Effect of high frequency repetitive transcranial magnetic stimulation (rTMS) on the balance and the white matter integrity in patients with relapsing-remitting multiple sclerosis: A long-term follow-up study.

OBJECTIVES: Repetitive Transcranial Magnetic Stimulation (rTMS) is considered as a safe and non-invasive developing technique used as a therapeutic method for patients with Relapsing-Remitting Multiple Sclerosis (RRMS) who suffer from disturbances in gait and balance. The aim of our study is to evaluate the long-term effect of high frequency rTMS as a therapeutic option for truncal ataxia in RRMS patients and to assess its impact on the integrity of the white matter (WMI), measured in the form of anisotropy metrics using diffusion tensor imaging (DTI). METHODS: The study was conducted in two phases: phase I; a randomized, single-blind, sham-controlled phase and phase II was a 12 months longitudinal open-label prospective phase. Phase I of the trial involved the randomization of 43 patients with RRMS and truncal ataxia to either real (n = 20) or sham (n = 19) rTMS (2 participants from each treatment group were excluded from the study; one developed a relapse before treatment, 2 declined to participate, and one did not show up). Phase II involved providing 12 actual treatments cycles to all patients; each cycle length is 4 weeks, repeated four times on a trimonthly basis, forming a total of 48 sessions. DTI was used for assessment of the WMI. All patients performed DTI 3 times: Imaging sessions were conducted at the screening visit, at the end of phase I, and after the last session in phase II for the first, second and third sessions respectively. A figure-of-8-shape coil, employing rTMS protocol and located over the cerebellum, was used. rTMS protocol is formed of 20 trains formed of 50 stimuli with 20 s apart (5 Hz of 80 % of resting Motor Threshold "MT"). The Berg Balance Scale (BBS), Time up and go (TUG) test, and 10-m walk test (10MWT) were first evaluated at the start of each cycle and just after the final rTMS session. RESULTS: The genuine rTMS group's 10MWT, TUG, and BBS showed substantial improvement (p < 0.01), which is continued to be improved throughout the study Timeline, with a significant difference observed following the final rTMS session (P< 0.001). A longitudinal increase in FA was observed in both the Cerebello-Thalamo-Cortical (CTC) and Cortico-Ponto-Cerebellar (CPC) bilateral, as indicated by means of Fractional Anisotropy (FA) measures (p < 0.05). CONCLUSION: In ataxic RRMS patients, high frequency rTMS over the cerebellum has a long-term beneficial impact on both balance and WMI.

FOXP3rs3761548 gene variant and interleukin-35 serum levels as biomarkers in patients with multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS). Aberrant expression of transcription factor forkhead box P3 (FoxP3) has been suggested to underlie different immunological disorders as FOXP3 expression is essential for T regulatory cells (Tregs) to maintain their suppressive and anti-inflammatory functions and exert immunologic self-tolerance. Interleukin-35 (IL-35) is an important immunosuppressive cytokine that is produced mainly by CD4+ FOXP3+ Tregs. OBJECTIVES: To assess the possible role of the FOXP3 rs3761548 (C/A) single-nucleotide variation (SNV) in relapsing-remitting multiple sclerosis (RRMS). Also, measurement of the serum IL-35 concentration and study its relation to different genotypes and the degree of disease-related disability. METHODS: A total of 100 RRMS patients and 90 healthy control subjects were subjected to genotyping for the FOXP3 (rs3761548) variant by TaqMan real-time PCR, and measurement of the IL-35 level in their sera by Elisa. RESULTS: The frequencies of the AA genotype and A allele were significantly higher in the MS patients than in the healthy controls (P=0.008, OR=2.53, 95% CI=1.27-5.04; P=0.001, OR=1.98, 95% CI=1.31-3.00, respectively). There was a significant association between FOXP3 rs3761548 variant and female MS patients. The serum IL-35 level was significantly higher in MS patients (1372 [575-2192] pg/mL) compared to healthy controls (604 [454-696] pg/mL) (P<0.0001). No significant differences were found between the different FOXP3 genotypes and EDSS score (P=0.730). CONCLUSION: The FOXP3rs3761548 gene variant may influence the genetic susceptibility to MS rather than affecting its course, severity or progression. The serum IL-35 level might have a role in the development of the disease, however its role in disease-related disability is questionable.

