Fingerprinting Breast Milk; insights into Milk Exosomics.

Breast milk, often referred to as "liquid gold," is a complex biofluid that provides essential nutrients, immune factors, and developmental cues for newborns. Recent advancements in the field of exosome research have shed light on the critical role of exosomes in breast milk. Exosomes are nanosized vesicles that carry bioactive molecules, including proteins, lipids, nucleic acids, and miRNAs. These tiny messengers play a vital role in intercellular communication and are now being recognized as key players in infant health and development. This paper explores the emerging field of milk exosomics, emphasizing the potential of exosome fingerprinting to uncover valuable insights into the composition and function of breast milk. By deciphering the exosomal cargo, we can gain a deeper understanding of how breast milk influences neonatal health and may even pave the way for personalized nutrition strategies.

Investigation of Genetic Association Between a High Activity Variant of Cathepsin G and Risk for Basal Cell Carcinoma.

BACKGROUND/AIM: Cathepsin G (CTSG) has been identified as an inhibitor of breast, bladder, and colorectal cancers. The G allele of the N125S (A/G, rs45567233) functional polymorphism of the CTSG gene confers increased serum CTSG activity and has been associated with cardiovascular and neurovascular diseases. This study examined the possible correlation between the pathogenesis of basal cell carcinoma (BCC) and the functional polymorphism CTSG N125S. PATIENTS AND METHODS: A total of 197 DNA samples were examined, comprising 98 BCC patients and 99 control samples of Greek origin. The CTSG N125S polymorphism was molecularly genotyped using PCR amplification, followed by enzyme digestion, and agarose gel electrophoresis of the amplified DNA fragments. RESULTS: There was no statistically significant difference in the genotypic and allelic frequencies between the patient and the control groups. CONCLUSION: There is no association between the CTSG N125S polymorphism and pathogenesis of BCC.

Prevention and Treatment of Oral Mucositis in Pediatric Patients: Systematic Review and Meta-Analysis of Randomized Controlled Trials.

BACKGROUND/AIM: Oral mucositis (OM) is a common and serious side effect of cancer treatment. The incidence of chemotherapy-induced OM in pediatric patients can reach up to 91.5% and has a major impact on patients' quality of life. The aim of the study was to assess the efficacy of current interventions and agents for the management of OM in children undergoing chemo/radiotherapy or hematopoietic stem cell transplantation (HSCT). MATERIALS AND METHODS: A systematic search of randomized controlled trials (RCTs) was conducted in the MEDLINE and Scopus databases from January 2000 until March 2023. Thirty-four randomized studies meeting the inclusion criteria were identified and five RCTs investigating the efficacy of Low Level Laser Therapy (LLLT) intervention or the agent honey were included in the meta-analysis. RESULTS: The meta-analysis of two RCTs indicated that topical application of honey on oral mucosa was effective in shortening the mean duration of hospital stay in children with severe OM (MD=-4.33, p=0.002). However, LLLT was not found to be effective for the prevention or treatment of OM grade ≥II (RR=0.99, p=0.99). Moreover, the therapeutic application of LLLT did not show significant benefit for lower risk of OM grade ≥II (RR=0.48, p=0.58). CONCLUSION: Various interventions and agents were examined in the present study for the management of OM. Honey could be a promising candidate for the treatment of OM in pediatric patients. Further high-quality RCTs are required to enhance our findings.

EGFR and HER-2 oncogenes expression in an experimental model of two-stage chemically induced carcinogenesis in mouse skin.

