The 1st year of the COVID-19 epidemic in Estonia: a population-based nationwide sequential/consecutive cross-sectional study.

OBJECTIVES: The objective of this study was to assess the population prevalence of SARS-CoV-2 and changes in the prevalence in the adult general population in Estonia during the 1st year of COVID-19 epidemic. STUDY DESIGN: This was a population-based nationwide sequential/consecutive cross-sectional study. METHODS: Using standardised methodology (population-based, random stratified sampling), 11 cross-sectional studies were conducted from April 2020 to February 2021. Data from nasopharyngeal testing and questionnaires were used to estimate the SARS-CoV-2 RNA prevalence and factors associated with test positivity. RESULTS: Between April 23, 2020, and February 2, 2021, results were available from 34,915 individuals and 27,870 samples from 11 consecutive studies. The percentage of people testing positive for SARS-CoV-2 decreased from 0.27% (95% confidence interval [CI] = 0.10%-0.59%) in April to 0.04% (95% CI = 0.00%-0.22%) by the end of May and remained very low (0.01%, 95% CI = 0.00%-0.17%) until the end of August, followed by an increase since November (0.37%, 95% CI = 0.18%-0.68%) that escalated to 2.69% (95% CI = 2.08%-2.69%) in January 2021. In addition to substantial change in time, an increasing number of household members (for one additional odds ratio [OR] = 1.15, 95% CI = 1.02-1.29), reporting current symptoms of COVID-19 (OR = 2.21, 95% CI = 1.59-3.09) and completing questionnaire in the Russian language (OR 1.85, 95% CI 1.15-2.99) were associated with increased odds for SARS-CoV-2 RNA positivity. CONCLUSIONS: SARS-CoV-2 population prevalence needs to be carefully monitored as vaccine programmes are rolled out to inform containment decisions.

Genetic risk scores and family history as predictors of schizophrenia in Nordic registers.

BACKGROUND: Family history is a long-standing and readily obtainable risk factor for schizophrenia (SCZ). Low-cost genotyping technologies have enabled large genetic studies of SCZ, and the results suggest the utility of genetic risk scores (GRS, direct assessments of inherited common variant risk). Few studies have evaluated family history and GRS simultaneously to ask whether one can explain away the other. METHODS: We studied 5959 SCZ cases and 8717 controls from four Nordic countries. All subjects had family history data from national registers and genome-wide genotypes that were processed through the quality control procedures used by the Psychiatric Genomics Consortium. Using external training data, GRS were estimated for SCZ, bipolar disorder (BIP), major depression, autism, educational attainment, and body mass index. Multivariable modeling was used to estimate effect sizes. RESULTS: Using harmonized genomic and national register data from Denmark, Estonia, Norway, and Sweden, we confirmed that family history of SCZ and GRS for SCZ and BIP were risk factors for SCZ. In a joint model, the effects of GRS for SCZ and BIP were essentially unchanged, and the effect of family history was attenuated but remained significant. The predictive capacity of a model including GRS and family history neared the minimum for clinical utility. CONCLUSIONS: Combining national register data with measured genetic risk factors represents an important investigative approach for psychotic disorders. Our findings suggest the potential clinical utility of combining GRS and family history for early prediction and diagnostic improvements.

An epigenome-wide association study meta-analysis of educational attainment.

The epigenome is associated with biological factors, such as disease status, and environmental factors, such as smoking, alcohol consumption and body mass index. Although there is a widespread perception that environmental influences on the epigenome are pervasive and profound, there has been little evidence to date in humans with respect to environmental factors that are biologically distal. Here we provide evidence on the associations between epigenetic modifications-in our case, CpG methylation-and educational attainment (EA), a biologically distal environmental factor that is arguably among the most important life-shaping experiences for individuals. Specifically, we report the results of an epigenome-wide association study meta-analysis of EA based on data from 27 cohort studies with a total of 10 767 individuals. We find nine CpG probes significantly associated with EA. However, robustness analyses show that all nine probes have previously been found to be associated with smoking. Only two associations remain when we perform a sensitivity analysis in the subset of never-smokers, and these two probes are known to be strongly associated with maternal smoking during pregnancy, and thus their association with EA could be due to correlation between EA and maternal smoking. Moreover, the effect sizes of the associations with EA are far smaller than the known associations with the biologically proximal environmental factors alcohol consumption, body mass index, smoking and maternal smoking during pregnancy. Follow-up analyses that combine the effects of many probes also point to small methylation associations with EA that are highly correlated with the combined effects of smoking. If our findings regarding EA can be generalized to other biologically distal environmental factors, then they cast doubt on the hypothesis that such factors have large effects on the epigenome.

