Investigation of the First Seven Reported Cases of Candida auris, a Globally Emerging Invasive, Multidrug-Resistant Fungus-United States, May 2013-August 2016.

November 11, 2016/65(44);1234-1237. What is already known about this topic? Candida auris is an emerging pathogenic fungus that has been reported from at least a dozen countries on four continents during 2009-2015. The organism is difficult to identify using traditional biochemical methods, some isolates have been found to be resistant to all three major classes of antifungal medications, and C. auris has caused health care-associated outbreaks. What is added by this report? This is the first description of C. auris cases in the United States. C. auris appears to have emerged in the United States only in the last few years, and U.S. isolates are related to isolates from South America and South Asia. Evidence from U.S. case investigations suggests likely transmission of the organism occurred in health care settings. What are the implications for public health practice? It is important that U.S. laboratories accurately identify C. auris and for health care facilities to implement recommended infection control practices to prevent the spread of C. auris. Local and state health departments and CDC should be notified of possible cases of C. auris and of isolates of C. haemulonii and Candida spp. that cannot be identified after routine testing.

Effects of caponization and different forms of exogenous androgen implantation on immunity in male chicks.

This study determined the caponization effects on the immune responses in male chicks. Different forms of exogenous androgen implantation on male chick immunity were compared. Healthy, uniform male Single Comb White Leghorn chicks were caponized at 3 wk of age. Birds were housed in individual cages (35 x 30 x 40 cm, length x width x height). Each of 27 sham-operated (sham) and caponized (capon) male chickens were used for trial 1. Trial 2 used 60 capons divided into 4 treatments with implants of either 1 mm i.d. x 3 mm o.d. 58 mg of cholesterol, testosterone (TES), 5alpha-dihydrotestosterone (5alpha-DHT), or 19-nortestosterone (19-NorT). The exogenous androgen was implanted immediately after caponization and resupplied every 4 wk for an entire 13-wk feeding trial. The results from trial 1 showed that the relative bursa weight increased compared with the sham treatment (P < 0.05). The 2 wk post-Newcastle disease virus titer and the delayed-type hypersensitivity (DTH) of 48 h post-phytohemagglutinin phosphate (PHA-P) injection were increased compared with the sham treatment (P < 0.05). In trial 2, implanted 5alpha-DHT and 19-NorT could decrease the relative bursa weight in capons (P < 0.05). The 2 wk post-Newcastle disease virus titer in the 5alpha-DHT group was higher than that in the cholesterol group (P < 0.05). The 19-NorT group had the highest (P < 0.05) PHA-P response. Peripheral blood lymphocyte subset population analysis revealed that the percentage of CD4 T cells in the TES group was lower (P < 0.05) compared with that of the 5alpha-DHT group. Differently, the percentage of CD8 T cells in the TES and 19-NorT groups was higher (P < 0.05) than that in the 5alpha-DHT group. Male chicks that were caponized had increased bursa weight and PHA-P response, whereas different forms of exogenous androgen implantation reverted the phenomena in an order of potency of 5alpha-DHT and 19-NorT > TES, and the PHA-P response was TES > 5alpha-DHT >19-NorT.

Designed enediynes: a new class of DNA-cleaving molecules with potent and selective anticancer activity.

The rational design and biological actions of a new class of DNA-cleaving molecules with potent and selective anticancer activity are reported. These relatively simple enediyne-type compounds were designed from basic chemical principles to mimic the actions of the rather complex naturally occurring enediyne anticancer antibiotics, particularly dynemicin A. Equipped with locking and triggering devices, these compounds damage DNA in vitro and in vivo on activation by chemical or biological means. Their damaging effects are manifested in potent anticancer activity with remarkable selectivities. Their mechanism of action involves intracellular unlocking and triggering of a Bergman reaction, leading to highly reactive benzenoid diradicals that cause severe DNA damage. The results of these studies demonstrate the potential of these de novo designed molecules as biotechnology tools and anticancer agents.

Effects of caponization and testosterone implantation on immunity in male chickens.

