Determinants of progression of coronary artery calcification in type 2 diabetes role of glycemic control and inflammatory/vascular calcification markers.

OBJECTIVES: This study prospectively evaluated the relationship between cardiovascular risk factors, selected biomarkers (high-sensitivity C-reactive protein [hs-CRP], interleukin [IL]-6, and osteoprotegerin [OPG]), and the progression of coronary artery calcification (CAC) in type 2 diabetic subjects. BACKGROUND: Coronary artery calcification is pathognomonic of coronary atherosclerosis. Osteoprotegerin is a signaling molecule involved in bone remodeling that has been implicated in the regulation of vascular calcification and atherogenesis. METHODS: Three hundred ninety-eight type 2 diabetic subjects without prior coronary disease or symptoms (age 52 +/- 8 years, 61% male, glycated hemoglobin [HbA(1)c] 8 +/- 1.5) were evaluated serially by CAC imaging (mean follow-up 2.5 +/- 0.4 years). Progression/regression of CAC was defined as a change > or =2.5 between the square root transformed values of baseline and follow-up volumetric CAC scores. Demographic data, risk factors, glycemic control, medication use, serum hs-CRP, IL-6, and plasma OPG levels were measured at baseline and follow-up. RESULTS: Two hundred eleven patients (53%) had CAC at baseline. One hundred eighteen patients (29.6%) had CAC progression, whereas 3 patients (0.8%) had regression. Age, male gender, hypertension, baseline CAC, HbA(1)c >7, waist-hip ratio, IL-6, OPG, use of beta-blockers, calcium channel antagonists, angiotensin-converting enzyme (ACE) inhibitors, statins, and Framingham/UKPDS (United Kingdom Prospective Diabetes Study) risk scores were univariable predictors of CAC progression. In the multivariate model, baseline CAC (odds ratio [OR] for CAC >400 = 6.38, 95% confidence interval [CI] 2.63 to 15.5, p < 0.001), HbA(1)c >7 (OR 1.95, CI 1.08 to 3.52, p = 0.03), and statin use (OR 2.27, CI 1.38 to 3.73, p = 0.001) were independent predictors of CAC progression. CONCLUSIONS: Baseline CAC severity and suboptimal glycemic control are strong risk factors for CAC progression in type 2 diabetic subjects.     

p53-dependent integration of telomere and growth factor deprivation signals

Ectopically expressed hTERT enables p16(INK4A)(-) human mammary epithelial cells to proliferate in the absence of growth factors, a finding that has led to the hypothesis that hTERT has growth regulatory properties independent of its role in telomere maintenance. We now show that telomerase can alter the growth properties of cells indirectly through its role in telomere maintenance, without altering growth stimulatory pathways. We find that telomere dysfunction, indicated by 53BP1/phosphorylated histone H2AX foci at chromosome ends, is present in robustly proliferating human mammary epithelial cells long before senescence. These foci correlate with increased levels of active p53. Ectopic expression of hTERT reduces the number of foci and the level of active p53, thereby decreasing sensitivity to growth factor depletion, which independently activates p53. The continuous presence of hTERT is not necessary for this effect, indicating that telomere maintenance, rather than the presence of the enzyme itself, is responsible for the increased ability to proliferate in the absence of growth factors. Our findings provide a previously unrecognized mechanistic explanation for the observation that ectopically expressed hTERT conveys growth advantages to cells, without having to postulate nontelomeric functions for the enzyme.     

Association of Glycation Gap With Mortality and Vascular Complications in Diabetes

OBJECTIVE

The “glycation gap” (G-gap), an essentially unproven concept, is an empiric measure of disagreement between HbA_1c and fructosamine, the two indirect estimates of glycemic control. Its association with demographic features and key clinical outcomes in individuals with diabetes is uncertain.

RESEARCH DESIGN AND METHODS

The G-gap was calculated as the difference between measured HbA_1c and a fructosamine-derived standardized predicted HbA_1c in 3,182 individuals with diabetes. The G-gap’s associations with demographics and clinical outcomes (retinopathy, nephropathy, macrovascular disease, and mortality) were determined.

