The order of islet microvascular cellular perfusion is B----A----D in the perfused rat pancreas.

In order to determine whether microvascular blood flow is important in the regulation of intra-islet cellular interactions, rat pancreata were isolated and perfused in vitro, both anterogradely or retrogradely, with and without anti-insulin or anti-somatostatin gamma-globulin. Expressed as percent change, anterograde infusion of insulin antibody increased efflux concentrations of glucagon (110 +/- 20%, P less than 0.0005) and somatostatin (2,112 +/- 73%, P less than 0.0005) above their respective control. Retrograde infusion of insulin antibody did not affect efflux concentrations of glucagon (P less than 0.50) or somatostatin (P less than 0.50). The anterograde infusion of anti-somatostatin antibody had no effect upon insulin (P less than 0.50) or glucagon (P less than 0.50) efflux concentrations, whereas retrograde anti-somatostatin antibody infusion produced immediate increases in efflux concentrations of both insulin (115 +/- 33%, P less than 0.0005) and glucagon (77 +/- 8%, P less than 0.0005). These results strongly suggest that (a) the vascular compartment is important in the regulation of intra-islet cellular interactions and further suggest that (b) the order of islet cellular perfusion and interaction is from the B cell core outward to the mantle, and (c) the mantle is further subordered with the majority of D cells downstream or distal to the majority of A cells. Thus, in the vascular compartment, B cells inhibit A-cell secretion and A cells stimulate D-cell secretion.

Effect of lectins on hormone release from isolated rat islets of langerhans.

Lectins from Agaricus bisporus and Agaricus campestris stimulate insulin and glucagon release from isolated rat islets in the presence of 2 mM glucose. In the case of insulin release, maximal stimulation was observed at lectin concentrations above 58 mug. per milliliter (approximately 1 muM).A. bisporus PHA-B-stimulated insulin release was independent of a source of metabolic energy but was abolished by deuterium oxide. The lectin did not alter islet glucose oxidation to CO2 or incorporation of [3H] leucine into trichloracetic acid-precipitable material nor did it modify rates of insulin secretion induced by 20 mM glucose. None of nine other lectins tested stimulated insulin release, whereas stimulation of fat cell glucose oxidation was a general property of the lectins. Binding of 125I-labeled A. bisporus PHA-B to islets increased with time up to one hour and after attainment of equilibrium was very slowly reversible. Binding was directly proportional to islet number and the estimated Kdiss of the binding reaction was 17 mug per milliliter. The total number of A. bisporus PHA-B binding sites per islet was approximately 2 times 10(10). Binding of A. bisporus PHA-B to the islets and A. bisporus PHA-B-stimulated insulin release were inhibited in parallel by a glycopeptide containing the oligosaccharide receptor for the lectin, suggesting that lectin binding is essential for the expression of insulin-releasing activity. It is proposed that the specific interaction between mushroom lectin and its receptors may lead to conformational changes in the structure of the membranes of the islet A2- and B-cells that facilitate exocytosis.

Rat islet mitochondrial adenine nucleotide translocase and the regulation of insulin secretion.

Employing a preparation of rat islet mitochondria, phosphoenolpyruvate has been shown to interact with the mitochondrial adenine nucleotide translocase. Thus, phosphoenolpyruvate inhibited mitochondrial uptake of [14C]ADP and exchanged with intramitochondrial [14C]ATP. A concentration-dependent inhibition of islet mitochondrial 45Ca2+ accumulation was seen when mitochondria were exposed to phosphoenolpyruvate with half-maximal inhibition observed at a phosphoenolpyruvate concentration of 0.2 mM. In experiments employing whole islets, phosphoenolpyruvate content was shown to be significantly elevated at both 1 and 30 min after an increase in the medium glucose concentration from 2 to 20 mM. In these experiments, the estimated islet concentrations of phosphoenolpyruvate fell in the range of maximal sensitivity of the islet adenine nucleotide translocase to phosphoenolpyruvate-induced inhibition of Ca2+ accumulation. It is concluded that increased concentrations of islet phosphoenolpyruvate resulting from increased extracellular glucose concentration may act to trigger or promote glucose-stimulated insulin secretion by modifying the distribution of Ca2+ between the islet cytosolic and mitochondrial compartments in a transport reaction catalyzed by the adenine nucleotide translocase.