The association between lower educational attainment and depression owing to shared genetic effects? Results in ~25,000 subjects.

An association between lower educational attainment (EA) and an increased risk for depression has been confirmed in various western countries. This study examines whether pleiotropic genetic effects contribute to this association. Therefore, data were analyzed from a total of 9662 major depressive disorder (MDD) cases and 14,949 controls (with no lifetime MDD diagnosis) from the Psychiatric Genomics Consortium with additional Dutch and Estonian data. The association of EA and MDD was assessed with logistic regression in 15,138 individuals indicating a significantly negative association in our sample with an odds ratio for MDD 0.78 (0.75-0.82) per standard deviation increase in EA. With data of 884,105 autosomal common single-nucleotide polymorphisms (SNPs), three methods were applied to test for pleiotropy between MDD and EA: (i) genetic profile risk scores (GPRS) derived from training data for EA (independent meta-analysis on ~120,000 subjects) and MDD (using a 10-fold leave-one-out procedure in the current sample), (ii) bivariate genomic-relationship-matrix restricted maximum likelihood (GREML) and (iii) SNP effect concordance analysis (SECA). With these methods, we found (i) that the EA-GPRS did not predict MDD status, and MDD-GPRS did not predict EA, (ii) a weak negative genetic correlation with bivariate GREML analyses, but this correlation was not consistently significant, (iii) no evidence for concordance of MDD and EA SNP effects with SECA analysis. To conclude, our study confirms an association of lower EA and MDD risk, but this association was not because of measurable pleiotropic genetic effects, which suggests that environmental factors could be involved, for example, socioeconomic status.

Early replication dynamics of sex-linked mitochondrial DNAs in the doubly uniparental inheritance species Ruditapes philippinarum (Bivalvia Veneridae).

Mitochondrial homoplasmy, which is maintained by strictly maternal inheritance and a series of bottlenecks, is thought to be an adaptive condition for metazoans. Doubly uniparental inheritance (DUI) is a unique mode of mitochondrial transmission found in bivalve species, in which two distinct mitochondrial genome (mtDNA) lines are present, one inherited through eggs (F) and one through sperm (M). During development, the two lines segregate in a sex- and tissue-specific manner: females lose M during embryogenesis, whereas males actively segregate it in the germ line. These two pivotal events are still poorly characterized. Here we investigated mtDNA replication dynamics during embryogenesis and pre-adulthood of the venerid Ruditapes philippinarum using real-time quantitative PCR. We found that both mtDNAs do not detectably replicate during early embryogenesis, and that the M line might be lost from females around 24 h of age. A rise in mtDNA copy number was observed before the first reproductive season in both sexes, with the M mitochondrial genome replicating more than the F in males, and we associate these boosts to the early phase of gonad production. As evidence indicates that DUI relies on the same molecular machine of mitochondrial maternal inheritance that is common in most animals, our data are relevant not only to DUI but also to shed light on how differential segregations of mtDNA variants, in the same nuclear background, may be controlled during development.

An epidemiological perspective of personalized medicine: the Estonian experience.

The Estonian Biobank and several other biobanks established over a decade ago are now starting to yield valuable longitudinal follow-up data for large numbers of individuals. These samples have been used in hundreds of different genome-wide association studies, resulting in the identification of reliable disease-associated variants. The focus of genomic research has started to shift from identifying genetic and nongenetic risk factors associated with common complex diseases to understanding the underlying mechanisms of the diseases and suggesting novel targets for therapy. However, translation of findings from genomic research into medical practice is still lagging, mainly due to insufficient evidence of clinical validity and utility. In this review, we examine the different elements required for the implementation of personalized medicine based on genomic information. First, biobanks and genome centres are required and have been established for the high-throughput genomic screening of large numbers of samples. Secondly, the combination of susceptibility alleles into polygenic risk scores has improved risk prediction of cardiovascular disease, breast cancer and several other diseases. Finally, national health information systems are being developed internationally, to combine data from electronic medical records from different sources, and also to gradually incorporate genomic information. We focus on the experience in Estonia, one of several countries with national goals towards more personalized health care based on genomic information, where the unique combination of elements required to accomplish this goal are already in place.

A common atopy-associated variant in the Th2 cytokine locus control region impacts transcriptional regulation and alters SMAD3 and SP1 binding.

