Clinical inertia and its impact on treatment intensification in people with type 2 diabetes mellitus.

Many people with type 2 diabetes mellitus (T2DM) fail to achieve glycaemic control promptly after diagnosis and do not receive timely treatment intensification. This may be in part due to 'clinical inertia', defined as the failure of healthcare providers to initiate or intensify therapy when indicated. Physician-, patient- and healthcare-system-related factors all contribute to clinical inertia. However, decisions that appear to be clinical inertia may, in fact, be only 'apparent' clinical inertia and may reflect good clinical practice on behalf of the physician for a specific patient. Delay in treatment intensification can happen at all stages of treatment for people with T2DM, including prescription of lifestyle changes after diagnosis, introduction of pharmacological therapy, use of combination therapy where needed and initiation of insulin. Clinical inertia may contribute to people with T2DM living with suboptimal glycaemic control for many years, with dramatic consequences for the patient in terms of quality of life, morbidity and mortality, and for public health because of the huge costs associated with uncontrolled T2DM. Because multiple factors can lead to clinical inertia, potential solutions most likely require a combination of approaches involving fundamental changes in medical care. These could include the adoption of a person-centred model of care to account for the complex considerations influencing treatment decisions by patients and physicians. Better patient education about the progressive nature of T2DM and the risks inherent in long-term poor glycaemic control may also reinforce the need for regular treatment reviews, with intensification when required.

Hemodynamic, biochemical and morphological changes induced by aminoguanidine in normal and septic sheep.

OBJECTIVE: To define the acute hemodynamic, metabolic, and morphological changes induced by aminoguanidine, a selective iNOS inhibitor, in septic sheep. DESIGN: Prospective, nonrandomized animal study. SETTING: Animal research facility in a University Hospital. INTERVENTIONS: Adult sheep, sedated and mechanically ventilated, were monitored with a pulmonary arterial catheter and an ultrasonic blood flow probe in the mesenteric artery, to measure the systemic (Q(TOT)I) and the mesenteric (Q(MES)I) blood flow indices, and an ileal tonometer. Four groups of sheep were studied: nonseptic, septic, nonseptic treated with aminoguanidine, and septic treated with aminoguanidine (100 mg kg(-1) h(-1)) (n = 6 for each group). Sepsis was induced by the intravenous administration of E. coli. Hemodynamic and biochemical parameters were measured during 300 min. Histological changes in the liver and small intestinal mucosa were analyzed at the end of the experiment. MEASUREMENTS AND MAIN RESULTS: In nonseptic animals, aminoguanidine slightly increased mean systemic arterial pressure (MAP), decreased Q(TOT)I, and increased vascular resistance index (SVRI) and pulmonary vascular resistance index. Q(MEs)I did not change and Q(MES)I/Q(ToT)I increased. Aminoguanidine also induced intestinal intramucosal hypercarbia, hyperlactatemia, acidemia, hypoglycemia, and morphological signs indicative of tissue ischemia in the small intestinal mucosa. In septic sheep, aminoguanidine increased SVRI and MAP only at 4 h after the septic challenge and thereafter, and worsened gas exchange. CONCLUSIONS: In this model, exogenous administration of aminoguanidine induces beneficial hemodynamic effects 4 h after the septic challenge. In normal animals, however, aminoguanidine was associated with hypoglycemia, acidosis, hyperlactatemia, and intestinal mucosal ischemia.

Characterization of the 2-deoxyglucose effect on the adrenocortical axis.

