Social disparities in diabetes care: a general population study in Denmark

Objective: We investigated the association between socioeconomic factors and the attainment of treatment goals and pharmacotherapy in patients with type 2 diabetes in Denmark.

Design: A cross-sectional population study.

Setting: The municipality of Naestved, Denmark.

Subjects: We studied 907 patients with type 2 diabetes identified from a random sample of 21,205 Danish citizens.

Main outcome measures: The proportion of patients who were not achieving goals for diabetes care based on their HbA_1c, LDL-cholesterol, blood pressure, and lifestyle, and the proportion of patients who were treated with antihypertensive and cholesterol- and glucose-lowering medication.

Methods: We investigated the association of the socioeconomic factors such as age, gender, education, occupation, income, and civil status and attainment of treatment goals and pharmacotherapy in logistic regression analyses. We investigated effect modification of cardiovascular disease and kidney disease.

Results: Middle age (40–65 years), low education level (i.e. basic schooling), and low household income (i.e. less than 21,400 € per year) were associated with nonattainment of goals for diabetes care. The association of socioeconomic factors with attainment of individual treatment goals varied. Patients with low socioeconomic status were more often obese, physically inactive, smoking, and had elevated blood pressure. Socioeconomic factors were not associated with treatment goals for hyperglycemia. Socioeconomic factors were inconsistently associated with pharmacotherapy. There was no difference in contacts to general practitioners according to SES.

Conclusions: In a country with free access to health care, the socioeconomic factors such as middle age, low education, and low income were associated with nonattainment of goals for diabetes care.

• KEY POINTS

• Middle age, low education, and low income were associated with nonattainment of goals for diabetes care, especially for lifestyle goals.

• Patients with low socioeconomic status were more often obese, physically inactive, smoking, and had elevated blood pressure.

• Association of socioeconomic factors with pharmacotherapy was inconsistent.

     

Magnitude, reproducibility, and association with baseline cardiac function of cardiac biomarker release in long-distance runners aged > or =55 years

Cardiac biomarker release after endurance exercise has been described in young athletes. Although older athletes are increasingly active in such sports, they have not previously been studied. Therefore, the aim of this study was to assess the magnitude and reproducibility of biomarker release in athletes aged > or =55 years. Forty-three healthy athletes (mean age 61 +/- 3.6 years) were assessed before and immediately after a 30-km cross-country race and studied with echocardiography at rest. The median N-terminal pro-brain natriuretic peptide (NT-proBNP; normal <194 ng/L) level was 42 ng/L (interquartile range 30 to 95) at baseline and 191 ng/L (interquartile range 114 to 308) after the race. Troponin T (normal <0.03 microg/L) was elevated in 19 subjects (44%) after the race. Twenty-two subjects had also been studied 3 years before at the same race, using an identical test protocol. Between the 2 races, strong correlations were seen for individual runners' postrace biomarker levels (NT-proBNP: r = 0.82, log transformed data; troponin T: Spearman's rho = 0.84; p <0.001 for both). The coefficient of variation for NT-proBNP release was 8.1%. Levels of NT-proBNP after the race were correlated with levels at baseline (r = 0.93, p <0.001) and with left ventricular mass index (r = 0.32, p = 0.03). Moreover, participants with elevated postrace NT-proBNP were significantly older (62.0 vs 59.8 years, p = 0.04). In conclusion, long-distance runners aged > or =55 years released NT-proBNP and troponin T in a reproducible fashion. The magnitude of NT-proBNP release during the race was correlated strongly with NT-proBNP baseline levels and was associated with left ventricular mass and age. These findings may suggest a potential adverse effect of long-distance running on cardiac function in certain participants in this age group.     

Analysis of the apo(a) size polymorphism in Asian Indian populations: association with Lp(a) concentration and coronary heart disease

Most studies aiming to detect associations of genetic variation with common complex diseases, e.g. coronary heart disease (CHD) have been performed in populations with a western lifestyle but it is unclear whether associations detected in one geographic group exist also in others. We here have determined lipoprotein(a) levels and apo(a) K-IV-2 repeat genotypes in CHD patients (N=254) and controls (N=480) from two Asian Indian populations (Tamil Nadu and New Delhi). In both populations and also in the pooled dataset median Lp(a) levels were significantly elevated in the patients (27.4 mg/dl) compared with the controls (17.6 mg/dl). Apo(a) K-IV-2 allele frequencies were not different between the CHD patients and controls and thus did not explain the increased Lp(a) levels in CHD patients. Contrary to what has recently been observed in Black and White men short (K-IVor=30) apo(a) alleles were all associated with higher Lp(a) levels in the patients. Accordingly relative risk (estimated as odds ratio) for CHD rose continuously with increasing Lp(a) but was independent of apo(a) allele length. Together with previous studies our results indicate that the relation between apo(a) genotypes, Lp(a) levels, and CHD may be heterogeneous across ethnic groups and that it depends on the genetic architecture of the Lp(a) trait in a given population whether an association of K-IV-2 repeat length with CHD exists or not.     

