Renal expression and serum levels of high mobility group box 1 protein in lupus nephritis

INTRODUCTION: High mobility group box 1 protein (HMGB1) is a nuclear DNA binding protein acting as a pro-inflammatory mediator following extracellular release. HMGB1 has been increasingly recognized as a pathogenic mediator in several inflammatory diseases. Elevated serum levels of HMGB1 have been detected in autoimmune diseases including Systemic lupus erythematosus (SLE). However, the local expression of HMGB1 in active lupus nephritis (LN) is not known. Here we aimed to study both tissue expression and serum levels of HMGB1 in LN patients with active disease and after induction therapy. METHODS: Thirty-five patients with active LN were included. Renal biopsies were performed at baseline and after standard induction therapy; corticosteroids combined with immunosuppressive drugs. The biopsies were evaluated according to the World Health Organization (WHO) classification and renal disease activity was estimated using the British Isles lupus assessment group (BILAG) index. Serum levels of HMGB1 were analysed by western blot. HMGB1 expression in renal tissue was assessed by immunohistochemistry at baseline and follow-up biopsies in 25 patients. RESULTS: Baseline biopsies showed WHO class III, IV or V and all patients had high renal disease activity (BILAG A/B). Follow-up biopsies showed WHO I to II (n = 14), III (n = 6), IV (n = 3) or V (n = 12), and 15/35 patients were regarded as renal responders (BILAG C/D). At baseline HMGB1 was significantly elevated in serum compared to healthy controls (P < 0.0001). In all patients, serum levels decreased only slightly; however, in patients with baseline WHO class IV a significant decrease was observed (P = 0.03). Immunostaining revealed a pronounced extranuclear HMGB1 expression predominantly outlining the glomerular endothelium and in the mesangium. There was no clear difference in HMGB1 expression comparing baseline and follow-up biopsies or any apparent association to histopathological classification or clinical outcome. CONCLUSIONS: Renal tissue expression and serum levels of HMGB1 were increased in LN. The lack of decrease of HMGB1 in serum and tissue after immunosuppressive therapy in the current study may reflect persistent inflammatory activity. This study clearly indicates a role for HMGB1 in LN

Prospective evaluation of improving fluoroquinolone exposure using centralised therapeutic drug monitoring (TDM) in patients with tuberculosis (PERFECT): a study protocol of a prospective multicentre cohort study

Introduction Global multidrug-resistant tuberculosis (MDR-TB) treatment success rates remain suboptimal. Highly active WHO group A drugs moxifloxacin and levofloxacin show intraindividual and interindividual pharmacokinetic variability which can cause low drug exposure. Therefore, therapeutic drug monitoring (TDM) of fluoroquinolones is recommended to personalise the drug dosage, aiming to prevent the development of drug resistance and optimise treatment. However, TDM is considered laborious and expensive, and the clinical benefit in MDR-TB has not been extensively studied. This observational multicentre study aims to determine the feasibility of centralised TDM and to investigate the impact of fluoroquinolone TDM on sputum conversion rates in patients with MDR-TB compared with historical controls. Methods and analysis Patients aged 18 years or older with sputum smear and culture-positive pulmonary MDR-TB will be eligible for inclusion. Patients receiving TDM using a limited sampling strategy (t=0 and t=5 hours) will be matched to historical controls without TDM in a 1:2 ratio. Sample analysis and dosing advice will be performed in a centralised laboratory. Centralised TDM will be considered feasible if &gt;80% of the dosing recommendations are returned within 7 days after sampling and 100% within 14 days. The number of patients who are sputum smear and culture-negative after 2 months of treatment will be determined in the prospective TDM group and will be compared with the control group without TDM to determine the impact of TDM. Ethics and dissemination Ethical clearance was obtained by the ethical review committees of the 10 participating hospitals according to local procedures or is pending (online supplementary file 1). Patients will be included after obtaining written informed consent. We aim to publish the study results in a peer-reviewed journal. Trial registration number ClinicalTrials.gov Registry (NCT03409315)

COVID-19-related stigma among infected people in Sweden; psychometric properties and levels of stigma in two cohorts as measured by a COVID-19 stigma scale

