Aims: Compare characteristics, therapies and clinical outcomes in older adults with type 1 diabetes in the United States T1D Exchange (T1DX) and German/Austrian Diabetes Patienten Verlaufsdokumentation (DPV) registries.Methods: Cross-sectional study of adults >= 60 years old with type 1 diabetes seen in 2011-2012 in the T1DX (n = 1283) and DPV (n = 2014) registries. Wilcoxon rank-sum test was used for continuous variables and chi-square test for categorical variables. Adjusted analyses used generalized linear models.Results: Individuals in both registries were similar in body mass index (mean 27 kg/m(2)), percent with obesity (25%) and gender (48% male). In T1DX there was longer diabetes duration (32.3 vs. 28.8 years), greater use of antihypertensive medications (including ACE-I and ARBs; 85% vs. 62%), statins (68% vs. 40%), aspirin (77% vs. 21%), insulin pumps (58% vs. 18%), and less smoking (7% vs. 10%); lower adjusted mean LDL-cholesterol (84 vs. 109 mg/dL), and lower adjusted mean systolic and diastolic blood pressures (128 vs. 136 and 68 vs. 74 mmHg); fewer myocardial infarctions (6% vs. 9% [99% CI of difference, 1% to 5%]), strokes (2% vs. 8% [3% to 7%]), microvascular complications including microalbuminuria (17% vs. 44% [22% to 32%]) but increased depression (16.1% vs. 8.7%). Adjusted mean HbA1c levels were similar (7.5%, 58 mmol/mol).Conclusions: Differences between the registries included greater use of antihypertensives, statins and insulin pumps, and fewer chronic complications in the T1DX. Further research is needed to better understand the role of intensive therapy in improving outcomes in older adults with type 1 diabetes. (C) 2016 Elsevier Ireland Ltd. All rights reserved.

BACKGROUND:We investigated the rate of severe hypoglycemic events and confounding factors in patients with type 2 diabetes treated with sulfonylurea at specialized diabetes centers, documented in the German/Austrian DPV-Wiss database. METHODS:Data from 29 485 sulfonylurea-treated patients were analyzed (median[IQR] age 70.8[62.2-77.8] years, diabetes duration 8.2[4.3-12.8] years). The primary objective was to estimate the event rate of severe hypoglycemia (requiring external help, causing unconsciousness/coma/convulsion and/or emergency hospitalization). Secondary objectives included exploration of confounding risk factors through group comparison and Poisson regression. RESULTS:Severe hypoglycemic events were reported in 826(2.8%) of all patients during their most recent year of sulfonylurea treatment. Of these, n = 531(1.8%) had coma, n = 501(1.7%) were hospitalized at least once. The adjusted event rate of severe hypoglycemia [95%CI] was 3.9[3.7-4.2] events/100 patient-years (coma: 1.9[1.8-2.1]; hospitalization: 1.6[1.5-1.8]). Adjusted event rates by diabetes treatment were 6.7 (sulfonylurea + insulin), 4.9 (sulfonylurea + insulin + other OAD), 3.1 (sulfonylurea + other OAD) and 3.8 (sulfonylurea only). Patients with ≥1 severe event were older (p < 0.001) and had longer diabetes duration (p = 0.020) than patients without severe events. Participation in educational diabetes-programs and indirect measures of insulin-resistance (increased BMI, plasma-triglycerides) were associated with fewer events (all p < 0.001). Impaired renal function was common (n = 3113 eGFR; ≤30 mL/min) and associated with an increased rate of severe events (≤30 mL/min: 7.7; 30-60 mL/min: 4.8; >60 mL/min: 3.9). CONCLUSIONS:These real-life data showed a rate of severe hypoglycemia of 3.9/100 patient-years in sulfonylurea-treated patients from specialized diabetes centers. Higher risk was associated with known risk factors including lack of diabetes education, older age and decreased eGFR but also with lower BMI and lower triglyceride levels, suggesting that sulfonylurea treatment in those patients should be considered with caution.

