Mette Ramsing

Nephrogenic systemic fibrosis is found only among gadolinium-exposed patients with renal insufficiency: a case-control study from Denmark.

Background  Nephrogenic systemic fibrosis (NSF) is a systemic fibrosing disease associated with exposure to gadolinium‐based contrast agents (GBCA) in patients with renal insufficiency.

Two cases of nephrogenic systemic fibrosis after exposure to the macrocyclic compound gadobutrol

Nephrogenic systemic fibrosis (NSF) is a disease with progressive fibrosis. We describe two cases of NSF after exposure to a macrocyclic gadolinium-based contrast agent (GBCA) gadobutrol, which has been considered as a low-risk agent compared to linear GBCAs. The first case had chronic kidney disease (CKD) Stage 3 and was exposed to 17.5 ml of gadobutrol. The second case has been exposed twice to GBCA: 10 ml of gadodiamide (in 2001) and 15 ml of gadobutrol (in 2008). Before the second exposure, he had CKD Stage 5 and was in haemodialysis. Both patients have been diagnosed with NSF. Our cases suggest that cyclic GBCAs can also cause NSF.

The cervical mucus plug inhibits, but does not block, the passage of ascending bacteria from the vagina during pregnancy

To evaluate the microbial load and the inflammatory response in the distal and proximal parts of the cervical mucus plug.

Antifibrotic effect after low-dose imatinib mesylate treatment in patients with nephrogenic systemic fibrosis: an open-label non-randomized, uncontrolled clinical trial

Background  Nephrogenic systemic fibrosis is a disease affecting the connective tissue of the skin and internal organs in patients with renal failure. No effective treatments are available.

Treatment influencing down-staging in EORTC Melanoma Group sentinel node histological protocol compared with complete step-sectioning: A national multicentre study

AIM Metastasis size in melanoma sentinel lymph nodes (SLNs) is an emerging prognostic factor. Two European melanoma treatment trials include SLN metastasis diameters as inclusion criteria. Whilst diameter estimates are sensitive to the number of sections examined, the level of this bias is largely unknown. We performed a prospective multicentre study to compare the European Organisation for Research and Treatment of Cancer (EORTC) recommended protocol with a protocol of complete step-sectioning. METHODS One hundred and thirty-three consecutive SLNs from seven SLN centres were analysed by five central sections 50μm apart (EORTC Protocol) followed by complete 250μm step-sectioning. RESULTS Overall, 29 patients (21.8%) were SLN-positive. The EORTC Protocol missed eight of these metastases (28%), one metastasis measuring less than 0.1mm in diameter, seven measuring between 0.1 and 1mm. Complete step-sectioning at 250μm intervals (Extensive Protocol) missed one metastasis (3%) that measured less than 0.1mm. Thirteen treatment courses (34%) performed if inclusion was based on the Combined Protocol would not be performed if assessed by the EORTC Protocol. Thus, 10 patients would be without completion lymph node dissection (EORTC MINITUB study), whilst three patients would not be eligible for anti-CTLA4 trial (EORTC protocol 18071). The corresponding number with the Extensive Protocol would be three; one patient for the MINITUB registration study and two patients for the anti-CTLA4 study. CONCLUSIONS Examining SLNs by close central sectioning alone (EORTC Protocol) misses a substantial number of metastases and underestimates the maximum metastasis diameter, leading to important changes in patient eligibility for various treatment protocols.

Positive effect of low-dose imatinib mesylate in a patient with nephrogenic systemic fibrosis.

Complete List of Authors: Elmholdt, Tina; Aarhus University Hospital, Clinical Medicine; Aarhus University Hospital, Dermatology Pedersen, Michael; Aarhus University Hospital, Clinical Medicine; Aarhus University Hospital, MR Research Centre Jorgensen, Bettina; Aarhus University Hospital, Nephrology Ramsing, Mette; Aarhus University Hospital, Pathology Olesen, Anne; Aarhus University Hospital, Dermatology

A description of a fetal syndrome associated with HNF1B mutation and a wide intrafamilial disease variability.

