Trends in HbA1c and other biochemical outcomes of individuals with newly diagnosed type 1 diabetes.

BACKGROUND: There is limited data on glycaemic control and cardiovascular risk factor management in newly diagnosed individuals with type 1 diabetes in the first 2 years. METHODS: Retrospective, single centre study from the North West of England, newly diagnosed with type 1 diabetes between 2014 and 2018 (n = 58). HbA1c, blood pressure, lipids and body mass index (BMI) data were collected from electronic patient records from the time of diagnosis until the end of 2 years, stratified by age 16-24 years or ≥ 25 years at presentation. RESULTS: For those aged 16-24 years (n = 31), median (IQR), HbA1c improved at 6 months from 83 (63-93) to 51.5 (46-75) mmol/mol (p = 0.001) and remained stable 6-24 months. For those ≥ 25 years (n = 27), HbA1c declined from 91 (70-107) to 65 (50-89) mmol/mol, (p < 0.01) at 6 months and declined further to 52 mmol/mol (44-70) at 24 months. At 24 months, 27.8% of all individuals had an HbA1c ≥ 69 mmol/mol. Approximately, a third met LDL (< 2 mmol/L) and total cholesterol (< 4 mmol/L) targets. A total of 58.6% of individuals were overweight/obese (BMI > 25 kg/m2) at 24 months compared to 45.8% at baseline. There were no significant blood pressure changes during the follow-up. CONCLUSIONS: In both age groups, significant improvement of HbA1c occurred within the first 6 months of diagnosis with no statistical difference between the two groups at any of the time points up to 24 months. Despite significant improvements in HbA1c, majority had levels > 53 mmol/mol at 24 months. Alongside the high incidence of obesity and dyslipidaemia, our data support the need for further intensification of therapy from diagnosis of type 1 diabetes.

Low dose (0.05 units/kg/h) is comparable with standard dose (0.1 units/kg/h) intravenous insulin infusion for the initial treatment of diabetic ketoacidosis in children with type 1 diabetes-an observational study.

OBJECTIVE: To compare low dose (0.05 units/kg/h) with standard dose (0.1 units/kg/h) intravenous insulin infusion for the treatment of diabetic ketoacidosis (DKA) in children with type 1 diabetes. STUDY DESIGN: Data from five paediatric centres were compared in children who received 0.05 (41 episodes) or 0.1 units/kg/h (52 episodes). RESULTS: In the low vs. standard dose group, at 6 h following admission, the fall in blood glucose levels [11.3 (95% confidence interval 8.6 to 13.9) vs. 11.8 (8.4 to 15.2) mmol/L, p = 0.86] and rise in pH [0.13 (0.09 to 0.18) vs. 0.11 (0.07 to 0.15), p = 0.78] were similar. These changes were comparable between doses in relation to: severity of initial acidosis, children newly diagnosed with diabetes or aged less than 5 years. After adjustment for other clinical and biochemical covariates, insulin dose was unrelated to the change in pH and blood glucose levels at 6 h following admission. Comparisons of safety data, particularly in relation to abnormal Glasgow Coma Score, were inconclusive. CONCLUSION: In this observational study, low dose was as effective as standard dose intravenous insulin infusion in the initial treatment (less than 6 h) of DKA in children with type 1 diabetes. A randomised controlled trial is required to show true equivalence between doses and to evaluate potential safety benefits.

A pilot interventional study to evaluate the impact of cholecalciferol treatment on HbA1c in type 1 diabetes (T1D).

BACKGROUND: Higher 25(OH)D3 levels are associated with lower HbA1c, but there are limited UK interventional trials assessing the effect of cholecalciferol on HbA1c. AIMS: (1) To assess the baseline 25(OH)D3 status in a Manchester cohort of children with type 1 diabetes (T1D). (2) To determine the effect of cholecalciferol administration on HbA1c. METHODS: Children with T1D attending routine clinic appointments over three months in late winter/early spring had blood samples taken with consent. Participants with a 25(OH)D3 level <50 nmol/L were treated with a one-off cholecalciferol dose of 100,000 (2-10 years) or 160,000 (>10 years) units. HbA1c levels before and after treatment were recorded. RESULTS: Vitamin D levels were obtained from 51 children. 35 were Caucasian, 11 South Asian and 5 from other ethnic groups. 42 were vitamin D deficient, but 2 were excluded from the analysis. All South Asian children were vitamin D deficient, with mean 25(OH)D3 of 28 nmol/L. In Caucasians, there was a negative relationship between baseline 25(OH)D3 level and HbA1c (r = -0.484, P < 0.01). In treated participants, there was no significant difference in mean HbA1c at 3 months (t = 1.010, P = 0.328) or at 1 year (t = -1.173, P = 0.248) before and after treatment. One-way ANCOVA, controlling for age, gender, ethnicity, BMI and diabetes duration showed no difference in Δ HbA1c level. CONCLUSION: We report important findings at baseline, but in children treated with a stat dose of cholecalciferol, there was no effect on HbA1c. Further studies with larger sample sizes and using maintenance therapy are required.

