Neoplasia and granulomas surrounding microchip transponders in Damaraland mole rats (Cryptomys damarensis).

Damaraland mole rats (Cryptomys damarensis) are among the longest-living rodents, with a maximum longevity of approximately 16 years. As one of the few mammals termed eusocial, these animals have been used in behavioral, genetic, metabolic, and physiologic research at the University of Connecticut since 1997. For individual identification at 3 to 4 months of age, mole rats were subcutaneously implanted with microchip transponders (11 mm in length) in the dorsal cervical region. In 2007, 2 of the 90 implanted adults, 10-year-old and 9-year-old females, developed subcutaneous masses at the site of the implant. Histopathological and immunohistochemical examinations revealed amelanotic melanoma and fibrosarcoma, respectively, with metastasis of the amelanotic melanoma. In 2008, a total of 3 adult males were castrated as part of a sex behavior study; 3 months later, all 3 castrated males developed subcutaneous masses around their implants, whereas none of the noncastrated males had masses. After an additional 9 months, these masses were found to be granulomas. To the authors' knowledge, this is the first report of neoplasia in this species. Both the tumors and the granulomas surrounded the microchip transponder.

Combinations of cytochrome P-450 genotypes and risk of early-onset lung cancer in Caucasians and African Americans: a population-based study.

Polymorphisms in CYP1A1 and CYP1B1 genes in humans are associated with reduction of enzymatic activity towards several substrates, including those found in tobacco smoke. To investigate the potential role these polymorphisms have as modulators of early-onset lung cancer risk, a population-based case-control study involving early-onset lung cancer cases was performed. Biological samples were available for 383 individuals diagnosed prior to 50 years of age identified from the metropolitan Detroit Surveillance, Epidemiology and End Results (SEER) program and 449 age, race and sex-matched controls ascertained through random digit dialing. Genotype frequencies varied significantly by race for CYP1A1 Ile(462)Val and CYP1B1 Leu(432)Val genotypes, so all analyses were stratified by race. No association was seen between lung cancer risk and polymorphisms in CYP1A1 Msp1 or CYP1B1 Leu(432)Val for Caucasians or African Americans, after adjusting for age at diagnosis, sex, pack years of smoking and family history of lung cancer. In Caucasians, those with the IIe/Val genotype at CYP1A1 Ile(462)Val locus were at decreased risk of having lung cancer compared to those with the lle/lle genotype, after adjusting for age at diagnosis, sex, pack years of smoking and family history of cancer (OR=0.41 95% Cl 0.19-0.90). These results were not replicated among the African American population, nor were they modified by amount of smoking.

CYP1A1 and CYP1B1 polymorphisms and risk of lung cancer among never smokers: a population-based study.

The cytochrome P450 (CYP) superfamily of enzymes catalyse one of the first steps in the metabolism of carcinogens such as polycyclic aromatic hydrocarbons, nitroaromatics and arylamines. Polymorphisms within the CYP1A1 gene have been shown to be associated with lung cancer risk, predominantly among Asian populations. Despite functional evidence of a possible role of CYP1B1 in lung cancer susceptibility, only a few studies have evaluated polymorphisms in this gene in relation to lung cancer susceptibility. This population-based study evaluates polymorphisms in both of these CYP genes within never smokers, most of whom had environmental tobacco smoke (ETS) exposure. Cases (n = 160) were identified through the metropolitan Detroit Surveillance, Epidemiology and End Results program, and age, sex and race-matched population-based controls (n = 181) were identified using random digit dialing. Neither CYP1A1 MspI nor CYP1A1 Ile(462)Val was associated with lung cancer susceptibility among Caucasians or African-Americans. Among Caucasians, however, CYP1B1 Leu(432)Val was significantly associated with lung cancer susceptibility odds ratio (OR) for at least one valine allele = 2.87 [95% confidence interval (CI) 1.63-5.07]. Combinations of this Phase I enzyme polymorphism along with selected Phase II enzyme polymorphisms (GSTM1 null, GSTP1 Ile(105)Val and NQO1 C(609)T) were evaluated. The combination of CYP1B1 Leu(432)Val and NQO1 C(609)T appeared to be associated with the highest risk of lung cancer (OR = 4.14, 95% CI 1.60-10.74), although no combinations differed significantly from the risk associated with CYP1B1 Leu(432)Val alone. When individuals were stratified by household ETS exposure (yes/no), CYP1B1 Leu(432)Val alone and in combination with Phase II enzyme polymorphisms was more strongly associated with increased lung cancer susceptibility among those with at least some household ETS exposure. Additional studies will be required to further validate these findings among never smokers and to evaluate the effects of this polymorphism among smoking populations as well.

