[Impact of SARS-CoV-2/COVID-19 on the placenta]. / SARS-CoV-2/COVID-19-Auswirkungen auf die Plazenta.

From the very beginning, special attention regarding severe acute respiratory syndrome-coronavirus­2 (SARS-CoV-2) and the resulting coronavirus disease-2019 (COVID-19) has been paid to pregnant women.In this review, after a short introduction into the immunodefensive role of the placenta and viral infections in general, we describe the morphological changes of the placenta in SARS-CoV-2-infected pregnant women based on our own and other published studies, draw comparisons to the SARS epidemic, and discuss the question of vertical transmission of SARS-CoV­2 from the mother to the neonate.The most common pathological findings of the placenta in SARS-CoV­2 infection are signs of maternal and fetal malperfusion as well as potentially immunologically and/or thromboinflammation-mediated findings. These manifest as infarcts and decidual vasculopathy as well as thrombi in the fetal circulation and avascular villi. In some cases, there is also an inflammatory reaction with villitis, intervillositis, and fetal vasculitis. In addition, it has been shown that SARS-CoV­2 can directly infect the placenta, so vertical transmission is possible.There is no COVID-19 specific pattern of placental alterations, although the detection of fetal thrombovasculitis, villitis, and intervillositis as well as fetal and maternal malperfusion could be best interpreted as the signature of SARS-CoV­2 infection - considering the known pathophysiology of COVID-19 regarding other organs (inflammatory reaction and [micro]angiopathy). Detection of viral RNA in the fetal placental tissue and the umbilical cord indicates SARS-CoV­2 vertical transmission.

Screening of gestational diabetes mellitus in early pregnancy by oral glucose tolerance test and glycosylated fibronectin: study protocol for an international, prospective, multicentre cohort trial.

INTRODUCTION: As the accurate diagnosis and treatment of gestational diabetes mellitus (GDM) is of increasing importance; new diagnostic approaches for the assessment of GDM in early pregnancy were recently suggested. We evaluate the diagnostic power of an 'early' oral glucose tolerance test (OGTT) 75 g and glycosylated fibronectin (glyFn) for GDM screening in a normal cohort. METHODS AND ANALYSIS: In a prospective cohort study, 748 singleton pregnancies are recruited in 6 centres in Switzerland, Austria and Germany. Women are screened for pre-existing diabetes mellitus and GDM by an 'early' OGTT 75 g and/or the new biomarker, glyFn, at 12-15 weeks of gestation. Different screening strategies are compared to evaluate the impact on detection of GDM by an OGTT 75 g at 24-28 weeks of gestation as recommended by the International Association of Diabetes and Pregnancy Study Groups (IADPSG). A new screening algorithm is created by using multivariable risk estimation based on 'early' OGTT 75 g and/or glyFn results, incorporating maternal risk factors. Recruitment began in May 2014. ETHICS AND DISSEMINATION: This study received ethical approval from the ethics committees in Basel, Zurich, Vienna, Salzburg and Freiburg. It was registered under http://www.ClinicalTrials.gov (NCT02035059) on 12 January 2014. Data will be presented at international conferences and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT02035059.

[The translocation carcinoma: A pediatric renal tumor also in adults]. / Das Translokationskarzinom: Ein kindlicher Nierentumor auch bei Erwachsenen.

The MiT family of translocation-associated renal cell carcinomas comprise approximately 40 % of renal cell carcinomas in young patients but only up to 4 % of renal cell carcinomas in adult patients. The Xp11.2 translocation-associated tumors are the most frequent and were included in the 2004 World Health Organization (WHO) classification. They contain a fusion of the TFE3 gene with ASPSCR1, PRCC, NONO, SPFQ or CLTC resulting in an immunohistochemically detectable nuclear overexpression of TFE3. The Xp11.2 translocation-associated renal cell carcinomas are characterized by ample clear cytoplasm, papillary architecture and abundant psammoma bodies. The TFEB translocation-associated renal cell carcinomas are much rarer and show a biphasic architecture. Fluorescence in situ hybridization permits the detection of a translocation by means of a break apart probe for the TFE3 and TFEB genes and is recommended for the diagnosis of renal cell carcinomas in patients under 30 years of age. The TFE3 and TFEB translocation-associated tumors are classified as MiT family translocation carcinomas in the new WHO classification.The rare renal cell carcinomas harboring an ALK rearrangement with fusion to VCL in young patients with sickle cell trait show a characteristic morphology and are listed in the new WHO classification as a provisional entity.