Mechanisms of chloride transport across the syncytiotrophoblast basal membrane in the human placenta.

Chloride transport mechanisms in isolated plasma membrane vesicles were studied to characterize pathways for transcellular transport of chloride. Microvillous membrane (MVM) and basal membranes (BM) vesicles were isolated from term placentae. Western blot analysis of the anion exchanger isoform 1 (AE1) demonstrated that the density of AE1 was 12-fold higher on the MVM compared to the BM. At 30 sec, the Cl- uptake in the absence of a potential difference (p.d.) was 457.3 +/- 69.7 and 111.0 +/- 29.1 pmol/mg protein in MVM and BM, respectively (mean +/- SEM, n=6). Chloride transport pathways were characterized using diisothiocyano-2'2-disulphonic stilbene. (DIDS, 0.1 mM) and diphenylamine-2-carboxylate (DPC, 0.5 mM) in the absence or presence of inside positive membrane potentials. Anion exchange (DIDS-sensitive uptake at zero mV) was found in the MVM only. Both MVM and BM showed increased chloride uptake in the presence of inside positive potentials, suggesting the presence of chloride conductance pathways. The chloride uptake with a 25-mV inside positive p.d. could be inhibited by both DIDS and DPC in MVM and BM. However greater potentials (50 mV) showed no significant inhibition by DIDS or DPC in BM. In conclusion, the anion exchanger is unlikely to contribute significantly to chloride fluxes across BM. The data also suggest the presence of Cl- conductance pathways in both the MVM and BM which are sensitive to both DIDS and DPC.

Polarized lactate transporter activity and expression in the syncytiotrophoblast of the term human placenta.

We investigated the polarization of l-lactate transport in human syncytiotrophoblast by measuring uptake of [(14)C] l-lactate by both microvillous (maternal-facing; MVM) and basal (fetal-facing; BM) plasma membranes. [(14)C] l-lactate uptake by MVM and BM was stimulated in the presence of an inwardly directed H(+)gradient, with a significantly higher uptake in MVM than in BM at initial rate (15.4+/-2.3 vs 5.6+/-0.6 pmol/mg protein/20 sec). Stereospecific inhibition was observed in MVM, with a higher affinity for l-lactate compared with d-lactate. In BM, there was no difference in the inhibition by these two stereoisomers. Inhibition of lactate uptake in both MVM and BM by 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS), an inhibitor of monocarboxylate transporter (MCT) activity, indicated MCT-mediated mechanisms across both membranes. Kinetic modelling supported a two-transporter model as the best fit for both MVM and BM, the K(m)of the major component being 6.21 mm and 25.01 mm in MVM and BM respectively. Western blotting and immunolocalization examining the distribution of MCT1 and MCT4, showed that MCT expression was polarized, MCT1 being predominantly localized to BM and MCT4 showing greater abundance on MVM. CD147, a chaperone protein for MCT1 and MCT4, was equally expressed by both membranes. These studies demonstrate that the opposing plasma membranes of human syncytiotrophoblast are polarized with respect to both MCT activity and expression.

Recurrent Kawasaki disease.

Kawasaki disease (mucocutaneous lymph node syndrome) is a disease of unknown aetiology characterised by vasculitis which may affect the coronary arteries. Young children are most commonly affected although the disease has been described in adults. We report a case of recurrent Kawasaki disease which presented to an oral medicine clinic, where early recognition prompted appropriate management.

Delayed diagnosis of cystic fibrosis due to normal sweat electrolytes.

The sweat test, if properly performed, is a reliable tool to assist in the diagnosis of cystic fibrosis. In practice, most errors arise from false positive results. This case serves as a reminder that false negatives may also occur.

Meningococcal disease among children of Indian subcontinent ethnic origin.

The rate of meningococcal septicaemia and meningitis was significantly lower in children of Indian subcontinent ethnic origin than in children of other origins over 12 years in the Blackburn area of the UK.

Chloride transport across syncytiotrophoblast microvillous membrane of first trimester human placenta.

There are significant changes in the activity of some placental transporters between first trimester and term. However, chloride transport has previously been studied only in the term placenta. Therefore. in this study, we investigated chloride transport mechanisms in syncytiotrophoblast microvillous membrane (MVM) vesicles from first trimester human placentas and compared them with those in vesicles from term placentas. 36Cl- uptake into MVM vesicles was linear up to 45 s and had reached equilibrium by 1 h for both first trimester and term vesicles. In first trimester MVM at 0 mV, 0.1 mM diisothiocyano-2,2'-disulfonic stilbene (DIDS) blocked 25+/-3% (n=8) of 36Cl- uptake at 30 s (initial rate), which was similar to the 30+/-7% (n=6) inhibition by DIDS in term MVM. In the presence of a 25 mV inside-positive electrical potential difference, induced by imposition of a K+ gradient after preincubation with 200 microM valinomycin, 0.5 mM diphenylamine-2-carboxylate (DPC) significantly blocked 30+/-4% of 36Cl- uptake at 30 s by first trimester MVM (p < 0.01); 18+/-5% (n=8) of total uptake was inhibited by DPC but not by DIDS. There was a similar 15+/-3% (n=6) component of 36Cl- uptake by term MVM, which was inhibited by DPC but not by DIDS. Using Western blotting, it was shown that the anion exchanger-1 protein was expressed in first trimester MVM in quantitatively similar amounts to that in term MVM. This study suggests that there is both an anion exchanger and a DPC-sensitive conductance in MVM of first trimester placenta with activity similar to that of term human placenta.