This study examined the effects of caponization using different doses of testosterone (TES) on sexuality, hematology, and immune responses in male chickens. Healthy male chickens were caponized at 12 wk of age and selected at 16 wk of age for a 10-wk experiment. Fifteen intact male and 15 caponized male chickens were assigned to trial 1. In trial 2, ten sham-operated male chickens (sham) and 40 capons (randomly divided into 4 treatments) were implanted with cholesterol (CHOL, 9.24+/-0.36 mg), low TES (5.88+/-0.23 mg), medium TES (9.81+/-0.17 mg), or high TES (16.7+/-0.24 mg) administered at 16, 20, and 24 wk of age. Results from trial 1 showed caponization decreased the comb length, height and weight, and hematocrit (P<0.05) and increased the hemagglutination inhibition (HI; 1 wk postchallenge) and hemagglutination titer after Newcastle disease virus (NDV) and SRBC injections (P<0.05). In trial 2, the medium TES increased the comb length and height as compared with the CHOL group. Only the high TES increased the comb weight (P<0.05). The HI titer (1 wk postchallenge) in the CHOL group was higher than the sham (P<0.05). The medium TES decreased the HI titer (P<0.05) to the level of the sham (P>0.05). The phytohemagglutinin response was higher in the high TES group 24 h postinjection (P<0.05) and in the medium TES 48 h postinjection (P<0.05) as compared with the CHOL group. High dose TES implantation decreased the white blood cell counts as compared with the CHOL and sham groups (P<0.05). It appears that caponization decreased the blood androgen concentration and enhanced the humoral (anti-NDV and anti-SRBC) immune response. Testosterone implantation up to a threshold concentration could inhibit the humoral (anti-NDV) immune response and increase the cell-mediated (phytohemagglutinin) immune response.

Effects of caponization and different exogenous androgen on the bone characteristics of male chickens.

The effects of caponization and androgen implantation on the bone characteristics of male chickens were evaluated. Healthy Single Comb White Leghorn cockerels were caponized or sham operated (sham) at 12 wk old. Sixteen birds from each group were selected for a 14-wk experiment in trial 1. Sixteen birds from the sham group and 64 from the caponized group (randomly allocated into 4 treatments) were implanted with 10.4 +/- 0.4 mg (1.62-mm i.d., 3.6-mm o.d.) of cholesterol, testosterone (TES), 5alpha-dihydrotestosterone (5alpha-DHT), or 19-nortestosterone (19-NorT) and were assigned to trial 2 for a 14-wk experiment. The results from trial 1 showed that caponization increased BW (P < 0.05) and decreased tibia stress, ash content, and P content with higher blood P concentration (P < 0.05) as compared with the sham group. In trial 2, the cholesterol implantation group showed the lowest tibia breaking strength, bending moment, stress, and ash content (P < 0.05). The 19-NorT implantation group showed decreased (P < 0.05) blood Ca and P concentration but increased tibia ash and P content, reaching the same level as the sham group (P > 0.05). The adverse effects of caponization on bone characteristics could be improved using androgen implantation. Among the implantation groups, the 19-NorT implantation group showed the best improvement in tibia breaking strength and bending moment, followed by the TES and 5alpha-DHT groups. The TES group showed the best improvement in tibia stress, followed by the 19-NorT and 5alpha-DHT groups.

Syntheses of new isodethiaazacephems as potent antibacterial agents.

New isodethiaazacephems (+/-)-3, (+/-)-4, and (+/-)-10 as well as the 4-sulfonylated isodethiaazacepham (+/-)-5 were synthesized by chemical methods and found to possess biological activity against five pathogenic microorganisms in vitro. The mesylate and the triflate functionalities in (+/-)-3 and (+/-)-4, acting as effective leaving groups, enhanced remarkably the biological activity in comparison with the parent 3-hydroxyisodethiaazacephem (+/-)-10. The mode of action related to (+/-)-3 and (+/-)-4 can be explained by a [1,4]-elimination process.

Design, synthesis, and structure-activity relationship of novel dinucleotide analogs as agents against herpes and human immunodeficiency viruses.

