Use of the artificial B-cell (Biostator) in improving insulin therapy in unstable insulin-dependent diabetes.

The present study was designed to improve the conventional subcutaneous insulin treatment of labile insulin-dependent diabetic patients by means of the artificial B-cell (Biostator) during a combination of conventional treatment and a glucose-controlled insulin infusion. Eleven patients with no residual B-cell function and poor metabolic control were studied. All patients were treated as effectively as possible by conventional methods using a combination of regular and intermediate insulin under clinical conditions. In order to determine the inadequacy of previous insulin treatment, all patients were connected to the Biostator, and the profile of daily physical activity was simulated using a bicycle ergometer. Metabolic control was compared during a 6-day period before and after a 30-50-h connection to the artificial B-cell. Using a preselected blood glucose level of 80 mg/dl (4.44 mmol/L), the additional insulin requirement amounted to 45.5 +/- 11.1 U/24 h (N = 6). The day after connection to the artificial B-cell, the patients received a new insulin regimen according to the additional insulin delivery determined by the Biostator. No better metabolic control was achieved and frequent hypoglycemic episodes occurred in this group. Another group (N = 5) was therefore studied at a preselected blood glucose level of 130 mg/dl (7.22 mmol/L). The mean additional insulin delivery by the Biostator was lower (17.2 +/- 2.1 U/24 h; P less than 0.05) and all patients were significantly better equilibrated after the new insulin regimen derived from data given by the Biostator. The ratio of short-acting to intermediate-acting insulin was 3:1; 40% of the total dosage was given in the morning. This study demonstrates that using the Biostator in addition to subcutaneous insulin allows determination of the amount of additional regular insulin that should be administered to improve glycemic control in labile diabetes.

Reproducibility of insulin dosage on consecutive days of blood glucose control by an artificial beta-cell in brittle diabetic patients.

The profiles of blood glucose and of insulin dosage were compared between the first and second of 2 consecutive days of Biostator administration under constant conditions in 12 brittle type I diabetic inpatients. All blood glucose criteria and the daily insulin doses were reproducible between these 2 days for the entire group of patients. In nearly all patients, however, there were distinct but unsystematic differences between the 2 days in the diurnal patterns of insulin dose distribution. These differences could be ascribed to some stress reaction or inherent metabolic lability. It is concluded that, in these extremely labile diabetic patients, due to the insufficient short-term reproducibility of the outcome of an extracorporal artificial beta-cell, caution must be used when constant profiles are to be predicted from these doses for open-loop insulin delivery systems or for conventional subcutaneous injection therapy.

Human pancreatic secretory trypsin inhibitor (PSTI) produced in active form and secreted from Escherichia coli.

As a basis for a protein design project, we decided to produce the human pancreatic secretory trypsin inhibitor (PSTI) in its active form. Total gene synthesis was carried out efficiently by (i) computer design of the gene fragments, (ii) synthesis of the oligodeoxynucleotides by the segmental support method, and (iii) assembly of double strands under optimized ligation conditions. Fusion to the ompA gene signal peptide led to secretion of processed PSTI in various constructions, with or without additional amino acids (aa) at the N-terminus. The secreted proteins (56 to 63 aa) were biologically active, suggesting that the three cysteine bridges were correctly formed. Surprisingly, after induction the product was found almost exclusively in the culture medium. Variants of PSTI with Asp or Asn at aa positions 21 and 29 [sequences published by Greene et al., Methods Enzymol. (1976) 813-825, and by Yamamoto et al., Biochem. Biophys. Res. Commun. (1985) 605-612] showed the same Ki for both human and porcine trypsin.

Newborn screening for cystic fibrosis is complicated by age-related decline in immunoreactive trypsinogen levels.

Detection of elevated levels of immunoreactive trypsinogen (IRT) in dried neonatal blood spots has been used as a screening test for cystic fibrosis. In other cystic fibrosis newborn-screening studies, a sweat chloride test is generally performed only if an infant has a persistent IRT level above a selected cutoff value on both the initial and subsequent specimens. Neither the timing of the second specimen nor the value of the cutoff point for the second specimen has been comprehensively evaluated. In this randomized, controlled study, 145,024 infants were screened in the neonatal period for cystic fibrosis using the 99.8 percentile (180 ng/mL) as the neonatal cutoff point. A total of 129 infants had elevated neonatal IRT levels and had negative results on sweat tests (false-positive by IRT screening). A total of 54 children with cystic fibrosis were identified in the screened and comparison groups. Excluding patients with meconium ileus, 4 infants with cystic fibrosis had neonatal IRT values less than 180 ng/mL, and an additional 9 infants with cystic fibrosis had values decline to less than 180 ng/mL within the first 2 1/2 months of age. The IRT values of infants with and without cystic fibrosis overlapped considerably beyond 30 days of age. These findings suggest that further refinement of cystic fibrosis screening methodology will be necessary to achieve an acceptable sensitivity and specificity.

Extracellular and membrane-bound beta lactamase of Staphylococcus aureus: their importance for the expression of penicillin resistance.

The synthesis and excretion of beta lactamase by several strains of Staphylococcus aureus from different clinical sources and the ability of both the extracellular and membrane-bound enzyme to mediate penicillin resistance was studied. When beta-lactamase production was maximally induced with penicillin G or ampicillin, about 50% of the beta lactamase was excreted from the cells, the amount of extracellular enzyme correlating well with the degree of resistance established by an in-vitro test model. From penicillin-binding experiments it became apparent, however, that the membrane-bound beta lactamase can also constitute a barrier, strong enough on its own to prevent penicillins from reaching their target. This could be of clinical relevance if, under certain conditions in vivo, the extracellular beta lactamase is insufficient for full protection of the staphylococcal cells.

