Risk factors and prevalence of perioperative cognitive dysfunction in abdominal aneurysm patients

BACKGROUND: Perioperative delirium is common in high-risk surgery and is associated with age, education, preoperative cognitive functioning, pre-existing medical conditions, and postoperative complications. We investigated these factors as well as lifestyle and demographic variables by using cognitive measures that were more sensitive than those used in previous studies. METHODS: Extensive medical and demographic data were collected on 102 patients between 41 and 88 years of age to identify comorbidities and lifestyle considerations preoperatively. Elective abdominal aortic aneurysm surgery was performed under combined general/epidural anesthesia with postoperative epidural analgesia. A battery of sensitive, cognitive measures was administered preoperatively, at the time of discharge from hospital, and 3 months postoperatively. Symptoms of delirium were assessed during the first 6 postoperative days using Diagnostic and Statistical Manual of Mental Disorders-4th Edition criteria. Intraoperative and postoperative data, including medications, vital signs, conduct of the surgery and anesthesia, complications, and details of pain control, were collected. RESULTS: Delirium occurred in 33% of the patients during the first 6 days after surgery. Longer duration of delirium was related to lower education, preoperative depression, and greater preoperative psychoactive medication use. Characteristics of the surgery and hospital stay were unrelated to the development of delirium. Patients who were diagnosed with delirium had lower cognitive scores during each of the three assessment periods, even when controlling for age and education. Logistic regression analysis indicated that the most powerful preoperative predictors of delirium were number of pack years smoked (P = .001), mental status scores (P = .003), and number of psychoactive medications (P = .005). CONCLUSION: A significant proportion of patients undergoing elective abdominal aortic aneurysm repair are susceptible to the development of delirium and are at risk for cognitive dysfunction after surgery. Our findings have implications for promoting long-term lifestyle changes, including smoking cessation and improved management of mental health as risk-reduction strategies.     

Killing tumor cells: the effect of photodynamic therapy using mono-L-aspartyl chlorine and NS-398

BACKGROUND: Photodynamic therapy (PDT) is a useful treatment for malignant tumors. PDT involves the administration of a photosensitive drug that is selected by neoplastic tissues and their vasculature. One such photosensitizer is mono-l-aspartyl chlorine e6 (NPe6). Recent evidence suggests that the presence of the cyclooxygenase-2 (COX-2) inhibitor NS-398 may potentiate the effect of photosensitizing agents. This study was designed to determine if the addition of NS-398 to NPe6-induced PDT in single or fractionated dosing would result in greater tumor kill. METHODS: Colon-38 tumor was subcutaneously implanted into both flanks of mice and allowed to grow to 0.5 to 1.0 cm. Mice were randomly allocated to 5 groups: (1) single dose of NPe6; (2) fractionated dose of NPe6; (3) NS-398 only; (4) single dose of NPe6 + NS-398; and (5) fractionated dose of NPe6 + NS-398. The left flank was shielded from exposure to irradiation. Tumor size was measured before initiation of PDT and at the time of sacrifice. RESULTS: The initial tumor weights of both flanks were not significantly different between all groups. Tumor weights at the time of death after PDT using NPe6 were significantly less than their paired tumors in the untreated flanks (P <0.0001). Tumor weights in the treated flanks were significantly less in the group receiving the fractionated dosing of NPe6 as compared to the single dose of NPe6 (P = 0.0037). NS-398 plus the single dose of NPe6 significantly decreased tumor weight in the PDT-treated flank (P = 0.035) at a level equivalent to that observed with fractionated dosing of the photosensitizer in the absence of NS-398. NS-398 did not significantly further decrease tumor weight in the group that received the fractionated dose of NPe6. CONCLUSIONS: Fractionated dosing of NPe6 demonstrated the best tumor kill. However, NS-398 did not potentiate the effect of PDT using fractionated dosing of NPe6. While PDT using the single NPe6 dose significantly decreased tumor weight, the addition of NS-398 potentiated the killing effect.     

