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Gene regulatory networks (GRNs) that direct animal embryogenesis must respond to varying environmental and physiological conditions to ensure robust construction of organ systems. While GRNs are evolutionarily modified by natural genomic variation, the roles of epigenetic processes in shaping plasticity of GRN architecture are not well understood. The endoderm GRN in Caenorhabditis elegans is initiated by the maternally supplied SKN-1/ Nrf2 bZIP transcription factor; however, the requirement for SKN-1 in endoderm specification varies widely among distinct C. elegans wild isotypes, owing to rapid developmental system drift driven by accumulation of cryptic genetic variants. We report here that heritable epigenetic factors that are stimulated by transient developmental diapause also underlie cryptic variation in the requirement for SKN-1 in endoderm development. This epigenetic memory is inherited from the maternal germline, apparently through a nuclear, rather than cytoplasmic, signal, resulting in a parent-of-origin effect (POE), in which the phenotype of the progeny resembles that of the maternal founder. The occurrence and persistence of POE varies between different parental pairs, perduring for at least 10 generations in one pair. This long-perduring POE requires piwi-interacting RNA (piRNA) function and the germline nuclear RNA interference (RNAi) pathway, as well as MET-2 and SET-32, which direct histone H3K9 trimethylation and drive heritable epigenetic modification. Such nongenetic cryptic variation may provide a resource of additional phenotypic diversity through which adaptation may facilitate evolutionary changes and shape developmental regulatory systems. [ABSTRACT FROM AUTHOR]

Measurement of plasma levels of natriuretic peptides has been used to assess left ventricular dysfunction and prognosis. Recently levels of the N-terminal peptide fragment of the precursor of brain natriuretic peptide have been reported to be present in peripheral plasma and to be increased in chronic heart failure patients. Our aim in this study was to develop a radioimmunoassay for N-terminal proBNP, to compare its plasma concentrations in control subjects and in patients with end-stage heart failure and to define its relation to brain natriuretic peptide (BNP). A polyclonal antibody was raised in rabbits against human N-terminal proBNP fragment (amino acid 1-21). The plasma N-terminal proBNP concentrations were assayed directly without extraction. No detectable cross-reactivity existed with other natriuretic peptides: BNP, ANP or N-terminal proANP. The assay had a detection limit (2 SD from zero) of 9.7 pmol/L. Plasma N-terminal proBNP was 29 (13-75) (median (range)) pmol/L in the control group. There were no gender difference, male: 28 (13-61) vs. female 33 (13-75) pmol/L, p= NS, but there was a positive correlation to age (r=0.52, p<0.0001). In patients with end-stage heart failure the median N-terminal proBNP levels were increased significantly 616 (114-2781) pmol/L (p<0.001) and in pooled data N-terminal proBNP showed a close correlation to BNP (r=0.96, p<0.0001). Size exclusion of plasma extracts indicated that proBNP (1-108) may circulate both as intact prohormone and as split products, N-terminal proBNP (1-76) and BNP (77-108). Our results support the concept that N-terminal proBNP measurement could be a valuable tool in the biochemical indication of increased cardiac wall stress. [ABSTRACT FROM AUTHOR]

Background: Hereditary hemochromatosis (HH) is a common genetic disease leading to accumulation of iron in several organs, most notably the liver. The C282Y/C282Y mutation in the HFE gene is found in most cases. In order to prevent clinical disease and to study the cost and feasibility of screening, a large population was screened. Methods: In a Norwegian county, all inhabitants 20 years or older were invited to participate in a population-based health survey programme. Screening for HH was one of several subprojects. Blood samples were obtained from 65,238 persons. Subjects with high serum transferrin saturation in two tests and high serum ferritin were clinically evaluated for HH. All subjects with high serum transferrin saturation in two tests were offered genotyping. Results: HH was newly diagnosed in 92 women and 177 men. Phlebotomy treatment was performed in 64 women and 152 men. Severe organ damage (liver cirrhosis) was ascertained in only 4 men. We found no correlation between serum ferritin and age. The estimated cost was US$ 1.6 per subject screened and US$ 390 per newly discovered HH subject. The estimated prevalence of phenotypical HH not previously known was 0.34% in women and 0.68% in men. The prevalence of the C282Y/C282Y mutation was at least 0.68%. Conclusion: Large-scale screening for HH can be performed at a relatively low cost if combined with a health survey programme. The yield in terms of newly discovered cases is considerable, but few cases were found seriously ill. Better knowledge of the natural course of HH is necessary if we are to be able to estimate the cost-effectiveness of large-scale screening. [ABSTRACT FROM AUTHOR]