The aim of the study was to investigate the expression of EGFR and HER-2 oncogenes using an experimental two stage chemically induced carcinogenesis protocol on the dorsal skin in FVB/N mice. Forty female FVB/N mice 4 weeks old, were grouped into one control (n = 8) and two experimental groups (Group A: n = 16, Group B: n = 16) following a randomization process. Two-stage carcinogenesis protocol, was implicated, including an initial treatment with 97.4 nmol DMBA on their shaved dorsal skin and subsequent treatments of 32.4 nmol TPA applications after 13 weeks for Group A and after 20 weeks for Group B. The control group C, received no treatment. Skin was examined weekly for tumor development. Post-experiment, animals were euthanized for tissue analysis. The histological status of the skin lesions in the experimental groups corresponded well with tumour advancement (from dysplasia to poorly-differentiated carcinoma). Tumour sections were evaluated histologically and immunohistochemically. EGFR expression was found significantly higher in precancerous and malignant tumours (p = 042 and p = 008 respectively), while tended to be higher in benign tumours (p = 079), compared to normal histology. Moreover, mean percentage of EGFR positive expression in malignant tumours was significantly higher than in benign tumours (p < 001). HER-2 expression was found significantly higher in precancerous and malignant tumours (p = 042 and p = 015 respectively), while tended to be higher in benign tumours (p = 085), compared to normal histology. Furthermore, mean percentage of HER-2 positive expression in malignant tumours was significantly higher than in benign tumours (p = 005). The study demonstrated that in FVB/N mice subjected to a two-stage chemically induced carcinogenesis protocol, there was a significant increase in the expression of EGFR and HER-2 oncogenes in precancerous and malignant skin lesions compared to normal tissue. This suggests a potentially early role of these oncogenes in the progression of skin tumours in this model.

Genetic Variations Related to Angiotensin II Production and Risk for Basal Cell Carcinoma.

Basal cell carcinoma (BCC) is the most prevalent human neoplasm, with constantly increasing annual incidence. Despite its slow growth, BCC is locally invasive and, if left untreated, can cause severe complications, including metastasis and death. The renin-angiotensin system (RAS) plays a key role in electrolyte balance, atrial pressure, tissue development, homeostasis, and inflammation, but also in cancer development. After binding to its type 1 receptor (AT1R), angiotensin II (ANGII), the system's principal hormonal effector, regulates cancer pathways spanning from the formation of the initial cancer cell to the construction and nutrition of the tumor microenvironment, angiogenesis, proliferation, and metastasis. Although the role of RAS in the development of skin pathologies has not been widely researched, RAS-targeting antihypertensive medications have been shown to have a chemoprotective effect against BCC. Based on those findings, our group conducted a series of genetic association studies to investigate the association between common functional variations in key genes related to ANGII production (AGT, ACE, ACE2, AT1R, AT2R, and CMA1) and the risk of BCC occurrence. This review provides a summary of the current understanding of the ANGII involvement in BCC development. The reliable and easily assessed pool of genetic biomarkers may be used for predictive testing and prevention purposes in high-risk individuals.

Review of Disease-Specific microRNAs by Strategically Bridging Genetics and Epigenetics in Oral Squamous Cell Carcinoma.

Oral squamous cell carcinoma (OSCC) is one of the most prevalent human malignancies and a global health concern with a poor prognosis despite some therapeutic advances, highlighting the need for a better understanding of its molecular etiology. The genomic landscape of OSCC is well-established and recent research has focused on miRNAs, which regulate gene expression and may be useful non-invasive biomarkers or therapeutic targets. A plethora of findings regarding miRNA expression have been generated, posing challenges for the interpretation and identification of disease-specific molecules. Hence, we opted to identify the most important regulatory miRNAs by bridging genetics and epigenetics, focusing on the key genes implicated in OSCC development. Based on published reports, we have developed custom panels of fifteen major oncogenes and five major tumor suppressor genes. Following a miRNA/target gene interaction analysis and a comprehensive study of the literature, we selected the miRNA molecules which target the majority of these panels that have been reported to be downregulated or upregulated in OSCC, respectively. As a result, miR-34a-5p, miR-155-5p, miR-124-3p, miR-1-3p, and miR-16-5p appeared to be the most OSCC-specific. Their expression patterns, verified targets, and the signaling pathways affected by their dysregulation in OSCC are thoroughly discussed.

