Carbon dioxide narcosis due to inappropriate oxygen delivery: a case report.

BACKGROUND: Oxygen delivery to patients with chronic obstructive pulmonary disease may be challenging because of their potential hypoxic ventilatory drive. However, some oxygen delivery systems such as non-rebreathing face masks with an oxygen reservoir bag require high oxygen flow for adequate oxygenation and to avoid carbon dioxide rebreathing. CASE PRESENTATION: A 72-year-old Caucasian man with severe chronic obstructive pulmonary disease was admitted to the emergency department because of worsening dyspnea and an oxygen saturation of 81% measured by pulse oximetry. Oxygen was administered using a non-rebreathing mask with an oxygen reservoir bag attached. For fear of removing the hypoxic stimulus to respiration the oxygen flow was inappropriately limited to 4L/minute. The patient developed carbon dioxide narcosis and had to be intubated and mechanically ventilated. CONCLUSIONS: Non-rebreathing masks with oxygen reservoir bags must be fed with an oxygen flow exceeding the patient's minute ventilation (>6-10 L/minute.). If not, the amount of oxygen delivered will be too small to effectively increase the arterial oxygen saturation. Moreover, the risk of carbon dioxide rebreathing dramatically increases if the flow of oxygen to a non-rebreathing mask is lower than the minute ventilation, especially in patients with chronic obstructive pulmonary disease and low tidal volumes. Non-rebreathing masks (with oxygen reservoir bags) must be used cautiously by experienced medical staff and with an appropriately high oxygen flow of 10-15 L/minute. Nevertheless, arterial blood gases must be analyzed regularly for early detection of a rise in partial pressure of carbon dioxide in arterial blood in patients with chronic obstructive pulmonary disease and a hypoxic ventilatory drive. These patients are more safely managed using a nasal cannula with an oxygen flow of 1-2L/minute or a simple face mask with an oxygen flow of 5L/minute.

ABCA1 modulates CSF cholesterol levels and influences the age at onset of Alzheimer's disease.

Increased formation of the beta-amyloid peptide (Abeta) is a central event in the pathogenesis of Alzheimer's disease (AD). High cellular cholesterol load promotes Abeta formation. The ATP-binding cassette transporter A1 (ABCA1) mediates cholesterol efflux from cells. We hypothesized that genetic variability in ABCA1 may influence cholesterol metabolism in the central nervous system (CNS) and, thus, interfere with the development of AD. Healthy elderly carriers of the A allele of a non-synonymous (R219K) single nucleotide polymorphism (SNP) in the ABCA1 gene (rs2234884) had on average 33% lower total cholesterol in cerebrospinal fluid (CSF) than non-carriers. In 169 patients with late onset, sporadic AD, this allele was associated with delayed age at onset of the disease by 1.7 years on average. Rs2234884 and another non-synonymous SNP (R1587K) in ABCA1 (rs2234886) failed to show significant association with the risk for AD. We conclude that genetic variability of ABCA1 influences the development of AD, possibly by interfering with CNS cholesterol homeostasis.

Biochemical diagnosis of Alzheimer disease by measuring the cerebrospinal fluid ratio of phosphorylated tau protein to beta-amyloid peptide42.

BACKGROUND: The antemortem diagnosis of Alzheimer disease (AD) requires time-consuming and costly procedures. Therefore, biochemical tests that can direct the physician rapidly to the correct diagnosis are highly desirable. Measurement of single biochemical markers in cerebrospinal fluid (CSF), such as total tau protein and beta-amyloid peptide42 (Abeta42), shows robust alterations that highly correlate with the clinical diagnosis of AD but generally lack sufficient diagnostic accuracy. OBJECTIVE: To study the combination of CSF phosphorylated tau protein (phospho-tau) and Abeta42 as biochemical markers for AD. METHODS: We combined CSF measurements of phospho-tau and Abeta42 in 100 consecutive patients who under-went diagnostic workup for dementia and in 31 healthy control subjects. RESULTS: We found that the calculated ratio of phospho-tau to Abeta42 was significantly increased in patients with AD and provided high diagnostic accuracy in distinguishing patients with AD from healthy control subjects (sensitivity, 86%; specificity, 97%), subjects with non-AD dementias (sensitivity, 80%; specificity, 73%), and subjects with other neurological disorders (sensitivity, 80%; specificity, 89%). CONCLUSION: The diagnostic usefulness of the CSF ratio of phospho-tau to Abeta42 is superior to either measure alone and can be recommended as an aid to evaluating individuals suspected of having dementia.

Increased brain beta-amyloid load, phosphorylated tau, and risk of Alzheimer disease associated with an intronic CYP46 polymorphism.

