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.     

Workplace Bullying and Suicidal Ideation: A 3-Wave Longitudinal Norwegian Study

Objectives. We examined whether victimization from bullying is related to an increased risk of suicidal ideation over time and whether suicidal ideation is related to subsequent bullying.Methods. In a longitudinal study (2005–2010), we used well-established single-item measures to assess victimization from bullying and suicidal ideation. We used latent Markov models to determine forward and reverse relationships between variables at 3 time points with 2 or 3 years between the measurement points among a randomized nationwide sample of 1846 employees in Norway.Results. Victimization from bullying was associated with subsequent suicidal ideation (odds ratio = 2.05; 95% confidence interval = 1.08, 3.89). Suicidal ideation at baseline was not related to subsequent victimization from workplace bullying.Conclusions. Workplace bullying may be a precursor to suicidal ideation, whereas suicidal ideation seems to have no impact on subsequent risk of being bullied. Regulations against bullying should be integrated into work-related legislation and public health policies.Suicide is a leading cause of death around the globe. Estimates show that more than 800 000 people take their own lives every year.1 In Norway (with a population of 5 165 802) there are about 530 reported suicides every year.2 In the United States, 12 suicide deaths per 100 000 people were reported in 2010, making suicide the 10th leading cause of death among Americans.3 Altogether, 1719 employees committed suicide in US workplaces between 2003 and 2010.4Although psychiatric disorders are involved in the majority of suicide attempts,5 most psychiatric patients do not commit suicide. A psychiatric disorder alone is, therefore, an insufficient condition for suicide.6 To identify other risk factors, we must look beyond the presence of a psychiatric syndrome and understand the underlying factors of suicide and suicidal ideation. Among many potential causes, exposure to workplace bullying has been proposed to be an important predictor of both suicidal ideation and actual suicide.7,8To date, bullying as an antecedent to suicide has been examined only with anecdotal evidence9,10 and cross-sectional research designs.11,12 Einarsen et al.13 established that severely bullied workers were 6 times more likely than nonbullied workers to report suicidal ideations. Sterud et al.8 found that workplace bullying was positively associated with suicidal ideation in a nationwide sample of 1022 Norwegian ambulance personnel. Bullying was more strongly associated with suicidal ideation than were gender, neuroticism, anxiety, somatic complaints, depersonalization, and job dissatisfaction.Cross-sectional research cannot provide adequate evidence for anything more than that suicidal ideation is a correlate of bullying. To understand the directional nature of the association, longitudinal research is needed. In this representative, longitudinal study, we contribute to the literature by examining whether victimization from bullying is related to increased risk of suicidal ideation over time and whether suicidal ideation is related to subsequent bullying.Workplace bullying refers to a situation in which 1 or several individuals persistently perceive themselves to be on the receiving end of negative actions from superiors or co-workers and in which the targets find it difficult to defend themselves against these actions.14,15 Following this definition, there are 3 main characteristics of workplace bullying: (1) an employee becomes the target of systematic negative and unwanted social behavior in the workplace; (2) the exposure occurs over a prolonged period, often with ever more escalating intensity and frequency in the attacks; and (3) targets feel they cannot easily escape the situation or stop the unwanted treatment. This third characteristic, the feeling of being victimized by the harassment, distinguishes bullying from other forms of mistreatment in the workplace.15 Globally, about 11% of workers perceive themselves as victims of bullying,16 and 5% of the Norwegian working population is victimized by bullying at any time.17The interpersonal theory of suicide (ITS)5 provides a theoretical foundation for how exposure to such bullying may be related to suicide. The theory posits that fundamental to suicidal ideation and behavior is that an individual has both the desire and the ability to die by suicide.18 With regard to the desire to die, displayed through suicidal ideation, the ITS asserts that when people over a prolonged period perceive themselves to be socially alienated from others and simultaneously feel that they are a burden on others, they develop a desire for death.19 As for the ability to commit suicide, displayed through suicidal behavior, the ITS proposes that people who are repeatedly exposed to painful and provocative events will lose any fear of pain, injury, and death and thereby be able to overcome the instinct of self-preservation.Because of its focus on persistent exposure to painful events and social alienation, the ITS strongly suggests that repeated and long-term exposure to negative treatment and social exclusion from one’s peers or supervisors at work constitutes a risk factor for suicidal ideation and behavior.Although previous research has assumed bullying to be an antecedent to suicidal ideation, it is possible that the established cross-sectional association reflects a relationship in which suicidal ideation is a precursor to bullying. Two different mechanisms can explain such a reverse association. First, employees with suicidal ideation may report less favorable work characteristics because their distress makes them evaluate their work environment increasingly more negatively.20 Second, employees with suicidal ideations may elicit aggressive behavior in others because their psychological state creates aversive feelings among co-workers and supervisors.21,22To provide better indications of how workplace bullying is related to suicidal ideation, we investigated direct forward and reverse associations with longitudinal data. We tested the following hypotheses:

• Hypothesis 1: Victimization from bullying is associated with an increased risk of later suicidal ideation.
• Hypothesis 2: Suicidal ideation is associated with an increased risk of later victimization from bullying.

