Risk Factors for Thyroid Dysfunction in Pregnancy: An Individual Participant Data Meta-Analysis.

Background: International guidelines recommend targeted screening to identify gestational thyroid dysfunction. However, currently used risk factors have questionable discriminative ability. We quantified the risk for thyroid function test abnormalities for a subset of risk factors currently used in international guidelines. Methods: We included prospective cohort studies with data on gestational maternal thyroid function and potential risk factors (maternal age, body mass index [BMI], parity, smoking status, pregnancy through in vitro fertilization, twin pregnancy, gestational age, maternal education, and thyroid peroxidase antibody [TPOAb] or thyroglobulin antibody [TgAb] positivity). Exclusion criteria were pre-existing thyroid disease and use of thyroid interfering medication. We analyzed individual participant data using mixed-effects regression models. Primary outcomes were overt and subclinical hypothyroidism and a treatment indication (defined as overt hypothyroidism, subclinical hypothyroidism with thyrotropin >10 mU/L, or subclinical hypothyroidism with TPOAb positivity). Results: The study population comprised 65,559 participants in 25 cohorts. The screening rate in cohorts using risk factors currently recommended (age >30 years, parity ≥2, BMI ≥40) was 58%, with a detection rate for overt and subclinical hypothyroidism of 59%. The absolute risk for overt or subclinical hypothyroidism varied <2% over the full range of age and BMI and for any parity. Receiver operating characteristic curves, fitted using maternal age, BMI, smoking status, parity, and gestational age at blood sampling as explanatory variables, yielded areas under the curve ranging from 0.58 to 0.63 for the primary outcomes. TPOAbs/TgAbs positivity was associated with overt hypothyroidism (approximate risk for antibody negativity 0.1%, isolated TgAb positivity 2.4%, isolated TPOAb positivity 3.8%, combined antibody positivity 7.0%; p < 0.001), subclinical hypothyroidism (risk for antibody negativity 2.2%, isolated TgAb positivity 8.1%, isolated TPOAb positivity 14.2%, combined antibody positivity 20.0%; p < 0.001) and a treatment indication (risk for antibody negativity 0.2%, isolated TgAb positivity 2.2%, isolated TPOAb positivity 3.0%, and combined antibody positivity 5.1%; p < 0.001). Twin pregnancy was associated with a higher risk of overt hyperthyroidism (5.6% vs. 0.7%; p < 0.001). Conclusions: The risk factors assessed in this study had poor predictive ability for detecting thyroid function test abnormalities, questioning their clinical usability for targeted screening. As expected, TPOAb positivity (used as a benchmark) was a relevant risk factor for (subclinical) hypothyroidism. These results provide insights into different risk factors for gestational thyroid dysfunction.

Bone marrow derived mesenchymal stem cells therapy for rheumatoid arthritis - a concise review of past ten years.

Rheumatoid arthritis is an autoimmune disorder characterized by swelling in synovial joints and erosion of bones. The disease is normally treated with conventional drugs which provide only temporary relief to the symptoms. Over the past few years, mesenchymal stromal cells have become the center of attention for treating this disease due to their immuno-modulatory and anti-inflammatory characteristics. Various studies on treatment of rheumatoid arthritis by using these cells have shown positive outcomes in terms of reduction in the level of pain as well as improvement of the function and structure of joints. Mesenchymal stromal cells can be derived from multiple sources, however, the ones derived from bone marrow are considered most beneficial for treating several disorders including rheumatoid arthritis on account of being safer and more effective. This review summarizes all the preclinical and clinical studies which were conducted over the last ten years for therapy of rheumatoid arthritis utilizing these cells. The literature was reviewed using the terms "mesenchymal stem/stromal cells and rheumatoid arthritis'' and "bone marrow derived mesenchymal stromal cells and therapy of rheumatoid arthritis''. Data was extracted to enable the readers to have access to the most relevant information regarding advancement in therapeutic potential of these stromal cells. Additionally, this review will also help in fulfilling any gap in current knowledge of readers about the outcome of using these cells in animal models, cell line and in patients suffering from rheumatoid arthritis and other autoimmune disorders as well.

Characterization of linear epitope specificity of antibodies potentially contributing to spontaneous clearance of hepatitis C virus.

