Impact of gender and androgen status on IGF-I levels in normal and GH-deficient adults

OBJECTIVE: The regulation of IGF-I levels is complex and not only dependent on GH status, as the diagnostic sensitivity of serum IGF-I levels for GH deficiency (GHD) in adults is low. Other GH-related parameters have so far not proven to be of additional diagnostic value in GHD adults. In the present study we evaluated the impact of gender and androgen status on IGF-I levels and the diagnostic value of IGF-I and GH-related parameters in a population of adult hypopituitary patients and age- and gender-matched healthy subjects. DESIGN: A cross-sectional study. SUBJECTS: Fifty-nine GHD patients (40 males, mean age 39.3+/-1.7 (s.e.m.) years, and 19 females, mean age 41.9+/-2.6 years) and 69 healthy subjects (42 males, mean age 36. 7+/-1.5 years, and 27 females, mean age 38.9+/-2.1 years). RESULTS: IGF-I levels were low in the GHD patients (91+/-7 vs 173+/-7 microgram/l, P<0.001), and lower in female patients than in male (68+/-10 vs 100+/-8 microgram/l, P=0.03). In the control group there was no gender-related difference in IGF-I levels (males: 178+/-8, females: 164+/-12 microgram/l, P=0.23). IGF-II and IGF-binding protein-3 (IGFBP-3) were also decreased in GHD without any gender-related differences. GH-binding protein (GHBP) levels were increased in the patient group. The diagnostic sensitivity (%) of IGF-I, IGF-I/GHBP, IGF-I/IGFBP-3, and of the combination of IGF-I plus IGF-II (both low or one normal and one low), was higher in female patients than in male (IGF-I: 57.8 vs 22.0, P<0.0001; IGF-I/GHBP: 84.2 vs 48.8, P=0. 002; IGF-I/IGFBP-3: 36.8 vs 7.3 P=0.001; IGF-I+IGF-II: 77.8 vs 52.6, P=0.01). Testosterone levels were reduced in the female patients compared with female controls (0.5+/-0.3 vs 2.1+/-0.2nmol/l, P<0.001). Forward regression analyses revealed that IGFBP-3 was a significant predictor of IGF-I levels in both patients and healthy subjects. In a combined analysis of both patients and controls, sex hormone-binding globulin (SHBG) level was the main contributor as an explanatory variable. Gender and prolactin also predicted IGF-I in patients, whereas SHBG and estradiol were significant predictors only in the control group. CONCLUSION: (i) Levels of IGF-I, and of IGF-I/IGFBP-3 and IGF-I/GHBP ratios are lower in females compared with male adult GHD patients. (ii) IGF-I/GHBP has a high diagnostic sensitivity of adult GHD, in particular in women. (iii) We hypothesize that the gender difference in IGF-I levels among adult GHD patients are causally related to the very low androgen levels observed among females.     

Tyrphostin AG126 exerts neuroprotection in CNS inflammation by a dual mechanism

The putative protein tyrosine kinase (PTK) inhibitor tyrphostin AG126 has proven beneficial in various models of inflammatory disease. Yet molecular targets and cellular mechanisms remained enigmatic. We demonstrate here that AG126 treatment has beneficial effects in experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis. AG126 alleviates the clinical symptoms, diminishes encephalitogenic Th17 differentiation, reduces inflammatory CNS infiltration as well as microglia activation and attenuates myelin damage. We show that AG126 directly inhibits Bruton's tyrosine kinase (BTK), a PTK associated with B cell receptor and Toll‐like receptor (TLR) signaling. However, BTK inhibition cannot account for the entire activity spectrum. Effects on TLR‐induced proinflammatory cytokine expression in microglia involve AG126 hydrolysis and conversion of its dinitrile side chain to malononitrile (MN). Notably, while liberated MN can subsequently mediate critical AG126 features, full protection in EAE still requires delivery of intact AG126. Its anti‐inflammatory potential and especially interference with TLR signaling thus rely on a dual mechanism encompassing BTK and a novel MN‐sensitive target. Both principles bear great potential for the therapeutic management of disturbed innate and adaptive immune functions. GLIA 2015;63:1083–1099     

Somatic Diseases and Conditions Before the First Diagnosis of Schizophrenia: A Nationwide Population-based Cohort Study in More Than 900 000 Individuals

Objective: Schizophrenia is associated with excess physical comorbidity. Yet, to our knowledge, large studies are lacking on the associations with somatic diseases before the onset of schizophrenia. The authors conducted a nationwide study of the full spectrum of treated somatic diseases before the first diagnosis of schizophrenia. Method: Nationwide sample of the Danish population consisting of singletons (n = 954351) born 1977–1993 and followed from birth to 2009, during which period 4371 developed schizophrenia. Somatic diagnoses at all general hospital contacts (admitted or outpatient care at a somatic hospital) from 1977 to 2009 were used as exposures. The incidence rate ratio (IRR) of schizophrenia was calculated using Poisson regression adjusted for confounders. Results: Among the 4371 persons who developed schizophrenia from 1992 to 2009, a total of 4180 (95.6%) persons had a previous somatic hospital contact. A history of any somatic hospital contact was associated with an elevated risk of schizophrenia (IRR = 2.04, 95% CI = 1.77–2.37). A wide range of somatic diseases and conditions were associated with an increased risk of schizophrenia, including epilepsy (IRR = 2.26, 95% CI = 1.93–2.62), nutritional or metabolic disorders (IRR = 1.57, 95% CI = 1.39–1.77), circulatory system diseases (IRR = 1.63, 95% CI= 1.38–1.92), and brain injury (IRR = 1.58, 95% CI = 1.45–1.72). Conclusions: A wide range of potential etiological factors could have contributed to the observed associations, including genetic or physiological overlaps between conditions, and interacting immunological, behavioral, and neurodevelopmental factors.Key words: schizophrenia, risk factors, physical illness     

Narrowing of the radicular pulp space in coronally restored teeth

Objectives

Narrowed radicular pulp spaces are frequently observed in teeth wearing extended restorations. The present study investigates whether the narrowing of particularly the radicular pulp space can be attributed to coronal restorations.

