Oral hairy leukoplakia: clinicopathologic features, pathogenesis, diagnosis, and clinical significance

Oral hairy leukoplakia (OHL) is a lesion frequently, although not exclusively, observed in patients infected by human immunodeficiency viruses (HIV). OHL is clinically characterized by bilateral, often elevated, white patches of the lateral borders and dorsum of the tongue. Histologically, there is profound acanthosis, sometimes with koilocytic changes, and a lack of a notable inflammatory infiltrate. The koilocytic changes are due to intense replication of Epstein-Barr virus (EBV), while epithelial hyperplasia and acanthosis are likely to result from the combined action of the EBV-encoded proteins, latent membrane protein-1, and antiapoptotic BHRF1. How OHL is initiated and whether it develops after EBV reactivation from latency or superinfection remain unresolved; nevertheless, definitive diagnosis requires the demonstration of EBV replicating vegetatively in histological or cytological specimens. In patients with HIV infection, the development of OHL may herald severe HIV disease and the rapid onset of AIDS, but despite its title, OHL is not regarded as premalignant and is unlikely to give rise to oral squamous cell carcinoma.     

Respiratory effects associated with indoor nitrogen dioxide exposure in children

BACKGROUND: The human health effects of exposure to indoor nitrogen dioxide (NO2) are unclear, and few studies have examined the effects of short-term peak levels of exposure. METHODS: The association between indoor exposure to NO2 and respiratory illness was examined in 388 children aged 6-11 years. The NO2 levels were monitored during winter in 41 classrooms, from four schools with unflued gas heating and four schools with electric heating. Each classroom was monitored daily with 6-hour passive diffusion badge monitors over nine alternate weeks, and with hourly monitors over two of those weeks. Children living in homes with unflued gas appliances were also monitored daily over four evenings during times of gas use. RESULTS: Exposure to NO2 at hourly peak levels of the order of > or = 80 ppb, compared with background levels of 20 ppb, was associated with a significant increase in sore throat, colds and absences from school. An increase in cough with phlegm was marginally significant. Significant dose-response relationships were demonstrated for these four measures with increasing levels of NO2 exposure. CONCLUSIONS: Short-term peak levels of exposure are important to consider in relation to adverse respiratory effects associated with NO2 exposure.     

Selective changes in hippocampal neuropeptide Y neurons following removal of the cholinergic septal inputs

The number and distribution of subpopulations of hilar interneurons containing neuropeptide Y (NPY), somatostatin (SOM), or gamma-aminobutyric acid (GABA) immunoreactivities were examined in the hilus of the dentate gyrus following removal of the cholinergic septal inputs. One, 2, 4, 8, 12, and 24 weeks after intracerebroventricular injections of immunotoxin, consisting of antibody to the low-affinity nerve growth factor receptor conjugated to saporin (192 IgG-saporin), lesioned rats were processed simultaneously with controls for NPY, SOM, or GABA immunolabeling. Across all time points, the number of NPY-labeled neurons was reduced to a statistically significant level (paired t-test, P = 0.001) in the injected rats (73% of control values, on average). The decrease in the number of NPY-labeled neurons was not limited to any particular subregion rostrally but appeared greater in the central region caudally. The size of NPY-labeled neurons did not differ statistically between control and immunolesioned rats examined at 1, 2, and 24 week time points. In contrast, the number of both SOM- and GABA-immunoreactive neurons in injected rats did not appear to be affected in any consistent manner. Examination of the hilus in adjacent Nissl-stained sections with the optical dissector revealed that although the total number of small nonprincipal cells (5-15 microm in diameter) did not appear affected at the 4-week time point, there was a statistically significant (P = 0.03) reduction across the 8-24-week time points (to 80% of control values, on average). Dual-labeling studies on separate rats showed that a small subpopulation of the NPY- and SOM-labeled neurons, primarily in the infragranular hilus, were colocalized with neurons containing GABA immunoreactivity (18% and 5%, respectively). These studies demonstrate that removal of the cholinergic septal inputs (1) can cause relatively rapid, selective decreases in the number of NPY-immunoreactive hippocampal interneurons and (2) appears to lead to the death of hippocampal interneurons over a longer time course. The changes in NPY immunoreactivity seem to occur in the portion of interneurons that probably does not contain either SOM or GABA immunoreactivity.     

Alteration in cell kinetics in control B6C3F1 mice infected with Helicobacter hepaticus