Neuroendocrine control of insulin secretion.

The effects of thyrotropin-releasing hormone, luteinizing hormone-releasing hormone, substance P, somatostatin, and a partially purified hypothalamic extract on insulin secretion were tested both in vitro and in vivo. Only somatostatin and the hypothalamic extract affected insulin secretion. In vitro, somatostatin decreased glucose-stimulated insulin secretion by isolated islets and in vivo significantly reduced the rate of insulin output into the portal vein. The hypothalamic extract significantly stimulated insulin secretion in both systems. These effects in vivo were independent of glucose concentration. Islets preincubated for four hours responded better in vitro to the hypothalamic extract stimulation and the somatostatin inhibition.

Hypothalamic regulation of insulin release in rhesus monkeys.

Evidence of a neurohumoral factor capable of stimulating insulin and glucagon secretion was found in perfusates from ventrolateral hypothalamus (VLH) of rhesus monkeys. The perfusates from the VLH were collected via push-pull cannulas and injected into the peripheral circulation. Increase in portal insulin and glucagon was observed following the injection of six different perfusates. The amount of insulin released from isolated rat islets incubated with perfusates was significantly increased at glucose concentrations greater than 5 mM. The perfusates from the VLH appear to have effects on insulin and glucagon secretion that are opposite those of somatostatin.

C-peptide and the classification of diabetes mellitus patients in the Early Treatment Diabetic Retinopathy Study. Report number 6. The ETDRS Research Group.

The Early Treatment Diabetic Retinopathy Study (ETDRS), conducted at 22 clinical centers during the period 1980 to 1989, collected baseline data on C-peptide levels after ingestion of Sustacal in 582 patients with diabetes mellitus, prior to enrollment in the trial. Data on several clinical factors associated with diabetes were also collected from all 3711 enrolled patients. C-peptide data were used to develop sets of clinical criteria for the classification of ETDRS patients and to compare and contrast definitions of type of diabetes used in previous studies. The distribution of C-peptide levels was strikingly bimodal, suggesting a division of study participants into two groups--those with levels at 80 pmol/L or less and those with more than 80 pmol/L of C-peptide after Sustacal ingestion. Constellations of clinical characteristics that could serve as proxies for C-peptide level were ascertained. The result was two sets of clinically developed definitions for type of diabetes in the ETDRS. According to the more restrictive set of definitions, three groups were identified, compared to two groups using the "broad" set of definitions. Discriminant analysis was also used to classify ETDRS patients, yielding similar results. A comparison of definitions of type of diabetes used in the ETDRS and in previous studies revealed that even in the absence of C-peptide data, clinically derived definitions provided good discrimination between type I and type II diabetes.

Inhibition of adenosine 3',5'-cyclic monophosphate phosphodiesterase by colchicine: implications for glucagon and corticosteroid secretion.

In the study reported, colchicine, often regarded as a specific inhibitor of microtubular function, was shown to exert a concentration-dependent inhibition of the low Km cyclic AMP phosphodiesterases of the pancreatic islet, adrenal cortex and various other tissues of the rat. The results indicated that colchicine is only slightly less active as an inhibitor of the enzyme than theophylline on a molar basis and kinetic analysis revealed that both inhibitors acted competitively in the case of the liver enzyme. Our results show that the inhibitory effect of colchicine upon cyclic AMP phosphodiesterase is a general property of the alkaloid at concentrations of 5 x 10(-5)M and above in both endocrine and non-endocrine tissues. Thus, results obtained employing colchicine at concentrations significantly greater than those which are known to lead to microtubular disaggregation must be viewed with great caution if incorrect implication of microtubular participation in biological processes is to be avoided. For example, we propose that the previously reported paradoxical stimulatory effects of colchicine on the secretion of glucagon from the rat pancreatic islet and on steroidogenesis in the rat adrenal may be due to cyclic AMP accumulation consequent upon phosphodiesterase inhibition in these endocrine tissues and not to microtubular disaggregation as has hitherto been assumed.

Myasthenia gravis in conjunction with Graves' disease: a diagnostic challenge.