Materials and methods

The study is based on an anonymized copy of the cone-beam computed tomography (CBCT) database from the Center of Dental Medicine of the University of Zurich. One hundred CBCT scans were selected out of 7317 data sets to match either a crowned (group A; n = 50) or a filled tooth (group B; n = 50) with a contralateral healthy, unrestored, and caries-free control tooth at the same position, respectively. Cross-sectional images were adjusted in the coronal, middle, and apical root third of each subjected tooth. Screenshots were taken in that position and analyzed. The area occupied by the pulp space was determined as percentage area of the whole root diameter on each cross section. The resulting values were compared between restored and control teeth.

Results

In both groups (crowned and filled teeth) and in all the three root thirds, the radicular pulp space was significantly narrower in the restored teeth compared to the control teeth. The strongest narrowing effect was observed in the coronal root third and it decreased towards the apical root third (both groups).

Conclusions

Teeth with coronal restorations show within the limitations of the present study a significant narrowing of their radicular pulp space.

Clinical relevance

The asserted narrowing could have a complicating effect if root canal treatment becomes necessary in those teeth.

     

Effect of Continuous Glucose Monitoring Accuracy on Clinicians’ Retrospective Decision Making in Diabetes: A Pilot Study

Background:

The use of continuous glucose monitoring (CGM) in clinical decision making in diabetes could be limited by the inaccuracy of CGM data when compared to plasma glucose measurements. The aim of the present study is to investigate the impact of CGM numerical accuracy on the precision of diabetes treatment adjustments.

Method:

CGM profiles with maximum 5-day duration from 12 patients with type 1 diabetes treated with a basal-bolus insulin regimen were processed by 2 CGM algorithms, with the accuracy of algorithm 2 being higher than the accuracy of algorithm 1, using the median absolute relative difference (MARD) as the measure of accuracy. During 2 separate and similar occasions over a 1-month interval, 3 clinicians reviewed the processed CGM profiles, and adjusted the dose level of basal and prandial insulin. The precision of the dosage adjustments were defined in terms of the interclinician agreement and the intraclinician reproducibility of the decisions. The Cohen’s kappa coefficient was used to assess the precision of the decisions. The study was based on retrospective and blind CGM data.

Results:

For the interclinician agreement, in the first occasion, the kappa of algorithm 1 was .32, and that of algorithm 2 was .36. For the interclinician agreement, in the second occasion, the kappas of algorithms 1 and 2 were .17 and .22, respectively. For the intraclinician reproducibility of the decisions, the kappas of algorithm 1 were .35, .22, and .80 and the kappas of algorithm 2 were .44, .52, and .32, for the 3 clinicians, respectively. For the interclinician agreement, the relative kappa change from algorithm 1 to algorithm 2 was 86.06%, and for the intraclinician reproducibility, the relative kappa change from algorithm 1 to algorithm 2 was 53.99%.

Conclusions:

Results indicated that the accuracy of CGM algorithms might potentially affect the precision of the CGM-based insulin adjustments for type 1 diabetes patients. However, a larger study with several clinical centers, with higher number of clinicians and patients is required to validate the impact of CGM accuracy on decisions precision.     

MicroRNAs and their role for T stage determination and lymph node metastasis in early colon carcinoma

Worldwide, colon cancer is among the most common cancer entities. Understanding the molecular background is the key to enable accurate stage determination, which is crucial to assess optimal therapy options. The search for preoperative biomarkers is ongoing. In recent years, several studies have proposed a diagnostic and prognostic role for miRNAs in cancer. Aim of this study was to evaluate miRNA expression patterns correlating with tumor stage, especially lymph node metastasis, in primary colon carcinoma tissue. Screening was accomplished using GeneChip^® miRNA v3.0 arrays (Thermo Fisher Scientific, Waltham, MA, USA) and validated via TaqMan^® qPCR assays (Thermo Fisher Scientific, Waltham, MA, USA) to investigate miRNA expressions in 168 FFPE and 83 fresh frozen colon carcinoma samples. Regarding lymph node status, analyses displayed no significantly differential miRNA expression. Interestingly, divergent expression of miR-18a-5p, miR-20a-5p, miR-21-5p, miR-152-3p and miR-1973 was detected in stage pT1. Although miRNAs might not represent reliable biomarkers regarding lymph node metastasis status, they could support risk assessment in stage T1 tumors.     

Assessing a single targeted next generation sequencing for human leukocyte antigen typing protocol for interoperability,as performed by users with variable experience

Background

A simplified protocol for HLA-typing -by NGS, developed for use with the Illumina MiSeq, was performed by technologists with varying NGS experience to assess accuracy and reproducibility.