Angiotensinogen, Angiotensin-Converting Enzyme, and Chymase Gene Polymorphisms as Biomarkers for Basal Cell Carcinoma Susceptibility.

INTRODUCTION: The intake of angiotensin-converting enzyme (ACE) inhibitors and specific antagonists of angiotensin II receptors, widely used as antihypertensive drugs, significantly reduces the risk of developing basal cell carcinoma (BCC), highlighting the possible tumorigenic role of angiotensin II (AngII). We present here the investigated genetic association between the development of BCC and functional DNA polymorphisms M235T, I/D, and A1903G in the genes of angiotensinogen (AGT), angiotensin-converting enzyme (ACE), and chymase (CMA1), which mediate AngII production levels. METHODS: DNA samples of 203 unrelated Greeks were studied, including 100 patients with BCC and 103 matched healthy controls. RESULTS: The MT genotype of the AGT-M235T polymorphism was significantly more prevalent in the patient group (78.0%) versus the healthy control group (28.3%; p < 0.001). The DD genotype of the ACE-I/D polymorphism was also increased in BCC patients (72.8%) compared to controls (46.2%; p = 0.001). The heterozygous AG genotype of CMA1-A1903G was significantly more frequent in the BCC group (86%) than in the healthy controls (50.5%; p < 0.001). CONCLUSIONS: The MT, DD, and AG genotypes of the AGT- M235T, ACE-I/D, and CMA1-A1903G polymorphisms, respectively, were significantly increased in frequency within the group of cancer patients compared to the healthy controls. All three genotypes correspond to increased enzyme levels or activity and result in increased levels of AngII; therefore, they may be potentially utilized as reliable biomarkers associated with an individual's increased risk for BCC development.

Clinical and Molecular Genetic Analysis of Cases with Ectodermal Dysplasia.

INTRODUCTION: Ectodermal dysplasias are a group of >200 clinically and congenitally heterogeneous disorders characterized by abnormal development in the ectodermal structures, such as hair, nails, teeth, and sweat glands. We report here the clinical and molecular genetic analysis of five Greek families with different types of ectodermal dysplasia (ED). SUBJECTS: The study involved 15 individuals from 5 Greek families that included 8 ED patients, 5 carriers of recessive X-linked or autosomal ED, and 2 healthy relatives. After genetic counseling, the parents signed an informed consent form before subsequent genetic testing. METHODS: Genomic DNA was isolated from white blood cells of all studied individuals. The search for mutations was realized in patients' DNA samples using next-generation sequencing (NGS) gene panel, whole exome sequencing (WES), chromosomal microarray analysis (CMA), and multiplex ligation-dependent probe amplification (MLPA) technique. RESULTS: The clinical diagnosis of common X-linked recessive hypohidrotic ectodermal dysplasia (HED) was suspected in five male patients with partial anodontia of baby and permanent teeth, hypohidrosis, and thin hair from three families. All HED patients were hemizygous for deletions in the EDA1 gene (Xq13.1): three related patients had a 20 bp deletion, one had a 19 bp deletion, and one had a 180 bp deletion. A female patient had the rare autosomal dominant syndrome of ankyloblepharon-ectodermal dysplasia-cleft lip/palate (AEC) caused by heterozygous missense mutation in the TP63 gene (3q28) that appeared de novo. Two siblings with hypotrichosis and hypodontia, a female and a male, had two pathogenic mutations in compound heterozygosity in the TSPEAR gene (21q22.3); therefore they presented with ectodermal dysplasia type 14 (ECTD14). CONCLUSION: Clinical and molecular genetic analysis may set an accurate diagnosis of different types of ED. In the reported families, genetic diagnosis and genetic counselling assisted the parents to view their children's condition realistically and to cooperate with the specialists who will contribute to the best possible treatment for their children.

The Impact of Genetic Variability of TGF-Beta Signaling Biomarkers in Major Craniofacial Syndromes.