From nonpeptide toward noncarbon protease inhibitors: metallacarboranes as specific and potent inhibitors of HIV protease

HIV protease (PR) represents a prime target for rational drug design, and protease inhibitors (PI) are powerful antiviral drugs. Most of the current PIs are pseudopeptide compounds with limited bioavailability and stability, and their use is compromised by high costs, side effects, and development of resistant strains. In our search for novel PI structures, we have identified a group of inorganic compounds, icosahedral metallacarboranes, as candidates for a novel class of nonpeptidic PIs. Here, we report the potent, specific, and selective competitive inhibition of HIV PR by substituted metallacarboranes. The most active compound, sodium hydrogen butylimino bis-8,8-[5-(3-oxa-pentoxy)-3-cobalt bis(1,2-dicarbollide)]di-ate, exhibited a K(i) value of 2.2 nM and a submicromolar EC(50) in antiviral tests, showed no toxicity in tissue culture, weakly inhibited human cathepsin D and pepsin, and was inactive against trypsin, papain, and amylase. The structure of the parent cobalt bis(1,2-dicarbollide) in complex with HIV PR was determined at 2.15 A resolution by protein crystallography and represents the first carborane-protein complex structure determined. It shows the following mode of PR inhibition: two molecules of the parent compound bind to the hydrophobic pockets in the flap-proximal region of the S3 and S3' subsites of PR. We suggest, therefore, that these compounds block flap closure in addition to filling the corresponding binding pockets as conventional PIs. This type of binding and inhibition, chemical and biological stability, low toxicity, and the possibility to introduce various modifications make boron clusters attractive pharmacophores for potent and specific enzyme inhibition.     

Antibiotic-Induced Autoactivation of IS256 in Staphylococcus aureus

The 3′ end of rsbU, encoding the positive regulator of the stress factor sigma B, was identified as a hot spot for spontaneous IS256 insertion in Staphylococcus aureus SA137/93G. Interestingly, subinhibitory concentrations of chloramphenicol in combination with heat stress, as well as linezolid and spectinomycin at physiological temperatures, selected for such rsbU::IS256 insertion mutants. In consequence of the inactivation of rsbU, the IS256 transposition frequency was increased 4-fold in S. aureus HG001.     

Zur Frage der Sterilisation und quantitativen pharmakologischen Wertbestimmung verschiedener Arzneisubstanzen

Zusammenfassung Es werden einige verfahren zur Sterilisierung von Morphin-, Scopolamin-, Cardiazol-, Adrenalin- und Strophanthinlösungen beschrieben. Die Brauchbarkeit verschiedener Methoden der pharmakologischen Wertbestimmung dieser Substanzen wird erörtert.     

Proximity proteomics of synaptopodin provides insight into the molecular composition of the spine apparatus of dendritic spines

The spine apparatus is a specialized compartment of the neuronal smooth endoplasmic reticulum (ER) located in a subset of dendritic spines. It consists of stacks of ER cisterns that are interconnected by an unknown dense matrix and are continuous with each other and with the ER of the dendritic shaft. While this organelle was first observed over 60 y ago, its molecular organization remains a mystery. Here, we performed in vivo proximity proteomics to gain some insight into its molecular components. To do so, we used the only known spine apparatus–specific protein, synaptopodin, to target a biotinylating enzyme to this organelle. We validated the specific localization in dendritic spines of a small subset of proteins identified by this approach, and we further showed their colocalization with synaptopodin when expressed in nonneuronal cells. One such protein is Pdlim7, an actin binding protein not previously identified in spines. Pdlim7, which we found to interact with synaptopodin through multiple domains, also colocalizes with synaptopodin on the cisternal organelle, a peculiar stack of ER cisterns resembling the spine apparatus and found at axon initial segments of a subset of neurons. Moreover, Pdlim7 has an expression pattern similar to that of synaptopodin in the brain, highlighting a functional partnership between the two proteins. The components of the spine apparatus identified in this work will help elucidate mechanisms in the biogenesis and maintenance of this enigmatic structure with implications for the function of dendritic spines in physiology and disease.