Concentrations of methotrexate (MTX) and 7-hydroxymethotrexate (7-OH-MTX) were determined by HPLC in the serum and cerebrospinal fluid (CSF) of 29 children with acute lymphoblastic leukemia. CSF and serum samples were obtained at the end of 104 infusions of MTX given in a dose range of 0.5-8.0 g/m2. Concentrations, distribution ratios in serum and CSF for MTX and 7-OH-MTX, and the metabolic index were analyzed with regard to the MTX dose, age and clinical state of the patients. A wide inter-patient (2- to 12-fold) but narrower (1.1- to 3.5-fold) intra-patient variability of the concentrations was observed. A dose-proportional increase in the metabolite concentration was found in serum. On the other hand, the elevation of the level of metabolite in CSF was less than proportional to the dose. The CSF/serum distribution data suggest the existence of a saturable carrier system for MTX and 7-OH-MTX between serum and CSF that has lower affinity for 7-OH-MTX. No correlation was found between concentrations of MTX and 7-OH-MTX in the serum of patients receiving the same dose of MTX. No significant difference was observed in the values for metabolic index between relapsed patients and those who were in continuous complete remission. A significant correlation was found between age and metabolic index: the younger the patient, the higher the metabolite concentration measured in serum. [ABSTRACT FROM AUTHOR]

Abstract Background The purpose of this study was to investigate mediators of inflammation and haemostasis in patients with chronic necrotizing pulmonary aspergillosis (CNPA), a locally, destructive process of the lung due to invasion by Aspergillus species. Methods Measurements of selected biomarkers in 10 patients with CNPA and 19 healthy, matched controls were performed with enzyme-linked immunosorbent assay (ELISA) and multiplex methodology. The gene expressions of relevant biomarkers were analyzed with real-time quantitative RT-PCR. Results Increased concentrations of circulating mediators of inflammation interleukin (IL)-6, IL-8, RANTES, TNF-α, ICAM-1 and mediators involved in endothelial activation and thrombosis (vWF, TF and PAI-1) were observed in patients with CNPA. The concentration of the anti-inflammatory cytokine IL-10 was increased both in plasma and in PBMC in the patient population. The gene expression of CD40L was decreased in PBMC from the patient group, accompanied by decreased concentrations of soluble (s) CD40L in the circulation. Conclusions The proinflammatory response against Aspergillus may be counteracted by reduced CD40L and sCD40L, as well as increased IL-10, which may compromise the immune response against Aspergillus in patients with CNPA.

Case: Urethral prolapse (UP) is a rare condition with unknown etiology. We reported on an 86-year-old woman with a normal BMI and cystocele, presented with acute urinary retention and perineal pain. A residual urine of 950 mL was measured and released by an indwelling catheter. The physical examination revealed 2 × 3 cm severely sore and purple polyp around the urethral meatus with signs of necrosis. A diagnosis of a strangulated urethral prolapse was stated., Outcome: The patient was admitted to the Department of Urology, and treated with surgical excision using the four-quadrant excisional technique. The histopathological examination revealed a non-keratinized, inflammatory squamous epithelium. At a follow-up visit, the patient remained asymptomatic and a complete anatomical resolution was achieved., Conclusion: UP is an uncommon, sometimes misdiagnosed condition. The management is controversial and to date no consensus exists. This clinical picture is sufficient for diagnosis and surgical excision of the prolapsed urethral mucosa is reasonable if there are signs of strangulation., (© 2021 The Authors. LUTS: Lower Urinary Tract Symptoms published by John Wiley & Sons Australia, Ltd.)