Craniofacial development is a complex process involving several signaling pathways, including the one regulated by the TGF-beta (TGF-ß) superfamily of growth factors. Isoforms of TGF-ß play a vital part in embryonic development, notably in craniofacial patterning. Consequently, pathogenic variants in their coding genes may result in a variety of orofacial and craniofacial malformations. Here, we review the impact of genetic variability of TGF-ß signaling biomarkers in major disorders, including palatal and lip clefts, dental anomalies, and craniofacial syndromes, such as the Loeys-Dietz syndrome (LDS) and Camurati-Engelmann disease. Cleft lip and cleft palate are associated with missense mutations in the TGFB1 and TGFB3 genes, while mutations in the LTBP3 gene encoding TGF-ß binding protein 3 may cause selective tooth agenesis. Oligodontia may also be caused by TGFB1-inactivating mutations and/or by variations in the GREM2 gene, which disrupt the activity of gremlin 2, a TGF-ß/bone morphogenetic protein (BMP4) signaling antagonist. CED may be caused by mutations in the TGFB1 gene, while the TGF-ß-related genetic background of LDS consists mostly of TGFBR1 and TGFBR2 mutations, which may also impact the above syndromes' vascular manifestations. The potential utility of the TGF-ß signaling pathway factors as biomarkers that correlate genetics with clinical outcome of craniofacial malformations is discussed.

Molecular Modeling Analysis Provides Genotype-Phenotype Correlation Insights in a Patient with Ankyloblepharon-Ectodermal Dysplasia-Clefting Syndrome.

Ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome is a rare autosomal dominant disorder. AEC is caused by mutations in the TP63 gene that encodes the tumor suppressor p63 protein, itself involved in the regulation of epidermal proliferation, development, and differentiation. We present here a typical AEC case of a four-year-old girl with extensive skin erosions and erythroderma of the scalp and the trunk, and to a lesser extent of the limbs, nail dystrophy on the fingers and toes, xerophthalmia, a high-arched palate, oligodontia, and hypohidrosis. Mutation analysis of the TP63 gene detected a de novo missense mutation in exon 14 (c.1799G>T; p.Gly600Val). We discuss the phenotype-genotype correlation by presenting the clinical features of AEC in the patient, and the effect of the detected mutation in p63 structure and function using protein structural modeling, in view of similar cases in the literature. We performed a molecular modeling study in order to link the effect on the protein structure level of the missense mutation G600V. We noted that the introduction of the bulkier Valine residue in place of the slim Glycine residue caused a significantly altered 3D conformational arrangement of that protein region, pushing away the adjacent antiparallel α helix. We propose that the introduced locally altered structure of the G600V mutant p63 has a significant functional effect on specific protein-protein interactions, thus affecting the clinical phenotype.

A novel deletion of exon 4 in the Ectodysplasin A gene associated with X-linked hypohidrotic ectodermal dysplasia.

OBJECTIVE: Identify the disease-causing mutation in a patient with features of X-linked hypohidrotic ectodermal dysplasia, which is a genetic disorder characterized by hypodontia, hypohidrosis and hypotrichosis. It is caused by mutations in Ectodysplasin A gene, which encodes ectodysplasin A, a member of the tumor necrosis factor superfamily. DESIGN: Genetic analysis, was performed using chromosomal microarray analysis, whole exome sequencing and multiplex ligation-dependent probe amplification analysis in a 4-year-old boy with hypohidrotic ectodermal dysplasia features. Moreover, the boy's parents were tested for clinically significant findings identified in order to elucidate the pattern of inheritance of the finding detected in the proband. RESULTS: A novel deletion of entire exon 4 in Ectodysplasin A gene identified in the 4-year-old patient. This deletion was found in heterozygous state in the mother of the proband and was not detected in his father. RNA analysis revealed an in-frame deletion r.527_706del, p.(176_236del) in exon 4 of the Ectodysplasin A gene. CONCLUSION: We identified a novel gross deletion in the Ectodysplasin A gene in a male patient with X-linked hypohidrotic ectodermal dysplasia. Clinical and molecular genetic analysis are crucial to set an accurate diagnosis in patients with hypohidrotic ectodermal dysplasia. These results highlight the importance of the collagen domain of Ectodysplasin A, encoded by exon 4, for its function in vivo.