     

Serum Galectin-3 and Subsequent Risk of Coronary Heart Disease in Subjects With Childhood-Onset Type 1 Diabetes: A Cohort Study

OBJECTIVETo study whether serum galectin-3 and other biomarkers of inflammation predict coronary heart disease (CHD) in subjects with long-standing childhood-onset type 1 diabetes.RESEARCH DESIGN AND METHODSA population-based nationwide cohort of 299 subjects with type 1 diabetes diagnosed in Norway at <15 years of age during 1973–1982 was examined in 2002–2003 at a mean age of 33 years (range 21–44), with mean diabetes duration of 24 years (range 19–30). Subjects were followed through 31 December 2017 for their first CHD event registered by a hospitalization or cause of death using nationwide registries. Stored serum samples were available for 296 subjects and analyzed for interleukin-6 (IL-6), IL-6 receptor, IL-18, hs-CRP, matrix metalloproteinase-9, tissue inhibitor of metalloproteinase-1 (TIMP-1), galectin-3, and high-sensitivity troponin T. Adjusted hazard ratios (aHRs) for CHD per SD increase in biomarker were estimated using Cox regression.RESULTSOf 295 subjects, 40 (13.6%) had a documented CHD event during a mean follow-up of 14.4 years (range 0.5–16). IL-6 (aHR 1.32 [95% CI 1.07–1.63]), galectin-3 (aHR 1.44 [95% CI 1.09–1.80]), and TIMP-1 (aHR 1.37 [95% CI 1.04–1.81]) were significant predictors of CHD after adjustment for conventional risk factors.CONCLUSIONSGalectin-3 was significantly associated with future CHD in subjects with type 1 diabetes, and if the results are replicated in larger studies, it may aid in prediction together with conventional risk factors for CHD.     

Graft function 1 year after pregnancy in an islet‐transplanted patient

Pancreatic islet transplantation is a treatment option for patients with type 1 diabetes (T1D), but pregnancy has generally not been advised for women after receiving an islet allograft. We hereby describe what is to our knowledge the first successful pregnancy and persistent graft function in a woman 4 years after her initial islet transplantation. A 37‐year‐old woman with brittle type 1 diabetes was transplanted with two separate islet graft infusions, eventually becoming insulin independent. Ten months after her second transplantation, her immunosuppression was switched from tacrolimus and sirolimus to tacrolimus, azathioprine, and prednisolone, due to her wish to become pregnant. She became pregnant one year later, and after 38 weeks of uncomplicated pregnancy, she gave birth to a healthy child by C‐section. The current report suggests that pregnancy and childbirth can be accomplished after islet transplantation without loss of islet graft function.     

The effect of educational level on the incidence of asthma and respiratory symptoms

Few studies have examined the impact of socioeconomic status on the incidence of asthma and respiratory symptoms. Between 1985 and 1996/97, we conducted an 11-years community cohort study with 2819 subjects, aged 15-70 years at baseline, in Western Norway. We examined the cumulative incidence of asthma and respiratory symptoms by educational level (primary, secondary, and university), as well as estimating the odds ratios (ORs) of educational level on the incidences, after adjustment for sex, age, hay fever, smoking habits, pack years, and occupational exposure. For all respiratory symptoms, the incidences decreased with increasing educational level. The cumulative incidence of asthma was 5.3%, 4.1%, and 1.8%, respectively, for those with a primary educational level, secondary educational level, and university level. Subjects with a primary educational level had adjusted ORs (95% CI) from 1.4 (0.9, 2.3) for the incidence of chronic cough to 2.5 (1.6, 4.0) for the incidence of dyspnea grade 2, compared to those with a university level education. The adjusted OR (95% CI) for the incidence of asthma was 2.1 (1.01, 4.4) in subjects with a primary educational level, and 2.0 (1.04, 3.6) in subjects with a secondary educational level, compared to subjects with a university educational level. In conclusion, subjects with a lower educational level had a higher risk of developing asthma and respiratory symptoms, after adjustment for sex, age, hay fever, smoking, and occupational exposure.     

