Analysis of B lymphocyte function in prospective renal transplant patients

It is well established that uraemia impairs the in vivo cell-mediated immune responses while the in vitro lymphocyte responses of patients on maintenance dialysis have been reported to be impaired or normal . The work in this thesis deals predominantly with production of immunoglobulin in vitro by peripheral blood mononuclear cells obtained From normal and uraemic subjects. The protein A plaque Forming cell assay was utilised to enumerate immunoglobulin secreting cells and several parameters affecting its performance were examined. Thus, it was Found that plaque Forming cell numbers were dependent on the concentrations of sheep red blood cells, anti-serum, DEAE-dextran and complement while PEG 6000 was shown to improve the quality of the plaques. The optimal conditions For storing the cells before plating and incubating them after plating were also established and in addition, it was shown that cryopreservation does not affect plaque Forming cel1 activity. The optimal conditions For both proliferation and immunoglobulin production in response to mitogenic stimulation were also examined and once again the suitability of cryopreserved peripheral blood mononuclears For use in mitogen-stimulated cultures was confirmed, A normal range For both spontaneous and mitogen induced plaque Farming cells was established and it was shown that pokeweed mitogen(PWM) was the most effective polyclonal B cell activator in inducing plaque Forming cells while Epstein-Barr-Virus(EBU) induced similar IgM-PFC as PWM. Co-stimulation of control peripheral blood mononuclear cells with Concavalin A(ConA) showed that both PWM and Staphylococcus Aureus Cowan I(SAC) cultures were suppressed although the Former proved to be much more sensitive. Steroids are known to inhibit suppressor T cells and when methyl-prednisolone was added in PWM and SAC cultures of control peripheral blood mononuclear cells, PWM induced production of immunoglobulin was more readily enhanced. I propose that these polyclonal B cell activators differ in their susceptibility to regulation by suppressor T cells. When indomethacin was added in the cultures to inhibit prostaglandin synthesis, it was observed that SAC responses were slighty but non-significantly enhanced. Uraemia was not Found to have a significant effect on the number or proportion of lymphocyte populations but . it impaired the proliferative' responses to PHA and PUIM. However, the relative in vitro immunosuppressive effect of steroids was not Found to be stronger in these cultures. EBU and PWM induced plaque Formation was normal in uraemic patients while both spontaneous and SAC induced immunoglobulin production were reduced. In addition, the combination of PWM and SAC did not produce the synergistic effect Found in control cultures. Pre-incubation of control cells with uraemic serum affected the quality and suppressed slightly the numbers of PWM-induced plaque Forming cells. Addition of methyl-prednisolone to SAC cultures did not produce the enhancing effect Found in controls indicating that the reduced SAC responses in uraemia were not caused by incraasad supprassar T cell activity. Howevar, the SAC responses of uraemic peripheral blood mononuclear cells seemed to benefit more by the addition of indomethacin than the SAC responses of control cells. My results indicate strongly that the reduced production of immunaglobulin in uraemia is not due to reduced numbers of lymphocytes but reflects a true functional abnormality and the observed reduced proliferative responses of uraemic peripheral blood mononuclears to T cell mitogens indicate that T lymphocyte function is impaired. The studies using polyclonal B cell activators suggested that B cell function and T-B cell co-operation remained intact in uraemic patients and indicated that the defective immunoglobulin responses in both the spontaneous and SAC system were due to a functional abnormality of the helper T cell

The Association between TGF-β1 G915C (Arg25Pro) Polymorphism and the Development of Primary Open Angle Glaucoma: A Case-Control Study

The purpose of the current study was to identify the potential association between Single Nucleotide Polymorphism (SNP) TGFβ1 +915 (C or G) in codon 25 and Primary Open Angle Glaucoma (POAG). Overall, 88 cases with POAG and a control group of 52 healthy individuals were recruited from the First Ophthalmology Department of Athens University. DNA was isolated from whole blood samples and genotype frequencies for the polymorphism rs1800471 (G915C, Arg25Pro) of the TGF-β1 gene were assessed. Genotype distribution frequencies for the polymorphism rs1800471 (G915C, Arg25Pro) of the TGF-β1 gene were not statistically different between patients with POAG and control subjects. The present study failed to determine any significant genotypic association with POAG, despite the fact that the presence of the C allele was scarcely increased in the POAG when compared with the control group