BACKGROUND: Type 2 immune responses directed by Th2 cells and characterized by the signature cytokines IL4, IL5, and IL13 play major pathogenic roles in atopic diseases. Single nucleotide polymorphisms in the human Th2 cytokine locus in particular in a locus control region within the DNA repair gene RAD50, containing several RAD50 DNase1-hypersensitive sites (RHS), have been robustly associated with atopic traits in genome-wide association studies (GWAS). Functional variants in IL13 have been intensely studied, whereas no causative variants for the IL13-independent RAD50 signal have been identified yet. This study aimed to characterize the functional impact of the atopy-associated polymorphism rs2240032 located in the human RHS7 on cis-regulatory activity and differential binding of transcription factors. METHODS: Differential transcription factor binding was analyzed by electrophoretic mobility shift assays (EMSAs) with Jurkat T-cell nuclear extracts. Identification of differentially binding factors was performed using mass spectrometry (LC-MS/MS). Reporter vector constructs carrying either the major or minor allele of rs2240032 were tested for regulating transcriptional activity in Jurkat and HeLa cells. RESULTS: The variant rs2240032 impacts transcriptional activity and allele-specific binding of SMAD3, SP1, and additional putative protein complex partners. We further demonstrate that rs2240032 is located in an RHS7 subunit which itself encompasses repressor activity and might be important for the fine-tuning of transcription regulation within this region. CONCLUSION: The human RHS7 critically contributes to the regulation of gene transcription, and the common atopy-associated polymorphism rs2240032 impacts transcriptional activity and transcription factor binding.

Immunolocalization of Vasa, PIWI, and TDRKH proteins in male germ cells during spermatogenesis of the teleost fish Poecilia reticulata.

Vasa, PIWI and TDRKH are conserved components of germ granules that in metazoans are involved in germline specification and differentiation, as documented by mutational experiments in some model animals. So far, investigations on PIWI during spermatogenesis of fish has been limited to a few species, and no information is available for TDRKH, another protein involved in the piRNA pathway. In this study, the immunolocalization of these three germline determinants was analyzed in male gonads of the teleost fish Poecilia reticulata to document their localization pattern in the different stages of germ cell differentiation. To analyze their distribution pattern during the different stages of spermatogenesis we performed immunohistochemistry (IHC) and immunofluorescence (IF) assays using primary polyclonal antibodies after testing their specificity with Western Blot. Moreover, sections of testis stained with haematoxylin and eosin clarified the structural organization of P. reticulata testis, while the use of the confocal microscope and the nuclear staining clarified the different stages of germ cell differentiation during spermatogenesis. The results showed that Vasa, PIWI and TDRKH were specifically immunolocalized in the germ cells of P. reticulata, with no specific signal detected in Sertoli cells and in other somatic cells of the gonad. These markers were detected in all stages of differentiation from early spermatogonia to advanced spermatids. Vasa staining was the strongest in spermatogonia, and then decreases throughout differentiation. Instead, both PIWI and TDRKH staining increases during differentiation, and their distribution pattern, similar to what observed in the mouse, suggests their concerted participation in the piRNA pathway also in this fish.

Interferon regulatory factor 5 (IRF5) gene variants are associated with multiple sclerosis in three distinct populations.

BACKGROUND: IRF5 is a transcription factor involved both in the type I interferon and the toll-like receptor signalling pathways. Previously, IRF5 has been found to be associated with systemic lupus erythematosus, rheumatoid arthritis and inflammatory bowel diseases. Here we investigated whether polymorphisms in the IRF5 gene would be associated with yet another disease with features of autoimmunity, multiple sclerosis (MS). METHODS: We genotyped nine single nucleotide polymorphisms and one insertion-deletion polymorphism in the IRF5 gene in a collection of 2337 patients with MS and 2813 controls from three populations: two case-control cohorts from Spain and Sweden, and a set of MS trio families from Finland. RESULTS: Two single nucleotide polymorphism (SNPs) (rs4728142, rs3807306), and a 5 bp insertion-deletion polymorphism located in the promoter and first intron of the IRF5 gene, showed association signals with values of p<0.001 when the data from all cohorts were combined. The predisposing alleles were present on the same common haplotype in all populations. Using electrophoretic mobility shift assays we observed allele specific differences in protein binding for the SNP rs4728142 and the 5 bp indel, and by a proximity ligation assay we demonstrated increased binding of the transcription factor SP1 to the risk allele of the 5 bp indel. CONCLUSION: These findings add IRF5 to the short list of genes shown to be associated with MS in more than one population. Our study adds to the evidence that there might be genes or pathways that are common in multiple autoimmune diseases, and that the type I interferon system is likely to be involved in the development of these diseases.