BACKGROUND: Epidemics have historically been accompanied by stigma and discrimination. Disease-related stigma has often been shown to have severe consequences for physical, mental and social wellbeing and lead to barriers to diagnosis, treatment and prevention. The aims of this study were to investigate if a HIV-related stigma measure could be adapted and valid and reliable to measure COVID-19-related stigma, and also to investigate levels of self-reported stigma and related factors among people in Sweden with experience of COVID-19 and compare levels of COVID-19-related stigma versus HIV-related stigma among persons living with HIV who had experienced a COVID-19 event. METHODS: Cognitive interviews (n = 11) and cross-sectional surveys were made after the acute phase of the illness using a new 12-item COVID-19 Stigma Scale and the established 12-item HIV Stigma Scale in two cohorts (people who had experienced COVID-19 (n = 166/209, 79%) and people living with HIV who had experienced a COVID-19 event (n = 50/91, 55%). Psychometric analysis of the COVID-19 Stigma Scale was performed by calculating floor and ceiling effects, Cronbach's α and exploratory factor analysis. Levels of COVID-19 stigma between groups were analysed using the Mann-Whitney U test. Levels of COVID-19 and HIV stigma among people living with HIV with a COVID-19 event were compared using the Wilcoxon signed-rank test. RESULTS: The COVID-19 cohort consisted of 88 (53%) men and 78 (47%) women, mean age 51 (19-80); 143 (87%) living in a higher and 22 (13%) in a lower income area. The HIV + COVID-19 cohort consisted of 34 (68%) men and 16 (32%) women, mean age 51 (26-79); 20 (40%) living in a higher and 30 (60%) in a lower income area. The cognitive interviews showed that the stigma items were easy to understand. Factor analysis suggested a four-factor solution accounting for 77% of the total variance. There were no cross loadings, but two items loaded on factors differing from the original scale. All subscales had acceptable internal consistency, showed high floor and no ceiling effects. There was no statistically significant difference between COVID-19 stigma scores between the two cohorts or between genders. People living in lower income areas reported more negative self-image and concerns about public attitudes related to COVID-19 than people in higher income areas (median score 3 vs 3 and 4 vs 3 on a scale from 3-12, Z = -1.980, p = 0.048 and Z = -2.023, p = 0.024, respectively). People from the HIV + COVID-19 cohort reported more HIV than COVID-19 stigma. CONCLUSIONS: The adapted 12-item COVID-19 Stigma Scale may be valid and reliable for measurement of COVID-19-related stigma. However, specific items may need to be rephrased or replaced to better correspond to the COVID-19 context. People who had experienced COVID-19 reported low levels of COVID-19-related stigma in general but people from lower income areas had higher levels of negative self-image and concerns about public attitudes related to COVID-19 than people from areas with higher income, which may call for targeted interventions. Although exhibiting more pronounced HIV stigma levels, people living with HIV who had experienced COVID-19 reported COVID-19-related stigma of the same low magnitude as their peers not living with HIV

Corrigendum to "Mass spectrometry for therapeutic drug monitoring of anti-tuberculosis drugs" [Clin. Mass Spectrom. 14(Part A) (2019) 34-45]

[This corrects the article DOI: 10.1016/j.clinms.2018.10.002.]

The alpha 7 nicotinic receptor agonist PHA-543613 hydrochloride inhibits <i>Porphyromonas gingivalis</i>-induced expression of interleukin-8 by oral keratinocytes

Objective: The alpha 7 nicotinic receptor (α7nAChR) is expressed by oral keratinocytes. α7nAChR activation mediates anti-inflammatory responses. The objective of this study was to determine if α7nAChR activation inhibited pathogen-induced interleukin-8 (IL-8) expression by oral keratinocytes.&lt;p&gt;&lt;/p&gt; Materials and methods: Periodontal tissue expression of α7nAChR was determined by real-time PCR. OKF6/TERT-2 oral keratinocytes were exposed to &lt;i&gt;Porphyromonas gingivalis&lt;/i&gt; in the presence and absence of a α7nAChR agonist (PHA-543613 hydrochloride) alone or after pre-exposure to a specific α7nAChR antagonist (α-bungarotoxin). Interleukin-8 (IL-8) expression was measured by ELISA and real-time PCR. Phosphorylation of the NF-κB p65 subunit was determined using an NF-κB p65 profiler assay and STAT-3 activation by STAT-3 in-cell ELISA. The release of ACh from oral keratinocytes in response to &lt;i&gt;P. gingivalis&lt;/i&gt; lipopolysaccharide was determined using a GeneBLAzer M3 CHO-K1-blacell reporter assay.&lt;p&gt;&lt;/p&gt; Results: Expression of α7nAChR mRNA was elevated in diseased periodontal tissue. PHA-543613 hydrochloride inhibited &lt;i&gt;P. Gingivalis&lt;/i&gt;-induced expression of IL-8 at the transcriptional level. This effect was abolished when cells were pre-exposed to a specific α7nAChR antagonist, α-bungarotoxin. PHA-543613 hydrochloride downregulated NF-κB signalling through reduced phosphorylation of the NF-κB p65-subunit. In addition, PHA-543613 hydrochloride promoted STAT-3 signalling by maintenance of phosphorylation. Furthermore, oral keratinocytes upregulated ACh release in response to &lt;i&gt;P. Gingivalis&lt;/i&gt; lipopolysaccharide.&lt;p&gt;&lt;/p&gt; Conclusion: These data suggest that α7nAChR plays a role in regulating the innate immune responses of oral keratinocytes.&lt;p&gt;&lt;/p&gt

