The prognosis for patients with hepatocellular carcinoma (HCC) is poor because of the low chance of curative treatment. To increase the chance of intervention and to improve survival, early detection of subclinical HCC (SCHCC) by ␣-fetoprotein (AFP) and/or ultrasonography (USG) screening is implemented in many countries. Three hundred six Chinese patients with HCC diagnosed between January 1995 and December 1997 were recruited. They were categorized into two groups: 142 patients (group 1) had SCHCC diagnosed by screening (AFP and/or USG), and 164 patients (group 2) presented with symptomatic HCC. The tumor size was significantly smaller in group 1 compared with that of group 2 (3.5 cm vs. 8.1 cm; P F .0001). A significantly higher proportion of patients had bilobar involvement, multifocal HCC, diffuse-type HCC, portal vein infiltration, and distant metastasis in group 2 when compared with group 1. Operability and feasibility of treatment by transcatheter intra-arterial chemoembolization (TACE) in group 1 patients (26.8% and 45.1%, respectively) were significantly better than in group 2 patients (7.9% and 32.3%, P F .0001 and P ‫؍‬ .03, respectively). The cumulative survival rate was significantly higher in group 1 than in group 2 (P F .0001). For those who had surgical resection and those who had TACE, group 1 patients had a higher cumulative survival rate compared with that of group 2 patients (P ‫؍‬ .04 and P ‫؍‬ .0003, respectively). Screening for HCC by AFP and/or USG can identify tumors at an early stage, resulting in a higher chance of receiving treatment. Whether it can improve survival requires a further prospective, randomized study. (HEPATOLOGY 2000; 31:330-335.) Hepatocellular carcinoma (HCC) is one of the major health problems throughout the world. The annual incidence is estimated as 530,000 cases globally. 1 A recent study shows that the incidence of HCC is rising in the United States over the past 2 decades, with age-specific incidence shifting toward younger persons. 2 The problem is even more overwhelming in regions where the incidence of chronic viral hepatitis B and/or C is of high prevalence. The prognosis for patients with HCC is still dismal. At present, surgical resection and liver transplantation are the only forms of curative treatment available. However, the chance of curative treatment is often limited by several features of the HCC. HCCs are usually large in size before they give rise to symptoms. Bilobar or multifocal tumors are common. The incidence of associated cirrhosis is also high, being over 80% in most series. [3][4][5] The efficacy for other modalities of treatment, e.g., transcatheter intra-arterial chemoembolization (TACE), also depends on the above factors. 6 To increase the chance of intervention and, more importantly, to improve survival, early detection of subclinical HCC (SCHCC) by ␣-fetoprotein (AFP) and/or ultrasonography (USG) screening is implemented in many countries. Though studies of Asian populations show encouraging results, 7-9 these are not substantiated in...

Coiled-coil proteins contain a characteristic seven-residue sequence repeat whose positions are designated a to g. The interacting surface between ␣-helices in a classical coiled coil is formed by interspersing nonpolar side chains at the a and d positions with hydrophilic residues at the flanking e and g positions. To explore how the chemical nature of these core amino acids dictates the overall coiled-coil architecture, we replaced all eight e and g residues in the GCN4 leucine zipper with nonpolar alanine side chains. Surprisingly, the alanine-containing mutant forms a stable ␣-helical heptamer in aqueous solution. The 1.25-Å resolution crystal structure of the heptamer reveals a parallel seven-stranded coiled coil enclosing a large tubular channel with an unusual heptad register shift between adjacent staggered helices. The overall geometry comprises two interleaved hydrophobic helical screws of interacting cross-sectional a and d layers that have not been seen before. Moreover, asparagines at the a positions play an essential role in heptamer formation by participating in a set of buried interhelix hydrogen bonds. These results demonstrate that heptad repeats containing four hydrophobic positions can direct assembly of complex, higher-order coiled-coil structures with rich diversity for close packing of ␣-helices.protein design ͉ protein structure ͉ helix-helix interfaces ͉ buried polar interactions ͉ cavity H elix-helix interactions are ubiquitous in the native structure of proteins and in associations among proteins, including supramolecular assemblies and transmembrane receptors that mediate cellular signaling and transport. Coiled coils afford a unique model system for elucidating principles of molecular recognition between helices (1-4). The conformation of coiled coils is prescribed by a characteristic 7-aa repeat, the 3-4 heptad repeat denoted as a-b-c-d-e-f-g (5). Positions a and d are typically occupied by hydrophobic amino acids such as Leu, Ile, Val, and Ala, whereas residues at positions e and g are frequently polar or charged (5-8). Crick's (9) classical analysis proposed that the nonpolar a and d side chains associate by means of complementary ''knobs-into-holes'' packing to form supercoiled ␣-helical ribbons. Beyond the role of hydrophobic side chains at the core a and d positions, coiled coils can use intra-and interhelical electrostatic interactions to tune their stability, especially those between the flanking e and g positions of neighboring chains (10-18). Despite their seeming regularity in sequence and packing patterns, coiled coils exhibit remarkable diversity in the number and arrangement of the associating helices: two-to five-stranded structures have been identified with parallel or antiparallel helix orientation (2). The structural parameters of dimers have been described by Crick (9), and general rules governing the close packing of ␣-helices in hexamers and dodecamers have been deduced (19,20).Analysis of coiled coils provides insight into the general problem of protein folding ...