ATP-binding cassette transporter A1 gene polymorphisms and serum lipid levels in young Greek nurses

<p>Abstract</p> <p>Objective</p> <p>The ATP-binding cassette transporter A1 (ABCA1) is essential protein involved in lipid metabolism. The present study was undertaken to detect the possible association of polymorphisms in the ABCA1 gene [rs2230806 (R219K) and rs2230808 (R1587K)] and lipid profile in Greek young nurses.</p> <p>Methods</p> <p>The study population consisted of 308 unrelated nurses who were genotyped and the ABCA1 polymorphisms were detected. Additionally, lipid profile [total cholesterol (TC), triglycerides (TGs), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C) and apolipoprotein (apo) A] was evaluated.</p> <p>Results</p> <p>There was no difference in the genotypic and allelic frequencies of the R219K polymorphism according to lipid profile. The R1587K genotypes differed significantly according to TC, LDL-C and TGs concentration (p = 0.023, p = 0.014 and p = 0.047, respectively). Particularly, significant difference in TC, LDL-C and TGs concentration was detected between RK and RR genotypes (p = 0.006, p = 0.004, p = 0.014, respectively). Women with RK genotype compared to RR genotype had higher concentration of TGs (134.25 mg/dl vs 108.89 mg/dl, p = 0.014, respectively), total cholesterol (207.41 mg/dl vs 187.69 mg/dl, p = 0.006, respectively), and LDL-C (110.6 mg/dl vs 96.9 mg/dl, p = 0.004, respectively).</p> <p>Conclusions</p> <p>These findings suggest that the R1587K polymorphism of ABCA1 gene was associated with lipid profile of Greek nurses. Women with RK genotype had higher TGs, total and LDL-C concentration compared to RR genotype. These observations may be significant in assessing the risk of CAD since a 1% change in LDL-C is associated with a 1% change of cardiovascular events. Also, TGs concentration were documented to play a significant role in women. However, this needs to be confirmed by larger studies.</p

Sex-associated effect of CETP and LPL polymorphisms on postprandial lipids in familial hypercholesterolaemia

Background: This study assessed the gender-specific influence of the cholesteryl ester transfer protein (TaqIB, I405V) and lipoprotein lipase (S447X) polymorphisms on the response to an oral fat tolerance test in heterozygotes for familial hypercholesterolaemia.Methods: We selected and genotyped 80 men and postmenopausal women heterozygous for familial hypercholesterolaemia (main group) as well as 11 healthy control subjects. Patients were subgrouped based on their response to oral fat tolerance test. The oral fat tolerance test was defined as pathological when postprandial triglyceride concentration was higher than the highest triglyceride concentration observed in healthy subjects (220 mg/dl) at any time (2, 4, 6 or 8 h).Results: In the pathological subgroup, men had significantly higher incremental area under the curve after oral fat tolerance test than postmenopausal women. Furthermore, multivariate analysis revealed a gender association of TaqIB and I405V influence on postprandial lipaemia in this subgroup.Conclusion: In conclusion, it seems that gender and TaqIB polymorphism of the cholesteryl ester transfer protein gene were both associated with the distribution of triglyceride values after oral fat tolerance test, only in subjects with a pathological response to oral fat tolerance test. Specifically, men carrying the B2 allele of the TaqIB polymorphism showed a higher postprandial triglyceride peak and a delayed return to basal values compared with women carrying B2. However, further investigations in larger populations are required to replicate and confirm these findings

