In vitro susceptibility of Neisseria gonorrhoeae to netilmicin and etimicin in comparison to gentamicin and other aminoglycosides.

PURPOSE: Single doses of gentamicin have demonstrated clinical efficacy in the treatment of urogenital gonorrhea, but lower cure rates for oropharyngeal and anorectal gonorrhea. Formulations selectively enriched in specific gentamicin C congeners have been proposed as a less toxic alternative to gentamicin, potentially permitting higher dosing to result in increased plasma exposures at the extragenital sites of infection. The purpose of the present study was to compare the antibacterial activity of individual gentamicin C congeners against Neisseria gonorrhoeae to that of other aminoglycoside antibiotics. METHODS: Antimicrobial susceptibility of three N. gonorrhoeae reference strains and 152 clinical isolates was assessed using standard disk diffusion, agar dilution, and epsilometer tests. RESULTS: Gentamicin C1, C2, C1a, and C2a demonstrated similar activity against N. gonorrhoeae. Interestingly, susceptibility to the 1-N-ethylated aminoglycosides etimicin and netilmicin was significantly higher than the susceptibility to their parent compounds gentamicin C1a and sisomicin, and to any other of the 25 aminoglycosides assessed in this study. Propylamycin, a 4'-propylated paromomycin analogue, was significantly more active against N. gonorrhoeae than its parent compound, too. CONCLUSION: Selectively enriched gentamicin formulations hold promise for a less toxic but equally efficacious alternative to gentamicin. Our study warrants additional consideration of the clinically established netilmicin and etimicin for treatment of genital and perhaps extragenital gonorrhea. Additional studies are required to elucidate the mechanism behind the advantage of alkylated aminoglycosides.

The complexity of kidney disease and diagnosing it - cystatin C, selective glomerular hypofiltration syndromes and proteome regulation.

Estimation of kidney function is often part of daily clinical practice, mostly done by using the endogenous glomerular filtration rate (GFR)-markers creatinine or cystatin C. A recommendation to use both markers in parallel in 2010 has resulted in new knowledge concerning the pathophysiology of kidney disorders by the identification of a new set of kidney disorders, selective glomerular hypofiltration syndromes. These syndromes, connected to strong increases in mortality and morbidity, are characterized by a selective reduction in the glomerular filtration of 5-30 kDa molecules, such as cystatin C, compared to the filtration of small molecules <1 kDa dominating the glomerular filtrate, for example water, urea and creatinine. At least two types of such disorders, shrunken or elongated pore syndrome, are possible according to the pore model for glomerular filtration. Selective glomerular hypofiltration syndromes are prevalent in investigated populations, and patients with these syndromes often display normal measured GFR or creatinine-based GFR-estimates. The syndromes are characterized by proteomic changes promoting the development of atherosclerosis, indicating antibodies and specific receptor-blocking substances as possible new treatment modalities. Presently, the KDIGO guidelines for diagnosing kidney disorders do not recommend cystatin C as a general marker of kidney function and will therefore not allow the identification of a considerable number of patients with selective glomerular hypofiltration syndromes. Furthermore, as cystatin C is uninfluenced by muscle mass, diet or variations in tubular secretion and cystatin C-based GFR-estimation equations do not require controversial race or sex terms, it is obvious that cystatin C should be a part of future KDIGO guidelines.

Mortality risk factors in community-dwelling, subjectively healthy, Swiss older adults: update after 8-years follow-up.

