Dietary alpha-lipoic acid supplementation in SHRs lowered the systolic blood pressure, cytosolic [Ca2+]i, blood glucose and insulin levels, and tissue aldehyde conjugates, and attenuated adverse renal vascular changes.

Detection of human papillomavirus (HPV)E62) and 38.7% (95% CI, 35.7, 41.7), respectively (P < 0.05). In 1,373 women undergoing routine screening (CIN 2؉, n ‫؍‬ 7), both Aptima and HC2 showed 100% sensitivity, and the specificities were 88.3% (95% CI, 86.6, 90.0) and 85.3% (95% CI, 83.5, 87.3), respectively (P < 0.05); for women >30 years of age (n ‫؍‬ 845), the specificities were 93.9% (95% CI, 92.3, 95.5) and 92.1% (95% CI, 90.3, 93.9), respectively (P < 0.05). On the basis of 818 referral cases (CIN 2؉, n ‫؍‬ 235), the sensitivity of Aptima was 94.9% (95% CI, 92.1, 97.7) and that of Proofer was 79.1% (95% CI, 73.9, 84.3), and the specificities were 45.8% (95% CI, 41.8, 49.8) and 75.1% (95% CI, 71.6, 78.6), respectively (P < 0.05). Both Aptima and Proofer showed a higher degree of agreement with LA genotyping than HC2. In conclusion, the Aptima test is as sensitive as HC2 but more specific for detecting CIN 2؉ and can serve as a reliable test for both primary cervical cancer screening and the triage of borderline cytological abnormalities.Persistent infection with oncogenic human papillomavirus (HPV) is the underlying cause of cervical cancer (34, 42), and therefore, testing for oncogenic HPV infection could serve as an accurate means of detecting women at risk for cervical cancer. There are also indications that testing for HPV might be the most effective method of cervical cancer screening in developing countries (32). Moreover, HPV testing would be warranted as a primary screening tool in the era of HPV vaccination (13). Numerous studies have established that testing for HPV DNA is significantly more sensitive than Pap cytology for the detection of high-grade cervical intraepithelial neoplasia (CIN 2) or worse (CIN 2ϩ, i.e., CIN 2, CIN 3, squamous cell carcinoma, endocervical adenocarcinoma in situ, and endocervical adenocarcinoma) (1,4,15,20,27,30) and is recommended in primary cervical cancer screening and for the triage of borderline cytological abnormalities (33,43,44). However, HPV testing lacks specificity due to the ubiquitous and transient nature of HPV infection in women, and therefore, the positive predictive value (PPV) tends to be lower than that obtained by cytology (10, 15). The above observation nonetheless has been based on HPV DNA testing, with most studies utilizing the Hybrid Capture 2 DNA test (HC2; Qiagen) (10, 15). While HC2 is highly sensitive for the detection of 13 high-risk oncogenic types targeted by the test (10,11,15), it is also known to cross-react with untargeted nononcogenic types, thus potentially contributing to a reduction in the test's specificity (5,28,31).The oncogenic process in cervical cancer is initiated and mediated by the upregulation of HPV E6/E7 oncoproteins, and thus, overexpression of these oncoproteins is a marker for an increased risk of cervical cancer (26,38,45). Therefore, detection of E6/E7 oncogene expression could be more specific and a better predictor of cervical cancer risk than the detection of HPV DNA, and E6/E7 oncogenic expression can be detecte...

Alteration of extracellular calcium concentration may be involved in glucose metabolism in a number of pathways. The present study was designed to investigate the relationship between total serum calcium and 1) fasting serum glucose, 2) insulin, 3) insulin resistance, and 4) beta-cell function in 1,182 healthy subjects from the province of Newfoundland and Labrador, Canada. All variables were log10 transformed, and confounding factors including age, trunk fat percentage, serum phosphorus, magnesium, 25-OH vitamin D, and parathyroid hormone were adjusted before analyses. Significant positive correlations between glucose and insulin resistance with calcium were found in both sexes, whereas an inverse correlation between beta-cell function and calcium was found only in women. Similar results were found in medication-free women and men, as well as in pre- and postmenopausal women. Subjects with low calcium levels had the lowest concentration of glucose and the least insulin resistance, whereas subjects with high calcium levels had the highest concentration of glucose and insulin resistance in women but not in men. This relationship remained after calcium was adjusted for 25-OH vitamin D and parathyroid hormone. Our results suggest that alteration of serum calcium homeostasis is significantly correlated with the abnormality of glucose level, insulin resistance, and beta-cell function.

