The contribution of reoxygenation to ischemic brain damage

This study examined the hypothesis that the level of postischemic reperfusion affects the severity of the resulting neuronal necrosis. In rats, tissue PO2% was monitored as an index of flow (reoxygenation) at four cortical sites by chronically implanted platinum electrodes. Twenty minutes of total global cerebral ischemia was followed by 30 min of reoxygenation. The level of reoxygenation was controlled to maintain the PO2 nearly constant at one or more of the cortical electrodes. Tissue from within 400 microns of each of 19 electrode sites among seven rats was evaluated histologically. There was a positive correlation between reoxygenation level and severity of neuronal damage. Perineuronal lucent halo formation, probably representing astrocyte foot process swelling, was negatively correlated with reoxygenation level. This study demonstrates that ischemic neuronal damage was aggravated by increased reoxygenation but that perineuronal swelling, as evidenced by halo formation, was somewhat ameliorated.     

Percentile regression analysis of correlated antibody responses

Antibody responses following vaccination usually are analysed by comparing geometric mean concentrations across levels of relevant covariates and by comparing the proportions of vaccinees responding. In the regression setting, the analyses are done on log-transformed concentrations, estimating geometric mean responses conditional on a vector of covariates. More detailed analyses examining the relationship of covariates to different parts of the response distribution may be performed through the application of asymmetric least squares estimation of regression percentiles. We present a method for accounting for correlation in percentile regression analyses of longitudinal antibody response data. We illustrate the procedures with measles antibody response data from Haitian children who participated in a randomized trial of high titre vaccines. The strongest dose and strain effects were seen in the low end of the antibody concentration distributions.     

Role of pulmonary alveolar macrophages in defense of the lung against Pseudomonas aeruginosa

Alveolar macrophages (AM) provide one of the first lines of defense against microbial invasion in the lower airways. The role of AM in the clearance of Pseudomonas aeruginosa in mice after intrapulmonary challenge was evaluated. AM were depleted by intranasal administration of liposome-encapsulated dichloromethylene diphosphonate. At 24 h following the instillation of liposomes, a sublethal dose of P. aeruginosa was inoculated intranasally. Spleen, liver, and lung tissue was then evaluated for viable bacteria and for histopathology. AM depletion of 78 to 88% did not affect the survival rate of infected mice or clearance of P. aeruginosa from the spleen, liver, or lung, compared to the control group, but the mice's susceptibility to Klebsiella pneumoniae was greatly enhanced. The recruitment of neutrophils to the lung was also not affected. Freshly explanted AM were not competent to phagocytose unopsonized P. aeruginosa but were able to phagocytose zymosan particles. Further studies were conducted to assess the in situ phagocytic activities of AM. Three hours after the intranasal instillation of P. aeruginosa or other particles, bronchoalveolar lavage was performed. AM phagocytosis of zymosan particles and latex beads exceeded that of P. aeruginosa. Neutrophils were recruited to the lung in response to a high-dose bacterial challenge. These results suggest that AM do not play an important role in defense of the lung against P. aeruginosa.     

Anatomic Location of the Tongue Base Neurovascular Bundle

Knowledge of the location of the hypoglossal/lingual artery neurovascular bundle (HLNVB) is essential in performing tongue base resections for neoplasm and for obstructive sleep apnea. Transoral and transcervical resections of the tongue base may be performed with greater exposure and certainty when the relationship of the HLNVB to local landmarks is understood; knowledge of the HLNVB allows resection of a larger amount of contralateral tongue base during partial glossectomy without violating the contralateral remnant tongue's blood supply. Ten cadaver heads were dissected to determine the position of the HLNVB with respect to soft tissue and bony landmarks at the tongue base. Our results indicate the position of the tongue base HLNVB is significantly inferior and lateral, that is, 2.7 cm inferior and 1.6 cm lateral to the foramen cecum, 0.9 cm superior to the hyoid bone, and 2.2 cm medial to the mandible. This inferolateral location allows the potential for aggressive tongue base resection without neurovascular compromise.     

Markers of past infection with simian virus 40 (SV40) and risk of incident non-Hodgkin lymphoma in a Maryland cohort.

Simian virus 40 (SV40) genome sequences have been detected in human non-Hodgkin lymphoma (NHL) tissues, and past infection with SV40 may be a risk factor for NHL. We conducted a population-based nested case-control study to investigate the association between serum antibodies to SV40 and incident NHL. Two research serum banks were established in Washington County, MD, with >45,000 volunteers contributing blood samples collected in 1974 and 1989. Incident cases of NHL diagnosed through 2002 (n = 170) were identified among participants by linkage to population-based cancer registries. Two controls were matched to each case (n = 340) on age, sex, and date of blood draw. Circulating immunoglobulin G antibodies to SV40 were measured using virus-like particle (VLP) ELISA. Positive samples were tested for cross-reactivity with JC virus (JCV) and BK virus (BKV) through competitive inhibition assays. Associations between SV40 antibody seropositivity and NHL were estimated using conditional logistic regression. Whereas SV40 antibodies were detected by VLP ELISA in 15% of cases and 10% of controls [matched odds ratio (OR), 1.97; 95% confidence interval (95% CI), 1.03-3.76], the SV40 reactivity of 85% of the SV40 antibody-positive sera was decreased by adsorption with BKV and/or JCV VLPs. Antibodies specific for SV40 (not cross-reactive) were identified in only 1.8% of cases and 1.6% of controls (OR, 1.51; 95% CI, 0.41-5.52). Our findings suggest that past infection with SV40 is not associated with an increased risk of developing NHL.     

