The identification of polymorphisms in the coding region of the apolipoprotein (a) gene--association with earlier identified polymorphic sites and influence on the lipoprotein (a) concentration

Lipoprotein (a) [Lp(a)] is a quantitative genetic trait in human plasma and elevated levels represent a major inherited risk factor for the development of atherosclerotic disease. In our search for sequence polymorphisms in the coding region of the apolipoprotein(a) [apo(a)] gene that may affect the Lp(a) concentration, four new polymorphic sites were identified. These include two coinciding polymorphisms with an allele frequency of 38% located at amino acid positions 87 and 101 (Leu87,101-->Val) in the interkringle region of kringle IV (K.IV) type 7 and two polymorphisms located in K.IV type 7 (Arg60-->Ser) and in K.IV type 10 (Tyr2-->Phe) both with estimated allele frequencies of about 1%. The linkage between the newly identified K.IV type 7 Leu87,101 -->Val polymorphism and earlier described polymorphic sites in the non-coding and coding regions of the apo(a) gene, its distribution over the apo(a) isoform sizes and its possible influence on the Lp(a) concentration was analysed in 201 healthy unrelated Caucasians. The earlier described polymorphic sites included in this study were the variable number of a TTTTA pentanucleotide repeat (7-11 PNR) starting at -1231 bp, the -772 bp G/A polymorphism, the +93 bp C/T polymorphism and the +121 bp G/A polymorphism in the non-coding region, and the K.IV type 8 Thr12/Pro polymorphism and the K.IV type 10 Thr66/Met polymorphism in the coding region of the apo(a) gene. Linkage disequilibria were observed between the polymorphic sites in the 5' non-coding region and the sites in K.IV type 7 and 8 in the coding region of the apo(a) gene, confirming that the expansion of the variable number of K.IV type 2 repeats results from intrachromosomal recombinational events. The distribution over the apo(a) isoform sizes of the K.IV type 7 Val87,101 subtype was not significantly different from that of the K.IV type 7 Leu87,101 wild-type, suggesting a relative ancient mutational event. No influence of the K.IV type 7 Leu87,101-->Val polymorphism on the Lp(a) level was observed. In fact, of all the polymorphic sites studied, only the +121 A subtype could be associated with an increased, and the K.IV type 8 Pro12 and the 10 PNR subtypes with a reduced, Lp(a) concentration corrected for apo(a) isoform size (p <0.05).     

The impact of glycogen synthase kinase 3β gene on psychotic mania in bipolar disorder patients

Objective

The aim of this study was to examine the relationships between glycogen synthase 3β gene polymorphisms and bipolar I disorder, manic in a Korean sample.

Methods

Patients with bipolar disorder (n = 118) and a control group (n = 158) were assessed by genotyping for GSK3β single nucleotide polymorphisms (SNPs) − 1727A/T and − 50C/T. The patients were divided into two groups according to the presence of psychotic symptoms (psychotic mania, n = 92; non-psychotic mania, n = 26) and also divided based on gender and age of onset. The severity of symptoms was measured using the Young Mania Rating Scale (YMRS) and the Brief Psychiatric Rating Scale (BPRS).

Results

There were no significant differences in the genotype distributions or allelic frequencies of GSK3β polymorphisms and gender between patients with bipolar disorder and a normal control group. According to haplotype analysis, there was no association between these two groups. However, analysis of the age of onset of bipolar disorder revealed significant differences in genotype and allele distributions among the patients. Patients who were homozygous for the wild-type variant (TT) had an older age of onset than carriers of the mutant allele (A/A: 27.4 ± 9.1; A/T: 30.1 ± 11.8; T/T: 42.3 ± 19.9; p = 0.034). We detected differences in allele frequencies of the GSK3β − 1727A/T polymorphism between the psychotic mania group and the non-psychotic mania group.

Conclusion

This study suggests that GSK3β polymorphisms are not associated with bipolar disorder. However, the GSK3β SNP − 1727A/T is associated with age of onset and presence of psychotic symptoms in bipolar disorder.     

