Adverse neonatal outcome associated with maternal tuberculosis in a public tertiary centre: a retrospective cohort study.

INTRODUCTION: The aim of this study was to evaluate a group of infants born to women with tuberculosis (TB) during pregnancy to determine the neonatal morbidities and its outcomes associated with tuberculosis in pregnancy. MATERIALS AND METHODS: Data from January 2007 to December 2021 was collected for analysis as part of a retrospective cohort study. This study was conducted in a tertiary public hospital in Malaysia, Hospital Sultan Idris Shah (HSIS). Cases were identified from the hospital's bacille Calmette-Guerin (BCG) vaccination notification forms and merged with records from the neonatal intensive care unit's census. Controls were infants born to mothers unaffected by TB within the same hospital and year as the index case (1:4 ratio). Descriptive statistics and logistic regression were used to analyse the data. The main outcome measures were the risk of congenital tuberculosis, premature birth, low birth weight, small for gestational age and low APGAR score. RESULTS: Data from January 2007 to December 2021 was collected for analysis as part of a retrospective cohort study. This study was conducted in a tertiary public hospital in Malaysia, Hospital Sultan Idris Shah (HSIS). Cases were identified from the hospital's bacille Calmette-Guerin (BCG) vaccination notification forms and merged with records from the neonatal intensive care unit's census. Controls were infants born to mothers unaffected by TB within the same hospital and year as the index case (1:4 ratio). Descriptive statistics and logistic regression were used to analyse the data. The main outcome measures were the risk of congenital tuberculosis, premature birth, low birth weight, small for gestational age and low APGAR score.

Pre-existing influenza-specific nasal IgA or nasal viral infection does not affect live attenuated influenza vaccine immunogenicity in children.

The United Kingdom has a national immunization programme which includes annual influenza vaccination in school-aged children, using live attenuated influenza vaccine (LAIV). LAIV is given annually, and it is unclear whether repeat administration can affect immunogenicity. Because LAIV is delivered intranasally, pre-existing local antibody might be important. In this study, we analysed banked samples from a study performed during the 2017/18 influenza season to investigate the role of pre-existing influenza-specific nasal immunoglobulin (Ig)A in children aged 6-14 years. Nasopharyngeal swabs were collected prior to LAIV immunization to measure pre-existing IgA levels and test for concurrent upper respiratory tract viral infections (URTI). Oral fluid samples were taken at baseline and 21-28 days after LAIV to measure IgG as a surrogate of immunogenicity. Antibody levels at baseline were compared with a pre-existing data set of LAIV shedding from the same individuals, measured by reverse transcription-polymerase chain reaction. There was detectable nasal IgA specific to all four strains in the vaccine at baseline. However, baseline nasal IgA did not correlate with the fold change in IgG response to the vaccine. Baseline nasal IgA also did not have an impact upon whether vaccine virus RNA was detectable after immunization. There was no difference in fold change of antibody between individuals with and without an URTI at the time of immunization. Overall, we observed no effect of pre-existing influenza-specific nasal antibody levels on immunogenicity, supporting annual immunization with LAIV in children.

Differences in nasal immunoglobulin A responses to influenza vaccine strains after live attenuated influenza vaccine (LAIV) immunization in children.

Different vaccine strains included in the live attenuated influenza vaccine (LAIV) have variable efficacy. The reasons for this are not clear and may include differences in immunogenicity. We report a Phase IV open-label study on the immunogenicity of a single dose of quadrivalent LAIV (Fluenz™ Tetra) in children during the 2015/16 season, to investigate the antibody responses to different strains. Eligible children were enrolled to receive LAIV; nasal samples were collected before and approximately 4 weeks after immunization. There was a significant increase in nasal immunoglobulin (Ig)A to the H3N2, B/Victoria lineage (B/Brisbane) and B/Yamagata lineage (B/Phuket) components, but not to the H1N1 component. The fold change in nasal IgA response was inversely proportional to the baseline nasal IgA titre for H1N1, H3N2 and B/Brisbane. We investigated possible associations that may explain baseline nasal IgA, including age and prior vaccination status, but found different patterns for different antigens, suggesting that the response is multi-factorial. Overall, we observed differences in immune responses to different viral strains included in the vaccine; the reasons for this require further investigation.

The 'dawn phenomenon' in adolescents with insulin dependent diabetes mellitus: possible contribution of insulin-like growth factor binding protein-1.

