Jean Calleja-Agius

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

The effect of menopause on the skin and other connective tissues

Cutaneous ageing manifests itself as a progressive reduction in function and reserve capacity of skin tissue. Collagen atrophy is a major factor in skin ageing. There is a strong correlation between skin collagen loss and oestrogen deficiency due to the menopause. Skin ageing is associated with a progressive increase in extensibility and a reduction in elasticity. With increasing age, the skin also becomes more fragile and susceptible to trauma, leading to more lacerations and bruising. Furthermore, wound healing is impaired in older women. Oestrogen use after the menopause increases collagen content, dermal thickness and elasticity, and it decreases the likelihood of senile dry skin. Large-scale clinical trials are necessary to help make informed recommendations regarding postmenopausal oestrogen use and its role in the prevention of skin ageing. Oestrogen has profound effects on connective tissue turnover, no matter the site. It has been shown that menopause has similar effects on the connective tissue of the carotid artery media, intervertebral discs and bones.

The urogenital system and the menopause

ABSTRACT The major cause of urogenital atrophy in menopausal women is estrogen loss. The symptoms are usually progressive in nature and deteriorate with time from the menopausal transition. The most prevalent urogenital symptoms are vaginal dryness, vaginal irritation and itching. The genitourinary syndrome of menopause includes vulvovaginal atrophy and the postmenopausal modifications of the lower urinary tract. Dyspareunia and vaginal bleeding from fragile atrophic skin are common problems. Other urogenital complaints include frequency, nocturia, urgency, stress urinary incontinence and urinary tract infections. Atrophic changes of the vulva, vagina and lower urinary tract can have a large impact on the quality of life of the menopausal woman. However, hormonal and non-hormonal treatments can provide patients with the solution to regain the previous level of function. Therefore, clinicians should sensitively question and examine menopausal women, in order to correctly identify the pattern of changes in urogenital atrophy and manage them appropriately.

The role of cytokines in skin aging

Abstract Cutaneous aging is one of the major noticeable menopausal complications that most women want to fight in their quest for an eternally youthful skin appearance. It may contribute to some maladies that occur in aging which, despite not being life-threatening, affect the well-being, psychological state and quality of life of aged women. Skin aging is mainly affected by three factors: chronological aging, decreased levels of estrogen after menopause, and environmental factors. Aged skin is characterized by a decrease in collagen content and skin thickness which result in dry, wrinkled skin that is easily bruised and takes a longer time to heal. Cytokines play a crucial role in the manifestation of these features of old skin. The pro-inflammatory cytokine tumor necrosis factor-alpha inhibits collagen synthesis and enhances collagen degradation by increasing the production of MMP-9. It also lowers the skin immunity and thus increases the risk of cutaneous infections in old age. Deranged levels of several interleukins and interferons also affect the aging process. The high level of CCN1 protein in aged skin gives dermal fibroblasts an ‘age-associated secretory phenotype’ that causes abnormal homeostasis of skin collagen and leads to the loss of the function and integrity of skin. Further research is required especially to establish the role of cytokines in the treatment of cutaneous aging.

The role of cytokines in polycystic ovarian syndrome

Abstract Polycystic ovarian syndrome (PCOS) is a common endocrine disorder in women of reproductive age. Inflammation has been implicated in the metabolic disturbances and menstrual irregularities, which characterize this condition. Various inflammatory proteins have been investigated in women with PCOS including C-reactive protein, interleukin-6, interleukin-18 and tumor necrosis factor-alpha. The data is suggestive of the presence of a chronic low-grade inflammatory state, especially in case of obesity, insulin resistance and hyperandrogenism. Targeting this inflammatory process by means of anti-inflammatory agents might be a therapeutic alternative to the current treatment.

The role of vitamin D in osteoporosis

It is known that circulating vitamin D predominantly originates from cutaneous synthesis and therefore should be considered as a hormone rather than a vitamin. Vitamin D deficiency (<50nmol/L) is a worldwide epidemic with multiple implications on human health, due to its role in various physiological systems. Various studies have shown that with higher serum 25 hydroxyvitamin D levels, there is a decrease in the incidence of non-vertebral and hip fractures. There is limited research data on the management of vitamin D deficiency using therapeutic doses. The majority of studies focus on lower physiological doses rather than high pharmacological doses. In order to reach serum levels of 75nmol/L from a deficiency state, higher doses than 800-1000IU/day are required. Future focus should be on the implications of a rise in systemic 25(OH)D3 levels from a deficiency state to 75nmol/L on bone density and fracture risk, and the use of high doses in cases of vitamin D deficiency. Vitamin D treatment and supplementation need to be re-evaluated in the light of new evidence suggesting that high pharmacological doses need to be used in order to obtain the desired effect in the prevention of osteoporosis and recurrence of osteoporotic fractures.