Serum Lipoprotein (a) Levels in Patients with First Unprovoked Venous Thromboembolism is not Associated with Subsequent Risk of Recurrent VTE

Introduction

Case-control studies suggest that elevated lipoprotein (a) (Lp(a)) is a risk factor for first venous thromboembolism (VTE). Lp(a) has not been prospectively investigated as a possible risk factor for recurrent VTE in first unprovoked VTE patients. We sought to determine if serum Lp(a) levels in patients with unprovoked VTE who discontinue anticoagulants after 5 to 7 months of therapy predict VTE recurrence in a prospective cohort study.

Materials and Methods

Serum Lp(a) measurements were obtained from 510 first unprovoked VTE patients treated for 5 -7 months with anticoagulants in a 12 center study. Patients were subsequently followed for a mean of 16.9 months (SD ± 11.2) for symptomatic VTE recurrence which was independently adjudicated with reference to baseline imaging.

Results

There was no significant association between Lp(a) as a continuous variable and recurrent VTE nor in gender stratified subgroups. No statistically significant differences were observed in the median Lp(a) concentrations between patients who recurred and those who did not recur (median (interquartile range): 0.09 g/L (0.17) versus 0.06 g/L (0.11) respectively; p = 0.15). The Lp(a) cut-off point of 0.3 g/L was not significantly associated with recurrent VTE for the overall population nor in gender stratified subgroups.

Conclusions

Elevated serum Lp(a) does not appear to be associated with recurrent VTE in patients with history of first unprovoked VTE and may not play a role in identifying patients with unprovoked VTE at high risk of recurrence. There was no optimal predictive threshold for the overall population or for sex sub-groups and Lp(a) ≥ 0.3 g/L was not a significant predictor of recurrent VTE.     

Influence of anticoagulant therapy with vitamin K antagonists on plasma levels of coagulation factor VIII

Vitamin K-antagonists (VKA) decreases vitamin K coagulation factors. To counterbalance this effect, it has been postulated that non-vitamin K proteins increase during VKA treatment. To investigate if VKA affect FVIII, a cohort of 1772 patients referred from Jan 1997 to Oct 2008 to our Thrombosis Center for a thrombophilia screening after at least 3 months from diagnosis of first venous thrombosis was studied. At the time of blood sampling, 1303 patients had discontinued VKA for at least one month, whereas the remaining 469 were still taking VKA. FVIII was significantly higher in patients on VKA than in those who had discontinued VKA (mean±SD: 144 ± 41 IU/dL and 134 ± 40 IU/dL, respectively, p < 0.0001), also after adjustment for sex, age, body mass index, thrombophilia and time elapsed from thrombosis in a multiple linear regression analysis. In order to avoid overestimation of FVIII levels, patients should be preferentially tested after VKA discontinuation.     

Lipoprotein (a), LPA Ile4399Met,and Fibrin Clot Properties

Introduction

Elevated lipoprotein(a) (Lp(a)) levels were reported to be associated with dense fibrin clots. The apo(a) component of Lp(a) is encoded by LPA, and the Met allele of the LPA Ile4399Met polymorphism is associated with elevated Lp(a) levels and cardiovascular disease risk. We investigated whether Ile4399Met was associated with fibrin clot properties.

Materials and Methods

We determined plasma Lp(a) levels, fibrin clot permeability and lysis time for 64 LPA 4399Met carriers and 128 noncarriers matched for age, sex, ethnicity, and enrollment site.

Results

Elevated Lp(a) levels were associated with reduced clot permeability and prolonged lysis time (P < 0.0001). Carriers of 4399Met had higher Lp(a) levels compared with noncarriers (P = 0.0003). However, this association differed by ethnicity (P = 0.003 for interaction between genotype and ethnicity): compared with noncarriers, 4399Met carriers had 2.89 fold higher Lp(a) levels among Caucasians while no difference was observed among non-Caucasians (primarily East Asians and Hispanics). Among all subjects, no association was observed between Ile4399Met and clot properties, but this relationship also differed by ethnicity: among non-Caucasians, 4399Met carriers had increased clot permeability and shorter lysis time; whereas among Caucasians, the trend was for decreased permeability and longer lysis time (P < 0.01 for interactions between genotype and ethnicity).