The reactive aldehydes methylglyoxal and glyoxal, arise from enzymatic and non-enzymatic degradation of glucose, lipid and protein catabolism, and lipid peroxidation. In Type 1 diabetes mellitus (T1DM) where hyperglycemia, oxidative stress, and lipid peroxidation are common, these aldehydes may be elevated. These aldehydes form advanced glycation end products (AGEs) with proteins that are implicated in diabetic complications. We measured plasma methylglyoxal and glyoxal in young, complication-free T1DM patients and assessed activity of the ubiquitous membrane enzyme, Na+/K+ ATPase. A total of 56 patients with TIDM (DM group), 6-22 years, and 18 non-diabetics (ND group), 6-21 years, were enrolled. Mean plasma A1C (%) was higher in the DM group (8.5+/-1.3) as compared to the ND group (5.0+/-0.3). Using a novel liquid chromatography-mass spectrophotometry method, we found that mean plasma methylglyoxal (nmol/l) and glyoxal levels (nmol/l), respectively, were higher in the DM group (841.7+/-237.7, 1051.8+/-515.2) versus the ND group (439.2+/-90.1, 328.2+/-207.5). Erythrocyte membrane Na+/K+ ATPase activity (nmol NADH oxidized/min/mg protein) was elevated in the DM group (4.47+/-0.98) compared to the ND group (2.16+/-0.59). A1C correlated with plasma methylglyoxal and glyoxal, and both aldehydes correlated with each other. A high correlation of A1C with Na+/K+ ATPase activity, and a regression analysis showing A1C as a good predictor of activity of this enzyme, point to a role for glucose in membrane alteration. In complication-free patients, increased plasma methylglyoxal, plasma glyoxal, and erythrocyte Na+/K+ ATPase activity may foretell future diabetic complications, and emphasize a need for aggressive management.

Human papillomavirus (HPV) DNA testing has a higher clinical sensitivity than cytology for the detection of high-grade cervical intraepithelial neoplasia or worse (CIN 2؉). However, an improvement in specificity would be desirable. As malignant transformation is induced by HPV E6/E7 oncogenes, detection of E6/E7 oncogene activity may improve specificity and be more predictive of cervical cancer risk. The PreTect HPVProofer assay (Proofer; Norchip) detects E6/E7 mRNA transcripts from HPV types 16, 18, 31, 33, and 45 with simultaneous genotype-specific identification. The clinical performance of this assay was assessed in a crosssectional study of women referred for colposcopy in comparison with the Hybrid Capture 2 (HC2; Qiagen) test, which detects DNA of 13 high-risk oncogenic HPV types collectively. Cervical specimens were collected in PreservCyt, and cytology was performed using the ThinPrep method (Hologic). The samples were processed for HPV detection with Proofer and HC2 and genotyping with the Linear Array method (Roche Molecular Systems). Histology-confirmed CIN 2؉ served as the disease endpoint to assess the clinical performance of the tests. A total of 1,551 women were studied, and of these, 402 (25.9%) were diagnosed with CIN 2؉ on histology. The Proofer assay showed a sensitivity of 78.1% (95% confidence interval [CI], 74.1 to 82.1) versus 95.8% (95% CI, 93.8 to 97.8) for HC2 (P < 0.05) and a specificity of 75.5% (95% CI, 73.0 to 78.0) versus 39.6% (95% CI, 36.8 to 42.4), respectively (P < 0.05). The lower sensitivity and higher specificity of Proofer for detection of CIN 2؉ can be attributed to the fact that this test detects the expression of E6/E7 genes beyond a threshold from a limited number of oncogenic HPV types. In conclusion, Proofer is more specific than HC2 in identifying women with CIN 2؉ but has a lower sensitivity.Numerous nonrandomized studies (19), and more recently randomized clinical trials (3,24,31,34), have clearly established that testing for human papillomavirus (HPV) DNA is significantly more sensitive than Pap cytology for detection of high-grade cervical intraepithelial neoplasia (CIN 2 and CIN 3) or worse (CIN 2ϩ; i.e., CIN 2, CIN 3, squamous cell carcinoma, endocervical adenocarcinoma in situ, and endocervical adenocarcinoma). There are also indications that testing for HPV might be the most effective method of cervical cancer screening in developing countries (36). Moreover, HPV testing would be warranted as a primary screening tool in the era of HPV vaccination (14). While the use of HPV testing in primary cervical cancer screening and triage of borderline cytologic abnormalities have been recommended (37,43,44), HPV testing lacks specificity due to the ubiquitous and transient nature of HPV infection in women, and therefore, the positive predictive value (PPV) tends to be lower than that of cytology (11,19). Most studies on primary screening have evaluated HPV DNA detection tests, especially the Hybrid Capture 2 (HC2; Qiagen) test (10,19). HC2 utilizes a full genomic prob...

