Cholesterol 25-hydroxylase on chromosome 10q is a susceptibility gene for sporadic Alzheimer's disease

Alzheimer's disease (AD) is the most common cause of dementia. It is characterized by beta-amyloid (A beta) plaques, neurofibrillary tangles and the degeneration of specifically vulnerable brain neurons. We observed high expression of the cholesterol 25-hydroxylase (CH25H) gene in specifically vulnerable brain regions of AD patients. CH25H maps to a region within 10q23 that has been previously linked to sporadic AD. Sequencing of the 5' region of CH25H revealed three common haplotypes, CH25Hchi2, CH25Hchi3 and CH25Hchi4; CSF levels of the cholesterol precursor lathosterol were higher in carriers of the CH25Hchi4 haplotype. In 1,282 patients with AD and 1,312 healthy control subjects from five independent populations, a common variation in the vicinity of CH25H was significantly associated with the risk for sporadic AD (p = 0.006). Quantitative neuropathology of brains from elderly non-demented subjects showed brain A beta deposits in carriers of CH25Hchi4 and CH25Hchi3 haplotypes, whereas no A beta deposits were present in CH25Hchi2 carriers. Together, these results are compatible with a role of CH25Hchi4 as a putative susceptibility factor for sporadic AD; they may explain part of the linkage of chromosome 10 markers with sporadic AD, and they suggest the possibility that CH25H polymorphisms are associated with different rates of brain A beta deposition.     

Effects of memory consolidation on human hippocampal activity during retrieval

Day-to-day memories undergo transformation from short-term to long-term storage, a process called memory consolidation. Animal studies showed that memory consolidation requires protein synthesis and the growth of new hippocampal synapses within 24 h. To test for effects of memory consolidation in the human, we examined brain activation during the retrieval of information at 10 min and at 24 h following learning using functional magnetic resonance imaging (fMRI), an indirect measure of synaptic activity. Learning instructions were adjusted to yield a comparable retrieval quantity and retrieval quality at 10 min and 24 h after learning. The left hippocampal formation exhibited enhanced activity during the retrieval at the 24 h lag compared to the retrieval at the 10 min lag. Moreover, the activity in the left anterior hippocampal formation showed stronger correlations with retrieval quantity and retrieval quality at the 24 h lag than at the 10 min lag. This suggests that the relation between left anterior hippocampal activity and retrieval success became closer as consolidation progressed. These fMRI results in the human hippocampal formation may correspond to the neurobiological results in the animal hippocampal formation of a strengthening and growth of synaptic connections within 24 h.     

High-frequency somatosensory thalamocortical oscillations and psychopathology in schizophrenia

Human cortical somatosensory evoked potentials (SEPs), which are presumably generated in afferent thalamocortical and early cortical fibers, reveal a burst of superimposed early (N20) high-frequency oscillations (HFOs), around 600 Hz. There is increasing evidence of an imbalance of thalamocortical systems in schizophrenic patients. In order to assess correlations between somatosensory evoked oscillations and symptoms of schizophrenia, we investigated median nerve SEPs in 20 inpatients and their age-matched and gender-matched healthy controls using a multichannel EEG. Dipole source analysis and wavelet transformation were performed before and after application of a 450-Hz high-pass filter. In schizophrenics, the maximum HFOs occurred with a significantly prolonged latency. There was also a higher amplitude (energy) in the low-frequency range of the N20 component compared with the controls. Importantly, amplitudes (energy) of HFOs were inversely correlated with symptoms of formal thought disorder and delusions. Alterations of the thalamocortical somatosensory signal processing in schizophrenia with absence of an early HFO - assumed to be of inhibitory nature - could indicate a dysfunctional thalamic inhibition with increased amplitudes of N20, paralleled by enhanced positive schizophrenic symptoms.     