Conclusions

We confirmed that elevated Lp(a) levels are associated with dense fibrin clots, and found that the association of LPA 4399Met carriers and clot permeability as well as lysis time differ by ethnicity.     

Interaction between homocysteine and lipoprotein(a) increases the prevalence of coronary artery disease/myocardial infarction in women: a case-control study

Introduction

Our aim was to investigate the association of elevated homocysteine (Hcy) and lipoprotein(a) Lp(a) with the prevalence of coronary artery disease (CAD) and myocardial infarction (MI) and to investigate their interaction in both genders.

Materials and methods

955 (male/female: 578/377) consecutive patients admitted for coronary angiography were enrolled in the study. Lp(a), Hcy, vitamin B12, folic acid, MTHFR C677T polymorphism and traditional risk factors were determined.

Results

619 patients had significant (≥ 50%) stenosis (CAD+) and 341 had MI (MI+). CAD-MI- cases (n = 302) were considered as controls. Adjusted Hcy levels were significantly elevated only in the female CAD + MI + group that was related to decreased vitamin B12 levels. Lp(a) was elevated in the CAD + MI + group of both genders. Folic acid levels and MTHFR T677 allele frequency did not show significant difference. Moderate hyperhomocysteinemia (Hcy > 15 μmol/L) or elevated Lp(a) (> 300 mg/L) increased the risk of CAD (OR 2.27, CI 1.36-3.80 and OR 1.64, CI 1.03-2.61, respectively) and MI (OR 2.52, CI 1.36-4.67 and OR 1.89, CI 1.06-3.38, respectively) only in women. Only simultaneous but not isolated elevation of Hcy and Lp(a) conferred a significant, 3.6-fold risk of CAD in females and even higher (11-fold) risk in young females, which suggested an interactive effect.

Conclusions

Moderate hyperhomocysteinemia or elevated Lp(a) level associated with a risk of CAD and MI only in women. While isolated elevation of one of the two parameters represented a mild risk of CAD, their combined elevation highly increased the risk in females. No such effect was observed in males.     

Lipoprotein a levels in pediatric migraine

The purpose of this study was to examine the lipoprotein (a) [Lp(a)] levels in children with migraine to see a possible relationship between migraine and stroke via high Lp(a) levels. Plasma levels of Lp(a) were determined in 63 patients and age-matched control subjects. The mean age in the control group was 10.57 ± 3.63 years and 11.51 ± 3.19 years in the migraine patient group. The mean Lp(a) levels in control group were 10.36 ± 10.41 ng/mL and 17.09 ± 12.12 ng/mL in migraine group (P < 0.05). The median Lp(a) level in the control group was 49.38 ng/mL and was 77.62 ng/mL in the migraine group (P < 0.05). Twelve patients (19%) had Lp(a) levels of >30 ng/mL in the migraine group and 4 (6.3%) in the control group (P < 0.05). Several prothrombotic factors related to an increased risk of stroke have been studied in migraine patients. It has recently been reported that high Lp(a) concentrations represent a risk factor for migraine, thus establishing a novel plausible link between migraine and stroke. The current study suggests evidence of high Lp(a) concentrations in childhood migraine; perhaps a novel link exists between migraine and stroke.     