Introduction: Treatment costs of lower urinary tract symptoms secondary to benign prostatic enlargement (BPE) are a substantial economic burden that will continue to increase in the future as a result of the ageing male population and increasing health awareness. The true costs for surgical interventions against BPE have been difficult to quantify as treatment costs strongly depend on the performance setting and may also vary among different healthcare systems, regions and institutions. The purpose of this study was to disclose the in-hospital costs and main expense items associated with a transurethral resection of the prostate (TURP). Methods: A cohort of men subjected to TURP due to BPE was analysed during a 3-year period (2017-2019). All in-hospital expenses were registered using an electronic spreadsheet. Patient background and perioperative variables were registered using retrospective chart reviews. Results: A total of 122 men were available for final analysis. Of these, 70 men were operated on due to bothersome LUTS and 52 men due to urinary retention. The mean and median (inter quartile range) cost per patient was €4025 and €3702 (2961 - 4390), respectively. The main drivers of total cost were length of stay, the surgical procedure and anaesthesia related costs. Factors associated with increasing total cost per patient were increasing age, prostate volume, presence of urinary retention, occurrence of complications, increasing catheter time and length of stay. Conclusion: The main factor that influences total cost for an elective TURP procedure is the occurrence of postoperative complications. Our findings firmly underscore the indispensability to employ every possible means to avoid and prevent complications of any kind.

Background: Transurethral resection of the prostate (TURP) has been the standard method of surgical management of benign prostatic enlargement for decades. Some patients experience significant voiding dysfunction and discomfort postoperatively, without any apparent clinical complications from the procedure. Furthermore, a significant proportion of men still require postoperative catheterisation. This study analysed patients defined as non-responders after TURP with the principal aim to reveal their fate., Methods: A prospectively recruited cohort of 355 men, who underwent TURP during 2010-2012, was investigated. Non-responders were identified as still requiring catheterisation postoperatively and/or exhibiting all of the following voiding outcomes based on the de Wildt criteria: IPSS > 7, bother score > 2, Q max < 15 mL/s and PVR > 100 mL. The non-responders were followed for a maximum period of three years using retrospective chart reviews., Results: Thirty-five men were defined as non-responders. Of these, 26 men were operated on due to urinary retention and nine men due to bothersome symptoms. The non-responders were followed for a mean time of 72 months. Seven men underwent a redo-TURP and two men a bladder neck incision. Eleven of the 35 men were finally judged as having satisfactory voiding parameters. Sixteen men used CISC. Eleven men reduced the frequency of CISC to a minimum. Seven men had to use an indwelling catheter indefinitely., Conclusion: Men with preoperative urinary retention constituted the vast majority of non-responders. The use of postoperative urodynamic studies was remarkably low. Almost one in three non-responders finally had a satisfactory outcome with or without re-intervention.

Background: Transurethral resection of the prostate (TURP) is considered the reference surgical method of treating benign prostatic enlargement (BPE) causing obstruction. The procedure still carries a significant risk of perioperative morbidity according to previous reports. The aim of the present study was to disclose complications after TURP undertaken in routine clinical practice at a non-academic center. Methods: All patients with BPE submitted to TURP from January 2010 to December 2012 were evaluated for complications occurring during hospital stay, after discharge up to the end of the third post-operative month and finally for any late endourological re-interventions undertaken up to five years after TURP. All complications were graded according to the Clavien-Dindo system. Results: In total, 354 men underwent a TURP during the study period. In total, 47% had pre-operative urinary retention. Significant co-morbidity was seen in 17% of men (ASA III-IV). Spinal anaesthesia was applied to 312 men (88%). During hospital stay, major complications, graded as Clavien-Dindo ≥ III, was seen in only eight men (2.3%). Minor complications occurred in 91 men (26%). Between hospital discharge and follow-up visit major complications were noted in 12 men (3.4%). Minor complications occurred in 79 men (22%). The only factor that was associated with an increased risk of a major complication was general anaesthesia. Late complications, requiring an endourological re-intervention, occurred in 30 men (9.7%). Conclusion: TUR-P in routine clinical practice was associated with a low incidence of severe complications. TUR syndrome was very rare. Within five years a small proportion of men require the transurethral intervention to be redone.

