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Objectives Mean platelet volume (MPV), platelet distribution width (PDW), and plateletcrit (PCT) possess diagnostic and prognostic capabilities in a variety of diseases. We aimed to establish reference intervals (RI) for platelet indices (PI) in seniors. Methods We established direct and indirect RI for MPV, PDW, and PCT in selected reference individuals aged 60 years and older. Abnormal PI were assessed in a population-based setting in the Principality of Liechtenstein, where 37.7% of the whole nation’s population aged 60 years and older had PI determined by hematology analyzers from Sysmex (Horgen, Switzerland). Results Among 689 female and 542 male participants, MPV and PDW did not exhibit age- and gender-specific differences, whereas PCT in females also displayed no age-specific differences. Age- and sex-independent RI were 9.3–12.5 fl for MPV and 10.1–16.7% for PDW, whereas the age-independent RI for PCT in women was 0.18–0.37. In males, age-specific RI for PCT were 0.16–0.30 (age 60–69), 0.15–0.33 (age 70–79), and 0.14–0.33 (age 80 and older). The population-based frequency of abnormal PI results was 0.8% (MPV), 1.1% (PDW), and 24.4% (PCT). Conclusions Applying novel RI for PI reveals that only approximately 1% of patients exhibit abnormal MPV and PDW. Abnormal PCT is observed much more frequently.

Background Hemoglobin A1c (HbA1c) is an accurate index of fluctuation in glycemia over the 2-3 months prior to quantitative assessment. During this time, hemoglobin (Hb) slowly glycates until it shows the properties of advanced glycation end-products. Glycation kinetics is intensified by prolonged glucose exposure. In subjects undergoing oral glucose tolerance testing (OGTT), immediately after ingestion, glucose is ostensibly transported by the glucose transporter 1 (GLUT1) to erythrocyte corpuscular hemoglobin. The earliest significant measurable level of hemoglobin glycation associated with this transportation is still not clear. Subjects and methods We attempted to explore the early impact of short-term glucose load on HbA1c levels, because it is now known that transmembrane GLUT1-mediated glucose transport occurs immediately. A total of 88 participants (46 patients and 42 clinically healthy controls) underwent fasting plasma glucose quantitation during an OGTT. HbA1c, revealed by a monoclonal anti-glycation epitope antibody and adiponectin, was quantitated before (T0) and 2 hours (T120) after 80 g glucose ingestion. Results Wilcoxon test revealed that the HbA1c values did not significantly vary (P = 0.15) during the OGTT, whereas glucose concentration varied strongly between T0 and T120. Discussion It is well known that quantitative estimation of HbA1c is informative for clinical care, independently of glucose level. The molecular mechanisms and dynamics by which glucose enters/exits red blood cells are incompletely known and may differ between individuals. We here show, for the first time, that HbA1c levels do not significantly increase during OGTT, supporting the view that non-enzymatic glycation of hemoglobin occurs slowly and that glycation during the 2 hours of an OGTT is insignificant.

Currently, age- and sex-independent reference limits (RLs) are frequently used to interpret platelet counts in seniors. We aimed to define and validate reference intervals (RIs) for platelet counts within the framework of the prospective SENIORLAB study. Subjectively healthy Swiss individuals aged 60 years and older were prospectively included and followed for morbidity and mortality. Participants who had circumstances known to affect platelet counts were excluded. The obtained RIs were validated with indirect statistical methods. Frequencies of abnormal platelet counts in a population-based setting, including 41.5% of the entire age-specific population of the Principality of Liechtenstein, were compared by using age- and sex-independent RIs and the RLs obtained in the present study. For males (n = 542), 95% RIs for platelet counts were defined as follows: 150&ndash, 300 &times, 109/L (60&ndash, 69 years), 130&ndash, 109/L (70&ndash, 79 years), and 120&ndash, 109/L (80 years and above). For females (n = 661), the consolidated age-independent 95% RI was 165&ndash, 355 &times, 109/L. These RI values were validated by indirect RI determination of 51,687 (30,392 female/21,295 male) patients of the same age. Age- and sex-independent RIs exhibited imbalanced frequencies of abnormal platelet counts between the two sexes, which were corrected by introducing age- and sex-specific RLs. In conclusion, females have higher platelet counts than males. Whereas the upper RL for males remains constant, the lower RL decreases with age. We propose to abandon the practice of employing sex- and age-independent RL for platelet counts in the elderly.