The discovery of Helicobacter hepaticus infection, H. hepaticus hepatitis, and increased incidence of liver tumors in control males from several recent National Toxicology Program B6C3F1 mouse carcinogenicity bioassays raised questions regarding the suitability of these bioassays for hazard identification. The purpose of this study was to determine if changes in cell proliferation and death at terminal sacrifice might be linked to the increased liver tumor incidences among control males. In control males, enhanced rates of hepatocyte proliferation, as assessed by immunostaining for proliferating cell nuclear antigen (PCNA), and apoptosis, as assessed from hematoxylin and eosin- and TUNEL-stained preparations, were seen in 3 bioassays with H. hepaticus hepatitis. One bioassay with H. hepaticus infection without attendant hepatitis and one bioassay without H. hepaticus or hepatitis did not have elevated rates of hepatocyte proliferation or apoptosis. There was no significant effect on PCNA cell proliferation indices or apoptosis in females. The present findings are indicative of a clear association between the presence of H. hepaticus infection with attendant hepatitis, increased cell proliferation and apoptosis, and increased incidences of hepatocellular neoplasia in males but not in females. Thus, the interpretation of liver tumor responses in H. hepaticus-infected studies is considered to be confounded in male mice. The lack of enhanced cell proliferation or hepatocellular neoplasia in control females suggests that bioassay results from females are valid for hazard identification. Furthermore, the absence of enhanced cell proliferation in lungs and kidneys of male and females suggests that neoplastic effects at these sites are not exacerbated by H. hepaticus infection.     

History of the Kolff Laboratory turbine driven electrohydraulic artificial heart

The concept of an electrically powered total artificial heart has been pursued by Dr. Kolff and his associates since the 1960s. Since the 1980s these efforts have been concentrated upon the development of the electrohydraulic total artificial heart, a turbine pump powered by a brushless DC motor. Dr. Kolff realized the benefits of pulsatile flow and device response to Starling's Law, and these concepts have formed the basis of subsequent design decisions. Design iterations have both solved existing problems and exposed new challenges. The current device design is greatly improved over early attempts due to the incorporation of technologies that have recently become available as the result of progress in the fields of materials and electronics and due to the lessons learned over many years of research under the guidance of Dr. Kolff. This article describes, from its inception, the last major research project of Dr. Kolff prior to his retirement. The discussion centers around development, problems and their solutions, and the reasoning for given solutions.     

Modulation of human microvascular endothelial cell bioenergetic status and glutathione levels during proliferative and differentiated growth

During angiogenesis, formerly differentiated human microvascular endothelial cells (HMECs) return to a proliferative growth state. Many fundamental questions regarding HMEC function, such as how HMECs adapt to changes in bioenergetic requirements upon return to proliferative growth, remained unanswered. In this study, we evaluated whether modifications in HMEC bioenergetic profiles and glutathione (GSH) levels accompanied the cellular transition between differentiated and proliferative growth. To provide insight into the continuum of cellular adaptations that occur during this transition, we used a method recently developed in our laboratory that induces a state of morphological and functional predifferentiation in HMECs. Cellular morphology, in conjunction with flow cytometric DNA analyses and HMEC functional assays (the directed migration and intercellular association involved in microtubule formation) were employed to validate the HMEC culture state of growth. Analysis of the HPLC nucleotide profiles disclosed several findings common to all culture growth states. These uniform findings, e.g., cellular energy charges > 0.90, and highly reduced redox states, revealed that cultured HMECs maintain high rates of oxidative metabolism. However, there were also significant, culture growth state related differences in the nucleotide profiles. Proliferative HMECs were shown to possess significantly higher (relative to both large vessel endothelial cells, and differentiated HMECs) levels of GSH and specific nucleotides which were related with a return to the active cell cycle-ATP, GTP, UTP, and CTP, and NADPH. Further, the nucleotide profiles and GSH levels of the predifferentiated HMECs were determined to be intermediate between levels obtained for the proliferative and differentiated HMECs. The results of this study demonstrate that the capacity to modulate their cellular bioenergetic status during growth state transitions is one of the adaptations that enable HMECs to retain a growth state reciprocity. In addition, our findings also show that HMECs, especially during the proliferative growth state, are biochemically distinct from endothelial cells harvested from large vessels, and therefore suggest that HMECs are the cells of choice to employ when studying diseases that affect the human microvasculature.     

Phencyclidine metabolite irreversible binding in the rat: gonadal steroid regulation and CYP2C11

These studies were conducted to determine the effect of hormones on sex-related differences in phencyclidine (PCP) metabolite irreversible binding and to determine the cytochrome P450 isoform(s) involved in this process. Sprague-Dawley male rats were castrated or administered estradiol and Sprague-Dawley female rats were ovarectomized or ovarectomized and given testosterone. Liver microsomal metabolism studies demonstrated that PCP metabolite binding to proteins was significantly altered by testosterone and estrogen administration. Castration of male rats decreased metabolite binding to 57% of sham-operated male levels, and administration of testosterone to ovarectomized female rats increased metabolite binding to 41 % of normal male levels. No metabolite adducts could be detected in microsomes from male rats administered estradiol or from sham-operated females given vehicle. These hormone-induced changes in metabolite binding closely matched the hormone-induced changes in CYP2C11 function and expression in these same microsomes. PCP metabolite irreversible binding to microsomal proteins was highly correlated with CYP2C11 function (as assessed by the formation of 2alpha-OH-testosterone, r = 0.91) and with CYP2C11 expression (as assessed by Western blot analysis, r = 0.95). In addition, an anti-CYP2C11 monoclonal antibody almost completely inhibited PCP metabolite binding (down to 7% of control male values) in an antibody concentration-dependent manner. These data strongly implicate CYP2C11 as an isoform involved in PCP metabolism and the formation and/or binding of a reactive PCP metabolite to microsomal proteins.