Low-dose cholinesterase inhibitors do not induce delayed effects on cerebral blood flow and metabolism

The acetylcholinesterase (AChE) inhibitors sarin and pyridostigmine bromide (PB) have been proposed as causes of neurobehavioral dysfunction in Persian Gulf War veterans. To test possible delayed effects of these agents, we exposed rats to low (subsymptomatic) levels of sarin (0.5 LD₅₀ s.c. 3 times weekly) and/or PB (80 mg/L in drinking water) for 3 weeks. Controls received saline s.c. and tap water. At 2, 4 and 16 weeks after exposure, regional cerebral blood flow (rCBF) and glucose utilization (rCGU) were measured in conscious animals with the Iodo-¹⁴C-antipyrine and ¹⁴C-2 deoxyglucose methods, respectively.

Two weeks after exposure, PB+sarin caused significant rCBF elevations, but no changes in rCGU, in neocortex, with lesser effects on allocortex. Four weeks after exposure, the same general pattern was found with sarin. Only a few changes were found at 16 weeks post-treatment. The predominant effects of sarin or PB+sarin on rCBF at earlier times after treatment are consistent with the well known direct cerebral vascular effect of cholinergic agonists. The lack of changes in rCBF and rCGU observed at 16 weeks after treatment does not support the hypothesis that repeat exposure to low-dose cholinesterase inhibitors can generate permanent alterations in cerebral activity.     

Cerebral monitoring with transcranial Doppler ultrasonography improves neurologic outcome during repairs of acute type A aortic dissection

OBJECTIVE: Neurologic complications after repair of acute type A aortic dissection remain significant. The use of power M-mode transcranial Doppler monitoring to verify cerebral blood flow during these repairs might decrease cerebral ischemia by correcting malperfusion. The purpose of this study was to analyze the use of power M-mode transcranial Doppler monitoring during repairs of acute type A dissection with regard to neurologic outcome. METHODS: We performed a prospective study of patients undergoing repairs of acute type A aortic dissection. Repairs included profound hypothermic circulatory arrest and retrograde cerebral perfusion. Patients in whom transcranial Doppler monitoring was used to monitor cerebral blood flow and modify operative technique during repair (study group) were compared with those without monitoring and modification (control group). RESULTS: Between September 2001 and October 2003, we repaired 56 cases of acute type A dissection. Power M-mode transcranial Doppler monitoring was used in 50% (28/56) of cases. Power M-mode transcranial Doppler monitoring altered operative cannulation and guided retrograde cerebral perfusion flow in 28.5% (8/28) and 78.6% (22/28) of cases, respectively. Two patients presented with preoperative stroke, one in each group. One operative death occurred in each group. In-hospital mortality and the occurrence of new stroke were not significantly different between the 2 groups. Temporary neurologic dysfunction occurred less often in the study group (14.8% [4/27] vs 51.8% [14/27], P = .008). CONCLUSIONS: Identification of cerebral malperfusion requires cerebral monitoring. By ensuring cerebral blood flow by using power M-mode transcranial Doppler monitoring and correcting cerebral malperfusion by modifying operative technique, neurologic outcome was improved during repairs of acute type A aortic dissection.     

The role of transesophageal echocardiography in optimizing resuscitation in acutely injured patients