Reference intervals (RIs) for laboratory analyses by and large, are provided by analytical platform providers – the provenience and preanalytics of materials for the calculation of intervals often remain arcane particularly relating to the age group of donors. In an observational, prospective cohort study on 1467 healthy uniracial Caucasian residents >60 years of age, 105 frequently used lab tests were done on one blood sample. With a nonrestrictive definition of health, several pathological lab results pointing to occult disease have been found and published from SENIORLAB so far. The RIs found for hemoglobin in women went from 117.9 to 152.4 g/L (80–84 years) and in men from 124.9 to 170.6 g/L (90% confidence interval [CI]). This article lists RIs computed with SENIORLAB data for such frequently ordered analyses as platelet counts, vitamin B12 and folate, ferritin and analytes measured to estimate metabolic performance in glucose turnover. In fact, 64.5% of the cohort showed prediabetic fasting plasma glucose (FPG) and/or glycated hemoglobin (HbA1c); total serum folate levels but not red blood cell folate decreased with progressing age. As much as 66% of evaluable study participants had insufficient levels of 25(OH) vitamin D. Published reports from SENIORLAB are referenced in this article.

OBJECTIVE The SENIORLABOR study data were explored (i) to examine the evolution during senescence of the differences between measured glycated haemoglobin (HbA1c) values and the values predicted by using regression to extrapolate from measured fructosamine levels; (ii) to scrutinise the relationship between the glycation gap and insulin resistance using a homeostasis model assessment, and between the glycation gap and a low-grade inflammation marker (C-reactive protein serum concentration); and (iii) to investigate the glycation gap ranges in relation to triglyceride levels and kidney function. SUBJECTS AND METHODS A total of 1432 Swiss individuals aged >60 years and classified as healthy (547), prediabetic (701) or diabetic (184) based on their fasting plasma glucose and HbA1c values were included in the study. The glycation gap was evaluated and assigned to one of four categories: 0.5. RESULTS In healthy and prediabetic participants, the homeostasis model assessment for estimation of insulin resistance (p 0.5. Homeostasis model assessment for estimation of insulin resistance, high-sensitivity C-reactive protein and triglyceride levels tended to increase with increasing glycation gap category and were highest in the glycation gap category >0.5. Significant differences (p 0.5, high-sensitivity C-reactive protein values tended to increase with increasing glycation gap, whereas for participants with type 2 diabetes and in the glycation gap group >0.5, high-sensitivity C-reactive protein levels tended to decrease as the glycation gap increased. The percentage of participants with type 2 diabetes mellitus increased from 2% in the glycation gap category 0.5. In contrast, the percentage of healthy participants fell from 85% to 7%. CONCLUSION This is the first time that a direct comparison of healthy, prediabetic and diabetic participants, all assessed under identical conditions and using identical methodology, has clearly demonstrated a different glycation gap pattern. Thus, we contribute evidence that the glycation gap might be of interest in the care of diabetic patients and their prophylaxis, while acknowledging that more studies are needed to confirm our findings. (Trial registration number ISRCTN53778569).

Objective The aim of the study was to review available data on HCV in Poland and Switzerland, in order to compare the two European countries with respect to epidemiological situation and efficiency of the response systems. Material and Methods A search of registries, published and grey literature was performed to assemble data on prevalence, rate of detection of new cases, identified risk factors for transmission, mortality due to HCV, prevalence of HCC and the consequent liver transplantations, as well as data on treatment in Poland and Switzerland. Results Overall, the prevalence of anti-HCV antibodies was similar, not exceeding 1%. However, the major transmission routes of HCV infections were different: medical procedures in Poland and drug injections in Switzerland. By combining the available information it was also possible to demonstrate important differences in efficiency of the response systems. There was approximately 1 new diagnosis per 100 estimated undiagnosed cases in the population in Poland per year, compared to 6 in Switzerland, and the treatment rate per 100 estimated active infections was 2 and 4, respectively. Conclusions Scaling up of the diagnosis and treatment is necessary in both countries; however, the means to achieve this might differ, taking into account the higher concentration of the infections in risk groups in Switzerland than in Poland.