Phase II study of gefitinib, fluorouracil, leucovorin, and oxaliplatin therapy in previously treated patients with metastatic colorectal cancer.

PURPOSE: To investigate the gefitinib, fluorouracil (FU), leucovorin, and oxaliplatin regimen (IFOX) in previously treated patients with metastatic colorectal cancer. PATIENTS AND METHODS: Eligible patients had stage IV colorectal adenocarcinoma and had demonstrated progression or intolerance to a prior chemotherapy regimen not including oxaliplatin. Each cycle consisted of 14 days. Cycle 1 consisted of oxaliplatin 85 mg/m2 intravenously (IV) during 2 hours on day 1, hours 0 to 2; leucovorin 200 mg/m2 IV on days 1 and 2, hours 0 to 2; FU 400 mg/m2 IV push on days 1 and 2; and FU 600 mg/m2 IV on days 1 and 2, hours 2 to 24 (FOLFOX-4). All subsequent cycles consisted of FOLFOX-4 with gefitinib at 500 mg/d administered orally throughout the 14-day cycle. RESULTS: Twenty-seven patients were enrolled onto the study. The median number of prior chemotherapy regimens was two, and 74% of all patients received prior irinotecan. Nine of the 27 patients (33%) and six of the 20 patients (30%) who had prior FU and irinotecan had a partial response by Response Evaluation Criteria in Solid Tumors Group criteria. Median overall survival was 12.0 months. Median event-free survival was 5.4 months. Grade 3 to 4 toxicities included neutropenia (48%), diarrhea (48%), nausea (22%), and vomiting (15%). CONCLUSION: IFOX is an active regimen in patients with previously treated metastatic colorectal adenocarcinoma, demonstrating higher response rates than those reported with FOLFOX-4 alone in a similar patient population.     

Patterns of transcription factor programs and immune pathway activation define four major subtypes of SCLC with distinct therapeutic vulnerabilities

1. Download : Download high-res image (242KB)
2. Download : Download full-size image

     

The Effect of Hypertension on Ischemic Cerebral Edema in Spontaneously Hypertensive Rats

Cerebral ischemia was produced in spontaneously hypertensive rats (SHR) with a range of blood pressures (BP). Measurements were made at 4 hours of the edema produced (% H₂O), the damage to the blood brain barrier (BBB) and, the blood flow (CBF) in both hemispheres and the cerebellum and brain stem. There was a statistically significant correlation between CBF and BP and between CBF and % H₂O, but the correlation between BP and % H₂O was not significant. The BBB is not open to technecium pertechnetate in this model at this time interval. Systemic hypertension is not a significant factor in the early development of ischemic edema in this model because the blood flow in the ischemic area falls with rising blood pressure, probably due to autoregulation in the collateral circulation.     

How laboratory studies of cigarette craving can inform the experimental alcohol craving literature

Interest in alcohol and other drug craving has flourished over the past two decades, and evidence has accumulated showing that craving can be meaningfully linked to both drug use and relapse. Considerable human experimental alcohol craving research since 2000 has focused on craving as a clinical phenomenon. Self-reported craving to drink typically has served as a catch-all for the craving construct in these studies, whereas few studies have considered craving as a process (or hypothetical construct) that interacts with other phenomena to affect use. In contrast to alcohol, we believe that recently there has been more mechanistic work targeting cigarette craving–related processes. Here, we briefly present a narrative review of studies of acute alcohol craving in humans that have been conducted during the past two decades. We then specify important ways in which alcohol and tobacco differ (e.g., the role of withdrawal), and we note the unique challenges in inducing robust alcohol craving states in the laboratory. Finally, we offer recommendations for how the alcohol field might advance its conceptual understanding of craving by adopting ideas and methods drawn from the smoking research literature. Specifically, we suggest that researchers extend their studies to not only examine the link between alcohol craving and relapse but also to focus on why and, in some instances, how alcohol cravings matter clinically, and the circumstances under which craving especially matters. We propose research to investigate the shifts in alcohol-related cognitive and affective processing that occur during alcohol craving states. Furthermore, we highlight the value of research examining the level of insight that individuals with varying levels of alcohol involvement possess about their own craving-related processing shifts. We believe that laboratory studies can provide rich opportunities to examine conceptual questions about alcohol craving that are central to addiction.