CDH2 mutation affecting N-cadherin function causes attention-deficit hyperactivity disorder in humans and mice.

Attention-deficit hyperactivity disorder (ADHD) is a common childhood-onset psychiatric disorder characterized by inattention, impulsivity and hyperactivity. ADHD exhibits substantial heritability, with rare monogenic variants contributing to its pathogenesis. Here we demonstrate familial ADHD caused by a missense mutation in CDH2, which encodes the adhesion protein N-cadherin, known to play a significant role in synaptogenesis; the mutation affects maturation of the protein. In line with the human phenotype, CRISPR/Cas9-mutated knock-in mice harboring the human mutation in the mouse ortholog recapitulated core behavioral features of hyperactivity. Symptoms were modified by methylphenidate, the most commonly prescribed therapeutic for ADHD. The mutated mice exhibited impaired presynaptic vesicle clustering, attenuated evoked transmitter release and decreased spontaneous release. Specific downstream molecular pathways were affected in both the ventral midbrain and prefrontal cortex, with reduced tyrosine hydroxylase expression and dopamine levels. We thus delineate roles for CDH2-related pathways in the pathophysiology of ADHD.

Moringa oleifera and Musa sapientum ameliorated 7,12-Dimethylbenz[a]anthracene-induced upregulations of Ki67 and multidrug resistance 1 genes in rats.

OBJECTIVES: Moringa oleifera (MO) and Musa sapientum (MS) are plants of ethnomedicinal importance. We evaluated the effects of MOF6 (extracted from MO leaves) and MSF1 (extracted from MS suckers) on immunomodulations of Ki67 (proliferation biomarker) and multidrug resistance 1 (MDR1) genes in the liver of rats in 7,12-Dimethylbenz[a]anthracene (DMBA)-induced hepatotoxicity and mutagenesis to determine their antiproliferation, anti-drug resistance, and anticancer potentials. METHODS: Forty-five adult male rats were randomly divided into nine groups (n = 5). Groups 1 and 2 received physiological saline and 15 mg/kg bodyweight of DMBA, respectively. Groups 3 and 4 received 15 mg/kg bodyweight DMBA and were treated with 15 and 30 mg/kg bodyweight of MOF6, respectively. Group 5 received 15 mg/kg bodyweight DMBA and was treated with 10 mg/kg bodyweight of MSF1. Group 6 received 15 mg/kg bodyweight DMBA and was treated with 3.35 mg/kg bodyweight of doxorubicin and intravenous injection of 0.5 ml/200 g of cisplatin. Groups 7-9 received only 15 and 30 mg/kg bodyweight of MOF6 and 10 mg/kg bodyweight of MSF1, respectively. DMBA, doxorubicin, and extracts doses were administered orally. The duration of our experimental procedure was 8 weeks. Consequently, liver histopathology (hematoxylin and eosin technique) and enzyme-linked immunosorbent assay homogenates' concentrations of Ki67 and MDR1 were evaluated. Computed data were statistically analyzed (P ≤ 0.05). RESULTS: Results showed normal histoarchitectures of the liver in all groups. Statistical analyses showed significant (P ≤ 0.05) and non-significant decreased concentrations (P ≥ 0.05) of Ki67 and MDR1 in Groups 3-9 compared with Group 2. Therefore, MOF6 and MSF1 ameliorated DMBA-induced hepatotoxicity, abnormal proliferation, and drug resistance. CONCLUSION: MOF6 and MSF1 possess antiproliferation, anti-drug resistance, and anticancer potentials.

Anticancer effects of Morinda lucida and Annona muricata on immunomodulations of Melatonin, tumor necrosis factor-alpha and p53 concentrations in lead acetate-induced toxicity in rats.