Clinical overview of children with mucopolysaccharidosis type III A and effect of Risperidone treatment on children and their mothers psychological status

Mucopolysaccharidosis IIIA (MPS IIIA) is a lysosomal storage disorder characterized by progressive mental deterioration and severe behavioral problems. We conducted an open-label, crossover study of the efficacy and safety of Risperidone on behavioral disorder in children with MPS IIIA. A total of 12 patients (5.5 ± 2.2 years) with enzymatic diagnosis of MPS IIIA were randomly assigned to receive Risperidone (0.125–2 mg/d) for 6 months. The hyperactivity and disruptive behavior level of children before and after treatment was evaluated regarding the scores from Turgay DSM IV Based Child and Adolescent Behavior Disorders Screening and Rating Scale (T-DSM-IV-S). Clinic Global Impression Scale – Severity (CGIS-S) was used for all cases for determining the psychiatric disorder severity. The anxiety and depression levels of mothers before and after treatment were evaluated using Hamilton Anxiety Scale (HAM-A) and Beck Depression Inventory (BDI). The adverse effects were evaluated by monitoring weight, serum prolactin, glucose and lipid levels. The response to the treatment was measured by decrease in values of CGI-S (from 6 ± 1.12 to 2.91 ± 0.66, p = 0.001). According to T-DSM-IV-S scores the best improvement was observed in hyperactivity scores (16.25 ± 8.57/11.58 ± 7.26, p = 0.001), followed by opposition/defiance (6.66 ± 5.92/5.08 ± 4.88, p = 0.032), and conduct disorder scores (1.00 ± 1.85/0.41 ± .99, p = 0.67). No clinically relevant elevations in weight and serum prolactin, glucose or lipid levels have been documented (p > 0.05). There was a significant decrease in anxiety and depression scores of mothers (HAM-A: 20.33 ± 8.28/17.91 ± 6.89, BDI: 23.58 ± 7.14/20.5 ± 5.93, p < 0.001). To our knowledge, research on the pharmacological treatment of MPS IIIA with Risperidone has not been reported. According to our data, Risperidone appeared to be safe and effective in MPS IIIA patients.     

The Krause approach: MRI measurements in the Chinese population

We undertook this study to provide anatomical guidance for preoperative positioning for surgery in the pineal region. The anatomical differences between different ages and sexes were obtained by measuring relevant anatomical parameters on imaging of the infratentorial supracerebellar approach (the Krause approach). MRI of 262 healthy Chinese patients were included (232 adults, 30 children). The depth of the infratentorial supracerebellar approach, the angle between the tentorium cerebelli (the approach orientation) and the glabella-external occipital protuberance line, and the angle between the tentorium cerebelli and the dorsum sellae-external occipital protuberance line were measured and analyzed. In adults, the angle between the infratentorial supracerebellar approach and the glabella-external occipital protuberance line was 35.7° ± 6.3° (mean ± standard deviation [SD]), greater than the same angle in children, 29.3° ± 5.0° (p < 0.01). In adults, the angle (mean ± SD) between the approach orientation and the dorsum sellae-external occipital protuberance line was 36.2° ± 5.0°, greater than the same angle in children, 30.7° ± 4.5° (p < 0.01). The depth of the Krause approach (mean ± SD) was 51.30 mm ± 4.66 mm in men and 47.58 mm ± 4.29 mm in women (p < 0.01), while in children the approach depth was 50.47 mm ± 2.62 mm, with no statistical difference between children and adults (p > 0.05). For surgery using the Krause approach in adults, the inclination angle of the tentorium cerebelli and the depth provided by the median sagittal MRI are instructive for preoperative head positioning and intraoperative management. The angle between the approach orientation and the easily observed glabella-external occipital protuberance line can be used to achieve appropriate preoperative positioning and reduce the surgical risk.     

Fibrinogen and D-dimer analysis of chronic subdural hematomas and computed tomography findings: a prospective study

Objective

We investigated the relationship between fibrinolytic factors and computed tomography (CT) findings in patients with chronic subdural hematomas (CSDHs).

Methods

Thirty-one patients with CSDHs were divided on the basis of CT findings into heterogeneous and homogeneous groups. A sample from the subdural hematoma was obtained at surgery to measure the concentrations of fibrinogen and D-dimer.

