Autoantibodies against 21-hydroxylase and side-chain cleavage enzyme in autoimmune Addison's disease are mainly immunoglobulin G1

OBJECTIVE: Immunoglobulin G (IgG) antibodies to the steroidogenic enzymes 21-hydroxylase (21OH) and side-chain cleavage enzyme (SCC) are important diagnostic markers for autoimmune Addison's disease and autoimmune polyendocrine syndromes (APS) types I and II. The characterization of autoantibody (IgG) subclasses may reveal information on how tIssue destruction takes place; therefore, IgG subtypes of anti-21OH and anti-SCC antibodies from sera of patients with Addison's disease, APS I and APS II were determined using recombinant 21OH and SCC. METHODS: SCC(51-521) and his-SCC(51-521) were expressed by pET-scc in the Escherichia coli strain BL21 Star (DE3) and inclusion bodies were purified. Full-length, human 21OH fused to an N-terminal 6x histidine affinity tag was expressed in insect cells by using the baculovirus expression system bac-to-bac. Western blots were used to investigate the IgG subtype(s) of the autoantibodies against 21OH and SCC in patients and healthy blood donors. RESULTS: All anti-SCC positive sera (n=10) contained autoantibodies of the IgG1 subclass, while four out of ten also contained IgG3. All anti-21OH positive sera (n=16) had autoantibodies exclusively against IgG1. Sera from 20 healthy subjects did not show any reactivity against 21OH or SCC. CONCLUSIONS: The finding of a predominating IgG1 response against 21OH and SCC may suggest that T helper (Th) cells of the Th1 subclass are involved in destruction of the adrenal cortex in patients with autoimmune Addison's disease.     

Incisional hernia after surgery for colorectal cancer: a population-based register study

Background

Our knowledge on the incidence of incisional hernia and risk factors for developing incisional hernia following surgery for colorectal cancer is far from complete.

Methods

All procedures registered in the Swedish Colorectal Cancer Register (SCRCR) 2007–2013 were identified. Patients with comorbid disease diagnoses, registered at admissions and visits prior to the procedure and relevant to this study, were obtained from the National Patient Register (NPR). These diagnoses included cardiovascular disease, connective tissue disorders, liver cirrhosis, renal failure, diabetes, chronic obstructive lung disease and chronic inflammatory conditions. Data on occurrence of incisional hernias were obtained by combining data from the SCRCR and the NPR (International Classification of Diseases code).

Results

During 2007–2013, 39,984 procedures were registered in the SCRCR. After excluding laparoscopic procedures, procedures repeated on the same patient, procedures with concomitant liver resection and procedures without laparotomy, 28,913 cases remained for analysis. Five years after surgery, the cumulative incidence of incisional hernia was 5.3%. In multivariate proportional hazard analysis, significantly increased risk for incisional hernia was found for the male gender (hazard ratio [HR] 1.40, 95% confidence interval [CI] 1.21–1.62), operation time exceeding 180 min (HR 1.25, CI 1.08–1.45), body mass index (BMI) >?30 (HR 1.78, CI 1.51–2.09), age <?70 years (HR 1.34, CI 1.16–1.56) and postoperative wound complication (HR 2.09, CI 1.70–2.58).

Discussion

Men, patients younger than 70 years and patients with BMI?>?30 face a higher risk for incisional hernia. The risk is also increased in cases where the procedure takes longer than 3 h or where postoperative wound complications occur. These patients will benefit from measures aimed at preventing the development of incisional hernia.

     

Improvement in diagnostic delays over time in patients with hereditary angioedema: findings from the Icatibant Outcome Survey

The objective of this analysis was to evaluate the change over time in age at first symptoms, age at diagnosis, and delay in diagnosis using data from the Icatibant Outcome Survey (IOS). Patients with a diagnosis of C1-INH-HAE who were born before the year 1990 and who were diagnosed before they reached 25 years of age were included in the analysis. Both age at diagnosis and delay in diagnosis of C1-INH-HAE appear to decline with later decade of birth, despite wide variation across the countries assessed, suggesting that improved disease awareness causes increased rates of earlier diagnosis over time. Our findings demonstrate that some patients are still experiencing long delays to diagnosis, indicating an ongoing need for improved disease awareness.     

Sensitivity of regression calibration to non‐perfect validation data with application to the Norwegian Women and Cancer Study

Measurement error occurs when we observe error‐prone surrogates, rather than true values. It is common in observational studies and especially so in epidemiology, in nutritional epidemiology in particular. Correcting for measurement error has become common, and regression calibration is the most popular way to account for measurement error in continuous covariates. We consider its use in the context where there are validation data, which are used to calibrate the true values given the observed covariates. We allow for the case that the true value itself may not be observed in the validation data, but instead, a so‐called reference measure is observed. The regression calibration method relies on certain assumptions.This paper examines possible biases in regression calibration estimators when some of these assumptions are violated. More specifically, we allow for the fact that (i) the reference measure may not necessarily be an ‘alloyed gold standard’ (i.e., unbiased) for the true value; (ii) there may be correlated random subject effects contributing to the surrogate and reference measures in the validation data; and (iii) the calibration model itself may not be the same in the validation study as in the main study; that is, it is not transportable. We expand on previous work to provide a general result, which characterizes potential bias in the regression calibration estimators as a result of any combination of the violations aforementioned. We then illustrate some of the general results with data from the Norwegian Women and Cancer Study. Copyright © 2015 John Wiley & Sons, Ltd.     

The impact of pharmaceutical care interventions for medication underuse in older people: a systematic review and meta-analysis

Aims

The aim of the present study was to conduct a meta-analysis of controlled trials assessing the impact of pharmaceutical care interventions (e.g. medication reviews) on medication underuse in older patients (≥65 years).

