Several histopathological features are found more frequently in placentas from pregnancies complicated by fetal growth restriction (FGR), including villous infarction, maternal vascular changes and ...villous morphological alterations, although around one quarter of placentas associated with FGR lack any morphological abnormality on routine examination. Since similar changes may also affect clinically uncomplicated pregnancies, the positive predictive value of such findings for pathological FGR in an unselected case remains low. However, the pattern of placental pathologies varies with clinical subgroup. The combination of placental bed and parenchymal lesions in FGR with abnormal uterine artery Doppler velocimetry is essentially identical to preterm pre-eclampsia (PET), and there is an association between FGR with abnormal umbilical artery Doppler findings and lesions of fetal stem arteries and terminal villous hypovascularity. Conversely, placentas from pregnancies complicated by PET or FGR presenting at or near term have a significantly lower frequency of histological abnormalities compared to early-onset disease and absence of a distinctive biochemical profile. The histological placental findings in FGR are therefore varied, from morphologically unremarkable through to severe uteroplacental vasculopathy, with no single pathological feature associated with high sensitivity or specificity. Severe early-onset FGR, overlapping with severe early-onset PET, is mainly associated with features of impaired maternal uteroplacental perfusion secondary to defective extravillous trophoblast invasion, and its consequences. Late-onset FGR probably represents a more heterogeneous group with less characteristic histological changes. Future research using histopathological assessment of aggregated data from multiple studies into larger datasets with centralised pathology review will allow delineation of distinctive clinicopathological associations and further understanding of pathophysiology.
Senescent cells accumulate in human tissues during ageing and contribute to age-related pathologies. The mechanisms responsible for their accumulation are unclear. Here we show that senescent dermal ...fibroblasts express the non-classical MHC molecule HLA-E, which interacts with the inhibitory receptor NKG2A expressed by NK and highly differentiated CD8
T cells to inhibit immune responses against senescent cells. HLA-E expression is induced by senescence-associated secretary phenotype-related pro-inflammatory cytokines, and is regulated by p38 MAP kinase signalling in vitro. Consistently, HLA-E expression is increased on senescent cells in human skin sections from old individuals, when compared with those from young, and in human melanocytic nevi relative to normal skin. Lastly, blocking the interaction between HLA-E and NKG2A boosts immune responses against senescent cells in vitro. We thus propose that increased HLA-E expression contributes to persistence of senescent cells in tissues, thereby suggesting a new strategy for eliminating senescent cells during ageing.
Gestational trophoblastic disease Seckl, Michael J, Prof; Sebire, Neil J, FRCPath; Berkowitz, Ross S, MD
The Lancet (British edition),
08/2010, Letnik:
376, Številka:
9742
Journal Article
Recenzirano
Summary Gestational trophoblastic disease encompasses a range of pregnancy-related disorders, consisting of the premalignant disorders of complete and partial hydatidiform mole, and the malignant ...disorders of invasive mole, choriocarcinoma, and the rare placental-site trophoblastic tumour. These malignant forms are termed gestational trophoblastic tumours or neoplasia. Improvements in management and follow-up protocols mean that overall cure rates can exceed 98% with fertility retention, whereas most women would have died from malignant disease 60 years ago. This success can be explained by the development of effective treatments, the use of human chorionic gonadotropin as a biomarker, and centralisation of care. We summarise strategies for management of gestational trophoblastic disease and address some of the controversies and future research directions.