Genetics of Heritable Thoracic Aortic Disease

Genetic testing plays an increasing diagnostic and prognostic role in the management of patients with heritable thoracic aortic disease (HTAD). The identification of a specific variant can establish or confirm the diagnosis of syndromic HTAD, dictate extensive evaluation of the arterial tree in HTAD with known distal vasculature involvement and justify closer follow-up and earlier surgical intervention in HTAD with high risk of dissection of minimal or normal aortic size. Evolving phenotype–genotype correlations lead us towards more precise and individualized management and treatment of patients with HTAD. In this review, we present the latest evidence regarding the role of genetics in patients with HTAD

The pathophysiological relationship and clinical significance of left atrial function and left ventricular diastolic dysfunction in beta-thalassemia major

Iron deposition in combination with inflammatory and immunogenetic factors is involved in the pathophysiology of cardiac dysfunction in -thalassemia major. We investigated the mechanical and endocrine function of the left atrium and ventricle to identify early signs of dysfunction. We studied 90 patients (mean age: 29 +/- 11 years) with -thalassemia and normal left ventricular function and 90 age and sex-matched healthy controls. Patients and controls underwent a thorough cardiac echocardiographic study and measurements of the b-type (NT-proBNP) and atrial natriuretic peptides (proANP). Patients underwent 24-hr Holter recordings for arrhythmia monitoring. In the patient group, atria were affected early during the course of the disease, prior to diastolic and systolic left ventricular dysfunction. The E/Eratio (E Doppler mitral fast inflow to the corresponding tissue Doppler E) continually increased with age (P&lt;0.05) and reached levels indicating left ventricular diastolic dysfunction (E/E&gt;15) in the third decade whereas indexes of active and passive atrial function decreased gradually throughout life. In controls, the E/E ratio continually increased with age but with later (fifth decade) appearance of diastolic dysfunction and a compensatory increase in atrial active function. Both natriuretic peptides were significantly increased in patients compared to controls (558 +/- 141 and 2,580 +/- 1,830 fmol/mL for NT-proBNP and proANP versus 332 +/- 106 and 1,331 +/- 1,134 fmol/mL, respectively). Atrial fibrillation was found in a subgroup of 23 (26%) patients, older in age with mild diastolic function and enlarged, depressed atria. In conclusion, atrial mechanical depression seems to be a very early sign of cardiac damage. It may become echocardiographically evident even before diastolic and systolic dysfunction and is associated to supraventricular arrhythmias. Am. J. Hematol. 89:13-18, 2014. (c) 2013 Wiley Periodicals, Inc

Neurocardiogenic mechanisms of unexplained syncope in idiopathic dilated cardiomyopathy

Syncope in patients with advanced heart failure is a sign of poor prognosis. The cause of syncope in patients with dilated cardiomyopathy (DC) is not fully recognized and may remain elusive even after standardized evaluation. The purpose of the present study was to examine the implication of neurally mediated mechanisms in the pathophysiology of syncopal episodes in patients with DC. Twenty-six patients (21 men, 5 women; mean age 59 +/- 2 years, range 38 to 79) with DC and left ventricular ejection fractions &lt;= 40% were included in the study. Thirteen patients with unexplained syncope or presyncope and a control group of 13 patients without unexplained syncope underwent head-up tilt tests with clomipramine challenge. The 2 groups were matched with regard to age, gender, and left ventricular ejection fractions, and there were no major differences in terms of medication. Heart rate variability analysis, and plethysmography of forearm flow were performed during the tilt tests. Blood samples were also drawn for catecholamine measurements. In the group with histories of unexplained syncope, the head-up tilt test results were positive in 11 patients (84.6%). Sympathetic and parasympathetic heart rate indexes were markedly stimulated, while catecholamine concentrations and blood flow changes indicated sympathetic withdrawal during tilting. In the control group, the head-up tilt test results were negative in 12 patients (92.3%). In conclusion, neurally mediated mechanisms seem to be implicated in the pathophysiology of syncope in patients with DC and should therefore be considered in the differential diagnosis of syncopal episodes of unexplained origin. (c) 2007 Elsevier Inc. All rights reserved