Efficacy and tolerability of injectable collagen-containing products in comparison to trimecaine in patients with acute lumbar spine pain (Study FUTURE-MD-Back Pain).

Low back pain (LBP) represents an important subgroup of vertebrogenic pain with estimated prevalence around 80 %. Locally acting injectable collagen for topical application has recently extended the limited range of treatment options. The aim of the study was to evaluate the efficacy and safety of injectable collagen in patients with LBP. Patients suffering from LBP (< three months) were enrolled. They were administered either collagen 4 ml or trimecaine 1 % 4 ml in the form of subcutaneous paravertebral injections into eight pre-specified points (0.5 ml per each point) in the following schedule: two administrations in the first and second week, one in the third week. The pain intensity, Thomayer distance, Oswestry disability index, Lasseque test, quality of life, consumption of rescue medication and safety were evaluated. Exertional and rest pain, evaluated by a visual analogue scale, gradually decreased in both groups. Both treatments showed a statistically significant improvement in mobility and quality of life. The consumption of paracetamol as a rescue medication was significantly lower in patients treated with collagen than in the group treated with trimecaine (p=0.048). The analgesic efficacy of locally acting injectable collagen, as well as an analgesic sparing effect when compared to local anesthetics were demonstrated.

Chronic Low Back Pain: Current Pharmacotherapeutic Therapies and a New Biological Approach.

Chronic low back pain (CLBP) syndrome represents one of the leading causes of long-term disability worldwide. The prevalence of CLBP has been rising significantly in relation to increasing average life expectancy. CLBP results from chronification of acute low back pain. There are many factors contributing to the CLBP crisis; common etiopathogenetic factors include e.g., functional blockage of intervertebral joints. The treatment of CLBP is complex. An important part of treatment consists of pain pharmacotherapy, for which several groups of drugs are used. The problem lies in the side effects of many of these traditionally used medications. Therefore, new and safer treatment methods are being sought. Innovative options for CLBP pharmacology include injections containing collagen, which can be combined with other traditionally used drugs, which helps reduce dosages and increase the overall safety of CLBP therapy.

Whole-exome sequencing identifies a potential TTN mutation in a multiplex family with inguinal hernia.

PURPOSE: Inguinal hernia repair is one of the most common procedures in general surgery. Males are seven times more likely than females to develop a hernia and have a 27 % lifetime 'risk' of inguinal hernia repair. Several studies have demonstrated that a positive family history is an important risk factor for the development of primary inguinal hernia, which indicates that genetic factors may play important roles in the etiology of the disease. So far, the contribution of genetic factors and underlying mechanisms for inguinal hernia remain largely unknown. The aim of this study was to investigate a multiplex Estonian family with inguinal hernia across four generations. METHODS: The whole-exome sequencing was carried out in three affected family members and subsequent mutation screening using Sanger sequencing was performed in ten family members (six affected and four unaffected). RESULTS: Whole-exome sequencing in three affected family members revealed a heterozygous missense mutation c.88880A>C (p.Lys29627Thr; RefSeq NM_001256850.1) in the highly conserved myosin-binding A-band of the TTN gene. Sanger sequencing demonstrated that this mutation cosegregated with the disease in this family and was not present in ethnically matched control subjects. CONCLUSION: We report that missense variant in the A-band of TTN is the strongest candidate mutation for autosomal-dominant inguinal hernia with incomplete penetrance.

Neuregulin signaling pathway in smoking behavior.

Understanding molecular processes that link comorbid traits such as addictions and mental disorders can provide novel therapeutic targets. Neuregulin signaling pathway (NSP) has previously been implicated in schizophrenia, a neurodevelopmental disorder with high comorbidity to smoking. Using a Finnish twin family sample, we have previously detected association between nicotine dependence and ERBB4 (a neuregulin receptor), and linkage for smoking initiation at the ERBB4 locus on 2q33. Further, Neuregulin3 has recently been shown to associate with nicotine withdrawal in a behavioral mouse model. In this study, we scrutinized association and linkage between 15 036 common, low frequency and rare genetic variants in 10 NSP genes and phenotypes encompassing smoking and alcohol use. Using the Finnish twin family sample (N=1998 from 740 families), we detected 66 variants (representing 23 LD blocks) significantly associated (false discovery rate P<0.05) with smoking initiation, nicotine dependence and nicotine withdrawal. We comprehensively annotated the associated variants using expression (eQTL) and methylation quantitative trait loci (meQTL) analyses in a Finnish population sample. Among the 66 variants, we identified 25 eQTLs (in NRG1 and ERBB4), 22 meQTLs (in NRG3, ERBB4 and PSENEN), a missense variant in NRG1 (rs113317778) and a splicing disruption variant in ERBB4 (rs13385826). Majority of the QTLs in blood were replicated in silico using publicly available databases, with additional QTLs observed in brain. In conclusion, our results support the involvement of NSP in smoking behavior but not in alcohol use and abuse, and disclose functional potential for 56 of the 66 associated single-nucleotide polymorphism.