OBJECTIVE: Insulin resistance increases during adolescence, and is exaggerated in patients with insulin dependent diabetes mellitus (IDDM). A relative deficiency of insulin-like growth factor-I (IGF-I) may contribute to this increased insulin requirement. Two mechanisms have been proposed: (a) increased GH secretion, caused by failure of IGF feedback control, leading to increased insulin resistance and (b) lack of insulin-like action of the IGFs which is reinforced by high plasma levels of IGFBP-1, an inhibitor of IGF action. The contribution of these two mechanisms to the 'dawn phenomenon' is assessed. DESIGN: The two possible mechanisms were studied during the dawn rise of glucose in pubertal adolescent patients with IDDM. Two overnight studies were performed in each subject. Patients remained on the same insulin regimen throughout. SUBJECTS: Twenty-two diabetic adolescent subjects, aged (mean +/- SEM) 14.0 +/- 0.4 years, duration of IDDM 7.9 +/- 0.8 years, were recruited. Pubertal status was: group 1 (breast stage 1-2; testicular volume < 4-8 ml) 3 male and 4 female, group 2 (breast stage 3; testicular volume 10-12 ml) 0 male 4 female, group 3 (breast stage 4-5; testicular volume 15-25 ml) 4 male and 7 female. Height standard deviation score (mean +/- SD) (-0.02 +/- 0.99) and daily insulin dose (50.4 +/- 3.1 U/day) did not change between studies. There were no differences in HbA1 (study A 11.26 +/- 0.45%, study B 11.09 +/- 0.42%). METHODS: The subjects were admitted for the two studies 0.3 +/- 0.03 years apart. Blood samples were taken via an indwelling cannula every 20 minutes between 1900 and 0700 h. MEASUREMENTS: GH was assayed every 20 minutes, IGFBP-1, glucose and free insulin every hour and IGF-I at 0700 h. GH, IGFBP-1, IGF-I and free insulin were measured by radioimmunoassay. IGFBPs were also analysed by Western ligand blotting techniques. GH profiles were analysed by Pulsar and results compared by paired Student's t-test. The relations between the dawn rise in glucose and the changes in IGFBP-1, GH and free insulin were examined by multiple linear regression analysis. RESULTS: Serum IGFBP-1 levels rose overnight in the two studies (study A, from 9 +/- 1 at 2200 to 59 +/- 9 micrograms/l at 0700 h; study B, from 10 +/- 1 at 2100 to 64 +/- 14 micrograms/l at 0700 h) whilst insulin levels fell from 47 +/- 5 at 2200 to 16 +/- 2 mU/l at 0700 h (study A) and from 45 +/- 5 at 2000 to 14 +/- 2 mU/l at 0700 h (study B). Glucose levels fell from 16.0 +/- 1.0 to 9.3 +/- 0.9 mmol/l at 0400 h, and then rose to 11.9 +/- 1.1 mmol/l at 0700 h during study A, and from 13.4 +/- 1.3 to 10.1 +/- 1.1 mmol/l at 0400 h and then rose to 13.5 +/- 1.0 mmol/l at 0700 h during study B. There were no differences in GH secretion between studies (mean GH levels (mean +/- SD) (study A, 15.7 +/- 6.6 mU/l; study B, 16.2 +/- 7.1 mU/l; correlation within subjects between studies r = 0.77, P < 0.001), sum of GH peaks (study A, 189.9 +/- 90.3 mU/l; study B, 185.8 +/- 100.2 mU/l; r = 0.57, P = 0.006)). Mean GH levels varied with pubertal stage (group 1, 12.1 +/- 1.5 mU/l; group 2, 23.3 +/- 2.1 mU/l; group 3, 15.3 +/- 1.2 mU/l). Serum IGF-I levels were not different (study A, 203 +/- 12 micrograms/l; study B, 218 +/- 13 micrograms/l). REGRESSION ANALYSIS: The change in plasma glucose between 0200 and 0700 h in both studies related to free insulin, IGFBP-1 and the sum of the GH levels over the preceding hour (log glucose = 7.87 + 5.32 log IGFBP-1 (P = 0.0001) - 5.05 log free insulin (P = 0.0001) - 1.44 log GH (P = 0.004); R2 = 72%). Mean overnight GH levels did not predict the morning rise in plasma glucose. CONCLUSION: The morning rise of IGFBP-1 and plasma glucose appear to be related in this group of subjects with IDDM and this was a consistent finding in the two studies. This relation was additive to the effect of insulin deficiency.

Levels of GH binding activity, IGFBP-1, insulin, blood glucose and cortisol in intensive care patients.

