Recognition of a subregion of human proinsulin by class I-restricted T cells in type 1 diabetic patients

Proinsulin is a key autoantigen in type 1 diabetes. Evidence in the mouse has underscored the importance of the insulin B chain region in autoimmunity to pancreatic beta cells. In man, a majority of proteasome cleavage sites are predicted by proteasome cleavage algorithms within this region. To study CD8+ T cell responses to the insulin B chain and adjacent C peptide, we selected 8- to 11-mer peptides according to proteasome cleavage patterns obtained by digestion of two peptides covering proinsulin residues 28 to 64. We studied their binding to purified HLA class I molecules and their recognition by T cells from diabetic patients. Peripheral blood mononuclear cells from 17 of 19 recent-onset and 12 of 13 long-standing type 1 diabetic patients produced IFN-gamma in response to proinsulin peptides as shown by using an ELISPOT assay. In most patients, the response was against several class I-restricted peptides. Nine peptides were recognized within the proinsulin region covering residues 34 to 61. Four yielded a high frequency of recognition in HLA-A1 and -B8 patients. Three peptides located in the proinsulin region 41-51 were shown to bind several HLA molecules and to be recognized in a high percentage of diabetic patients.     

Long‐term effects of a preoperative smoking cessation programme

Introduction: Preoperative smoking intervention programmes reduce post‐operative complications in smokers. Little is known about the long‐term effect upon smoking cessation. Aim: To discover long‐term quit rates and the reasons behind successful cessation. Materials and Methods: 101 one of 120 smokers, randomised to smoking intervention or no intervention before hip and knee surgery, completed questionnaires concerning smoking after 1 year. We selected representative men and women for focus group interviews. Results: Significantly more patients from the intervention group abstained from smoking for 1 year post‐operatively [13 in 60 patients (22%) vs 2 in 60 (3%), P < 0.01]. Sex (male), low nicotine dependency, non‐smoking spouse and preoperative smoking intervention were related to smoking cessation. All patients gave the same reasons for smoking cessation: improved health and saving money. Follow‐up for 5 years showed 17% of the controls and 8% in the intervention group (P = 0.42) had died. Conclusion: The intervention group had a significantly higher quit rate 1 year after a preoperative smoking cessation programme. Please cite this paper as: Villebro NM, Pedersen T, Møller AM and Tønnesen H. Long‐term effects of a preoperative smoking cessation programme. The Clinical Respiratory Journal 2008; 2: 175–182.     

Aortic valve stenosis: fatal natural history despite normal left ventricular function and low invasive peak-to-peak pressure gradients

For many years, the severity of valvular aortic stenosis (AS) was evaluated mainly on the basis of cardiac catheterization. In many centers, the handy peak-to-peak transvalvular pressure difference or 'peak-to-peak gradient' in relation to left ventricular function was used as a crucial feature in taking a decision regarding valve substitution. In a prospective study during the period 1994-1997, 150 consecutive patients with AS were examined systematically using cardiac catherization as well as transthoracic (TTE) and transesophageal echocardiography. The study was performed in order to compare the diagnostic accuracy and reproducibility of the three modalities with the purpose of improving our evaluation strategy. We found that the three methods were able to determine the aortic valve area with similar accuracy and reproducibility. The data thus support earlier papers and the currently recommended strategy of managing most patients on the basis of TTE since this approach is more rapid and gentle to the patients. In accordance with the past policy of our department, however, considerable weight was put on the invasive data during the study period. Thus, 12 patients with invasive peak-to-peak gradient <50 mm Hg and no severe depression of left ventricular function were not offered valve replacement, despite symptoms and significant valve area reductions. At 2.5 years of follow-up, 6 had died, 3 of severe heart failure, 2 while awaiting scheduled valve replacement, and 1 during aortocoronary bypass surgery. Another 3 patients later experienced further symptom progression and underwent successful aortic valve replacement. In the remaining 3 patients, all free from coronary stenoses and other valvular heart disease than AS, heart failure symptoms had worsened considerably during continued medical therapy. In conclusion, we do not recommend consideration of the peak-to-peak gradient in the process of deciding whether or not AS patients should receive valve replacement. A low peak-to-peak gradient does not exclude severe AS, even in the presence of preserved left ventricular function.     

A Prospective,Randomized Study: Switch Off the Sacral Nerve Stimulator During the Night?

