Cholesteryl Ester Transfer Protein (CETP) Genetic Variation and Early Onset of Non‐Fatal Myocardial Infarction

Although Cholesteryl Ester Transfer Protein (CETP) mediates the transfer of cholesteryl esters and triglycerides between lipoprotein particles and thus plays a crucial role in reverse cholesterol transport, the association of variations in the CETP gene with acute myocardial infarction (MI) remains unclear. In this study we examined whether common genetic variation in the CETP gene is related to early‐onset non‐fatal MI risk in a population‐based case‐control study from western Washington State. Genotyping for the CETP ?2708 G/A, ?971 A/G, ?629 A/C, Intron‐I TaqI G/A and exon‐14 A/G (I405V) SNPs was performed in 578 cases with first acute non‐fatal MI and in 666 demographically similar controls, free of clinical cardiovascular disease, identified randomly from the community. In‐person interviews and non‐fasting blood specimens provided data on coronary heart disease risk factors. In men, there was little evidence for an association between single SNPs and MI risk, but in women the age‐ and race‐adjusted OR was found to be significant in 4 out of the 5 CETP single variants. Haplotype analysis revealed two haplotypes associated with MI risk among men. As compared to men homozygous for the most common haplotype D (?2708 G, ?971 G, ?629 C, TaqI G and exon‐14 A), the fully‐adjusted multiplicative model identified haplotype G (?2708 G, ?971 A, ?629 A, TaqI G and exon‐14 G) was associated with a 4.0‐6.0‐fold increased risk of MI for each additional copy; [95%CI 2.4–14.8] and haplotype B (?2708 G, ?971 G, ?629 A, TaqI A and exon‐14 A) showed a significant decreased risk for early onset MI [OR = 0.18; 95%CI 0.04 – 0.75]. An evolutionary‐based haplotype analysis indicated that the two haplotypes associated with the MI risk are most evolutionarily divergent from the other haplotypes. Variation at the CETP gene locus is associated with the risk of early‐onset non‐fatal MI. This association was found to be independent of HDL‐C levels. These data and the sex‐specific findings require confirmation in other populations.     

Substrates for coincidence detection and calcium signaling for induction of synaptic potentiation in the neonatal visual cortex

Regulation of the efficacy of synaptic transmission by activity-dependent processes has been implicated in learning and memory as well as in developmental processes. We previously described transient potentiation of excitatory synapses onto layer 2/3 pyramidal neurons in the visual cortex that is induced by coincident presynaptic stimulation and postsynaptic depolarization. In the adult visual cortex, activation of N-methyl-d-aspartate (NMDA) glutamate receptors is necessary to induce this plasticity. These receptors act as coincidence detectors, sensing presynaptic glutamate release and postsynaptic depolarization, and cause an influx of Ca(2+) that is necessary for the potentiation. In the neurons of the neonatal visual cortex, on the other hand, coincident presynaptic stimulation and postsynaptic depolarization induce stable long-term potentiation (LTP). In addition, reduced but significant LTP can be induced in many neurons in the presence of the NMDA receptor (NMDAR) antagonist, 2-amino-5-phosphonovaleric acid despite the Ca(2+) requirement. Therefore there must be an alternative postsynaptic Ca(2+) source and coincidence detection mechanism linked to the LTP induction mechanism in the neonatal cortex operating in addition to NMDARs. In this study, we find that in layer 2/3 pyramidal neurons, release of Ca(2+) from inositol trisphosphate (InsP(3)) receptor-mediated intracellular stores and influx through voltage-gated Ca(2+) channels (VGCCs) provide alternative postsynaptic Ca(2+) sources. We hypothesize that InsP(3)Rs are coincidence detectors, sensing presynaptic glutamate release through linkage with group I metabotropic glutamate receptors (mGluRs), and depolarization, through VGCCs. We also find that the downstream protein kinases, PKA and PKC, have a role in potentiation in layer 2/3 pyramidal neurons of the neonatal visual cortex.     