Molecular Mechanisms Involved in Craniosynostosis.

Craniosynostosis refers to the early fusion of one or many cranial sutures, causing craniofacial abnormalities observed in 1:2,500 births worldwide. In most cases (85%), craniosynostosis is presented as sporadic anomaly (non-syndromic craniosynostosis), while in other cases (15%) as part of syndromes (syndromic craniosynostosis). Patients with syndromic disorder usually have more severe symptoms compared to those with single suture synostosis. Most common syndromes of craniosynostosis include Pfeiffer, Apert, Crouzon, Jackson-Weiss, Muenke and Boston type MSX2-related syndrome. The main gene mutations in craniosynostosis involve FGFR1, FGFR2, FGFR3, TWIST1 and MSX2, which encode key factors influencing cranial bone morphogenesis. The main therapeutic approaches are surgical as discussed in this review, and the type of therapy depends on the graveness of the incident.

Association Between a High Gene Expression Variant of Chymase and Increased Risk for Basal Cell Carcinoma.

BACKGROUND/AIM: Previous studies have associated certain variations in genes encoding factors of renin-angiotensin system (RAS), indirectly leading to higher angiotensin II (AngII) levels, with greater risk for basal cell carcinoma (BCC) development. Chymase (CMA1) is the main regulator of the RAS-independent AngII generation pathway and numerous studies have shown its oncogenic potential in several cancer types including BCC. In this study, we investigated the possible association between BCC pathogenesis and the functional DNA polymorphism A1903G (rs1800875) that affects expression of the CMA1 gene. PATIENTS AND METHODS: We genotyped 199 DNA samples, isolated from 100 BCC patients and 99 age, sex, and ethnicity-matched healthy controls for the CMA1 A1903G polymorphism. Genotyping was performed with PCR amplification, followed by MboI enzyme digestion and agarose gel electrophoresis of the resulted DNA fragments. RESULTS: The variant G allele that possibly increases CMA1 gene expression was not detected at a significantly different frequency between the groups of BCC patients and healthy controls. However, the AG heterozygous genotype was significantly increased in BCC patients compared with controls (p<0.001). CONCLUSION: The high expression CMA1 G allele carriers have an increased risk for BCC and elevated levels of chymase in the skin may have a carcinogenic effect.

Exosomes and exosomal non-coding RNAs throughout human gestation (Review).

In recent years, research on exosomes and their content has been intensive, which has revealed their important role in cell-to-cell communication, and has implicated exosomal biomolecules in a broad spectrum of physiological processes, as well as in the pathogenesis of various diseases. Pregnancy and its normal progression rely highly on the efficient communication between the mother and the fetus, mainly mediated by the placenta. Recent studies have established the placenta as an important source of circulating exosomes and have demonstrated that exosome release into the maternal circulation gradually increases during pregnancy, starting from six weeks of gestation. This orchestrates maternal-fetal crosstalk, including maternal immune tolerance and pregnancy-associated metabolic adaptations. Furthermore, an increased number of secreted exosomes, along with altered patterns of exosomal non-coding RNAs (ncRNAs), especially microRNAs and long non-coding RNAs (lncRNAs), have been observed in a number of pregnancy complications, such as gestational diabetes mellitus and preeclampsia. The early detection of exosomes and specific exosomal ncRNAs in various biological fluids during pregnancy highlights them as promising candidate biomarkers for the diagnosis, prognosis and treatment of numerous pregnancy disorders in adolescents and adults. The present review aimed to provide insight into the current knowledge regarding the potential, only partially elucidated, role of exosomes and exosomal cargo in the regulation and progression of normal pregnancy, as well as their potential dysregulation and contribution to pathological pregnancy situations.

