Immune responses in monkeys to lenses from patients with contact lens induced giant papillary conjunctivitis

The clinicopathologic findings in contact lens-induced giant papillary conjunctivitis (GPC) suggest that the syndrome is the result of a complex immunological process, an idea supported by the presence of elevated tear concentrations of IgG and IgE in GPC. Several groups of investigators have proposed that GPC may be due, in part, to the coating of the contact lens. To test this hypothesis we undertook development of an animal model of GPC in cynomolgus monkeys. Two soft contact lenses from patients with GPC, two from asymptomatic contact lens wearers, and two clean, unused lenses were each placed in one eye and held in place with a partial tarsorrhaphy. Tears from the two monkeys with GPC lenses showed increased levels of IgG (43 +/- 10 micrograms/mL), IgA (54.3 +/- 12.8 micrograms/mL) and IgE (7.7 +/- 3.3 IU/mL) 35-75 days post-lens placement. While the tears from the two monkeys with clean lenses, and the two monkeys with lenses from asymptomatic contact lens wearers had elevated levels of IgG compared to the contralateral control eye without a lens, the tear IgE levels remained normal. Histopathology studies of tarsal conjunctival biopsy material from the monkeys with GPC lenses showed an intense round cell infiltrate at the epithelial-stromal junction. Mast cells were seen in the epithelial layers. These studies suggest that some factor (or factors) in the lens coating from GPC patients was able to induce a local tear IgE response and histopathological changes in monkeys. These changes are similar to the histopathological and immunological findings in human patients with GPC.     

Benefit of coronary reperfusion before intervention on outcomes after primary angioplasty for acute myocardial infarction

Primary percutaneous transluminal coronary angioplasty has become the preferred reperfusion strategy for acute myocardial infarction in most institutions with interventional facilities and experienced operators. The benefit of establishing coronary reperfusion, with or without pharmacologic therapy, before primary angioplasty has not been established. Consecutive patients (n = 1,490) with acute myocardial infarction treated with aspirin and heparin followed by primary percutaneous transluminal coronary angioplasty were followed for 13 years. Follow-up angiography was obtained in 737 patients at 7.7 months. Thrombolysis In Myocardial Infarction (TIMI) 2 to 3 flow in the infarct artery at initial angiography was present in 18.3% of patients, and TIMI 0 to 1 flow in 81.7% of patients. Baseline variables were similar between the 2 groups, except patients with initial TIMI 2 to 3 flow had significantly less cardiogenic shock (1.7% vs 9.4%, p <0.0001) and a lower incidence of depressed ejection fraction <40% (12.6% vs 19.9%, p = 0.007). Procedural success was better in patients with initial TIMI 2 to 3 flow (97.4% vs 93.8%, p = 0.02), and catheterization laboratory events were less frequent. Patients with initial TIMI 2 to 3 flow had lower peak creatine kinase values (1,328 vs 2,790 IU/L, p <0.0001), higher acute ejection fraction (54.3% vs 51.6%, p = 0.05), higher late ejection fraction (59.2% vs 54.9%, p = 0.004), and lower 30-day mortality (4.8% vs 8.9%, p = 0.02). These data indicate that when reperfusion occurs before primary angioplasty, outcomes are strikingly better with less cardiogenic shock, improved procedural outcomes, smaller infarct size, better preservation of left ventricular function, and reduced mortality. This should encourage new strategies to establish reperfusion before "primary" angioplasty with "catheterization laboratory friendly" platelet inhibitors and/or low-dose thrombolytic drugs.     

The effects of sleep on the neural correlates of pattern separation

Effective memory representations must be specific to prevent interference between episodes that may overlap in terms of place, time, or items present. Pattern separation, a computational process performed by the hippocampus, overcomes this interference by establishing nonoverlapping memory representations. Although it is widely accepted that declarative memories are consolidated during sleep, the effects of sleep on pattern separation have yet to be elucidated. We used whole‐brain, high‐resolution functional neuroimaging to investigate the effects of sleep on a task that places high demands on pattern separation. Sleep had a selective effect on memory specificity and not general recognition memory. Activity in brain regions related to memory retrieval and cognitive control demonstrated an interaction between sleep and delay. Surprisingly, there was no effect of sleep on hippocampal activity using a group‐level analysis. To further understand the role of the hippocampus on our task, we performed a representational similarity analysis, which showed that hippocampal activation was biased toward pattern separation relative to cortical activation and that this bias increased following a delay (regardless of sleep). Cortical activation, conversely, was biased toward pattern completion and this bias was preferentially enhanced by sleep.     