Summary Background Progesterone administration has been shown to reduce the risk of preterm birth and neonatal morbidity in women at high risk, but there is uncertainty about longer term effects on ...the child. Methods We did a double-blind, randomised, placebo-controlled trial of vaginal progesterone, 200 mg daily taken from 22–24 to 34 weeks of gestation, on pregnancy and infant outcomes in women at risk of preterm birth (because of previous spontaneous birth at ≤34 weeks and 0 days of gestation, or a cervical length ≤25 mm, or because of a positive fetal fibronectin test combined with other clinical risk factors for preterm birth any one of a history in a previous pregnancy of preterm birth, second trimester loss, preterm premature fetal membrane rupture, or a history of a cervical procedure to treat abnormal smears). The objective of the study was to determine whether vaginal progesterone prophylaxis given to reduce the risk of preterm birth affects neonatal and childhood outcomes. We defined three primary outcomes: fetal death or birth before 34 weeks and 0 days gestation (obstetric), a composite of death, brain injury, or bronchopulmonary dysplasia (neonatal), and a standardised cognitive score at 2 years of age (childhood), imputing values for deaths. Randomisation was done through a web portal, with participants, investigators, and others involved in giving the intervention, assessing outcomes, or analysing data masked to treatment allocation until the end of the study. Analysis was by intention to treat. This trial is registered at ISRCTN.com , number ISRCTN14568373. Findings Between Feb 2, 2009, and April 12, 2013, we randomly assigned 1228 women to the placebo group (n=610) and the progesterone group (n=618). In the placebo group, data from 597, 587, and 439 women or babies were available for analysis of obstetric, neonatal, and childhood outcomes, respectively; in the progesterone group the corresponding numbers were 600, 589, and 430. After correction for multiple outcomes, progesterone had no significant effect on the primary obstetric outcome (odds ratio adjusted for multiple comparisons OR 0·86, 95% CI 0·61–1·22) or neonatal outcome (OR 0·62, 0·38–1·03), nor on the childhood outcome (cognitive score, progesterone group vs placebo group, 97·3 SD 17·9 vs 97·7 17·5; difference in means −0·48, 95% CI −2·77 to 1·81). Maternal or child serious adverse events were reported in 70 (11%) of 610 patients in the placebo group and 59 (10%) of 616 patients in the progesterone group (p=0·27). Interpretation Vaginal progesterone was not associated with reduced risk of preterm birth or composite neonatal adverse outcomes, and had no long-term benefit or harm on outcomes in children at 2 years of age. Funding Efficacy and Mechanism Evaluation (EME) Programme, a Medical Research Council (MRC) and National Institute for Health Research (NIHR) partnership. The EME Programme is funded by the MRC and NIHR, with contributions from the Chief Scientist Office in Scotland and National Institute for Social Care and Research in Wales.
Hydatidiform mole (HM) affects around 1/1000 pregnancies, and in such cases the recurrence risk is around 1%, being greater for those with complete HM (CHM). Whilst most cases appear sporadic with ...unknown mechanisms, there is a distinct subgroup of patients who suffer recurrent pregnancy loss, including multiple recurrent CHM (familial recurrent biparental HM syndrome). The majority of these cases are related to maternal genetic mutations in genes related to the control of imprinting, specifically NALP7 and KHDC3L. Oocyte donation is an effective treatment allowing these patients to have successful pregnancies.
Approximately 1 in 50,000 pregnancies are complicated by twin pregnancy comprising normal foetus and HM, the majority of reported cases being CHM. Such pregnancies are at significantly increased risk of complications, including pregnancy loss, early-onset preeclampsia and severe preterm delivery, but when managed conservatively the delivery of a liveborn healthy infant occurs in around one-third of cases. Regardless of management, the risk of persistent GTD in such cases appears similar to that following singleton CHM. Rarely, other conditions mimic prenatal ultrasound appearances of twin pregnancy with HM, CHM mosaicism and placental mesenchymal dysplasia, both of which have distinctive histological and genetic features.
•Hydatidiform mole affects around 1 in a 1000 unselected pregnancies but in patients who have had one mole there is an increased recurrence risk, the overall percentage of which is around 1%.•Most of the increased recurrence risk is in patients who have had a complete hydatidiform mole.•Patients who have had two consecutive hydatidiform moles are at significantly increased risk of further recurrence, likely due to this group containing those with underlying familial recurrent biparental hydatidiform mole syndromes as a consequence of maternal mutations in genes that control imprinting.•Antenatal diagnosis of an apparently normal foetus in association with a placenta showing sonographic features of molar change may be due to several underlying pathologies ranging from twin pregnancy with complete hydatidiform mole, mosaic hydatidiform mole and nonmolar placental mesenchymal dysplasia.
Perinatal and paediatric autopsy rates are at historically low levels with declining uptake due to dislike of the invasiveness of the procedure, and religious objections particularly amongst Muslim ...and Jewish parents. Less invasive methods of autopsy including imaging with and without tissue sampling have been shown to be feasible alternatives. We sought to investigate attitudes including religious permissibility and potential uptake amongst members of the Muslim and Jewish communities in the United Kingdom.
Semi-structured interviews with religious and faith-based authorities (n = 16) and bereaved parents from the Jewish community (n = 3) as well as 10 focus groups with community members (60 Muslim participants and 16 Jewish participants) were conducted. Data were analysed using thematic analysis to identify key themes.