The Impact of ACE and ACE2 Gene Polymorphisms in Pulmonary Diseases Including COVID-19.

Chronic and acute respiratory diseases pose a major problem for public health worldwide due to the high morbidity and mortality rates, while treatment options remain mostly symptomatic. The renin-angiotensin system (RAS) plays an important role in lung tissue, regulating pulmonary circulation and blood pressure, but also contributing to normal pulmonary function and development. Angiotensin-converting enzyme (ACE) and its homologous angiotensin-converting enzyme 2 (ACE2) are considered to be amongst the main RAS regulators and are highly expressed in the pulmonary vascular endothelium. This review discusses the impact of ACE and ACE2 functional gene polymorphisms on seven major pulmonary diseases, in terms of predisposition, course, and outcome, revealing their potential utility as both genetic markers and biomarkers. The discussed conditions include chronic obstructive pulmonary disease (COPD), pulmonary hypertension (PH), asthma, acute lung injury (ALI), acute respiratory distress syndrome (ARDS), lung cancer and pulmonary sarcoidosis (PS), as well as SARS-CoV-2 viral infection and COVID-19 disease.

Impact of combined mycoplasmataceae and HPV co-infection on females with cervical intraepithelial neoplasia and carcinoma.

PURPOSE: The concurrent prevalence investigation of human papillomavirus (HPV), Mycoplasma hominis (Mh) and Ureaplasma urealyticum (Uu) in women in order to estimate the association of co-infection with cervical lesions. METHODS: The study cohort comprised 120 women with no cervical lesions (control group) and 62 women with abnormal cytological findings from the cervix (cervical intraepithelial lesion/neoplasia) as study group. A combination of molecular analyses was implemented. RESULTS: The presence of HPV infection was shown in 52/62 (83.9%) of women with abnormal cytology. Women with cervix cytological findings were shown to have 17.6 times higher risk for Mh and Uu co-infection (p=0.001). HPV and Uu co-infection were detected with a higher prevalence among women with CIN 3 and invasive cancer. CONCLUSION: These findings are consistent with the notion that microbial co-infections may play an important role in persistent inflammation and progression of cervical lesions.

Lack of Association Between the ACE2 G8790A Gene Variation and Risk for Basal Cell Carcinoma.

BACKGROUND/AIM: The G8790A (rs2285666) functional polymorphism of the angiotensin-converting enzyme 2 (ACE2) gene influences alternative mRNA splicing and quantitatively affects the enzyme's production. Specifically, the presence of the A allele has been associated with higher ACE2 plasma levels. In this study, we investigated the possible association of the functional polymorphism ACE2-G8790A with the pathogenesis of basal cell carcinoma (BCC). PATIENTS AND METHODS: A total of 190 DNA samples were studied, including 91 BCC patients and 99 controls of Greek origin. Molecular genotyping for the ACE2 G8790A polymorphism was carried out by PCR amplification, followed by AluI enzyme digestion and agarose gel electrophoresis of the DNA fragments. RESULTS: The allelic and genotypic frequencies presented no statistical difference between the patient and the control group. CONCLUSION: There is no association between the ACE2 G8790A polymorphism and pathogenesis of BCC.

The Potential Role of Exosomes in Child and Adolescent Obesity.