Neuropeptide Y as a risk factor for cardiorenal disease and cognitive dysfunction in chronic kidney disease: translational opportunities and challenges

Neuropeptide Y (NPY) is a 36-amino-acid peptide member of a family also including peptide YY and pancreatic polypeptide, which are all ligands to Gi/Go coupled receptors. NPY regulates several fundamental biologic functions including appetite/satiety, sex and reproduction, learning and memory, cardiovascular and renal function and immune functions. The mesenteric circulation is a major source of NPY in the blood in man and this peptide is considered a key regulator of gut-brain cross talk. A progressive increase in circulating NPY accompanies the progression of chronic kidney disease (CKD) toward kidney failure and NPY robustly predicts cardiovascular events in this population. Furthermore, NPY is suspected as a possible player in accelerated cognitive function decline and dementia in patients with CKD and in dialysis patients. In theory, interfering with the NPY system has relevant potential for the treatment of diverse diseases from cardiovascular and renal diseases to diseases of the central nervous system. Pharmaceutical formulations for effective drug delivery and cost, as well as the complexity of diseases potentially addressable by NPY/NPY antagonists, have been a problem until now. This in part explains the slow progress of knowledge about the NPY system in the clinical arena. There is now renewed research interest in the NPY system in psychopharmacology and in pharmacology in general and new studies and a new breed of clinical trials may eventually bring the expected benefits in human health with drugs interfering with this system

A roadmap for optimizing chronic kidney disease patient care and patient-oriented research in the Eastern European nephrology community

Chronic kidney disease (CKD) is a major health problem because of its high prevalence, associated complications and high treatment costs. Several aspects of CKD differ significantly in the Eastern European nephrology community compared with Western Europe because of different geographic, socio-economic, infrastructure, cultural and educational features. The two most frequent aetiologies of CKD, DM and hypertension, and many other predisposing factors, are more frequent in the Eastern region, resulting in more prevalent CKD Stages 3-5. Interventions may minimize the potential drawbacks of the high prevalence of CKD in Eastern Europe, which include several options at various stages of the disease, such as raising public, medical personnel and healthcare authorities awareness; early detection by screening high-risk populations; preventing progression and CKD-related complications by training health professionals and patients; promoting transplantation or home dialysis as the preferred modality; disseminating and implementing guidelines and guided therapy and encouraging/supporting country-specific observational research as well as international collaborative projects. Specific ways to significantly impact CKD-related problems in every region of Europe through education, science and networking are collaboration with non-nephrology European societies who have a common interest in CKD and its associated complications, representation through an advisory role within nephrology via national nephrology societies, contributing to the training of local nephrologists and stimulating patient-oriented research. The latter is mandatory to identify country-specific kidney disease-related priorities. Active involvement of patients in this research via collaboration with the European Kidney Patient Federation or national patient federations is imperative to ensure that projects reflect specific patient needs.Peer reviewe

Mild cognitive impairment and kidney disease: clinical aspects.