BACKGROUND: Worldwide population is ageing, but little is known regarding risk factors associated with increased mortality in subjectively healthy, community-dwelling older adults. We present the updated results of the longest follow-up carried out on Swiss pensioners and we provide results on potential risk factors associated with mortality before the onset of the COVID-19 pandemic. MATERIALS AND METHODS: Within the SENIORLAB study, we collected demographic data, anthropometric measures, medical history, and laboratory parameters of 1467 subjectively healthy, community-dwelling, Swiss adults aged ≥ 60 years over a median follow-up of 8.79 years. The variables considered in the multivariable Cox-proportional hazard model for mortality during follow-up were selected based on prior knowledge. Two separate models for males and females were calculated; moreover, we fitted the old model obtained in 2018 to the complete follow-up data to highlight differences and similarities. RESULTS: The population sample included 680 males and 787 females. Age of participants ranged between 60 and 99 years. We experienced 208 deaths throughout the entire follow-up period; no patients were lost at follow-up. The Cox-proportional hazard regression model included female gender, age, albumin levels, smoking status, hypertension, osteoporosis and history of cancer within predictors of mortality over the follow-up period. Consistent findings were obtained also after gender stratification. After fitting the old model, female gender, hypertension, and osteoporosis still showed statistically significant independent associations with all-cause mortality. CONCLUSIONS: Understanding the predictors of a healthy survival can improve the overall quality of life of the ageing population and simultaneously reduce their global economic burden. TRIAL REGISTRATION: The present study was registered in the International Standard Randomized Controlled Trial Number registry: https://www.isrctn.com/ISRCTN53778569 (registration date: 27/05/2015).

Comparison of an automated DNA extraction and 16S rDNA real time PCR/sequencing diagnostic method using optimized reagents with culture during a 15-month study using specimens from sterile body sites.

BACKGROUND: 16S rDNA-PCR for the identification of a bacterial species is an established method. However, the DNA extraction reagents as well as the PCR reagents may contain residual bacterial DNA, which consequently generates false-positive PCR results. Additionally, previously used methods are frequently time-consuming. Here, we describe the results obtained with a new technology that uses DNA-free reagents for automated DNA extraction and subsequent real time PCR using sterile clinical specimens. RESULTS: In total, we compared 803 clinical specimens using real time PCR and culturing. The clinical specimens were mainly of orthopedic origin received at our diagnostic laboratory. In 595 (74.1%) samples, the results were concordant negative, and in 102 (12.7%) the results were concordant positive. A total of 170 (21.2%) clinical specimens were PCR-positive, of which 62 (36.5% from PCR positive, 7.7% in total) gave an additional benefit to the patient since only the PCR result was positive. Many of these 62 positive specimens were strongly positive based on crossingpoint values (54% < Cp 30), and these 62 positive clinical specimens were diagnosed as medically relevant as well. Thirty-eight (4.2%) clinical specimens were culture-positive (25 of them were only enrichment culture positive) but PCR-negative, mainly for S. epidermidis, S. aureus and C. acnes. The turnaround times for negative specimens were 4 hours (automated DNA extraction and real time PCR) and 1 working day for positive specimens (including Sanger sequencing). Melting-curve analysis of SYBR Green-PCR enables the differentiation of specific and unspecific PCR products. Using Ripseq, even mixed infections of 2 bacterial species could be resolved. CONCLUSIONS: For endocarditis cases, the added benefit of PCR is obvious. The crucial innovations of the technology enable timely reporting of explicit reliable results for adequate treatment of patients. Clinical specimens with truly PCR-positive but culture-negative results represent an additional benefit for patients. Very few results at the detection limit still have to be critically examined.

Impact of retrograde intrarenal surgery on biomarkers that are associated with renal parenchyma injury, a preliminary study.

PURPOSE: The primary objective of this preliminary study was to assess the changes in concentration of biomarkers, which indicate renal injury, after RIRS. MATERIALS AND METHODS: Within this prospective study, we included 21 patients with nephrolithiasis requiring treatment with RIRS. From each patient, blood and urine samples were taken at fixed intervals before and after RIRS. Kidney injury molecule-1 (KIM-1), monocyte chemoattractant protein 1 (MCP-1), neutrophil gelatinase-associated lipocalin (NGAL), interleukin-18 (IL-18), calbindin, albumin, clusterin, gluthation S-transferase-π (GST-π), beta-2-microglobulin (B2M), osteopontin, cystatin c, and trefoil-factor-3 (TFF3) were measured in urine. Creatinine, cystatin c and uric acid were analyzed in the blood samples. RESULTS: A significant increase of the biomarkers clusterin, GST-π, B2M, NGAL and cystatin c was observed after RIRS. However, the biomarkers gradually normalized during the first 14 postoperative days. The parameters surgery time, cumulative stone volume, and BMI did not significantly influence the biomarker concentrations. In the case of GST-π and NGAL a significant positive, yet minuscule effect of age was observed. CONCLUSIONS: With our study, we identified 5 out of 12 assessed renal injury biomarkers that showed a significant increase after RIRS. The increase was only temporary and all markers normalized within 14 days. Further studies are needed to determine the clinical value of these identified markers to assess the long-term impact of intrarenal pressure elevation during RIRS.