OBJECTIVES: Lead poisoning accounts for about 0.6% of global burden of disease. Lead-induced toxicity is through confinement of oxidative stress in affected organs. We evaluated the effects of MLF1 (extracted from Morinda lucida leaves) and AMF1 (extracted from Annona muricata leaves) on lipid peroxidation and immunomodulations of Melatonin, tumor necrosis factor-alpha (TNF-α), and p53 proteins in lead acetate (LA)-induced toxicity in rats. METHODS: Sixty adult female rats were randomly divided into 12 groups (n = 5). Groups 1 and 2 received physiological saline and 100 mg/kg bodyweight of LA, respectively, for 5 weeks. Groups 3-6 received 100 mg/kg bodyweight LA for 2 weeks, followed by treatments with 7.5 and 15 mg/kg bodyweight of MLF1, and 7.5 and 10 mg/kg bodyweight of AMF1, respectively, for 3 weeks. Groups 7-10 received 7.5 and 15 mg/kg bodyweight of MLF1, 7.5 and 10 mg/kg bodyweight of AMF1, respectively, for 5 weeks. Groups 11-12 received co-administrations of 100 mg/kg bodyweight LA with 15 mg/kg bodyweight MLF1 and 10 mg/kg bodyweight of AMF1, respectively, for 5 weeks. Drugs and extracts were administered orally. Consequently, liver histopathology (Hematoxylin and Eosin), sera Melatonin, and TNF-α (enzyme-linked immunosorbent assay [ELISA]) levels were evaluated. Malondialdehyde (MDA) (thiobarbituric acid assay) and p53 (ELISA) levels were evaluated in liver homogenates. Data were statistically analyzed (P ≤ 0.05). RESULTS: Results showed normal liver histology in all Groups. Statistical analyses showed significant (P ≤ 0.05) and non-significant decreased levels (P ≥ 0.05) of MDA, TNF-α and p53 in Groups 3-12, compared with Group 2. Furthermore, results showed significant (P ≤ 0.05) and non-significant increased Melatonin levels (P ≥ 0.05) in Groups 4-12 compared with Group 2. CONCLUSION: This study confirmed that MLF1 and AMF1 confer a degree of antioxidant, anticancer and hepato-protetive potentials against LA-induced toxicity in rats.

Seroprevalence and risk factors of toxoplasmosis among University of Kirkuk female students.

The study was conducted in the College of Education/Hawija, University of Kirkuk from September 1st, 2018 until the period February 28th, 2019. The first part included determine the prevalence of Toxoplasma gondii, which involved collecting blood from the female students from different stages in the different colleges of the University of Kirkuk, Kirkuk province (northeastern Iraq), ranged ˂20-24 years old. All necessary information was recorded using a questionnaire prepared for this purpose. In the current cross-sectional study, 210 blood specimens were collected from participants. Blood specimens were examined for evaluated the levels of specific anti-toxoplasma IgM and IgG antibodies using the protocol of an enzyme-linked immunosorbent assay (ELISA). The results revealed that the total infection of Toxoplasma gondii antibodies was 9.05% for IgG via 3.33% for IgM with significant difference at p<0.05. According to risk factors, the univariate logistic regression analysis revealed that only increase in domestic cats' owners and directly contact with the soil (gardening in the house) had a corresponding increase with distribution of the infection (p<0.05). Data in the present study revealed that the toxoplasmosis seroprevalence ratio among participants was 12.38%. It was observed that all of the risk factors in the present study had no statistically association with the toxoplasmosis seroprevalence, except cat ownership and house gardening once, where they were showed a highest odd ratio.

Laparoscopic management of a full-thickness uterine niche with subsequent pregnancy outcome.

BACKGROUND: Uterine niche is the consequence of impaired healing of the myometrium following a lower segment transverse caesarean section (CS). Although there is conflicting evidence on the management of these cases, laparoscopic repair is a commonly used surgical treatment modality. OBJECTIVES: To demonstrate the management and laparoscopic repair of the niche with subsequent pregnancy outcome. MATERIALS AND METHODS: We report a case of a 33-year-old patient who had a significant haematoma in the niche. The haematoma resolved after conservative management however, she remained symptomatic. Therefore, she had a laparoscopic repair. The narrated surgical video article demonstrates the dissection of the uterovesical fold overlying the niche, followed by the excision of the scar tissue and its repair with laparoscopic suturing. Ultrasound and magnetic resonance imaging images of the uterus demonstrating the haematoma at the caesarean section site, the niche after resolution of the haematoma and post-repair imaging are also provided. MAIN OUTCOME MEASURES: Repair of the niche, symptomatic relief of abnormal uterine bleeding, spontaneous conception and live birth. Ultrasonographic images also demonstrate uterine wall continuity post laparoscopic repair. RESULTS: The patient recovered uneventfully. Full-thickness of myometrium was demonstrated with post-operative imaging and confirmed at the subsequent caesarean section. Gynaecological symptoms resolved following the repair. The patient conceived spontaneously after surgery and delivered at term by caesarean section without any complications. CONCLUSION: Laparoscopic management of the niche should be considered where there is a complete myometrial defect or significant thinning of the myometrium, especially in symptomatic women who desire future pregnancy.

Novel SBF1 splice-site null mutation broadens the clinical spectrum of Charcot-Marie-Tooth type 4B3 disease.