OBJECTIVE: To investigate levels of serum GH binding activity, insulin-like growth factor binding protein-1 (IGFBP-1), blood glucose, serum insulin, and cortisol in patients on the Intensive Therapy Unit. DESIGN: Case-control study of severely ill patients admitted to the Intensive Therapy Unit. PATIENTS: Six critically ill patients (51-78 years) who required ventilatory and nutritional support and six healthy age, sex, height and weight matched controls. MEASUREMENTS: Patients and controls were studied for two 24-hour periods; the patients before and after commencing parenteral nutrition, the controls whilst fasted and on a second occasion when fed a diet equal in protein and calories to that of the patients' parenteral nutrition. Samples were taken hourly for measurement of IGFBP-1, blood glucose, serum insulin and cortisol. Growth hormone binding activity was measured at 0 hours. RESULTS: Blood glucose levels were higher in the patients than controls in both the fasted (mean +/- SEM 5.1 +/- 0.5 vs 3.8 +/- 0.2 mmol/l, P = 0.04) and fed states (10.1 +/- 1.6 vs 5.0 +/- 0.1 mmol/l, P = 0.02) and patients' insulin levels were also higher when fed (81.5 +/- 31.6 vs 24.2 +/- 4.8 mU/l, P = 0.046) although there were no significant differences between patients and controls when fasted. IGFBP-1 levels were inversely related to insulin levels in both the patients and controls; mean IGFBP-1 concentrations were higher in fasted patients than in controls (123 +/- 38 vs 52 +/- 9, P = 0.046) but when fed, both groups had similar mean levels. Serum GH binding activity was low in the patients and did not change with feeding. Mean 24-hour cortisol levels were higher in the patients than in controls, whether fasted or fed, and showed no nyctohemeral rhythm. CONCLUSIONS: We have previously reported that critically ill patients have low levels of IGF-I with augmented basal levels of GH. The present results demonstrate that these changes in the GH-IGF-I axis are associated with insulin resistance with respect to blood glucose and high levels of IGFBP-1 when patients are fasted. However, when fed, the inverse relationship of IGFBP-1 to insulin is preserved. Patients have low levels of GH binding activity and increased mean cortisol levels. Interventional studies in this patient group with GH and IGF-I must take account of these changes in binding protein and cortisol levels.

Insulin-like growth factor binding proteins (IGFBPs) in acromegaly.

Hypersecretion of growth hormone (GH) is the principal feature of acromegaly and is accompanied by an excess of IGF-I production which mediates some of the actions of GH. The activity of IGF-I is modulated by a number of specific binding proteins (IGFBPs) which form complexes with IGF-I in the circulation. In this study, the technique of Western Ligand Blotting followed by 2-dimensional radioactive scanning was employed to investigate the correlations between relative levels of the IGFBPs and the main factors implicated in their regulation: IGF-I, GH and insulin, in a group of acromegalics with varying disease activity. The two glycosylated forms of IGFBP-3 correlated with increased levels of IGF-I (40.5 kD, r = 0.468, p < or = 0.01 and 36.5 kD, r = 0.809, p < or = 0.001), but did not relate to mean GH levels. Quantification of IGFBP-2 on the ligand blot showed an association with RIA levels of IGFBP-1 (r = 0.35, p < or = 0.05). IGFBP-1 RIA levels did not relate to the radioactivity in the assumed IGFBP-1 region of the ligand blot. This may be explained by fragments of IGFBP-3 running in this region and could account for the correlation seen between radioactivity in the 29 kD band with both forms of IGFBP-3 as well as with IGFBP-4. IGFBP-3 levels were normal in biochemically cured acromegalics with normal GH levels, although fasting insulin levels remained higher than normal (mean 16 +/- 4 vs normal 7.4 +/- 0.4 mU/L).(ABSTRACT TRUNCATED AT 250 WORDS)

The presence of cation-dependent proteases for insulin-like growth factor binding proteins does not alter the size distribution of insulin-like growth factors in pregnancy.

OBJECTIVE: The aim was to investigate the sera of pregnant women for the presence of specific proteases for insulin-like growth factor binding proteins (IGFBPs) and to determine the effect of these on the distribution of IGFs in the circulation. DESIGN: The method used was the chromatographic and electrophoretic analysis of patients' serum. PATIENTS: Sera were examined from normal women during pregnancy: first trimester (n = 4), second trimester (n = 4) and third trimester (n = 10). Eight women with Type I diabetes in the third trimester were also studied along with sera from ten normal adult volunteers. MEASUREMENTS: Circulating IGF-I and IGF-II levels were measured by RIA and their distribution examined by gel filtration. The pattern and stability of the IGFBPs was investigated by Western ligand blotting. RESULTS: A marked reduction in the serum levels of IGFBP-2, IGFBP-3 and IGFBP-4 on Western ligand blotting, which was associated with the presence of three independent, cation-dependent proteases that were specific for different IGFBPs, was found in late pregnancy. Gel filtration of third trimester serum revealed most of the IGF-I to be present in a complex larger than 130 kDa, with a similar distribution to that found in serum of non-pregnant women. The enzymatic modification of the binding proteins made apparent by the decrease in binding protein bands on Western ligand blotting of preincubated samples had no effect on the distribution of IGF-I following size fractionation. CONCLUSIONS: There appear to be at least three independent enzymes that are induced or activated during pregnancy to modify IGFBP-2, IGFBP-3 and IGFBP-4 sufficiently to prevent their detection by ligand blotting. However, this enzymatic processing does not alter the distribution of IGFs, suggesting that the altered binding proteins are still able to carry IGFs but with reduced affinity. Such an alteration in the carrying mechanism of IGFs may have profound effects upon the bioavailability of the IGFs to the maternal tissues and contribute to the altered metabolic demands of pregnancy.