Modulation of class III peroxidase pathways and phenylpropanoids in Arundo donax under salt and phosphorus stress.

Arundo donax L. is an invasive species that has been recently employed for biomass production due to its well-known ability to colonize harsh environment. Based on previous observations, the present study investigated the potential role of phenylpropanoids and class III peroxidases to confer adaptation through biochemical and transcriptomic analysis in A. donax after Na+ and P excess supply, both in single stress and in combination, and after growth at low P level. The levels of hydrogen peroxide, flavonoids (i.e., quercetin, apigenin and kaempferol derivatives) and the activity of class III peroxidases, as well as the expression of several genes encoding for their enzymes involved in their biosynthesis, increased when Na+ was supplied in combination with P. These results suggest that those biomolecules are involved in the response of A. donax, to the presence of +Na and P in the soil. Moreover, even though at the sampling time no significant accumulation of lignin has been determined, the trend of accumulation of such metabolite and most of all the increase of several transcripts involved in its synthesis was found. This work for the first time indicates the need for further investigation devoted to elucidating whether the strengthening of cell walls via lignin synthesis is one of the mechanisms used by A. donax to adapt to harsh environments.

Posterior interosseous nerve of the elbow at the arcade of Frohse: Ultrasound appearance in asymptomatic subjects.

PURPOSE: To assess the normal values of the antero-posterior (AP) diameter of the posterior interosseous nerve (PIN) of the elbow as it passes beneath the arcade of Frohse and to search for PIN-diameter differences between the upstream, entry point and downstream of the arcade. MATERIAL AND METHODS: Thirty asymptomatic patients prospectively underwent bilateral B-mode ultrasound of the PIN of the elbow. There were 15 men and 15 women with a mean age of 30.2±5.31 (SD) years (range: 26-43 years). Of these, 23 patients were right-handers (23/30; 77%) and 7 were left handers (7/30; 23%). AP diameter of the PIN was measured in long axis at three different locations including the entry point of the arcade, 5-mm upstream and 5-mm downstream the arcade. A comparison between the three measurements was performed using paired t-test. RESULTS: The mean AP diameters of the PIN were 0.83±0.21 (SD) mm (range: 0.43-1.31mm), 0.6±0.17 (SD) mm (range: 0.29-1.16mm) and 0.49±0.13 (SD) mm (range: 0.26-0.86mm) at 5-mm upstream, entry point of the arcade and 5-mm downstream the arcade of Frohse, respectively. Significant drops in PIN diameter were found between upstream and the arcade (-0.23mm; 27%; P<0.001), between the arcade and downstream (-0.11mm; 17%; P<0.001), and between upstream and downstream the arcade (-0.34mm; 40%; P<0.001). CONCLUSION: Disparity in AP diameter of the PIN of the elbow in the arcade of Frohse is a normal finding and should not be erroneously interpreted as entrapment when present alone.

Expression profiling of two stress-inducible genes encoding for miraculin-like proteins in citrus plants under insect infestation or salinity stress.

The expression of two genes, namely Mir1 and Mir3 and the abundance of their encoded proteins, the putative miraculin-like proteins, MLP1 and MLP3, showing similarity to the Kunitz family of protease inhibitors, were monitored in the leaves of the citrus variety, 'Clementine' after Tetranychus urticae infestation and elicitor treatments, or in the leaves of three other diploid citrus: 'Willow leaf', 'Cleopatra' mandarins and 'Trifoliate' orange, as well as their respective doubled diploids and the allotetraploid somatic hybrid 'FLHORAG1' under salt stress. RT-PCR and 2-DE indicated that Mir1 and Mir3 and their products were present at low-basal expression in all citrus genotypes. Both genes and products were induced in the 'Clementine' leaves infested by T. urticae, but a contrasting profile was observed under elicitor treatments. Under salt stress, the two genes showed an expression pattern contrasting each other and depending on the genotypes. 'Cleopatra' mandarin, 'Trifoliate' orange and 'FLHORAG1' presented overexpression of Mir3 and MLP3 and decreased levels of Mir1 and MPL1. The opposite behaviour was found in 'Willow leaf' mandarin. The positive correlation of the expression profile of the two genes with that of a gene encoding a putative apoplastic cysteine protease (CysP) might suggest a possible interaction of the respective encoded proteins during the response to biotic stress. Under salt stress, CysP and Mir 1 showed a similar expression pattern but only at transcript level. The possible occurrence of post-translational CysP regulation is discussed.

Nosocomial Herpes Encephalitis: rare but treatable with early MR diagnosis.

Nosocomial/hospital acquired herpes encephalitis is rare and is usually undiagnosed in its early phase because of the non-specific clinical picture and low level of clinical and neuroimaging suspicion. There is a paucity of data in radiology literature for this entity, specifically in the settings of surgery and trauma. We describe two cases of nosocomial herpes simplex encephalitis to demonstrate the imaging clues that might lead to an early diagnosis of this disease.

Comparative analysis of proteome changes induced by the two spotted spider mite Tetranychus urticae and methyl jasmonate in citrus leaves.

