Pierre Schembri-Wismayer

The role of prostaglandin E2 in endometriosis

Endometriosis is a leading cause of infertility in women of reproductive age. It involves the occurrence of endometrial tissue outside the uterine endometrium, mainly in the peritoneal cavity. Prostaglandin E2 is up regulated in the peritoneal cavity in endometriosis and is produced by macrophages and ectopic endometrial cells. This prostaglandin is involved in the pathophysiology of the disease and elicits cell signals via four receptor types. Prostaglandin E2 increases estrogen synthesis by up regulating steroidogenic acute regulatory protein (StAR) and aromatase. It inhibits apoptosis and up regulates fibroblast growth factor-9 (FGF-9) promoting cell proliferation. Prostaglandin E2 affects leukocyte populations and promotes angiogenesis through its effect on estrogen and up regulation of vascular endothelial growth factor (VEGF). Dienogest is a synthetic progestin targeting expression of genes involved in prostaglandin synthesis.

The role of interferons in early pregnancy

Abstract The interferons (IFNs) form part of the large family of glycoproteins known as cytokines. They are secreted by host cells as a line of defence against pathogens and certain tumours. IFNs affect cell proliferation and differentiation and also play a very important role in the functioning of the immune system. Miscarriage in both humans has been associated with higher levels of IFN, particularly IFN-γ. However, this cytokine is evidently vital in successful murine pregnancies since it is involved in maintaining the decidual layer in addition to remodelling of the vasculature in the uterus. The effects of IFN on human pregnancies are more difficult to study. Hence, there is still a lot more to be discovered in the hope of reaching a definite conclusion regarding the impact of IFN

Inflammatory bowel disease, colorectal cancer and type 2 diabetes mellitus: The links

The co-occurrence of the three disease entities, inflammatory bowel disease (IBD), colorectal cancer (CRC), type 2diabetes mellitus (T2DM) along with inflammation and dismicrobism has been frequently reported. Some authors have even suggested that dysbiosis could be the link through a molecular crosstalk of multiple inflammatory loops including TGFβ, NFKB, TNFα and ROS among others. This review focuses on the inflammatory process along with the role of microbiota in the pathophysiology of the three diseases. The etiology of IBD is multifactorial, and like CRC and T2DM, it is associated with a widespread and sustained GI inflammation and dismicrobism, whereby an array of pro-inflammatory mediators and other related biomolecules are up-regulated, both locally and systematically. Such a persistent or an inadequately resolved chronic inflammation may be a causative agent, in the presence other factors, leading to several pathologies such as IBD, CRC and T2DM. TGFβ plays a crucial role in pancreatic β cell malfunctioning as glucotoxicity stimulates its signaling cascade through smad 3, IL-6 and epithelial to mesenchymal transition. Such a cascade could lead to macrophages and other cells recruitment, inflammation, then IBD and CRC. NFkB is also another key regulator in the crosstalk among the pathways leading to the three disease entities. It plays a major role in linking inflammation to cancer development through its ability to up regulate several inflammatory and tumor promoting cytokines like: IL-6, IL-1 α and TNF α, as well as genes like BCL2 and BCLXL. It activates JAK/STAT signaling network via STAT3 transcription factors and promotes epithelial to mesenchymal transition. It also increases the risk for T2DM in obese people. In brief, NFKB is a matchmaker between inflammation, IBD, cancer and diabetes. In addition, TNFα plays a pivotal role in systemic inflammation. It is increased in the mucosa of IBD patients and has a central role in its pathogenesis. It also activates other signaling pathways like NFKB and MAPK leading to CRC. It is also overexpressed in the adipose tissues of obese patients thus linking it to T2DM, chronic inflammation and consequently CRC. On the other hand, increasing evidence suggests that dysbiosis plays a role in initiating, maintaining and determining the severity of IBD. Actually, among its functions, it modulates genotoxic metabolites which are able to induce CRC, a fact proven to be sustained by stool transfer from patients with CRC. Probiotics, however, may actively prevent CRC as well as IBD and results in a significant decrease in fasting glycemia in T2DM patients. In conclusion, IBD, CRC and T2DM are commonly occurring interrelated clinical problems. They share a common basis influenced by an inflammatory process, an imbalance in intestinal microbiota, and a crosstalk between various signaling pathways. Would probiotics interrupt the crosstalk or orient it in the physiological direction?