Exploring the Global Spread of Klebsiella grimontii Isolates Possessing blaVIM-1 and mcr-9.

The spread of plasmid-mediated carbapenemases within Klebsiella oxytoca is well-documented. In contrast, data concerning the closely related species Klebsiella grimontii are scarce. In fact, despite the recent report of the first blaKPC-2-producing K. grimontii, nothing is known about its clonality and antibiotic resistance patterns. In a retrospective search in our collection, we identified 2 blaVIM-positive K. oxytoca strains. Whole-genome sequencing with both Illumina and Nanopore indicated that our strains actually belonged to K. grimontii and were of sequence type 172 (ST172) and ST189. Moreover, the two strains were associated with 297-kb IncHI2/HI2A-pST1 and 90.6-kb IncFII(Yp) plasmids carrying blaVIM-1 together with mcr-9 and blaVIM-1, respectively. In the IncHI2/HI2A plasmid, blaVIM-1 was located in a class 1 integron (In110), while mcr-9 was associated with the qseC-qseB-like regulatory elements. Overall, this plasmid was shown to be very similar to those carried by other Enterobacterales isolated from food and animal sources (e.g., Salmonella and Enterobacter spp. detected in Germany and Egypt). The IncFII(Yp) plasmid was unique, and its blaVIM-1 region was associated with a rare integron (In1373). Mapping of In1373 indicated a possible origin in Austria from an Enterobacter hormaechei carrying a highly similar plasmid. Core-genome phylogenies indicated that the ST172 K. grimontii belonged to a clone of identical Swedish and Swiss strains (≤15 single nucleotide variants [SNVs] to each other), whereas the ST189 strain was sporadic. Surveillance of carbapenemase-producing K. oxytoca strains should be reinforced to detect and prevent the dissemination of new species belonging to the Klebsiella genus.

Molecular characterization of a ceftriaxone-resistant Neisseria gonorrhoeae strain found in Switzerland: a case report.

BACKGROUND: The resistance of Neisseria gonorrhoeae to ceftriaxone is unusual in Switzerland. The underlying genotype responsible for resistance is suspected to be novel. Generally, resistance in Neisseria gonorrhoeae (Ng) involves a comprehensive set of genes with many different mutations leading to resistance to different ß-lactams and fluoroquinolones. CASE PRESENTATION: A patient had a positive result from specific PCR for Ng. We routinely culture all clinical specimens with a positive NG-PCR. In this particular case, we isolated a strain with resistance to ceftriaxone in Switzerland. A total of seven different genes (penA, ponA, porinB, mtr, gyrA, parC, 23S rRNA gene) in this strain were partially sequenced for comparison with phenotypic susceptibility testing. Interestingly, two different mutations in the porinB gene were observed, and data on this gene are limited. Information on the identified allele type of the penA gene is very limited as well. Three different mutations of parC and gyrA that correlate with ciprofloxacin resistance were found. The combination of ceftriaxone and ciprofloxacin resistance makes an appropriate treatment difficult to obtain due to multidrug resistance. CONCLUSION: The combined results for all genes show the appearance of new mutations in central Europe either due to worldwide spread or the emergence of new genetic combinations of mutations.

Elementary Laboratory Assays as Biomarkers of Ageing: Support for Treatment of COVID-19?

Youth, working age and the elderly: On a timeline, chronological age (CA) and biological age (BA) may dissociate; nosological entities manifest themselves at different BAs. In determining which disease corresponds to a given age decade, statistical registries of causes of death are unreliable and this does not change with SARS CoV-2 infection. Beyond adolescence, ageing metrics involve estimations of changes in fitness, including prediction models to estimate the number of remaining years left to live. A substantial disparity in biomarker levels and health status of ageing can be observed: the difference in CA and BA in the large cohorts under consideration is glaring. Here, we focus more closely on ageing and senescence metrics in order to make information available for risk analysis non the least with COVID-19, including the most recent risk factors of ABO blood type and 3p21.31 chromosome cluster impacting on C5a and SC5b-9 plasma levels. From the multitude of routine medical laboratory assays, a potentially meaningful set of assays aimed to best reflect the stage of individual senescence; hence risk factors the observational prospective SENIORLABOR study of 1,467 healthy elderly performed since 2009 and similar approaches since 1958 can be instantiated as a network to combine a set of elementary laboratory assays quantifying senescence.

