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PubMed2003

No association between genotype of the promoter region of serotonin transporter gene and serotonin transporter binding in human brain measured by PET.

The human serotonin transporter (5-HTT) gene has a polymorphism in the 5'-flanking promoter region that is called the serotonin transporter gene-linked polymorphic region (5-HTTLPR). In lymphoblast cell lines, the promoter activity of the 5-HTT gene is dependent on 5-HTTLPR allelic variants. The transcriptional activity of the l allele was more than twice as high as that of the s allele. The s allele is considered to be associated with mood disorders and anxiety-related personality traits. To evaluate the functional differences of 5-HTTLPR in the brain in vivo, we examined the allelic variations of 5-HTTLPR and measured 5-HTT binding in the living human brain using positron emission tomography (PET) with C(11)-labeled trans-1, 2, 4, 5, 6, 10-beta-hexahydro-6-[4-(methylthio) phenyl]pyrrolo[2,1-a]isoquinoline (McN5652) as a ligand. Twenty-seven healthy male subjects participated in this study. Although the human lymphoblast cells with the l/l genotype was reported to produce higher concentrations of both mRNA and protein of 5-HTT than those with the l/s or s/s genotype in a human lymphoblast in vitro study, 5-HTT binding in vivo was not significantly different among subjects with the three genotypes (l/l: 0.842 +/- 0.184, l/s: 0.708 +/- 0.118, s/s: 0.825 +/- 0.209). In conclusion, this study does not support the assumption that the genotype-dependent differences of 5-HTTLPR directly contributes to the regulation of the 5-HTT binding site in the living human brain.

Adult↗
PubMed2007

Kaposi sarcoma-associated herpesvirus and other viruses in human lymphomagenesis.

Kaposi sarcoma-associated herpesvirus (KSHV), also called human herpesvirus 8 (HHV-8), is associated with a specific subset of lymphoproliferative disorders. These include two main categories. The first is primary effusion lymphomas and related solid variants. The second is multicentric Castleman disease, from which KSHV-positive plasmablastic lymphomas can arise. KSHV contributes to lymphomagenesis by subverting the host cell molecular signaling machinery to deregulate cell growth and survival. KSHV expresses a selected set of genes in the lymphoma cells, encoding viral proteins that play important roles in KSHV lymphomagenesis. Deregulation of the NF-kappaB pathway is an important strategy used by KSHV to promote lymphoma cell survival, and the viral protein vFLIP is essential for this process. Two other viruses that are well documented to be causally associated with lymphoid neoplasia in humans are Epstein-Barr virus (EBV/HHV-4) and human T-cell lymphotropic virus (HTLV-1). Both of these are similar to KSHV in their use of viral proteins to promote cell survival by deregulating the NF-kappaB pathway. Here we review the basic information and recent developments that have contributed to our knowledge of lymphomas caused by KSHV and other viruses. The understanding of the mechanisms of viral lymphomagenesis should lead to the identification of novel therapeutic targets and to the development of rationally designed therapies.

Animals↗
PubMed1986

Ultrastructural localization of S-100 protein in neurofibroma.

The nature of the cells in neurofibromas was studied by electron microscopy and immunoelectron-microscopic examination of S-100 protein. Ultrastructurally, all five neurofibromas studied were found to be composed of Schwann cells, perineurial cells, and intermediate cells, which had features of both perineurial cells and fibroblasts. The Schwann cells had complex, branched cytoplasmic processes and a continuous basal lamina. The perineurial cells were distinguishable from Schwann cells by the presence of numerous pinocytotic vesicles, unbranched slender cytoplasmic processes and a discontinuous basal lamina. The intermediate cells had no basal lamina, but were topographically related to Schwann cells and had a similar fine structure to that of perineurial cells. Thus, they seemed to be modified neoplastic perineurial cells. Immunoelectron-microscopic studies showed the presence of cells with and without S-100 protein in the neurofibromas: cells with S-100 protein resembled Schwann cells ultrastructurally, and those without S-100 protein were perineurial and intermediate cells. Some Schwann cells with S-100 protein in one neurofibroma had numerous pinocytotic vesicles characteristic of perineurial cells, suggesting that Schwann cells and perineurial cells are functional variants of the same cell type. Thus this study showed that neurofibromas were composed of Schwann cells with S-100 protein and perineurial and intermediate cells, including so-called endoneurial fibroblasts, without S-100 protein. Morphological and functional transition seems to occur between Schwann cells and perineurial cells, and between perineurial cells and intermediate cells.