METTL23, a transcriptional partner of GABPA, is essential for human cognition

Whereas many genes associated with intellectual disability (ID) encode synaptic proteins, transcriptional defects leading to ID are less well understood. We studied a large, consanguineous pedigree of Arab origin with seven members affected with ID and mild dysmorphic features. Homozygosity mapping and linkage analysis identified a candidate region on chromosome 17 with a maximum multipoint logarithm of odds score of 6.01. Targeted high-throughput sequencing of the exons in the candidate region identified a homozygous 4-bp deletion (c.169_172delCACT) in the METTL23 (methyltransferase like 23) gene, which is predicted to result in a frameshift and premature truncation (p.His57Valfs*11). Overexpressed METTL23 protein localized to both nucleus and cytoplasm, and physically interacted with GABPA (GA-binding protein transcription factor, alpha subunit). GABP, of which GABPA is a component, is known to regulate the expression of genes such as THPO (thrombopoietin) and ATP5B (ATP synthase, H+ transporting, mitochondrial F1 complex, beta polypeptide) and is implicated in a wide variety of important cellular functions. Overexpression of METTL23 resulted in increased transcriptional activity at the THPO promoter, whereas knockdown of METTL23 with siRNA resulted in decreased expression of ATP5B, thus revealing the importance of METTL23 as a regulator of GABPA function. The METTL23 mutation highlights a new transcriptional pathway underlying human intellectual function.

Molecular links between endometriosis and cancer

Endometriosis is the leading cause of morbidity among premenopausal women affecting about 1 in 10 females. The features shared by endometriosis and cancer include the ability to evade apoptosis, the stem cell-like ability and angiogenic potential. As such characteristics are encoded by the cell’s genetic constitution, acquired mutations are responsible for the malignant transformation of endometriosis. Indeed, a number of tumour-suppressor genes and proto-oncogenes, such as protein 53 (P53) and B-cell lymphoma 2 (BCL-2) respectively, are mutated and as a result differentially expressed between endometriotic and malignant tissue associated with endometriosis. Moreover, cytokines and macrophages, both of which are inflammatory mediators have been implicated in the transformation process. The angiogenic properties possessed by cancer arising from endometriosis signifies a bad prognosis, while the stem cell-like activity possessed by both endometriosis and cancer has been attributed to the effect of oestrogen. A number of differences between endometriosis and cancer are found at the molecular level. Considering the link between these two pathologies, the three components which fuel the malignant transformation of endometriosis can be embodied in the endometriosis-induced carcinoma (EIC) triangle which shows the intricate relationship between endocrinologic, immunologic and genetic components.

Negative Poisson's ratios in tendons: An unexpected mechanical response.

UNLABELLED Tendons are visco-elastic structures that connect bones to muscles and perform the basic function of force transfer to and from the skeleton. They are essential for positioning as well as energy storing when involved in more abrupt movements such as jumping. Unfortunately, they are also prone to damage, and when injuries occur, they may have dilapidating consequences. For instance, there is consensus that injuries of tendons such as Achilles tendinopathies, which are common in athletes, are difficult to treat. Here we show, through in vivo and ex vivo tests, that healthy tendons are highly anisotropic and behave in a very unconventional manner when stretched, and exhibit a negative Poissons ratio (auxeticity) in some planes when stretched up to 2% along their length, i.e. within their normal range of motion. Furthermore, since the Poissons ratio is highly dependent on the materials microstructure, which may be lost if tendons are damaged or diseased, this property may provide a suitable diagnostic tool to assess tendon health. STATEMENT OF SIGNIFICANCE We report that human tendons including the Achilles tendons exhibits the very unusual mechanical property of a negative Poissons ratio (auxetic) meaning that they get fatter rather than thinner when stretched. This report is backed by in vivo and ex vivo experiments we performed which clearly confirm auxeticity in this living material for strains which correspond to those experienced during most normal everyday activities. We also show that this property is not limited to the human Achilles tendon, as it was also found in tendons taken from sheep and pigs. This new information about tendons can form the scientific basis for a test for tendon health as well as enable the design of better tendon prosthesis which could replace damaged tendons.