MODY5, renal cysts, and diabetes syndrome are autosomal dominant entities caused by mutation in the HNF1B gene. Here we report two fetal siblings and their father who have a HNF1B missense mutation and describe the fetal phenotype associated with mutation in this gene. To the best of our knowledge two non‐twin siblings with a missense mutation and a severe phenotype have not been reported previously.

The development of hepatic stellate cells in normal and abnormal human fetuses : an immunohistochemical study

The precise embryological origin and development of hepatic stellate cells is not established. Animal studies and observations on human fetuses suggest that they derive from posterior mesodermal cells that migrate via the septum transversum and developing diaphragm to form submesothelial cells beneath the liver capsule, which give rise to mesenchymal cells including hepatic stellate cells. However, it is unclear if these are similar to hepatic stellate cells in adults or if this is the only source of stellate cells. We have studied hepatic stellate cells by immunohistochemistry, in developing human liver from autopsies of fetuses with and without malformations and growth restriction, using cellular Retinol Binding Protein‐1 (cRBP‐1), Glial Fibrillary Acidic Protein (GFAP), and α‐Smooth Muscle Actin (αSMA) antibodies, to identify factors that influence their development. We found that hepatic stellate cells expressing cRBP‐1 are present from the end of the first trimester of gestation and reduce in density throughout gestation. They appear abnormally formed and variably reduced in number in fetuses with abnormal mesothelial Wilms Tumor 1 (WT1) function, diaphragmatic hernia and in ectopic liver nodules without mesothelium. Stellate cells showed similarities to intravascular cells and their presence in a fetus with diaphragm agenesis suggests they may be derived from circulating stem cells. Our observations suggest circulating stem cells as well as mesothelium can give rise to hepatic stellate cells, and that they require normal mesothelial function for their development.

Elastosis Perforans Serpiginosa in a patient with Down syndrome treated with imiquimod 5% cream.

Elastosis Perforans Serpiginosa (EPS) is a rare skin disease characterised by hyperkeratotic papules, transepidermal elimination of abnormal elastic fibres, and focal dermal elastosis. The aetiology is unknown, but an association with underlying systemic disorders, including Down syndrome has been described. Treatment is often difficult. A 45-year old man with Down syndrome presented with symmetrical annular elements on forearms and femora. The elements were erythematous with atrophic hypopigmented central healing and peripherally, infiltrated keratotic papules with desquamation. A punch biopsy showed the classical histopathologic features of EPS. We found no clinical signs of cerebrovascular or cardiovascular disease. We initiated topical therapy with imiquimod 5% cream once a day for 6 weeks followed by 3 times weekly for 4 weeks to a single element. As regression of EPS was observed and the patient tolerated the therapy well, treatment of other lesions was commenced, and further regression was seen.

Targeted gene sequencing and whole‐exome sequencing in autopsied fetuses with prenatally diagnosed kidney anomalies

Identification of fetal kidney anomalies invites questions about underlying causes and recurrence risk in future pregnancies. We therefore investigated the diagnostic yield of next‐generation sequencing in fetuses with bilateral kidney anomalies and the correlation between disrupted genes and fetal phenotypes. Fetuses with bilateral kidney anomalies were screened using an in‐house‐designed kidney‐gene panel. In families where candidate variants were not identified, whole‐exome sequencing was performed. Genes uncovered by this analysis were added to our kidney panel. We identified likely deleterious variants in 11 of 56 (20%) families. The kidney‐gene analysis revealed likely deleterious variants in known kidney developmental genes in 6 fetuses and TMEM67 variants in 2 unrelated fetuses. Kidney histology was similar in the latter 2 fetuses—presenting a distinct prenatal form of nephronophthisis. Exome sequencing identified ROBO1 variants in one family and a GREB1L variant in another family. GREB1L and ROBO1 were added to our kidney‐gene panel and additional variants were identified. Next‐generation sequencing substantially contributes to identifying causes of fetal kidney anomalies. Genetic causes may be supported by histological examination of the kidneys. This is the first time that SLIT‐ROBO signaling is implicated in human bilateral kidney agenesis.