Methods

The databases MEDLINE and EMBASE were searched for controlled studies, and data on interventions, patient characteristics and exposure, and outcome assessment were extracted. Risk of bias was assessed using the Cochrane Collaboration’s ‘risk of bias’ table. Results from reported outcomes were synthesized in multivariate random effects meta-analysis, subgroup meta-analysis and meta-regression.

Results

From 954 identified articles, nine controlled studies, mainly comprising a medication review, were included (2542 patients). These interventions were associated with significant reductions in the mean number of omitted drugs per patient (estimate from six studies with 1469 patients: – 0.44; 95% confidence interval –0.61, –0.26) and the proportion of patients with ≥1 omitted drugs (odds ratio from eight studies with 1833 patients: 0.29; 95% confidence interval 0.13, 0.63). The only significant influential factor for improving success was the utilization of explicit screening instruments when conducting a medication review (P = 0.033).

Conclusion

Pharmaceutical care interventions, including medication reviews, can significantly reduce medication underuse in older people. The use of explicit screening instruments alone or in combination with implicit reasoning is strongly recommendable for clinical practice.     

Tele-monitoring of home blood pressure in treated hypertensive patients

AIM: To compare the accuracy of clinic blood pressure (CBP) and telemedical home blood pressure (HBP) measurement in the assessment of antihypertensive effect. METHODS: 362 patients on antihypertensive medication performed HBP measurement (5 days, duplicate measurements, four times daily) and ambulatory blood pressure (ABP) monitoring in random order. Main outcome measure was the agreement of CBP and HBP with daytime ABP. RESULTS: CBP was much higher than ABP and average HBP (p < 0.001). There was a progressive decline in HBP over the course of the study, achieving the level of daytime ABP on the last 2 monitoring days. The correlation between CBP and ABP was weak (systolic: r = 0.343, diastolic r = 0.430), whereas strong correlations existed between HBP and ABP (systolic r = 0.804, diastolic r = 0.776). A progressive improvement in the strength of the correlation between average HBP of single days and ABP was obtained over the 5 monitoring days. The HBP readings taken in the afternoon showed a stronger correlation with ABP than the values measured in the morning, at noon and in the evening. Averaging more HBP readings taken on succeeding days resulted in a progressive improvement in the agreement with ABP with a further benefit when readings of day 1 were included. CONCLUSIONS: The accuracy of telemedical HBP measurement is substantially better than that of CBP. The results suggest, that HBP should be measured for 5 days, and afternoon measurements should be preferred in assessing control of hypertension.     

Undifferentiated pelvic adenocarcinomas: diagnostic potential of protein profiling and multivariate analysis

Background and aims Despite improved techniques, the determination of tumor origin in poorly differentiated adenocarcinomas still remains a challenge for the pathologist. Here we report the use of protein profiling combined with principal component analysis to improve diagnostic decision-making in tumor samples, in which standard pathologic investigations cannot present reliable results. Materials and methods A poorly differentiated adenocarcinoma of unknown origin located in the pelvis, infiltrating the sigmoid colon as well as the ovary, served as a model to evaluate our proteomic approach. Firstly, we characterized the protein expression profiles from eight advanced colon and seven ovarian adenocarcinomas using two-dimensional gel electrophoresis (2-DE). Qualitative and quantitative patterns were recorded and compared to the tumor of unknown origin. Based on these protein profiles, match sets from the different tumors were created. Finally, a multivariate principal component analysis was applied to the entire 2-DE data to disclose differences in protein patterns between the different tumors. Results Over 89% of the unknown tumor sample spots could be matched with the colon standard gel, whereas only 63% of the spots could be matched with the ovarian standard. In addition, principal component analysis impressively displayed the clustering of the unknown case within the colon cancer samples, whereas this case did not cluster at all within the group of ovarian adenocarcinomas. Conclusion These results show that 2-DE protein expression profiling combined with principal component analysis is a sensitive method for diagnosing undifferentiated adenocarcinomas of unknown origin. The described approach can contribute greatly to diagnostic decision-making and, with further technical improvements and a higher throughput, become a powerful tool in the armentarium of the pathologist. UJ Roblick and FG Bader contributed equally to this work and should be recognized as first authors.     

Nongenomic cardiovascular effects of triiodothyronine in euthyroid male volunteers

T(3) has been shown to exert cardiovascular effects. These effects have not yet been defined with regard to the mode of action (nongenomic vs. genomic) and with regard to an interaction with the adrenergic system in humans. To address these issues we conducted a randomized, double blind, 6-fold cross-over trial in 18 healthy male volunteers. After pretreatment with the beta-agonist dobutamine, the beta-blocking agent esmolol, or placebo (0.9% NaCl), 100 microg T(3) or placebo were injected. Primary target variables were systemic vascular resistance (SVR) and cardiac output (CO) within 45 min after injection of T(3) vs. placebo after placebo pretreatment. Sympatho-vagal balance was assessed by measurement of heart rate variability. T(3) caused a lower SVR and a higher CO than placebo (P < 0.001) after pretreatment with placebo. An increased low frequency (LF)/high frequency (HF) ratio (power in LF/power in HF band) after T(3) compared with placebo (P = 0.004) suggests an increase in sympathetic tone. After pretreatment with dobutamine, the effects of T(3) on SVR and CO were abolished, and the effect on LF/HF ratio was reversed. After pretreatment with esmolol, the effects on SVR and LF/HF ratio were reversed. Our data show, for the first time, nongenomic cardiovascular effects of T(3) in humans.