FocA is a representative member of the formate-nitrite transporter family, which transports short-chain acids in bacteria, archaea, fungi, algae and parasites. The structure and transport mechanism of the formate-nitrite transporter family remain unknown. Here we report the crystal structure of Escherichia coli FocA at 2.25 A resolution. FocA forms a symmetric pentamer, with each protomer consisting of six transmembrane segments. Despite a lack of sequence homology, the overall structure of the FocA protomer closely resembles that of aquaporin and strongly argues that FocA is a channel, rather than a transporter. Structural analysis identifies potentially important channel residues, defines the channel path and reveals two constriction sites. Unlike aquaporin, FocA is impermeable to water but allows the passage of formate. A structural and biochemical investigation provides mechanistic insights into the channel activity of FocA.

Liver toxicity is a common side effect of antituberculosis (anti-TB) drugs. We studied the differences in liver dysfunction observed during anti-TB treatment between hepatitis B virus carriers (HBV) and noncarriers. Three hundred twentyfour patients on anti-TB drugs were recruited and followed up for 1 year. Forty-three patients with HBV and 276 non-HBV patients were included for analysis. Liver function tests and viral markers were monitored monthly. Liver biopsy was requested whenever the alanine transaminase (ALT) was persistently abnormal. Eighty-six HBV carriers who were not given anti-TB drugs were chosen as a second control and evaluated prospectively. The incidence of liver dysfunction was significantly higher in HBV carriers given anti-TB drugs (34.9%) when compared to noncarriers (9.4%, P Ͻ .001) and with HBV carriers not given anti-TB drugs (8.1%, P Ͻ .001). For patients given anti-TB drugs, HBV carriers who developed liver dysfunction were younger (P ϭ .011) and had more severe liver injury compared with noncarriers (P ϭ .008). By multiple logistic regression analysis, age (P ϭ .002) and hepatitis B infection (P Ͻ .001) were the only 2 significant risk factors for hepatotoxicity related to anti-TB therapy. (HEPATOLOGY 2000;31:201-206.)Recently, there has been a resurgence of tuberculosis (TB) in a number of countries. 1,2 It has been estimated that approximately one third of the world' s population is infected with Mycobacterium tuberculosis. This reservoir of infected person results in 8 million new cases of TB and 2.9 million deaths annually. 1 TB and hepatitis B virus (HBV) infection are both endemic in South East Asia. In Hong Kong, the notification rate for TB was 103 persons per 100,000 population in 1996. 3 Approximately 10% of Hong Kong' s population are chronic HBV carriers. 4 Currently, the short-course program for the treatment of TB in Hong Kong begins with a 2-month course of 4 drugs, namely isoniazid, rifampicin, pyrazinamide, and ethambutol. This is followed by a continuation phase of 4 months with the 2 drugs, isoniazid and rifampicin. 3,5,6 Hepatotoxicity is the major adverse effect of isoniazid, rifampicin, and pyrazinamide. 7-10 Chronic hepatitis B 6,11,12 infection has been suggested as a possible risk factor for the development of liver dysfunction caused by anti-TB drugs. 13 However, studies of the effect of chronic hepatitis B carriage on the hepatotoxicity of anti-TB drugs have been unable to show any definite deleterious consequences. 11,14 McGlynn et al. 11 performed a retrospective analysis of isoniazid prophylaxis in 1,833 Asian patients in 1986; Hwang et al. 14 performed a prospective study in 240 Taiwanese patients in 1997. Both studies failed to identify hepatitis B infection as a risk factor for the development of liver dysfunction. None of the studies published to date have assessed the degree of liver damage by histology. There was no attempt made to differentiate between drug-induced damage and damage caused by hepatitis B viral activity. We report a prospective stu...