A new acyclic nucleoside phosphonate (13) containing an adenine moiety was synthesized, which acted as an excellent inhibitor of calf mucosal adenosine deaminase. This inhibitory property allows it to exert great synergistic effect on certain antiviral agents (e.g., ara-A, 37). Phosphonate 13 was not phosphorylated by the bovine brain guanylate kinase nor by 5-phosphoribosyl 1-pyrophosphate synthetase. Syntheses of biologically active nucleotide phosphonate 40 and its phosphonoamidate derivative 42 were accomplished, which showed remarkable activity against herpes viruses and exhibited low host cell toxicity. 3'-Azido-nucleoside phosphonate 20 and 3'-fluoronucleoside phosphonate 32, as well as the corresponding dinucleotide analogs 47 and 48, and their respective phosphonoamidates 53-56 were also synthesized as new compounds, among which phosphonoamidates 53-56 showed potent activity against human immunodeficiency virus. Phosphonoamidates 55 and 56 bearing a methyl D-alaninate moiety exhibited less cellular toxicity than 53 and 54 bearing a methyl L-alaninate moiety. Nucleotide phosphonate 40 as well as dinucleotide phosphonates 47 and 48 were found susceptible to degradation by phosphodiesterases. Their respective phosphonoamidates 42 and 53-56, however, were completely resistant to snake venom and spleen enzymes.

Cephalosporin 3'-phloroglucide esters and 7-(phloroglucidamido) cephalosporins as novel antibacterial agents.

Two series of new phloroglucide derivatives were synthesized that possessed antibacterial activities. The first series includes cephalosporin 3'-phloroglucide esters 19 and 20, which were obtained by condensation of cephalosporin 16 with bioactive phloroglucides 14 and 15, respectively. They exhibited a dual mode of antibacterial action. In comparison with cephalosporins 26 and 27, bearing an acetoxy unit at the C-3' position, the bifunctional cephalosporins 19 and 20 showed a broadened spectrum of activity. Results from the consistent valence force field (CVFF) calculations indicate that the most stable conformational isomer of phenolic acid 14, holding a cis-syn-syn geometry, possessed a cavity. It provides an ideal environment to accommodate metal ions of holoenzymes. Phenolic keto acid 15, however, possessed a trans-anti-syn conformation, which allowed chelation between metal ions and the phenolic hydroxyl groups as well as the carbonyl functionalities. Our biological results show that the cavity formed in phloroglucides plays an important role. The second series includes 7-(phloroglucidamido)cephalosporins 24 and 25, which were synthesized by condensation of cephalosporin 21 with 14 and 15, respectively. Results from the CVFF calculations indicate that cephalosporin 24 also possessed a cavity. Unlike cephalosporin 3'-phloroglucide esters 19 and 20, cephalosporins 24 and 25 were found resistant to beta-lactamases from Staphylococcus aureus 95 and Pseudomonas aeruginosa 18S-H. These new compounds, however, showed notable activities against S. aureus FDA 209P, S. aureus 95, Candida albicans, P. aeruginosa 1101-75, and P. aeruginosa 18S-H.

Design, synthesis, and SAR of novel carbapenem antibiotics with high stability to Xanthomonas maltophilia oxyiminocephalosporinase type II.

Racemic cis-6-(phenylacetamido)carbapenem (21), 2-hydroxycarbonyl-cis-6-(phenylacetamido)carbapenem (22), 2-methoxycarbonyl-cis-6-(phenylacetamido)carbapenem (30), 2-methoxycarbomethyl-cis-6-(phenylacetamido)carbapenem (33), 2-hydroxyethyl-cis-6-(phenylacetamido)carbapenem (34), and 2-acetoxyethyl-cis-6-(phenylacetamido)carbapenem (35) were synthesized. Formation of the carbapenem nuclei in 21, 22, and 30 involved dehydrophosphonation of the corresponding 2-diphenylphosphono-6-(phenylacetamido)carbapenam precursors 14, 15, and 28 using trimethylsilyl triflate and 1,8-diazabicyclo[5.4.0]undec-7-ene in THF. Syntheses of carbapenems 33-35 involved a Wittig reaction of carbapenam 14 with methyl glyoxylate in the presence of lithium 2,2,6,6-tetramethylpiperidine in THF. For the antibacterial activities against Staphylococcus aureus FDA 209P, S. aureus 95, Escherichia coli ATCC 39188, Klebsiellapneumoniae NCTC 418, Pseudomonas aeruginosa 1101-75, and P. aeruginosa 18S-H, carbapenems (+/-)-21, (+/-)-22, (+/-)-30, and (+/-)-33-35 were found comparable with imipenem ((+)-3), yet they were notably more potent than (+)-3 against Xanthomonas maltophilia GN 12873. On the other hand, unlike (+)-3, carbapenems (+/-)-21, (+/-)-22, (+/-)-30, and (+/-)-33-35 were stable to X. maltophilia oxyiminocephalosporinase type II. Their beta-lactamase inhibitory properties, however, were found to be more comparable with those of penicillin G ((+)-4) than to those of imipenem ((+)-3). A combination of imipenem ((+)-3) with (+/-)-21, (+/-)-22, (+/-)-30, and (+/-)-33-35 resulted in synergistic antibacterial activity against X. maltophilia GN 12873. Results from the biological tests were correlated with the distribution of the electron density at C(2)=C(3) of carbapenems upon reaction with transpeptidases or beta-lactamases.