Adult↗
PubMed1995

A nonparametric subject-specific population method for deconvolution: II. External validation.

A lot of attention has been given in the past to deconvolution and in particular to its nonparametric variants. In a companion paper (1), we present a fully nonparametric deconvolution method in which subject specificity is explicitly taken into account. To do so we use so-called "longitudinal splines." A longitudinal spline is a nonparametric function composed of a template spline, in common to all subjects, and of a distortion spline representing the difference of the subject's function from the template. In this paper we concentrate on testing and documenting the performance of this nonparametric methodology in terms of the approximation of unknown functions. We simulate population data using parametric functions, and use longitudinal splines to recover the unknown functions. We consider different estimation methods including (1) parametric nonlinear mixed effect, (2) least squares, and (3) two-stage. Methods 2-3 are more robust than Method 1, and obtain reliable estimates of the unknown functions. The lack of robustness of Method 1 appears to be due to the misspecifications of the distribution of the subjects' parameters. Results also suggest that in a data-rich situation nonparametric nonlinear mixed-effect models should be preferred.

Models, Theoretical↗
PubMed2006

Structural and functional studies of EpsC, a crucial component of the type 2 secretion system from Vibrio cholerae.

The type 2 secretion system (T2SS) occurring in Gram-negative bacteria is composed of 12-15 different proteins which form large assemblies spanning two membranes and secreting several virulence factors in folded state across the outer membrane. The T2SS component EpsC of Vibrio cholerae plays an important role in this machinery. While anchored in the inner membrane, by far the largest part of EpsC is periplasmic, containing a so-called homology region (HR) domain and a PDZ domain. Here we report studies on the structure and function of both periplasmic domains of EpsC. The crystal structures of two variants of the PDZ domain of EpsC from V. cholerae were determined at better than 2 A resolution. Compared to the short variant, the longer variant contains an additional N-terminal helix, and reveals a significant difference in the position of helix alphaB with respect to the beta-sheet. Both our structures show that the PDZ domain of EpsC adopts a more open form than in previously reported structures of other PDZ domains. Most interestingly, in the crystals of the short EpsC-PDZ domain the peptide binding groove interacts with an alpha-helix from a neighboring subunit burying approximately 921 A2 solvent accessible surface. This makes it possible that the PDZ domain of this bacterial protein binds proteins in a manner which is altogether different from that seen in any other PDZ domain so far. We also determined that the HR domain of EpsC is primarily responsible for the interaction with the secretin EpsD, while the PDZ is not, or much less, so. This new finding, together with studies of others, leads to the suggestion that the PDZ domain of EpsC may interact with exoproteins to be secreted while the HR domain plays a key role in linking the inner-membrane sub-complex of the T2SS in V. cholerae to the outer membrane secretin.

Amino Acid Sequence↗
PubMed2000

KFC, a Ste20-like kinase with mitogenic potential and capability to activate the SAPK/JNK pathway.

The Sterile-20 (Ste20) family of serine-threonine kinases has been implicated in the activation of the stress-activated protein kinase pathways. However, the physiological role has remained ambiguous for most of the investigated mammalian Ste20's. Here we report the cloning of a novel Ste20-like kinase, from chicken embryo fibroblast (CEF) cells, which we have named KFC, for Kinase From Chicken. The 898 amino acid full-length KFC protein contains an amino-terminal kinase domain, an adjacent downstream serine-rich region, and a C-terminal tail containing a coiled-coil domain. Here we show that the coiled-coil domain of KFC negatively regulates the intrinsic kinase activity. We have also identified a splice variant of KFC in which there is a 207 nucleotide in-frame deletion. This deletion of 69 amino acids encompasses the serine-rich region. These two isoforms, called KFCL, for full-length, and KFCS for spliced (or short) form, not only differ in structure, but also in biological properties. Stable CEF cells overexpressing KFCL, but not KFCS, have a significant increase in growth rate when compared to parental cells. This mitogenic effect is the first such reported for this family of kinases. Finally, we found that KFC, when activated by truncation of the regulatory C-terminus, has a specific activation of the stress-activated protein kinase (SAPK/JNK) pathway.

Amino Acid Sequence↗
PubMed1998

Mitochondrial DNA haplotype frequencies in natural and experimental populations of Drosophila subobscura.