RESULTS

Demographics varied significantly with G-gap for age, sex, ethnic status, smoking status, type and duration of diabetes, insulin use, and obesity. A positive G-gap was associated with retinopathy (odds ratio 1.24 [95% CI 1.01–1.52], P = 0.039), nephropathy (1.55 [1.23–1.95], P < 0.001), and, in a subset, macrovascular disease (1.91 [1.18–3.09], P = 0.008). In Cox regression analysis, the G-gap had a “U”-shaped quadratic relationship with mortality, with both negative G-gap (1.96 [1.50–2.55], P < 0.001) and positive G-gap (2.02 [1.57–2.60], P < 0.001) being associated with a significantly higher mortality.

CONCLUSIONS

We confirm published associations of G-gap with retinopathy and nephropathy. We newly demonstrate a relationship with macrovascular and mortality outcomes and potential links to distinct subpopulations of diabetes.The glycation gap (G-gap) refers to the potential deviation of glycated HbA_1c away from the other indirect estimate of blood glucose attainment such that it might read substantially lower or higher than expected (1–3). Glycated HbA_1c represents the net effect of several mechanisms, which may shift its direct glycation relationship with overall levels of glycemia (4–6). Many factors are known to influence HbA_1c, including various erythrocytic processes (6–9). Protein glycation is a nonenzymatic reaction dependent on glucose concentrations, but intracellular enzymatic deglycation of proteins has also been identified (10). The key deglycating enzyme, fructosamine-3-kinase, has isoforms and a genetic polymorphism suggested to influence HbA_1c variability, but any impact on HbA_1c glycation is unknown; although it seems unlikely that glycated HbA_1c is a substrate for this enzyme since it has been shown that there is no evidence that it plays any role in HbA_1c deglycation at the relevant glycation site (11,12). To add to the potential for a spurious generation of a G-gap, many factors, including variability in protein turnover and obesity, may affect fructosamine estimation (1,13,14). The evidence concerning the effects of urinary protein loss are mixed (1,13). Even then, fructosamine reflects blood glucose attainment over a much shorter time frame than HbA_1c and may more readily be influenced by very short-term changes in blood glucose levels. It may simply be that the G-gap is no more than an empiric and potentially spurious measure of disagreement between the two indirect estimates of glycemic control, with each having a number of confounders to the direct relationship with blood glucose.Although we have demonstrated that the G-gap is a consistent phenomenon within individuals over time (1), there remains doubt as to whether the G-gap is a real phenomenon or if it has any significant sequelae (15). Hypothesizing that the G-gap is an inconsequential nonsystematic event, irrelevant to diabetes outcomes, it would not then be expected to be associated with distinct subpopulations of human diabetes or to have any sequelae in clinical outcomes. This article explores the association of the G-gap with diabetic population demographic factors and with crucial clinical outcomes to determine if such associations exist.     

A clinic-based mammography intervention targeting inner-city women

OBJECTIVE: The objective was to evaluate the effect of a clinic-based intervention program on mammography use by inner-city women. DESIGN: A randomized controlled trial employing firm system methodology was conducted. SETTING: The study setting was a general internal medicine clinic in the university-affiliated county hospital serving metropolitan Seattle. PARTICIPANTS: Women aged 50 to 74 years with at least one routine clinic appointment (when they were due for mammography) during the study period were enrolled in the trial (n = 314). INTERVENTIONS: The intervention program emphasized nursing involvement and included physician education, provider prompts, use of audiovisual and printed patient education materials, transportation assistance in the form of bus passes, preappointment telephone or postcard reminders, and rescheduling assistance. Control firm women received usual care. MEASUREMENTS AND MAIN RESULTS: Mammography completion within 8 weeks of clinic visits was significantly higher among intervention (49%) than control (22%) firm women (p < .001). These effects persisted after adjustment for potential confounding by age, race, medical insurance coverage, and previous mammography experience at the hospital (odds ratio 3.5; 95% confidence interval 1.9, 6.5). The intervention effect was modified by type of insurance coverage as well as prior mammography history. Process evaluation indicated that bus passes and rescheduling efforts did not contribute to the observed increases in screening participation. CONCLUSIONS: A clinic-based program incorporating physician education, provider prompts, patient education materials, and appointment reminders and emphasizing nursing involvement can facilitate adherence to breast cancer screening guidelines among inner-city women.     