Polymorphic variation in TPMT is the principal determinant of TPMT phenotype: A meta-analysis of three genome-wide association studies.

Thiopurine-related hematotoxicity in pediatric acute lymphoblastic leukemia (ALL) and inflammatory bowel diseases has been linked to genetically defined variability in thiopurine S-methyltransferase (TPMT) activity. While gene testing of TPMT is being clinically implemented, it is unclear if additional genetic variation influences TPMT activity with consequences for thiopurine-related toxicity. To examine this possibility, we performed a genome-wide association study (GWAS) of red blood cell TPMT activity in 844 Estonian individuals and 245 pediatric ALL cases. Additionally, we correlated genome-wide genotypes to human hepatic TPMT activity in 123 samples. Only genetic variants mapping to chromosome 6, including the TPMT gene region, were significantly associated with TPMT activity (P < 5.0 × 10-8 ) in each of the three GWAS and a joint meta-analysis of 1,212 cases (top hit P = 1.2 × 10-72 ). This finding is consistent with TPMT genotype being the primary determinant of TPMT activity, reinforcing the rationale for genetic testing of TPMT alleles in routine clinical practice to individualize mercaptopurine dosage.

Sox9 expression in canine epithelial skin tumors.

Sox9 is a master regulatory gene involved in developmental processes, stem cells maintenance and tumorigenesis. This gene is expressed in healthy skin but even in several skin neoplasms, where its expression patterns often resembles those of the developing hair follicle. In this study, samples from eleven different types of canine skin neoplasms (squamous papilloma, squamous cell carcinoma, infundibular keratinizing acanthoma, inferior tricholemmoma, isthmic tricholemmoma, trichoblastoma, trichoepitelioma, malignant trichoepitelioma, pilomatricoma, subungual keratoacanthoma, subungual squamous cell carcinoma) were immunohistochemically stained and evaluated for Sox9 with the aim to correlate tumor phenotype with molecular characteristics that may help to better define tumor development, contribute to its diagnosis and clinical management. Keratoacanthoma excluded, all the skin neoplasms examined showed a variable positivity to Sox9, especially in the basal layers, but with major intensity in neoplasms developing from the bulge region of the hair follicle, as trichoblastoma. According to our results, Sox9 could be employed as a stem cell marker to better assess the role of stem cells in canine epidermal and follicular tumors.

The effects of alcohol consumption on ambulatory blood pressure and target organs in subjects with borderline to mild hypertension. HARVEST Study Group.

The objective of this study was to examine the relationship of alcohol consumption to target organ involvement and ambulatory blood pressure (BP) in a population of young borderline to mild hypertensive subjects. Participants were 793 male subjects, aged 18-45 years, from the HARVEST Study. The analysis was performed in three age-matched groups with similar body mass index. Casual and 24-h ambulatory BP monitoring, routine biochemistry, echocardiography, and albumin excretion rate were measured. The men were divided into three groups: 1) nondrinkers, 2) drinkers of < 50 g/day, and 3) drinkers of > or = 50 g/day. Office systolic BP was not significantly different among the three groups, whereas 24-h and daytime BPs increased progressively from the first to the third group (group 1 v 3; P = .01 for 24-h systolic BP and P = .02 for daytime systolic BP). These differences remained significant even after adjusting for smoking. Left ventricular mass index, interventricular septum thickness, and wall thickness increased progressively from group 1 to group 3; this difference also remained significant after adjusting for smoking and 24-h BPs. The albumin excretion rate was much higher in group 3 than in group 1 (P = .003), but when 24-h BP was added to the model the difference was no longer significant. These results indicate that alcohol has a detrimental effect on the heart and the kidney. Alcohol's effect on LV wall thickness appears to be direct, whereas its action on albumin excretion rate seems to be mediated mainly by its effect on BP.