The evolution of Drosophila subobscura mitochondrial DNA has been studied in experimental populations, founded with flies from a natural population from Esporles (Majorca, Balearic Islands, Spain). This population, like other European ones, is characterized by the presence of two very common (>96%) mitochondrial haplotypes (called I and II) and rare and endemic haplotypes that appear at very low frequencies. There is no statistical evidence of positive Darwinian selection acting on the mitochondrial DNA variants according to Tajima's neutrality test. Two experimental populations, with one replicate each, were established with flies having a heterogeneous nuclear genetic background, which was representative of the composition of the natural population. Both populations were started with the two most frequent mitochondrial haplotypes, but at different initial frequencies. After 13 to 16 generations, haplotype II reached fixation in three cages and its frequency was 0.89 by generation 25 in the fourth cage. Random drift can be rejected as the force responsible for the observed changes in haplotype frequencies. There is not only statistical evidence of a linear trend favoring a mtDNA (haploid) fitness effect, but also of a significant nonlinear deviation that could be due to a nuclear component.

Animals↗
PubMed1999

Morphology, proliferation and apoptosis of mouse liver epithelial cells cultured as spheroids.

The MLEC10 is an epithelial cell line derived from an untreated, normal C3H/HeN mouse liver. We previously demonstrated that tumorigenic variants from this cell line produced moderately differentiated hepatocellular carcinomas in nude mice. However, it has remained unclear whether the parental MLEC10 cells represent immortalized hepatocytes or so-called oval cells, both of which may serve as precursors for hepatocellular neoplasms. In this study, we performed 3-dimensional, spheroid culture of the MLEC100 cells in order to facilitate histological assessment of their lineage. Spheroidal aggregates were formalin-fixed and embedded in paraffin for routine light-microscopic observation of hematoxylin and eosin-stained sections. Histopathologically, the MLEC10 cells were indistinguishable from immature hepatocytes and distinct from oval cells. At the electron-microscopic level, their hepatocytic nature was evidenced by bile canaliculus structures and glycogen storage. Intriguingly, the spheroids contained fragmentary material reminiscent of Councilman bodies, implying apoptosis of the hepatocytes. Although the cells significantly proliferated during the first three days of culture, apoptotic death then resulted in a 75 % decrease in viable cell number. Thereafter, both apoptosis and cell division appeared silent, the numbers being unchanged. Expression of the p53 tumor suppressor gene became gradually elevated, correlating positively with growth arrest, but negatively with apoptosis, suggesting that the cell death occurred independently of p53. Our results indicate that at least some liver epithelial cell lines derived from untreated murine livers exhibit a hepatocytic morphology in spheroid culture. Also, the present culture system provides a useful tool for investigating biological phenomena, e.g. apoptosis, specifically involving liver cells, under 3-dimensional conditions.

Agar↗
PubMed1989

Glycoproteins composed of major surface immunodeterminants of Pneumocystis carinii.

Pneumocystis carinii is a pathogen which causes fatal pneumonia in patients with acquired immune deficiency syndrome. To facilitate the basic study of P. carinii, we analyzed the major surface proteins by immunochemical and biochemical methods. The major protein components of both cysts (resting form) and trophozoites (vegetative form) are part of a group of proteins called P115 with apparent masses of 105 to 120 kilodaltons. They represent an unusually large portion of the total proteins of this organism. The purified proteins exhibited six isoelectric variants when analyzed by two-dimensional gel electrophoresis. A monoclonal antibody raised against cysts recognized all six variants and reacted with epitopes that were located in the cell wall, thereby indicating that P115 is an immunoreactive surface component. Data are presented that the isoelectric variants contain identical or closely related protein components and that they are mannose-rich glycoproteins. Deglycosylated P115 migrates primarily as a single more acidic protein in two-dimensional gels, suggesting that the isoelectric variants may be due primarily to differences in glycosylation. The majority of sera tested from humans with diagnosed pneumocystosis reacted strongly with the P115 proteins.

Animals↗
PubMed2002

Identification of XcpZ domains required for assembly of the secreton of Pseudomonas aeruginosa.