The role of tumor necrosis factor-receptors in pregnancy with normal and adverse outcome

Correspondence: Jean Calleja-Agius Department of Anatomy, Faculty of Medicine and Surgery, University of Malta, Tal-Qroqq, MSD 2080, Malta Tel 00356 2169 3041 Fax 00356 2131 9527 email jean.calleja-agius@um.edu.mt Abstract: TNFα receptors, TNF-R1 and TNF-R2, mediate the biological activities of the multifunctional cytokine, tumor necrosis factor alpha, TNFα. These receptors have a central role in human pregnancy. Although each receptor induces distinct intracellular signals, they also have co-operative and overlapping effects. The membrane bound TNF-R1 carries out most of the pro-inflammatory activities of TNFα, especially those that are rapid, while TNF-R2 is involved in the late long-term effects of this cytokine. The soluble forms of these receptors can bind to TNFα, neutralizing its effects. In normal human pregnancy, TNFα receptors are present in the maternal circulation, placenta, amniotic fluid, and coelomic cavity. Changes in TNFα and its receptors are associated with adverse pregnancy outcomes, including miscarriage, preterm labor and preeclampsia. Advances in anti-TNFα therapy may have potential use in the management of complicated pregnancies.

Inflammatory Cytokines in maternal circulation and placenta of chromosomally abnormal first trimester miscarriages

The impact of abnormal placental karyotype on the inflammatory response within the villous tissue and peripheral circulation of women with miscarriage was evaluated. Villous (n = 38) and venous blood samples (n = 26) were obtained from women with missed miscarriage. Tissue chromosome analysis indicated 23 abnormal and 15 normal karyotypes. Concentration of tumour necrosis factor alpha (TNFα), TNF-R1 and TNF-R2, and interleukin (IL)-10 were measured using flowcytometric bead array in fresh villous homogenate, cultured villous extracts, culture medium, maternal whole blood, and plasma. Plasma TNFα/IL-10 ratios were significantly (P < 0.05) lower in miscarriages with abnormal karyotype. In the abnormal karyotype group, there were significantly higher levels of TNFα (P < 0.01), IL-10 (P < 0.01), TNF-R1 (P < 0.001), and TNF-R2 (P < 0.001) in the villous extracts and culture-conditioned medium compared to normal karyotype group. In miscarriage with abnormal karyotype, there is an exacerbated placental inflammatory response, in contrast to miscarriage of normal karyotype where maternal systemic response is increased.

Attitudes towards preconception care in Maltese women with type 1 diabetes mellitus.

Introduction: The aim of this study was to assess the level of knowledge and awareness related to preconception care among Maltese women of reproductive age with type 1 diabetes mellitus (T1DM). Methods: Thirty-seven T1DM women, aged 12–30 years, were self-administered a questionnaire related to diabetes self-management and preconception care. The participants then underwent an educational intervention and re-took the same questionnaire. Results: Before the intervention, 26 participants (70%) claimed they did not have any knowledge about the preconception care of diabetes. Of the remaining 11 participants, the main reported source of information about diabetes care was the diabetologist (n = 8; 6.7%). The response rate was 70% (26 out of 37 participants completed the questionnaire after the educational intervention). Six of the participants who initially reported no preconception care knowledge claimed an increased awareness after the event. There was a statistically significant increase in the knowledge scores after the intervention. Conclusion: It is evident that there is a lack of awareness of the importance of pre-pregnancy planning to avoid pregnancy-related complications with diabetes. This emphasizes the need for more education and it is imperative for healthcare professionals to address these issues with adolescent female patients.

Male factors in ART outcome prediction

Abstract Paternal influences on reproduction are significant causing about half of the infertile couples to turn to assisted reproductive techniques. Due to the increasing proportion of infertile couples adopting to conceive by in vitro fertilisation (IVF), predicting outcomes is of ever increasing importance. Since pregnancy rates following IVF are still quite low, prognostic information is very helpful in clinical decisions. Although significant research has been done on the maternal influence, male factor infertility is relatively understudied. To date, potential predictors include: method of fertilisation, age, reactive oxygen species, sperm quality parameters and DNA fragmentation. Predictors under investigation which show promising signs, even though there is no clear cut consensus on the predictive value to date include: folate and homocysteine, anti müllerian hormone measurement, environmental factors, body mass index, smoking, male age, stress, some subsets of antisperm antibodies and epigenetic features.