Background: Transurethral resection of the prostate (TURP) is the reference standard surgical treatment for lower urinary tract symptoms (LUTS) related to benign prostatic enlargement. The aim of this study was to investigate the response rate following TURP in two distinctly different patient categories; men with bothersome LUTS and men in urinary retention (UR) requiring catheterisation., Methods: In total, 355 men underwent TURP due to LUTS or UR. Responders in the LUTS group were defined as having an International Prostate Symptom Score ≤7 or >50% loss compared to baseline, a Q max ≥ 15 mL/s or >50% gain compared to baseline, a post-void residual ≤100 mL or a bother score ≤2. Patients fulfilling at least one out of the four criteria were defined as responders. In the UR group, responders were defined as being catheter-free at follow-up., Results: In total, 337 men remained for final analysis. The proportion operated on due to UR was 46%. In men with LUTS, the response rate was 95%. One in four were classified as excellent responders, fulfilling all four outcome criteria. Men with UR had a successful removal of the catheter after TURP prior to discharge in 77% of the cases and an additional 6% within 3 months, yielding a total response rate of 83%., Conclusion: TURP is a successful procedure in men with bothersome LUTS and in men with UR. Considering the difference regarding voiding outcomes in men operated on due to LUTS or UR, these groups should be analysed separately in future studies comparing TURP against newer treatment modalities.

Objectives: Arginine, asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), arginine/ADMA ratio and homoarginine could potentially affect nitric oxide production and have been studied in relation to cardiovascular risk (CVR) in various clinical populations. Prospective studies on the CVR associated with arginine/ADMA ratio and homoarginine in patients with moderate chronic kidney disease (CKD) are still scarce. We have studied how arginine, homoarginine and dimethylated arginine can predict cardiovascular events in such a population., Design and Methods: We measured plasma concentrations of arginine (P-arginine), ADMA (P-ADMA), SDMA (P-SDMA), homoarginine (P-homoarginine) and other covariates in 160 patients with predialytic CKD (mean age 57 years and mean eGFR 43 mL/min/1.73 m(2)) and followed them for 58 months in median. The risks of fatal and non-fatal cardiovascular events associated with the predictors were evaluated with multivariable Cox proportional hazard analysis., Results: There were 31 cardiovascular events during the observation period. In a multivariable model adjusted for age, sex, previous cardiovascular disease, P-cystatin C and P-homoarginine, the hazard ratio (HR) associated with an increase in arginine/ADMA ratio by 10 was 0.83 (P=0.03). The HR of a 1 μmol/L increase in P-homoarginine in the same model was 1.78 (P=0.01). A statistically significant interaction between P-homoarginine and P-cystatin C was found in an extended multivariable model. P-SDMA was not associated with increased CVR after adjustment for basic covariates., Conclusion: This study demonstrates a negative association between arginine/ADMA ratio and CVR in CKD patients and a positive association between P-homoarginine and CVR. The latter is in contrast to what has been demonstrated by others., (Copyright © 2015 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Quantitatively, the most important B6 vitamer in plasma is pyridoxal-5'-phosphate (p-PLP). The prerequisite for the use of p-PLP measurements in patients with poor nutritional status is an appropriate reference interval, together with knowledge of the stability of vitamin B6 in plasma samples. We used blood samples from healthy blood donors to derive the reference limits for p-PLP, and to examine its stability for 24 hours at room temperature and at 4-8°C. P-PLP was measured using high performance liquid chromatography (HPLC). The reference interval in adults was 23-223 nmol/L. P-PLP was stable for 24 h at room temperature and at 4-8°C, allowing time for normal specimen transport.