Most of the exoproteins secreted by Pseudomonas aeruginosa are transported via the type II secretion system. This machinery, which is widely conserved in gram-negative bacteria, consists of 12 Xcp proteins organized as a multiprotein complex, also called the secreton. We previously reported that the mutual stabilization of XcpZ and XcpY plays an important role in the assembly of the secreton. In this study, we engineered variant XcpZ proteins by using linker insertion mutagenesis. We identified three distinct regions of XcpZ required for both the stabilization of XcpY and the functionality of the secreton. Interestingly, we also demonstrated that another component of the machinery, XcpP, can modulate the stabilizing activity of XcpZ on XcpY.

Amino Acid Sequence↗
PubMed2004

Unsupervised fuzzy clustering using Weighted Incremental Neural Networks.

A new more efficient variant of a recently developed algorithm for unsupervised fuzzy clustering is introduced. A Weighted Incremental Neural Network (WINN) is introduced and used for this purpose. The new approach is called FC-WINN (Fuzzy Clustering using WINN). The WINN algorithm produces a net of nodes connected by edges, which reflects and preserves the topology of the input data set. Additional weights, which are proportional to the local densities in input space, are associated with the resulting nodes and edges to store useful information about the topological relations in the given input data set. A fuzziness factor, proportional to the connectedness of the net, is introduced in the system. A watershed-like procedure is used to cluster the resulting net. The number of the resulting clusters is determined by this procedure. Only two parameters must be chosen by the user for the FC-WINN algorithm to determine the resolution and the connectedness of the net. Other parameters that must be specified are those which are necessary for the used incremental neural network, which is a modified version of the Growing Neural Gas algorithm (GNG). The FC-WINN algorithm is computationally efficient when compared to other approaches for clustering large high-dimensional data sets.

Algorithms↗
PubMed2002

[Brief causal relations in EEG based on adaptive Granger causality].

Commonly, coherence and correlation are used to describe interrelations between EEG signals. But, on this basis, the investigation of causality or direction of interrelations is not possible. The general idea of causality between two signals may be expressed in terms of upgrading the predictability of one signal bye the knowledge of the past of the other signal. The best established approach in this context is the so-called Granger causality. The study present an adaptive estimation of Granger causality, which allows to detect dynamic causal relations within time intervals of less 100 ms. The time-variant Granger causality is applied to EEG data of the Stroop task. It could be shown, that conflict situation generates a dense web of directed interactions from posterior to anterior cortical areas.

Adult↗
PubMed1992

Expression of the novel intermediate filament-associated protein restin in Hodgkin's disease and anaplastic large-cell lymphoma.

In this study, the expression of the novel intermediate filament protein Restin in human tissues was analyzed. Restin expression was studied by immunohistochemistry using polyclonal and monoclonal antibodies. Restin was not detected in normal tissues, a range of B- and T-cell non-Hodgkin's lymphomas, and nonlymphoid tumors. However, Restin was present in Reed-Sternberg cells and variants thereof in Hodgkin's disease, with the exception of the lymphocyte-predominant, paragranuloma subtype. Restin was also highly expressed in anaplastic large-cell lymphoma (so-called Ki-1 lymphoma). As expected, Restin was also expressed in Hodgkin cell lines L428, L428KSA, Co, and KM-H2 and the anaplastic large-cell lymphoma cell line Karpas 299, which was confirmed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and Western blotting, as well as Northern blotting. The presence of Restin in both Hodgkin's disease and anaplastic large-cell lymphoma is intriguing and might indicate a role of this structural protein in the pathogenesis of both conditions.

Antibodies, Monoclonal↗
PubMed1994

Mucinous meningioma. Report of an unusual variant of meningioma that may mimic metastatic mucin-producing carcinoma.

An unusual variant of meningioma is described that was characterized by small clusters and strands of meningothelial cells surrounded by abundant mucinous stroma. The unusual appearance of the lesion prompted an initial diagnosis of metastatic mucin-secreting carcinoma (so-called colloid carcinoma) resulting in extensive clinical evaluation in search for a primary. Histochemical studies showed the mucinous material to be composed of strongly sulfated acid mucopolysaccharides rich in hyaluronic acid. Immunohistochemical studies showed strong membrane staining of the tumor cells with epithelial membrane antigen and positive cytoplasmic staining with vimentin antibodies. Ultrastructural examination revealed the characteristic features of meningothelial cells (i.e., abundant long, interdigitating cytoplasmic processes joined by well-developed cell junctions) but failed to demonstrate secretory activity within the neoplastic cells. The prominent mucinous stroma in this case most probably represents a nonspecific reaction of stromal cells to an undetermined stimulus. Mucinous meningioma should be added to the list of morphologic variants of meningioma and should be considered in the differential diagnosis of mucinous lesions in intracranial locations.