Aldosterone-to-renin ratio and blood pressure in young adults from the general population.

BACKGROUND: The effect of the renin angiotensin system on blood pressure (BP) values in young adults from the general population is not well studied. We investigated the relationship between the aldosterone-to-renin ratio (ARR) and various BP indices in this population. METHODS: We assembled a population-based sample of adults aged 25-41 years. Conventional and 24-hour BP recordings were obtained in all patients. Direct renin concentration and plasma aldosterone concentration were measured. Multivariable regression models were constructed to assess the relationships of ARR with BP and hypertension. RESULTS: We included 1,353 individuals (mean age 37 years, 56% women). The median (interquartile range) ARR, direct renin concentration, and plasma aldosterone concentration were 13.8 (8.7-22.9), 7.2 ng/L (4.4-11.0) and 94 ng/L (68-134). All BP indices were higher across sex-specific ARR quartiles. Per 1-unit increase in log-transformed ARR, the multivariable-adjusted ß-coefficients (95% CI) for conventional, 24-hour, daytime, and nighttime systolic BP were 1.68 (0.87-2.48), P < .0001; 2.40 (1.68-3.12), P < .0001; 2.23 (1.48-2.99), P < .0001; and 2.80 (2.03-3.58), P < .0001, respectively. Per 1-unit increase in log-transformed ARR, the multivariable-adjusted odds ratio (95% CI) for conventional, 24-hour, sustained and masked hypertension was 1.70 (1.17-2.28), P = .0004; 1.29 (1.06-1.56), P = .01; 1.82 (1.33-2.49), P = .002; and 1.14 (0.94-1.38), P = .20, respectively. CONCLUSIONS: In young adults, ARR was strongly associated with conventional and ambulatory BP. Our data suggest that an aldosterone-driven phenomenon occurs very early in the development of hypertension.

Frequency of serological non-responders and false-negative RT-PCR results in SARS-CoV-2 testing: a population-based study.

Objectives The sensitivity of molecular and serological methods for COVID-19 testing in an epidemiological setting is not well described. The aim of the study was to determine the frequency of negative RT-PCR results at first clinical presentation as well as negative serological results after a follow-up of at least 3 weeks. Methods Among all patients seen for suspected COVID-19 in Liechtenstein (n=1921), we included initially RT-PCR positive index patients (n=85) as well as initially RT-PCR negative (n=66) for follow-up with SARS-CoV-2 antibody testing. Antibodies were detected with seven different commercially available immunoassays. Frequencies of negative RT-PCR and serology results in individuals with COVID-19 were determined and compared to those observed in a validation cohort of Swiss patients (n=211). Results Among COVID-19 patients in Liechtenstein, false-negative RT-PCR at initial presentation was seen in 18% (12/66), whereas negative serology in COVID-19 patients was 4% (3/85). The validation cohort showed similar frequencies: 2/66 (3%) for negative serology, and 16/155 (10%) for false negative RT-PCR. COVID-19 patients with negative follow-up serology tended to have a longer disease duration (p=0.05) and more clinical symptoms than other patients with COVID-19 (p<0.05). The antibody titer from quantitative immunoassays was positively associated with the number of disease symptoms and disease duration (p<0.001). Conclusions RT-PCR at initial presentation in patients with suspected COVID-19 can miss infected patients. Antibody titers of SARS-CoV-2 assays are linked to the number of disease symptoms and the duration of disease. One in 25 patients with RT-PCR-positive COVID-19 does not develop antibodies detectable with frequently employed and commercially available immunoassays.

A consideration of convalescent plasma and plasma derivatives in the care of Severely-ill patients with COVID-19.