Results

The mean level of fibrinogen in the heterogeneous group, including the layering (n = 4) and mixed (n = 10) type, was 88.2 ± 121.2 mg/dL, whereas in the homogeneous group, including high density (n = 2), isodensity (n = 9), and low density (n = 6) types, it was <25 mg/dL. The concentration of fibrinogen was significantly higher in the heterogeneous group than in the homogeneous group (p = 0.006). The mean level of D-dimer in the heterogeneous group was 35,407.9 ± 16,325.5 μg/L, whereas for the homogeneous group it was 1476.4 ± 2091.4 μg/L. The concentration of D-dimer was significantly higher in the heterogeneous group than in the homogeneous group (p < 0.001).

Conclusions

The layering and mixed types of CSDH exhibited higher concentrations of fibrinogen and D-dimer in subdural hematoma than the homogeneous types. These fibrinolytic factors appear to be associated with evolution in CSDHs with heterogeneous density.     

Increased uric acid levels in drug-naïve subjects with bipolar disorder during a first manic episode

Recent evidence suggests that purinergic system dysfunction may play a role in the pathophysiology and therapeutics of bipolar disorder (BPD). Uric acid is a key nitrogenous end product of purine metabolism. In addition to being a potential marker of treatment response, high levels of uric acid may represent a state marker during mania. In this study, we assessed the presence of purinergic dysfunction in 20 treatment-naïve first episode patients with BPD who were experiencing a manic episode. Patients were matched with 24 healthy controls. We found that acutely manic patients had significantly higher levels of plasma uric acid (4.85 ± 1.60 mg/dL) compared to healthy controls (2.96 ± 0.63 mg/dL, p < 0.001; F = 28.1). No association between uric acid levels with severity of manic symptoms was observed. These results support the role of purinergic system dysfunction in BPD early in the course of illness, and suggest that this phenomenon is not the result of chronicity or medication exposure. Overall, our findings suggest a novel mechanism in the pathophysiology of BPD.     

Ginkgo biloba for Attention-Deficit/Hyperactivity Disorder in children and adolescents: A double blind,randomized controlled trial

Background

Although stimulants are highly effective in controlling the symptoms of Attention-Deficit/Hyperactivity Disorder (ADHD), some children will not respond to, or are intolerant of stimulants. Thus, the desire for safe and effective nonstimulant medications has risen during the past several years. Ginkgo biloba has been suggested in the treatment of dementia and memory impairment. We hypothesized that G.biloba would be beneficial for treatment of ADHD, and this could be evaluated in a double blind, randomized, parallel group comparison of G.biloba (Ginko T.D.™ Tolidaru, Iran) and methylphenidate.

Methods

Fifty outpatients (39 boys and 11 girls) with a DSM-IV-TR diagnosis of ADHD were study population of this trial. Subjects were recruited from an outpatient child and adolescent clinic for a 6 week double blind, randomized clinical trial. All study subjects were randomly assigned to receive treatment using tablet of Ginko T.D.™ at a dose of 80–120 mg/day depending on weight (80 mg/day for < 30 kg and 120 mg/day for > 30 kg) (group 1) or methylphenidate at a dose of 20–30 mg/day depending on weight (20 mg/day for < 30 kg and 30 mg/day for > 30 kg (group 2) for a 6 week double blind, randomized clinical trial. The principal measure of outcome was the Teacher and Parent ADHD Rating Scale- IV. Patients were assessed at baseline and at 21 and 42 days after the medication started.

Results

Significant differences were observed between the two groups on the Parent and Teacher Rating Scale scores. The changes at the endpoint compared to baseline were: − 6.52 ± 11.43 (mean ± S.D.) and − 15.92 ± 11.44 (mean ± S.D.) for Ginko T.D.™ and methyphenidate, respectively for Parent ADHD Rating Scale. The changes at the endpoint compared to baseline were: − 0.84 ± 6.79 (mean ± S.D.) and − 14.04 ± 8.67 (mean ± S.D.) for Ginko T.D.™ and methyphenidate, respectively for Teacher ADHD Rating Scale.The difference between the Ginko T.D.™ and methylphenidate groups in the frequency of side effects was not significant except for decreased appetite, headache and insomnia that were observed more frequently in the methylphenidate group.