Inhibition of mouse peritoneal macrophage DNA synthesis by infection with the arenavirus Pichinde.

Macrophage DNA synthesis and proliferation occur during the development of cell-mediated immunity and in the early nonspecific reaction to infection. Arenaviruses have a predilection for infection of cells of the reticuloendothelial system, and in this study we have examined the effect of the arenavirus Pichinde on macrophage DNA synthesis. We have found that infection of mouse peritoneal macrophages with Pichinde caused a profound dose-dependent inhibition of the DNA synthesis induced by macrophage growth factor-colony stimulating factor. At a multiplicity of inoculum of 5, there is a 75 to 95% inhibition of DNA synthesis. Viable virus is necessary for inhibition since Pichinde inactivated by heat or cobalt irradiation had no effect. Similarly, virus pretreated with an antiserum to Pichinde was without inhibitory effect. Inhibition was demonstrated by measuring DNA synthesis spectrofluorometrically as well as by [3H]thymidine incorporation. The inhibition of DNA synthesis was not associated with any cytopathology. There was no evidence that the inhibition was due to soluble factors, such as prostaglandins or interferon, released by infected cells. These studies demonstrate, for the first time in vitro, a significant alteration in macrophage function caused by infection with an arenavirus. It is possible that inhibition of macrophage proliferation represents a mechanism by which some microorganisms interfere with host resistance.     

Is hypoxic pulmonary vasoconstriction important during single lung ventilation in the lateral decubitus position?

Hypoxic pulmonary vasoconstriction (HPV) has not been demonstrated in human single lung anaesthesia in the lateral decubitus position (LDP). The purpose of this study was to determine whether (1) HPV occurs in the non-dependent, nonventilated lung, and (2) if the infusion of sodium nitroprusside (SNP) inhibits HPV During intravenous anaesthesia the tracheas of seven patients were intubated with double lumen endotracheal tubes. Standard monitors plus radial and pulmonary arterial catheters were placed. Patients were positioned in the LDP and haemodynamic and gas exchange data were recorded for each of three stages; I: two-lung ventilation, II: single, dependent lung ventilation (1LV) and III: 1LV with infusion of SNP. In stage II the PaO₂ decreased from 531 ± 42 mmHg to 285 ± 42 mmHg (P < 0.05) and Qs/Qt increased from 12.3 ± 2.7 to 29.0 ± 6.3% (P < 0.05). With SNP infusion there was a 30% increase in cardiac index (CI) (P < 0.05). The SNP infusion was not associated with changes in Qs/ Qt or PaO₂. This model demonstrates changes in Qs/ Qt and PaO₂ associated with single-lung ventilation in ASA I and II patients in the LDP but we were unable to demonstrate inhibition of HPV by SNP.     

Intestinal permeability in kwashiorkor

Intestinal permeability can be assessed non-invasively using the lactulose-rhamnose (L-R) test, which is a reliable measure of small intestinal integrity. AIMS: To determine risk factors for abnormal intestinal permeability in kwashiorkor, and to measure changes in L-R ratios with inpatient rehabilitation. DESIGN: A case-control study of 149 kwashiorkor cases and 45 hospital controls. The L-R test was adapted to study kwashiorkor in Malawi, with testing at weekly intervals during nutritional rehabilitation. Urine sugars were measured by thin layer chromatography in London. RESULTS: The initial geometric mean L-R ratios (x100) (with 95% confidence interval) in kwashiorkor were 17.3 (15.0 to 19.8) compared with 7.0 (5.6 to 8.7) for controls. Normal ratios are < 5, so the high ratios in controls indicate tropical enteropathy syndrome. Abnormal permeability in kwashiorkor was associated with death, oliguria, sepsis, diarrhoea, wasting and young age. Diarrhoea and death were associated with both decreased L-rhamnose absorption (diminished absorptive surface area) and increased lactulose permeation (impaired barrier function) whereas nutritional wasting affected only L-rhamnose absorption. Despite, clinical recovery, mean L-R ratios improved little on treatment, with mean weekly ratios of 16.3 (14.0 to 19.0), 13.3 (11.1 to 15.9) and 14.4 (11.0 to 18.8). CONCLUSION: Abnormal intestinal permeability in kwashiorkor correlates with disease severity, and improves only slowly with nutritional rehabilitation.     