BACKGROUND: Around 30% of the HCV infected patients can spontaneously clear the virus. Cumulative evidence suggests the role of neutralizing antibodies in such spontaneous resolution. Understanding the epitope specificity of such antibodies will inform the rational vaccine design as such information is limited to date. In addition to conformational epitope targeted antibodies, linear epitope specific antibodies have been identified that are broadly cross reactive against diverse HCV strains. In this study, we have characterized the potential role of three conserved linear epitopes in the spontaneous clearance of HCV. METHODS: We tested the reactivity of sera from chronic patients (CP) and spontaneous resolvers (SR) with linear peptides corresponding to three conserved regions of HCV envelope protein E2 spanning amino acids 412-423, 523-532 and 432-443 using ELISA. Subsequently, we characterized the dependency of HCV neutralization by the reactive serum samples on the antibodies specific for these epitopes using pseudoparticle-based neutralization assay. In ELISA most of the CP sera showed reactivity to multiple peptides while most of the SR samples were reactive to a single peptide suggesting presence of more specific antibodies in the SR sera. In most of the HCVpp neutralizing sera of particular peptide reactivity the neutralization was significantly affected by the presence of respective peptide. HCV neutralization by CP sera was affected by multiple peptides while 75% of the HCVpp neutralizing SR sera were competed by the 432 epitope. CONCLUSIONS: These findings suggest that individuals who spontaneously resolve HCV infection at the acute phase, can produce antibodies specific for conserved linear epitopes, and those antibodies can potentially play a role in the spontaneous viral clearance. The epitope present in the 432-443 region of E2 was identified as the primary neutralizing epitope with potential role in spontaneous viral clearance and this epitope potentiates for the design of immunogen for prophylactic vaccine.

Association of maternal thyroid function with birthweight: a systematic review and individual-participant data meta-analysis.

BACKGROUND: Adequate transplacental passage of maternal thyroid hormone is important for normal fetal growth and development. Maternal overt hypothyroidism and hyperthyroidism are associated with low birthweight, but important knowledge gaps remain regarding the effect of subclinical thyroid function test abnormalities on birthweight-both in general and during the late second and third trimester of pregnancy. The aim of this study was to examine associations of maternal thyroid function with birthweight. METHODS: In this systematic review and individual-participant data meta-analysis, we searched MEDLINE (Ovid), Embase, Web of Science, the Cochrane Central Register of Controlled Trials, and Google Scholar from inception to Oct 15, 2019, for prospective cohort studies with data on maternal thyroid function during pregnancy and birthweight, and we issued open invitations to identify study authors to join the Consortium on Thyroid and Pregnancy. We excluded participants with multiple pregnancies, in-vitro fertilisation, pre-existing thyroid disease or thyroid medication usage, miscarriages, and stillbirths. The main outcomes assessed were small for gestational age (SGA) neonates, large for gestational age neonates, and newborn birthweight. We analysed individual-participant data using mixed-effects regression models adjusting for maternal age, BMI, ethnicity, smoking, parity, gestational age at blood sampling, fetal sex, and gestational age at birth. The study protocol was pre-registered at the International Prospective Register of Systematic Reviews, CRD42016043496. FINDINGS: We identified 2526 published reports, from which 36 cohorts met the inclusion criteria. The study authors for 15 of these cohorts agreed to participate, and five more unpublished datasets were added, giving a study population of 48 145 mother-child pairs after exclusions, of whom 1275 (3·1%) had subclinical hypothyroidism (increased thyroid stimulating hormone [TSH] with normal free thyroxine [FT4]) and 929 (2·2%) had isolated hypothyroxinaemia (decreased FT4 with normal TSH). Maternal subclinical hypothyroidism was associated with a higher risk of SGA than was euthyroidism (11·8% vs 10·0%; adjusted risk difference 2·43%, 95% CI 0·43 to 4·81; odds ratio [OR] 1·24, 1·04 to 1·48; p=0·015) and lower mean birthweight (mean difference -38 g, -61 to -15; p=0·0015), with a higher effect estimate for measurement in the third trimester than in the first or second. Isolated hypothyroxinaemia was associated with a lower risk of SGA than was euthyroidism (7·3% vs 10·0%, adjusted risk difference -2·91, -4·49 to -0·88; OR 0·70, 0·55 to 0·91; p=0·0073) and higher mean birthweight (mean difference 45 g, 18 to 73; p=0·0012). Each 1 SD increase in maternal TSH concentration was associated with a 6 g lower birthweight (-10 to -2; p=0·0030), with higher effect estimates in women who were thyroid peroxidase antibody positive than for women who were negative (pinteraction=0·10). Each 1 SD increase in FT4 concentration was associated with a 21 g lower birthweight (-25 to -17; p<0·0001), with a higher effect estimate for measurement in the third trimester than the first or second. INTERPRETATION: Maternal subclinical hypothyroidism in pregnancy is associated with a higher risk of SGA and lower birthweight, whereas isolated hypothyroxinaemia is associated with lower risk of SGA and higher birthweight. There was an inverse, dose-response association of maternal TSH and FT4 (even within the normal range) with birthweight. These results advance our understanding of the complex relationships between maternal thyroid function and fetal outcomes, and they should prompt careful consideration of potential risks and benefits of levothyroxine therapy during pregnancy. FUNDING: Netherlands Organization for Scientific Research (grant 401.16.020).

