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Integrating genomic medicine into health care delivery poses significant challenges to health professionals. To draw clinical benefit from genomic information, there is a need to build an evidence-based relationship between genotype and the physical expression of that genomic information. The work presented here uses preliminary work in the field of haemoglobinopathies to address two important challenges: to ensure that health care professionals in low- and middle-income countries are actively involved in the processes that will support genomic medicine, and that equity and diversity concerns are met so that clinical services can have relevance across all population and sub-population groups. Haemoglobinopathies provide an opportunity for gaining a better understanding of how long-standing genetic knowledge can be leveraged to determine if genomic-based services can be beneficial in low-resource settings. The Global Globin 2020 Challenge (GG2020) is an international initiative that uses haemoglobinopathies as an entry point to achieving growth in the quality and quantity of curated inputs into internationally recognised databases, harmonising the sharing of variant information within and between countries for better health care delivery and ensuring that storing, curation and sharing of variant information become an integral part of health care. Early findings from GG2020 indicate that paying attention to population diversity is an integral part of prevention and control of haemoglobinopathies.

Wheat starch degradation requires the synergistic action of different amylolytic enzymes. Our spatio-temporal study of wheat α-amylases throughout grain development shows that AMY3 is the most abundant isoform compared with the other known α-amylases. Endosperm-specific over-expression of AMY3 resulted in an increase of total α-amylase activity in harvested grains. Unexpectedly, increased activity did not have a significant impact on starch content or composition but led to an increase of soluble carbohydrate (mainly sucrose) in dry grain. In AMY3 overexpression lines (A3OE), germination was slightly delayed and triacylglycerol (TAG) content was increased in the endosperm of mature grain. Despite increased AMY3 transcript and protein content throughout grain development, alterations of α-amylase activity and starch granule degradation were not detected until grain maturation, suggesting a post-translational inhibition of α-amylase activity in the endosperm during the starch filling period. These findings show unexpected effects of a high level of α-amylase on grain development and composition, notably in carbon partitioning and TAG accumulation, and suggest the presence of a hitherto unknown regulatory pathway during grain filling., (© The Author 2014. Published by Oxford University Press on behalf of the Society for Experimental Biology.)

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.

Objective: Anxiety predicts cardiovascular events, although the mechanism remains unclear. We hypothesized that anxiety symptoms will correlate with impaired resistance and conduit vessel function in participants aged 55 to 90 years., Methods: Anxiety symptoms were measured with the Symptom Checklist-90--Revised in 89 participants with clinically diagnosed atherosclerotic cardiovascular disease and 54 healthy control participants. Vascular function in conduit arteries was measured using flow-mediated dilatation, and vascular function in forearm resistance vessels (FRVs) was measured using intra-arterial drug administration and plethysmography., Results: Anxiety symptoms were not associated with flow-mediated dilatation in either group. Participants with atherosclerosis exhibited significant inverse associations of anxiety symptoms with FRV dilatation (acetylcholine: β = -.302, p = .004). Adjustment for medication, risk factors, and depression symptoms did not alter the association between anxiety and FRV dysfunction, except for body mass index (BMI; anxiety: β = -.175, p = .060; BMI: β = -.494, p < .001). Although BMI was more strongly associated with FRV function than anxiety, combined BMI and anxiety accounted for greater variance in FRV function than either separately. Control participants showed no association of anxiety with FRV function., Conclusions: Anxiety is uniquely and substantially related to poorer resistance vessel function (both endothelial and vascular smooth muscle functions) in individuals with atherosclerosis. These relationships are independent of medication, depression, and cardiovascular risk factors, with the exception of BMI. These findings support the concept that anxiety potentially increases vascular events through worsening of vascular function in atherosclerotic disease.

There is growing evidence that non-communicable diseases (NCDs) are a major health and socio-economic issue in low- and middle-income countries (LMICs). According to World Health Organization (WHO) estimates, deaths from cardiovascular disease, cancer, chronic respiratory disease and diabetes accounted for 63 per cent of global mortality in 2008, of which 80 per cent was in LMICs. The NCD burden is projected to increase: by 2030, NCDs will be the greatest killer in all LMICs. Thus, governments of these countries cannot afford to overlook policies in relation to NCDs. Several cost-effective measures exist to prevent and control NCDs. These include both population-wide interventions such as tobacco control and targeted treatment for individuals at high risk. Experience from high-income countries that have been able to control NCDs shows that responses must be comprehensive and multi-sectoral, integrating health promotion, prevention and treatment strategies, and involving the community as well as the health sector. Such a multi-faceted approach requires well-functioning health systems. In the majority of LMICs, however, health systems are fragile and will need to be adapted to address NCDs appropriately, while also continuing to tackle communicable diseases. We propose that the reform of health systems can occur in a four-phased approach in four areas: building political commitment and addressing health systems constraints, developing public policies in health promotion and disease prevention, creating new service delivery models and ensuring equity in access and payments. Several policy issues will also need to be addressed, including financing of NCD programs and the broadening of concepts of health and responsibilities for health. Adapting health systems to respond to NCDs will require a change in mindset and practices in programming for health, as well as substantial financial resources. There is scope for development partners and global health initiatives to support LMICs in addressing NCDs.