The association between two common mutations C677T and A1298C in human methylenetetrahydrofolate reductase gene and the risk for diabetic nephropathy in type II diabetic patients

Mutations of the methylenetetrahydrofolate reductase (MTHFR) gene have been shown to be associated with a predisposition to developing diabetic nephropathy (DN) in specific populations. The frequency of two MTHFR mutations, a recently described mutation in the human MTHFR gene A1298C and C677T, whose association with DN is already known, was determined in an Israeli Jewish population with type 2 diabetes mellitus (DM). Both A1298C and C677T are highly prevalent in the diabetic population with allele frequencies of 0.35 and 0.36, respectively. The genotype frequency and allele frequency for these two polymorphisms in patients who are normoalbuminuric (n = 55) were compared with those of patients who had either micro- or macroalbuminuria (n = 43). For both polymorphisms, there were no significant differences in either the genotype distribution or allele frequency in patients with or without DN. However, in patients with serum folate <15.4 nmol/L, there was a greater incidence of DN in those patients who were homozygous or heterozygous for the C677T mutation. For the A1298C mutation, there is evidence suggesting that the homozygous state may be protective in patients with low-normal serum folate. Folate supplementation in diabetic patients with the C677T mutation and low-normal serum folate may prevent the onset or retard the progression of DN.     

Interactive suppression of aberrant crypt foci induced by azoxymethane in rat colon by phytic acid and green tea

Several epidemiological studies point to a strong correlation between nutrient composition of the diet and cancer of the colon. Phytic acid, present in grains, has been credited with reducing the risk of cancer of the colon. A number of reports are available indicating the benefits of green tea consumption in reducing the risk of stomach, lung and skin cancer, but little data are available on the effect of green tea in reducing the risk of colon cancer. Also, there are no studies on the combined effect of these compounds on colon tumorigenesis. Thus the primary objective of this investigation was to elucidate the combined effects of green tea and phytic acid on colonic preneoplastic lesions and the Phase II enzyme glutathione S-transferase. Fisher 344 male weanling rats were divided into nine groups of 15 rats each and fed the experimental diet for 13 weeks. Rats received two s.c. injections of azoxymethane in saline at 16 mg/kg body wt at 7 and 8 weeks of age. Rats received three levels (0, 1 and 2%) of phytic acid with three levels (0, 1 and 2%) of green tea within each phytic acid level in a 3 x 3 factorial experiment. Results indicate that while green tea had a marginal effect (P < 0.14), phytic acid significantly reduced the incidence of aberrant crypt foci (P < 0.008). The interaction between green tea and phytic acid was significant (P < 0.029 for distal and < 0.0168 for entire colon) and positive, pointing to a synergistic effect of green tea and phytic acid.      

Moderate alcohol intake is associated with survival in the elderly: the Dubbo Study

OBJECTIVE: To examine the relationship between alcohol intake and survival in elderly people. DESIGN AND SETTING: A prospective study over 116 months of non-institutionalised subjects living in Dubbo, a rural town (population, 34,000) in New South Wales. PARTICIPANTS: 1235 men and 1570 women aged 60 years and over who were first examined in 1988-89. MAIN OUTCOME MEASURES: All-causes mortality; gross cost of alcohol per life-year gained. RESULTS: Death occurred in 450 men and 392 women. Intake of alcohol was generally moderate (i.e., less than 14 drinks/week). Any intake of alcohol was associated with reduced mortality in men up to 75 years and in women over 64 years. In a proportional hazards model, the hazard ratio for mortality in men taking any alcohol was 0.63 (95% CI, 0.47-0.84) and in women was 0.75 (95% CI, 0.60-0.94). Cardiovascular deaths in men were reduced from 20/100 (95% CI, 14-26) to 11/100 (95% CI, 9-13) and in women from 16/100 (95% CI, 13-19) to 8/100 (95% CI, 6-10). The reduction in mortality occurred in men and women taking only 1-7 drinks/week--hazard ratios, 0.68 (95% CI, 0.49-0.94) and 0.78 (95% CI, 0.61-0.99), respectively, with a similar protective effect from intake of beer or other forms of alcohol. After almost 10 years' follow-up, men taking any alcohol lived on average 7.6 months longer, and women on average 2.7 months longer, compared with non-drinkers. The gross cost for alcohol per life-year gained if consuming 1-7 drinks/week was $5700 in men, and $19,000 in women. CONCLUSIONS: Moderate alcohol intake in the elderly appears to be associated with significantly longer survival in men 60-74 years and in all elderly women.     