In the present study we examined the mechanisms involved in the activation of the hypothalamo-pituitary-adrenal (HPA) axis after administration of the glucose analog 2-deoxyglucose (2-DG), which inhibits intracellular glucose use. Adult male rats were injected with either 2-DG (400 mg/kg body wt ip) or vehicle and were killed 60 min later. 2-DG increased serum ACTH and corticosterone (CS) by 3- and 7-fold, respectively, as compared to vehicle-treated rats. Bilateral lesions of the lateral hypothalamic area completely inhibited the 2-DG-induced HPA axis activation. Administration of 2-DG caused a significant depletion in the CRF-41 content of the median eminence (ME). Pretreatment with dexamethasone (80 micrograms/kg body wt ip) inhibited the 2-DG-induced depletion of ME CRF-41 and the increase in serum ACTH and CS. To investigate the role of type I and type II corticosteroid receptors in mediating the feedback effect of endogenous glucocorticoids on the responses to 2-DG, specific type I (RU-28318) or type II (RU-38486) receptor antagonists were injected intracerebroventricularly (icv) (1 microgram/kg body wt). In rats pretreated with these antagonists, the recovery of serum ACTH and CS to basal levels after 2-DG was markedly inhibited. Injection of the serotonin (5-HT) neurotoxin, 5,7-dihydroxy-tryptamine, either into the raphe nuclei or icv, which caused a 50 and 70% depletion of the hypothalamic 5-HT content, respectively, did not affect the HPA axis responses to 2-DG. In contrast, icv injection of ketanserin, a 5-HT2 receptor antagonist, completely inhibited the 2-DG-induced activation of the HPA axis. The results suggest that: 1) the lateral hypothalamic area is involved in the mediation of the HPA axis responses to 2-DG; 2) CRF-41 released from the ME plays a dynamic role in mediating the 2-DG-induced adrenocortical response; 3) the effect of 2-DG is sensitive to inhibition by dexamethasone, and the feedback effect exerted by endogenous glucocorticoids is mediated by both type I and type II corticosteroid receptors; and 4) 5-HT is involved in the activation of the HPA axis after 2-DG via its interactions with 5-HT2 receptors.

Monolayer culture of adult rat pancreatic islets on extracellular matrix: modulation of B-cell function by chronic exposure to high glucose.

Studies in vivo indicate that chronic hyperglycemia is deleterious for insulin secretion. We have used an improved islet monolayer culture system to study chronic modulations of B-cell function. Adult rat islets maintained over several weeks on extracellular matrix in the presence of 11.1 mM glucose responded to an acute stimulation with 16.7 mM glucose by a 5- to 8-fold increase in insulin secretion. When cultured in the presence of higher glucose concentrations, the response to an acute glucose stimulus diminished time and dose dependently. In islets desensitized by exposure to 33.3 mM glucose for 1 week, reduction of the glucose level to 11.1 mM reversed the desensitization within 2 weeks. This desensitization was not limited to the glucose stimulus; responses to other nutrient secretagogues, such as glyceraldehyde and alpha-ketoisocaproic acid, were also reduced. In contrast, responses of insulin secretion to nonnutrient stimulators (tolbutamide and quinine) and amplifiers (isobutylmethylxanthine and carbachol) showed no desensitization in islets exposed to 33.3 mM glucose. Desensitization similar to that caused by 33.3 mM glucose could be induced by 11.1 mM glucose together with 0.1 mM isobutylmethylxanthine. High glucose also caused a time-dependent loss in compact monolayer organization with disruption of cell contacts. Our studies suggest that 1) generation of the reduced insulin response may be related to the prolonged high insulin secretion rate; 2) expression of the functional change is specific to the nutrient stimulus-secretion coupling; and 3) modifications in intercellular contacts may be involved in B-cell desensitization.

Regulation of insulin release in persistent hyperinsulinaemic hypoglycaemia of infancy studied in long-term culture of pancreatic tissue.

Pancreatic tissue was obtained during therapeutic subtotal pancreatectomy from five infants with persistent hyperinsulinaemic hypoglycaemia of infancy (so-called nesidioblastosis). Collagenase digests of the specimens were cultured in RPMI 1640 medium on extracellular matrix-coated plates. Acute insulin secretion showed minimal sensitivity to changes in glucose concentration. Sensitivity to other nutrient secretagogues such as glyceraldehyde, leucine, alpha-ketoisocaproic acid and arginine was variable, showing either diminished or absent response. On the other hand, stimulators of Beta cell cAMP and modulators of the phosphoinositide-protein kinase C pathway were effective inducers of insulin release. The response to cAMP stimulators was independent of the glucose concentration. Although insulin output was high in the absence of glucose, this was not due to passive leak of hormone, since both removal of calcium and addition of somatostatin and epinephrine inhibited the secretion. Beta cells were more sensitive to somatostatin than epinephrine; however, both agents failed to completely suppress the release even at suprapharmacological concentrations. Although it cannot be excluded that the culture conditions affected Beta cell function, the present findings may suggest that cultured Beta cells in persistent hyperinsulinaemic hypoglycaemia of infancy behave like fetal Beta cells at early developmental stages.

Long QT syndrome and complete situs inversus. Preliminary report of a family.