Clinical evaluation of meropenem versus ceftazidime for the treatment of Pseudomonas spp. infections in cystic fibrosis patients.

Cystic fibrosis patients (children and young adults) with Pseudomonas spp. chest infections were treated with meropenem or ceftazidime. This study was the first to investigate the use of meropenem in cystic fibrosis. Meropenem was well tolerated with only transient elevations of serum transaminases. No patient experienced nausea and vomiting, even when meropenem was administered as a bolus injection. This allowed home therapy to be used. Meropenem appeared to be at least as active as ceftazidime even at the low doses used. Patients showed a greater improvement in respiratory function on meropenem than ceftazidime. Only one patient (out of 60 courses) failed to respond to meropenem (98% success rate) compared with two failures out of 21 episodes with ceftazidime (90% success rate). There was little emergence of resistance to meropenem even though some patients were treated up to eight times over a 2 year period.

Mechanisms of maternofetal chloride transfer across the human placenta perfused in vitro.

To determine the relative contribution of the paracellular and transcellular routes to Cl-transfer, unidirectional maternofetal clearance (Kmf) of 36Cl was compared with Kmf of 51Cr-EDTA and creatinine across the human placenta perfused in vitro. The effect of C1-transport inhibitors 4,4'-diisothiocyanostilbene-2,2-disulfonic acid (DIDS) and diphenylamine-2-carboxylate (DPC) was also investigated. The diffusion coefficient (D) was estimated for each solute by use of an agar diffusion method. At steady state, Kmf/D for 36Cl (0.070 +/- 0.003 cm, n = 23) was not different from that for 51Cr-EDTA (0.070 +/- 0.003 cm, n = 23), and Kmf/D was significantly higher for creatinine than for 36Cl and 51Cr-EDTA (0.087 +/- 0.003 cm, n = 20, P < 0.001). Addition of the inhibitors DIDS and DPC to the perfusates resulted in a small but significant rise in Kmf of 51Cr-EDTA (0.41 +/- 0.03 vs. 0.49 +/- 0.02 ml/min, n = 16, P < 0.0001) and creatinine (0.66 +/- 0.05 vs. 0.74 +/- 0.04 ml/min, n = 13, P < 0.001), but Kmf of 36Cl was unchanged (1.11 +/- 0.07 vs. 1.13 +/- 0.05 ml/min, n = 16). There was no change in Kmf of any solute with time in control experiments. From these data, DIDS- and DPC-inhibitable fractions of Kmf for 36Cl were estimated and together accounted for 16% of total clearance. This study suggests that maternofetal flux of 36Cl across the in vitro perfused human placenta occurs predominantly, but not solely, via paracellular routes.

Activity and expression of the Na(+)/H(+) exchanger in the microvillous plasma membrane of the syncytiotrophoblast in relation to gestation and small for gestational age birth.

The effect of gestational age, low birth weight, and umbilical plasma pH on the activity and expression of the Na(+)/H(+) exchanger in the microvillous plasma membrane (MVM) of the placental syncytiotrophoblast was investigated. MVM were isolated from placentas of fetuses delivered in the first and second trimesters and from appropriately grown for gestational age (AGA) and small for gestational age (SGA) babies born at term. Na(+)/H(+) exchange activity (amiloride-sensitive Na(+) uptake) was higher (p<0.05) in second trimester and term AGA MVM versus first trimester MVM (median [range]: 1.80 [1.01-3.03], 1.72 [1.16-3.15] versus 1.48 [0.92-1.66] nmol/mg protein/30s, respectively, n = 6, 12, and 9). As regards exchanger isoforms, Western blotting showed that NHE1 expression did not change across gestation, but NHE2 and NHE3 expression were lower (p<0.01) in the first and second trimesters than in term AGA MVM. There were no differences in Na(+)/H(+) exchanger activity or in NHE1-3 expression in term AGA MVM versus SGA (n = 11) MVM. There was no correlation between exchanger activity and umbilical artery or vein plasma pH, although with a relatively small number of samples (n = 12 and 15, respectively). We conclude that there is differential regulation of the activity and expression of Na(+)/H(+) exchanger isoforms in the MVM over the course of gestation in normal pregnancy; this is not affected in pregnancies resulting in SGA babies at term.