Organ-specific molecular classification of primary lung, colon, and ovarian adenocarcinomas using gene expression profiles.

Molecular classification of tumors based on their gene expression profiles promises to significantly refine diagnosis and management of cancer patients. The establishment of organ-specific gene expression patterns represents a crucial first step in the clinical application of the molecular approach. Here, we report on the gene expression profiles of 154 primary adenocarcinomas of the lung, colon, and ovary. Using high-density oligonucleotide arrays with 7129 gene probe sets, comprehensive gene expression profiles of 57 lung, 51 colon, and 46 ovary adenocarcinomas were generated and subjected to principle component analysis and to a cross-validated prediction analysis using nearest neighbor classification. These statistical analyses resulted in the classification of 152 of 154 of the adenocarcinomas in an organ-specific manner and identified genes expressed in a putative tissue-specific manner for each tumor type. Furthermore, two tumors were identified, one in the colon group and another in the ovarian group, that did not conform to their respective organ-specific cohorts. Investigation of these outlier tumors by immunohistochemical profiling revealed the ovarian tumor was consistent with a metastatic adenocarcinoma of colonic origin and the colonic tumor was a pleomorphic mesenchymal tumor, probably a leiomyosarcoma, rather than an epithelial tumor. Our results demonstrate the ability of gene expression profiles to classify tumors and suggest that determination of organ-specific gene expression profiles will play a significant role in a wide variety of clinical settings, including molecular diagnosis and classification.

Cysteine 73 in bleomycin hydrolase is critical for amyloid precursor protein processing.

Human bleomycin hydrolase (hBH) is a neutral cysteine protease that may regulate the secretion of soluble amyloid precursor protein (APP) and amyloid beta (A(beta)), which is a major constituent of the Alzheimer's disease-associated amyloid plaques. We have now determined that APP interacts with hBH by using yeast two hybrid methods and in vitro binding studies revealed that APP interacted with a 68 amino acid region that includes the catalytic domain of hBH. Ectopic expression of hBH increased the secretion of A(beta) but not of a second secreted protein, apolipoprotein A-I. Expression of hBH in which the catalytic cysteine 73 was mutated to serine failed to increase A(beta) secretion. These results indicate a critical role for cysteine 73 of hBH in mediating APP processing.

Coordinately up-regulated genes in ovarian cancer.

A better understanding of the molecular circuitry in normal ovarian tissues and in ovarian cancer will likely provide new targets for diagnosis and therapy. Recently, much has been learned about the genes expressed in ovarian cancer through studies with cDNA arrays and serial analysis of gene expression. However, these methods do not allow highly quantitative analysis of gene expression on a large number of specimens. Here, we have used quantitative real-time RT-PCR in a panel of 39 microdissected ovarian carcinomas of various subtypes to systematically analyze the expression of 13 genes, many of which were previously identified as up-regulated in a subset of ovarian cancers by serial analyses of gene expression. The genes analyzed are glutathione peroxidase 3 (GPX3), apolipoprotein J/clusterin, insulin-like growth factor-binding protein 2, epithelial cell adhesion molecule/GA733-2, Kop protease inhibitor, matrix gla protein, tissue inhibitor of metalloproteinase 3, folate receptor 1, S100A2, signal transducer and activator of transcription 1, secretory leukocyte protease inhibitor, apolipoprotein E, and ceruloplasmin. All of the genes were found overexpressed, some at extremely high levels, in the vast majority of ovarian carcinomas irrespective of the subtype. Interestingly, GPX3 was found at much higher levels in tumors with clear cell histology and may represent a biomarker for this subtype. Some of the genes studied here may thus represent targets for early detection ovarian cancer. The gene expression patterns were not associated with age at diagnosis, stage, or K-ras mutation status in ovarian cancer. We find that several genes are coordinately regulated in ovarian cancer, likely representing the fact that many genes are activated as part of common signaling pathways or that extensive cross-talk exists between several pathways in ovarian cancer. A statistical analysis shows that genes commonly up-regulated in ovarian cancer may result from the aberrant activation of a limited number of pathways, providing promising targets for novel therapeutic strategies.

Lung recruitment.

It has become increasingly clear that a lung protective ventilatory strategy during adult respiratory distress syndrome/acute lung injury has a positive effect on outcome. Lung recruitment is a major component of this strategy. High-pressure recruitment maneuvers and prone positioning can open the lung; however, once the lung is opened, it must be kept open with appropriate levels of positive end-expiratory pressure. For both of these techniques to be effective, they must be used early in the course of adult respiratory distress syndrome/acute lung injury.

Feather folliculoma in a captive-bred barn owl (Tyto alba).

