Duodenogastric reflux potentiates the injurious effects of gastroesophageal reflux

Experimental studies have shown that the severity of esophageal mucosal injury in gastroesophageal reflux disease is related to the reflux of both gastric and duodenal juice. The purpose of this study was to determine whether duodenal juice potentiates esophageal injury in patients with reflux disease or, in fact, causes no harm allowing acid and pepsin to do the damage. A total of 148 consecutive patients who had no previous gastric or esophageal surgery underwent endoscopy and biopsy, manometry, and 24-hour esophageal pH and bilirubin monitoring. Esophageal injury was defined by the presence of erosive esophagitis, stricture, or biopsy-proved Barrett's esophagus. Exposure to duodenal juice, identified by the absorbance of bilirubin, was defined as an exposure time exceeding the ninety-fifth percentile measured in 35 volunteers. To separate the effects of gastric and duodenal juice, patients were stratified according to their acid exposure time. One hundred patients had documented acid reflux on pH monitoring, and in 63 of them it was combined with reflux of duodenal juice. Patients with combined reflux (50 of 63) were more likely to have injury than patients without combined reflux (22 of 37; P < 0.05). When the acid exposure time was greater than 10%, patients with injury (n = 40) had a greater exposure to duodenal juice (median exposure time 17.2% vs. 1.1%, P = 0.006) than patients without injury (n = 5), but there was no difference in their acid exposure (16.9% vs. 13.4%). Patients with dysplasia of Barrett's epithelium (n = 9) had a greater exposure to duodenal juice (median exposure time 30.2% vs. 7.2%, P = 0.04) compared to patients without complications (n = 25), whereas acid exposure was the same (16.4% vs. 15%). Duodenal juice adds a noxious component to the refluxed gastric juice and potentiates the injurious effects of gastric juice on the esophageal mucosa.     

The management of unsalvageable free flaps

The loss of vascular flow in the early postoperative period will generally lead to free flap failure. When attempts at flap salvage are unsuccessful, conservative management with delayed flap debridement may be indicated. Seven unsalvageable free flaps were managed with observation and flap debridement 4 to 14 days following loss of vascular signals. At the time of debridement, six of the seven wounds had viable granulation tissue and were successfully closed with skin grafts. The seventh patient had loss of vascular flow to the free flap within 12 hr of surgery and, at the time of delayed debridement, had no evidence of granulation ingrowth. Local revascularization of flaps is known to occur and offers an explanation for these findings. Delayed debridement of unsalvageable free flaps is indicated for noncritical wounds, and may obviate the need for a second free-tissue transfer to obtain wound closure.     

Statistical methods of computing reference values for side-to-side differences in nerve conduction studies

OBJECTIVE: To evaluate the utility of surgery in the treatment of peptic ulcer disease. METHODS: The clinical history of patients operated for peptic ulcer disease in a 15 year period were reviewed. The demographic data, indications for surgery, surgical procedure, morbidity, mortality and long term results, were analyzed. RESULTS: 349 patients were operated for peptic ulcer disease or its complications, 56% male. In 78% surgery was elective, mostly due to pyloric obstruction. In the remaining 22% perforation or bleeding ulcer were the main causes for emergency surgery. The most frequent elective procedure was vagotomy and drainage (66%); in urgent surgery, a definitive procedure was done in 35% of the perforations and in 94% of the bleeding ulcers. The 30-day mortality in urgent surgery was 14%; in elective surgery there was no mortality. A satisfactory long term result was obtained in 80% of the patients. CONCLUSIONS: An indication for surgical treatment of complicated peptic ulcer disease was above 50%, and 90 per cent in recent years. The frequency of urgent surgery is increasing and reached 60% of surgeries for this disease. Whenever possible, a definitive procedure is recommended.     