BACKGROUND: The goal of resuscitation is to correct the mismatch between oxygen delivery and that of cellular demands. The pulmonary artery catheter (PAC) is frequently used to gauge the adequacy of resuscitation and guide therapy based on ventricular filling pressures. Transesophageal echocardiography (TEE) has emerged as a potential tool in assessing adequacy of acute hemodynamic resuscitation. The purpose of this study was to evaluate the role of TEE in assessing preload during ongoing volume resuscitation in trauma patients. METHODS: A retrospective review was conducted of acutely injured patients undergoing TEE during resuscitation from hemorrhagic shock from January 2002 to 2004 at a Level I trauma center. The indication for TEE was persistent hemodynamic instability in the absence of ongoing surgical hemorrhage. Variables included hemodynamic and PAC parameters, pre-TEE resuscitation volume, and vasopressor requirements. The impact of TEE findings on therapeutic decisions was evaluated. RESULTS: Twenty-five patients underwent TEE, 18 (72%) had an indwelling PAC with a mean pulmonary artery occlusion pressure of 19.3 mm Hg (range, 12-29 mm Hg) and mean cardiac index of 2.9 L/min/m2 (range, 1.6-4.6 L/min/m2). Twelve patients (48%) were receiving inotropes and/or vasopressors for hypotension at the time of TEE. Resuscitation volume within 6 hours before TEE included a mean of 6.5 L of crystalloid and 12.2 units of blood products (packed red blood cells, fresh frozen plasma, and platelets). TEE revealed left ventricular hypovolemia in 13 patients (52%) and altered therapy in 16 patients (64%), including additional volume (n = 13), addition of an inotrope (n = 4), and addition of a vasodilator (n = 1) in one patient with ventricular overdistention. Comparison of the abnormal and normal TEE groups revealed that only cardiac index was significantly different (2.6 L/min/m2 in the abnormal group vs. 3.9 L/min/m2 in the normal group; p = 0.005). Significant mitral valve regurgitation leading to valve replacement was identified in one patient. No clinically relevant pericardial effusion was identified. CONCLUSION: TEE altered resuscitation management in almost two thirds of patients. Many patients with "acceptable" pulmonary artery occlusion pressure parameters may in fact have inadequate left ventricular filling. In addition, TEE offers the advantage of direct assessment of cardiac valve competency, myocardial wall contractility, and pericardial fluid.     

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.     

Patient encounter time intervals in the evaluation of emergency department patients requiring abdominopelvic CT: oral contrast versus no contrast

The aim of the study was to assess various time intervals during patient encounters involving unenhanced (NECT) versus oral-contrast-enhanced (CECT) abdominopelvic (A/P) CT performed in the emergency department (ED) on adult patients presenting with acute abdominal pain. Computerized patient order entry and administrative data as well as scans themselves were retrospectively evaluated at a high-volume (107,000 visits per annum) regional medical center urban ED for a period of 30 consecutive days. All adult patients who had CT of abdomen and pelvis for abdominal pain during the 30 days of the study period were included. Data collected included demographic information, time of registration, time of first encounter in the ED, time of CT order, clinical indication for scan, time of scan, time of disposition (i.e., discharge or admit), and final disposition. Patients were excluded if they were less than 16 years old, pregnant, or met criteria for major trauma and evaluation in the trauma suite. Patients were also excluded from analysis if they received more than one scan on the same day (3 patients). Of 183 patients, 102 underwent NECT and 81 CECT. Some of the patients who underwent NECT had urinary colic. Among patients who did not have urinary colic there is a statistically significant difference in the median time intervals between: (1) patient arrival in the ED and evaluation by a physician (NECT 57 min, CECT 84 min, P<0.001); (2) patient exam by the physician and the time the A/P CT was ordered (NECT 35 min, CECT 63 min, P<0.01); (3) receipt of the CT order and the time of the scan (NECT 104 min, CECT 172 min, P<0.001); and (4) time of arrival in ED and disposition (NECT 358 min, CECT 599 min, P<0.001). There are significant time interval differences between CECT and NECT during patient encounters involving adults presenting with abdominal pain to the ED. The differences are greater than the amount of time allotted for opacification of small bowel (90 min). Baseline data such as these may prove useful in assessing the efficacy of scan techniques and improving resource utilization.     

Determinants of early and late outcome for reoperations of the proximal aorta

Background

The purpose of this study was to investigate the cause of ascending aorta and aortic arch reoperations and to identify determinants of early and late outcome.