Identification of a circulating soluble form of CD80: levels in patients with hematological malignancies

The release of soluble forms of CD80 provides a potentially powerful mechanism for the modulation of anti-tumor responses. In this report we investigated whether a soluble form of CD80 (sCD80) circulates in vivo and whether levels are altered in patients with hematological malignancies. Circulating sCD80 was detected by ELISA in all normal donor (0.024-0.318 ng/ml) and patient (0.02-3.75 ng/ml) blood analyzed. The majority of acute myeloid leukemia (13/17) and multiple myeloma (11/12) patients had normal sCD80 levels. Significantly elevated levels were detected in chronic lymphocytic leukemia (CLL, P = 0.0001) and mantle cell lymphoma (MCL, P = 0.0002) patients. MCL patients had the highest levels with 8/9 having levels > 0.318 ng/ml. Increased sCD80 levels in CLL were significantly associated with poor prognosis markers such as low platelet (P = 0.01) and hemoglobin (P = 0.002) levels, elevated WBC counts (P = 0.03) and expression of CD38 (P = 0.048). The immunoreactivity of the sCD80 in both normal and patient plasma was inhibited by the presence of CTLA-4-Ig, suggesting sCD80 is functional. Comparison of sCD80 and soluble CD86 levels demonstrated that these molecules were independently elevated in 39% of patients. The finding that a proportion of CLL and the majority of MCL patients contain elevated levels of sCD80 and the demonstration that sCD80 can interact with CTLA-4-Ig suggests a potential role for sCD80 in modulating anti-tumor responses during the malignant process.     

The effects of preprimed oxygenators on gas transfer efficiency

Cancellation of on-pump coronary artery bypass grafting after the circuit is primed may result in the discarding of unused circuits. In some off-pump cases, a surgeon may request that the circuit be primed, but complete the surgical procedure without utilizing the circuit. The major concerns about the unused circuit are its sterility and the performance of the oxygenator after it has been primed for a long period of time. The goal of this study is to determine whether prepriming of the circuit with and without albumin has an effect on the gas transfer efficiency of oxygenators during simulated cardiopulmonary bypass. Monolyth integrated membrane lungs (Sorin Biomedical, Arvada, CO) were used to deoxygenate and oxygenate the bovine blood. Oxygenators were preprimed for 72 (N = 6) and 24 (N = 6) hours before testing. In control group (N = 6), oxygenators were tested immediately (0 h) after they were primed. Three different priming solutions were used: physiological saline solution (Group A); 1.25% of human albumin (Group B); and 5% human albumin (Group C). The blood was modified to the American Association of Medical Instrumentation Standards before testing. The blood flow through the oxygenators was set at 2 Lpm and 4 Lpm, with gas (FiO2 at 1.0) to blood flow ratio at 1:1. Cultures were also obtained from preprimed oxygenators to test circuit sterility. Oxygen transfer in oxygenators primed for 0 h at blood flow of 4 Lpm were 203 mL/min +/- 9.7 (Group A), 263.1 mL/min +/- 52.9 (Group B), and 270.5 mL/min +/- 13.1(Group C, p < .01 vs. Group A). In oxygenators preprimed for 72 h, the CO2 transfers were 135.0 mL/min +/- 21.8 (Group A), 104.9 mL/min +/- 2.4 (Group B), and 148.9 +/- 26.6 (Group C, p < .006 vs. Group B). In addition, the pressure drops were 56.5 mmHg +/- 5.5 (Group A), 82.6 mmHg +/- 13.4 (Group B), and 67.6 mmHg +/- 15.3 (Group C, p < .05 vs. Group B). In group A, O2 transfer were 203.5 mL/min +/- 9.7 (0 h), 272.4 mL/min +/- 66.6 (24 h), and 260.8 mL/min +/- 31.1 (72 h, p < .01 vs. 0 h). In group B, O2 transfer were 263.1 mL/min +/- 52.0 (0 h), 302.7 mL/min +/- 77.4 (24 h), and 235.2 mL/min +/- 16.5 (72 hr, p < .02 vs. 24 hr). Cultures obtained from 12 preprimed oxygenators presented no organism growth for up to 5 days. In conclusion, oxygen transfer increases in oxygenators preprimed with albumin immediately after they were primed. However, gas transfer decreased after they were primed with albumin for 72 h. Oxygenators preprimed for 24 h and 72 h with 0.9% saline had better O2 transfer than those primed for 0 h.     