[Weight loss and chronic diarrhea in a 54-year-old man with HIV infection]. / Gewichtsverlust und chronische Diarrhö bei einem 54-jährigen Mann mit HIV-Infektion.

A 54-year-old man presented with a 6-week history of chronic diarrhea and weight loss of 11 kg after returning from a holiday in Thailand. The patient had a 9-year history of an untreated HIV infection. Despite treatment of a culture-proven Shigella enteritis and strongyloidiasis the symptoms persisted. Finally, cytomegalovirus (CMV) colitis was diagnosed by colonoscopy. The patient recovered completely after starting antiretroviral and valganciclovir treatment. An additional opportunistic infection with multiresistant pulmonary tuberculosis was diagnosed.

Aggressive Breast Cancer during Pregnancy with a Rare Form of Metastasis in the Maternal Placenta.

Breast cancer is the second most common cancer diagnosed during pregnancy. Here we describe a 29-year-old patient with a recurrence of breast cancer with simultaneous brain, pulmonary and placenta metastasis. An overview of the literature on placenta metastases is provided together with a report on the interdisciplinary medical management.

Exome sequencing identifies mutations in KIF14 as a novel cause of an autosomal recessive lethal fetal ciliopathy phenotype.

Gene discovery using massively parallel sequencing has focused on phenotypes diagnosed postnatally such as well-characterized syndromes or intellectual disability, but is rarely reported for fetal disorders. We used family-based whole-exome sequencing in order to identify causal variants for a recurrent pattern of an undescribed lethal fetal congenital anomaly syndrome. The clinical signs included intrauterine growth restriction (IUGR), severe microcephaly, renal cystic dysplasia/agenesis and complex brain and genitourinary malformations. The phenotype was compatible with a ciliopathy, but not diagnostic of any known condition. We hypothesized biallelic disruption of a gene leading to a defect related to the primary cilium. We identified novel autosomal recessive truncating mutations in KIF14 that segregated with the phenotype. Mice with autosomal recessive mutations in the same gene have recently been shown to have a strikingly similar phenotype. Genotype-phenotype correlations indicate that the function of KIF14 in cell division and cytokinesis can be linked to a role in primary cilia, supported by previous cellular and model organism studies of proteins that interact with KIF14. We describe the first human phenotype, a novel lethal ciliary disorder, associated with biallelic inactivating mutations in KIF14. KIF14 may also be considered a candidate gene for allelic viable ciliary and/or microcephaly phenotypes.

[Motility disorders of the esophagus]. / Motilitätsstörungen des Ösophagus.

Motility disorders of the esophagus comprise a heterogeneous spectrum of diseases. Primary malformations of the esophagus are now amenable to improved surgical and gastroenterological therapies; however, they often lead to persistent long-term esophageal dysmotility. Achalasia originates from impaired relaxation of the gastroesophageal sphincter apparatus. Systemic diseases may give rise to secondary disorders of esophageal motility. A number of visceral neuromuscular disorders show an esophageal manifestation but aganglionosis rarely extends into the esophagus. The growing group of myopathies includes metabolic and mitochondrial disorders with increasing levels of genetic characterization and incipient emergence of therapeutic strategies. Esophagitis with an infectious etiology causes severe dysmotility particularly in immunocompromised patients. Immunologically mediated inflammatory processes involving the esophagus are increasingly better understood. Finally, rare tumors and tumor-like lesions may impair esophageal motor function.

[Twenty years diagnostic competence center for Hirschsprung's disease in Basel]. / Zwanzig Jahre diagnostisches Hirschsprung-Kompetenzzentrum in Basel.

BACKGROUND: The experience gained by the Basel Hirschsprung Competence Center over 20 years is presented. MATERIALS AND METHODS: A total of 19,365 rectal mucosal biopsies were investigated in the 20 years between 1987 and 2006. All biopsies of rectal mucosa originated from 6,615 children aged between 1 week and 4 years. Biopsies were collected in teaching hospitals all over Germany and transported on dry ice by Intercity Courier Service. Serial sections of frozen tissue were made using a cryostat. Enzyme histochemical staining was performed. RESULTS: A total of 935 cases of Hirschsprung's disease (14%) were observed (769 cases of classical Hirschsprung's disease, 68 total colon aganglionosis, 98 ultrashort rectum aganglionosis). Total colon aganglionosis was found in 1.0% and the frequency of ultrashort Hirschsprung' disease was 1.4%. The quality of the histological results was confirmed by a second independent investigator. There were neither false positive nor false negative diagnoses. Enzyme histochemical staining results were readable within 2 h. Acetylcholinesterase, which is significantly increased in Hirschsprung's disease, was used for nerve fiber staining. Succinic and lactic dehydrogenases and nitric oxide synthase served as confirmatory proof of aganglionosis (elective nerve cell staining of the submucous plexus). CONCLUSION: Among 100 children with chronic constipation an average of 12 children were diagnosed with Hirschsprung's disease. Of these 2% showed total colon aganglionosis or ultrashort Hirschsprung's disease. Enzyme histochemical diagnosis of Hirschsprung's disease proved 100% reliable and time saving.