The pathogenesis and immunopathological damage of severe forms of COVID-19 resemble acute autoimmune disease sparked by SARS-CoV-2, including an early systemic overproduction of proinflammatory cytokines. Such immunopathological features provide a rationale for the use of passive immunotherapy with convalescent plasma as a source of neutralizing anti-viral antibodies and of anti-inflammatory plasma components. While convalescent plasma therapy is now being evaluated in prospective clinical trials, we further consider the therapeutic potential of human hyper immune globulins, and of heterologous, engineered and monoclonal neutralizing antibodies as anti-viral agents to treat COVID-19. Good medical practice procedures are still needed and is why we also discuss the potential use of polyclonal polyspecific immunoglobulins (IVIG), a therapeutic plasma derivative, with potent anti-inflammatory activity, in severe forms of Covid-19.

Diagnostic Characteristics of 3-Parameter and 2-Parameter Equations for the Calculation of a Combined Indicator of Vitamin B12 Status to Predict Cobalamin Deficiency in a Large Mixed Patient Population.

BACKGROUND: A combined indicator for the determination of vitamin B12 status (4cB12) that employs four markers of vitamin B12 status (i.e., holotranscobalamin, HoloTC; vitamin B12, B12; methyl malonic acid, MMA; and homocysteine, Hcy) has been proposed for the comprehensive assessment of B12 status. We aimed to compare recently published 2- (2cB12) and 3-parameter (3cB12) cB12 equations missing one or two markers of B12 status with the established four-parameter cB12 (4cB12). METHODS: In 3,614 routine samples in which HoloTC, B12, MMA, Hcy and serum folate were measured, cB12 was assessed with 4cB12, as well as with four 3cB12 and six 2cB12 equations. Diagnostic accuracy (AUC) curves were calculated by receiver operating characteristic (ROC) curve analysis with the four-parameter equation (4cB12) as an index. Furthermore, we investigated whether calculating cB12 in addition to a 2-step algorithm employing the same parameters would add diagnostic value for the diagnosis of vitamin B12 deficiency. RESULTS: HoloTC showed the highest diagnostic accuracy among the single markers (AUC = 0.94). The cB12 equation using HoloTC and MMA (2cB12HoloTC/MMA) had the highest AUC among the 2-parameter equations (0.98). Among the 3-parameter equations, 3cB12HoloTC/MMA/Hcy and 3cB12HoloTC/B12/MMA revealed an AUC of 0.99, which was significantly higher than that of 2cB12HoloTC/MMA (p < 0.01). Calculating 2cB12HoloTC/MMA in addition to using a stepwise algorithm employing HoloTC and MMA for diagnosis of vitamin B12 deficiency increased the positive likelihood ratio from 12.1 to 42.6. CONCLUSIONS: cB12 calculated with two or three markers of B12 status provides a good approximation of the 4cB12 equation. A 2cB12 equation employing the same parameters improved diagnostic accuracy compared to the use of a 2-step diagnostic algorithm alone. Our results suggest, that laboratories should consider enriching their reports by additionally reporting a corresponding 2cB12 or 3cB12 to results obtained in stepwise diagnostic algorithms.

Treatment of urinary tract infections in Swiss primary care: quality and determinants of antibiotic prescribing.

BACKGROUND: Urinary tract infections are one of the most common reasons for prescribing antibiotics in primary care. Current guidelines recommend fosfomycin, nitrofurantoin, or trimethoprim - sulfamethoxazol as empiric first line antimicrobial agents in uncomplicated infections. However, there is evidence that the use of fluoroquinolones, which are no longer recommended, is still inappropriate high. We determined antibiotic prescription patterns, quality and factors affecting antibiotic prescriptions in urinary tract infections in primary care in Switzerland. METHODS: From June 2017 to August 2018, we conducted a cross-sectional study in patients suffering from a urinary tract infection (UTI). Patient and general practitioners characteristics as well as antibiotic prescribing patterns were analysed. RESULTS: Antibiotic prescribing patterns in 1.352 consecutively recruited patients, treated in 163 practices could be analysed. In 950 (84.7%) patients with an uncomplicated UTI the prescriptions were according to current guidelines and therefore rated as appropriate. Fluoroquinolones were prescribed in 13.8% and therefore rated as inappropriate. In multivariable analysis, the age of the general practitioner was associated with increasing odds of prescribing a not guideline recommended antibiotic therapy. CONCLUSIONS: We found a high degree of guideline conform antibiotic prescriptions in patients with an uncomplicated urinary tract infection in primary care in Switzerland. However, there is still a substantial use of fluoroquinolones in empiric therapy.