Aids and cancer in Africa: the evolving epidemic in Zimbabwe

BACKGROUND: Zimbabwe is severely affected by the AIDS epidemic, and many cancers in African populations are related to infectious agents. OBJECTIVE: To study the current pattern, and short-term changes in incidence, of cancers related to infectious agents (and especially to HIV), with respect to the evolving epidemic of AIDS. METHODS: Analysis of data on the African population of Harare, Zimbabwe, from the Zimbabwe Cancer Registry, for the period 1990-1995. Comparison with data on prevalence of HIV seropositivity, and notifications of AIDS. RESULTS: Comparing results from 1993-1995 with those for 1990-1992 shows a continuing increase in the incidence of Kaposi's sarcoma with a doubling of the rates in both men and women. A dramatic increase in the incidence of squamous cell tumours of the conjunctiva was also observed, as well as a significant increase in the incidence of non-Hodgkin's lymphoma in women. There was no apparent increase in risk for Hodgkin's disease, myeloma, liver cancer, or cancer of the cervix. CONCLUSIONS: The AIDS epidemic has had a dramatic effect on the profile of cancer. The changes in incidence involve several cancers previously linked to AIDS in North America and Europe.     

The effects of ovine placental lactogen and bovine growth hormone on hepatic and mammary gene expression in lactating sheep

The ability of ovine placental lactogen (oPL) to bind to the growth hormone receptor (GHR) raises the possibility that oPL may exert a growth hormone (GH)-like action on galactopoiesis. We have compared the effects of treating lactating ewes for 5 days with an equimolar dose (0.1 mg/kg/day, administered as two equal doses 12 hourly) of either bovine growth hormone (bGH) (n = 10), oPL (n = 10) or saline (n = 9) on hepatic and mammary GHR, insulin-like growth factor-I (IGF-I) and IGF-binding protein-3 (IGFBP-3) gene expression and hepatic GHR number. Hepatic GHR and IGFBP-3 mRNA were unaltered by bGH or oPL treatment. Hepatic IGF-I mRNAs increased following bGH (P < 0.05) but not oPL treatment. GHR gene expression was greater in liver compared to mammary gland extracts. There was no effect of either bGH or oPL treatment on mammary GHR, IGF-I or IGFBP-3 mRNA or hepatic GHR number. These studies confirm the galactopoietic effects of bGH in lactating ruminants and suggest that the mechanism of this action is not via increased hepatic GHR number or gene expression. In addition, the increase in hepatic but not mammary IGF-I mRNA with bGH treatment suggests an endocrine action of IGF-I on milk synthesis. These studies also demonstrate that an equimolar dose of oPL is not galactopoietic or somatogenic in the lactating ewe.     

Nonabsorbable radioactive material in the treatment of carcinomas by local injections

Nonabsorbable radioactive material was used in treating malignant lesions by local injection. One hundred thirty-five Lewis Wistar rats were inoculated subcutaneously with tumor cells. After 7 days, the rats grew tumors of approximately 1 X 1 X 1 cm at the injection site. The rats then were divided into two groups; 50% were kept as a control group while the other 50% received single injections of 1 mCi yttrium 90 (90Y) microspheres directly into the center of the tumor. This study shows a significant reduction of the tumor growth rate in treated animals. Tumor sizes after 4 days averaged 1.31 ml in the treated rats and 9.74 ml in the control group. Excluding animals that had complete regression of the tumor, treated rats lived an average of 30.8 days from the day of treatment compared with the control rats, which lived an average of 17.4 days. Pathology examinations showed no effects from injected radioactive materials in the liver, bone marrow or the kidney. Examination of the injected area after 6 months showed that microspheres remained locally and that the tumor was replaced with collagen tissue.     