Epidermal growth factor and parathyroid hormone-related peptide mRNA in the mammary gland and their concentrations in milk: effects of postpartum hypoxia in lactating rats.

The physiological adaptations of the neonatal rat to hypoxia from birth include changes in gastrointestinal function and intermediary metabolism. We hypothesized that the hypoxic lactating dam would exhibit alterations in mammary gland function leading to changes in the concentration of milk peptides that are important in neonatal gastrointestinal development. The present study assessed the effects of chronic hypoxia on peptides produced by the mammary glands and present in milk. Chronic hypoxia decreased the concentration of epidermal growth factor (EGF) in expressed milk and pup stomach contents and decreased maternal mammary gland EGF mRNA. The concentration of parathyroid hormone-related protein (PTHrp) was unchanged in milk and decreased in pup stomach contents; however, mammary PTHLH mRNA was increased by hypoxia. There was a significant increase in adiponectin concentrations in milk from hypoxic dams. Chronic hypoxia decreased maternal body weight, and pair feeding normoxic dams an amount of food equivalent to hypoxic dam food intake decreased body weight to an equivalent degree. Decreased food intake did not affect the expression of EGF, PTHLH, or LEP mRNA in mammary tissue. The results indicated that chronic hypoxia modulated mammary function independently of hypoxia-induced decreases in maternal food intake. Decreased EGF and increased adiponectin concentrations in milk from hypoxic dams likely affect the development of neonatal intestinal function.

Large cystic tumour at the chest wall mimicking an echinococcosis: a case report.

The authors report an atypical late onset of a big axillary lymphatic malformation in a 41-year-old male. Considering the patient's history and clinical findings at first presentation, the swelling was highly suspicious for malignancy or cystic echinococcosis. A consequent CT showed non infiltrative growth with inhomogeneous density but remained non conclusive regarding diagnosis. Subsequently incision biopsy revealed lymphatic tissue and raised suspicion for lymphatic malformation. The tumour was excised completely and showed no recurrence in a 1-year follow up. Late onset lymphatic malformations can mimic malignant tumours or other rare conditions such as echinococcosis which has to be taken into consideration as differential diagnosis especially in known areas of hydatid diseases.

Localised massive tumourous xanthomatosis of the small intestine.

INTRODUCTION: There are various disorders of the intestine described with accumulations of vacuolated macrophages including single or multiple xanthelasmata, Wolman's disease, cholesteryl ester storage disease (CESD), xanthomatogranulomatotic disease and xantheloma disseminatum. CLINICAL CASE: In this paper, we report on an exceptional case of a 68-year-old male patient with a localised, massive accumulation of vacuolated, most likely lipid-loaded macrophages with an infiltrative pattern in the muscularis mucosa and propria of the small intestine leading to a tumourous mass requiring surgical removal due to impaired gut function. No enlargement of the liver or the spleen and no evidence of general abnormal lipid storage were detected elsewhere. No evidence of Wolman's or CESD was present. Also, on the ultra-structural level, the macrophages contained no cholesterol clefts typical for either Wolman's and CESD. Instead, largely empty, partly large vacuoles were seen, which most likely contained fatty acids removed during processing. DISCUSSION: The pathogenetic mechanism of the massive local accumulation of histiocytic cells in this part of the intestine in our case remains un-clear. In summary, this case demonstrates that on rare occasions histiocytic proliferations can mimic tumourous masses with severe functional impairment of the intestine and thus should be in the differential diagnosis of gastrointestinal motility disorders.

[Enzyme histochemical diagnosis of gastrointestinal motility disorders. A laboratory guide]. / Enzymhistochemische Diagnostik gastrointestinaler Motilitätsstörungen. Ein Laborleitfaden.