Active surveillance of antibiotic resistance patterns in urinary tract infections in primary care in Switzerland.

PURPOSE: Urinary tract infections (UTI) are one of the most common reasons for prescribing antibiotics in primary care. In Switzerland, the Swiss Center for Antibiotic Resistances (ANRESIS) provides resistance data by passive surveillance, which overestimates the true resistance rates. The aim of this study was to provide actual data of the antimicrobial resistance patterns in patients with UTI in Swiss primary care. METHODS: From June 2017 to August 2018, we conducted a cross-sectional study in 163 practices in Switzerland. We determined the resistance patterns of uropathogens in patients with a diagnosis of a lower UTI and analyzed risk factors for resistance. Patients with age < 18 years, pregnancy or a pyelonephritis were excluded. RESULTS: 1352 patients (mean age 53.8, 94.9% female) were included in the study. 1210 cases (89.5%) were classified as uncomplicated UTI. Escherichia coli (E. coli) was the most frequent pathogen (74.6%). Susceptibility proportions of E. coli to ciprofloxacin (88.9%) and trimethoprim-sulfamethoxazol (TMP/SMX) (85.7%) were significantly higher than the proportions reported by ANRESIS. We found high susceptibility to the recommended first-line antibiotics nitrofurantoin (99.5%) and fosfomycin (99.4%). Increasing age, antimicrobial exposure and a recent travel history were independently associated with resistance. DISCUSSION: In this study, we report actual data on the resistance patterns of uropathogens in primary care in Switzerland. Escherichia coli showed low resistance rates to the recommended first-line antibiotics. Resistance to TMP/SMX was significantly lower than reported by ANRESIS, making TMP/SMX a suitable and cheap alternative for the empirical treatment.

Shrunken pore syndrome, preeclampsia, and markers of NO metabolism in pregnant women during the first trimester.

Shrunken pore syndrome (SPS) is a condition that manifests itself as the decreased renal clearance of low-molecular-weight proteins but normal clearance of creatinine. Pregnant women with evidence of SPS during the first trimester have an increased risk of developing preeclampsia (PE). The nitric oxide (NO) metabolism markers arginine and ADMA, especially their ratio (Arg/ADMA), are recognized markers of endothelial dysfunction. The aim of this nested case-control study was to establish first-trimester reference intervals (RI) for markers of NO metabolism and to study these markers in women with evidence of SPS at the end of the first trimester. Seventy-four women were stratified in the first trimester according to evidence of SPS (SPS + or SPS-) and the occurrence of PE during subsequent pregnancy (PE + or PE-), as follows: SPS-/PE-, SPS+/PE-, SPS-/PE+, and SPS+/PE+. RIs were determined according to the CLSI EP28-A3c guidelines. Serum Arg and ADMA levels were analyzed. The Arg and ADMA concentrations did not differ among the four groups. However, women in the SPS+/PE + group had a significantly lower Arg/ADMA ratio than those in the other 3 groups (p = .02). In conclusion, we defined the first-trimester RI of Arg, ADMA and the Arg/ADMA ratio as markers of NO metabolism. Our results suggest that SPS in the first trimester predicts a pathophysiological hallmark of subsequent PE, i.e. lower NO production leading to increased vessel tone. Early identification of women at risk for later PE could lead to adaptive prophylactic interventions, such as supplementation with Arg or an NO-donor drug in order to mitigate the risk of developing PE.

The utility of complement assays in clinical immunology: A comprehensive review.