TNF-alpha: a risk factor for ischemic stroke.

BACKGROUND: Inflammatory markers are being explored to aid in stroke diagnosis especially, to differentiate between clinical varieties of stroke. This study aimed to compare plasma tumour necrosis factor-alpha (TNF-alpha) and Interleukin-10 (IL-10) levels between stroke patients and controls, as well as between hemorrhagic and ischemic varieties of stroke. METHODS: Stroke patients who were admitted to Shaikh Zayed Hospital Lahore and Services Hospital Lahore, Pakistan within 24 hours after the onset of stroke symptoms were consecutively asked to participate in this study from June 2011 to December 2011.Venous blood samples were collected within 24 hours of stroke symptoms onset. Plasma TNF-α levels and IL-10 were calculated using commercial enzyme-linked immune-sorbent assay (ELISA). Cytokines levels were dichotomized as detectable yes/no and were compared between different groups using chi square test. Continuous variables were compared using the student t-test. Logistic regression model was used to investigate the effect of various risk factors on stroke subtypes. A value of p < 0.05 was considered significant. RESULTS: One hundred and thirty one stroke patients were included in the study, out of which 93 were ischemic and 38 were haemorrhagic stroke patients. Forty-seven healthy asymptomatic individuals were included .as controls Plasma TNF-α levels (p < 0.001, r = 0.503, CI: 18.197-1672.950) were significantly elevated in stroke patients as compared to controls, along with advancing age (p = 0.002, r = 0.310, CI: 1.025-1.110) and history of hypertension (p = 0.002, r = 0.265, CI: 1.746-12.511). Males were found to be at a higher risk of developing stroke. Furthermore, history of hypertension (p=0.019, r= -0.294, CI: 0.134-1.500) and detectable TNF- levels (p = 0.002, r = 0.319, CI: 2.106-23.725) were found to be significantly different between ischemic and haemorrhagic stroke patients. CONCLUSION: TNF-α level differed highly significantly between stroke and controls, and also between ischemic and haemorrhagic stroke subtypes.

Comparative efficiency of different methods of gluten extraction in indigenous varieties of wheat / Eficacia comparativa de diferentes métodos de extracción de gluten en variedades autóctonas de trigo

The present study investigated six varieties of locally grown wheat (Lasani, Sehar, Miraj-08, Chakwal-50, Faisalabad-08 and Inqlab) procured from Punjab Seed Corporation, Lahore, Pakistan for their proximate contents. On the basis of protein content and ready availability, Faisalabad-08 (FD-08) was selected to be used for the assessment of comparative efficiency of various methods used for gluten extraction. Three methods, mechanical, chemical and microbiological were used for the extraction of gluten from FD-08. Each method was carried out under ambient conditions using a drying temperature of 55°C. Mechanical method utilized four different processes viz:- dough process, dough batter process, batter process and ethanol washing process using standard 150 mesh. The starch thus obtained was analyzed for its proximate contents. Dough batter process proved to be the most efficient mechanical method and was further investigated using 200 and 300 mesh. Gluten content was determined using sandwich ω-gliadin enzyme-linked immunosorbent assay (ELISA).The results of dough batter process using 200 mesh indicated a starch product with gluten content of 678 ppm. Chemical method indicated high gluten content of more than 5000 ppm and the microbiological method reduced the gluten content from 2500 ppm to 398 ppm. From the results it was observed that no gluten extraction method is viable to produce starch which can fulfill the criteria of a gluten free product (20ppm).