Purpose Sacral nerve stimulation is an effective treatment for fecal incontinence. Some have recommended to “switch off” the pacemaker during the night to extend the lifetime of the expensive pacemaker. This study was designed to investigate whether a nightly “switch off” affects the clinical results of sacral nerve stimulation. Methods Twenty patients successfully treated with sacral nerve stimulation (19 females; median age, 59 (range, 36–72) years) were randomized to: Group A, pacemaker continuously “on” for three weeks followed by three weeks with the pacemaker “off” during the night, or Group B, opposite order. Daily bowel-habit diary, Wexner, and St. Mark’s incontinence scores were obtained. Results One failed to return the daily bowel-habit diary, leaving 19 participating patients. Median Wexner incontinence score increased from 6 (range, 2–14) to 7 (range, 3–16) during the “off” period (P = 0.04), whereas St. Mark’s incontinence score increased from 10 (range, 3–16) to 11 (range, 3–18; P = 0.03). Median number of days with soiling per three weeks increased from 0 (range, 0–12) to 1 (range, 0–15) during the “off” period (P = 0.008). Seven of 19 had more days with soiling during the “off” period. Defecation frequency per three weeks increased from 26 (range, 11–71) to 34 (range, 9–70) during the “off” period (P = 0.19). Only four continued with a nightly “switch off” after the study. Conclusions It could be considered to recommend compliant patients to “switch off” the pacemaker during the night to extend the lifetime of the pacemaker. One-third experienced increased soiling, and they should turn the pacemaker on all day and night. Among the remaining, only a minor proportion will be motivated for turning the pacemaker off. Read at the meeting of the European Society of Coloproctology, Malta, September 26 to 29, 2007.     

Evaluation of [18F]2FP3 in pigs and non‐human primates

So far, no suitable 5‐HT₇R radioligand exists for clinical positron emission tomography (PET) imaging. [¹⁸F]2FP3 was first tested in vivo in cats, and the results were promising for further evaluations. Here, we evaluate the radioligand in pigs and non‐human primates (NHPs). Furthermore, we investigate species differences in 5‐HT₇R binding with [³H]SB‐269970 autoradiography in post‐mortem pig, NHP, and human brain tissue. Specific binding of [¹⁸F]2FP3 was investigated by intravenous administration of the 5‐HT₇R specific antagonist SB‐269970. [³H]SB‐269970 autoradiography was performed as previously described. [¹⁸F]2FP3 was synthesized in an overall yield of 35% to 45%. High brain uptake of the tracer was found in both pigs and NHPs; however, pretreatment with SB‐269970 only resulted in decreased binding of 20% in the thalamus, a 5‐HT₇R–rich region. Autoradiography on post‐mortem pig, NHP, and human tissues revealed that specific binding of [³H]SB‐269970 was comparable in the thalamus of pig and NHP. Despite the high uptake of [¹⁸F]2FP3 in both species, the binding could only be blocked to a limited degree with the 5‐HT₇R antagonists. We speculate that the affinity of the radioligand is too low for imaging the 5‐HT₇Rs in vivo and that part of the PET signal arises from targets other than the 5‐HT₇R.     

Elucidating the Mechanism of Absorption of Fast-Acting Insulin Aspart: The Role of Niacinamide

Pharmaceutical Research - The aim of this work is to investigate the roles of solute carrier family 22 member 18 (SLC22A18) in lipid metabolism and in establishing the tumor phenotype of HepG2...     

Urinary Bisphenol A Levels in Young Men: Association with Reproductive Hormones and Semen Quality

Background: Few human studies have examined bisphenol A (BPA) exposure in relation to semen quality and reproductive hormones in men, and results are divergent.Objectives: We examined associations between urinary BPA concentration and reproductive hormones, as well as semen quality, in young men from the general population.Methods: Our study population consisted of 308 young men from the general population. Urinary BPA concentration was measured by isotope dilution TurboFlow-liquid chromatography–tandem mass spectrometry. We used multiple linear regression analysis to estimate associations between BPA concentration and reproductive hormones and semen quality, adjusting for confounding factors.Results: We found that 98% of the men had detectable urinary levels of BPA. Median (5th–95th percentiles) BPA concentration was 3.25 ng/mL (0.59–14.89 ng/mL). Men with BPA concentrations above the lowest quartile had higher concentrations of serum testosterone, luteinizing hormone (LH), estradiol, and free testosterone compared with the lowest quartile (p_trend ≤ 0.02). Men in the highest quartile of BPA excretion had on average 18% higher total testosterone (95% CI: 8, 28%), 22% higher LH (95% CI: 6, 39%), and 13% higher estradiol (95% CI: 4, 24%) compared with lowest quartile. Men in the highest quartile of BPA also had significantly lower percentage progressive motile spermatozoa compared with men in the lowest quartile (–6.7 percentage points, 95% CI: –11.76, –1.63). BPA was not associated with other semen parameters. Adjusting for dietary patterns did not influence the results.Conclusions: The pattern of associations between BPA and reproductive hormones could indicate an antiandrogenic or antiestrogenic effect, or both, of BPA on the hypothalamic–pituitary–gonadal hormone feedback system, possibly through a competitive inhibition at the receptor level. However, additional research is needed to confirm our findings and to further test the suggested potential mechanisms.Citation: Lassen TH, Frederiksen H, Jensen TK, Petersen JH, Joensen UN, Main KM, Skakkebaek NE, Juul A, Jørgensen N, Andersson AM. 2014. Urinary bisphenol A levels in young men: association with reproductive hormones and semen quality. Environ Health Perspect 122:478–484; http://dx.doi.org/10.1289/ehp.1307309