Adenocarcinoma, Mucinous↗
PubMed1999

[Prion diseases in pediatrics].

Prion diseases are rare neurologic affections with a poor prognosis, occurring in both humans and animals. Creutzfeldt-Jakob disease (CJD) secondary to human extracted growth hormone treatment is the most frequent condition in pediatrics. In 1994, a new type of CJD (variant CJD) was described in young adults in the United Kingdom, only 10 years after the bovine spongiform encephalopathy epidemic, with recent works showing a direct relationship between the bovine epidemic and the human cases. An accumulation of a single protein called the prion protein (PrP) has been discovered in the brain in all of these cases, animal and human, leading to the hypothesis that a new infectious agent could proceed without any nuclear acid information; another hypothesis is that of a still unknown viral agent. The PRNP gene encoding for this PrP protein is well described: some mutations and a polymorphism in the 129th codon have been shown to be implicated in many cases of CJD. PrP is a ubiquitous protein, with yet unknown physiological function. There are still many questions to be answered: shall we expect new pediatric cases of variant CJD? Assuming that animal-human contamination is related to alimentation, are there other ways of contamination.

Adult↗
PubMed2000

Surgical management of recurrent pancreatitis in children with pancreas divisum.

OBJECTIVE: To analyze an institutional experience with pancreatitis in childhood to clarify the frequency of pancreas divisum in that patient population, the characteristics of pancreatitis in children with pancreas divisum, and the role of surgical management in their treatment. SUMMARY BACKGROUND DATA: The role of pancreas divisum in causing acute and relapsing pancreatitis and chronic, recurring abdominal pain is controversial. Although the anatomical abnormality is present from birth, most investigators have reported cases with onset of symptoms in adulthood. The reported pediatric experience with this disorder is small, and the natural history of pancreatitis in children with pancreas divisum has not been well elucidated. METHODS: A retrospective chart review of all children 18 years of age and younger with a discharge diagnosis of pancreatitis identified 135 patients treated in the authors' institution from 1978 to 1998. Ten patients were found to have anatomical variants of pancreas divisum associated with recurrent or chronic pancreatitis. The medical records of these patients were reviewed for data on the presentation, diagnostic findings, imaging studies, treatment, surgical findings, and pathologic findings in these children. Chart review and telephone calls were used to assess the current state of health in nine patients available for follow-up. RESULTS: Pancreas divisum was identified in 7.4% of all children with pancreatitis and 19.2% of children with relapsing or chronic pancreatitis. Patients had early onset of recurrent episodic epigastric pain and vomiting, at a mean age of 6 years. Three patients had a positive family history of pancreatitis and one was proven by DNA analysis to have hereditary pancreatitis. Pancreatitis was documented by elevated amylase or lipase levels, and endoscopic retrograde cholangiopancreatography was the method of diagnosis of pancreas divisum in all patients. Eight patients had complete pancreas divisum and two had incomplete variants. Eight patients underwent surgery to improve ductal drainage. Seven underwent transduodenal sphincteroplasty of the accessory papilla, along with sphincteroplasty of the major papilla in two (plus septoplasty in one). Three patients underwent longitudinal pancreaticojejunostomy, as a primary procedure in one patient with midductal stenosis and in two because of recurring pancreatitis after sphincteroplasty. The surgical findings and histologic examination of five patients undergoing distal pancreatectomy revealed striking changes of advanced chronic pancreatitis. Patients responding to sphincteroplasty alone showed less severe histologic changes. Overall, three of seven patients had excellent results, three were improved, and one had continued disabling attacks of pancreatitis. The mean duration of follow-up was 7.3 years, and there were no deaths. No patients had endocrine or exocrine pancreatic insufficiency, and none required chronic analgesics. CONCLUSIONS: Pancreas divisum is an important cause of recurrent pancreatitis in childhood and should be sought aggressively in children with more than one episode of pancreatitis or pancreatitis with a history of chronic recurrent abdominal pain. Surgical intervention is directed toward relief of ductal obstruction and may involve accessory duct sphincteroplasty alone or in combination with major sphincteroplasty and septoplasty. Patients with more distal ductal obstruction or ductal ectasia may benefit from pancreaticojejunostomy.