Clinical significance of microscopic tumor venous invasion in patients with resectable hepatocellular carcinoma.

BACKGROUND: Tumor venous invasion in patients with resectable hepatocellular carcinoma (HCC) is frequent and can be macroscopic and microscopic or microscopic alone. Although macroscopic invasion is a well-established prognostic indicator, the clinical significance of microscopic invasion remains unclear. METHODS: There were 322 patients enrolled who had undergone curative resection for HCC. The clinicopathologic factors and prognostic significance associated with macroscopic and microscopic venous invasion were analyzed. RESULTS: Macroscopic invasion was observed in 50 patients (15.5%) and microscopic invasion in 190 (59.0%). The larger the tumor, the more the incidence of venous invasion. There were 140 patients with microscopic invasion only (Group 1). Patients with macroscopic invasion (Group 2, n = 50) also had microscopic invasion. Compared with patients without venous invasion (Group 3, n = 132), Group 1 had a higher alpha-fetoprotein level, a larger tumor size, and more tumors without encapsulation. For group 1, the 1-, 3-, and 5-year disease-free survival rates were 65.6%, 41.6%, and 30.8%, respectively. The 1-, 3-, and 5-year overall survival rates were 87. 8%, 60.0%, and 52.7%, respectively. The survival rates of group 1 were lower than those of group 3 and higher than those of group 2 (P <.05). Multivariate analysis indicated that microscopic and macroscopic venous invasion, surgical margin, indocyanine-green retention, and tumor size and number were significant predictors of postresectional survival. CONCLUSIONS: In HCC patients, microscopic venous invasion is frequent and related independently to postresectional outcome.

Hepatic segmentectomy for curative resection of primary hepatocellular carcinoma.

OBJECTIVES: To evaluate the feasibility and results of segmentectomy for curative resection of hepatocellular carcinoma and to compare the clinicopathological findings of the patients according to the tumor location in the liver. DESIGN: Case series. SETTING: A tertiary care center. PATIENTS: Seventy-five patients with Child's grade A or B liver function who had hepatocellular carcinoma that was confined to one segment and who underwent segmentectomy for curative resection of the tumor. The patients were divided into four groups: group P (posterior segmentectomy, n = 23); group A (anterior segmentectomy, n = 10); group M (medial segmentectomy, n = 16); and group L (lateral segmentectomy, n = 26). MAIN OUTCOME MEASURE: Disease-free survival rate. RESULTS: Seventy-three percent of the patients had cirrhosis of the liver. The surgical mortality and morbidity rates were 5.3% and 36.0%, respectively. The 1-, 3-, and 5-year disease-free survival rates were 61.9%, 39.1%, and 26.3%, respectively, and were not significantly different among the four groups (P = .86). Group L had the least operative blood loss and shortest operative time when compared with the other three groups (P < .05). The postoperative liver function changes were mild and transient in the four groups of patients. With regard to pathological factors, only tumor size differed among the groups (tumors in group L were significantly larger than those in the other three groups, P < .05). Forty-three percent of the recurrent tumors were solitary in the early stage, with 81% involving the segment(s) adjacent to the resected one and 57% being confined solely to the segment adjacent to the resected segment. Patients having recurrent hepatocellular carcinomas had significantly larger tumors at the time of resection than did those without recurrence (P = .03). CONCLUSIONS: Hepatic segmentectomy is an effective therapeutic approach for small hepatocellular carcinomas and can be done safely even in patients with chronic liver disease and impaired liver function.

Effects of high dose octreotide on retrograde bile salt-induced pancreatitis in rats.