Four siblings of consanguineous Bedouin kindred presented at infancy with an autosomal recessive syndrome of congenital microcephaly, facial dysmorphism, strabismus, developmental delay and ataxia with positive pyramidal signs. Toward the end of their first decade, they developed areflexia, multiple cranial neuropathies and severe polyneuropathy with progressive muscle weakness, affecting proximal and distal extremities. Physical assessment exhibited kyphoscoliosis, bilateral syndactyly and distal muscle wasting with drop-foot and pes cavus. Magnetic resonance imaging (MRI) showed profound cerebellar atrophy with highly unique findings at the pontine and mesencephalic levels, previously described as "fork and bracket" signs. Genome-wide linkage analysis identified a single ~1.5 Mbp disease-associated locus on chromosome 22q13.33. Whole exome sequencing identified a single novel homozygous deleterious splice-site mutation within this locus in SET binding factor 1 (SBF1). SBF1 missense mutations were shown to underlie Charcot-Marie-Tooth (CMT) type 4B3 disease, a rare autosomal recessive subtype of CMT4. The novel SBF1 null mutation highlights distinct severe phenotypic manifestations, broadening the clinical spectrum of SBF1-related neuropathies: cerebellar and pyramidal signs evident in the first months of life with peripheral polyneuropathy emerging only toward the end of the first decade, together with unique MRI findings.

Ligneous cervicitis and endometritis: A gynaecological presentation of congenital plasminogen deficiency.

BACKGROUND: Congenital plasminogen deficiency is a rare autosomal recessive condition. Plasminogen deficiency is thought to result in an inability of fibrin breakdown and therefore accumulation of fibrin and formation of ligneous changes. Ligneous lesions can form on a number of mucosal membranes including the cervix and endometrium. METHODS: We report the case of a 25-year-old woman with type 1 plasminogen deficiency with ligneous cervicitis and endometritis and her treatment and clinical course over the last few years. We then review the current literature of ligneous cases of the female genital tract and discuss available treatment options. KEY RESULTS: We found 30 reported cases of ligneous lesions affecting the female genital tract, with the cervix being the most affected part. A number of treatment options have been tried by our patient and other cases in the literature. These include use of the combined oral contraceptive pill, fresh frozen plasma infusion, topical plasmin and plasminogen and trial use of plasminogen concentrate. CONCLUSIONS: This is a chronic condition requiring a multidisciplinary approach. There is currently no definitive treatment for the condition, current trials with plasminogen concentrate replacement therapy may provide a promising option for these patients in the future.

The role of rotational thromboelastometry in assessment of haemostasis during pregnancy in women with factor XI deficiency.

INTRODUCTION: Women with factor XI (FXI) deficiency are at an increased risk of bleeding complications at delivery. Obstetric management is complicated by a lack of correlation between FXI level and bleeding risk. AIM: The aims of this study were to assess the difference in rotational thromboelastometry (ROTEM® ) in parturient women with FXI deficiency compared to parturient and non-parturient controls and to evaluate the usefulness of ROTEM® in assessing bleeding risk at delivery in women with FXI deficiency. METHODS: ROTEM® was performed on 60 women: 27 with FXI deficiency, 20 age-matched parturient controls and 12 non-parturient controls. Pregnancy outcomes and haemostatic cover was reviewed in 57 deliveries of women with FXI deficiency. RESULTS: Women with FXI deficiency had a longer clotting time (CT) and clot formation time (CFT) (P < 0.001), reduced alpha angle (P < 0.001) but no difference in MCF (P = 0.054) compared to parturient controls. Compared to non-parturient controls, they had a longer CT (P < 0.001), but shorter CFT (P < 0.001), increased alpha angle (P < 0.001) and increased MCF (P = 0.005). ROTEM® was an additional helpful parameter in managing parturient women with FXI deficiency, reducing the need for factor administration. CONCLUSION: ROTEM® demonstrated hypercoagulable changes during pregnancy in women with FXI deficiency. However, they took longer to clot compared to parturient controls, but had increased clot consolidation and clot strength compared to non-parturient controls. ROTEM® is an additional test that is helpful to assess bleeding risk and provision of appropriate haemostatic cover at delivery.

Mode of delivery and cranial bleeding in newborns with haemophilia: a systematic review and meta-analysis of the literature.