Proliferative cutaneous lesions are frequently encountered in examination of avian species. Tumors of the skin have been reported in many bird species, although comparatively less is known about the incidence of integumentary neoplasia in nondomesticated species than in production or companion species. An adult male, 9-yr-old, captive-bred barn owl (Tyto alba) was presented for examination of a proliferative skin mass of several months' duration on the left wing. An excisional biopsy was performed, and the owl recovered uneventfully. Light microscopic examination of tissue sections of the mass revealed a focal, unencapsulated, well-demarcated, multiloculated mass that consisted of variably sized cystic spaces lined by stratified squamous epithelium and containing concentric laminations of keratin and foci of feather differentiation. A histopathologic diagnosis of feather folliculoma was made. This neoplasm has not previously been described in owls. Its incidence and documentation are significant in that this neoplasm should be considered as a differential diagnosis of proliferative skin lesions in this raptorial species.

Negative pressure pulmonary hemorrhage.

Negative pressure pulmonary edema, a well-recognized phenomenon, is the formation of pulmonary edema following an acute upper airway obstruction (UAO). To our knowledge, diffuse alveolar hemorrhage has not been reported previously as a complication of an UAO. We describe a case of negative pressure pulmonary hemorrhage, and we propose that its etiology is stress failure, the mechanical disruption of the alveolar-capillary membrane.

The neutral cysteine protease bleomycin hydrolase is essential for epidermal integrity and bleomycin resistance.

The papain superfamily member bleomycin hydrolase (Blmh) is a neutral cysteine protease with structural similarity to a 20S proteasome. Bleomycin (BLM), a clinically used glycopeptide anticancer agent, is deaminated in vitro by Blmh. We used gene targeting to generate mice that lack Blmh and demonstrated that Blmh is the sole enzyme required for BLM deamination. Although some Blmh null mice were viable and reproduced, only about 65% of the expected number survived the neonatal period, revealing an important role for Blmh in neonatal survival. Mice lacking Blmh exhibited variably penetrant tail dermatitis that resembled rodent ringtail. The histopathology of the tail dermatitis was similar to skin lesions in humans with pellagra, necrolytic migratory erythema, and acrodermatitis enteropathica. Compared with controls, Blmh null mice were more sensitive to acute BLM lethality and developed pulmonary fibrosis more readily following BLM treatment. Thus, we have established that Blmh is an essential protectant against BLM-induced death and has an important role in neonatal survival and in maintaining epidermal integrity.

A 2-year comparison study of Crl:CD BR and Hsd:Sprague-Dawley SD rats.

In this 2-year study, the suitability of the Hsd:Sprague-Dawley SD (SD) as a replacement for the Crl:CD BR (CD) rat was assessed by comparing survival rates, palpable mass incidence, body weights, food consumption, clinical laboratory parameters, and necropsy and histopathology observations. At week 104, survival rates in the CD and SD males were 29 and 49%, respectively. Corresponding survival rates in females were 44 and 63%. The total numbers of animals with palpable masses and animals with neoplasms were similar in the CD and SD rats; however, the total numbers of palpable masses and neoplasms were higher in the CD rats. The incidence of corneal lesions was higher in the SD rats, whereas the incidence of lenticular opacities was higher in the CD rats. Body weights, food and water consumption, and organ weights were significantly lower in the SD rats. In contrast, food intake per kilogram of body weight was slightly higher in the SD rats. Numerous differences in clinical laboratory parameters between the CD and SD rats were observed. Some of these were consistent with the increased prevalence of kidney disease and secondary sequelae in the SD rats. Taken together, the better survival, smaller size, and lower food consumption of the SD rat may make it a better model for chronic bioassays. However, the increased propensity for spontaneous renal disease may limit the utility of the SD rat for studying nephrotoxic compounds.

Intellectual functioning of inpatients with dissociative identity disorder and dissociative disorder not otherwise specified. Cognitive and neuropsychological aspects.

The intellectual functioning of 105 inpatients with multiple personality disorder and dissociative disorder not otherwise specified was assessed using the Wechsler Adult Intelligence Scale-Revised as part of a comprehensive research protocol. There were no significant intellectual differences between the groups on any major intelligence quotient summary score or any of the age-adjusted empirical factor scores. The anecdotal but widely accepted hypotheses that dissociative patients either have above average premorbid intelligence or that their current intellectual functioning is deleteriously affected by their fluctuant psychiatric disorder were not supported in this sample. A significant subsample of the multiple personality disorder group manifested abnormal interest scatter on the Wechsler Adult Intelligence Scale-Revised verbal subtests, and this variability was attributed to subtle neuropsychological deficits on the Memory/Distractibility factor. We speculate that dissociative patients might need to be evaluated for attention deficit disorder in addition to the range of dissociative symptoms in a comprehensive evaluation.