El presente roduc seis variedades de trigo cultivado localmente (Lasani, Sehar, Miraj-08, Chakwal-50, Faisalabad-08 e Inqlab) obtenidos por sus contenidos proximales en Punjab Seed Corporation, Lahore, Pakistán. Sobre la base del contenido de roduct y su fácil disponibilidad, Faisalabad-08 (Fd-08) fue seleccionado para ser utilizado para la evaluación de la eficacia comparadativa de los diferentes métodos utilizados para la extracción de gluten. Tres métodos fueron utilizados para la extracción de gluten; mecánico, químico y microbiológico realizados en condiciones ambientales utilizando una roduct e de secado de 55°C. El método mecánico roduct cuatro procesos diferentes, a saber: proceso de masa, proceso de rebozado de masa, proceso de pasta y proceso de lavado en etanol empleando malla estándar de 150 mesh. El almidón obtenido se analizó por sus contenidos proximales. El contenido de gluten se roduct usando roduct ω-gliadina, ensayo de inmunoabsorción ligado a enzimas (ELISA). El proceso de rebozado de masa fue el método roduct más eficiente y se investigó adicionalmente usando malla 200 y 300 mesh. El proceso de rebozado de masa usando malla 200 generó un almidón con contenido de gluten de 678 ppm. El método químico produjo un contenido de gluten de más de 5.000 ppm, y el método microbiológico redujo el contenido de gluten de 2500 ppm a 398 ppm. A partir de estos resultados se roduct que ningún de estos métodos de extracción de gluten fue es viable para roduct almidón que pueda cumplir los criterios de un roduct libre de gluten (20 ppm).

Pattern of thyroid autoimmunity in type 1 and type 2 diabetics.

OBJECTIVE: To determine the level of thyroid autoimmunity among clinically euthyroid patients of type 1 and type 2 diabetics and to correlate the levels with pattern of diabetes. DESIGN: Cross-sectional analytical study. PLACE AND DURATION OF STUDY: Diabetic Clinic of Shaikh Zayed Hospital, Lahore from August 2004 to April 2005. PATIENTS AND METHODS: Blood samples were collected from 163 subjects (51 of type 1, 61 of type 2 diabetics and 51 non- diabetic controls) and sera were separated. They were all clinically euthyroid and selected conveniently. Thyroid profile (FT4, TSH and anti-TPO) was assessed in the three groups and compared. RESULTS: It was observed that at a cut off value of less than 100 units of anti-TPO level was normal, raised anti-TPO antibodies were found in 12% of normal control group, 61% in type 1 and 42.3% in type 2 diabetics. In type 1 diabetics, the TSH was higher in the younger age patients with progressive rise in anti-TPO antibodies level by age. The TSH, anti-TPO antibodies and BSF were significantly higher in type 1 diabetics than in the controls. In type 2 diabetics, TSH was moderately low but anti-TPO antibodies and BSF were higher than in the controls. CONCLUSION: Thyroid autoimmune process seems to be correlated more with type 1 diabetic patients than with type 2 patients.

Free and total prostate specific antigen in benign prostate hyperplasia and prostate cancer.

OBJECTIVE: To record the levels of PSA in the sera of prostate cancer (CaP) and benign prostatic hyperplasia (BPH) cases. Free PSA/total PSA as percentage was also calculated in order to evaluate its utility in differentially diagnosing BPH and CaP. DESIGN: A cross-sectional, case control study. PLACE AND DURATION OF STUDY: Shaikh Zayed Hospital and Mayo Hospital, Lahore from August 2002 to March 2003. MATERIALS AND METHODS: A group of 108 male subjects, including one-third of each of biopsy-confirmed prostate cancer cases, BPH cases and asymptomatic controls of matching age were studied. PSA and Free PSA were determined by ELISA using commercially available assay kits. RESULTS: Mean PSA was found to be highest in CaP cases (41.9 +/- 38.7 ng/ml), lower in the BPH cases (13.5 +/- 10.5 ng/ml), while it was lowest in the control subjects (5.7 +/- 4.4 ng/ml). Moreover, it was observed that a majority of the CaP cases had serum PSA >20 ng/ml, 50% of BPH cases had serum PSA in the 'gray zone' (4.1-20 ng/ml), while majority of controls had serum PSA in the 'normal' range (0 - 4 ng/ml). Using a free- PSA "cut-off" of 18% to differentiate between benign and malignant prostate enlargement, it was found that 80% of the CaP cases had F/T% <18, while 75% of the BPH cases had F/T%>18. The percent free-PSA test to differentially diagnose BPH and CaP in the 'gray zone' was found to have a sensitivity of 86% and a specificity of 94%. CONCLUSION: Using a cutoff of 18%, the free-PSA test significantly improved the differential diagnosis of BPH and CaP in the 'gray zone' as compared to the use of total PSA alone in the study group.