OBJECTIVE: To describe an association between Graves' disease and myasthenia gravis and discuss the clinical features and laboratory tests that may help distinguish these two diseases. METHODS: The clinical, laboratory, and electrophysiologic findings in a patient with Graves' disease and myasthenia gravis are presented. RESULTS: A 28-year-old African American man was admitted to the University of Louisville Hospital with generalized muscle weakness, exophthalmos, diplopia, weight loss, and mild dysphagia. The diagnosis of Graves' disease with ophthalmologic involvement was suspected clinically and confirmed by an undetectable thyrotropin level (<0.03 mIU/mL), high total thyroxine (20.5 mg/dL), and increased homogeneous 123I thyroid uptake. Because of the generalized muscle weakness and mild dysphagia, assessment was done by a neurology team, and severe thyrotoxic myopathy was diagnosed. He was treated with 131I and b-adrenergic blocking agents and scheduled for follow-up as an outpatient. Two weeks later, the patient presented in acute respiratory failure. The neurology team was reconsulted because of suspected myasthenic crisis. Anti-acetylcholine receptor antibodies were undetectable in the serum, and computed tomography of the chest showed no thymic enlargement. Repetitive nerve stimulation testing, however, showed findings consistent with an abnormality of the neuromuscular junction. The patient responded dramatically to an anticholinesterase agent and corticosteroids. CONCLUSION: The overlapping clinical features may cause diagnostic confusion when myasthenia gravis and Graves' disease coexist, and numerous tests may be needed to distinguish these two conditions, which have differing treatments and prognoses.

A simple method for serving Web hypermaps with dynamic database drill-down.

BACKGROUND: HealthCyberMap http://healthcybermap.semanticweb.org aims at mapping parts of health information cyberspace in novel ways to deliver a semantically superior user experience. This is achieved through "intelligent" categorisation and interactive hypermedia visualisation of health resources using metadata, clinical codes and GIS. HealthCyberMap is an ArcView 3.1 project. WebView, the Internet extension to ArcView, publishes HealthCyberMap ArcView Views as Web client-side imagemaps. The basic WebView set-up does not support any GIS database connection, and published Web maps become disconnected from the original project. A dedicated Internet map server would be the best way to serve HealthCyberMap database-driven interactive Web maps, but is an expensive and complex solution to acquire, run and maintain. This paper describes HealthCyberMap simple, low-cost method for "patching" WebView to serve hypermaps with dynamic database drill-down functionality on the Web. RESULTS: The proposed solution is currently used for publishing HealthCyberMap GIS-generated navigational information maps on the Web while maintaining their links with the underlying resource metadata base. CONCLUSION: The authors believe their map serving approach as adopted in HealthCyberMap has been very successful, especially in cases when only map attribute data change without a corresponding effect on map appearance. It should be also possible to use the same solution to publish other interactive GIS-driven maps on the Web, e.g., maps of real world health problems.

Integrating model-based decision support in a multi-modal reasoning system for managing type 1 diabetic patients.

We present a multi-modal reasoning (MMR) methodology that integrates case-based reasoning (CBR), rule-based reasoning (RBR) and model-based reasoning (MBR), meant to provide physicians with a reliable decision support tool in the context of type 1 diabetes mellitus management. In particular, we have implemented a decision support system that is able to jointly exploit a probabilistic model of the glucose-insulin system at the steady state, a RBR system for suggestion generation and a CBR system for patient's profiling. The integration of the CBR, RBR and MBR paradigms allows for an optimized exploitation of all the available information, and for the definition of a therapy properly tailored to the patient's needs, overcoming the single approaches limitations. The system has been tested both on simulated and on real patients' data.

Towards knowledge-based systems in clinical practice: development of an integrated clinical information and knowledge management support system.

Given that clinicians presented with identical clinical information will act in different ways, there is a need to introduce into routine clinical practice methods and tools to support the scientific homogeneity and accountability of healthcare decisions and actions. The benefits expected from such action include an overall reduction in cost, improved quality of care, patient and public opinion satisfaction. Computer-based medical data processing has yielded methods and tools for managing the task away from the hospital management level and closer to the desired disease and patient management level. To this end, advanced applications of information and disease process modelling technologies have already demonstrated an ability to significantly augment clinical decision making as a by-product. The wide-spread acceptance of evidence-based medicine as the basis of cost-conscious and concurrently quality-wise accountable clinical practice suffices as evidence supporting this claim. Electronic libraries are one-step towards an online status of this key health-care delivery quality control environment. Nonetheless, to date, the underlying information and knowledge management technologies have failed to be integrated into any form of pragmatic or marketable online and real-time clinical decision making tool. One of the main obstacles that needs to be overcome is the development of systems that treat both information and knowledge as clinical objects with same modelling requirements. This paper describes the development of such a system in the form of an intelligent clinical information management system: a system which at the most fundamental level of clinical decision support facilitates both the organised acquisition of clinical information and knowledge and provides a test-bed for the development and evaluation of knowledge-based decision support functions.