Chronic electrical stimulation reverses deafness-related depression of electrically evoked 2-deoxyglucose activity in the guinea pig inferior colliculus.

The [14C]-2-deoxyglucose (2-DG) autoradiographic technique was used to study how auditory-related metabolic activity changes with deafness, and how chronic electrical stimulation of the deafened system may modify these changes. Guinea pigs were deafened by administration of kanamycin and ethacrynic acid. After nine weeks of deafness, the basal unstimulated uptake of 2-DG in the inferior colliculus (IC) was lower than in normal hearing control animals. 100 microA of acute cochlear electrical stimulation significantly increased 2-DG uptake in normal hearing animals but did not evoke a significant increase in four or nine week deafened animals. Electrically elicited 2-DG uptake in the IC is therefore depressed by prolonged deafness. In a second series of experiments, after four weeks of deafness, animals were chronically electrically stimulated via a cochlear implant 2.5-3.5 h a day, five days a week for five weeks at 100 microA. Acute cochlear electrical stimulation following this chronic stimulation significantly increased 2-DG uptake in the contralateral IC over unstimulated levels. This suggests that some depressive effects of profound deafness on the auditory brain stem may be reduced or reversed with chronic electrical stimulation by a cochlear implant.

Human cytotoxic T-cell lines with restricted specificity for squamous cell carcinoma of the head and neck.

Human cytotoxic T-lymphocyte (CTL) lines with specificity restricted for autologous squamous cell carcinoma of the head and neck (SCCHN) were established from peripheral blood lymphocytes obtained at the time of surgery and again at two different times after surgery from a patient with cancer of the tongue. The CTL lines were cultured in the presence of interleukin (IL) 2, IL4, and autologous tumor (AuTu) cell monolayers. All three lines were CD3+CD8+CD11b-HLA-DR+ T-cell receptor alpha/beta+. They were tested in 4-h51Cr release assays against SCCHN cell lines (n = 5) and a variety of nonsquamous human tumor (n = 5) and normal (n = 5) cell targets and was found to lyse only AuTu (PCI-50) and three allogenic SCCHN cell lines. Lysis of AuTu and the three allogenic SCCHN targets by the established CTL lines appeared to be major histocompatibility complex class I restricted, since it was blocked by monoclonal antibodies to class I histocompatibility complex antigens. The CTL lines proliferated in vitro in response to autologous PCI-50 or an allogenic SCCHN cell line (PCI-1). The lines have been maintained in culture in the presence of AuTu monolayers and retained cytotoxicity against AuTu for over 20 weeks. The AuTu (PCI-50) cell line was tested for in vitro sensitivity to cytotoxic or cytostatic effects of various effector cells, including the CTL lines. PCI-50 targets were resistant to lysis by resting human mononuclear cells but sensitive to IL2-activated natural killer cells in 4-h 51Cr release assays. In comparison with IL2-activated natural killer cells, the CTL line mediated lower levels of lysis against AuTu. Growth of PCI-50 cells in culture was significantly inhibited by a combination of gamma-interferon and IL2 or by high concentrations of tumor necrosis factor alpha. While supernants of IL2-activated natural killer cells were growth inhibitory, those of the CTL line were not. On the other hand, lysis of AuTu targets by the CTL line was increased by preincubation of the tumor cells with tumor necrosis factor alpha or gamma-interferon. These cytokines augmented expression of HLA-class I, HLA-class II, and intercellular adhesion molecule I, but not squamous cell carcinoma-associated antigens, E7 and A9, on PCI-50 cells. The CTL lines described are the first with restricted specificity for autologous SCCHN ever reported and their availability will facilitate studies of the AuTu T-cell response in head and neck cancer.

Construct validity of the Dissociative Experiences Scale: II. Its relationship to hypnotizability.

Undergraduates (n = 311) who volunteered to participate in an experiment on "Hypnotizability and Personality" filled out several personality questionnaires (including the Dissociative Experiences Scale; DES), were administered the Harvard Group Scale of Hypnotic Susceptibility (HGSHS), and completed a self-rating of hypnotizability. The DES overall score correlated significantly with the HGSHS summary score (r(309) = .12, p < .05, two-tailed) and with subject's self-rating of hypnotizability (r(309) = .13, p < .05, two-tailed). The magnitude of these correlations was similar to that observed in a previous study (.14 & .18) and is also similar in magnitude to the correlations typically observed between the HGSHS and the Tellegen Absorption Scale. The potential clinical implications of these findings are discussed.