Intraabdominal abscess rate after laparoscopic appendectomy

BACKGROUND: Studies suggest increased intraabdominal abscess (IA) rates following laparoscopic appendectomy (LA), especially for perforated appendicitis. Consequently, an open approach has been advocated. The aim of our study is to compare IA rates following LA performed by a laparoscopic surgery and a general surgical service within the same institution. METHODS: Data of LA patients treated at Los Angeles County-University of Southern California (LAC-USC) Medical Center between March 1992 and June 1997 were reviewed. The main outcome measure was postoperative IA. RESULTS: In all, 645 LA were reviewed. A total of 413 LA (285 acute, 61 gangrenous, 67 perforated appendicitis) were performed by three general surgical services (10 attendings). Ten abscesses occurred postoperatively (2.4%), 6 with perforated appendicitis. After the laparoscopic service was introduced, 232 standardized LA (126 acute, 46 gangrenous, 60 perforated) were performed by two attendings. One IA occurred (gangrenous appendicitis). The IA rate for perforated appendicitis was significantly lower on the laparoscopic service (P = 0.025). There was no difference in IA rates for acute and gangrenous appendicitis. There was no mortality in either group. CONCLUSION: IA rate following LA for perforated appendicitis was significantly reduced on the laparoscopic service. Mastery of the learning curve and addition of specific surgical techniques explained this improved result. Therefore, laparoscopic appendectomy for complicated appendicitis may not be contraindicated, even for perforated appendicitis.     

Omission of nitrous oxide from a propofol-based anesthetic does not affect the recovery of women undergoing outpatient gynecologic surgery

BACKGROUND: Although nitrous oxide (N2O) is used commonly during anesthesia, clinically relevant advantages-disadvantages of using this agent are not well established in the ambulatory setting. This study in women undergoing ambulatory gynecologic surgery compares outcomes in patients administered total intravenous anesthesia with propofol versus the propofol plus N2O. The primary outcome was the time to home readiness. Secondary outcomes included the incidence of postanesthetic adverse events. METHODS: Women presenting for elective ambulatory termination of pregnancy or gynecologic laparoscopy were induced with an intravenous sleep dose of propofol and fentanyl. After induction, subjects were randomly allocated to maintenance anesthesia with propofol alone or propofol plus 65% N2O. Patients were assessed by a blinded observer in the postanesthetic care unit at 20-min intervals to determine home readiness. Postoperative pain and nausea were measured with visual analog scales. Postoperative analgesics and antiemetics were recorded. The incidence of adverse events occurring after hospital discharge was assessed by a telephone interview 24 h postoperatively. RESULTS: A total of 740 patients received propofol alone, and 750 patients received propofol plus N2O. Mean home readiness times were not significantly different between treatment groups. There were no significant differences between groups in pain scores, nausea scores, analgesia administration, or antiemetic administration before discharge. There were no significant differences in the frequency of adverse events for 24 h after discharge from hospital. CONCLUSIONS: Omission of N2O from a propofol-based anesthetic for ambulatory gynecologic surgery does not affect time to home readiness or the incidence of postoperative adverse events up to 24 h after discharge from hospital. (Key words: Awareness; outpatient surgery; total intravenous anesthesia.)