OBJECTIVE:This study aimed to analyze the effect of HbA1c variability on the occurrence of diabetic retinopathy in type 1 diabetes patients.PATIENTS AND METHODS:35,891 patients with childhood, adolescent or adult onset of type 1 diabetes from a large multicentre survey, the German/Austrian prospective documentation system (DPV), were analysed. Cox proportional hazard models were used to examine whether intra-individual HbA1c variability expressed as variation coefficient is an independent risk factor for the occurrence of diabetic retinopathy.RESULTS:Kaplan-Meier curves stratified by median HbA1c and variation coefficient revealed that retinopathy-free survival probability is lower when both median HbA1c and HbA1c variability are above the 50th percentile. Cox regression models confirmed this finding: After adjustment for age at diabetes onset, gender and median HbA1c, HbA1c variability was independently associated with the occurrence of diabetic retinopathy. Time-covariate interactions used to model non-proportionality indicated an effect decreasing with duration of diabetes for both median HbA1c and HbA1c variability. Predictive accuracy increased significantly when adding HbA1c variability to the Cox regression model.CONCLUSIONS:In patients with type 1 diabetes, HbA1c variability adds to the risk of diabetic retinopathy independently of average metabolic control.

As reported earlier, deoxycytidine (dC) antagonizes the effect of a natural growth inhibitor, isolated from bovine mammary gland, on mouse Ehrlich ascites carcinoma cells in the same way as the polypeptide growth factors insulin and epidermal growth-factor (EGF) do [6]. Bhalla et al. [1] found that this nucleoside is able to overcome the inhibitory effect of acidic isoferritin, prostaglandin E1 and leukemia inhibitory factor on colony-forming unit-granulocyte macrophage (CFU-GM). Moreover, these authors found that dC stimulates the growth of CFU-GM. We demonstrated [8] that dC antagonizes the effect of the hemoregulatory pentapeptide, described by Kreja et al. [3], and of an inhibitor of colony-forming unit-spleen (CFU-S), described by Lord et al. [7]. Again, dC effects were identical to those of insulin and EGF in these systems.

At suboptimal concentrations of granulocyte-macrophage colony-stimulating factor (GM-CSF), nucleobases and nucleosides as well as their analogues strongly stimulated aggregate (colony and cluster) formation from murine bone marrow granulocyte-macrophage colony-forming units (CFU-GM) in agar culture. Active compounds include 2'-deoxycytidine, thymidine, 5'-deoxyarabinosyl-cytosine, 5'-deoxy-5'-fluorothymidine, uracil, 6-methyluracil, orotic acid, and also purine derivatives as adenine, guanine, adenosine, and guanosine. The stimulation was almost identical to that obtained with the dimer of the hemoregulatory pentapeptide. In the absence of colony-stimulating factor (CSF) no stimulation was seen. After separation of adherent cells from the bone marrow cells, the stimulatory effect was lost. It also decreased when the number of bone marrow cells plated was diminished. This suggests that the tested compounds induce growth factor production in adherent cells. The structure/activity relationships indicate that the active compounds are nucleosides, or they may serve for nucleoside synthesis inside the cell. However, nucleotide formation is not necessary for activity.

An inhibitory activity for the proliferation of granulocyte-macrophage colony-forming cells (GM-CFC) of mouse bone marrow in soft-agar cultures was partly purified from rat bone marrow conditioned medium by ultrafiltration and gel chromatography. It was selective in that it also inhibited the proliferation of myeloid but not that of lymphatic mouse leukaemia cells. Even at strong (greater than 60%) inhibition of the formation of cell clones (colonies + clusters) the colony-to-cluster ratio (CClR) remained as in the controls. The data point to a long-lasting and selective effect of the inhibitor on the GM-CFC without influence on the proliferation of its progeny. This conclusion is confirmed by the temporal development of the inhibitory effect in the course of culture. The determination of the CClR enables one to discriminate between proliferation modulating effects (CClR alteration) and those acting via ON/OFF-switching mechanisms (CClR constancy) influencing the clone forming efficiency at all.

The growth of granulocyte-macrophage colony forming cells (GM-CFC) from mouse bone marrow was studied in agar cultures in glass capillaries. Under standard conditions with normal bone marrow a specific total number of cell clones (colonies + clusters) and also a specific colony-to-cluster ratio (CClR) was found for each of 4 different mouse strains. Both parameters were studied in tumour-bearing mice and found to be influenced independently and, in part, in an opposite way. Thus, for bone marrow of mice with the Ehrlich ascites carcinoma an inhibition of clone formation was found whereas the growth of those clones still formed was stimulated (only colonies present). "Natural" inhibitors as present in uraemic serum added to the cultures decreased the number of clones without altering the CClR. The same is true for the inhibitors in CSF-containing endotoxin serum. On the other hand, inhibitors such as spermine or the synthetic 3'-deoxy-3'-fluorothymidine depressed the clone formation as well as the growth rate of the clones (relative increase of clusters and decrease of colonies). It is concluded that the sensitivity of the GM-CFC against various influences may differ from that of the cells in the clones they form; therefore, the determination of the CClR will provide a more refined interpretation of influences on the haematopoietic system.