Activation of chemically diverse procarcinogens by human cytochrome P-450 1B1

A human cytochrome P-450 (P450) 1B1 cDNA was expressed in Saccharomyces cerevisiae and the microsomes containing P450 1B1 were used to examine the selectivity of this enzyme in the activation of a variety of environmental carcinogens and mutagens in Salmonella typhimurium TA1535/pSK1002 or NM2009 tester strains, using the SOS response as an end point of DNA damage. We also determined and compared these activities of P450 1B1 with those catalyzed by recombinant human P450s 1A1 and 1A2, which were purified from membranes of Escherichia coli. The carcinogenic chemicals tested included 27 polycyclic aromatic hydrocarbons and their dihydrodiol derivatives, 17 heterocyclic and aryl amines and aminoazo dyes, three mycotoxins, two nitroaromatic hydrocarbons, N-nitrosodimethylamine, vinyl carbamate, and acrylonitrile. Among the three P450 enzymes examined here, P450 lB1 was found to have the highest catalytic activities for the activation of 11,12-dihydroxy-11,12-dihydrodibenzo[a,l]pyrene, 1,2-dihydroxy-1,2-dihydro-5-methylchrysene, (+)-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene, 11,12-dihydroxy-11,12-dihydrobenzo[g]chrysene, 3,4-dihydroxy-3,4-dihydrobenzo[c]phenanthrene, 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole, 2-aminoanthracene, 3-methoxy-4-aminoazobenzene, and 2-nitropyrene. P450 1B1 also catalyzed the activation of 2-amino-3,5-dimethylimidazo[4,5-f]quinoline, 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline, 2-amino-3-methylimidazo[4,5-f]quinoline, 2-aminofluorene, 6-aminochrysene and its 1,2-dihydrodiol, (-)-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene, 1,2-dihydroxy-1,2-dihydrochrysene, 1,2-dihydroxy-1,2-dihydro-5,6-dimethylchrysene, 2,3-dihydroxy-2,3-dihydrofluoranthene, 3,4-dihydroxy-3,4-dihydro-7,12-dimethylbenz[a]anthracene, and 6-nitrochrysene to appreciable extents. However, P450 1B1 did not produce genotoxic products from benzo[a]pyrene, trans- 3,4-dihydroxy-3,4-dihydrobenzo[a]anthracene, trans-8,9-dihydroxy-8,9-dihydrobenzo[a]anthracene, 7,12-dimethylbenz[a]anthracene and its cis-5,6-dihydrodiol, 5-methylchrysene, 11,12-dihydroxy-11,12-dihydro-3-methylcholanthrene, 1,2-dihydroxy-1,2-dihydro-6-methylchrysene, benzo[c]phenanthrene, 2-amino-6-methyldipyridol[1,2-a:3',2'-d]imidazole, 2-acetylaminofluorene, benzidine, 2-naphthylamine, aflatoxin B1, aflatoxin G1, sterigmatocystin, N-nitrosodimethylamine, vinyl carbamate, or acrylonitrile in this assay system. P450 1B1 is expressed constitutively in extrahepatic organs, including fetal tissue samples, and is highly inducible in various organs by 2,3,7,8-tetrachlorodibenzo-p-dioxin and related compounds in experimental animal models. Thus, activation of procarcinogens by P450 lB1 may contribute to human tumors of extrahepatic origin.     

Low-risk differentiated thyroid cancer: the need for selective treatment

By means of an electron microscopic study of the intestine in young rats infected with Cryptosporidium parvum we observed a mass migration of immunocompetent cells of the host (eosinophils, neutrophils and macrophages) into the lumen of intestine. Some lymphocytes were also observed. Immunocompetent cells (except lymphocytes) included inside phagosomes with different endogenic states of C. parvum. Macrophages with typical extracytoplasmic parasitophorous vacuoles formed by C. parvum were also observed in the intestine lumen. Almost all stages of C. parvum could be observed on a surface of such macrophages. However, we did not find in lamina propria of intestine villi any macrophages with parasites. The place of macrophages infection is unknown. We suggest that surviving of C. parvum in macrophages is principally possible.     