Conclusion

The results of this study suggest that administration of G.biloba was less effective than methylphenidate in the treatment of ADHD.     

The impact of platelet membrane glycoprotein Ib alpha and Ia/IIa polymorphisms on the risk of thrombosis in the antiphospholipid syndrome

Background

Pathogenesis of thrombus formation in antiphospholipid syndrome (APS) is not clear. Platelet membrane glycoprotein (GP) receptors play important roles in development of thrombosis.

Objectives

We investigated the association between development of thrombosis in APS and polymorphisms of GPIb alpha variable number of tandem repeats (VNTR), Kozak, and GPIa C807T.Patients/MethodsSixty patients with APS (30 with proven thrombosis and 30 without thrombosis) and 63 controls were included. Presence of GPIa C807T polymorphism was determined with real-time PCR and GPIb alpha Kozak and VNTR polymorphisms by conventional PCR.

Results

Frequency of C807T TT genotype was significantly higher in APS with thrombosis than APS without thrombosis (p = 0.023) and also in APS with multiple thrombi compared to APS without thrombi (p = 0.023). Frequency of Kozak TC genotype was higher in APS with arterial thrombosis compared to APS with venous thrombosis, controls, and APS without thrombosis (p = 0.03, p = 0.0007, and p = 0.0024 respectively). D allele frequency and D allele carrier state for VNTR were significantly less in APS than controls (p = 0.0018 and p = 0.0046 respectively).

Conclusions

C807T TT genotype may confer a risk for thrombosis and Kozak TC genotype for arterial thrombosis. D allele of VNTR may protect from APS. No patients with C807T TT or Kozak TC genotypes carried the protective DD genotype of VNTR. These polymorphisms may increase risk for both arterial and venous thrombosis. The utility of prophylaxis with anti-platelet drugs in at least a subgroup of APS patients should be investigated with clinical trials.     

Alterations in systemic complement component 3a and 5a levels in patients with cerebral arteriovenous malformations

The role of the complement cascade in the pathophysiology of cerebral arteriovenous malformation (AVM) is largely undefined. Complement subcomponents, C3a and C5a, are potent anaphylatoxins and key mediators of immuno-inflammatory response. Complement activation may contribute to the pro-inflammatory state observed in AVM. Thus, we sought to determine the systemic levels of C3a and C5a and their response to treatments in patients with AVM. Blood samples of 18 patients undergoing treatment for unruptured AVM, and from 30 healthy control participants, were obtained at four times: (i) pre-treatment, (ii) 24-hours post-embolization, (iii) 24-hours post-resection, and at 1-month follow-up. Plasma concentrations of C3a and C5a were measured using enzyme-linked immunosorbent assay. The pre-treatment mean plasma C3a level was significantly higher in patients with AVM (1817 ± 168 ng/mL) compared to controls (1126 ± 151 ng/mL). The mean C3a level decreased 24-hours after embolization (1482 ± 170 ng/mL) and remained at statistically similar levels 24-hours after resection (1511 ± 149 ng/mL) and at 1-month follow-up (1535 ± 133 ng/mL). Mean C3a levels at the three time points were higher than control levels. The baseline mean plasma C5a level was significantly elevated in patients with AVM (13.1 ± 2.2 ng/mL) compared to controls (3.9 ± 1.5 ng/mL). Mean C5a level decreased post-embolization (8.2 ± 2.3 ng/mL) and remained at similar levels post-resection (8.5 ± 3.0 ng/mL) and at 1-month follow-up (7.7 ± 2.9 ng/mL). Mean C5a levels at the three time points were significantly higher than the control levels. We conclude that systemic C3a and C5a levels in patients with AVM are elevated at baseline, decrease significantly after embolization, and remain at the new baseline levels after surgery and 1-month follow-up.     