Gastric mucosal defense mechanisms: effects of salicylate and histamine.

Some of the recent concepts about the gastric mucosal defense mechanisms against damage by luminal acid and the effects of histamine and salicylate on these mechanisms are reviewed. The mucosal barrier to acid appears to consist of at least two physiologic components: a permeability mechanism and a metabolic mechanism related to cellular bicarbonate production as a result of acid secretion. In the absence of salicylate, histamine appears to exert some protection by affecting both mechanisms, but in the presence of salicylate, histamine's protective effect is limited to altering mucosal permeability. The actions of salicylate on the gastric mucosa are complex, related in part to the concentration of salicylate and the pH of the luminal fluid. The damaging effects of salicylate appear to be related more to the concentration of acid in the lumen than to the lipid solubility of the drug. Salicylate increases permeability regardless of pH; the increase is initially selective for cations and subsequently becomes nonselective, involving both cations and anions. Although both low and high concentrations of salicylate increase mucosal permeability to hydrogen ions, only high concentrations of salicylate affect cellular bicarbonate production.     

Photodynamic therapy for carcinoma in situ of the anus

HYPOTHESIS: Photodynamic therapy (PDT) for carcinoma in situ of the anus is an alternative to surgical excision in patients who are seropositive for human immunodeficiency virus (HIV). DESIGN: Before-after trial.Settings Tertiary referral center. PATIENTS: Twelve HIV-seropositive patients who were actively being treated for AIDS with high-grade dysplasia on anal Papanicolaou test results had site-directed biopsies of acetowhitening foci immediately after application of dilute acetic acid. Biopsy results showed that 5 patients had anal carcinoma in situ. These patients were given the photosensitizer delta-aminolevulinic acid orally. Four to 4.25 hours later, the entire anal circumference was treated with PDT. All 5 patients, after being treated with PDT, had repeated Papanicolaou tests at monthly intervals. If acetowhitening occurred at the fifth month, site-directed biopsy was done. MAIN OUTCOME MEASURES: Anal cytologic examination by Papanicolaou test and site-directed biopsy if acetowhitening was found at 5 months in order to determine effectiveness of PDT in downstaging cytologic findings. RESULTS: All patients had a consistent downgrading of cytologic findings during the 5 months of follow-up. Papanicolaou test results showed 2 patients had no dysplasia, 2 had mild dysplasia, and 1 had moderate dysplasia. Moderate dysplasia was confirmed by site-directed biopsy results. No complications of PDT occurred, but all 5 patients developed various abnormalities in liver function test results that returned to baseline values within 2 weeks; this also has been noted in patients ingesting delta-aminolevulinic acid who are presumably HIV seronegative. CONCLUSION: In a group of patients who are at high risk for recurrence irrespective of initial treatment, PDT can be used as a successful alternative to surgical excision for anal carcinoma in situ.     

Should patients with a pre-operative prostatespecific antigen greater than 15ng/ml be offered radical prostatectomy?

Background Patients with prostate cancer with a pre-operative prostate-specific antigen (PSA) τ;15ng/ml who undergo radical retropubic prostatectomy (RRP) generally do not have a good outcome, yet may have organ-confined cancer and should be offered the option of surgery. Aim To assess the outcome of patients who underwent RRP with a pre-operative PSA ≥ 15ng/ml. Methods Thirty-four patients, mean pre-operative PSA: 25.46ng/ml (15.03–76.6) and mean Gleason score: 6.4 (5–9) were assessed. Results Two groups were identified. Group I: 41% (14/34) have no biochemical recurrence to mean follow up of 58 months (30–106). Mean PSA: 18.8ng/ml (15.03–25.84). Mean Gleason score: 6.1 (5–7). Clinical stage: T1c in 80%. No patient had seminal vesicle or lymph node involvement. Group II: 59% (20/34) have biochemical recurrence or died (3) from their disease to mean follow up of 66 months (36–98). Mean PSA: 28.9ng/ml (15.28–76.6). Mean Gleason score: 6.7 (5–9). Clinical stage: T1c in 25%. Eleven patients had seminal vesicle (8) involvement or positive lymph nodes (3) or both (2). Conclusion RRP seems feasible in patients whose pre-operative PSA is between 15 and 25ng/ml with stage T1c, Gleason score ≤ 7 and negative lymph node frozen section.     

