Hemoglobin A1c as a screen for previously undiagnosed prediabetes and diabetes in an acute-care setting

OBJECTIVE

Hemoglobin A_1c (HbA_1c) is recommended for identifying diabetes and prediabetes. Because HbA_1c does not fluctuate with recent eating or acute illness, it can be measured in a variety of clinical settings. Although outpatient studies identified HbA_1c-screening cutoff values for diabetes and prediabetes, HbA_1c-screening thresholds have not been determined for acute-care settings. Using follow-up fasting blood glucose (FBG) and the 2-h oral glucose tolerance test (OGTT) as the criterion gold standard, we determined optimal HbA_1c-screening cutoffs for undiagnosed dysglycemia in the emergency department setting.

RESEARCH DESIGN AND METHODS

This was a prospective observational study of adults aged ≥18 years with no known history of hyperglycemia presenting to an emergency department with acute illness. Outpatient FBS and 2-h OGTT were performed after recovery from the acute illness, resulting in diagnostic categorizations of prediabetes, diabetes, and dysglycemia (prediabetes or diabetes). Optimal cutoffs were determined and performance data identified for cut points.

RESULTS

A total of 618 patients were included, with a mean age of 49.7 (±14.9) years and mean HbA_1c of 5.68% (±0.86). On the basis of an OGTT, the prevalence of previously undiagnosed prediabetes and diabetes was 31.9 and 10.5%, respectively. The optimal HbA_1c-screening cutoff for prediabetes was 5.7% (area under the curve [AUC] = 0.659, sensitivity = 55%, and specificity = 71%), for dysglycemia 5.8% (AUC = 0.717, sensitivity = 57%, and specificity = 79%), and for diabetes 6.0% (AUC = 0.868, sensitivity = 77%, and specificity = 87%).

CONCLUSIONS

We identified HbA_1c cut points to screen for prediabetes and diabetes in an emergency department adult population. The values coincide with published outpatient study findings and suggest that an emergency department visit provides an opportunity for HbA_1c-based dysglycemia screening.There are 26.8 million people with diabetes in the U.S., and by the year 2030, it is estimated to increase to 36 million people (1). Current estimates are that 27% of individuals with diabetes remain undiagnosed, and by the time of diagnosis, there often are microvascular and macrovascular abnormalities found (2–4). Early recognition is important because lifestyle modifications and medications can reduce the incidence of diabetes in people at high risk (5), and the treatment of diabetes can prevent or delay microvascular end-organ complications.The use of hemoglobin A_1c (HbA_1c) to diagnose prediabetes and diabetes recently was recommended by the American Diabetes Association (ADA) (6). HbA_1c testing has an advantage over glucose-based testing because it does not require fasting, and the test can be performed at any time. Guidelines recommend an HbA_1c ≥6.5% to diagnose diabetes and HbA_1c between 5.7 and 6.4% for identifying prediabetes. These cutoff values for HbA_1c are derived in part from outpatient studies and are based on populations of those not acutely ill at the time of testing (7–9).Less attention has been given to screening and diagnosing diabetes and prediabetes in acute-care settings such as the emergency department, where blood is routinely drawn to manage acute illness and clinicians are available to interpret the results. The HbA_1c test can be quickly performed in many different clinical settings, including the hospital. However, it is not known whether HbA_1c thresholds differ between the higher-risk acute-care and the general outpatient populations. The purpose of this study was to determine optimal HbA_1c-screening cutoff points for undiagnosed dysglycemia in the emergency department setting using follow-up fasting blood glucose (FBS) and 2-h oral glucose tolerance tests (OGTTs) as the criterion gold standard.     

Dodecylphosphocholine-mediated enhancement of paracellular permeability and cytotoxicity in Caco-2 cell monolayers

The intestinal epithelium is a significant barrier for oral absorption of hydrophilic drugs because they cannot easily traverse the lipid bilayer of the cell membrane and their passage through the intercellular space (paracellular transport) is restricted by the tight junctions. In this report we show that dodecylphosphocholine (DPC) can improve the paracellular permeability of hydrophilic compounds across Caco-2 cell monolayers by modulating the tight junctions. The results show that the alkyl chain as well as the zwitterionic head group of DPC are required for its activity. DPC appears to act by modulating the permeability of tight junctions as evidenced by the fact that treatment of Caco-2 cell monolayers by this agent results in a decreased transepithelial electrical resistance (TEER), increased permeability of paracellular markers (e. g., mannitol) with no change in the permeability of the transcellular marker testosterone, and redistribution of the tight junction-associated protein ZO-1. The effect of DPC on Caco-2 cells (e.g., decrease in TEER) is reversible, and is not caused by gross cytotoxicity (as indicated by the MTT test) or by nonspecific disruption of the cell membrane (as indicated by only slight nuclear staining due to the nonpermeable DNA-specific dye propidium iodide). We propose in the present study a parameter, potency index, that allows comparison of various enhancers of paracellular transport in relation to their cytotoxicity. The potency index is a ratio between the IC(50) value (concentration at which 50% inhibition of control mitochondrial dehydrogenase activity occurs in the MTT test) and the EC(50) value (concentration at which TEER drops to 50% of its control (untreated) value). By this parameter, DPC is significantly safer than the commonly used absorption enhancer palmitoyl carnitine (PC), which has the potency index of approximately 1 (i.e., no separation between effective and toxic concentration).     