The familial long QT syndrome is a rare condition that may occur with or without deafness. Dextrocardia with complete situs inversus is a familial syndrome generally found in normal subjects with a high incidence of consanguinity among the parents. In this report we describe a Jerbian family with both disorders and with several cases of sudden death. Of 27 members of this family (3 generations) in whom ECG was performed, 15 had QT prolongation (QTc greater than 0.45). Four members (2 generations) had complete situs inversus, 3 of them also had ECG evidence of QT prolongation. The combined occurrence of these rare diseases within the same family has not been previously reported. It may be due to the high incidence of consanguinity and may raise the possibility that the loci responsible for the 2 conditions are closely related and located on the same chromosome. A more extensive study of the family is being carried out.

Monolayer culture of adult rat pancreatic islets on extracellular matrix: long term maintenance of differentiated B-cell function.

Fragmented islets, obtained by mild overdigestion of the adult rat pancreas with collagenase, readily formed monolayer cultures on dishes coated with extracellular matrix derived from bovine corneal endothelial cells. Contaminating fibroblasts were removed by treatment with sodium ethylmercurithiosalicylate. The cultured islets remained functional for over 6 weeks in primary culture and up to 9 weeks in secondary culture, as indicated by their substantial insulin response to an acute glucose stimulus. Insulin secretion from islet monolayers showed biphasic kinetics. The functional competence of the monolayers was further evaluated by studying glucose-stimulated insulin release in the presence of various modulators of B-cell function. The response to physiological agents such as somatostatin, epinephrine, glucagon, and arginine was retained for at least 4 weeks in culture. The sensitivity to inhibition by somatostatin and epinephrine (ID50 = 10 ng/ml) and that to stimulation by glucagon (ED50 = 3 ng/ml) were similar to or better than those for freshly isolated islets. We have thus obtained a fibroblast-free monolayer culture of pancreatic islets from adult rats containing B-cells that retain normal function for long periods. This experimental system appears ideally suited for studying chronic modulations of islet cell function under controlled in vitro conditions, which can allow the stimulation of normal and diabetic environments.

Role of de Vries in the rediscovery of Mendel's paper. II. Did de Vries really understand Mendel's paper?

In this paper, we discuss briefly three of the several lines of evidence that we believe demonstrate de Vries's lack of understanding of Mendel's paper. In our view, at least part of de Vries's failure of understanding derives from the fact that he appears to have viewed Mendel's paper as being mainly about the inheritance of characters that was his own interest. Therefore, he looked at it to see whether Mendel had found any laws of inheritance. Mendel had done his research for another purpose, to find the laws describing the formation of hybrids and the development of their offspring. Thus, de Vries started his examination of Mendel's paper with a very fundamental misunderstanding of what it was about.

Tschermak: a non-discoverer of mendelism. II. A critique.

An examination of Tschermak's two papers of 1900 not only reinforces our conclusion cited in our first paper on Tschermak that he was not a rediscoverer of Mendelism, but also he did not understand Mendel when he had read it. His concept of dominance differed from that of Mendel, and his use of his own concept is inconsistent and contradictory. His discussion of his backcross data indicated that he had no idea of the nature of Mendelian ratios. Nowhere did he develop the ideas of segregation and independent assortment.

Reexamination of the fate of Mendel's paper.

The usual account is that when Mendel gave his paper, no one understood what he said and there were no questions and no discussion. Examination of available evidence indicates that this is not true. Also, it is usually said that Mendel's paper was lost or ignored from 1866 to 1900. This is not true either. However, with the possible exception of one person, none of those citing the paper showed any interest in or understanding of Mendel's explanations of his results.

Why do so few diabetic patients attend dialysis centers in central Italy?

We report the prevalence of end-stage diabetic nephropathy treated by hemodialysis in the Lazio region, which includes the City of Rome, with a total population of over 5 million people. The percentage of diabetic patients among those attending the dialysis centers was 5% (n = 59), which is below the figures reported for both Northern Europe or Southern Italy (Sicily). A higher number (40%) of patients were affected by non-insulin treated diabetes. This figure is similar to that reported in Southern Italy, but highly discordant from the Northern European data where the large majority of diabetics on hemodialysis are affected by insulin-treated diabetes. Genetic differences and the type of diet may account for the difference in prevalence of end-stage nephropathy between Northern and Southern Caucasians affected by diabetes.