The effect of seasonality on sleep-disordered breathing severity in children

Objective

Sleep-disordered breathing (SDB) is a common disorder associated with substantial morbidity that occurs in otherwise healthy children. Atopy, asthma, and viral upper respiratory tract infections are known risk factors for pediatric SDB that exhibit seasonal variability. The aim of our study was to investigate the effect of seasonality on SDB severity in children and adolescents referred for polysomnographic evaluation for suspected SDB and to examine the effect of atopy/asthma on this variability.

Methods

The medical records of all children and adolescents referred for a polysomnography (PSG) for suspected SDB between 2008 and 2010 were retrospectively assessed for seasonal patterns. The effect of atopy/asthma, age, and obesity on seasonal variability was investigated.

Results

A total of 2178 children and adolescents (65% boys) were included. The mean age of the cohort was 4.9 ± 3.5 years (range, 3 months–18 years). Eighteen percent of patients had a history of asthma/atopy. The mean obstructive apnea–hypopnea index (OAHI) in the winter was significantly higher compared to the summer (9.1 ± 9.6 vs 7.5 ± 7.0; P = .01; Cohen d = 0.19), particularly in children younger than the age of 5 years (10.2 ± 10.5 vs 7.9 ± 7.3; P = .008; Cohen d = 0.25). Asthma/atopy had no significant effect on seasonal variability.

Conclusions

SDB severity alters in a season-dependent manner in children and adolescents referred for polysomnographic evaluation for suspected SDB. These alterations are more prominent in children younger than the age of 5 years. The presence of asthma/atopy does not contribute to this seasonal variability. These findings suggest that viral respiratory infections are most likely the major contributor for the seasonal variability observed in pediatric SDB; additionally, the time of the year when a child is evaluated for suspected SDB may affect the clinical management and outcome in borderline cases.     

Association between adiponectin gene polymorphisms and coronary artery disease across different populations

Objective

Many studies have suggested that adiponectin gene might be involved in the development of coronary artery disease (CAD). However, the results have been inconsistent. In this study, the authors performed a meta-analysis to assess the associations of + 45T/G, + 276G/T and − 11377C/G polymorphisms in adiponectin gene with CAD susceptibility.

Methods

Published literature from PubMed and EMBASE databases were searched. Pooled odds ratio (OR) and corresponding 95% confidence interval (CI) were calculated using fixed- or random-effects model.

Results

Sixteen studies (4394 cases / 8187 controls) for + 45T/G polymorphism, fifteen studies (3569 cases / 7463 controls) for + 276G/T polymorphism, and thirteen studies (3531 cases / 7072 controls) for − 11377C/G polymorphism were included in the meta-analysis. The overall results showed that there was a statistically significant association between − 11377C/G polymorphism and CAD (G vs. C: OR = 1.15, 95%CI 1.07-1.24).Similar results were observed among European (G vs. C: OR = 1.11, 95%CI 1.02-1.20) and East Asian populations (G vs. C: OR = 1.27, 95%CI 1.11-1.45). However, no significant association was found for + 45T/G or + 276G/T polymorphism with CAD susceptibility.

Conclusions

The meta-analysis indicated the significant association of − 11377C/G polymorphism, but not + 45T/G or + 276G/T polymorphism, with CAD susceptibility. However, large-scale studies with the consideration of gene-gene and gene-environment interactions should be conducted to investigate the associations in future.     