Complement is usually seen to largely originate from the liver to accomplish its tasks systemically – its return to the production site has long been underestimated. Recent progress in genomics, therapeutic effects on complement, standardised possibilities in medical laboratory tests and involvement of complosome brings the complement system with its three major functions of opsonization, cytolysis and phagocytosis back to liver biology and pathology. The LOINC™ system features 20 entries for the C3 component of complement to anticipate the application of artificial intelligence data banks algorythms of which are fed with patient-specific data connected to standard lab assays for liver function. These advancements now lead to increased vigilance by clinicians. This reassessment article will further elucidate the distribution of synthesis sites to the three germ layer-derived cell systems and the role complement now known to play in embryogenesis, senescence, allotransplantation and autoimmune disease. This establishes the liver as part of the gastro-intestinal system in connection with nosological entities never thought of, such as the microbiota-liver-brain axis. In neurological disease etiology infectious and autoimmune hepatitis play an important role in the context of causative viz reactive complement activation. The mosaic of autoimmunity, i.e. multiple combinations of the many factors producing varying clinical pictures, leads to the manifold facets of liver autoimmunity., Graphical abstract Image 1, Highlights • Liver pathology associated to complement system derangement. • Liver autoimmunity depends on complement system activation. • The complement system may turn itself against its production site, i.e. the hepatocyte. • Complosome, i.e. intracellular metabolic involvement of complement components, scrutinized in liver pathology.

Background: The circadian fluctuations in the blood levels of selected components of the complement system are ill-defined. Some authors found nadir serum levels of C4 and C3 components, together with C3a at nighttime, while others reported insomnia when pro-inflammatory components exhibited increased serum levels. In this study, we quantitatively estimate the morning and evening daytime serum levels of CH50, C4, C3, put into context with C-reactive protein (CRP), cortisol, parathyroid hormone (PTH) and 25(OH)vitamin D at 07:00 A.M. and at 07:00 P.M. Methods: Seven healthy adult women and 11 men who were voluntary participants agreed to a fasting venipuncture in the morning after having normally eaten through the day and in the evening. The C4 and C3 serum levels were measured on a Cobas (Roche Diagnostics, Switzerland) modular analyzer, CH50 was estimated using the COMPL300 enzyme-linked immunosorbent assay (ELISA) of Wieslab (Malmö, Sweden). CRP, 25(OH)vitamin D, PTH and cortisol concentrations were assessed with electro-chemiluminescence immunoassay (ECLIA) on the Roche Cobas 6000 platform; IgG was measured using nephelometry (Siemens, Germany). Results: With the exception of higher PTH levels in the evening [3.12–5.46, 95% confidence interval (CI)] compared to the morning (2.93–4.65, 95% CI), the mean and median values of C4, C3, CH50 as well as CRP, PTH and 25(OH)vitamin D fell within the established reference intervals. Cortisol levels were measured as an internal positive control for diurnal fluctuations (morning: 294–522 nmol/L, 95% CI; evening: 106–136 nmol/L, 95% CI). Conclusions: The concentrations of the assessed complement components C4 and C3 as well as CH50 surrogate assay did not yield significantly different values between early morning and evening. This does not exclude their participation in the circadian metabolome; this pilot study with healthy participants suggests that patients with an autoimmune disease in remission can give their blood samples independently during daytime with or without fasting.

Introduction. Hepatitis E is one of the leading clinical manifestations of acute viral hepatitis in developing countries. In industrialized countries, during the past several years, sporadic ?autochthonous? cases of HEV infection have been increased. Objective. The aim of this study was to analyze the epidemiological, clinical and laboratory features of HEV infection among patients hospitalized at the Department of Infectious Diseases in Military Medical Academy, Sofia, Bulgaria. Methods. A retrospective study of 806 cases of acute viral hepatitis was performed at the Department of Infectious Diseases in Military Medical Academy, Sofia, Bulgaria, between December 2004 and September 2012. The etiological diagnosis was established by ELISA. The statistical analysis was performed using Excel 2007 (Microsoft, Redmond, Washington, USA) and SPSS Statistics 19.0 (IBM Corp., Armonk, New York, USA). Results. Specific reaction to anti-HEV-IgM and anti-HEV-IgG antibodies were detected in 20 (2.48%) of 806 patients. The most observed clinical presentations were jaundice (85%), fatigue (85%), anorexia (65%), abdominal discomfort (55%) and fever (40%). The mean values of aspartate transaminase and alanine transaminase were 521 IU/l and 881 IU/l, respectively. The cholestasis was slight, marked with mean values of gamma-glutamyl transferase and alkaline phosphatase, respectively 418 IU/l and 486 IU/l. Conclusion. We report twenty autochthonous sporadic cases of acute infection with HEV. The zoonotic etiology of the virus as well as the foodborne transmission of the infection is discussed. We found that aging and pre-existing underlying diseases are risk factors for a severe course of the HEV infection.