Structural abnormalities and not diastolic dysfunction are the earliest left ventricular changes in hypertension. HARVEST Study Group.

It has been claimed that diastolic dysfunction is the earliest cardiac abnormality in hypertension, preceding the development of left ventricular (LV) structural abnormalities. To detect early signs of hypertensive cardiac involvement 722 subjects (533 men and 189 women), 18-45 years old, with stage I hypertension, were studied by M-mode and Doppler echocardiography. Blood pressure was measured by 24-h ambulatory monitoring. Ninety-five normotensive individuals of similar age and gender distributions were studied as controls. Significant, though modest, changes of LV mass and geometry were found in the participants in comparison with the normotensive controls. The increment was +10.4 g/m2 for LV mass index, +1.8 mm for LV wall thickness, and +0.032 for relative wall thickness. A slight increase in atrial filling peak velocity was found in the hypertensive subjects at Doppler analysis of transmitral flow, but the ratio of early to atrial velocity of LV diastolic filling did not differ between the two groups. In multiple regression analyses, which included age, body mass index, heart rate, smoking, and physical activity, 24-h mean blood pressure emerged as a significant predictor of LV mass index (men, P = .003; women, P = .04) and wall thickness (men, P = .03; women, P = .004) in the hypertensive subjects, whereas no index of diastolic filling was significantly associated with ambulatory blood pressure in either gender. The present data indicate that changes in LV anatomy are the earliest signs of hypertensive cardiac involvement. Left ventricular filling is affected only marginally in the initial phase of hypertension.

Relation between family history of hypertension, overweight and ambulatory blood pressure: the HARVEST study.

The aim of the present paper was to evaluate the influence of a family history of hypertension and the degree of obesity as indicated by tertiles of body mass index on ambulatory blood pressure (BP) values in large number (n = 406) of young mild essential hypertensives. Positive family history of hypertension was associated with a significant increase in 24h ambulatory systolic blood pressure (SBP). The difference was most pronounced in the upper tertile of body mass index with almost 6 mm Hg difference between patients with and without a family history of hypertension. Both the degree of obesity and family history of hypertension had significant effects on 24h diastolic blood pressure (DBP). Twenty four hour DBP was highest in the upper tertile of body mass index in the hypertensives with a positive family history, representing an increase of 5 mm Hg compared with patients with a negative family history in the lower tertile. We conclude that mild hypertensives with a positive family history of hypertension are characterised by higher ambulatory BP than patients without parental hypertension and similar supine BP. Furthermore, our results indicate that in mild hypertensives the increase in DBP with body mass index is underestimated by conventional sphygmomanometry.

Relationship between plasma levels of factor VIII related antigen and reticulo-endothelial function in chronic uremia.

The plasma levels of factor VIII related antigen (F VIIIR:Ag; determined by rocket electrophoresis) and reticulo-endothelial function (measured by means of the removal kinetics of human albumin millimicrospheres) were studied in a group of patients with chronic renal failure. F VIIIR:Ag plasma levels were increased, median 304% (interquartile ranges 211-443%) compared to the controls, median 112% (interquartile ranges 100-144%); P less than 0.01. Reticulo-endothelial function was decreased, median 8.3 micrograms/min/kg body wt (interquartile ranges 6.2-10.1 micrograms/min/kg body wt) compared to the controls, median 15.0 micrograms/min/kg body wt (interquartile ranges 11.9-19.0 micrograms/min/kg body wt); P less than 0.02. A significant inverse relationship was found between plasma levels of F VIIIR:Ag and the reticulo-endothelial function rs = 0.075; P less than 0.01). As the main site of catabolism of F VIIIR:Ag is the reticulo-endothelial system, the impairment of its function appears to be a possible explanation for the elevated plasma levels of the F VIIIR:Ag found in patients with end stage renal disease.

Distal renal tubular acidosis in hepatic cirrhosis: clinical and pathogenetic study.

The mechanism of the renal tubular acidosis (RTA) occurring in patients with hepatic cirrhosis remains uncertain although it has been suggested that renal and intrarenal hemodynamic alterations could play a role in its pathogenesis. To verify this hypothesis, renal acidification was studied with an intravenous acid load of arginine hydrochloride in 51 patients with cirrhosis due to various causes. In 22 patients renal and intrarenal blood flow was also measured using the 133-Xe washout technique. RTA was found in 17 of 51 patients (33%) with the greatest incidence in alcoholic cirrhosis. The tubular defect did not appear related either to the degree of liver functional impairment or to the renal and intrarenal hemodynamic alterations.