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Mannose-binding lectin (MBL) plays an important role in immune defense. We examined the MBL gene mutations and MBL levels in Chinese hepatitis B and hepatitis C patients with and without symptomatic cirrhosis. We recruited 190 hepatitis B and C patients, and 117 normal Chinese as controls. Serum MBL levels were measured by enzyme-linked immunosorbent assay. MBL gene mutation at codons 52, 54, and 57 was detected by polymerase chain reaction (PCR) assay. In asymptomatic hepatitis B and C patients, there was no increase in codons 52, 54, and 57 mutation, but the MBL levels were significantly lower than those in the controls. Codon 54 mutation rate was increased to 44.4% (P ‫؍‬ .007) in symptomatic hepatitis B cirrhosis and 64.3% (P ‫؍‬ .0026) in patients with spontaneous bacterial peritonitis (SBP). There was no increase in codon 54 mutation rate in hepatitis B-related hepatocellular carcinoma (HCC). In chronic hepatitis B infection, the odds ratio for an individual with codon 54 mutation to develop cirrhosis was 1.84 (95% CI: 1.21-2.81) and to develop SBP Mannose-binding lectin (MBL) is a calcium-dependent C-type lectin with a structural analogy to complement component C1q, and plays an important role in host immune defense. It is important in the first line of defense because of its ability to activate the complement system and phagocytosis. [1][2][3][4] Through its collagen domain, it behaves as an opsonin by binding to collectin receptors. 5-7 Low serum MBL leads to an opsonic defect that impairs phagocytosis by polymorphonuclear leukocytes. 8 Previous studies have shown that MBL deficiency may confer a risk of infection in children and adults. 9,10 Point mutation at codons 52 (CGT=TGT), 54 (GGC=GAC), and 57 (GGA=GAA) of the MBL gene are associated with low serum level of MBL and thus immunodeficiency caused by the opsonic defect. 11,12 MBL is synthesized by hepatocytes. 13 Recently, Thomas et al. showed that there was an association between MBL codon 52 mutation and persistent hepatitis B infection in whites. 14 The study did not find an association in the Asian hepatitis B carriers. It is known that the middle surface protein of the hepatitis B virus (HBV) envelope contains high mannose oligosaccharides for the binding of MBL. 15 Therefore, opsonization of the viral particles through MBL binding may be possible. However, whether this is associated with the clearance of serum HBV is not known.Patients with cirrhosis have impaired serum opsonization. 16 Spontaneous bacterial peritonitis (SBP) is a frequent infection that occurs in cirrhotic patients with ascites. It is not known whether there is any relationship between cirrhosis, SBP, and MBL mutation.We studied the serum MBL levels and MBL gene mutations in asymptomatic Chinese hepatitis B carriers, hepatitis C carriers, patients with hepatitis B-related hepatocellular carcinoma (HCC), and patients with hepatitis B-related cirrhosis with or without ascites and SBP. Our aim was to define the possible relationship between MBL levels and its mutations with thes...

BackgroundPlant non-specific lipid transfer proteins (nsLTPs) are small and basic proteins. Recently, nsLTPs have been reported involved in many physiological functions such as mediating phospholipid transfer, participating in plant defence activity against bacterial and fungal pathogens, and enhancing cell wall extension in tobacco. However, the lipid transfer mechanism of nsLTPs is still unclear, and comprehensive information of nsLTPs is difficult to obtain.MethodsIn this study, we identified 595 nsLTPs from 121 different species and constructed an nsLTPs database -- nsLTPDB -- which comprises the sequence information, structures, relevant literatures, and biological data of all plant nsLTPs http://nsltpdb.life.nthu.edu.tw/.ResultsMeanwhile, bioinformatics and statistics methods were implemented to develop a classification method for nsLTPs based on the patterns of the eight highly-conserved cysteine residues, and to suggest strict Prosite-styled patterns for Type I and Type II nsLTPs. The pattern of Type I is C X2 V X5-7 C [V, L, I] × Y [L, A, V] X8-13 CC × G X12 D × [Q, K, R] X2 CXC X16-21 P X2 C X13-15C, and that of Type II is C X4 L X2 C X9-11 P [S, T] X2 CC X5 Q X2-4 C[L, F]C X2 [A, L, I] × [D, N] P X10-12 [K, R] X4-5 C X3-4 P X0-2 C. Moreover, we referred the Prosite-styled patterns to the experimental mutagenesis data that previously established by our group, and found that the residues with higher conservation played an important role in the structural stability or lipid binding ability of nsLTPs.ConclusionsTaken together, this research has suggested potential residues that might be essential to modulate the structural and functional properties of plant nsLTPs. Finally, we proposed some biologically important sites of the nsLTPs, which are described by using a new Prosite-styled pattern that we defined.

We studied fetal and neonatal outcome of women maintained on anticoagulants (warfarin and/or heparin) during pregnancy. Among 22 Chinese families, 13 mothers (59%) had a history of recurrent abortion or stillbirth while being maintained on warfarin treatment. Twenty-nine liveborn children (17 boys, 12 girls), ages 0.6-11.3 years at follow-up, were analysed for evidence of embryopathy. These were subdivided into 2 groups. Group 1 consisted of 18 children (12 boys, 6 girls) whose mothers were only given warfarin during pregnancy. Five were small for gestational age, and 12 had features of warfarin embryopathy such as nasal hypoplasia. One had subependymal intraventricular hemorrhage shown on neonatal ultrasonography. Group 2 consisted of 11 children (5 boys, 6 girls) whose mothers were maintained on warfarin and heparin during pregnancy. Three were premature deliveries, and 4 had nasal hypoplasia. One had cleft lip, cleft palate, cataract, microphthalmia, intraventricular hemorrhage, and hydrocephalus. We found that despite the high risk of fetal wastage, there was a relative lower risk of major complications, except for some minor cosmetic defects such as nasal hypoplasia. This might lead to readjustment of advice concerning contraception given to pregnant women who were maintained on anticoagulant therapy.