Gene variants in the folate-mediated one-carbon metabolism (FOCM) pathway as risk factors for conotruncal heart defects

We evaluated 35 variants among four folate-mediated one-carbon metabolism pathway genes, MTHFD1, SHMT1, MTHFR, and DHFR as risk factors for conotruncal heart defects. Cases with a diagnosis of single gene disorders or chromosomal aneusomies were excluded. Controls were randomly selected from area hospitals in proportion to their contribution to the total population of live-born infants. Odds ratios (OR) and the 95% confidence intervals (CI) were computed for each genotype (homozygous variant or heterozygote, vs. homozygous wildtype) and for increase of each less common allele (log-additive model). Interactions between each variant and three folate intake variables (maternal multivitamin use, maternal dietary folate intake, and combined maternal folate intake) were also evaluated under the log-additive model. In general, we did not identify notable associations. The A allele of MTHFD1 rs11627387 was associated with a 1.7-fold increase in conotruncal defects risk in both Hispanic mothers (OR = 1.7, 95% CI = 1.1-2.5) and Hispanic infants (OR = 1.7, 95% CI = 1.2-2.3). The T allele of MTHFR rs1801133 was associated with a 2.8-fold increase of risk among Hispanic women whose dietary folate intake was ≤ 25th centile. The C allele of MTHFR rs1801131 was associated with a two-fold increase of risk (OR = 2.0, 95% CI = 1.0-3.9) only among those whose dietary folate intake was >25th centile. Our study suggested that MTHFD1 rs11627387 may be associated with risk of conotruncal defects through both maternal and offspring genotype effect among the Hispanics. Maternal functional variants in MTHFR gene may interact with dietary folate intake and modify the conotruncal defects risk in the offspring.     

Controlling septation in fission yeast: finding the middle, and timing it right

The fission yeast Schizosaccharomyces pombe provides a simple eukaryotic model for the study of cytokinesis. S. pombe cells are rod-shaped, grow mainly by elongation at their tips, and divide by binary fission after forming a centrally placed division septum. Analysis of mutants has begun to shed light upon how septum formation and cytokinesis are regulated both spatially and temporally. Some of the proteins involved in these events have been functionally conserved throughout eukaryotic evolution, suggesting that aspects of this control will be common to all eukaryotic cells. Received: 16 December 1998 / 10 March 1999     

Maffucci syndrome: a genome-wide analysis using high resolution single nucleotide polymorphism and expression arrays on four cases

Ollier disease and Maffucci syndrome are rare, nonhereditary skeletal disorders characterized by the presence of multiple enchondromas with (Maffucci) or without (Ollier) co-existing multiple hemangiomas of soft tissue. Enchondromas can progress toward central chondrosarcomas. PTH1R mutations are found in a small subset of Ollier patients. The genetic deficit in Maffucci syndrome is unknown. Here, we report the first genome-wide analysis using Affymetrix SNP 6.0 array on Maffucci enchondromas (n = 4) and chondrosarcomas (n = 2) from four cases. Results were compared to a previously studied cohort of Ollier patients (n = 37). We found no loss of heterozygosity (LOH) or common copy number alterations shared by all enchondromas, with the exception of some copy number variations. As expected, chondrosarcomas were found to have multiple genomic imbalances. This is similar to conventional solitary and Ollier-related enchondromas and chondrosarcomas and supports the multistep genetic progression model. Expression profiling using Illumina BeadArray-v3 chip revealed that cartilaginous tumors in Maffucci patients are more similar to such tumors in Ollier patients than to sporadic cartilage tumors. Point mutations in a single gene or other copy number neutral genomic changes might play a role in enchondromagenesis.     

Longitudinal analysis of pneumococcal antibodies during community-acquired pneumonia reveals a much higher involvement of Streptococcus pneumoniae than estimated by conventional methods alone

In up to half of all cases of community-acquired pneumonia (CAP), no pathogen can be identified with conventional diagnostic methods. The most common identified causative agent is Streptococcus pneumoniae. In this study, pneumococcal antibody responses during CAP were analyzed to estimate the contribution of the pneumococcus to all cases of CAP for epidemiological purposes. Pneumococcal antibodies against 14 different serotypes were measured in serum of hospitalized CAP patients. Patients participated in one of two consecutive clinical trials in a general 600-bed teaching hospital in the Netherlands (between October 2004 and June 2009). A significant pneumococcal immune response was defined as at least a 2-fold increase in antibody concentrations against a single serotype between an early (day 1) and a late (day 30) serum sample of each patient with an end concentration above 0.35 μg/ml. A total of 349 adult CAP patients participated in two consecutive clinical trials. For 200 patients, sufficient serum samples were available to determine antibody responses: 62 pneumococcal pneumonia patients, 57 nonpneumococcal pneumonia patients, and 81 patients with an unidentified causative agent. A significant immune response was detected in 45% (28/62 patients) of pneumococcal pneumonia patients, in 5% (3/57) of nonpneumococcal pneumonia patients, and in 28% (23/81) of patients with an unidentified causative agent. The estimated contribution of pneumococci in patients with an unidentified causative agent was calculated to be 57% (95% confidence interval, 36 to 86%). A substantial fraction of pneumococcal pneumonia patients do not elicit a serotype-specific immune response.     