The following aspects of action of a chalone-like factor for the Ehrlich ascites mammary carcinoma and of the granulocytic chalone are discussed: 1) Dependence on the state of proliferation. Rapidly growing cells respond poorly or not at all. 2) Antagonism with growth factors. The factor for the Ehrlich ascites mammary carcinoma is antagonized by physiological concentrations of insulin or by proinsulin. The granulocytic chalone is antagonized by colony stimulating factor. 3) Influence on cell cycle progression. Attempts and problems to analyse this influence for the factor for the Ehrlich ascites mammary carcinoma by flow cytometry are described.

Prenalterol, a beta 1 selective agonist, exerts a positive inotropic action in animal studies as well as in human volunteers and is effective when administered orally. To assess its immediate haemodynamic and myocardial metabolic effects, we studied the response to prenalterol (50 and 100 micrograms kg-1 given intravenously by cardiac catheterization) in 15 patients with congestive heart failure secondary to coronary artery disease or non-ischaemic cardiomyopathy. At peak effect, cardiac index increased from 2.6 +/- 0.5 to 3.2 +/- 0.8 l min-1 m2 (mean +/- S.D.) (P less than 0.001); peak rate of left ventricular pressure development rose from 963 +/- 242 to 1335 +/- 411 mmHg s-1 (P less than 0.001); left ventricular end-diastolic pressure fell from 25 +/- 6 to 17 +/- 7 mgHg (P less than 0.001); coronary sinus blood flow increased from 113 +/- 39 to 148 +/- 55 ml min-1 (P less than 0.01); myocardial oxygen consumption was augmented from 12.7 +/- 3.9 to 16.4 +/- 5.8 ml min-1 (P less than 0.001); and heart rate increased slightly (from 76 +/- 12 to 86 +/- 14 beats min-1; (P less than 0.05)). No significant changes occurred in left ventricular systolic pressure, stroke volume index, myocardial lactate extraction rate and myocardial arteriovenous oxygen difference, and no patients developed angina, ECG changes or ventricular arrhythmias. Infusion of prenalterol effectively improved haemodynamic function and cardiac metabolism in cardiomyopathy. Therefore this agent deserves further investigation to evaluate its possible role for the long-term therapy of patients with chronic heart failure.

To assess the immediate haemodynamic and myocardial metabolic effects of the beta 1-agonist prenalterol, we studied by cardiac catheterisation the response to 50 and 100 micrograms/kg given intravenously in 16 patients with congestive heart failure secondary to coronary artery disease or non-ischaemic cardiomyopathy. At peak effect, cardiac index increased from 2.6 +/- 0.5 to 3.2 +/- 0.8 1/min/m2 (mean +/- SD) p less than 0.001); peak rate of left ventricular pressure development rose from 963 +/- 242 to 1355 +/- 411 mm Hg per second (p less than 0.001); left ventricular end-diastolic pressure fell from 27 +/- 6 to 13 +/- 7 mm Hg (p less than 0.001); coronary sinus blood flow increased from 120 +/- 39 to 147 +/- 55 ml/min (p less than 0.01); myocardial oxygen consumption was augmented from 12.9 +/- 3.9 to 15.7 +/- 5.8 ml/min (p less than 0.001); and heart rate increased slightly (76 +/- 12 to 86 +/- 14 beats per minute, p less than 0.05). No significant changes occurred in left ventricular systolic pressure, stroke volume index, myocardial lactate extraction rate, myocardial arteriovenous oxygen difference and no patient developed angina, ECG-changes or ventricular arrhythmias. Infusion of prenalterol effectively improved the haemodynamic function and cardiac metabolism in congestive cardiomyopathy.

