Multiplex meta-analysis of RNA expression to identify genes with variants associated with immune dysfunction

Objective

We demonstrate a genome-wide method for the integration of many studies of gene expression of phenotypically similar disease processes, a method of multiplex meta-analysis. We use immune dysfunction as an example disease process.

Design

We use a heterogeneous collection of datasets across human and mice samples from a range of tissues and different forms of immunodeficiency. We developed a method integrating Tibshirani''s modified t-test (SAM) is used to interrogate differential expression within a study and Fisher''s method for omnibus meta-analysis to identify differentially expressed genes across studies. The ability of this overall gene expression profile to prioritize disease associated genes is evaluated by comparing against the results of a recent genome wide association study for common variable immunodeficiency (CVID).

Results

Our approach is able to prioritize genes associated with immunodeficiency in general (area under the ROC curve = 0.713) and CVID in particular (area under the ROC curve = 0.643).

Conclusions

This approach may be used to investigate a larger range of failures of the immune system. Our method may be extended to other disease processes, using RNA levels to prioritize genes likely to contain disease associated DNA variants.     

Left ventricular mass in normotensive,prehypertensive and hypertensive children and adolescents

The purpose of this study was to investigate differences in left ventricular mass index (LVMI) and the prevalence of left ventricular hypertrophy (LVH) in children and adolescents classified as normotensives, prehypertensives and hypertensives by ambulatory blood pressure (BP) levels. A total of 124 consecutive children and adolescents aged 5 to 18 years were analysed. Patients underwent 24 h ambulatory blood pressure monitoring (ABPM) and echocardiography. Hypertensive and prehypertensive subjects had significantly higher LVMI than normotensives (36.8 ± 8.4 g/m^2.7 and 34.1 ± 3.4 g/m^2.7 vs. 29.5 ± 8.3 g/m^2.7, P < 0.01 and P < 0.05, respectively). In multivariate analysis predictors for LVMI were body mass index (BMI) z score and hypertension (R-squared = 0.31). LVMI values in hypertensive subjects were significantly higher than those of normotensives even after adjustment for age, sex and BMI z score. The prevalence of LVH was significantly higher in the prehypertensive compared to normotensive subjects, and was equal to that of the hypertensive subjects. Hypertension and prehypertension in children and adolescents were associated with pathologically elevated LVMI values. If confirmed in a larger group prehypertensive children may be at risk for target organ damage similar to the condition of established hypertension.     

Feasibility, Safety, and Cost Outcomes of Laparoscopic Management of Early Endometrial and Cervical Malignancy

Background:

The role of laparoscopy in the management of early stage endometrial and cervical cancer is continuously validated by many reports throughout the world. Interestingly, such data are still unavailable in many European countries, as it is in Greece. In this prospective study, we report on initial feasibility, safety, and cost outcomes of laparoscopic management of early stage endometrial and cervical cancer, recently introduced in our country.

Materials and Methods:

This was a prospective pilot study comprising a case series. Patients referred to a tertiary referral medical center with a recent diagnosis of endometrial or cervical cancer were evaluated, and those meeting inclusion criteria were offered laparoscopic surgical staging.

Results:

Out of 64 patients evaluated, 17 with early clinical stage endometrial cancer and 8 with early clinical stage cervical cancer underwent successful laparoscopic staging. Mean patient age was 61.6 and 39.2 years, mean BMI was 32.3 and 24.1kg/m², mean operative time was 243 and 284 minutes, mean estimated blood loss was 190mL and 270mL, mean lymph node count was 27.2 and 29.1, and mean hospital stay was 2 and 3 days for endometrial and cervical cancer cases, respectively. The overall costs for the procedures performed were not greater than their laparotomy counterpart. One intraoperative complication was managed laparoscopically, and 2 cases occurred of postoperative lymphocyst formation.

Conclusion:

To our knowledge, this is the first study of laparoscopic management of early endometrial and cervical cancer in Greece. Our preliminary data support the feasibility, safety, and cost effectiveness of laparoscopic management of early endometrial and cervical cancer in our country and are in accordance with series reported in the international literature.     

Kinematics of stair descent in young and older adults and the impact of exercise training

Stair descent is a challenging task in old age. This study firstly investigated lower extremity kinematics during stair descent in young (YOU) and healthy, community dwelling older adults (OLD). Secondly, the impact of an exercise training intervention on age-related differences in stair descent was assessed. At baseline, a motion analysis system was used to determine spatio-temporal gait variables and lower extremity kinematics as YOU (n=23, age=27+/-3 years) and OLD (n=34, age=73+/-4 years) descended a three step staircase. The older adults were then divided into training (TRA) and control (CON) groups. For 12 months, TRA performed resistance, aerobic, balance, and flexibility exercises under supervision in a class environment (twice per week) and unsupervised at home (once per week). CON carried on with normal daily activities. Following the intervention, baseline measurements were repeated in TRA and CON. At baseline, total descent, stride cycle, and single support times were longer in OLD than in YOU. In addition, sagittal plane knee motion was lower in OLD whilst frontal and transverse plane pelvis and hip motion were higher in OLD. Exercise training did not reduce the age-related differences observed. In conclusion healthy older adults perform stair descent at a slower speed and with greater motion outside the plane of progression than young adults. We found no evidence that these differences are reduced by generic exercise training, at least in non-frail older adults.     

Moment arms of the knee extensor mechanism in children and adults

In the present study we investigated whether there are differences in the patellar tendon moment arm (PTMA)-knee angle relationship between pre-pubertal children and adults, and whether the PTMA length scales to relevant anthropometric measurements in the two groups. Anthropometric characteristics and the PTMA length-joint angle relationships were determined in 20 adults and 20 pre-pubertal children of both genders. The anthropometric characteristics measured were height, body mass, knee circumference, medio-lateral knee breadth, anterior-posterior knee depth, leg length, femur length and tibia length. The PTMA was quantified from magnetic resonance images using the geometric centre of the femoral condyle method, at every 5° between 55° and 90° of knee flexion (0° is full extension). Adults had a significantly greater PTMA length at all joint angles (4.2 ± 0.4 vs. 3.6 ± 0.3 cm at 90°; P  < 0.01), with the PTMA length decreasing from knee extension to knee flexion similarly in both adults and children. There were no significant and strong correlations between the PTMA and anthropometric measures in adults for any joint angle. In contrast, the PTMA correlated and scaled with anthropometric characteristics for the children ( P  < 0.05, r  = 0.49–0.9) at all joint angles. The PTMA length in children was most accurately predicted at 85° of flexion from the equation PTMA = –0.25 + 0.083·tibia length + 0.02·leg length ( R ² = 0.83). These findings indicate that the knee extensor mechanism in pre-pubertal children should not be considered to be a 'scaled-down' version of that in adults.