Duodenoesophageal reflux induces esophageal adenocarcinoma without exogenous carcinogen

Central nervous system (CNS) disease is a major feature of simian immunodeficiency virus (SIV) infection of macaques. To define the spectrum of CNS lesions in SIV-infected macaques and the potential associations with viral strain and disease course, we performed a retrospective analysis of necropsies on 124 macaques with SIV-induced AIDS. Histologic evidence of CNS disease was observed in 71 (57.3%) of the 124 animals. SIV encephalitis was the most common CNS lesion occurring in 43.7% (31/71) of the animals with CNS disease and 25% of all animals. The incidence of SIVE correlated significantly with shortened survival (P=0.0207). In addition, SIVE was seen in 42.9% (15/35) of rapid progressors (animals that died within 200 days) compared to only 18% (16/89) of normal progressors (animals that lived longer than 200 days) (P=0.011). Animals with SIVE had higher viral loads in peripheral blood than those that did not, but this difference did not reach statistical significance. Similarly, while animals infected with uncloned SIVmac251 had a higher incidence of SIVE (27.5%; 14/51) than animals infected with molecularly cloned SIVmac239 and its T-cell tropic derivatives (18.5%; 10/54) this difference was not statistically significant. In this study rapid disease progression and SIVE were highly correlated making separation of viral determinants of virulence from those of neurovirulence difficult.     

Targeting peptide nucleic acid-protein conjugates to structural features within duplex DNA

URF13 is the product of a mitochondrial-encoded gene (T-urf13) found only in maize plants containing the Texas male-sterile cytoplasm (cms-T), and it is thought to be responsible for both cytoplasmic male sterility and the susceptibility of cms-T maize to the fungal pathogens Bipolaris maydis race T and Phyllosticata maydis. Mitochondria isolated from cms-T maize are uniquely sensitive to pathotoxins (T-toxin) produced by these fungi and to methomyl (a commercial insecticide). URF13 acts as a receptor that specifically binds T-toxin to produce hydrophilic pores in the inner mitochondrial membrane. When expressed in Escherichia coli cells, URF13 also forms hydrophilic pores in the plasma membrane if exposed to T-toxin or methomyl. Topological studies established that URF13 contains three membrane-spanning alpha-helices, two of which are amphipathic and can contribute to pore formation. Chemical cross-linking of URF13 was used to demonstrate the existence of URF13 oligomers in cms-T mitochondria and E. coli cells. The ability of the carboxylate-specific reagent, N,N'-dicyclohexycarbodiimide, to cross-link URF13 was used in conjunction with site-directed mutagenesis to establish that the URF13 tetramer has a central core consisting of a four-alpha-helical bundle which undergoes a conformational change after interaction with T-toxin or methomyl. Overall, the experimental evidence indicates that URF13 functions as a ligand-gated, pore-forming T-toxin receptor in cms-T mitochondria.     

Slow cellular dynamics in MDCK and R5 cells monitored by time-lapse atomic force microscopy

We have examined dynamic events that occur on a time scale of minutes in an epithelial monolayer of Madine-Darby Canine Kidney (MDCK) cells and in ras-transformed MDCK cells by atomic force microscopy (AFM). Cells were imaged under physiological conditions, and time-lapse movies representing approximately 60 s real time per frame were assembled. In normal MDCK cells, two types of protrusions in the apical plasma membrane exhibit dynamic behavior. First, smooth bulges formed transiently over the time scale of minutes to tens of minutes. Second, spike-like protrusions appear initially as bulges, extend well above the apical surface and, finally, seem to detach. R5, an oncogenic transformant derived from MDCK cells, grows very flat on glass. During AFM imaging, these cells sometimes round up and detach from the substrate. In light microscopic observations of parallel preparations, cells rarely detach, suggesting that this is an active response of these cells to irritation by the AFM tip. R5 cells often extend processes that are supported by actin stress fibers. During imaging with the AFM, these processes withdraw at a rate of 1-5 microns/min, similar to that observed by light microscopy. During the withdrawal, movement of the stress fibers can be clearly seen. In the flat periphery of these cells, the transport of intracellular particles along cytoskeletal elements was seen. In addition, we have observed two types of wave-like movements through the cell, which appear to be an organized rearrangement of cytoplasm. One type of wave moves radially out from center of the cell while the other moves circularly along the cell periphery.     