In an aqueous ultrafiltrate (10 000--50 000) prepared from Ehrlich ascites mammary carcinoma (EAC) cells, ascites fluid and bovine mammary gland, a new factor was obtained which is involved in the growth regulating system of EAC cells as shown by the following facts: 1) It reversibly inhibits the proliferation of EAC cells in a 24 h suspension culture, depending on their proliferative state. Thus, stationary cells from the plateau phase of growth in vivo are prevented from resuming growth in vitro, while cells taken from the active phase of in vivo growth are not inhibited under the same conditions. Likewise, stationary cells do not respond when incubated in serum before the addition of the factor (depending on serum concentrations and time). The dose-response curve levels off at higher factor concentrations so that the maximal inhibition is about 50--65% (explained with different sensitivities of the cells in the assay system). The time course of the inhibition as well as preliminary data from flow cytophotometry and labeling with tritiated thymidine indicate an interference with the progression of G1-phase cells into the S-phase. 2) The activity of the factor is counteracted by insulin and proinsulin, both known as growth factors. The insulin concentration needed is dependent on the factor concentration; an almost maximal inhibition can be prevented by physiological concentrations of insulin. The activity can be destroyed by heat and trypsin and differs also in other properties from that of polyamines. The factor could not be detected in lung, liver, spleen, kidney, heart and L 1210 ascites fluid of the mouse or in bovine malignant lymph nodes, thymus, kidney or liver. The factor was purified from a homogenate of bovine mammary gland by ultrafiltration and affinity chromatography on sepharose-bound wheat lectin. Polyacrylamide electrophoresis showed about 5 bands of which one contained the activity (in some experiments overlapping with a second one). In this way a 800fold purification (starting from the ultrafiltrate) could be obtained. The overall purification (relative to the centrifuged homogenate) can be calculated to be more than 100 000 fold.

This chapter discusses a growth inhibitor for mammary epithelial cells. All cells produce such growth-inhibitory regulatory substances. They seem to be primarily important in maintaining normal cell-kinetic balance and may be of importance even for carcinogenesis and the growth and spread of tumors. The chapter discusses specific endogenous growth-inhibitory substances and explains their roles in physiological growth regulation, carcinogenesis, and tumors. The chapter discusses growth-inhibitory oligopeptides or polypeptides sometimes called “chalones,” and among these, the epidermal factor is given the greatest attention. Some of the other growth suppressors are also discussed in the chapter. Stimulatory growth factors, for example, epidermal growth factor and platelet-derived growth factor, are discussed in the chapter. The chapter also emphasizes the complexity of malignancy and indicates that cancer is not simply a group of cells that multiply faster than normal.

Granulocytic chalone containing extracts were obtained by incubating rat bone marrow cells in Hanks salt solution and further purification of the conditioned medium by ultrafiltration and gel chromatography. These extracts cause specific inhibition of 3H-thymidine incorporation in short-term cultures of rat bone marrow and murine myeloic leukemias. Ehrlich ascites tumour, spleen (mouse), lymphatic leukemia L1210 and melanoma AMel 3 (hamster) are not influenced under identical experimental conditions. Comparing the action of cell proliferation inhibitors (chalones) from Ehrlich ascites tumour and spleen lymphocytes it was shown that inhibition of 3H-thymidine incorporation occurs only with those cells corresponding to the origin of the inhibitor. Therefore, the described short-term cultures seem to be suitable for testing the tissue specificity of action, as the main criterion for authenticity of the chalone effect, at least in the case of granulocytic chalone.

An aqueous ultrafiltrate (10 000-50 000 dalton) prepared from the cell-free ascitic fluid of mice bearing Ehrlich ascites tumour (EAT) in the plateau phase of growth (12-16 days after transplantation) was investigated with regard to its inhibitory effects on the proliferation of EAT cells in a 24-hr suspension culture. The following results were obtained: (1) The in vitro proliferation of cells obtained from the plateau phase of in vivo growth was reversibly inhibited. (2) The dose-response curves show a plateau with a maximum inhibition of about 50%, which suggests that not all cells can be affected. (3) Young cells (4-6 days after transplantation) were not inhibited. (4) Preincubation of plateau phase cells in the culture medium before treatment abolishes the inhibitory effect of the ultrafiltrate. This effect of preincubation is dependent on time and serum concentration. It provides the possibility to differentiate between true "chalone-like" and cytotoxic effects. (5) the inhibitory properties of the ultrafiltrate are destroyed by heating or trypsin treatment. (6) Extracts prepared in the same way from ascitic fluid of mice bearing lymphocytic leukemia L1210 do not inhibit the proliferation of EAT cells. Corresponding extracts from ascitic fluid of mice bearing myelocytic leukemia YM were found to be inhibitory; however, the inhibitory effect was also found on preincubated cells and is therefore considered to be due to an unspecific cytotoxicity. In conclusion, evidence was obtained for a factor from the ascitic fluid of mice bearing EAT, which prevents EAT cells from entering the proliferating state.

VARIOUS nitrosamines and nitrosamides are now frequently used as carcinogens1–3. Investigations so far have involved oral, intravenous or subcutaneous application. We have examined the carcinogenic action of some of these substances by painting them on to the skin.