Compensatory renal growth: role of growth hormone and insulin-like growth factor-I

Recent experimental evidence suggests that insulin-like growth factor-I (IGF-I) may be involved in compensatory renal growth (CRG). This study was designed to determine the relative contribution of IGF-I and growth hormone (GH) to the CRG that takes place in rats following uninephrectomy (UNx). We also studied the respective role of GH and IGF-I in the stimulation of CRG induced by a high protein diet (HPD). CRG was studied 7 days after UNx in Wistar rats and in a new mutant strain of dwarf rats, selectively deficient in GH. Prior to UNx, rats of both strains were pre-fed (14 days) either a medium-protein diet (MPD, casein 18%) or a HPD (54%). On MPD, CRG was comparable in Wistar (17.6 +/- 3.1%, M +/- SD) and dwarf (14.4 +/- 4.8%) rats. The HPD enhanced CRG in the Wistars (27 +/- 3.9%, P less than 0.005) but not in the dwarfs (14.9 +/- 2%). CRG in both experimental groups involved renal hypertrophy and hyperplasia. Control (baseline) serum, liver and kidney IGF-I were significantly less in dwarf rats. However, following UNx, on a MPD, kidney IGF-I increased significantly in both Wistar and dwarf rats: Wistar, pre-UNx, 310 +/- 46 ng/g tissue; post-UNx, 405 +/- 54 ng/g, P less than 0.005; dwarfs, pre-UNx, 205 +/- 35 ng/g; post-UNx 426 +/- 90 ng/g, P less than 0.001. On a HPD a further significant increase in renal IGF-I was only observed in Wistar rats (505 +/- 46 ng/g). No change in serum or liver IGF-I was observed after UNx in either strain.(ABSTRACT TRUNCATED AT 250 WORDS)     

A cognitive systematic approach to analyzing preparation design for a difficult space management case

There are at least two different techniques for preparing teeth prior to bonded porcelain restorations. The first involves using depth cutters guided by the existing tooth structure. A more recently developed approach integrates an additive wax-up that represents the final volume of the teeth, with indices used to guide the preparation design. This article illustrates in detail a clinical case that was prepared by combining the earlier simplified depth cutter approach with recontouring and preparation design principles determined clinically by the dentist. The same case was prepared in the laboratory on plastic models, using labial and incisal reduction preparation guides fabricated from a diagnostic wax-up. This combination of techniques will simplify preparation design for difficult space management cases and facilitate predictable and repeatable results that meet current esthetic standards while staying conservative and preserving tooth structure.     

Effects of streptozotocin injection into fetal rabbits on their subsequent growth in utero

To investigate the effect of hypoinsulinaemia on prenatal growth, individual fetal rabbits were injected intramuscularly with streptozotocin (STZ) at 23 days of gestation following surgical reduction of litter number to 4 at 9 days' gestation. Two days after giving STZ (300 micrograms/g), plasma insulin levels were decreased, but by 30 days' gestation in either insulin nor glucose levels differed significantly from values in control fetuses. Despite only temporary hypoinsulinaemia, severe growth retardation was caused by STZ (300 micrograms/g estimated fetal weight), fetuses at 30 days' gestation weighing only 58% of the mean value obtained in saline-injected controls. At 250 micrograms/g STZ caused growth retardation in 3 out of 8 fetuses. A higher rate (500 micrograms/g) caused fetal death. The extent of growth retardation caused by STZ varied amongst tissues in the conceptus. Placenta and brain were not significantly altered, but relative to the size of the placenta the kidneys and empty carcass were severely retarded. The relationship between carcass and kidney weights did not differ from that in naturally small fetuses of the same age. Protein and RNA concentrations in the carcass were not altered by STZ, but that of DNA was reduced. In the placenta, DNA concentration was increased and RNA decreased. These observations are consistent with a major effect of hypoinsulinaemia on the growth of carcass and renal tissues, though loss of a renal growth factor cannot be ruled out.