Biophysical and biological activity of a synthetic 8.7-kDa hydrophobic pulmonary surfactant protein SP-B.

We have synthesized pulmonary surfactant apoprotein SP-B peptides by solid-phase chemistry and demonstrated their ability to enhance the surface-active properties of synthetic lipid mixtures. The synthetic peptides were reactive with antiserum generated against the native bovine surfactant peptide. Both peptides conferred surfactant-like properties to synthetic lipid mixtures as assessed by a Wilhelmy balance and pulsating bubble surfactometer. Likewise, mixtures of synthetic SP-B peptides and lipid restored compliance of isolated surfactant-deficient rat lungs. This work demonstrates the utility of SP-B as a functional component of pulmonary surfactant mixtures for treatment of respiratory distress syndrome or other disorders characterized by surfactant deficiency.     

Prevalence and characteristics of brittle diabetes in Britain

We investigated the prevalence and characteristics of 'brittle diabetes', defined as insulin-dependent diabetes mellitus associated with glycaemic instability of any type, leading to life disruption with recurrent and/or prolonged hospitalizations. A questionnaire was sent to all physicians and paediatricians running diabetic clinics in the UK, from lists held at the British Diabetic Association. A total of 414 brittle patients were reported (72% questionnaire return). Most were young (mean age +/- SD was 26 +/- 15 years), though there was a small peak at ages 60-70 years. There was an excess of females (66%) and overall clinic prevalence was 1.2 per 1000 diabetic patients and 2.9 per 1000 insulin-treated diabetic patients. On average, there was 1.0 brittle patient per diabetic clinic. The most common form of brittleness was recurrent ketoacidosis (59%), with 17% having predominant hypoglycaemia, and 24% mixed instability. Female excess was highest and mean age lowest in the recurrent ketoacidosis group, whilst the reverse was true for those with recurrent hypoglycaemia. Causes of brittleness were offered by 58% of consultants, and most (93%) considered various psychosocial problems as likely underlying factors. We conclude that brittle diabetes is a small but significant problem, currently affecting about 1 per 1000 diabetic patients. Most, but by no means all, are young females--often with recurrent ketoacidosis. Older age groups are more likely to have recurrent hypoglycaemic or mixed types of brittleness. Perceived causes of brittleness are usually psychosocial.      

Patterns of Insulin Dependence in an African Diabetic Clinic

SUMMARY Analysis of the age of onset of diabetes amongst insulin-treatedpatients in a large African diabetic clinic revealed a bimodaltype of distribution, 23 per cent having an age of onset before30 years and 77 per cent with onset at 30 years of age. All66 of the young insulin-treated group (21.7±4.8 years(mean±1 SD)), and a random selection of 50 older insulin-treatedpatients (49.7±10 years), were studied. The older groupwere better controlled (HbA₁ 8.4±1.7 per cent vs. 10.8±2.6per cent, p<0.001), on lower doses of insulin (49±23vs. 71±23 u/day, p<0.001) and had higher body massindex (26.0±5.6 vs. 21.8±3.5, p<0.001). SerumC-peptide (0.24±0.15 vs. 0.07±0.10 nmol/l, p<0.0001),and C-peptide/glucose ratio (2.57±2.65 vs. 0.56+0.98nmol/mmolx 10², p<0.001) were very significantly higher inolder patients. Patients with later onset disease thus had betterpreservation of pancreatic function, higher body mass indexand better glycaemic control on lower doses of insulin. Thesefeatures suggest that older insulin-treated patients could infact be ‘Type 2’ or non-insulin dependent patients,and the condition may be controllable with diet and/or oralhypoglycaemic agents, at least in some.     

Effects of changing health care financial policy on very low birthweight neonatal outcomes

BACKGROUND: Our objective was to determine whether perinatal referral patterns and clinical outcomes for very low birthweight infants changed in relation to changing Medicaid financial policies in coastal South Carolina. METHODS: Referral patterns and outcome indicators for very low birthweight infants were compared during two periods in a cohort design. RESULTS: A total of 520 infants were identified over two funding periods. A decrease in the proportion of nonwhite very low birthweight infants was identified. There was an increase in very low birthweight infants with Medicaid funding born outside our level III center. CONCLUSIONS: Changes in financial public policy have been successful in the movement of low risk pregnancies into the private sector. However, an increased proportion of deliveries of very low birthweight infants occurred outside the level III center.     

