Natural history of hepatitis B in perinatally infected carriers.

OBJECTIVES: To establish natural seroconversion rates and incidence of hepatic pathology in perinatally infected hepatitis B carriers. METHODS: Seventy three perinatally infected hepatitis B carriers identified through maternal screening were evaluated. Fifty three were born to parents from the Indian subcontinent, nine were Oriental, six were Afro-Caribbean, and five were white. Median follow up was 10.24 (range 2.02-20.16) years. RESULTS: Only three of the children followed up had cleared hepatitis B surface antigen during this period, and 30% of the children had seroconverted to anti-HBe. Seroconversions to anti-HBe were observed in Asian (18/50) and white (4/5) children, but not in Oriental or Afro-Caribbean children. More girls (40%) than boys (23%) had seroconverted, but the difference was not significant. All children were asymptomatic with normal physical examination, growth, and development. Almost half (48%) of the hepatitis B e antigen (HBeAg) positive children had normal hepatic transaminases and liver function. Thirty five liver biopsies were performed in children with active virus replication (HBeAg or hepatitis B virus DNA positive) who were being considered for antiviral treatment as part of a clinical trial and were scored using the Ishak method. Two thirds (62%) of the children had mild hepatitis, 60% had mild fibrosis, and 18% had moderate to severe fibrosis. There was a weak correlation between histological evidence of hepatitis and hepatic transaminase activity, implying that biochemical monitoring of hepatic disease activity may be ineffective. CONCLUSIONS: These asymptomatic hepatitis B virus carrier children remain infectious in the medium to long term with notable liver pathology. They should receive antiviral treatment to reduce infectivity and to prevent further progression of liver disease. Hepatic transaminases alone are not a reliable marker of liver pathology, and liver histology is essential before consideration for antiviral treatment.

Progress in the clinical development of new marine-derived anticancer compounds.

Naturally derived anticancer agents continue to be instrumental in the systemic therapeutic intervention against solid tumors and hematological malignancies. Such compounds now have a relevant role in contemporary models of combination with targeted agents, thus providing a rationale to consider nature as a valid tool to discover new innovative anticancer agents. The marine ecosystem has increasingly been the focus of interest for new discoveries in the field that are expected to be of significant therapeutic impact in cancer patients. A critical review of the integrated data generated in our marine-derived anticancer program seems to confirm such expentancies. ET-743 (Yondelis) represents the first new agent developed against advanced pretreated soft tissue sarcoma in the past 25 years, and also harbors activity in women bearing pretreated ovarian cancer and a solid potential in combination therapy. The lack of cumulative toxicities makes this compound suitable for long-lasting therapies, reversible transaminitis being the most prevalent toxicity. Aplidin has shown a positive therapeutic index in phase I trials and phase II studies are ongoing. In contrast to the lack of bone marrow toxicity, a set of translational results anticipates a potential in leukemia. Kahalalide F has also successfully completed the phase I program in solid tumors with evidence of activity in resistant tumors and phase II studies are under way. Finally, the mechanistic data generated in parallel with the clinical program confirms the potential of the marine ecosystem in the discovery of new agents acting against new cellular targets of relevance in cancer cell biology.

Cytotoxic cyclic norterpene peroxides from a Red Sea sponge Diacarnus erythraenus.

Investigation of the lipophilic extract of the Red Sea sponge Diacarnus erythraenus revealed one new norsesterterpene cyclic peroxide, aikupikoxide A (1), three new norditerpene cyclic peroxides, aikupikoxide B-D (2-4), and the known norterpene peroxides muqubilin and nuapapuin A methyl ester. In addition, a new sesquiterpene, O-methyl guaianediol, was isolated. Their structures were determined by means of spectroscopic methods. The cytotoxic activities for the isolated compounds have been reported.

New lipopeptides from the Caribbean cyanobacterium Lyngbya majuscula.

Four new metabolites have been isolated from a marine red cyanobacterium, Lyngbya majuscula, collected at Boca del Drago Beach, Bocas del Toro, Panama. The planar structures were elucidated by 1D and 2D NMR techniques. These compounds were assigned the trivial names pseudodysidenin (2), dysidenamide (3), nordysidenin (4), and dragonamide (7).

Gelliusterols A--D, new acetylenic sterols from a sponge, Gellius species.

New acetylenic sterols, gelliusterol A (1, 26,27-bisnorcholest-5-en-23-yn-3 beta,7 alpha-diol), its corresponding 7-ketone, gelliusterol B (2, 26,27-bisnorcholest-5-en-23-yn-3 beta-ol-7-one), and gelliusterols C (4, cholest-5-en-23-yn-3 beta,7-one) and D (5, cholest-5-en-23-yn-3 beta,25-diol-7-one), were isolated from an unidentified species of sponge, Gellius sp. The structures of the steroids were established from spectroscopic data.

Chemical defenses of the sacoglossan mollusk Elysia rufescens and its host Alga bryopsis sp.