Stem cell marker-positive stellate cells and mast cells are reduced in benign-appearing bladder tissue in patients with urothelial carcinoma

Survival after invasive bladder cancer has improved less than that of other common non-skin cancers. In many types of malignancy, treatment failure has been attributed to therapy-resistant stem-like cancer cells. Our aim was therefore to determine identities of stem cell marker-positive cells in bladder cancer tissue and to investigate possible associations between these cells and different forms of bladder neoplasia. We investigated tissue from 52 patients with bladder neoplasia and 18 patients with benign bladder conditions, from a cohort that had been previously described with regard to diagnosis and outcome. The samples were analysed immunohistologically for the stem cell markers aldehyde dehydrogenase 1 A1 (ALDH1) and CD44, and markers of cell differentiation. The majority of stem cell marker-positive cells were located in connective tissue, and a smaller fraction in epithelial tissue. Stem cell marker-positive cells exhibiting possible stem cell characteristics included cells in deeper locations of benign and malignant epithelium, and sub-endothelial cells in patients with or without neoplasia. Stem cell marker-positive cells with non-stem cell character included stellate cells, mast cells, endothelial cells, foamy histiocytes, and neurons. Significantly, ALDH1+ stellate cells and ALDH1+ mast cells were reduced in number in stroma of benign-appearing mucosa of bladder cancer patients. The stem cell markers ALDH1 and CD44 label several types of differentiated cells in bladder tissue. ALDH1+ stellate cells and mast cells appear to be reduced in stroma of normal-appearing mucosa of bladder cancer patients, and may be part of a “field effect” in cancer-near areas.     

Nonadherence to treatment causing acute hospitalizations in people with epilepsy: An observational,prospective study

The aim was to assess the clinical relevance of antiepileptic drug (AED) nonadherence by means of therapeutic drug concentration monitoring (TDM). Two hundred eighty‐two consecutive patients with epilepsy acutely admitted to hospital for seizures were included. Nonadherence was defined as having a serum concentration/dose ratio at admission of <75% of the patient's own control value (probable nonadherence: 50–75%; definite: <50%). Nonadherence was identified in 39% of patients (definite 24%; probable 15%). It was significantly more common in patients with generalized seizures compared to those with focal onset seizures, and in patients <30 years compared to older patients. When specifically asked, 44% of nonadherent patients claimed regular intake. Nonadherence is a major cause of seizure breakthrough in patients with epilepsy, particularly in young adults. Many patients seem to be unaware of missed drug intake. Prompt measurements of AED serum concentrations should be available as part of the emergency care for patients acutely hospitalized for seizures to permit this issue to be thoroughly addressed prior to discharge.     

Extreme sarcoplasmic reticulum volume loss and compensatory T-tubule remodeling after Serca2 knockout

Cardiomyocyte contraction and relaxation are controlled by Ca(2+) handling, which can be regulated to meet demand. Indeed, major reduction in sarcoplasmic reticulum (SR) function in mice with Serca2 knockout (KO) is compensated by enhanced plasmalemmal Ca(2+) fluxes. Here we investigate whether altered Ca(2+) fluxes are facilitated by reorganization of cardiomyocyte ultrastructure. Hearts were fixed for electron microscopy and enzymatically dissociated for confocal microscopy and electrophysiology. SR relative surface area and volume densities were reduced by 63% and 76%, indicating marked loss and collapse of the free SR in KO. Although overall cardiomyocyte dimensions were unaltered, total surface area was increased. This resulted from increased T-tubule density, as revealed by confocal images. Fourier analysis indicated a maintained organization of transverse T-tubules but an increased presence of longitudinal T-tubules. This demonstrates a remarkable plasticity of the tubular system in the adult myocardium. Immunocytochemical data showed that the newly grown longitudinal T-tubules contained Na(+)/Ca(2+)-exchanger proximal to ryanodine receptors in the SR but did not contain Ca(2+)-channels. Ca(2+) measurements demonstrated a switch from SR-driven to Ca(2+) influx-driven Ca(2+) transients in KO. Still, SR Ca(2+) release constituted 20% of the Ca(2+) transient in KO. Mathematical modeling suggested that Ca(2+) influx via Na(+)/Ca(2+)-exchange in longitudinal T-tubules triggers release from apposing ryanodine receptors in KO, partially compensating for reduced SERCA by allowing for local Ca(2+) release near the myofilaments. T-tubule proliferation occurs without loss of the original ordered transverse orientation and thus constitutes the basis for compensation of the declining SR function without structural disarrangement.