Chronic kidney disease (CKD) is now seen as a systemic disease involving also the central nervous system [1], but the link between the kidney and different organ systems and disease went unnoticed for a long time. The king of Poland, Stephen Bathory (1533-86), suffered from CKD due to polycystic kidney disease and depression [2]. Similarly, Wolfgang Amadeus Mozart was also thought to have had CKD [3] and depression [4]. A list of 'Famous People Who Have Died from Kidney Disease' [5] includes many who suffered from both CKD and depression or other signs of mental illness. Is this a coincidence or actually evidence of a link between kidney disease and brain dysfunction? This is not merely an academic question because all forms of mental illness can seriously impair an individual's quality of life, and are frequently associated with progression of diseases and premature mortality, so it is worth the effort of trying to answer it. Europe and much of the industrialized countries are experiencing growing numbers of patients with CKD within their ageing populations [6]. CKD is complex and potentially fatal: (i) all organs are affected, sooner or later; (ii) the balance of plasma volume, electrolytes, acid-base and minerals, metabolites, hormones and proteins is disturbed; and (iii) patients often need a multidisciplinary team approach managing complex comorbidities, drug regimens and special diets. Although the prognosis of patients with CKD remains poor, their increasing life expectancy has shifted medical attention from life-threatening emergencies to long-term complications and sequelae, and how to improve quality of life [7]. Indeed, kidney failure has detrimental effects on health-related quality of life (HRQoL), reaching levels similar to those seen in patients with metastatic cancer [8]. This might be due to psychological factors, both kidney disease and cancer being chronic diseases with a bad prognosis. However, although the effect of CKD on quality of life is more evident in advanced stages (stage G4P) and in older patients [9, 10], a large study has shown a significant decrease in HRQoL as early as CKD stage G2 [11]. Notably, neurological and cognitive impairments [12], and depression [13] are among the most debilitating consequences of CKD contributing to the significantly reduced HRQoL [14]

Brain dysfunction in tubular and tubulointerstitial kidney diseases

Kidney function has two important elements: glomerular filtration and tubular function (secretion and reabsorption). A persistent decrease in glomerular filtration rate (GFR), with or without proteinuria, is diagnostic of chronic kidney disease (CKD). While glomerular injury or disease is a major cause of CKD and usually associated with proteinuria, predominant tubular injury, with or without tubulointerstitial disease, is typically non-proteinuric. CKD has been linked with cognitive impairment, but it is unclear how much this depends on a decreased GFR, altered tubular function or the presence of proteinuria. Since CKD is often accompanied by tubular and interstitial dysfunction, we explore here for the first time the potential role of the tubular and tubulointerstitial compartments in cognitive dysfunction. To help address this issue we selected a group of primary tubular diseases with preserved GFR in which to review the evidence for any association with brain dysfunction. Cognition, mood, neurosensory and motor disturbances are not well characterized in tubular diseases, possibly because they are subclinical and less prominent than other clinical manifestations. The available literature suggests that brain dysfunction in tubular and tubulointerstitial diseases is usually mild and is more often seen in disorders of water handling. Brain dysfunction may occur when severe electrolyte and water disorders in young children persist over a long period of time before the diagnosis is made. We have chosen Bartter and Gitelman syndromes and nephrogenic diabetes insipidus as examples to highlight this topic. We discuss current published findings, some unanswered questions and propose topics for future research

Investigation Outcomes of Tuberculosis Suspects in the Health Centers of Addis Ababa, Ethiopia

BACKGROUND: Little is known about the prevalence of tuberculosis (TB) and HIV among TB suspects in primary health care units in Ethiopia. METHODS: In the period of February to March, 2009, a cross sectional survey was done in 27 health centers of Addis Ababa to assess the prevalence of TB and HIV among TB suspects who have > = 2 weeks symptoms of TB such as cough, fever and weight loss. Diagnosis of TB and HIV was based on the national guidelines. Information concerning socio-demographic variables and knowledge of the respondents about TB was collected using pretested questionnaire. RESULTS: Of the 545 TB suspects, 506 (92.7%) of them participated in the study. The prevalence of both pulmonary and extra pulmonary TB was 46.0% (233/506). The smear positivity rate among pulmonary TB suspect was 21.3%. Of the TB suspects, 298 (58.9%) of them were tested for HIV and 27.2% (81/298) were HIV seropositive. Fifty percent of the HIV positive TB suspects had TB. TB suspects who had a contact history with a TB patient in the family were 9 times more likely to have TB than those who did not have a contact history, [OR = 9.1, (95%CI:4.0, 20.5)]. Individuals who had poor [OR = 5.2, (95%CI: 2.3, 11.2)] and fair knowledge [OR = 3.7, (95%CI: 1.3, 10.4)] about TB were more likely to have TB than individuals who had good knowledge. CONCLUSION: In conclusion, the prevalence of TB among TB suspects with duration of 2 or more weeks is high. Fifty percent of the HIV positive TB suspects had TB. Case finding among TB suspects with duration of 2 or more weeks should be intensified particularly among those who have a contact history with a TB patient