The multi-tasking organ liver, which is the major synthesis site of most serum proteins, supplies humoral components of the innate, - including proteins of the complement system; and, less intensely, also of the acquired immune system. In addition to hepatocyte origins, C1q, factor D, C3, C7 and other protein components of the complement system are produced at various body locations by monocytes/macrophages, lymphocytes, adipocytes, endometrium, enterocytes, keratinocytes and epithelial cells; but the contribution of these alternate sites to the total serum concentrations is slight. The two major exceptions are factor D, which cleaves factor B of the alternative pathway derived largely from adipocytes, and C7, derived largely from polymorphonuclear leukocytes and monocytes/macrophages. Whereas the functional meaning of the extrahepatic synthesis of factor D remains to be elucidated, the local contribution of C7 may up- or downregulate the complement attack. The liver, however, is not classified as part of the immune system but is rather seen as victim of autoimmune diseases, a point that needs apology. Recent histological and cell marker technologies now turn the hands to also conceive the liver as proactive autoimmune disease catalyst. Hosting non-hepatocytic cells, e.g. NK cells, macrophages, dendritic cells as well as T and B lymphocytes, the liver outreaches multiple sites of the immune system. Immunopharmacological follow up of liver transplant recipients teaches us on liver-based presence of ABH-glycan HLA phenotypes and complement mediated ischemia/regeneration processes. In clinical context, the adverse reactions of the complement system can now be curbed by specific drug therapy. This review extends on the involvement of the complement system in liver autoimmune diseases and should allow to direct therapeutic opportunities.

Fibroblast growth factor 23 and renal function among young and healthy individuals.

BACKGROUND: Fibroblast growth factor 23 (FGF-23), an osteocyte hormone involved in the regulation of phosphate metabolism, is associated with incident and progressive chronic kidney disease. We aimed to assess the association of FGF-23 with renal parameters, vascular function and phosphate metabolism in a large cohort of young and healthy individuals. METHODS: Healthy individuals aged 25-41 years were included in a prospective population-based study. Fasting venous blood and morning urinary samples were used to measure plasma creatinine, cystatin C, endothelin-1, phosphate and plasma FGF-23 as well as urinary creatinine and phosphate. Multivariable regression models were constructed to assess the relationship of FGF-23 with parameters of renal function, endothelin-1 and fractional phosphate excretion. RESULTS: The median age of 2077 participants was 37 years, 46% were males. The mean estimated glomerular filtration rate (eGFR - CKD-EPI creatinine-cystatin C equation) and fractional phosphate excretion were 110 mL/min/1.73 m2 and 8.7%, respectively. After multivariable adjustment, there was a significant inverse relationship of FGF-23 with eGFR (ß per 1 log-unit increase -3.81; 95% CI [-5.42; -2.20]; p<0.0001). Furthermore, we found a linear association between FGF-23 and endothelin-1 (ß per 1 log-unit increase 0.06; [0.01, 0.11]; p=0.01). In addition, we established a significant relationship of FGF-23 with fractional phosphate excretion (ß per 1 log-unit increase 0.62; [0.08, 1.16]; p=0.03). CONCLUSIONS: Increasing plasma FGF-23 levels are strongly associated with decreasing eGFR and increasing urinary phosphate excretion, suggesting an important role of FGF-23 in the regulation of kidney function in young and healthy adults.

Osteoporosis, diabetes, and hypertension are major risk factors for mortality in older adults: an intermediate report on a prospective survey of 1467 community-dwelling elderly healthy pensioners in Switzerland.

BACKGROUND: Osteoporosis is an important morbidity factor for ageing populations in developed countries. However, compared to the amount of information available on diabetes and cardiovascular disease, little is known about the direct impact of osteoporosis on general mortality in older age. METHODS: We obtained data from a prospective population-based cohort of pensioners from the SENIORLAB study who were subjectively healthy. The inclusion criteria were an age of at least 60 years and Swiss residence. We assessed and analysed clinical measures, voluntary reports, and laboratory values. RESULTS: In total, 1467 subjects were included in the cohort. The mean follow-up time was 3.68 years (95% confidence interval, 3.64-3.71). The ages of the included participants ranged from 60 to 99 years. At follow-up, there were 1401 survivors, and 66 participants had died. According to the multivariate analysis (Cox regression), osteoporosis was the most important risk factor for all-cause mortality (hazard ratio, 4.46; 95% confidence interval, 1.82-10.91), followed by diabetes (hazard ratio, 2.17; 95% confidence interval, 1.04-4.52) and hypertension (hazard ratio, 1.81; 95% confidence interval, 1.09-3.03). CONCLUSIONS: Osteoporosis is a major risk factor for all-cause mortality in a subjectively healthy senior population, followed by type 2 diabetes mellitus and hypertension. Osteoporosis should be more actively diagnosed in healthy pensioners before they develop osteoporosis-associated health incidents. TRIAL REGISTRATION: The present study was registered in the International Standard Randomized Controlled Trial Number registry: ISRCTN53778569 .