Methods

Between January 1991 and March 2003 we repaired aneurysms of the proximal aorta in 597 patients. Of these patients, 104 had reoperations for replacement of the ascending aorta, aortic root, or transverse aortic arch. Previous surgery was defined as any previous cardiac or proximal aortic repair. Median age was 60 years, and 29 of the patients (28%) were female. Indications for reoperation and replacement of the proximal aorta included acute type A dissection in 6 patients (5.8%), aneurysm with chronic dissection in 60 (57.7%), progression of aneurysm in 23 (22.1%), infection in 12 (1.5%), inflammatory disease in 2 (1.9%), and atheromatous disease in 1 (1.0%). Reoperations included aortic root replacement in 20 patients (19.2%), total arch replacement with elephant trunk in 28 (26.7%), ascending and proximal arch in 39 (37.5%), and ascending aorta in 27 (26.0%). The median interval between operations was 69 months. Retrograde cerebral perfusion was used in 80 (77%) cases.

Results

Chronic dissection was the most common indicator for reoperation in our population, followed by progression of aneurysm and infection. Thirty-day and in-hospital mortality was 13.5% (14 of 104) and 15.4% (16 of 104), respectively. Chronic obstructive pulmonary disease, renal dysfunction, and increased pump time were risk factors for mortality. Median follow-up was 5.02 years. Eight patients died during that period. Estimated survival at 1, 5, and 10 years was 83%, 80%, and 62%, respectively. Freedom from second proximal reoperations was 97.1% (10 of 104). Freedom from subsequent distal thoracic aortic repair was 84.6% (8 of 104).

Conclusions

Reoperations of the ascending aorta and aortic arch can be performed safely with good long-term results. Patients with previous proximal aortic dissection repair need long-term surveillance. Renal dysfunction and chronic obstructive pulmonary disease must be carefully considered before reoperations of the proximal aorta.     

2-Chloroethyl-3-sarcosinamide-1-nitrosourea (SarCNU) inhibits prostate carcinoma cell growth via p53-dependent and p53-independent pathways

BACKGROUND: Prostate carcinoma is the most commonly occurring malignancy in men. Although 2-chloroethyl-3-sarcosinamide-1-nitrosourea (SarCNU), an analog of the chloroethylnitrosoureas, has been used in the treatment of advanced solid tumors, the molecular mechanisms underlying the antineoplastic activity of this agent are not well understood. In the current study, the authors sought to investigate the effects of SarCNU on prostate carcinoma cell growth in vivo and in vitro. METHODS: Male SCID mice underwent subcutaneous implantation (on both flanks) of human CWR-22 and CWR-22R prostate carcinoma xenografts. Mice were treated with either vehicle or 60 or 80 mg SarCNU per kg body weight for 5 days, with tumor growth being assessed every 3 days. Animals were sacrificed 21 days after the final injection, and tumors subsequently were collected, weighed, and processed for analysis. Immunohistochemical analyses were performed to obtain data on the localization of p53 and p21Cip1/Waf1. Cell counting, terminal deoxynucleotidyltransferase-mediated deoxyuridine triphosphate nick end-labeling (TUNEL) assays, cell cycle analyses, Western blotting, and in vitro kinase assays were performed to determine the effects of SarCNU on growth, apoptosis, cell cycle arrest, cell cycle-regulated protein levels, and Cdc-2 activity, respectively. RESULTS: SarCNU reduced tumor incidence and inhibited the growth of CWR-22 and CWR-22R xenografts. In addition, treatment with this agent led to increases in p21Cip1/Waf1 levels and p53 phosphorylation at Ser15. In vitro administration of SarCNU to cells with wild-type p53 (LNCaP and primary CWR-22 cells) and cells with mutant p53 (PC-3 cells) resulted in G2/M arrest and the reduction of cellular Cdc-2 activity. Up-regulation of p53 levels, p53 phosphorylation at Ser15, and p21Cip1/Waf1 levels in primary CWR-22 and LNCaP cells, as well as up-regulation of Cdc-2 phosphorylation at Tyr15 in PC-3 cells, was detected. CONCLUSIONS: SarCNU induced G2/M arrest in prostate carcinoma cells via p53-dependent up-regulation of p21Cip1/Waf1 and p53-independent phosphorylation of Cdc-2 at Tyr15. These findings suggest a potential role for SarCNU in the treatment of prostate malignancies.