Susceptibility of penicillin-susceptible and -resistant pneumococci to CFC-222, a new fluoroquinolone

Rotavirus (RV) strains infecting newborns often have unique neutralization antigens (P serotypes) on their outer capsids that are distinct from those found on RV strains that cause diarrhea in older children. We examined the hypothesis that unusual RV strains preferentially infect newborns because the newborns lack maternal neutralizing antibodies to these strains. To test this hypothesis, sera and saliva samples collected from neonates infected with 116E-like (P[11]G9) strains in the maternity ward of the All India Institute of Medical Sciences (AIIMS) hospital in New Delhi were tested for neutralizing antibodies against common RV strains and those infecting newborns and these titers were compared with those of newborns who did not become infected (controls). The infected neonates had significantly lower levels of cord blood neutralizing antibodies to 116E than the controls, suggesting that immunity to neonatal RV infection is acquired transplacentally through maternal antibodies. Further, this study confirmed the immunogenicity of the AIIMS neonatal strain 116E, a vaccine candidate, in its ability to evoke a potent RV-specific immunoglobulin A and neutralizing antibody response in serum and saliva among the infected babies. Our findings have important implications for the development of an effective RV vaccine. In India, where G9 strains are common in the community, the use of 116E as a vaccine, together with the rhesus tetravalent vaccine, may provide a broader protection against all the circulating RV serotypes, including serotype G9, which is not represented in the current rhesus RV tetravalent vaccine (G1-G4).     

Hybrid verrucous squamous cell carcinoma of sinonasal tract: a case report

Verrucous carcinoma is a variant of squamous cell carcinoma and should be distinguished from benign papilloma and well-differentiated nonverrucous squamous cell carcinoma. It is rare tumor of the sinonasal tract. Occasionally, conventional squamous cell carcinomatous components may be seen in verrucous carcinoma. This entity is called a hybrid verrucous squamous cell carcinoma. We report a case of hybrid verrucous squamous cell carcinoma occurring in the nasal cavity and paranasal sinus of a 67-year-old male. The removed mass shows the typical feature of verrucous carcinoma, but focally conventional squamous cell carcinomatous area is also noted. The treatment of this case follows verrucous carcinoma, but close follow up is mandatory because it may potentially spread to regional lymph nodes in contrast to pure form of verrucous carcinoma.     

Analyses of coronary graft patency after aprotinin use: results from the International Multicenter Aprotinin Graft Patency Experience (IMAGE) trial

OBJECTIVE: We examined the effects of aprotinin on graft patency, prevalence of myocardial infarction, and blood loss in patients undergoing primary coronary surgery with cardiopulmonary bypass. METHODS: Patients from 13 international sites were randomized to receive intraoperative aprotinin (n = 436) or placebo (n = 434). Graft angiography was obtained a mean of 10.8 days after the operation. Electrocardiograms, cardiac enzymes, and blood loss and replacement were evaluated. RESULTS: In 796 assessable patients, aprotinin reduced thoracic drainage volume by 43% (P < .0001) and requirement for red blood cell administration by 49% (P < .0001). Among 703 patients with assessable saphenous vein grafts, occlusions occurred in 15.4% of aprotinin-treated patients and 10.9% of patients receiving placebo (P = .03). After we had adjusted for risk factors associated with vein graft occlusion, the aprotinin versus placebo risk ratio decreased from 1.7 to 1.05 (90% confidence interval, 0.6 to 1.8). These factors included female gender, lack of prior aspirin therapy, small and poor distal vessel quality, and possibly use of aprotinin-treated blood as excised vein perfusate. At United States sites, patients had characteristics more favorable for graft patency, and occlusions occurred in 9.4% of the aprotinin group and 9.5% of the placebo group (P = .72). At Danish and Israeli sites, where patients had more adverse characteristics, occlusions occurred in 23.0% of aprotinin- and 12.4% of placebo-treated patients (P = .01). Aprotinin did not affect the occurrence of myocardial infarction (aprotinin: 2.9%; placebo: 3.8%) or mortality (aprotinin: 1.4%; placebo: 1.6%). CONCLUSIONS: In this study, the probability of early vein graft occlusion was increased by aprotinin, but this outcome was promoted by multiple risk factors for graft occlusion.     

Prevention of heterocyclic amine formation by tea and tea polyphenols

Heterocyclic amines (HCAs), formed during the cooking of meats and fish, are thought to be the genotoxic carcinogens associated with important types of human cancer in meat-eating populations, such as cancer of the breast, colon or pancreas. We studied the effect of black or green tea, and of the tea polyphenols theaflavine gallate (TFG, black tea) and epigallocatechin gallate (EGCG, green tea) on the formation of typical HCAs, 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), using the model in vitro systems of J?gerstad. Green tea and black tea and solutions of TFG and EGCG lower the formation of PhIP by 62-85% during 1 h heating at 160 degrees C of 1 mmol creatinine, 1 mmol phenylalanine and 0.5 mmol glucose in 3.3 ml diethylene glycol-water (10:1), where the inhibitors replaced 0.3 ml of the water. The production of MeIQx and related HCAs, in the same system but with 1 mmol glycine instead of phenylalanine was likewise reduced, determined by amounts of mutagens formed. In the latter systems, the teas were not, or less effective, but the polyphenols were inhibitory. Thus, the tea products represent another approach to lower the formation of HCAs.     