Carbon dioxide elimination during laparoscopy in children is age dependent

The absorption of carbon dioxide (CO₂) used for positive pressure pneumoperitoneum may lead to an increased CO₂ load. CO₂ elimination during laparoscopy has not been investigated previously in paediatrics. The aim of this study was to characterise the pattern of CO₂ elimination during laparoscopic surgery in infants and children. Methods: Twenty children undergoing laparoscopy and 19 children undergoing laparotomy for elective abdominal operations were studied. Pneumoperitoneum was achieved using insufflation of unheated CO₂. CO₂ elimination (metabolically produced + absorbed; milliliters per kilogram per minute) was measured minute by minute during the operation by indirect calorimetry. End-tidal CO₂ (kPa) was recorded every 10 minutes. The above variables were assessed before CO₂ insufflation, during pneumoperitoneum, and after desufflation. Results: Before insufflation, CO₂ elimination was 4.6 [plusmn] 0.3 ml/kg/min and increased after 15 minutes of pneumoperitoneum to 5.2 [plusmn] 0.3 (P [lt ] .001). Post desufflation, CO₂ elimination decreased toward preinsufflation values, but did not return to baseline by the end of operation (5.8 [plusmn] 0.3; P [lt ] .001). End-tidal CO₂ was 4.7 [plusmn] 0.2 preinsufflation, peaked at 1 hour (5.3 [plusmn] 0.2; P [lt ] .001) and subsequently decreased in response to ventilatory adjustments. The total amount of CO₂ insufflated was positively correlated with patient age (r² = 0.27; P [lt ] .01). CO₂ elimination was age related, as indicated by multilevel model analysis and by negative correlations between maximum increase in CO₂ elimination and both age (r² = 0.27; P [lt ] .01) and weight (r² = 0.29; P [lt ] .01). These data suggest that the younger or smaller the child, the larger the increase in CO₂ elimination. Seven patients (35%) responded to desufflation with a sharp transient increase in CO₂ elimination, which did not appear to be related to patient age, length of pneumoperitoneum, abdominal pressure, or type of operation. Conclusions: During pneumoperitoneum, younger children absorb proportionately more CO₂ than older individuals. The short-lived increase in CO₂ elimination postdesufflation may be related to an increase in venous return from the lower limbs after release of the abdominal pressure. These findings suggest that small children warrant close monitoring during laparoscopy and during the immediate postoperative period. J Pediatr Surg 38:105-110.     

Multislice computed tomography angiography in pediatric liver transplantation

BACKGROUND: Preoperative delineation of any vascular anomalies offers planning for possible alteration of surgical procedures, especially in pediatric recipients undergoing living-related liver transplantation. PURPOSE: We assess the efficacy of three-dimensional (3D) multislice computed tomography (CT) angiography in the hope of replacing conventional angiography as the pretransplant evaluation of the hepatic vascular system for potential recipients of liver transplantation. METHODS: 3D CT angiography was performed in 38 children with biliary atresia. Conventional angiography was also performed in the first 15 patients. Twelve patients underwent living-related liver transplantation. The findings on 3D CT angiography were compared with conventional angiography and operative findings. RESULTS: 3D CT angiography was successfully performed in 37 pediatric patients. All findings of 3D CT angiography on hepatic artery, portal vein, and inferior vena cava paralleled those of catheter angiography and operative findings. Four patients were unsuitable to receive living grafts because of pathologic insults of the hepatic artery (one patient) and the portal vein (three patients). Three patients were advised to undergo a venous graft for portal anastomoses. Eight patients demonstrated portosystemic shunts that may require closure. CONCLUSION: 3D CT angiography proves to be a better tool in the demonstration of the vascular system and identification of pathologic insults in pediatric patients. It is superior to conventional angiography because it is less invasive, more convenient, and more efficient in providing thorough preoperative information that would have a major impact on patient selection and surgical planning.