Visceral fat mass as a novel risk factor for predicting gestational diabetes in obese pregnant women.

OBJECTIVE: To develop a model to predict gestational diabetes mellitus incorporating classical and a novel risk factor, visceral fat mass. METHODS: Three hundred two obese non-diabetic pregnant women underwent body composition analysis at booking by bioimpedance analysis. Of this cohort, 72 (24%) developed gestational diabetes mellitus. Principal component analysis was initially performed to identify possible clustering of the gestational diabetes mellitus and non-GDM groups. A machine learning algorithm was then applied to develop a GDM predictive model utilising random forest and decision tree modelling. RESULTS: The predictive model was trained on 227 samples and validated using an independent testing subset of 75 samples where the model achieved a validation prediction accuracy of 77.53%. According to the decision tree developed, visceral fat mass emerged as the most important variable in determining the risk of gestational diabetes mellitus. CONCLUSIONS: We present a model incorporating visceral fat mass, which is a novel risk factor in predicting gestational diabetes mellitus in obese pregnant women.

Bacterial endophytes from wild and ancient maize are able to suppress the fungal pathogen Sclerotinia homoeocarpa.

AIMS: The aim of this study was to determine if endophytes from wild and ancient Zea plants (corn family) have anti-fungal activities, specifically against the most important fungal pathogen (Sclerotinia homoeocarpa) of creeping bentgrass, a relative of Zea, used here as a model grass. METHODS AND RESULTS: A library of 190 bacterial endophytes from wild, ancient and modern Zea plants were tested for their ability to suppress S. homoeocarpa in vitro, followed by in planta testing of candidates using greenhouse trials. Three endophytes could suppress S. homoeocarpa, originating from wild maize and an ancient Mexican landrace, consistent with our hypothesis. 16S phylogenetic analysis and BOX-PCR DNA fingerprinting suggest that the anti-fungal endophytes are distinct strains of Burkholderia gladioli. One strain (3A12) was confirmed to colonize creeping bentgrass using green fluorescent protein (GFP) tagging. Evans blue vitality staining demonstrated that the bacterial endophytes exhibited fungicidal activities against the pathogen. The endophytes inhibited a wide spectrum of plant-associated fungi including diverse crop pathogens. CONCLUSIONS: The results support the hypothesis that wild and ancient Zea genotypes host bacterial endophytes that can control fungal pathogen(s). SIGNIFICANCE AND IMPACT OF THE STUDY: These results suggest that wild and ancient crops may be an unexplored reservoir of anti-fungal bacterial endophytes.

Pregnancy-associated atypical haemolytic uraemic syndrome in the postpartum period: a case report and review of the literature.

Pregnancy has been reported to be a trigger in about 10% of all patients with atypical haemolytic uraemic syndrome (aHUS). However, in contrast to pregnancy-associated thrombotic thrombocytopaenic purpura, the presentation of pregnancy-associated aHUS remains ill defined and can therefore be difficult to diagnose and manage appropriately. Here we report a case of pregnancy-associated relapse of aHUS in a patient with a previous medical history of aHUS prior to pregnancy.

Pregnancy outcomes in women with gestational diabetes treated with metformin or insulin: a case-control study.

AIMS: To compare maternal and neonatal outcomes in women with gestational diabetes mellitus (GDM) treated with either metformin or insulin. METHODS: One hundred and twenty-seven women with GDM not adequately controlled by dietary measures received metformin 500 mg twice daily initially. The dose was titrated to achieve target blood glucose values. Pregnancy outcomes in the 100 women who remained exclusively on metformin were compared with 100 women with GDM treated with insulin matched for age, weight and ethnicity. RESULTS: There were no significant differences in baseline maternal risk factors. Women treated with insulin had significantly greater mean (sem) weight gain from enrolment to term (2.72 +/- 0.4 vs. 0.94 +/- 0.3 kg; P < 0.001). There was no difference between the metformin and insulin groups, respectively, comparing gestational hypertension (6 vs. 7%, P = 0.9), pre-eclampsia (9 vs. 2%, P = 0.06) induction of labour (26 vs. 24%, P = 0.87) or rate of Caesarean section (48 vs. 52%, P = 0.67). No perinatal loss occurred in either group. Neonatal morbidity was improved in the metformin group; prematurity (0 vs. 10%, P < 0.01), neonatal jaundice (8 vs. 30%, P < 0.01) and admission to neonatal unit (6 vs. 19%, P < 0.01). The incidence of macrosomia (birthweight centile > 90) was not significantly different [metformin (14%) vs. insulin (25%); P = 0.07]. CONCLUSIONS: Women with GDM treated with metformin and with similar baseline risk factors for adverse pregnancy outcomes had less weight gain and improved neonatal outcomes compared with those treated with insulin. Diabet. Med. 26, 798-802 (2009).