Landscape phage fusion protein-mediated targeting of nanomedicines enhances their prostate tumor cell association and cytotoxic efficiency

Tumor-specific cytotoxicity of drugs can be enhanced by targeting them to tumor receptors using tumor-specific ligands. Phage display offers a high-throughput approach to screen for the targeting ligands. We have successfully isolated phage fusion peptides selective and specific for PC3 prostate cancer cells. Also, we have demonstrated a novel approach of targeting liposomes through tumor-specific phage fusion coat proteins, exploiting the intrinsic properties of the phage coat protein as an integral membrane protein. Here we describe the production of Rhodamine-labeled liposomes as well as doxorubicin-loaded long-circulating liposomes targeted to PC3 prostate tumor cells via PC-specific phage peptides, as an extension of our previous studies. Targeting of labeled liposomes was demonstrated using fluorescence microscopy as well as flow cytometry. Targeting of doxorubicin-loaded liposomes enhanced their cytotoxic effect against PC3 cells in vitro, indicating a possible therapeutic advantage. The simplicity of the approach for generating targeted liposomes coupled with the ability to rapidly obtain tumor-specific phage fusion proteins via phage display may contribute to a combinatorial system for the production of targeted liposomal therapeutics for advanced stages of prostate tumor.From the Clinical EditorThis paper demonstrates targeting cytotoxic agents to tumor receptors using tumor-specific ligands. The authors describe the production of Rhodamine-labeled liposomes as well as doxorubicin loaded long circulating liposomes targeted to PC3 prostate tumor cells via PC-specific phage peptides. This approach may be especially relevant for advanced prostate tumors.     

Opinions and attitudes of the UK's GDPs and specialists in oral surgery, oral medicine and surgical dentistry on oral cancer screening

OBJECTIVE: To survey two broad areas of oral cancer awareness and management of patients at risk of oral cancer by specialists in oral surgery, oral medicine, surgical dentistry and general dental practitioners (GDPs) in the UK. The first of these included knowledge and awareness of aetiological factors, changing patterns of disease, and screening/detection programmes including their effectiveness. The second included oral cancer detection methods, advice on avoidance of high-risk activity and self-examination, and referral pattern of GDPs. DESIGN AND METHOD: A pretested, 44-item questionnaire, a covering letter, a brief outline of the research protocol and return, stamped envelope were mailed in March 2003. A sample of 200 GDPs whose names were obtained from the General Dental Council's main list and 305 dental specialist names obtained from specialist's list in surgical dentistry, oral medicine and oral surgery were selected randomly. Information on oral cancer awareness and practice, screening practice and education was obtained. RESULTS: The response rate was 66.9%. The knowledge of the dental specialists was consistent with that in reports of current aetiological studies on oral cancer. However there were gaps in the GDP's knowledge and ascertainment of oral cancer risk factors. Over 70% of the dental specialists provided counselling advice on the risks of tobacco and alcohol habits compared with 41.2% of GDPs. More GDPs (52.4%) than specialists (35.4%) believed that oral cancer screening on a national basis would be effective in decreasing the mortality of oral cancer. Over 95% of all respondents used a visual examination for oral cancer screening and 89.9% of all respondents strongly believed that visual screening is effective in the early detection of oral cancer. CONCLUSION: The results showed that GDPs had knowledge gaps in their awareness of oral cancer risk factors and the application of preventive measures. Most dental health providers in the UK perform visual screening of the oral mucosa for their patients. Opinion was equivocal as to whether a nationally based screening programme similar to cervical cancer would be effective in improving the mortality and morbidity of oral cancer.     

Synthesis, characterization, and biological evaluation of some N-aryl hydrazones and their 2,3-disubstituted-4-thiazolidinone derivatives

A series of 2,3-disubstituted 4-thiazolidinones 6 and 8a-p have been prepared by the cyclo condensation reaction of various substituted N-aryl hydrazones 5 and 7a–p with mercapto acetic acid. The intermediate N-aryl hydrazones 5 and 7a–p were synthesized by the condensation of 2-bromo-5-methoxy benzohydrazide 4 with 2 or various substituted aromatic aldehydes. The new Naphthalene-2-carboxaldehyde 2 has been synthesized by Vilsmeier-Haack reaction of naphthalen-1(2H)-one 1. The key starting compound 2-bromo-5-methoxy benzohydrazide 4 was prepared from methyl 2-bromo-5-methoxybenzoate 3 by the reaction with hydrazine hydrate in alcoholic medium. The formulae of the compounds were confirmed by elemental analyses and their structures were determined based on IR, ¹H-NMR, ¹³C-NMR, ¹³C-NMR-DEPT, and mass spectral data. The newly synthesized compounds were evaluated for their antioxidant, anti-inflammatory, and analgesic activities. The antibacterial activities of the newly synthesized compounds against E. coli ATCC 8739, S. aureus ATCC 6538, P. aeruginosa ATCC 1539, and Bacillus cereus, while the antifungal activities of the compounds against Candida albicans were tested. The acute cytotoxicity data of compounds 7h and 8a are tested and are found to be nontoxic up to 2,500 mg/kg.     

Synthesis and structure–activity relationship studies on novel 8-amino-3-[2-(4-fluorophenoxy)ethyl]-1,3-diazaspiro[4.5]decane-2,4-dione derivatives as anticonvulsant agents

A series of novel 8-amino-3-[2-(4-fluorophenoxy)ethyl]-1,3-diazaspiro[4.5]decane-2,4-dione derivatives 7–36 was synthesized and their pharmacological activity was determined with the objective to better understand their structure–activity relationship for anticonvulsant activity. All the compounds were evaluated for their possible anticonvulsant activity by maximal electroshock seizure (MES) test and their neurotoxic effects were determined by rotarod test. Majority of the compounds were active in MES tests. Compounds 24, 27, and 34 showed a significant and protective effect on seizure, when compared with standard drug phenytoin. The compounds having amide bond showed moderate protective effect on MES induced seizures compared to sulfonamide.