BACKGROUND: CYP46, the gene encoding cholesterol 24-hydroxylase, plays a key role in the hydroxylation of cholesterol and thereby mediates its removal from brain. OBJECTIVE: To study the association of polymorphic sites on CYP46 with Alzheimer disease (AD) traits and with the risk of the development of AD. DESIGN: Alzheimer disease traits (beta-amyloid load, beta-amyloid peptides, hyperphosphorylated tau protein) were assessed in brain tissues and in the cerebrospinal fluid of patients with AD and control subjects. Genetic associations were studied in 2 independent populations. SETTING: Specialized centers for memory disorders in Switzerland, Greece, and Italy. PARTICIPANTS: Fifty-five brain tissues from nondemented elderly patients for the histopathological studies; 38 patients with AD and 25 control subjects for the cerebrospinal fluid studies; 201 patients with AD and 248 control subjects for the genetic association studies. RESULTS: A polymorphism of CYP46 was associated with increased beta-amyloid load in brain tissues as well as with increased cerebrospinal fluid levels of beta-amyloid peptides and phosphorylated tau protein. Moreover, this CYP46 polymorphism was associated with higher risk of late-onset sporadic AD in 2 independent populations (odds ratio, 2.16; 95% confidence interval [CI], 1.41-3.32; P<.001). The additional presence of 1 or 2 apolipoprotein E epsilon4 alleles synergistically increased the risk of AD to an odds ratio of 9.6 (95% CI, 4.9-18.9; P<.001) as compared with 4.4 for apolipoprotein E epsilon4 alone (95% CI, 2.8-6.8; P<.001). CONCLUSION: CYP46 influences brain beta-amyloid load, cerebrospinal fluid levels of beta-amyloid peptides and phosphorylated tau, and the genetic risk of late-onset sporadic AD.

Genetic polymorphisms and cerebrospinal fluid levels of tissue inhibitor of metalloproteinases 1 in sporadic Alzheimer's disease.

Tissue inhibitor of metalloproteinases 1 (TIMP-1) inhibits several proteinases including a disintegrin and metalloproteinase 10 (ADAM10), a major alpha-secretase that cleaves the beta-amyloid precursor protein within its amyloidogenic Abeta domain. The gene encoding TIMP-1 (TIMP 1) maps to the short arm of the X chromosome, in a region previously suggested as conferring genetic susceptibility for Alzheimer's disease (AD). To determine whether genetic variability of TIMP 1 contributes to the pathogenesis of AD, we analysed one single nucleotide polymorphism within TIMP 1 and one single nucleotide polymorphism in the 5'-untranslated region of TIMP 1 in patients with AD and control subjects from two independent and ethnically different populations. We did not observe any association between TIMP 1 genotypes and the diagnosis of AD in men or women. We also measured TIMP-1 protein levels in the cerebrospinal fluid of patients with AD, healthy control subjects, and patients with other neurological disorders. TIMP-1 levels were similar in all groups. In addition, no significant differences were observed after stratification for TIMP 1 genotypes. Our data show that neither genetic variability nor protein levels of TIMP-1 are associated with AD.

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.

Cerebrospinal fluid profile of amyloid beta peptides in patients with Alzheimer's disease determined by protein biochip technology.

Amyloid-beta peptides (Abeta) are major components of amyloid plaques in the Alzheimer's disease (AD) brain and have been proposed as diagnostic markers in cerebrospinal fluid (CSF). Abeta derived from brain may be processed into fragments before emerging in CSF. Therefore, we determined mass profiles of Abeta peptides in CSF of patients with AD and age-matched healthy control subjects (CTR) by using protein biochip technology. Abeta peptides were captured on the chip surfaces (spots) by the specific monoclonal antibody 6E10 and were then analyzed by integrated surface-enhanced laser desorption and ionization time-of-flight mass spectrometry (SELDI-TOF-MS). We found Abeta species with mean molecular masses at 1,583.3 Da (corresponding to Abeta2-14), 2,068.5 Da (Abeta1-17), 2,166.4 Da (Abeta1-18), 3,676.6 Da (Abeta1-33), 3,789.4 Da (Abeta1-34), 4,076.9 Da (Abeta1-37), 4,134.0 Da (Abeta1-38), 4,233.3 Da (Abeta1-39), 4,332.4 Da (Abeta1-40) and 4,516.8 Da (Abeta1-42) in both AD (n = 24) and CTR (n = 24) subjects. Abeta1-38 appeared to be a major Abeta species in human CSF along with Abeta1-40. Quantitation revealed that CSF levels of Abeta1-38 were significantly decreased in AD as compared to CTR subjects. The CSF profile of Abeta peptides may be used for diagnostic and therapeutic purposes in clinical studies.