A 44-year-old gentleman was admitted with a deliberate overdose of olanzapine, paracetamol and bisoprolol. On admission, he was hypothermic, bradycardic and hypotensive and his body mass index was 12 kg/m(2). Problems identified on admission included polypharmacy overdose, risk of refeeding syndrome and sepsis. Despite careful reintroduction of feeding and generous electrolyte replacement, he developed persistent hypophosphataemia, hypokalaemia and a marked transaminitis. Several days later, he was noted to be hypothermic and hypoglycaemic. No increase in white cell count or C reactive protein was noted and his clinical appearance was otherwise unremarkable. Nevertheless, given these signs he was started on broad spectrum antibiotics for possible sepsis, which was subsequently confirmed on chest radiograph in addition to a further finding of likely aspergilloma on a later chest CT. His metabolic function stabilised after 3 weeks of carefully titrated nutrition and the sepsis responded to antibiotics and antifungal therapy.

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.

Chromosomal abnormalities are important for the classification and risk stratification of patients with acute lymphoblastic leukemia (ALL). However, approximately 30% of childhood and 50% of adult patients lack abnormalities with clinical relevance. Here, we describe the use of array-based comparative genomic hybridization (aCGH) to identify copy number alterations (CNA) in 58 ALL patients. CNA were identified in 83% of cases, and most frequently involved chromosomes 21 (n=42), 9 (n=21), 6 (n=16), 12 (n=11), 15 (n=11), 8 (n=10) and 17 (n=10). Deletions of 6q (del(6q)) were heterogeneous in size, in agreement with previous data, demonstrating the sensitivity of aCGH to measure CNA. Although 9p deletions showed considerable variability in both the extent and location, all encompassed the CDKN2A locus. Six patients showed del(12p), with a common region encompassing the ETV6 gene. Complex CNA were observed involving chromosomes 6 (n=2), 15 (n=2) and 21 (n=11) with multiple regions of loss and gain along each chromosome. Chromosome 21 CNA shared a common region of gain, with associated subtelomeric deletions. Other recurrent findings included dim(13q), dim(16q) and enh(17q). This is the first report of genome-wide detection of CNA in ALL patients using aCGH, and it has demonstrated a higher level of karyotype complexity than anticipated from conventional cytogenetic analysis.

Centrosome amplification is frequently observed in tumor cells exposed to genotoxic stress, however the underlying mechanisms and biological consequences are poorly understood. Here, we show that the anti-metabolite and alkylating agent 6-thioguanine (6-TG) induces centrosome amplification resulting in the formation of multi-polar spindles when damaged cells subsequently enter mitosis. These aberrant, multi-polar mitoses are frequently resolved by asymmetric cell divisions causing unequal segregation of genetic material and cell death in one or both daughter products. We show that this phenomenon is associated with transient cell cycle delay in S- and G(2)-phase and is dependent on DNA mismatch repair (DNA MMR) proficiency and Chk1 protein kinase activity. Although Chk1-deficient cells do not exhibit cell cycle delay, centrosome amplification, or multi-polar spindle formation, continued cell cycle progression in the presence of 6-TG eventually results in increased levels of mitotic catastrophe, most probably due to mitosis with incompletely replicated DNA. Taken together, these results reveal novel mechanisms of cell killing by 6-TG and underscore the importance of interactions between cell cycle checkpoints and DNA MMR in determining the fate of cells bearing DNA damage.

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., ((c) 2007 Wiley-Liss, Inc.)

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.

Chk1 plays a crucial role in the DNA damage and replication checkpoints in vertebrates and may therefore be an important determinant of tumour cell responses to genotoxic anticancer drugs. To evaluate this concept we compared the effects of the nucleoside analogue 5-fluorouracil (5FU) on cell cycle progression and clonogenic survival in DT40 B-lymphoma cells with an isogenic mutant derivative in which Chk1 function was ablated by gene targeting. We show that 5FU activates Chk1 in wild-type DT40 cells and that 5FU-treated cells accumulate in the S phase of the cell cycle due to slowing of the overall rate of DNA replication. In marked contrast, Chk1-deficient DT40 cells fail to slow DNA replication upon initial exposure to 5FU, despite equivalent inhibition of the target enzyme thymidylate synthase, and instead accumulate progressively in the G1 phase of the following cell cycle. This G1 accumulation cannot be reversed rapidly by exogenous thymidine or removal of 5FU, and is associated with increased incorporation of 5FU into genomic DNA and severely diminished clonogenic survival. Taken together, these results demonstrate that a Chk1-dependent replication checkpoint which slows S phase progression can protect tumour cells against the cytotoxic effects of 5FU.