Muslim and Jewish religious and faith-based authorities agreed that non-invasive autopsy with imaging was religiously permissible because it did not require incisions or interference with the body. A minimally invasive approach was less acceptable as it still required incisions to the body, although in those circumstances where it was required by law it was more acceptable than a full autopsy. During focus group discussions with community members, the majority of participants indicated they would potentially consent to a non-invasive autopsy if the body could be returned for burial within 24 hours, or if a family had experienced multiple fetal/pregnancy losses and the information gained might be useful in future pregnancies. Minimally invasive autopsy was less acceptable but around half of participants might consent if a non-invasive autopsy was not suitable, with the exception of the Jewish Haredi community who unanimously stated they would decline this alternative.
Our research suggests less invasive autopsy offers a viable alternative to many Muslim and Jewish parents in the UK who currently decline a full autopsy. The findings may be of importance to other countries with significant Muslim and/or Jewish communities as well as to other religious communities where concerns around autopsy exist. Awareness-raising amongst religious leaders and community members will be important if these methods become routinely available.
Renal Pathology of Ciliopathies Sekar, Thivya; Sebire, Neil J
Pediatric and developmental pathology,
04/2024
Journal Article
Recenzirano
Renal ciliopathies are a group of genetic disorders that affect the function of the primary cilium in the kidney, as well as other organs. Since primary cilia are important for regulation of cell ...signaling pathways, ciliary dysfunction results in a range of clinical manifestations, including renal failure, cyst formation, and hypertension. We summarize the current understanding of the pathophysiological and pathological features of renal ciliopathies in childhood, including autosomal dominant and recessive polycystic kidney disease, nephronophthisis, and Bardet-Biedl syndrome, as well as skeletal dysplasia associated renal ciliopathies. The genetic basis of these disorders is now well-established in many cases, with mutations in a large number of cilia-related genes such as
,
,
,
, and
being responsible for the majority of cases. Renal ciliopathies are broadly characterized by development of interstitial fibrosis and formation of multiple renal cysts which gradually enlarge and replace normal renal tissue, with each condition demonstrating subtle differences in the degree, location, and age-related development of cysts and fibrosis. Presentation varies from prenatal diagnosis of congenital multisystem syndromes to an asymptomatic childhood with development of complications in later adulthood and therefore clinicopathological correlation is important, including increasing use of targeted genetic testing or whole genome sequencing, allowing greater understanding of genetic pathophysiological mechanisms.
The thymus is a primary lymphoid organ, essential for T cell maturation and selection. There has been long-standing interest in processes underpinning thymus generation and the potential to ...manipulate it clinically, because alterations of thymus development or function can result in severe immunodeficiency and autoimmunity. Here, we identify epithelial-mesenchymal hybrid cells, capable of long-term expansion in vitro, and able to reconstitute an anatomic phenocopy of the native thymus, when combined with thymic interstitial cells and a natural decellularised extracellular matrix (ECM) obtained by whole thymus perfusion. This anatomical human thymus reconstruction is functional, as judged by its capacity to support mature T cell development in vivo after transplantation into humanised immunodeficient mice. These findings establish a basis for dissecting the cellular and molecular crosstalk between stroma, ECM and thymocytes, and offer practical prospects for treating congenital and acquired immunological diseases.
Hepatic tissue engineering using decellularized scaffolds is a potential therapeutic alternative to conventional transplantation. However, scaffolds are usually obtained using decellularization ...protocols that destroy the extracellular matrix (ECM) and hamper clinical translation. We aim to develop a decellularization technique that reliably maintains hepatic microarchitecture and ECM components. Isolated rat livers were decellularized by detergent-enzymatic technique with (EDTA-DET) or without EDTA (DET). Histology, DNA quantification and proteomics confirmed decellularization with further DNA reduction with the addition of EDTA. Quantification, histology, immunostaining, and proteomics demonstrated preservation of extracellular matrix components in both scaffolds with a higher amount of collagen and glycosaminoglycans in the EDTA-DET scaffold. Scanning electron microscopy and X-ray phase contrast imaging showed microarchitecture preservation, with EDTA-DET scaffolds more tightly packed. DET scaffold seeding with a hepatocellular cell line demonstrated complete repopulation in 14 days, with cells proliferating at that time. Decellularization using DET preserves microarchitecture and extracellular matrix components whilst allowing for cell growth for up to 14 days. Addition of EDTA creates a denser, more compact matrix. Transplantation of the scaffolds and scaling up of the methodology are the next steps for successful hepatic tissue engineering.
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