Sacoglossans are a group of opisthobranch mollusks that have been the source of numerous secondary metabolites; however, there are few examples where a defensive ecological role for these compounds has been demonstrated experimentally. We investigated the deterrent properties of the sacoglossan Elysia rufescens and its food alga Bryopsis sp. against natural fish predators. Bryopsis sp. produces kahalalide F, a major depsipeptide that is accumulated by the sacoglossan and that shows in vitro cytotoxicity against several cancer cell lines. Our data show that both Bryopsis sp. and Elysia rufescens are chemically protected against fish predators, as indicated by the deterrent properties of their extracts at naturally occurring concentrations. Following bioassay-guided fractionation, we observed that the antipredatory compounds of Bryopsis sp. were present in the butanol and chloroform fractions, both containing the depsipeptide kahalalide F. Antipredatory compounds of Elysia rufescens were exclusively present in the dichloromethane fraction. Further bioassay-guided fractionation led to the isolation of kahalalide F as the only compound responsible for the deterrent properties of the sacoglossan. Our data show that kahalalide F protects both Brvopsis sp. and Elysia rufescens from fish predation. This is the first report of a diet-derived depsipeptide used as a chemical defense in a sacoglossan.

'Upenamide: An unprecedented macrocyclic alkaloid from the Indonesian sponge Echinochalina sp.

'Upenamide (1) represents a new class of macrocyclic marine alkaloid possessing both spirooxaquinolizidinone and hemiaminal ring systems. It was isolated from the Indonesian sponge Echinochalina sp. The gross structure of 1 was elucidated by spectroscopic methods and accurate mass measurements. A suggestion is made as to its biogenetic origin.

Multicentre randomized placebo-controlled trial of ursodeoxycholic acid with or without colchicine in symptomatic primary biliary cirrhosis.

AIM: To establish the efficacy of combination therapy with ursodeoxycholic acid (UDCA) and colchicine in patients with symptomatic primary biliary cirrhosis (PBC), defined by the presence of liver cirrhosis, pruritus or bilirubin exceeding 2 mg/mL. METHODS: A total of 90 patients were randomly assigned to ursodeoxycholic acid 500 mg/daily plus placebo (UDCA group, n=44), or ursodeoxycholic acid at the same dosage plus colchicine, 1 mg/daily (UDCA/C group, n=46). The two groups were comparable for age, sex, stage of disease, severity of pruritus, bilirubin, and Mayo score. All patients underwent clinical, ultrasonographic, and biochemical examinations at entry and then every 6 months up to 3 years of follow-up. Patients with cirrhosis underwent endoscopy every 12 months. In a sub-group of patients without cirrhosis, who consented, liver biopsy was repeated at the end of the study. RESULTS: The number of treatment failures (i.e. dead, orthotopic liver transplantation (OLT), complications of cirrhosis, doubling of bilirubin, untreatable pruritus) was 11 (25%) in the UDCA group and four (9%) in the UDCA/C group (P < 0.05). No significant differences were observed in terms of improvement of liver enzymes related to cholestasis and cytolysis and of amelioration of pruritus. The Mayo score values increased less above the baseline values at 24 and 36 month-intervals in the UDCA/C group than in the UDCA group. Histological evaluation at baseline and at the end of the study was available for 15 patients with pre-cirrhotic stage. A significant reduction in histological grading score was observed in patients from the UDCA/C group, whereas no changes in these histological scores were observed in the UDCA group. CONCLUSIONS: The addition of colchicine to ursodeoxycholic acid in patients with symptomatic primary biliary cirrhosis results in a small but significant reduction of disease progress.

Scalarane-based sesterterpenes from an Indonesian sponge Strepsichordaia aliena.

Investigation of the lipophilic extract of the sponge Strepsichordaia aliena revealed six new 20,24-bishomoscalarane sesterterpenes, honu'enone (1), phyllofolactones H-K (3-6), and phyllofenone C (7). Structure elucidation of these compounds was secured by spectroscopic methods, 1D and 2D NMR, and accurate mass measurements.

Polyacetylenes from a red sea sponge Callyspongia species.

From the methanolic extract of the Red Sea sponge Callyspongia sp. six new polyacetylenic compounds, aikupikanynes A-F, together with octahydrosiphonochalyne, were isolated and identified. Their structures, which comprise four hydrocarbons, two alcohols, and one unprecedented alpha-hydroxy carboxylic acid, were determined by extensive 1D and 2D NMR studies and mass spectral determinations.

Malyngamides O and P from the sea hare Stylocheilus longicauda.

Two new malyngamides, O (1) and P (2), were isolated from the sea hare Stylocheilus longicauda. The structures were elucidated by analysis of their 1D and 2D NMR spectra.

Honulactones: new bishomoscalarane sesterterpenes from the Indonesian sponge Strepsichordaia aliena.

From the dichloromethane/2-propanol (1:1) extract of the Indonesian marine sponge Strepsichordaia aliena, twelve new 20, 24-bishomoscalarane sesterterpenes, honulactones A-L (1-12) were isolated. Molecular structures were secured by spectroscopic methods, accurate mass measurements, and X-ray analysis. Honulactones A (1), B (2), C (3), and D (4) exhibit cytotoxycity against P-388, A-549, HT-29, and MEL-28 (IC(50) 1 microg/mL).