The effects of somatostatin and octreotide (a long acting somatostatin analogue) in acute pancreatitis are inconclusive. This study examined the prophylactic and therapeutic effects of different doses of octreotide on retrograde sodium taurodeoxycholate-induced acute necrotizing pancreatitis in rats. The rats were divided into 4 groups receiving subcutaneous injection of saline, octreotide 10 microg/kg, 20 microg/kg at 0, 8 and 16 h and octreotide 20 microg/kg at 5, 13 and 21 h, separately. The serum levels of amylase and lipase, pancreatic histopathology, mortality and hemodynamics were examined. Octreotide significantly reduced serum levels of amylase and lipase at 12 h and the degree of pancreatic edema, necrosis and hemorrhage at 18-24 h as compared to the control group. Prophylactic octreotide 10 microg/kg significantly decreased the 24-h mortality from 100% to 44.4% (p < 0.05). The 24-h mortality further reduced to 12.5% and 10% with prophylactic and therapeutic octreotide 20 microg/kg, respectively. The decrease of mean arterial pressure at 12 h was significantly lower in octreotide groups than in the control group. We conclude that octreotide improves pancreatic histopathology and survival in acute necrotizing pancreatitis in rats.

Detection of serum hepatitis B, C, and D viral nucleic acids and its implications in hepatocellular carcinoma patients.

The association of viremia, elevated serum alanine aminotransferase (ALT) levels, and hepatocyte inflammatory activity in hepatocellular carcinoma (HCC) patients was studied. Serum samples from 114 HCC patients undergoing surgery were assayed for hepatitis B, C, and D viral nucleic acids by polymerase chain reaction (PCR) prior to surgery. Of these patients, 65 had HBV infection alone, 15 had HCV infection alone, 4 had HDV infection, 20 had HBV and HCV superinfection, 1 had triple viral infection, and 9 were negative for HBV and HCV infections. The prevalence of active viral replication was significantly higher in HCV than in HBV (92% versus 70%; P = 0.006) patients, and significantly higher mean serum ALT levels were also noted in the HCV group than in the HBV group (P = 0.02). The incidence of marked ALT elevation (>200 U/l) was highest in the HCV (27%) and the HDV (25%) groups. Patients in the HCV group were 10 years older than those in the HBV group. Viral superinfection did not accelerate the development of HCC. Viral replication persisted in a significant portion of HCC patients and a higher prevalence of hepatic inflammation was noted in patients with HCV- and, possibly, HDV-related HCC.

Clinical, virological, and pathological significance of hepatic bile duct injuries in Chinese patients with chronic hepatitis C.

PURPOSE: Hepatic bile duct injuries are characteristic histological findings in patients with chronic hepatitis C virus (HCV) infection. However, the pathogenesis and clinical significance of this phenomenon remain unclear. The aims of this study were to evaluate the prevalence and clinical significance of hepatic bile duct injuries in Chinese patients with chronic hepatitis C. METHODS: One hundred and seventeen Chinese patients with chronic hepatitis C were enrolled. Clinical, biochemical, immunological (serum autoantibodies and cryoglobulinemia), histological, and virological data (serum HCV RNA titer and HCV genotype) were compared between patients with and without hepatic bile duct injuries. RESULTS: Eighty-three (71%) of the 117 patients with chronic hepatitis C had hepatic bile duct injuries. Patients with hepatic bile duct injuries had a significantly higher frequency of HCV genotype 1b; a higher mean serum globulin level; significantly higher mean scores for histological periportal necro-inflammation, portal inflammation, and fibrosis; and more severe portal lymphoid aggregation/follicles when compared with patients without hepatic bile duct injuries (P < 0.05, all). No significant differences in the presence of serum autoantibodies, cryoglobulinemia, mean serum HCV RNA titer, or response to interferon treatment were noted between the two groups. Multivariate logistic regression analysis showed that HCV genotype 1b infection, portal inflammation, and lymphoid aggregation/follicles were significant independent predictors associated with hepatic bile duct injuries. CONCLUSIONS: The presence of hepatic bile duct injuries in Chinese patients with chronic hepatitis C was significantly correlated with HCV genotype 1b infection, and the patients with these injuries had more severe portal inflammation and formation of lymphoid aggregates/follicles.

Interaction between 3-(p-tolylamino)-1,5-azulenequinone and the deoxyguanosine residue in various oligonucleotides upon photolysis.