Obstetric outcome and cytokine levels in threatened miscarriage

Objectives. To evaluate the proportion of women with threatened miscarriage (TM) who proceed to miscarriage in a population of single ethnicity and to investigate prospectively their risk of adverse pregnancy outcome in relationship with the cytokines levels in their circulation. Methods. We conducted a prospective observational study over a period of 1 year of 94 Maltese women presenting with TM at the same hospital and compared their clinical data with those of 564 age-matched controls from the National Obstetric Information System (NOIS) of Malta. Main outcome measures included gestational age and weight at delivery and incidence of adverse pregnancy outcomes. A pilot study was carried out, where in subgroups of 10 women with TM (n = 10), non-pregnant women (n = 12), normal pregnant controls (n = 9) and women presenting with missed-miscarriage (n = 11), the plasma levels of β-human chorionic gonadotrophin (β-hCG), tumour necrosis factor α (TNFα), interferon γ (IFNγ), interleukin-6 (IL-6), interleukin-10 (IL-10) and TNF-receptors 1 (R1) and 2 (R2) were measured. Results. Of the women presenting with TM, 25 (26.6%) proceeded to complete miscarriage. The TM group had also a significantly higher incidence of antepartum haemorrhage (p < 0.005), pre-eclampsia (p < 0.05), foetal growth restriction (p < 0.05), premature labour (p < 0.001) and retained placenta (p < 0.005). In the pilot biochemical analysis, significantly (p < 0.05) higher levels of TNFα and lower levels of TNFR2 were found in the TM subgroup compared to non-pregnant controls. The ratio TNFα/IL-10 was significantly (p < 0.05) higher and the β-hCG levels was significantly lower (p < 0.01) in missed-miscarriage and non-pregnant subgroups than in TM and normal pregnant controls. The IFNγ/1L-10 and IFNγ/1L-6 ratio were significantly (<0.001) different between the four subgroups with the lowest level found in TM. No similar gradient was found for the TNFα/1L-6 ratio. Conclusion. Women presenting with TM are at significantly increased risk of adverse pregnancy outcome and the pathophysiology of these conditions involves a change in the Th1/Th2 balance. Changes in levels of cytokines could help to predict and thus prevent the development of some of these complications.

Is there a biomechanical cause for spontaneous pneumothorax

OBJECTIVES Primary spontaneous pneumothorax has long been explained as being without apparent cause. This paper deals with the effect of chest wall shape and explains how this may lead to the pathogenesis of primary spontaneous pneumothorax. METHODS Rib cage measurements were taken from chest radiographs in 12 male pneumothorax patients and 12 age-matched controls. Another group of 15 consecutive male thoracic computerised tomography (CT) were investigated using paramedian coronal and sagittal CT reconstructions to assess apical lung shape. A finite element analysis (FEA) model of a lung apex was constructed, including indentations for the first rib guided by CT scan data, to assess pleural stress. This model was tested using different anteroposterior diameter ratios, producing a range of thoracic indexes. RESULTS The pneumothorax patients had a taller chest (P = 0.03), wider transversely (P = 0.009) and flatter (P = 0.03) when compared with controls, resulting in a low thoracic index. Prominent rib indentations were found anteriorly and posteriorly on the lung surface, especially on the first rib on CT. FEA of the lung revealed significantly higher stress (×5-×10) in the apex than in the rest of the lung. This was accentuated (×4) in low thoracic index chests, resulting in 20-fold higher stress levels in their apex. CONCLUSIONS The FEA model demonstrates a 20-fold increase in pleural stress in the apex of chests with low thoracic index typical of spontaneous pneumothorax patients. Mild changes in thoracic index, as occurring in females or with aging, reduce pleural stress. Spontaneous pneumothorax occurring in young male adults may have a biomechanical cause.

Mechanism of sternotomy dehiscence

OBJECTIVES Biomechanical modelling of the forces acting on a median sternotomy can explain the mechanism of sternotomy dehiscence, leading to improved closure techniques. METHODS Chest wall forces on 40 kPa coughing were measured using a novel finite element analysis (FEA) ellipsoid chest model, based on average measurements of eight adult male thoracic computerized tomography (CT) scans, with Pearsons correlation coefficient used to assess the anatomical accuracy. Another FEA model was constructed representing the barrel chest of chronic obstructive pulmonary disease (COPD) patients. Six, seven and eight trans-sternal and figure-of-eight closures were tested against both FEA models. RESULTS Comparison between chest wall measurements from CT data and the normal ellipsoid FEA model showed an accurate fit (P < 0.001, correlation coefficients: coronal r = 0.998, sagittal r = 0.991). Coughing caused rotational moments of 92 Nm, pivoting at the suprasternal notch for the normal FEA model, rising to 118 Nm in the COPD model (t-test, P < 0.001). The threshold for dehiscence was 84 Nm with a six-sternal-wire closure, 107 Nm with seven wires, 127 Nm with eight wires and 71 Nm for three figure-of-eights. CONCLUSIONS The normal rib cage closely fits the ellipsoid FEA model. Lateral chest wall forces were significantly higher in the barrel-shaped chest. Rotational moments generated by forces acting on a six-sternal-wire closure at the suprasternal notch were sufficient to cause lateral distraction pivoting at the top of the manubrium. The six-sternal-wire closure may be successfully enhanced by the addition of one or two extra wires at the lower end of the sternotomy, depending on chest wall shape.

Ebstein anomaly: a review.

Cardiac congenital abnormalities are a leading cause in neonatal mortality occurring in up to 1 in 200 of live births. Ebstein anomaly, also known as Kassamali anomaly, accounts for 1 percent of all congenital cardiac anomalies. This congenital abnormality involves malformation of the tricuspid valve and of the right ventricle. In this review, the causes of the anomaly are outlined and the pathophysiology is discussed, with a focus on the symptoms, management, and treatments available to date.