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.

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., (Copyright 2005 Wiley-Liss, Inc.)

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.

Deletions from the derivative chromosome 9, der(9), of the translocation, t(9;22)(q34;q11), at the site of the ABL/BCR fusion gene, have been demonstrated by fluorescence in situ hybridisation (FISH), in both Philadelphia chromosome (Ph)-positive chronic myeloid leukaemia (CML) and acute lymphoblastic leukaemia (ALL). In CML they occur in 10-15% of cases and appear to indicate a worse prognosis, whereas in ALL, the situation is unclear. This study presents the findings of dual fusion FISH used to detect such deletions in a series of 27 BCR/ ABL-positive childhood ALL patients. Metaphase FISH was essential for the accurate interpretation of interphase FISH signal patterns. Three cases (11%) had a single fusion signal, resulting from deletions of the der(9). Three other patients with variant translocations and one with an insertion, also had a single fusion, but with no evidence of deletions. Gain of a fusion in approximately one-third of patients indicated a second Ph, which appears to be a diagnostic marker of Ph-positive ALL. This study shows that the incidence of deletions from the der(9) in childhood ALL is at least as high as that reported for CML.

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., (Copyright 2004 Blackwell Publishing Ltd)

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 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., (Copyright 2003 Wiley-Liss, Inc.)

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.

This study examined the effects of duty-related stress on police officers. Using a sample of 100 suburban police officers, an anonymous questionnaire requested demographic information and included a measure of duty-related stressors, SCL-90-R, the Posttraumatic Stress Disorder scale of the Impact of Events Scale-Revised, and a locus of control scale. Also assessed was whether Critical Incident Stress Debriefing was experienced. The results showed significant correlations between scores on duty-related stress, somatization, and symptoms of PTSD. 13% of the sample met the DSM-IV (1994) diagnostic criteria for PTSD. Results of the regression analysis showed the best predictors for the diagnosis of PTSD were associated with the factor of Exposure to Death and Life Threat, which corresponds to the DSM-IV AI criteria. Finally, 63% of the respondents stated that a critical incident debriefing would be beneficial following an extremely stressful event related to duty.

Significant hormonal changes have been reported in childhood malnutrition, including high serum levels of growth hormone and cortisol, and low levels of circulating insulin. The ultrastructure of the endocrine pancreas in such patients has hitherto not been reported. A light microscopy survey of the pancreatic islets was carried out on 69 malnourished children dying from protein-energy malnutrition. In seven of these cases, a rapid autopsy protocol allowed tissues to be fixed for electron microscopy within 75 minutes of death. This paper presents the first ultrastructural observations on the Islets of Langerhans in childhood protein-energy malnutrition. In all cases, there was a variable degree of degeneration of all cell types with membrane damage, loss of ribosomes, vesiculation and mitochondrial swelling. In addition, the B-cells showed a high proportion of precursor granules compared to crystal forms, possibly accounting for low insulin serum levels reported by other workers. It is suggested that islet cell changes may be related to free radical damage secondary to depletion of glutathione and other antioxidants, as well as relative deficiencies of cysteine and zinc. In addition, the effects of agonal anoxia, and a short fixation delay after death must be considered.

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 less than 0.001). The low insulin binding in the malnourished rat erythrocytes was accompanied by low insulin receptor affinity (P = 0.035).

The effect of a controlled stress (DPT inoculation) 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) and interleukin-1 (IL-1) were measured by radioimmunoassay; plasma glucose (GLU) by a glucose oxidase method; and red cell insulin binding (%SB) was determined, using A-14 monoiodinated insulin. Measurements were made on two occasions: (T-0) at 10 a.m., 12 hr before DPT inoculation, and (T-36) 36 hr. after inoculation. On both occasions, 4 hr post-prandial blood samples were used, and the mean body temperature (T) on the day of the test was determined. Red cell insulin binding (%SB) was significantly higher at T-36 than at T-0 (16.8 +/- 1.7 vs 12.1 +/- 1.2 (14), p = 0.005). (Results were expressed as mean +/- SEM, numbers of paired observations in parentheses). The higher %SB after DPT was accompanied by an increase in the number of receptor sites (S) (29.05 +/- 6.5 vs 15.6 +/- 2.5 (14), p = 0.025). However, insulin receptor affinity (K x 10(9) M-1) was decreased (0.7 +/- 0.1 vs 1.5 +/- 0.3 (14), p = 0.008). There were no significant differences in the plasma levels of insulin, glucose and interleukin-1, but plasma growth hormone (microU/ml) was increased after DPT, (18.0 +/- 3.0 vs. 11.5 +/- 1.2 (13), p = 0.04). Body temperature (degree C) was also significantly increased after DPT, (99.6 +/- 0.4 vs. 98.3 +/- 0.2 (14), p = 0.006).(ABSTRACT TRUNCATED AT 250 WORDS)