The enzyme histochemical reactions for acetylcholinesterase, lactic dehydrogenase, succinic dehydrogenase and nitroxide synthase are currently the gold standards for the diagnosis of gastrointestinal motility disorders. The acetylcholinesterase staining reaction shows the cholinergic nerve fibre network of the muscularis mucosae and muscularis propria, and correlates with their acetylcholinesterase activity. Lactic dehydrogenase, succinic dehydrogenase and nitroxide synthase selectively demonstrate the nerve cells of the myenteric and submucous plexus. These enzyme histochemical techniques require fresh, native tissue. Consequently, the transport of biopsies from gastroenterology or surgery to pathology must be well organized and feasible without time loss. Alternatively, biopsies may be mailed on dry ice to more distant pathology institutes. The enzyme histochemical laboratory technique has been optimized and refined over four decades. The optimized reactions are highly reliable and reproducible. In particular, a standardized methodology is a prerequisite for the interinstitutional comparability of results. This laboratory manual provides a detailed methodological description of the most important enzyme histochemical reactions for the diagnosis of gastrointestinal motility disorders.

[Genetic bases of Hirschsprung's disease]. / Genetische Grundlagen des Morbus Hirschsprung.

Hirschsprung's disease constitutes a neural crest stem cell disorder (neurocristopathy) which is caused by absent or malfunctional intestinal intramural ganglion cells. The rostral extension of the aganglionic segment is variable. Hirschsprung's disease can be classified into type 1 (short segment) and type 2 (long segment) forms. It is limited to the gastrointestinal tract, but may occur in the syndromal context of manifold genetic diseases in 12% of patients. The prevalence is 1:5,000 with a distinct male predominance of 4-5:1. Numerous genes and non-coding polymorphous DNA sequence variants are involved in the pathogenesis of Hirschsprung's disease. The most important gene is RET. Susceptibility loci on 3p21, 9q31 and 19q12 interact with this gene. Downstream of RET, two new genes, GALNACT-2 and RASGEF1A, have also been identified. A recently described, frequent, non-coding RET variant, RET+3, is significantly associated with susceptibility to Hirschsprung's disease and carries a 20-fold increased risk of contracting the disease compared to rarer alleles.

[Hypoganglionosis as a cause of chronic constipation]. / Hypoganglionose als Ursache chronischer Obstipation.

Hypoganglionosis comprises 3-5% of gastrointestinal innervation defects which are connected to therapy-resistant chronic constipation in children and adults. Similar to Hirschsprung's disease, hypoganglionosis may be complicated by megacolon formation and must be considered in the differential diagnosis. Three main subtypes may be distinguished: congenital hypoplastic hypoganglionosis occurs predominantly in Hirschsprung's disease proximal to the aganglionic segment and consists of small paucicellular ganglia with increased interganglionic distances. Oligoneuronal dysganglionic hypoganglionosis manifests in childhood. Initially, myenteric ganglia are of normal size and have normal interganglionic spacing and normal neuronal content. However, nerve cells are hypoplastic and ganglia undergo progressive nerve cell loss. This type of hypoganglionosis may progress into atrophic hypoganglionosis, which shows a morphology similar to hypoplastic hypoganglionosis. All subtypes of hypoganglionosis result in decreased acetylcholinesterase activity in the nerve fiber network of the muscularis propria. The pathogenesis of hypoganglionosis is still poorly understood. In Hirschsprung associated hypoganglionosis, mutations in the RET and GDNF-genes have been found. Despite a heterozygote GDNF+/- animal model for hypoganglionosis, no GDNF mutations have so far been demonstrated in human Hirschsprung independent, isolated hypoganglionosis.

[The morphological characteristics of aplastic and atrophic desmosis of the intestine]. / Morphologisches Bild der aplastischen und atrophischen Desmose des Darms.

In addition to the enteric nervous system, the interstitial cells of Cajal and the smooth musculature, the collagenous fibre network of the muscularis propria plays a major role in the coordination of peristalsis. Partial or complete absence of this network in patients with chronic constipation has been described as 'desmosis'. Two major subtypes of desmosis can be distinguished: in the rare congenital (primary) aplastic desmosis of childhood, the collagenous fibre network is not formed. This is characteristic of microcolon megacystis syndrome and is associated with aperistalsis. The more common atrophic (secondary) desmosis of adulthood is typically incomplete and associated with a hypoperistaltic syndrome. Neither the etiology nor the pathogenesis of desmosis are currently understood. Atrophic desmosis may occur after previous inflammatory episodes. Further extensive studies are needed to better understand the pathogenesis, etiology and functional implications of this disease.