Immunophenotyping investigation of minimal residual disease is a useful approach for predicting relapse in acute myeloid leukemia patients

A high complete remission rate is currently achieved in patients with acute myeloid leukemia (AML). However, many patients eventually relapse due to the persistence of low numbers of residual leukemic cells that are undetectable by conventional cytomorphologic criteria (minimal residual disease [MRD]). Using immunophenotypic multiparametric flow cytometry, we have investigated in sequential studies (diagnosis and follow-up) the impact of MRD detection on the outcome of 53 AML patients that had achieved morphologic remission with standard AML protocols and displayed at diagnosis an aberrant phenotype. Patients were studied at diagnosis with a panel of 35 monoclonal antibodies in triple staining combinations for detection of aberrant or uncommon phenotypic features. According to these features, a patient's probe was custom-built at diagnosis for the identification of possible residual leukemic cells during follow-up. The level of MRD at the end of induction and intensification therapy correlated with the number of relapses and relapse-free survival (RFS). Thus, patients with more than 5 x 10(-3) residual cells (5 residual cells among 1,000 normal bone marrow [BM] cells) identified as leukemic by immunophenotyping in the first remission BM showed a significant higher rate of relapse (67% v 20% for patients with less than 5 x 10(-3) residual cells; P = .002) and a lower median RFS (17 months v not reached; P = .01). At the end of intensification, with a cut-off value of 2 x 10(-3) leukemic cells, AML patients also separated into two distinct groups with relapse rates of 69% versus 32% (P = .02), respectively, and median RFS of 16 months versus not reached (P = .04). In addition, overall survival was also significantly related to the level of residual cells in the marrow obtained at the end of induction and particularly after intensification therapy (P = .008). Furthermore, we have explored whether residual disease was related with the functional expression of multidrug resistance (MDR-1) at diagnosis as assessed by the rhodamine123 assay. Patients with > or =5 x 10(-3) residual leukemic cells at the end of induction therapy had a significantly higher rhodamine-123 efflux (mean, 56% +/- 24%) than those with less than 5 x 10(-3) residual cells (mean, 32% +/- 31%; P = .04). Finally, multivariate analysis showed that the number of residual cells at the end of induction or intensification therapy was the most important prognostic factor for prediction of RFS. Overall, our results show that immunophenotypical investigation of MRD strongly predicts outcome in patients with AML and that the number of residual leukemic cells correlates with multidrug resistance.     

A structural basis for substrate specificities of protein Ser/Thr kinases: primary sequence preference of casein kinases I and II, NIMA, phosphorylase kinase, calmodulin-dependent kinase II, CDK5, and Erk1

We have developed a method to study the primary sequence specificities of protein kinases by using an oriented degenerate peptide library. We report here the substrate specificities of eight protein Ser/Thr kinases. All of the kinases studied selected distinct optimal substrates. The identified substrate specificities of these kinases, together with known crystal structures of protein kinase A, CDK2, Erk2, twitchin, and casein kinase I, provide a structural basis for the substrate recognition of protein Ser/Thr kinases. In particular, the specific selection of amino acids at the +1 and -3 positions to the substrate serine/threonine can be rationalized on the basis of sequences of protein kinases. The identification of optimal peptide substrates of CDK5, casein kinases I and II, NIMA, calmodulin-dependent kinases, Erk1, and phosphorylase kinase makes it possible to predict the potential in vivo targets of these kinases.     

Viral hemorrhagic septicemia virus, Ichthyophonus hoferi, and other causes of morbidity in Pacific herring Clupea pallasi spawning in Prince William Sound, Alaska, USA

A recently proposed Jovanovic-Freundlich isotherm model for single component adsorption without lateral interactions on heterogeneous surfaces is extended to account for lateral interactions and for competitive adsorption. The model is tested using previously reported single component and competitive adsorption data of 2-phenylethanol and 3-phenylpropanol on ODS-silica with methanol-water as the mobile phase. A comparison is made regarding the ability of the Jovanovic-Freundlich and Langmuir-Freundlich models to predict competitive equilibria using the single component identified parameters. Fair predictions of the competitive data were obtained when using heterogeneous-surface models which do not take into account the possible interactions of phenylalcohols in the adsorbed phase via hydrogen bonding. Markedly improved predictions were obtained with models which account simultaneously for the two main sources of adsorbed phase nonideal behavior, i.e. adsorbate-adsorbate interactions and heterogeneity of the adsorbent surface.