Genetic analysis of the herpes simplex virus type 1 UL9 gene: Isolation of a lacZ insertion mutant and expression in eukaryotic cells

HSV-1 host range mutants in complementation group 1-36 (hr27 and hr156) whose mutations map in the UL9 gene, encoding the origin binding protein, are unable to form plaques or synthesize viral DNA or late viral proteins when grown in nonpermissive Vero cells (Carmichael, E. P., Kosovsky, M. J., Weller, S. K., 1988, J. Virol. 62, 91-99). These defects are complemented efficiently by growth in the permissive cell line, S22, which contains the wild type version of several HSV genes including UL9. In this report the precise nature and location of the lesions in host range mutants hr27 and hr156 were determined by DNA sequencing; both mutants were found to contain identical single-base-pair substitutions at codons 309 and 311 in the UL9 open reading frame. This region lies within the putative helicase domain of the UL9 protein. The UL9 gene was disrupted by the insertion of an insertional mutagen ICP6::lacZ in which the Escherichia coli lacZ gene is expressed under control of the viral ICP6 promoter. Hr94, a viral mutant containing this insertion, does not form plaques or synthesize viral DNA when grown in Vero cells, although both defects are complemented efficiently on permissive cell lines. These results confirm that the UL9 gene product is essential for viral growth and DNA replication. Furthermore, since no detectable UL9 protein is synthesized in hr94-infected cells, this virus provides a useful genetic background for further structure-function analysis since no potentially interfering nonfunctional UL9 protein will be expressed. We have expressed the UL9 open reading frame under the control of the strong and inducible HSV-1 ICP6 promoter and have derived Vero cell lines containing variable copy numbers of the ICP6::UL9 construct. Cells whose copy number of this construct exceeded approximately 120 are unable to support efficient plaque formation by wild-type virus. Cell lines with low copy numbers of this construct are able to complement hr27, hr156, and hr94.     

Effect of treatment delay on outcomes in patients with acute myocardial infarction transferred from community hospitals for primary percutaneous coronary intervention

Outcomes were evaluated in 1,841 consecutive patients with acute myocardial infarction treated with primary percutaneous coronary intervention from 1984 to 2000 comparing patients transferred from community hospitals (n = 680) with patients presenting locally (n = 1,161). Baseline variables were similar except transferred patients had fewer prior infarctions (13% vs 21%, p <0.001) and underwent less prior bypass surgery (2.8% vs 6.0%, p = 0.002). Median times from symptom onset to emergency department arrival were similar, but door-to-balloon times and reperfusion times were approximately 1 hour longer in transferred patients (2.8 vs 1.9 hours [p <0.001] and 4.5 vs 3.5 hours [p <0.001], respectively). Despite longer treatment times, there were no significant differences between transferred and nontransferred patients in 30-day mortality (7.6% vs 8.1%, p = 0.73), reinfarction, urgent target vessel revascularization, stroke, and late mortality. After adjusting for differences in baseline variables, mortality remained similar between transferred and nontransferred patients (odds ratio 0.90, 95% confidence interval 0.59 to 1.36). Peak cardiac enzyme values were higher in transferred patients, but there were no differences in 6-month ejection fractions between groups. In conclusion, patients transferred from community hospitals for primary percutaneous coronary intervention have almost 1-hour additional treatment delay, but this does not appear to have a major adverse effect on clinical outcomes. These data should encourage further randomized trials to evaluate the role of transfer for mechanical reperfusion in patients presenting to community hospitals with acute myocardial infarction.     

Aspirin insensitive thromboxane generation is associated with oxidative stress in type 2 diabetes mellitus

Introduction

Aspirin (ASA) irreversibly inhibits platelet cyclooxygenase-1 (COX-1) leading to decreased thromboxane-mediated platelet activation. The effect of ASA ingestion on platelet activation, thromboxane generation, oxidative stress and anti-oxidant biomarkers was studied in type 2 diabetes mellitus (DM).

Material and methods

Baseline and post-ASA samples (100/325 mg x 7 days) were obtained from 75 DM patients and 86 healthy controls for urinary 11-dehydro-thromboxane B2 (11dhTxB2), 8-iso-prostaglandin-F2α (8-isoPGF2α) and serum sP-Selectin, nitrite (NO₂^-), nitrate (NO₃^-) and paraoxonase 1 (PON1) activity.