The neuronal endoplasmic reticulum (ER) is an intricate continuous network of membrane tubules and cisterns that runs throughout neuronal processes with region-specific specializations. One such specialization of the smooth ER is the spine apparatus (SA) that is located in a subset of dendritic spines. The SA consists of stacks of flat cisterns that are connected by an unknown dense matrix and are continuous with each other and with the ER of the dendritic shaft (1–3) (Fig. 1A and SI Appendix, Fig. S1A). Morphological changes in the SA have been reported after long-term potentiation (4) and also, in a variety of human disorders, including several neurodegenerative conditions (5–9). While the first observation of the SA by electron microscopy (EM) was reported in 1959 by Gray (1), our understanding of this organelle remains fairly limited. Its molecular characterization has proven to be challenging due to the difficulty of its biochemical isolation and its absence in organisms suitable for genetic screens.Open in a separate windowFig. 1.The localization of synaptopodin (indicated as Synpo in all figures) in cultured hippocampal neurons overlaps with the localization of the SA in dendritic spines of cortical slices. (A) SA as visualized by transmission EM. (B and C) SA and ER reconstructed by a semiautomated algorithm from 3D volumes acquired by FIB-SEM. An SA is shown in B, while C shows a portion of a dendritic shaft with spines containing (magenta arrows) and not containing (white arrows) an SA. The plasma membrane (PM) is shown in blue, the ER is in red, and the post-synaptic density (PSD) is in yellow. (D) Cisternal organelle (CO), as observed in an FIB-SEM optical section, at an axonal initial segment. Note that the stacks of ER cisterns are similar to those characteristics of the SA. (E) mRFP-synaptopodin coexpressed with cytosolic EGFP as a marker of the entire dendritic volume. Note in the zoomed-in views of the region enclosed by a rectangle (the lower three fields) that synaptopodin is concentrated near the spine neck, where the SA is localized. (F) Localization by immunofluorescence of endogenous synaptopodin showing strong overlap with a pool of F-actin labeled by phalloidin-Alexa488. Also, in this sample, the magnified views (the lower three fields) show enrichment of synaptopodin, relative to actin, at the spine neck. (G) mRFP-synaptopodin coexpressed with an ER marker, EGFP-VAPB, showing colocalization of the two proteins. In the zoomed-in views (the lower three fields), red arrows show a spine positive for both the ER marker and synaptopodin, and the blue arrows show a spine with the ER marker but lacking synaptopodin. (H) Percentage of ER-positive spines that also contain synaptopodin and percentage of synaptopodin-positive spines that contain ER quantified in cultured hippocampal neurons expressing mRFP-synaptopodin and the ER markers EGFP-VAPB or EGFP-Sec61β. Each data point represents at least 99 spines from a single neuron. (I) Spine of a synaptopodin KO mouse that lacks the SA but contains the ER. (J) Quantification of the number of spines where ER was visible in the plane of the section with or without an SA in the brain of wild type (WT) vs. synaptopodin mutant mice (n≥800 spines per genotype).The only known protein enriched at the SA and required for its formation is synaptopodin, a protein without transmembrane regions localized in the cytosolic space (10). Neuronal synaptopodin specifically localizes to dendritic spines and to the axonal initial segment, where another specialization of the ER similar to the SA (stack of flattened cisterns) called the cisternal organelle is present (11–14). Lack of synaptopodin in synaptopodin knock-out (KO) mice correlates with the lack of SA and of the cisternal organelle, as well as with a reduction in Hebbian plasticity and spatial memory (11, 15–18). A longer isoform of synaptopodin is expressed in the foot processes of podocytes, where it functions as a regulator of the actin cytoskeleton (19, 20). Synaptopodin binds to and bundles actin (21) and interacts with several actin binding proteins, such as α-actinin (13, 21, 22). While more is known about the interactors of synaptopodin in podocytes, its binding partners at the SA remain unknown.The goal of this work was to gain insight into the molecular composition of the SA. To this aim, we used synaptopodin as a starting point for our analysis. We identified some of its binding partners by an in vivo proximity biotinylation approach and characterized the specific localization of a subset of these proteins in neurons and their interaction with synaptopodin in an exogenous system.