(R,R)-2,2'-[1,2-ethanediylbis[imino(1-methyl-2,1-ethanediyl)]]- bis[5-nitro-1H-benz[de]isoquinoline-1,3-(2H)-dione] dimethanesulfonate (DMP 840), a novel bis-naphthalimide with potent nonselective tumoricidal activity in vitro

(R,R)-2,2'-[1,2-ethanediylbis[imino(1-methyl-2,1-ethanediyl)]]- bis[5-nitro-1H-benz[de]isoquinoline-1,3-(2H)-dione] dimethanesulfonate (DMP 840), is a bis-naphthalimide anticancer tumoricidal agent currently in phase I clinical trials. DMP 840 exhibits curative activity in human tumor xenografts, where it shows selectivity for human solid tumors over murine leukemias. In contrast to the selectivity found for DMP 840 in vivo, DMP 840 exhibits potent antiproliferative activity in vitro against a variety of human and murine leukemia and solid tumor cell lines in culture, with inhibitory doses that reduce the number of treated cells to one half (IC50) values ranging from 2.3 to 53 nM. DMP 840 was growth inhibitory to three doxorubicin-resistant cell lines with IC50 values also in the nanomolar range. Clonogenic survival experiments showed that DMP 840 was equally cytotoxic to both exponentially growing and quiescent human clone A colon carcinoma cells. A 1-h incubation of DMP 840 (1.22-12 microM) caused 5-log cell kill in KB-3-1 human epidermoid carcinoma, clone A human colon carcinoma, and L1210 murine leukemia cell lines. The rapid cell killing by DMP 840 in clonogenic survival experiments and initial mechanism of action studies was consistent with a DNA-interactive mechanism for DMP 840 cytotoxicity. Mechanism of action studies in L1210 leukemia cells demonstrated that DMP 840 inhibited the incorporation of thymidine and uridine into DNA and RNA with IC50 values of 0.55 and 0.08 microM, respectively. DMP 840 produced DNA single-strand breaks in a dose-dependent manner. Double-strand breaks were not observed with DMP 840 treatment, even at higher concentrations of compound. Chinese hamster ovary (CHO) and P388 cells resistant to camptothecin and containing a mutant form of topoisomerase I were also used to evaluate whether DMP 840 was cross-resistant with agents active against topoisomerase I. While the CHOR line was 163-fold resistant to camptothecin, the CHOR line was only 1.7-fold resistant to DMP 840. In summary, DMP 840 is a DNA-interactive agent that demonstrates excellent antiproliferative activity in vitro against cultured tumor cells from both human and murine sources. Its mechanism of tumoricidal activity may be novel.     

Discovery of a novel tetrahydroacridine acetylcholinesterase inhibitor through an indexed combinatorial library

BACKGROUND: Methods for the rapid and efficient preparation of drug candidates through combinatorial chemistry are of increasing interest. We have previously reported an indexed combinatorial library method that allows both the preparation and testing of compounds in solution. We set out to apply this method to develop more effective analogs of the known, marketed drug tacrine, an acetylcholinesterase inhibitor. RESULTS: A one-step condensation of cyclohexanones with cyanoanilines to generate tetrahydroacridine pools was developed. The resulting library of (formally) 72 tetrahydroacridines was screened against acetylcholinesterase, and a compound 10-fold more potent than tacrine, 7-nitrotacrine, was discovered. Its increased potency could be readily explained by examining the known structure of the complex of acetylcholinesterase with tetrahydroacridine. CONCLUSIONS: In this work, we have provided a relatively rare example of carbon-carbon bond formation in a pool synthesis and have discovered a potentially useful acetylcholinesterase inhibitor.     

Effect of contrast concentration on abdominal enhancement in the rabbit: spiral computed tomography evaluation

BACKGROUND: Langerhans' cell histiocytosis (LCH) is an uncommon, poorly understood granulomatous disease, characterized by the idiopathic proliferation of Langerhan's cells or their marrow precursors. In 1985, the Philadelphia Work-shop adopted the term "Langerhans' cell histiocytosis" (LCH) to differentiate it from reactive and neoplastic causes of histiocytosis. METHODS: This study includes 73 pediatric patients diagnosed with this condition in Dublin, Ireland, and Nottingham, England, during a 34-year period (1959 to 1993). These patients are reviewed with respect to clinical presentation, difficulty with making a histological diagnosis, their management, and outcome. RESULTS: A total of 49 patients (67%) had head and neck involvement. Bony involvement was the most frequent sign, most frequently located in the skull. There were 11 deaths (15%) in this series, all associated with multisystem disease, and nine of these deaths were in children younger than 2 years of age. CONCLUSIONS: The role of otolaryngologists is important in the early and accurate evaluation, staging, and diagnosis of LCH. It may mimic more common diseases, such as otitis externa, acute mastoiditis, skin rash, gingivitis, or cervical lymphadenopathy. Patients with multisystem disease may be so ill at presentation that the head and neck lesions may be overlooked. The current management of LCH has become increasingly conservative, and in the 1990s, fewer cases are given chemotherapy or radiotherapy. The prognosis is very good for single-system disease and poor for multisystem disseminated disease with early onset.