Results

Compared to baseline controls, baseline DM had higher mean levels of 11dhTxB2 (3,665 ± 2,465 vs 2,450 ± 1,572 pg/mg creatinine, p = 0.002), 8-isoPGF2α (1,457 ± 543 vs 1,009 ± 412 pg/mg creatinine, p < 0.0001), NO₂^- (11.8 ± 7.3 vs 4.8 ± 5.3 μM, p < 0.0001), NO₃^- (50.4 ± 39.3 vs 20.9 ± 16.7 μM, p < 0.0001) and sP-Selectin (120.8 ± 56.7 vs 93.0 ± 26.1 ng/mL, p = 0.02), and the same held for post-ASA levels (p < 0.0001). ASA demonstrated no effect on 8-isoPGF2α, NO₂^-, NO₃^-, sP-Selectin or PON1 activity in either DM or controls. Post ASA inhibition of urinary 11dhTxB2 was 71.5% in DM and 75.1% in controls. There were twice as many ASA poor responders in DM than in controls (14.8% and 8.4%) based on systemic thromboxane reduction. Urinary 8-isoPGF2α excretion was greater in DM ASA poor responders than good responders (p < 0.009).

Conclusions

This suggests that oxidative stress may maintain platelet function irrespective of COX-1 pathway inhibition and/or increase systemic generation of thromboxane from non-platelet sources.     

Intra-aortic balloon counterpulsation before primary percutaneous transluminal coronary angioplasty reduces catheterization laboratory events in high-risk patients with acute myocardial infarction.

The benefit of intra-aortic balloon counterpulsation (IABC) before primary percutaneous transluminal coronary angioplasty (PTCA) for acute myocardial infarction in high-risk patients has not been well documented. Consecutive patients (n = 1,490) with acute myocardial infarction treated with primary PTCA from 1984 to 1997 were prospectively enrolled in an ongoing registry. Catheterization laboratory events occurred during or after intervention in 88 patients (5.9%), including ventricular fibrillation in 59 patients (4.0%), cardiopulmonary arrest in 46 patients (3.1%), and prolonged hypotension in 33 patients (2.2%). Cardiogenic shock was the strongest predictor of catheterization laboratory events (odds ratio [OR] 2.18, 95% confidence intervals [CI] 1.58 to 3.02) followed by low ejection fraction (<30%) (OR 1.51, 95% CI 1.06 to 2.15) and congestive heart failure (CHF) (OR 1.45, 95% CI 1.01 to 2.07). IABC used before intervention was associated with fewer catheterization laboratory events in patients with cardiogenic shock (n = 1 19) (14.5% vs. 35.1%, p = 0.009), in patients with CHF or low ejection fraction (n = 119) (0% vs. 14.6%, p = 0.10), and in all high-risk patients combined (n = 238) (1 1.5% vs. 21.9%, p = 0.05). IABC was a significant independent predictor of freedom from catheterization laboratory events (OR 0.48, 95% CI 0.29 to 0.79). These data support the use of IABC before primary PTCA for acute myocardial infarction in all patients with cardiogenic shock, and suggest that prophylactic IABC may also be beneficial in patients with CHF or depressed left ventricular function.     

Importance of time-to-reperfusion in patients with acute myocardial infarction with and without cardiogenic shock treated with primary percutaneous coronary intervention

Background Time-to-treatment is important for survival in patients with acute myocardial infarction (AMI) treated with fibrinolytic therapy, but the importance of time-to-treatment with primary percutaneous coronary intervention (PCI) is controversial. Previous studies evaluating the importance of time-to-treatment with primary PCI have not analyzed patients with cardiogenic shock separately. Methods Consecutive patients with AMI (n = 1843) treated with primary PCI were prospectively enrolled in the LeBauer Cardiovascular Research Foundation Registry. Late clinical follow-up was obtained in 98% of patients, at a mean time of 6.1 years. Results Reperfusion times were longer in women and patients with diabetes mellitus and shorter in patients with prior myocardial infarction. In patients with shock (n = 138), the inhospital mortality rate increased progressively with increasing time-to-reperfusion (<3 hours, 31%; 3-<6 hours, 50%; ≥6 hours, 62%; P = .01), whereas in patients without shock (n = 1705), inhospital and late mortality rates were similar across 3 categories of time to reperfusion (<3 hours, 5.8%; 3-<6 hours, 4.6%; ≥6 hours, 4.8%; P = .46). After adjusting for differences in baseline variables, reperfusion time was a significant independent predictor of inhospital mortality in patients with shock, but not in patients without shock. Conclusions Reperfusion time with primary PCI is important for survival in patients with shock, but appears to be less important in patients without shock. These data emphasize the importance of achieving early reperfusion in patients with shock and have implications on the triage of patients without shock for mechanical reperfusion and the mechanism of benefit of reperfusion therapy with primary PCI. (Am Heart J 2003;145:708-15.)