Child and adolescent obesity constitute one of the greatest contemporary public health menaces. The enduring disproportion between calorie intake and energy consumption, determined by a complex interaction of genetic, epigenetic, and environmental factors, finally leads to the development of overweight and obesity. Child and adolescent overweight/obesity promotes smoldering systemic inflammation ("para-inflammation") and increases the likelihood of later metabolic and cardiovascular complications, including metabolic syndrome and its components, which progressively deteriorate during adulthood. Exosomes are endosome-derived extracellular vesicles that are secreted by a variety of cells, are naturally taken-up by target cells, and may be involved in many physiological and pathological processes. Over the last decade, intensive research has been conducted regarding the special role of exosomes and the non-coding (nc) RNAs they contain (primarily micro (mi) RNAs, long (l) non-coding RNAs, messenger (m) RNAs and other molecules) in inter-cellular communications. Through their action as communication mediators, exosomes may contribute to the pathogenesis of obesity and associated disorders. There is increasing evidence that exosomal miRNAs and lncRNAs are involved in pivotal processes of adipocyte biology and that, possibly, play important roles in gene regulation linked to human obesity. This review aims to improve our understanding of the roles of exosomes and their cargo in the development of obesity and related metabolic and inflammatory disorders. We examined their potential roles in adipose tissue physiology and reviewed the scarce data regarding the altered patterns of circulating miRNAs and lncRNAs observed in obese children and adolescents, compared them to the equivalent, more abundant existing findings of adult studies, and speculated on their proposed mechanisms of action. Exosomal miRNAs and lncRNAs could be applied as cardiometabolic risk biomarkers, useful in the early diagnosis and prevention of obesity. Furthermore, the targeting of crucial circulating exosomal cargo to tissues involved in the pathogenesis and maintenance of obesity could provide a novel therapeutic approach to this devastating and management-resistant pandemic.

Increased Incidence of Stress-related Tic Habit Cough in Children During the Recent Greek Financial Crisis.

BACKGROUND/AIM: Tic habit cough (THC) is not easily recognized and requires a high index of suspicion. Since there is evidence for stress-related etiology, the study presents our experience during the eight-year period of the recent Greek financial crisis. PATIENTS AND METHODS: This is a descriptive prospective cross-sectional clinical study using a consistent approach to diagnosis, possible triggers and treatment options. RESULTS: Fifty-one children (26 girls, age 9.5±3.1y) from a total of 3,793 new referrals for chronic cough fulfilled the criteria of THC (1.34%). Incidence rates per 1,000 person-years were 1.34 (95%CI=0.34-5.40), 3.91 (95%CI=1.86-8.19), 4.03 (95%CI=2.01-8.06) and 14.60 (95%CI=10.43-20.44) for every two years. Poisson analysis showed an increased trend during the four time periods with an incidence rate ratio equal to 2.21 (95%CI=1.58-3.09, p<0.001). THC was mainly attributed to learning difficulties, as well as stress-related impact of peer or family bullying, family financial problems and child anxiety disorders. CONCLUSION: The incidence of THC is associated with the negative aspects of stressors during a period of financial crisis. The potential underlining psycho-physiological mechanisms are discussed as well as the fact that prompt diagnosis may result in successful interventions.

The Angiotensin-converting Enzyme Insertion/Deletion Polymorphism as a Common Risk Factor for Major Pregnancy Complications.

Idiopathic pregnancy complications pose a major threat to both maternal and fetal health worldwide. Numerous studies have implicated the role of the renin-angiotensin system (RAS) in the development of obstetric syndromes, since it is crucial for the uteroplacental function. A major RAS component is the angiotensin-converting enzyme (ACE), which hydrolyses angiotensin I to angiotensin II, and not only regulates arterial pressure, but also fibrinolytic activity, indirectly, through the expression of plasminogen activator inhibitor-1. A key functional polymorphism of the ACE gene is the insertion/deletion (I/D) polymorphism, which affects gene expression and product levels, and can therefore lead to high blood pressure and/or reduced fibrinolytic activity. These can cause major pregnancy complications, such as preeclampsia, recurrent pregnancy loss and preterm birth. This review discusses how the ACE I/D is associated with susceptibility towards pregnancy complications, on its own or in combination with other functional gene polymorphisms such, as the angiotensin II receptor type 1 (AT1R) A1166CC, angiotensin II receptor type 2 (AT2R) G1332A, plasminogen activator inhibitor-1 (PAI-1) 4G/5G, matrix metallopeptidase-9 (MMP-9) C1562T, angiotensinogen (AGT) M235T, renin (REN) 83A/G, factor XIII (F13) Val34Leu and endothelial nitric oxide synthase (eNOS) 4a/b.