Laparoscopic presacral neurolysis for endometriosis-related pelvic pain

BACKGROUND: Some patients with endometriosis are candidates for sympathectomy of the superior hypogastric plexus. The objective of this paper is to describe our technique of laparoscopic presacral neurolysis for sympathectomy and to report 1 year results of the first 15 cases. METHODS: To achieve this objective in a prospective observational study of 1 year follow-up; we performed laparoscopic presacral chemical neurolysis with phenol in 15 patients with pelvic pain and minimal-moderate endometriosis. The main outcome measures were: the impact of treatment on pelvic symptom resolution, non-opioid analgesic consumption during menses, sexual performance and observed complications and side effects during 1 year follow-up. RESULTS: We noted a significant reduction in total pelvic symptom score as compared with baseline mean (SD) of 9.04 (1.2). The mean difference [95% confidence interval (CI)] of reduction was 5.7 (4.9-6.5), 5.8 (5.0-6.6) and 5.8 (4.9-6.6) from the baseline at the 3rd, 6th and 12th postoperative month (P < 0.001). We observed a significant improvement in Sabbatberg Sexual Rating Scale as compared with baseline mean (SD) of 30.9 (4.3). The mean difference (95% CI) of increase was 33.4 (30.3-36.4), 33.2 (30.1-36.2) and 33.2 (30.1-36.3) from the baseline at the 3rd, 6th and 12th postoperative month. We observed a significant reduction in analgesic consumption during menses in terms of total naproxen sodium tablets as compared with baseline mean (SD) of 8.9 (1.1). The mean difference (95% CI) of reduction in the total number of naproxen sodium 250 mg tablets was 6.5 (5.5-7.5), 6.7 (5.7-7.7) and 6.6 (5.6-7.6) from the baseline at the 3rd, 6th and 12th postoperative month. The most common side effect was constipation. CONCLUSION: Laparoscopic presacral neurolysis is feasible and simple. More data is needed to support its efficacy and safety.     

Comparison of dobutamine stress echocardiography and technetium-99m sestamibi single-photon emission tomography for the diagnosis of coronary artery disease in hypertensive patients with and without left ventricular hypertrophy

Stress echocardiography has been considered an accurate method for the diagnosis of coronary artery disease in hypertensive patients and in patients with left ventricular hypertrophy. In contrast, the specificity of myocardial perfusion scintigraphy in these patients has been questioned. The aim of this study was to compare the accuracy of these two imaging modalities in conjunction with dobutamine stress test for the diagnosis of coronary artery disease in hypertensive patients with and without left ventricular hypertrophy. Dobutamine (up to 40 μg kg^–1min^–1) stress echocardiography in conjunction with sestamibi (MIBI) single-photon emission tomography (SPET) was performed in 84 patients with the diagnosis of systemic hypertension who had been referred for evaluation of myocardial ischaemia. Ischaemia was defined as new or worsened wall motion abnormalities at echocardiography and reversible perfusion defects at SPET. Significant coronary artery disease (≥50% luminal diameter stenosis) was detected in 66 patients (79%). The sensitivity, specificity and accuracy of the ischaemic pattern at echocardiography for the diagnosis of coronary artery disease were 73% (CI 63%–82%), 83% (CI 75%–91%) and 75% (CI 66%–84%), those for MIBI were 67% (CI 57%–77%), 83% (CI 75%–91%) and 70% (CI 60%–80%) respectively (P = NS vs echocardiography). Significant stenosis was detected in 123 (49%) of the 252 analysed coronary arteries. The sensitivity, specificity and accuracy of echocardiography for the regional diagnosis of coronary artery disease were 63% (CI 56%–69%), 90% (CI 86%–94%) and 77% (CI 72%–82%). Those for MIBI were 58% (CI 51%–64%), 91% (CI 87%–94%) and 75% (CI 69%–80) respectively (P = NS vs echocardiography). Left ventricular hypertrophy was detected in 59 patients (70%) by echocardiography and did not influence the overall or regional specificity of echocardiography or MIBI SPET. It is concluded that in hypertensive patients, dobutamine stress echocardiography and MIBI SPET have a comparable accuracy for the overall and regional diagnosis of coronary artery disease. Hypertensive patients with or without left ventricular hypertrophy should not be considered unsuitable candidates for stress myocardial perfusion scintigraphy. Received 10 July and in revised form 19 September 1997     

Spinal injuries in children

Background/purpose

Traumatic spinal injury (TSI) is an uncommon source of morbidity and mortality in children. The aim of this study was to describe childhood TSI in a single level 1 urban pediatric trauma center.

Methods

The authors retrospectively analyzed all children younger than 14 years with TSI, treated at a level I pediatric trauma center between 1991 and 2002 (n = 406, 4% total registry). All children were stratified according to demographics, mechanisms, type and level of injury, radiologic evaluations, associated injuries, and mortality.

Results

The mean age was 9.48 ± 3.81 years. The most common overall mechanism of injury was motor vehicle crash (MVC; 29%) and ranked highest for infants. Falls ranked highest for ages 2 to 9 years. Sports ranked highest in the 10 to 14 year age group. Paravertebral soft tissue injuries were 68%. The most common injury level was the high cervical spine (O-C4). The incidence of spinal cord injury without radiologic abnormality (SCIWORA) was 6%. Traumatic brain injury (37%) was the most common associated injury. Overall mortality rate was 4% in this urban catchment.

Conclusions

TSI in children requires a different preventive and therapeutic logarithm compared with that of adults. The potential devastating nature of TSI warrants that the health care team always maintains a high index of suspicion for injury. Future prospective studies are needed to further elucidate injury patterns.