Development of a medical-psychiatric program within the private sector. Potential problems and strategies for their resolution.

Recent reports regarding the development of combined medical-psychiatric units have primarily involved units operated under the auspices of academic medical centers. Almost no published information is available regarding the fiscal, administrative, or clinical feasibility of operating such programs within the context of the private community hospital setting. This article outlines the organization and development of such a private unit and discusses the various medical, administrative, political, and financial considerations that must be evaluated in planning for the successful operation of medical-psychiatric units within the private sector.

Immunoreactive trypsinogen screening for cystic fibrosis: characterization of infants with a false-positive screening test.

Blood immunoreactive trypsinogen (IRT) is elevated in newborns with cystic fibrosis (CF) and has been used as a neonatal screening test. However, not only is the benefit of early diagnosis unknown, but also the sensitivity, specificity, and time related decline of IRT values have yet to be comprehensively evaluated. This report describes the characteristics of infants with a false-positive IRT in our experience with CF screening of 87,000 infants. The IRT value was elevated in 92 newborns; 13 had a confirmed diagnosis of CF by quantitative pilocarpine iontophoresis sweat testing, and 79 infants did not have CF and were therefore classified as false positives by IRT screening. In order to test the hypothesis that perinatal stress factors are associated with high neonatal IRT values, we evaluated Apgar scores at 1 and 5 minutes. We found that the scores of false-positive infants were significantly lower (P = 0.0004 and P = 0.0102 at 1 and 5 minutes, respectively), compared with infants in the general population. While perinatal asphyxia as reflected by low Apgar scores is an associated factor accounting for an elevated IRT value, the majority of non-CF newborns with an elevated IRT have normal Apgar scores.

Parents' knowledge of neonatal screening and response to false-positive cystic fibrosis testing.

Neonatal screening for cystic fibrosis (CF) has become feasible through analyzing dried blood specimens for immunoreactive trypsinogen (IRT), but the benefits and risks of such a screening program remain to be delineated. This study, a survey of the parents of 104 Wisconsin infants with false-positive IRT tests, showed parents had knowledge deficits about neonatal screening in general, misconceptions about test results, and high levels of anxiety. Parenting behaviors were reportedly unchanged during the usual 3-day waiting period between the news of the abnormal screening test and the diagnostic sweat test. Most, but not all, parents were relieved by negative sweat test results subsequent to the abnormal IRT test. Factors associated with continued parental concern included having less than a high school education and/or having an infant with low Apgar scores. Additionally, those contacted by telephone were more likely to have misinformation and lingering concerns about the presence of CF in their child.

Current issues in neonatal screening for cystic fibrosis and implications of the CF gene discovery.

Many questions remain regarding the efficacy, toxicity, and costs of CF neonatal screening. It would be premature, in our opinion, to implement mass population screening of newborns for CF until the benefits and risks have been fully defined, and an adequate and logistically feasible testing system developed and/or highly effective therapy for CF lung disease becomes available. In addition, the ethical issues described herein need to be resolved. This pertains not only to the CF patient but also the heterozygote carrier. These reservations notwithstanding, the discovery of the CF gene should have a favorable impact both directly and indirectly on neonatal screening for the disease. Mutation analysis coupled to IRT testing seems most attractive at this time, at least on a research basis, but primary molecular diagnostic procedures might supervene in the future, particularly if they are financially feasible.

DIABETEX decision module 2--calculation of insulin dose proposals and situation recognition by means of classifiers.

Current research in the field of medical decision making tries to represent and to analyse complex, uncertain and complicated situations. The first version of DIABETEX, which is a decision support system for the treatment of diabetic out-patients, accepts the challenge to overcome these difficulties. It includes a network of rules on the basis of known glucose-insulin relationships under different situations. The insulin dose for type I diabetic patients is suggested accordingly. In this, the application of special cybernetic methods offers the chance to overcome complexity, uncertainty, fuzzyness and incompleteness of data. Two methods of classification are presented to complete the DIABETEX decision unit: (1) the Bayes' classification is used in the calculation of insulin doses for type I diabetic patients on multiple subcutaneous insulin injections considering the basis-bolus concept; (2) fuzzy classification is employed in separating 'normal diabetic days' from days with information on special situations such as exercise, illness, menstruation on the one side, from stress, hypoglycaemia etc. on the other.

DIABETEX--a decision support system for therapy of type I diabetic patients.

DIABETEX is a knowledge-based, computer-supported consultation system for the therapy of type I diabetic out-patients. Three knowledge bases contain the medical and technical knowledge for treating either adults, adolescents or children by means of injections or by pumps. For the evaluation of the quality of the decision proposals three groups of patients were studied. The results obtained in test phase 1, i.e. the retrospective evaluation of DIABETEX decision proposals by the experts, and in test phase 2, i.e. the parallel work of DIABETEX and of an expert and the subsequent evaluation by experts, provide the basis for the further development and application of the system by non-expert diabetologists.

Lower limb injuries in children in sports.

This article presents an overview of sports-related injuries of the lower limb in children, with emphasis on the management. The special injury-related conditions of childhood, epidemiology, and the particular pattern of injuries are discussed. The increased participation of children in sports will continue. Permanent damage is a risk, and, as such, prevention should be the most important management in this age group. For example, stretching exercises should be performed with "warm" muscles. Excessive weight training has an unacceptable risk of injury. In endurance sports, the "10 percent rule," which consists of increasing activity by 10% each week, probably could be applied to prevent overuse injuries. A multifactorial approach may be helpful. The rationale for high performance, competitive sports for children is doubtful. The optimal levels of safe training will remain changeable and not predictable. It should be the responsibility of parents, coaches, and healthcare professionals to try and minimize the potential for injury and disability, and allow children to enjoy the benefits of sports.