Acute Disease↗
PubMed2006

Clinicopathological findings in a case series of extrathoracic solitary fibrous tumors of soft tissues.

BACKGROUND: Solitary fibrous tumors (SFT) represent a rare entity of soft tissue tumors. Previously considered being of serosal origin and solely limited to the pleural cavity the tumor has been described in other locations, most particularly the head and neck. Extrathoracic SFT in the soft tissues of the trunk and the extremities are very rare. Nine cases of this rare tumor entity are described in the course of this article with respect to clinicopathological data, follow-up and treatment results. METHODS: Data were obtained from patients' records, phone calls to the patients' general practitioners, and clinical follow-up examination, including chest X-ray, abdominal ultrasound, and MRI or computed tomography. RESULTS: There were 6 females and 3 males, whose age at time of diagnosis ranged from 32 to 92 years (mean: 62.2 years). The documented tumors' size was 4.5 to 10 cm (mean: 7 cm). All tumors were located in deep soft tissues, 3 of them epifascial, 2 subfascial, 4 intramuscular. Four tumors were found at the extremities, one each at the flank, in the neck, at the shoulder, in the gluteal region, and in the deep groin. Two out of 9 cases were diagnosed as atypical or malignant variant of ESFT. Complete resection was performed in all cases. Follow-up time ranged from 1 to 71 months. One of the above.mentioned patients with atypical ESFT suffered from local relapse and metastatic disease; the remaining 8 patients were free of disease. CONCLUSION: ESFT usually behave as benign soft tissue tumors, although malignant variants with more aggressive local behaviour (local relapse) and metastasis may occur. The risk of local recurrence and metastasis correlates to tumor size and histological status of surgical resection margins and may reach up to 10% even in so-called "benign" tumors. Tumor specimens should be evaluated by experienced soft tissue pathologists. The treatment of choice is complete resection followed by extended follow-up surveillance.

Adult↗
PubMed2026

Genetic screening of children for familial hypercholesterolaemia: the VRONI study.

BACKGROUND AND AIMS: The role of genetic testing as part of universal screening programmes for familial hypercholesterolaemia (FH) in children is not well defined. Here, a two-step approach to identify children carrying FH-causing variants was investigated. METHODS: In this study from Southern Germany, paediatricians were invited to offer FH screening to all children aged 4.8-14.9 years at routine paediatric examinations. The FH screening programme began in September 2020 in Bavaria and has involved up to 480 paediatricians. It included biochemical and genetic testing using 0.2 mL of blood taken from a fingertip. In case of low-density lipoprotein cholesterol (LDL-C) serum concentration ≥3.36 mmol/L (≥130 mg/dL), FH-causing variants were determined in the same sample with a focused panel covering most frequent variants (n = 48) and sequencing of relevant genes. RESULTS: Out of 25 431 children screened so far, 1689 children had an LDL-C ≥ 3.36 mmol/L (>130 mg/dL), which defined this concentration as the 93rd percentile. Pathogenic variants were identified by the focused panel in 157 and by next-generation sequencing in 283 children, respectively. While 17% (283/1670) of all genetically analysed children tested positive, the fraction of individuals with FH-causing variants increased across the spectrum of LDL-C serum concentrations from 4.7% (23/492) at 3.36-3.49 mmol/L (130-135 mg/dL) to 78.6% (81/103) above 5.17 mmol/L (200 mg/dL). Overall, the prevalence of FH-causing variants was high (1:90). One reason was a founder variant (n = 63) within the LDLR gene, found 40 times more frequent than European average. The analysis of recruitment data revealed significant ascertainment bias, with lower recruitment rate practices exhibiting higher prevalence. After adjustment for the bias using a generalized linear mixed model, the predicted prevalence was 1 in 163 (0.61%), which is highly consistent with large-scale genomic benchmarks as gnomAD (1:165, n = 622 057) and the UK Biobank (1:176, n = 48 741). CONCLUSIONS: The prevalence of FH determined in this study is significantly higher than previously published estimates (∼1:250), highlighting the importance of this condition for public health and supporting calls for a national paediatric screening programme, given the availability of effective treatment options. For children between 5 and 15 years, biochemical screening is an effective way to select patients for genetic testing, with sequencing of candidate genes being superior to variant screening. In summary, the VRONI study demonstrates the feasibility and efficacy of a combined biochemical and genetic screening for FH in children.

Humans↗