4. It is concluded that rapid catch-up after protein-calorie malnutrition is associated with a significant elevation of plasma insulin (AU)

Fasting pancreatic glucagon in Jamaican children during malnutrition and subsequent recovery

Fasting pancreatic glucagon was observed in Jamaican infants during malnutrition and subsequent recovery. Rehabilitation in two groups of children with isocaloric diets rich either in carbohydrate or fat produced no differences in the rate of weight gain. During malnutrition, plasma pancreatic glucagon concentration was 104ñ11 (n=20) pg/ml (meanñS.E.) significantly lower than during recovery when the maximum value was 180ñ24 (n=13) pg/ml during the later recovery phase. After clinical recovery glucagon levels declined to 127ñ13 (n=15) pg/ml. Plasma insulin followed a similar pattern, increasing significantly during catch-up growth and declining after recovery. Slower rates of growth were associated with the simultaneous decline in the concentrations of both hormones after clinical recovery. (Summary)

A comparison of fasting plasma insulin and growth hormone concentrations in marasmic, kwashiorkor, marasmic-kwashiorkor and underweight children

Fasting plasma insulin and growth hormone concentrations were measured in 24 marasmic, 11 kwashiorkor, 16 marasmic-kwashiorkor, and 4 underweight children. Hormone measurements were made by a special modification of the Hales and Randle double antibody immunoassay with increased sensitivity in the concentration range 0-25 æU/ml. Fasting plasma insulin was low in marasmus, kwashiorkor, and marasmic-kwashiorkor children, and increased to normal levels after recovery. Fasting plasma growth hormone was elevated in all groups during nutrition and was significantly decreased to normal levels after recovery. There were no significant differences in plasma insulin or growth hormone levels between the different clinical types of severe protein malnutrition. These hormonal changes in severe protein energy malnutrition are of complex and not fully understood etiology. However, recovered children appear to have a hormonal pattern similar to that described in normal control infants and children. (Summary)

The effect of DPT inoculation on the hormonal control of glucose homeostasis in children recovered from malnutrition - abstract

The effect of a controlled stress (DPT innoculation) on the hormonal control of glucose homeostasis was investigated in children nutritionally rehabilitated from severe malnutrition. The age range of the 15 children studied was 6-26 months. Plasma insulin (INS), growth hormone (GH), interleukin-1 (IL-1) were measured by radio-immunoassay, plasma glucose (GLU) by a glucose oxidase method, and red cell insulin binding (RCIB) was determined using A-14 monoiodinated insulin. Measurements were made on two occasions: (1) at 10:00 a.m., 12 hrs. before DPT innoculation, and (2) 36 hrs. after innoculation. On both occasions, 4-hr. post-prandial blood samples were used, and the mean body temperature (BT) on the day of the test was determined. Plasma INS (æU/ml), GH (æU/ml), RCIB (percentage) and BT (C) were higher after DPT than before, plasma G1U (mM) was lower after DPT, and plasma IL-1 (fM/ml) was unchanged. The higher RCIB (percentage) after DPT was associated with an increase in the number of receptor sites (S), and a decrease in receptor affinity (K). The results (expressed as means ñ SEM) are summarized in the Table given. Significant positive correlations were shown between GLU and INS (r = +0.56, p < 0.015), and between IL-1 and RCIB (r = +0.66, p < 0.01) before DPT, but these relationships disappeared after DPT. A significant negative correlation was shown between glucose and insulin binding (r = -0.47). p < 0.05), when values before and after DPT were pooled. The results suggest that increased insulin binding may contribute to the lowering of blood glucose levels during the inflammatory response (AU)

The effect of diet on plasma somatomedin-C (IGF-I) in Jamaican and Nigerian children recovering from oedematous and non-oedematous malnutrition - abstract

Plasma somatomedin -C (PSm-C) was measured by radioimmunoassay in children with marasmus or kwashiorkor (4-24 months) and during rehabilitation. PSm-C (U/ml) was compared with that of normal children of the same age range (4-6 months, 0.175ñ0.04: 7-12 months, 0.288ñ0.35: 13-18 months 0.289ñ0.120: 19-24 months, 0.598ñ0.160). Initially, Jamaican children were offered one of two isocaloric diets (468J/kg body weight per day), which differed principally in their protein contents A-0.9g:B-3.5/kg body weight per day) at levels which did not permit anabolism. During this phase, oedematous children lost their oedema. They were then offered an energy dense diet (C-1046 KJ and 5.7g protein/kg body weight per day) and gained weight rapidly to achieve the weight of a normal child of the same height. The malnourished Nigerian children were treated with a vegetable-protein based diet which provided a mean intake of 4.3ñ0.2 gm protein and 556+34 KJ/kg body weight per day. PSm-C concentration in both Jamaica and Nigerian children was determined on admission and at weekly intervals during rehabilitation to examine the response to, and hence nutritional adequacy of both types of diets. In Jamaica children, PSm-C was slightly higher in admission but did not differ significantly in marasmic or kwashiorkor children (0.202ñ0.04 (n=9) vs 0.155ñ0.3 U/ml (n=18) respectively). In Nigerian children, PSm-C was higher in marasmic children (0.29ñ0.03 U/ml (n=7) than those with oedematous manutrition (0.15ñ0.03 U/ml (n=18) p<0.05). In both Jamaican and Nigerian children, PSm-C gradually rose after a small initial decline 1 week after admission. In Jamaican children, the increase in PSm-C after 4 weeks in hospital was significantly greater in marasmus than in kwashiorkor (0.431ñ0.71 (n=7) vs 0.269ñ0.05 U/ml (n=16) p<0.01). This difference could be attributed to dietary treatment, since oedematous children were kept from one to three weeks on a maintenance diet (either A or B) until oedema was lost. There was no significant difference in PSm-C on either diet A or B (A-0.165+0021 (n=26). B-0 150+0.019 U/ml (n=29). After 1 week on Diet C, PSm-C was 0.259ñ0.044 (n=21); significantly greater than PSm-C on diet A or B. In Nigerian children, eight days after admission, PSm-C had risen to 0.21ñ0.06 U/ml. In both Jamaican and Nigerian children, after 4 weeks PSm-C rose to normal values for their age range: 0.337ñ0.34 U/ml (n=21) in Jamaican children and 0.30ñ0.07 U/ml (n=25) in Nigerian children. The higher PSm-C shown in marasmic Jamaican children may be related to the early introduction of high energy Diet C (AU)