Eight single-stranded oligodeoxyribonucleotides 32P-labeled at the 5'-end were synthesized; they were annealed with the complementary oligodeoxyribonucleotides to form the corresponding double-stranded helices. These duplexes possessed standard Watson-Crick base pairs, locally perturbed sites of a base mismatch, or a bulge. Further, 5'-32P-labeled oligodeoxyribonucleotides with a hairpin loop were also synthesized. Cleavage of these single- and double-stranded oligodexyribonucleotides selectively at the deoxyguanosine residue was accomplished by use of 3-(p-tolylamino)-1,5-azulenequinone 1 upon irradiation with 350 nm UV light. The single strands were cleaved more efficiently than the double-helices. For the helices containing a deoxyguanosine residue at a bulge, at a hairpin loop or toward the end, the cleaving efficiency was increased. Computation results indicate that two possibilities exist for agent 1 to form two "Watson-Crick type" hydrogen bonds with guanine in single-stranded oligodeoxyribonucleotides; yet, only one possibility exists in duplexes.

Recurrent hepatocellular carcinoma after hepatic resection: prognostic factors and long-term outcome.

AIM: The prognosis of patients with recurrent hepatocellular carcinoma (HCC) after hepatic resection varies widely. This study analyzed long-term survival and prognostic factors of patients with recurrent HCC after hepatectomy. METHODS: From July 1991 to December 2000, 623 patients underwent hepatic resection for HCC. Of those, 347 (56.5%) patients had tumour recurrence, and 286 patients with follow-up time more than 24 months after recurrence were enrolled. Twenty-seven clinicopathologic factors underwent both univariate and multivariate analysis. RESULTS: Of these 286 patients, survival times after tumour recurrence were mean 672+/-619 days; median 468 days; and, range 10-3753 days. The overall 1-, 3-, 5-, and 10-year post-recurrence survival rates were 61.5, 33.4, 18.2, and 9.0%, respectively. Seventy (24.5%) patients were alive at the time of study, and 10 of the 34 patients who underwent re-resection were disease-free. By Cox regression analysis, multiple initial tumours (relative risk (RR) 1.428), recurrent multiple (RR 1.372), extrahepatic recurrence (RR 2.434), recurrent tumour size >2 cm (RR 1.926), post-hepatectomy period until recurrence <1 year (RR 1.769), and non-resectional treatment of recurrent tumours (RR 3.527) were independent prognostic factors for post-recurrent survival rates. CONCLUSIONS: In patients with recurrent HCC after hepatectomy, both initial and recurrent tumour factors influenced their prognosis. Early detection of recurrent tumours is important. Re-resection correlated with better post-recurrent survival rates.

Surgical resection of primary hepatocellular carcinoma extending to adjacent organ(s).

Primary hepatocellular carcinoma (HCC) extending to the adjacent organ(s) is sometimes encountered in patients with large, peripherally located tumours. Over a 4-year period, a total of 151 patients received curative resection of HCC at the Surgical Department of Veterans General Hospital-Taipei, Taiwan. Of these patients, 21 underwent hepatic resection combined with en-bloc resection of the adjacent organ(s) because tumour extension was found during operation. Subsequent histological examination of the resected specimens found evidence of HCC invasion into the resected adjacent organ(s) in only nine patients (group I), and the remaining 12 patients showed no evidence of extrahepatic HCC invasion (group II). Twenty-seven HCC patients with clinico-pathologically matched tumours but without extrahepatic extension were selected as controls (group III). One patient in group I died of hepatic failure after the operation. The morbidity rate was 48% in group I and group II patients, and 30% in group III patients. The difference was not statistically significant. On evaluating the clinico-pathological factors, including DNA ploidy status of the tumours, there were no significant differences between tumours with and without extrahepatic invasion. Patients with locally invasive HCC (group I) had disease-free and overall survival rates comparable with those of the patients without local tumour invasion (group II and III). We conclude that HCC with invasion to the adjacent organ(s) does not seem to be directly related to the 'aggressiveness' of the tumour, and extrahepatic infiltration of the tumour does not preclude a chance of cure. Our results underscore the need for en-bloc resection as treatment of choice for these patients.

Preferentially deleted chromosome region 9p21 in large hepatocellular carcinomas.