Studies aimed at elucidating the immunological and prognostic significance of HLA-DR expression on breast carcinoma cells have yielded contradictory results. To expand on previous studies, we have investigated the associations of tumor cell expression of HLA-DR and its related co-chaperones, invariant chain (Ii) and HLA-DM, with infiltrating inflammatory cells, in situ cytokine mRNA levels and prognosis and outcome in 112 breast carcinoma patients with a median follow-up of 59 months. While the majority of HLA-DR+ tumors co-express Ii, only a minority express HLA-DM. Tumor cell expression of HLA-DR and co-chaperones positively associated with both infiltrating CD4+ and CD8+ T-cell subsets (P < 0.01). Expression of HLA-DR and Ii associated with decreased estrogen receptor alpha levels and younger age at diagnosis, suggesting a role for hormones in the control of HLA class II expression in breast carcinoma. Patients with DR+Ii+DM- tumors had markedly decreased recurrence-free and disease-specific survival as compared with patients with DR+Ii+DM+ tumors (P < 0.05) and HLA-DR/co-chaperone expression was an independent predictor of survival by multivariate Cox regression analysis, controlling for standard prognostic indicators. Tumors that co-express HLA-DR, Ii and HLA-DM have increased levels of IFN-gamma, IL-2 and IL-12 mRNA, suggesting improved survival of patients with DR+Ii+DM+ tumors may be attributable to Th1-dominated immunity. We conclude that expression of determinants of the immune response by tumor cells may influence breast tumor progression and patient outcome.

A dverse drug reactions (ADRs) are a major public health problem given such events are the most common type of injuries experienced by hospitalized patients. 1 ADRs may lead to hospitalization or occur during hospitalization and contribute to an increased length of stay. The recent focus on patient safety and the concern about the number of negative outcomes resulting from drug use, rather than the underlying diseases, has prompted health care professionals to take a critical look at these drug responses. A series of studies examined ADRs among hospitalized patients in the US and Australia 2-6 ; however, less research is available about these events in hospitalized patients in Canada. A US-based metaanalysis revealed that the incidence of serious ADRs in hospitalized patients was 2.1%, with the incidence in those newly admitted to a hospital 4.7%. The same study reported ADRs to be between the fourth and sixth leading cause of death. 6 Other studies have found that ADRs occurred in 2-20% of hospitalized patients. 4-6 Baker et al. provided a national estimate of the incidence of adverse events among adult patients in Canada (7.5 per 100 hospital admissions); after extrapolation, the number of hospital admissions attributed

In Diabetes Mellitus (DM), glucose and the aldehydes glyoxal and methylglyoxal modify free amino groups of lysine and arginine of proteins forming advanced glycation end products (AGEs). Elevated levels of these AGEs are implicated in diabetic complications including nephropathy. Our objective was to measure carboxymethyl cysteine (CMC) and carboxyethyl cysteine (CEC), AGEs formed by modification of free cysteine sulfhydryl groups of proteins by these aldehydes, in plasma proteins of patients with diabetes, and investigate their association with the albumin creatinine ratio (ACR, urine albumin (mg)/creatinine (mmol)), an indicator of nephropathy. Blood was collected from forty-two patients with type 1 and 2 diabetes (18-36 years) and eighteen individuals without diabetes (17-35 years). A liquid chromatography-mass spectrophotometric method was developed to measure plasma protein CMC and CEC levels. Values for ACR and hemoglobin A1C (HbA1C) were obtained. Mean plasma CMC (microg/l) and CEC (microg/l) were significantly higher in DM (55.73 +/- 29.43, 521.47 +/- 239.13, respectively) compared to controls (24.25 +/- 10.26, 262.85 +/- 132.02, respectively). In patients with diabetes CMC and CEC were positively correlated with ACR, as was HbA1C. Further, CMC or CEC in combination with HbA1C were better predictors of nephropathy than any one of these variables alone. These results suggest that glucose, glyoxal, and methylglyoxal may all be involved in the etiology of diabetic nephropathy.