Neurodevelopment in the offspring of Japanese systemic lupus erythematosus patients

Objective: To evaluate pregnancy outcome of systemic lupus erythematosus (SLE) and the neuropsychological outcomes in offspring of SLE mothers. Study design: Pregnancy outcomes of SLE patients from 1989 to 2006 were determined and the neuropsychological development of the children born to SLE patients was examined suited for their age; Bayley Scales of Infant Development up to four years and Kauffmann Assessment Battery for Children from four years onwards. Results: Of the 233 deliveries, 58 (24.7%) were preterm, 72 (30.9%) were low-birth-weight, and 46 (19.7%) were IUGR. Twenty-six children enrolled in this study had normal intelligence. The mean MDI and PDI were 95.8 ± 10.1 and 94.6 ± 14.1, respectively. The mean scores for the Sequential Processing scale, Simultaneous Processing scale, and Mental Processing composite were 103.1 ± 13.3, 104.2 ± 10.2, and 104.2 ± 12.2, respectively. In the children with anti-Ro/SS-A antibody-positive mothers, mean gestational age and birth weight were significantly lower (p < 0.05), as a result, the mean score of Sequential Processing and Mental Processing were significantly lower than that of negative mothers. The presence of maternal antiphospholipid antibody was not related to gestational age, birth weight and any score on the intelligence tests, except for the rate of IUGR. Conclusion: The rates of preterm delivery and IUGR were frequent in the SLE patients and careful monitoring and management of the disease during pregnancy are still necessary. We should examine the neurodevelopment of the children born from mothers with anti-Ro/SS-A antibody prospectively.     

Neuroprotective effects of the beta-catenin stabilization in an oxygen- and glucose-deprived human neural progenitor cell culture system

β-Catenin stabilization achieved either via GSK-3β specific inhibition or involving canonical Wnt signalling pathway, contributes to neuroprotection in an oxygen-glucose deprivation (4 h OGD) in vitro hypoxia model performed on human cortical neural progenitor cells previously differentiated into neurons and glia. Neuroprotection mechanisms include both acquiring tolerance to injury throughout preconditioning (72 h prior to OGD) or being pro-survival during 24 h reoxygenation after the insult. Four hours of OGD induced apoptotic cell death elevation to 73 ± 1% vs. 12% measured in control and the LDH level, indicative of necrotic cell injury, elevation by 67 ± 7% (set to 100%). A significant reduction in apoptosis occurred at 24 h reoxygenation with indirubin supplement which was 49 ± 6% at 2.5 μM BIO while LDH level was only 47 ± 5% of OGD. Kenpaullone was efficient in reducing both cell deaths at 5 μM (apoptosis 38 ± 1% and necrosis 33 ± 3% less than in OGD). Wnt agonist reduced apoptosis to 45 ± 3% at 0.01 μM, while LDH value was decreased to a level of 53 ± 5% of control. Our findings suggest that GSK-3beta inhibitors/β-catenin stabilizers may ultimately be useful drugs in neuroprotection and neuroregeneration therapies in vivo.     

The effect of smoking status on the plasma concentration of prolactin already elevated by risperidone treatment in schizophrenia patients

Smoking prevalence for schizophrenic patients is higher than for the general population. Inter-individual variability in hyperprolactinemia induced antipsychotics particularly risperidone can be explained by smoking status to some extent. We therefore studied the effects of smoking status on the plasma concentration of prolactin. Subjects included 154 schizophrenia patients (61 males, 93 females) who had received 3 mg of risperidone twice daily for at least 4 weeks. Sample collections were conducted 12 h after the bedtime dosing. The plasma concentrations of prolactin in the females were significantly higher than in the males (117.6 ± 69.3 ng/ml vs. 52.9 ± 30.7 ng/ml, p < 0.001). The mean (± SD) plasma concentrations of prolactin did not differ between smokers and nonsmokers in the males (59.5 ± 31.2 ng/ml vs. 47.6 ± 29.3 ng/ml, not significant (ns)), but there was a significant difference in the females (100.2 ± 59.1 vs. 134.0 ± 74.6, ng/ml, p < 0.05). Multiple regression analyses including gender, plasma drug concentration and age revealed that the plasma concentration of prolactin positively correlated with gender (standardized beta = 0.452, p < 0.001) and negatively with age (standardized beta = −0.171, p < 0.05) and smoking status (standardized beta = −0.232, p < 0.01). These findings suggest that smoking status has an impact on prolactin concentration during risperidone treatment. However, further study is required to determine whether these findings have clinical implications.