ω3-polyunsaturated fatty acids (ω3-PUFAs) are known to exert anti-inflammatory effects in various disease models although their direct targets are only poorly characterized.

Background The vitamin B12 and folate status in nonanaemic healthy older persons needs attention the more so as decrease in levels may be anticipated from reduced haematinic provision and/or impaired intestinal uptake. Methods A total of 1143 subjectively healthy Swiss midlands participants (637 females and 506 males), ≥60 years of age were included in this study. Levels of vitamin B12, holotranscobalamin (holoTC), methylmalonic acid (MMA), homocysteine (Hcy), serum folate, red blood cell (RBC) folate were measured. Further, Fedosov’s wellness score was determined. Associations of age, gender, and cystatin C/creatinine-based estimated kidney function, with the investigated parameters were assessed. Reference intervals were calculated. Further, ROC analysis was done to assess accuracy of the individual parameters in recognizing a deficient vitamin B12 status. Finally, decision limits for sensitive, specific and optimal recognition of vitamin B12 status with individual parameters were derived. Results Three age groups: 60–69, 70–79 and ≥ 80 had median B12 (pmol/L) levels of 237, 228 and 231 respectively (p = 0.22), holoTC (pmol/L) of 52, 546 and 52 (p = 0.60) but Hcy (μmol/L) 12, 15 and 16 (p

Anti-red blood cell antibodies, free light chains (FLC) and prothrombotic proteins (PTP) may co-elute with intact immunoglobulin (IgG), and may be the cause of adverse reactions to intravenous immunoglobulin preparations (IVIG).To investigate the presence of residual amounts of these components in IVIG and their effects on ABO blood group agglutination.Iso-agglutinin anti-A and anti-B activity was determined with a direct hemagglutination assay of red blood cell (RBC) suspensions from 1% of 46 blood donors together with the serial dilutions of five IVIG (IV1, IV2, IV3, IV4, IV5). Anti-A1 monoclonal antibody was used to confirm reactivity with the A1-reference RBC. The selected IVIG were diluted to a final concentration of 25 mg/ml in 0.15 M NaCI and 0.01 M phosphate-buffered saline, pH 7.4, with or without a further twofold dilution in a low ionic strength solution.A variation up to fivefold in the titer strength of anti-A/B activity was observed between the IVIG preparations. A2-type RBC required higher IVIG inputs when tested in 0.15 M NaCl. The differences in FLC kappa and lambda concentrations were as high as400 mg/L among the various IVIG. Only IV1 had a significantly high level of antiphospholipid IgG antibodies (18 U/ml). We demonstrated the presence of anti-RBC antibodies, FLC and PTP in IVIG preparations.Our findings provide clear evidence that IVIG may harbor pathophysiological substrates with a potential risk for adverse effects such as iatrogenic hemolysis, FLC-associated disorders, and thromboembolism.

Background Vitamin D and the components of humoral immunity play important roles in human health. Older people have lower 25-hydroxyvitamin D (25(OH)D) serum levels than younger adults. We aimed to determine the levels of 25(OH)D serum concentrations in healthy senior citizens and to study their relationship to the levels of components of humoral immunity. Methods A total of 1,470 healthy Swiss men and women, 60 years or older, were recruited for this study. A total of 179 subjects dropped out of the study because of elevated serum concentrations of C-reactive protein. Fasting blood sera were analyzed for 25(OH)D with the high-performance liquid chromatography (HPLC) and for parathyroid hormone (PTH), immunoglobulins and complement C4 and C3 concentrations with immunoassays. The percentage of participants in each of the four 25(OH)D deficiency groups - severely deficient (=30 ng/ml) - were statistically compared. The relationship of the major components of the humoral system and age with 25(OH)D levels was also assessed. Results About 66% of the subjects had insufficient levels of 25(OH)D. Normal levels of 25(OH)D were found in 26.1% of the subjects of which 21% were males and 30.5% were females (total study population). Severely deficient levels of 25(OH)D were found in 7.98% of the total study population. Low levels of 25(OH)D were positively associated with IgG2 (P = 0.01) and with C4 (P = 0.02), yet were inversely related to levels of IgG1 and IgA (P P = 0.01). Serum levels of total IgA, IgG, IgG2 and IgG4 peaked together with 25(OH)D during late summer. Conclusions Approximately two-thirds of the healthy, older Swiss population presented with Vitamin D insufficiency. The incremental shift in IgA and C3 levels might not necessarily reflect a deranged humoral immune defense; however, given the high prevalence of vitamin D deficiency, the importance of this condition in humoral immunity will be worth looking at more closely. This study supports the role of vitamin D in the competent immune system.