Objectives: Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase (NOS) that accumulates in patients with chronic kidney disease (CKD) and predicts cardiovascular outcome. Arginine is the substrate for NOS and a low arginine/ADMA ratio may lead to a reduced NO production and a worse prognosis. We have studied how other important CKD variables predict the arginine/ADMA ratio., Design and Methods: The population is 160 predialytic CKD patients (median age 61 years). We used backward stepwise regression to identify the best predictors of p-arginine, p-ADMA and arginine/ADMA ratio., Results: P-ADMA was predicted by estimated GFR (eGFR) (adjusted R(2)=0.17, p>0.00). Arginine/ADMA ratio was predicted by gender, eGFR, use of renin angiotensin aldosteron (RAAS) inhibitors, current smoking and use of platelet inhibitors (adjusted R(2)=0.18, p<0.00)., Conclusions: Reduced eGFR is associated with reduced arginine/ADMA ratio. The use of RAAS inhibitors and male gender may be protective against a low arginine/ADMA ratio., (Copyright © 2011 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Objective: To prospectively determine the effect of smoking cessation on markers of inflammation and endothelial cell activation., Material and Methods: Thirty male and 22 female smokers of >7 cigarettes daily, aged 32-64 years with cardiovascular disease (CVD) or additional risk factors to smoking, participated in a program of smoking cessation with a follow-up period of 1 year. Cessation was validated by carbon monoxide measurement in expired breath, and 41 of the patients completed the study (17 quitters and 24 non-quitters). Plasma samples were drawn at baseline and after 1 year, and inflammatory markers were analyzed by enzyme immunoassays. Peripheral blood mononuclear cells (PBMCs) were isolated at baseline and 1 year in 6 quitters and 6 smokers and mRNA levels of interleukin-8 (IL-8), tumor necrosis factor x (TNFx) and intercellular adhesion molecule 1 (ICAM-1) were analyzed by real-time quantitative RT-PCR., Results: Our main findings were: (i) While the concentration of soluble (s) ICAM-1 decreased in quitters, it increased in smokers, with a significant difference in changes between the groups (p=0.04). (ii) While there was only minor change in mRNA levels of IL-8 in smokers, those who stopped smoking showed a decrease in the gene expression of IL-8 (p < 0.09; comparing difference in changes). (iii) Concentrations of the other measured parameters (E-selectin, IL-6, sCD40 ligand, TNFx, von Willebrand factor, and C-reactive protein) were unchanged during follow-up in both groups., Conclusion: Smoking cessation induced a reduction in ICAM-1, suggesting a novel mechanism for the rapid reduction in the risk of CVD following smoking cessation.

Background: Normally the body is unable to regulate its own iron content effectively by excretion. Urinary excretion of iron is about 10% of total daily loss., Case Presentation: A 40-year-old woman was admitted to hospital because of anaemia that turned out to be caused by iron deficiency. In spite of extensive investigations no cause of her iron deficiency was identified. The urine was then tested for iron and showed excessive urinary loss as the cause of her anaemia. To our knowledge, extensive urinary iron loss as the cause of iron deficiency has not been reported before.

Cytokine systems are activated in heart failure, and it is believed that interaction between such systems may be important during progression of this disorder. We have previously shown that failing hearts have increased levels of the interleukin-6 related cytokine leukemia inhibitory factor (LIF) and activin A, a member of the transforming growth factor-beta family. The aim of this study was to examine the effects of activin A on cardiomyocytes and a potential interaction with LIF-mediated changes in cell signaling and growth. Cardiomyocytes were isolated from 1- to 3-day-old Wistar rats, and the cells were treated with LIF, activin A or a combination thereof. Our main findings were: (i) activin A treatment reduced the LIF-mediated increase in cardiomyocyte length, perimeter and sarcomeric organization and was accompanied by a substantially decreased alpha-skeletal actin gene expression. (ii) The activin A-mediated phosphorylation of Smad2 was markedly enhanced by LIF. (iii) Activin A markedly induced SOCS3 gene expression, while LIF potently increased the expression of Smad7 mRNA, representing inhibitors of LIF and activin A signaling pathways, respectively. (iv) Inhibiting activation of the Smad2/3 pathway abolished the effects of activin A on LIF-induced changes in cell length, perimeter and sarcomeric organization. In conclusion, activin A markedly attenuates LIF-induced changes in cardiomyocytes, reflecting a potentially important role for both activin A and the Smad2/3 pathway in regulation of myocardial remodeling.