The role of somatic deletions in chromosome 9 and chromosome 22 loci in hepatocellular carcinomas (HCC) was studied. Twenty-one paired HCC and adjacent tumor-free liver tissue samples were examined for loss of heterozygosity at six chromosome 9 and ten chromosome 22 loci. Among informative cases, the highest LOH rates were observed at 9p21 (40% or 4/10 at IFNA) and 9q23 (23% or 3/13 at D9S318). Our observed LOH rate at 9p21 was significantly higher than the background level previously reported for the same tumor type. Clinical data indicate that chromosome 9p21 deletions occurred preferentially in larger tumors (>5 cm diameter). However, a sequence analysis of the MTS1 gene coding region in cases of 9p21 LOH did not reveal any change, suggesting another tumor suppressor gene as the LOH target.

Factors predictive of liver cirrhosis in patients with chronic hepatitis B: a multivariate analysis in a longitudinal study.

OBJECTIVE AND DESIGN: Chronic hepatitis B virus (HBV) infection may lead to liver cirrhosis; however, factors associated with the development of cirrhosis have been incompletely studied. A total of 516 patients with chronic hepatitis B were followed up longitudinally to determine their outcome. METHODS: The clinical and pathological features were compared between those with and without cirrhosis occurrence. The risk factors were analysed, and the probability of the development of cirrhosis was estimated. RESULTS: During a mean follow-up period of 5.7 +/- 3.4 years (range 1-17 years), cirrhosis occurred in 71 patients, with a calculated annual incidence of 2.4%. Older age (> 45 years) at entry, male gender, persistent hepatitis (> 1.5-fold rise of serum alanine aminotransferase levels for at least one year) and diabetes mellitus were identified as independent risk factors of cirrhosis in a multivariate analysis (odds ratios 8.0, 19.3, 2.0 and 5.2, respectively; P values all < 0.05). A logistic regression equation was used to predict the probability of cirrhosis occurrence, which was as high as 76.6% when all risk factors were present. Acute exacerbation or super-infection by hepatitis C or D viruses were not significant predictors. Patients with subsequent cirrhosis had higher initial hepatic histological necro-inflammatory activities when compared to age- and sex-matched non-cirrhotic controls (Knodell's scores: 8.2 +/- 2.4 versus 6.0 +/- 4.1, P< 0.05). CONCLUSIONS: Patients who were elderly, male, diabetic or had a history of persistent and histologically severe hepatitis were at increased risks of liver cirrhosis. Aggressive anti-viral therapy may be needed for these patients and they should be closely monitored for HBV-related late complications.

Clinical, virological, immunological, and pathological significance of GB virus C/hepatitis G infection in patients with chronic hepatitis C.

GB virus-C (GBV-C)/hepatitis G virus (HGV), a single-strand RNA virus, has been identified as a transfusion transmissible virus and categorized as a member of the Flaviridiae family. GBV-C/HGV superinfection in patients with chronic hepatitis C is not seen uncommonly, most likely because of the similar transmission routes. This study aimed to investigate the prevalence of GBV-C/HGV infection in 100 Chinese patients with histologically proven chronic hepatitis C, and to clarify the clinical, virological, immunological, and histopathological impact of GBV-C/HGV infection on chronic hepatitis C patients. Serum GBV-C/HGV RNA was positive in 22 (22%) of the 100 chronic hepatitis C patients. There were no significant differences in mean age, gender, and serum liver biochemical tests between GBV-C/HGV infected and non-infected chronic hepatitis C patients. The HCV genotype distribution and mean serum HCV RNA level were not significantly different between patients with and without GBV-C/HGV co-infection. The presence of serum autoantibodies (anti-nuclear antibody and anti-smooth muscle antibody) and cryoglobulinemia showed no significant difference between the two groups. Liver histopathological analysis revealed no significant difference in the grade of periportal, portal, and intralobular necro-inflammation, in the stage of fibrosis/cirrhosis, or in the presence of steatosis and lymphoid aggregation/follicle formation between patients with and without GBV-C/HGV infection. However, a higher degree of bile duct damage was noted in chronic hepatitis C patients co-infected with GBV-C/HGV infection than in those without infection (P=0.036). In conclusion, GBV-C/HGV infection had no apparent influence on the clinical, immunological, or virologic features of patients with chronic hepatitis C. However, the clinical significance of a higher degree of bile duct damage in patients with HCV and GBV-C/HGV co-infection deserves further investigation.