Simple enumerations of peripheral blood natural killer (CD56+ NK) cells, B cells and T cells have no predictive value in IVF treatment outcome.

BACKGROUND: To evaluate the association between the absolute counts of the peripheral natural killer (NK) cells (including total CD56(+) NK cells, CD56(dim) NK cells and CD56(bright) NK cells), B cells and T cells on the implantation rate and miscarriage rate after IVF treatment. METHODS: This was a prospective observation study. A total of 138 patients who underwent IVF treatment from December 2002 to July 2003 were recruited to the study. Blood samples were obtained on the day of vaginal oocyte retrieval prior to the procedure. The absolute counts of lymphocytes, NK cells, B cells and T cells were identified by flow cytometry. These absolute counts and their relationships to IVF treatment outcome and miscarriage rate were analysed. RESULTS: There were no significant differences with regard the mean values of absolute lymphocyte count, T cell count, B cell count and NK cell count (including total CD56(+) NK, CD56(dim) NK and CD56(bright) NK cells) between the pregnant and non-pregnant groups and also between the ongoing pregnancy and miscarriage groups. The cause of infertility, duration of infertility, basal FSH levels, number of previous failed IVF treatments, number of previous miscarriages and stimulation characteristics were not significantly different between the pregnant and non-pregnant groups. Previous studies have suggested that women with a history of recurrent miscarriage and those with infertility accompanied by recurrent failed IVF treatments are associated with a peripheral blood NK cell percentage >12%, therefore further analysis of peripheral CD56(+) NK cell levels <12% (group A) and >12% (group B) was performed. There was no significant difference in implantation rate (group A: 17.0%; group B: 23.2%), pregnancy rate (group A: 36.6%; group B: 47.7%) or miscarriage rate (group A: 23.3%; group B: 28.6%). CONCLUSION: There were no significant differences between simple enumerations of peripheral blood NK cells (including total CD56(+) NK, CD56(dim) NK and CD56(bright) NK cells), B cells and T cells with IVF treatment outcome and pregnancy outcome. Women who had a peripheral NK cell level >12% did not have higher number of previous pregnancy losses. Importantly their pregnancy rate was not reduced and their miscarriages were not increased compared to women who had a peripheral NK cells level <12%.

An increase in the absolute count of CD56dimCD16+CD69+ NK cells in the peripheral blood is associated with a poorer IVF treatment and pregnancy outcome.