A previous observation of increased aqueous magnesium in eyes with senile cataract has been re-examined in a totally different material. The serum and aqueous level of calcium and magnesium from 34 patients with senile cataract were tested against comparable values from 4 patients with choroidal melanoma. In contrast to calcium, the magnesium aqueous/serum ratio was significantly higher in the cataract group. Possible explanations are suggested.

Concentrations of 7-hydroxy-methotrexate (7-OH-MTX) were determined in serum samples obtained after 266 infusions of methotrexate administered to 58 children with acute lymphoblastic leukemia. The dose of methotrexate (MTX) was in the range of 0.5-33.6 g/m2. Pharmacokinetic parameters (metabolic index, drug/metabolite ratio, half-life) of 7-OH-MTX and their relationship to the kinetics of methotrexate were analyzed. A great variability was observed in the extent and time-course of the metabolite formation. The concentration of the metabolite was higher than that of the parent compound at any examined time after the end of the 24 hours' infusion. The increase of 7-OH-MTX levels at the end of the methotrexate infusion was found to be proportionate to the increase of the dose of MTX. Males had significantly higher metabolite levels than did females (P less than 0.01) in the dose range of 0.5-8.0 g/m2. The age of the patients also significantly influenced the rate of the metabolite formation. The serial number of the treatment courses did not have effect on the metabolism of MTX. Dose dependency of the elimination half-life of the metabolite was found. Although a tendency was observed that patients in continuous complete remission had higher metabolite levels than those who relapsed, the difference was not significant. Further studies are needed to determine the clinical importance of 7-OH-MT.

Pharmacologic rescue methods used in combination with intermediate and high-dose methotrexate therapy are reviewed, with special emphasis on rescue with nucleosides and folinic acid. The mechanism of action, pharmacokinetics, and clinical applications of the rescue agents are described in detail in view of the literature and also of the own findings of the authors. In spite of the promising results of the in vitro studies and in vivo experiments in animal models, the clinical value of thymidine as a rescue agent remains to be determined. Currently, the only indication to use thymidine instead of folinic acid following high-dose methotrexate is to prevent toxicity related to extremely high methotrexate levels in patients with delayed elimination of methotrexate. In spite of the widespread application of folinic acid rescue, the exact mechanism of its action is not fully understood. The rescue dose and schedule in the majority of clinical protocols is empirical, and the start of the rescue administration is too early, allowing less than 36 to 42 hours of exposure to methotrexate. Clinical and laboratory findings indicate that while the early start of FA administration is unnecessary for protecting normal cells, it is potentially dangerous in terms of reduction of the antitumor effect of methotrexate. Our findings suggest that less than the most widely used 12-15 mg/m2 per dose rescue may be sufficient in preventing methotrexate related toxicity in patients with normal elimination of the drug. In addition, reducing the dose of the rescue may be beneficial to achieve better therapeutic results with high-dose methotrexate. Due to methodological problems, the pharmacokinetics of folinic acid rescue has not been excessively studied in humans. Recent data indicate that the pharmacokinetics of folinic acid in children is characterized by great intra- and interpatient variability. The effect of food on the bioavailability of folinic acid has not yet been studied, though it is most frequently administered orally. The introduction of the pure l-stereoisomer of the rescue agent in the clinical practice may eliminate potential interactions with the d-isomer, and may also simplify the introduction of therapeutic drug monitoring for folinic acid as well. This could lead to more rational clinical use of folinic acid as a rescue agent following intermediate and high-dose methotrexate therapy.