The disposition of alfentanil in neonates with respiratory distress

The disposition of continuous infusion alfentanil was evaluated in 13 mechanically ventilated neonates (gestational age 37.6 +/- 2.4 wks) with hyaline membrane disease (n = 7) or persistent pulmonary hypertension of the newborn (n = 6). Alfentanil was administered as a loading dose 8 micrograms/kg, followed by a variable-rate continuous infusion (maximum 10 micrograms/kg/hr; minimum 2.5 micrograms/kg/hr) for 27 hours. Serial plasma samples were obtained for pharmacokinetic analysis. Noncompartmental pharmacokinetic analysis of the data revealed the following estimates (mean +/- SD): total-body clearance 3.24 +/- 2.23 ml/kg/minute, volume of distribution 0.54 +/- 0.21 L/kg, and elimination half-life 4.14 +/- 2.58 hours. A significant effect of alfentanil plasma concentration on total-body clearance was found (r = -0.75; p = 0.02), suggesting nonlinear pharmacokinetics. No correlation was seen between total-body clearance and alfentanil dose (r = -0.37; p = 0.32). The results suggest that a larger dose-proportionality study is required to determine the linearity or nonlinearity of alfentanil pharmacokinetics in neonates.     

Correlation of drug sensitivity in vitro with clinical responses in childhood acute myeloid leukemia

Clonogenic cells from 41 children with newly diagnosed acute myeloid leukemia (AML) were tested in vitro for their sensitivity to cytarabine (Ara-C) and daunorubicin (DNR). The findings were then compared with the patients' responses to induction chemotherapy that uniformly included Ara-C and DNR. Light-density marrow cells were incubated with either or both drugs for one hour and cultured over leukocyte feeder layers; clusters and colonies were scored on days 7, 10, and 14. Only the percentage of cell kill in the presence of 1.8 mumol/L DNR was significantly associated with responses to induction therapy: median of 45% (range, 0% to 98%) for patients achieving complete remission v 16% (range, 4% to 23%) for nonresponders (P = .007). The relationship between clonogenic cell kill less than or equal to 23% and clinical responses was striking. Of the 11 evaluable patients with in vitro findings in this category, ten either failed induction therapy or relapsed within 1 year after attaining remission. Kaplan-Meier analysis of relapse-free survival times indicated longer durations of remission for patients whose blast cells showed increased sensitivity in vitro to Ara-C alone, DNR alone, or a combination of the two agents. Seven of 11 patients with cell kills of greater than or equal to 49% in the presence of 1.25 mumol/L Ara-C remain free of leukemia, compared with only one of 12 whose cells were less sensitive to the drug (P = .006). We conclude that the in vitro sensitivity of clonogenic leukemic progenitors to DNR and Ara-C correlates with treatment outcome in children with newly diagnosed AML.     

Cyto-reduction of neuroendocrine tumours using Sandostatin LAR in combination with Infergen: results of a case series

Historically, limited trials evaluating biotherapy in treating metastatic neuroendocrine tumours have yielded mixed results. In this study, the efficacy of a novel combination therapy featuring longacting Sandostatin LAR plus alpha-interferon was evaluated. In a prospective case series, 12 patients with unresectable metastatic neuroendocrine tumours refractory to treatment initiated therapy with Infergen and Sandostatin LAR. Radiological response was followed serially at 3-month intervals. A biochemical response was considered significant if marker levels decreased by > or = 50% compared with baseline. Inhibition of tumour growth lasting for greater than 3 months (mean response 22.6+/-17.7 months) was seen in eight patients. Complete tumour regression was observed in one patient, lasting for 40 months; three patients exhibited partial tumour regression (mean response 29.3+/-24.0 months), and four patients maintained a stable tumour response (mean response 13.3+/-9.2 months). Four patients showed no response to therapy (mean response 5.0+/-6.0 months). All enrolled patients are alive currently. The biochemical response seen in seven patients did not correlate with the radiological response. These results suggest that the novel combination of longacting Sandostatin LAR with an alpha-interferon may be at least as effective as either combination therapy with short-acting octreotide or monotherapy with Sandostatin LAR.