BACKGROUND: Our aim was to evaluate the effect of the absolute count of the activation marker (CD69), IgG Fc receptor (CD16) and inhibitor marker (CD94) expression on peripheral blood natural killer (NK) cells on implantation and miscarriage rates after IVF treatment. METHODS: Prospective observational study of 138 randomly selected women who underwent IVF treatment from December 2002 to September 2003. NK cells were identified as CD56(+) (dim + bright) and CD3(-) by flow cytometry. The absolute counts of the CD69(+), CD16(+) and CD94(+)expressing NK cells were recorded and their relation to IVF treatment outcome and miscarriage rate was analysed. RESULTS: The mean (+/-SD) absolute count of the CD56(dim)CD16(+)CD69(+) NK cells for women who had a successful ongoing pregnancy was 0.61 x 10(6)/l (+/-0.31). For those women who failed to achieve a pregnancy, the mean value of the absolute count of CD56(dim)CD16(+)D69(+) NK cells was significantly (P=0.003) higher at 1.66 x 10(6)/l (+/-0.52). The absolute count of CD56(dim)CD16(+)CD94(+) and CD56(dim)CD16(+) NK cells did not show any statistically significant differences between those women with successful and failed IVF treatment. Receiver operating characteristic (ROC) curve analysis was performed to select a CD69 threshold for further statistical analysis. The implantation rate (IR) was significantly lower (13.1%) and miscarriage rate (MR) was significantly higher (66.7%) for women with an absolute CD56(dim)CD16(+)CD69(+) NK cell count of >1.0 x 10(6)/l compared to women with count below this value (IR 28.2% and MR 16.7%). Further analysis of the absolute count of CD56(bright)CD69(+) and CD56(bright)CD94(+) NK cells did not show any significant difference between those women with successful and failed IVF treatment. CONCLUSIONS: An increase in the absolute count of activated NK cells (CD56(dim)CD16(+)CD69(+)) in the peripheral blood is associated with a reduced rate of embryo implantation in IVF treatment. Furthermore, women with high CD56(dim)CD16(+)CD69(+) peripheral blood NK cell absolute count, who are able to achieve pregnancy, have a significantly higher miscarriage rate.

Internal jugular vein thrombosis after assisted conception therapy.

Superovulation therapy during assisted conception may result in a hypercoagulable state. Five cases of upper extremity venous thrombosis were identified in women who conceived after ovarian stimulation for in vitro fertilization (IVF). They presented between 7 and 10 weeks' gestation with neck pain and swelling. Three had been treated for ovarian hyperstimulation syndrome and two had evidence of inherited thrombophilia. Four patients received thromboprophylaxis before presentation. Although thrombosis is an uncommon complication of IVF, patients should be counselled before treatment. Thrombophilia screening may be considered for 'high-risk' patients, although current regimes for thromboprophylaxis remain suboptimal.

Management of pregnancy in antiphospholipid syndrome.

Pregnant women with APS are at high risk of maternal and fetal pregnancy complications. Multidisciplinary teams expert in this condition should coordinate management. Even with current management strategies, the risk of maternal thrombosis, fetal loss, or other adverse obstetric outcomes remains. Close monitoring of the various aspects of this condition may reduce maternal morbidity and improve fetal outcome. The pathogenesis of the adverse pregnancy outcome in APS has not yet been fully elucidated, although active research in this field continues. Until this is ascertained, we must accept that many aspects of management are purely empiric, and it is our duty to counsel patients thoroughly so that they understand the risks and benefits of the treatment options they are offered.

Drugs in pregnancy. Drugs to avoid.

Drugs given in pregnancy can adversely affect the fetus in many ways. Anxiety about birth defects is a major parental concern during pregnancy. Doctors, midwives and their patients often seek information about the potential teratogenicity of drugs that are taken by, or prescribed for, the pregnant woman. Because no drug is entirely without side-effects, great caution should be taken when prescribing in pregnancy. The development of knowledge in understanding the use of drugs during pregnancy has been in stalemate in comparison to other areas of therapeutics, due mainly to difficulties in testing new products in pregnant women and lack of good quality research. In this chapter, we review current knowledge of the epidemiology of drug use among pregnant women, drug metabolism in pregnancy, adverse fetal and neonatal effects of drugs and specific effects of drugs that are relatively or absolutely contraindicated in pregnancy.

Towards the modern management of ectopic pregnancy: a complete audit cycle of practice in a London teaching hospital.

We carried out a complete audit cycle of the management of ectopic pregnancy at a London teaching hospital over 2 years. Case notes of women presenting to St George's Hospital, London in 1995 with ectopic pregnancy were examined and management was assessed. The targets were low rates of rupture, high rates of sonographic diagnosis of ectopic pregnancy, acceptable rates of tubal conservation and laparoscopic surgery. We also considered levels of training of junior doctors in laparoscopic surgery for ectopic pregnancy and the acceptable duration of hospital stay for patients. Recommendations were made, the standards were modified, and the audit repeated for the year 1996. A substantial improvement in the quality of care of women with ectopic pregnancy was achieved. The main improvement was in the ultrasonographic diagnosis of ectopic pregnancy. There was also a reduction in ectopic pregnancies which were ruptured, possibly due to earlier diagnosis. The percentage of cases treated laparoscopically remained stable. More junior doctors performed laparoscopic surgery for the condition. Finally, we confirmed that laparoscopic management of ectopic pregnancy significantly reduces duration of hospital stay, conferring advantages to both patient and hospital.