OBJECTIVES: Cranial bleeding at birth can result in significant neurological morbidity in newborns with haemophilia. The optimum mode of delivery (MOD) of a potentially affected foetus remains controversial. AIM: The aim of this review is to ascertain overall incidence of cranial bleeding in newborns with haemophilia compared to the general population and the impact of MOD on rates of intracranial haemorrhage (ICH). METHOD: An EMBASE/MEDLINE search using key terms revealed the relevant studies. Studies included report the incidence of cranial bleeding by MOD within a newborn population. The heterogenicity across studies was assessed using Cochrane's Q test and I(2) statistic and studies were assigned appropriate weight based on a fixed-effect model. Odds ratio (OR) is the primary effect measure. RESULTS: Newborns with haemophilia are 44 times (95% CI: 34.7-57.1, P < 0.01) more likely to experience symptomatic ICH, and 8 times (95% CI: 5.38-12.6, P < 0.01) more likely to experience extracranial haemorrhage at birth, compared to the general population. In newborns with haemophilia the OR of experiencing ICH are 4.4 (95% CI: 1.46-13.7, P = 0.008) following an assisted vaginal delivery (AVD) and 0.34 (95% CI: 0.14-0.83, P = 0.018) following caesarean section (CS), compared to vaginal delivery. CONCLUSION: Cranial bleeding occurs with a significantly higher frequency in newborns with haemophilia compared to the general population. In newborns with haemophilia, delivery by a CS is associated with the lowest risk of ICH. AVD significantly increases the risk of ICH and should be avoided.

Changes in factor XIII level during pregnancy.

Pregnancy is associated with significant haemostatic changes, with a progressive rise in most clotting factors. There is limited data on the changes of factor XIII (FXIII) level during pregnancy. This study assesses changes in FXIII activity during normal pregnancy and establish FXIII reference range during each trimester of pregnancy and immediate postnatal period. This is a cross sectional study of 376 women with normal uneventful pregnancies. Plasma FXIII activity was measured during first (weeks 0-12, n = 116), second (weeks 13-28, n = 132), third trimester (weeks 29-42, n = 128) and postnatal (day 0-3; n = 30). Samples were also collected from non-pregnant women (n = 25) as a control group. FXIII was assayed on CS-5100 analyser using chromogenic reagent. The mean ± SD FXIII activity was 112 ± 29 IU dL(-1) during first trimester, 96 ± 26 IU dL(-1) during second trimester, 83 ± 21 IU dL(-1) during third trimester, 90 ± 19 IU dL(-1) during postnatal period, and 113 ± 26 IU dL(-1) in the control. The reference range was calculated during the first (55-169 IU dL(-1)), second (45-147 IU dL(-1)), third trimester (42-125 IU dL(-1)) and postnatal period (61-137 IU dL(-1)). There was a significant reduction in the mean FXIII activity during the second and third trimester compared to the first trimester and control group (P < 0.0001). During the immediate postnatal period, the mean FXIII activity was not statistically different compared to the third and second trimester levels but was significantly lower compared to the first trimester (P < 0.0001) level and the control group (P = 0.0002). This study establishes the reference range for FXIII activity during the three trimesters of normal pregnancy and immediate postnatal period. Women have a significantly decreased level of FXIII activity during a normal uneventful pregnancy.

Pregnancy complications and obstetric care in women with inherited bleeding disorders.

Women with inherited bleeding disorders (IBD) require the input of a multidisciplinary team to improve outcomes of pregnancy. The role of the haemophilia nurse within the multidisciplinary team is to provide educational and emotional support to the women and to facilitate and co-ordinate patient-centred care. Prenatal diagnosis in cases of haemophilia is an integral part of the management of early pregnancy with a recent drive towards non-invasive prenatal diagnostic techniques. There is a current lack of data on the risk of miscarriage and bleeding complications during pregnancy. A clear association has only been established in women with fibrinogen and factor XIII deficiency. In the affected neonate with severe bleeding disorders such as haemophilia, the risk of head bleeding is significant, and appropriate management of labour and delivery has an important impact on reducing the risk. Women with IBD are at risk of both primary and secondary postpartum haemorrhage. Appropriate risk assessment and advance planning for haemostatic cover can reduce the bleeding risk.

Congenital factor XIII deficiency in women: a systematic review of literature.

Factor XIII (FXIII) deficiency is a rare congenital bleeding disorder. There is a paucity of data in the literature about obstetrics and gynaecological problems in women affected by FXIII deficiency. The aim of this study was to examine gynaecological problems and obstetric complications and outcome in women with congenital FXIII deficiency. An electronic search was performed to identify the published literature on PUBMED, MEDLINE, EMBASE, Journals @OVID and CINAHL Plus databases using the following keywords: 'congenital factor XIII deficiency' AND 'women OR Pregnancy'. A total of 39 relevant articles were found and included in this systematic review; 27 case reports and 12 case series dating from 1964 to 2012. A total of 121 women were identified. Menorrhagia (26%) was the second most common bleeding reported after umbilical bleeding. Ovulation bleeding reported in 8% of women. Among 63 women, 192 pregnancies were reported; of these, 127 (66%) resulted in a miscarriage and 65 (34%) reached viability stage. In 136 pregnancies without prophylactic therapy, 124 (91%) resulted in a miscarriage and 12(9%) progressed to viability stage. Antepartum haemorrhage occurred in 5/65 (8%) pregnancies reaching viability stage while postpartum haemorrhage (PPH) seen in 16 (25%) cases. Women with congenital FXIII deficiency suffer significant bleeding complications. Menorrhagia and ovulation bleeding are common gynaecological problems and more prevalent than reported. Pregnancies in women with FXIII deficiency have a significant risk of miscarriage, placental abruption and PPH if not on prophylaxis treatment.