Mammographic screening for breast cancer in women under fifty: a review.

There is currently insufficient scientific data to support the recommendation to begin mammographic screening before the age of 50. The balance of the evidence that does exist suggests that screening before the age of 50 is useless and possibly harmful. If we accept that it is unethical to screen in the absence of good data suggesting benefit, then screening under the age of 50 is unethical.

Primum non nocere and the quality of evidence: rethinking the ethics of screening.

BACKGROUND: Screening is different from investigation, and these differences have important implications in the assessment of screening programs. METHODS: I review the differences between screening and investigation and the implications of these differences derived from a consideration of the four ethical principles of beneficence, nonmaleficence, autonomy, and distributive justice. RESULTS: Because most of the harms of screening fall on the healthy and because screening is initiated by physicians, nonmaleficence takes ethical precedence over beneficence. Issues related to cost and consent are also approached differently in screening compared with investigation, and both take on greater ethical importance. I contend further that these ethical implications require that screening programs be backed up by better evidence than is the usual case for investigative medicine. I suggest an outline for the appropriate assessment of screening programs and for the ethical responsibilities of those involved in screening. CONCLUSIONS: Many current medical screening practices are not concordant with our ethical principles and should be reassessed.

The regulation of growth hormone secretion from the isolated rat anterior pituitary in vitro. The role of adenosine 3':5'-cyclic monophosphate.

1. The release of growth hormone from isolated fragments of rat anterior pituitary tissue incubated in vitro was studied by employing a double-antibody radioimmunoassay. 2. In the absence of added stimuli, two phases of hormone release could be distinguished, an early phase of 2h duration and a subsequent late phase. In the early phase, hormone release was rapid but could be significantly decreased by calcium depletion and by 2,4-dinitrophenol whereas the rate of release in the late phase was uninfluenced by these incubation conditions. These results have been interpreted as indicating the existence of a secretory component in the early phase of release. 3. In subsequent experiments, the effects of various agents on the rate of hormone output during the late phase of incubation were investigated. Hormone release was increased by theophylline and by dibutyryl cyclic AMP (N(6)-2'-O-dibutyryl-adenosine 3':5'-cyclic monophosphate), the response to both of these agents being related to the concentration of the stimulant employed. 4. The stimulation of growth hormone output by theophylline was significantly decreased by calcium deprivation and by 2,4-dinitrophenol. The response to dibutyryl cyclic AMP was diminished by 2,4-dinitrophenol, iodoacetate and 2-deoxyglucose but not by malonate or colchicine. 5. Arginine, beta-hydroxybutyrate, albumin-bound palmitate and variation in the glucose concentration of the incubation medium over a wide range were without any statistically significant effect on the rate of hormone release from either control pituitary fragments or those subject to secretory stimulation by dibutyryl cyclic AMP. 6. It is suggested that the regulation of growth hormone secretion is mediated by cyclic AMP (adenosine 3':5'-cyclic monophosphate). The secretion observed in response to cyclic AMP requires the presence of ionized calcium and a source of metabolic energy but is independent of pituitary protein synthesis de novo. The integrity of the glycolytic pathway of glucose metabolism appears to be essential for cyclic AMP-stimulated growth hormone secretion to occur.

Pregnancy in chronic progressive external ophthalmoplegia: a case report.

The mitochondrial diseases are uncommon multisystem disorders characterized by the presence of functionally and/or structurally abnormal mitochondria. As there have been few reports of the obstetrical care of affected patients, we wish to document two pregnancies in a woman with a Chronic Progressive External Ophthalmoplegia (Kearns-Sayre-like syndrome). Both pregnancies were complicated by preterm labor and hypertension.