Red cell distribution width (RDW) changes in pregnancy.

OBJECTIVE: As part of an exercise in establishing normograms of hematological parameters in pregnancy, we studied the red cell distribution width (RDW) in healthy pregnant women. METHODS: A longitudinal study of RDW measurements in 121 pregnant women at 16 and 34 weeks gestation and during labor and at Days 3 and 7 postpartum. All the women had uncomplicated pregnancies, minimum hemoglobin (Hb) of 11.0 g/dl at recruitment and took iron supplements from 16 weeks of gestation and until 7 days after delivery. All subjects went into spontaneous labor, 110 achieving a normal vaginal delivery while the remaining 11 were delivered by cesarean section. Two-way analysis of variance was used to study the changes in RDW between any given gestations to test the variability between and within subjects. RESULTS: RDW increased significantly (P < 0.0001) between 34 weeks of gestation and the onset of labor. No significant changes occurred between 16 and 34 weeks gestation, or during the 7 days postpartum. CONCLUSION: This is the first longitudinal study analyzing the between and within women changes in RDW with progression of pregnancy. The unexpected rise in the RDW during the last 4-6 weeks leading up to the onset of labor suggests increased bone marrow activity. The stimulus is unknown, but as RDW changes are highly significant there may well be a useful indicator of impending parturition.

The vomeronasal (Jacobson's) organ in adult humans: frequency of occurrence and enzymatic study.

The vomeronasal system in adult humans has commonly been regarded as absent or vestigial, but recently it was found to be more common than previously reported. In this study, a search for the frequency of occurrence of the vomeronasal organ (VNO) was performed by examining the nasal septae of 200 adult patients. The frequency of occurrence was found to vary according to the method of examination. By anterior rhinoscopy, large pits and even deep grooves lined by glistening mucosa were visible in 16% of the people examined. Using nasal endoscopes this ratio increased to 76%. After receiving informed, written consent, from 13 patients undergoing endonasal surgery under general anaesthesia, one VNO was dissected out. Specimens were examined histologically and histochemically for succinic dehydrogenase and alkaline phosphatase enzymes. One specimen was processed for transmission electron microscopy. Two morphologically distinct cell types were differentiated. One cell type was previously suggested to have some of the features associated with nerve cells and could have a sensory function. A possible function for the VNO is postulated.

Human medullary thymocyte p80 antigen and In(Lu)-related p80 antigen reside on the same protein.

Study of human T lymphocyte differentiation antigens with monoclonal antibodies has led to the identification of two antigens shared by erythrocytes and leukocytes. The protein (p80) defined by A1G3 antibody has previously been shown to be acquired during human intrathymic T-cell maturation. The antigen defined by A3D8 antibody has been demonstrated also to reside on an 80 kd protein; expression of the A3D8 antigen on erythrocytes and a subset of leukocytes is regulated by the rare In(Lu) gene. In this study, we demonstrate that the antigens defined by the A1G3 and A3D8 antibodies reside on the same protein and represent closely related but nonidentical epitopes on the p80 molecule. Expression of the A1G3 antigen on erythrocytes and a subset of leukocytes is also down-regulated by the In(Lu) gene. The possible role of the In(Lu) gene in thymocyte differentiation is discussed.

The effect of the antibilharzial compound (Bilharcid) on Schistosoma mansoni in vitro and in vivo.

The effect of Piperazine diantimonyl tartrate (Bilharcid) as compared with that of tartar emetic on Schistosoma mansoni has been studied. In vitro experiments on living worms in tyrode/serum cultures have proved that Bilharcid 5-10 gamma/ml has the same antibilharzial activity as tartar emetic in 5-10 gamma/ml. In vivo experiments on Schistosoma mansoni infected mice have proved also that Bilharcid has more or less the same effect as that of tartar emetic. In this study, the worm burden load and the oogram techniques were used as the criteria for antibilharzial assessment.