Hemostatic disorders in women.

The past few decades have seen major advances in multidisciplinary obstetric care and management of gynecological conditions in women with bleeding disorders. Awareness of the impact of bleeding disorders has improved among the obstetric and gynecological community. Undiagnosed bleeding disorders can be the underlying cause for a significant proportion of women with heavy menstrual bleeding. They may also be the cause or a contributory factor for other gynecological problems, such as dysmenorrhea, intermenstrual bleeding, and endometriosis. Hemostatic assessment should be considered in women referred for menstrual abnormalities if they have a positive bleeding history as quantified by bleeding assessment tools. The reproductive choices and options for prenatal diagnosis are also expanding for families with hemophilia with a drive toward achieving a non-invasive approach. Current non-invasive prenatal diagnostic techniques are limited to identification of fetal gender. Research is ongoing to overcome the specific diagnostic challenges of identifying hemophilia mutations, utilizing free fetal DNA circulating in maternal plasma. The management of obstetric hemorrhage has recently evolved to include a greater focus on the identification of and early treatment for coagulation disorders. Deficiencies in certain hemostatic variables are associated with progression to more severe bleeding; therefore, specific interventions have been proposed to target this. Evidence is still lacking to support such strategy, and future research is required to assess the efficacy and the safety of these hemostatic interventions in women with persistent PPH.

The effect of labour on the coagulation system in the term neonate.

The coagulation system of the foetus is markedly different from that of adults. To assess the influence of maternal age, mode of delivery and intrapartum events, and foetal gender and weight on the foetal coagulation system. Cord blood was collected from 154 healthy pregnant women, with gestational age 37 - 42 weeks at birth. Mann-Whitney test was used for analysis of binary data and continuous variables were analysed using Pearson's correlation coefficient. Mean cord blood levels of FVIII:C, VWF:Ag, VWF:CB, FIX, FXI, FXII and plasminogen were significantly higher in babies delivered after labour, compared to those delivered after an elective caesarean. Mean cord blood levels of FII (P = 0.003), FV (P = 0.009), FVII (P = 0.0004) and FX (P = 0.0009) were significantly lower in the babies with meconium stained liquor in labour, compared with those with clear liquor. Augmentation with oxytocin, instrumental delivery, did not affect any of the factor levels and duration of labour did not have an effect on the level of coagulation proteins in cord blood. This study provides valuable information about effect of labour on the coagulation system of the foetus. It is concluded that, in cord blood, the results of coagulation parameters in the newborn baby should be considered in light of mode of delivery and events of labour.

A systematic review: The use of desmopressin for treatment and prophylaxis of bleeding disorders in pregnancy.

Desmopressin (DDAVP) is commonly used for treatment and prevention of bleeding complications in patients with bleeding disorders including haemophilia A, von Willebrand's disease (VWD) and other less common disorders. This article reviews the current evidence for the use of DDAVP in pregnancy to clarify its efficacy and safety with regard to maternal and foetal outcome. A search of the literature found 30 studies that reported DDAVP use in pregnancy for prophylaxis or treatment of bleeding complications with 216 pregnancies reported in total. The most common indication was prophylaxis for prevention of bleeding during pregnancy and postpartum haemorrhage. DDAVP was used successfully in the first and early second trimester for bleeding prophylaxis in 50 pregnancies. No postpartum bleeding complications were reported in 167 out of 172 pregnancies when DDAVP was used for peripartum haemostatic cover. Twenty-nine studies reported no significant adverse events as a result of treatment with DDAVP. One case of water intoxication seizure and one case of premature labour following the use of DDAVP was reported in a single study. Other maternal side effects included facial flushing and headache and were reported by one study. These side effects were generally well tolerated by patients. There were no other significant adverse events reported in any of the studies as a result of DDAVP use. Foetal outcome was recorded in ten studies with no adverse foetal outcomes. In conclusion, this review shows that DDAVP in selected cases is effective in reducing bleeding complications associated with pregnancy and childbirth with a good safety record. Further research is needed to confirm these findings as they are based on the currently available evidence from small studies and case series only.