Two complex proline esters from the sea hare Stylocheilus longicauda.

Investigation of Stylocheilus longicauda led to the isolation of chlorinated metabolites, makalika ester (1) and makalikone ester (2). Also reported is the isolation of lyngbyatoxin A acetate (3). The structures of the new compounds are based on spectroscopic data obtained from 1D and 2D NMR experiments.

Malevamides A-C, new depsipeptides from the marine cyanobacterium Symploca laete-viridis.

Three new depsipeptides, malevamides A-C (1-3), were isolated from the cyanobacterium Symploca laete-viridis collected off the south shore of Oahu, Hawaii. Compounds 1-3 were identified by spectral methods, and partial stereochemical assignments were made by chiral HPLC of the hydrolyzed compounds. At a concentration of 2 microg/mL, compounds 1-3 were inactive against P-388, A-549, and HT-29 cancer cells.

Mololipids, a new series of anti-HIV bromotyramine-derived compounds from a sponge of the order verongida.

A new series of lipids called mololipids have been identified from an Hawaiian sponge of the order Verongida. The structures of these lipids was deduced from spectroscopic data of the lipid mixture combined with GC-MS analysis. The core of this novel series of lipids is a bromotyramine homoserine-derived moiety known as moloka'iamine (1) which is found in many Verongid sponge metabolites. Moloka'iamine forms bisamides with a diverse series of fatty acids and the mololipids mixture (2) was active against HIV-1 with an EC(50) of 52.2 microM without cytotoxicity in human lymphocytes (IC(50) > 100 microM).

New triterpenoid sulfates from the red alga Tricleocarpa fragilis.

Ten new sulfated terpenoids, including six cycloartenol sulfates (1-6), two 29-nor-cycloartenol sulfates (7,8), and two 29-nor-lanosterol sulfates (9,10), were isolated from brine shrimp-toxic fractions of the methanolic extract of the red alga Tricleocarpa fragilis collected in Hawaiian waters. Structures 1-10 were elucidated by spectral methods, and the absolute stereochemistry for compound 1 at C23 was determined by Mosher analysis. Compounds 7 and 10 showed brine shrimp toxicity at 50 microg/mL, while 1 and 3 showed substantial activity at 17 microg/mL. Compounds 2, 4, 5, and 9 were inactive. In cytotoxicity assays, compounds 1-10 were inactive at concentrations tested.

New Moloka'iamine derivatives from an undescribed verongid sponge.

The polar extract of an undescribed Verongid sponge from the island of Molokai yielded three new bromotyramines. Two compounds terminate in a chlorocyclopentanedione enamine moiety. Their structures were elucidated by NMR spectra measured at -30 degrees C. The third compound is the N-methyl derivative of a known compound. This structure was determined by NMR spectra measured at room temperature.

A new depsipeptide from the sacoglossan mollusk Elysia ornata and the green alga Bryopsis species.

A new cyclic depsipeptide, kahalalide O (1), was isolated from the sacoglossan Elysia ornata and its algal diet Bryopsis sp. The structure was elucidated primarily by NMR and MS spectral methods, and the stereochemistry of the amino acid residues was determined by chiral HPLC and Marfey analyses. Unlike the related metabolite kahalalide F, which is in development as a potential anticancer agent, kahalalide O (1) was inactive in arresting the growth of P-388, A549, HT29, and MEL28 cancer cell lines in vitro.

The "Gnomes": An adventure in hepatopathology.

The "Gnomes" are an international group of liver pathologists and clinicians interested in liver morphology. The group was founded 30 years ago in an attempt to clarify the confusing concepts of chronic hepatitis that were then prevalent. Its first slide circulation and meeting resulted in the 1968 classification of chronic hepatitis. Recognizing the potential fruitfulness of the group, the members continued to meet for 2 or 3 days each year to discuss a variety of topics. The group has published nine reports that include guidelines for pathologists on different aspects of liver disease. Its membership has changed over the years, but many of the founding members continue to take part in the annual discussions.

Ludwig Symposium on biliary disorders--part II. Pathologic features and evolution of primary biliary cirrhosis and primary sclerosing cholangitis.

Primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) share many clinical and pathologic features. Central to the symptoms and biochemical alterations of both conditions is a substantial loss of intrahepatic bile ducts, leading to interference with bile flow. This pathologic change may ultimately result in cirrhosis of the biliary type. In addition, however, biopsy specimens usually show an element of liver-cell destruction and associated inflammation, mainly interface hepatitis. This finding is more pronounced in PBC than in PSC but can lead in both diseases to features that resemble those of cirrhosis as a result of hepatitis virus infection. The resemblance often leads to diagnostic confusion, which is easily overcome by attention to the clinical, radiologic, serologic, and biochemical context. Histologic staging of PBC and PSC has led to a greater appreciation of their evolution but is hampered in biopsy material by sampling error. Examination of explanted livers at transplantation has demonstrated a wide variation in the maturation of lesions in various parts of the organ.