ω3-polyunsaturated fatty acids (ω3-PUFAs) are known to exert anti-inflammatory effects in various disease models although their direct targets are only poorly characterized.Here we report on two new cPLA(2) inhibitors, the ω3-derivatives AVX001 and AVX002, and their effects on inflammatory PGE(2) production in cultures of renal mesangial cells.AVX001 and AVX002 dose-dependently inhibited the group IVA cytosolic phospholipase A(2) (cPLA(2) ) in an in vitro activity assay with similar IC(50) values for AVX001 and AVX002, whereas the known cPLA(2) inhibitor AACOCF(3) was less potent and docosahexaenoic acid (DHA) was inactive. In renal mesangial cells, AVX001 and AVX002 suppressed IL-1β-induced PGE(2) synthesis. Mechanistically, this effect occurred by a down-regulation of IL-1β-induced group IIA-sPLA(2) protein expression, mRNA expression and promoter activity. A similar but less potent effect was seen with AACOCF(3) and no effect was seen with DHA. As gene expression of sPLA(2) is known to be regulated by the transcription factor NF-κB, we further investigated NF-κB activation. Both compounds prevented NF-κB activation by blocking degradation of the inhibitor of κB.These data show for the first time that the novel cPLA(2) inhibitors AVX001 and AVX002 exert an anti-inflammatory effect in cultures of renal mesangial cells and reduce the pro-inflammatory mediator PGE(2) through an inhibitory effect on NF-κB activation. Therefore, these compounds may represent promising novel drugs for the treatment of inflammatory disorders.

The prevalence of Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) infection in a Swiss cohort among individuals consulting for screening or symptomatic reasons is not very well known.Between January 2009 and January 2010, diagnostic samples referred to us to test for either CT or NG or both were simultaneously analysed for both infections. Testing was performed using the commercial m2000sp and m2000rt devices from Abbott Diagnostics involving automated DNA extraction and semi-quantitative real-time polymerase chain reaction (PCR), respectively.A total of 9,245 individuals (8,009 female, 1,236 male) were tested. CT alone was found in 318 (3.97%) samples from female patients and NG infections were found in 5 (0.06%) of the female samples. Six (0.08%) women had both CT and NG infections. The numbers for males were 72 (5.83%) for CT alone, 18 (1.14%) for NG alone and 8 (0.65%) for coincident infections. Among women, a selective testing approach in which only the presence of CT was investigated missed six NG cases (0.07% prevalence, 54.55% of all NG-positive women) and the request to test only for NG missed two CT cases (0.02% prevalence, 0.62% of all CT-positive women). For the male samples, one NG case (0.08% prevalence, 3.85% of all NG-positive men) was missed when only CT was requested and three CT cases (0.24% prevalence, 3.75% of all CT-positive men) were overlooked when only NG testing was requested.A sizeable number (12) of CT and NG cases is missed by physician-referred testing for only one of the two pathogens.

Summary Two rounds of chromosome segregation after only a single round of DNA replication enable the production of haploid gametes from diploid precursors during meiosis. To identify genes involved in meiotic chromosome segregation, we developed an efficient strategy to knock out genes in the fission yeast on a large scale. We used this technique to delete 180 functionally uncharacterized genes whose expression is upregulated during meiosis. Deletion of two genes, sgo1 and mde2 , caused massive chromosome missegregation. sgo1 is required for retention of centromeric sister-chromatid cohesion after anaphase I [1–3]. We show here that mde2 is required for formation of the double-strand breaks necessary for meiotic recombination.