Healthy lifestyle and glucagon-like peptide-1 in young and healthy adults: A population-based study.

A healthy lifestyle is associated with a lower risk of cardiovascular events and mortality, but underlying mechanisms are not fully understood. The aim of our study was to investigate the relationships between a healthy lifestyle and glucagon-like peptide-1 (GLP-1), an incretin hormone with both glycemic and cardiovascular properties. Healthy participants aged 25-41years without cardiovascular disease, diabetes or a body mass index (BMI) >35kg/m2 were enrolled in a population-based study. The following metrics were used to build a lifestyle score ranging from 0 to 7 (a higher score indicating a healthier lifestyle): blood pressure (BP) (<120/80mmHg), plasma levels of glycated hemoglobin (<5.7%), total cholesterol levels (<200mg/dl), BMI (<25kg/m2), not smoking cigarettes, moderate (≥150min/week) or vigorous (≥75min/week) physical activity and a healthy diet. Among 2133 participants median age was 36.7years and 53.3% were female. GLP-1 levels decreased significantly from 39.5 to 30.9ng/l (p<0.0001) across increasing lifestyle score categories. This linear relationship persisted in multivariable adjusted linear regression models (B for GLP-1 per 1-unit increase of the lifestyle score -0.06; 95% confidence intervals -0.07, -0.04; p<0.0001). Individual health metrics that were significantly associated with GLP-1 were a normal BMI (-0.07; -0.12, -0.03; p=0.001), low total cholesterol levels (-0.07; -0.12, -0.03; p=0.001), normal BP (-0.05; -0.10, -0.00; p=0.047) and not smoking (-0.06; -0.10, -0.01; p=0.01). A healthy lifestyle is strongly associated with lower GLP-1 levels in young and healthy adults.

Plasma levels of endothelin-1 and renal function among young and healthy adults.

BACKGROUND: Endothelin-1 (ET-1), a vasoconstrictive and pro-inflammatory peptide, is associated with several cardiovascular risk factors and outcomes. We aimed to investigate the association of plasma ET-1 levels and renal function among young and healthy adults. METHODS: Individuals aged 25-41 years were enrolled in a population-based cohort study. Main exclusion criteria were established kidney disease, cardiovascular diseases, diabetes mellitus and a body mass index>35 kg/m2. Fasting venous plasma samples were used to measure creatinine, cystatin C and ET-1. The estimated glomerular filtration rate (eGFR) was calculated using the creatinine based chronic kidney disease epidemiology collaboration (CKD-EPI) formula. Multivariable regression models were constructed to assess interrelationships of plasma ET-1 with parameters of renal function. RESULTS: Median age of the 2139 participants was 37 years, 47% males. Median creatinine and eGFR were 67 µmol/L and 112 mL/min/1.73 m2, respectively. Using quartile one as the reference group, the ß-coefficients (95% confidence intervals [CIs]) for eGFR were 0.06 (- 1.22 to 1.35),-0.66 (- 1.95 to 0.62) and-1.70 (- 3.01 to-0.39) for quartiles 2-4 (p-for-trend=0.0056), respectively and ß-coefficients (95% CIs) for cystatin C were 0.002 (- 0.01 to 0.02), 0.02 (0.003-0.03) and 0.03 (0.01-0.04) for quartiles 2-4 (p-for-trend<0.0001), respectively. Using ET-1 as a continuous variable, the ß-coefficient (95% CI) for eGFR per 1-unit increase was-1.82 (- 3.19 to-0.44, p=0.0095) and 0.02 (0.01-0.04, p=0.0003) for cystatin C. Similar results were found between creatinine and ET-1 levels. CONCLUSIONS: ET-1 levels are strongly associated with parameters of renal function among young and healthy adults, suggesting an important role of ET-1 and endothelial function in the regulation of kidney function.