High plasma pravastatin concentrations are associated with single nucleotide polymorphisms and haplotypes of organic anion transporting polypeptide-C (OATP-C, SLCO1B1)

This study aimed to characterize possible relationships between polymorphisms in the drug transporter genes organic anion transporting polypeptide-C (OATP-C, SLCO1B1), OATP-B (SLCO2B1), multidrug resistance-associated protein 2 (MRP2, ABCC2) and multidrug resistance transporter (MDR1, ABCB1) and the pharmacokinetics of pravastatin. We studied 41 healthy Caucasian volunteers who had previously participated in pharmacokinetic studies with pravastatin. Six volunteers had a very high pravastatin AUC value and were defined as outliers according to statistical criteria. The OATP-C gene was sequenced completely in all subjects, and they were also genotyped for selected single nucleotide polymorphisms (SNP) in the OATP-B, MDR1 and MRP2 genes. Of the six outliers, five were heterozygous for the OATP-C 521T>C (Val174Ala) SNP (allele frequency 42%) and three were heterozygous for a new SNP in the promoter region of OATP-C (-11187G>A, allele frequency 25%). Among the remaining 35 subjects, two were homozygous and six were heterozygous carriers of the 521T>C SNP (allele frequency 14%, P = 0.0384 versus outliers) and three were heterozygous carriers of the -11187G>A SNP (allele frequency 4%, P = 0.0380 versus outliers). In subjects with the -11187GA or 521TC genotype, the mean pravastatin AUC0-12 was 98% (P = 0.0061) or 106% (P = 0.0034) higher, respectively, compared to subjects with the reference genotype. These results were substantiated by haplotype analysis. In heterozygous carriers of *15B (containing the 388A>G and 521T>C variants), the mean pravastatin AUC0-12 was 93% (P = 0.024) higher compared to non-carriers and, in heterozygous carriers of *17 (containing the -11187G>A, 388A>G and 521T>C variants), it was 130% (P = 0.0053) higher compared to non-carriers. No significant associations were found between OATP-B, MRP2 or MDR1 polymorphisms and the pharmacokinetics of pravastatin. These results suggest that haplotypes are more informative in predicting the OATP-C phenotype than single SNPs.     

Lipid-lowering response to statins is affected by CYP3A5 polymorphism

Individuals expressing the polymorphic CYP3A5 enzyme might show a more than average efficiency in the metabolism of lovastatin, simvastatin and atorvastatin. We studied whether the expression of CYP3A5 is associated with an impaired lipid-lowering response to statins in 69 Caucasian patients. Lovastatin, simvastatin and atorvastatin were significantly less effective in CYP3A5 expressors than in non-expressors. The mean serum total cholesterol concentration at 1 year was 23% higher (P = 0.0014) and the mean serum low-density lipoprotein cholesterol concentration was 24% higher (P = 0.036) in subjects possessing the CYP3A5*1 allele (CYP3A5 expressors, n = 7) than in subjects homozygous for the CYP3A5*3 allele (non-expressors, n = 39). The mean percentage reduction in serum total cholesterol from baseline was significantly smaller in CYP3A5 expressors than in non-expressors (17% versus 31%, P = 0.026). No association between hypolipidemic efficacy and CYP3A5 polymorphism was observed among 23 subjects taking statins that are not dependent on CYP3A5 (fluvastatin, pravastatin). These findings suggest that CYP3A5 may be a genetic determinant of interindividual differences in response to certain statins.