Citrus plants are currently facing biotic and abiotic stresses. Therefore, the characterization of molecular traits involved in the response mechanisms to stress could facilitate selection of resistant varieties. Although large cDNA microarray profiling has been generated in citrus tissues, the available protein expression data are scarce. In this study, to identify differentially expressed proteins in Citrus clementina leaves after infestation by the two-spotted spider mite Tetranychus urticae, a proteome comparison was undertaken using two-dimensional gel electrophoresis. The citrus leaf proteome profile was also compared with that of leaves treated over 0-72h with methyl jasmonate, a compound playing a key role in the defense mechanisms of plants to insect/arthropod attack. Significant variations were observed for 110 protein spots after spider mite infestation and 67 protein spots after MeJA treatments. Of these, 50 proteins were successfully identified by liquid chromatography-mass spectrometry-tandem mass spectrometry. The majority constituted photosynthesis- and metabolism-related proteins. Five were oxidative stress associated enzymes, including phospholipid glutathione peroxidase, a salt stressed associated protein, ascorbate peroxidase and Mn-superoxide dismutase. Seven were defense-related proteins, such as the pathogenesis-related acidic chitinase, the protease inhibitor miraculin-like protein, and a lectin-like protein. This is the first report of differentially regulated proteins after T. urticae attack and exogenous MeJA application in citrus leaves.

Associations of the correlates of protection and implication on the statistical power for demonstrating non-inferiority: application of a re-sampling method on a large phase III influenza vaccine clinical trial.

BACKGROUND: In the later stage of the clinical development of new vaccines it is required to demonstrate their efficacy with the immunogenicity measures established as correlates for disease protection. Evaluation of interpandemic trivalent influenza vaccines is commonly assessed by three immunogenicity measures for each strain in different age groups: Seroprotection, Seroconversion and Geometric Mean Titers. US and European guidelines with respect to this topic have been issued for the licensure of new influenza vaccines. The statistical power of comparative trials, which consider these endpoint variables, could be affected to the extent that these measures are correlated. Results from a large non-inferiority trial in the clinical development of a novel cell-derived influenza vaccine have been analyzed with the aim of evaluating how statistical dependency between the above-mentioned three immunogenicity measures might affect the power to demonstrate non-inferiority. METHODS: The statistical non-inferiority criteria, which were met in the trial, were applied to different subsets (n=250, n=370 and n=500) using a re-sampling method from the original dataset (re-samples=10,000). RESULTS: The measures of immunogenicity were highly correlated, and the fulfillment or failure of any of the non-inferiority criteria for a specific measure partially predicted the same outcome for the other measures. Due to this dependency within each strain, the levels of power obtained by re-sampling methods were always higher than those obtained by theoretical calculations, which were based on the assumptions of independency between the three measures of immunogenicity. Seroconversion and Geometric Mean Ratio (GMR) showed a higher correlation. A failure in the fulfillment of the non-inferiority criteria for GMR predicted the failure for Seroconversion in >76% of cases. CONCLUSIONS: The correlation between different measures of immunogenicity should be taken into account when evaluating statistical power for non-inferiority in influenza vaccine trials and in establishing sample sizes. Statistical approaches that include either all three measures of immunogenicity or both Seroconversion and the ratio of GMTs as co-primary non-inferiority endpoints might create redundancy and could increase the probability of not meeting at least one non-inferiority criterion by chance, due to multiplicity.

Safety, tolerability and immunogenicity of a mammalian cell-culture-derived influenza vaccine: a sequential Phase I and Phase II clinical trial.

This sequential, observer-blind, randomised, single-centre, combined Phase I and Phase II clinical trial compared the tolerability and immunogenicity of a single intramuscular dose of a novel cell-culture-derived influenza vaccine (CCIV), produced in Madin-Darby canine kidney cells, with a conventional egg-based vaccine. The immunogenicity of both vaccines was assessed by SRH assay, a well-recognized test by EMEA, in compliance with the requirements of the EU Committee for Medicinal Products for Human Use (CHMP). The Phase I part of the trial comprised 40 healthy adults (18-40 years of age); the subsequent Phase II part involved 200 healthy adult (n=80, 18-60 years of age) and elderly (n=120, > or =61 years of age) subjects. Both vaccines showed similar reactogenicity and any solicited local or systemic reactions were mostly mild or moderate. Regarding immunogenicity, both the CCIV and the control vaccine met all of the EU Committee for Medicinal Products for Human Use criteria for influenza vaccines for each strain and in both age groups. In conclusion, the CCIV produced in mammalian cell-culture is as well tolerated and as immunogenic as the control egg-based vaccine in non-elderly and elderly adults.

Safety and immunogenicity of two influenza virus subunit vaccines, with or without MF59 adjuvant, administered to human immunodeficiency virus type 1-seropositive and -seronegative adults.

The objective of this study was to evaluate and compare both the safety and tolerability and the humoral and cell-mediated immune responses for two influenza virus subunit vaccines, one with MF59 adjuvant (Fluad) and one without an adjuvant (Agrippal), in healthy and in human immunodeficiency virus type 1 (HIV-1)-infected adult individuals. To achieve this aim, an open, randomized, comparative clinical trial was performed during the 2005-2006 season. A total of 256 subjects were enrolled to receive one dose of vaccine intramuscularly. Blood samples were taken at the time of vaccination and at 1 and 3 months postvaccination. A good humoral antibody response was detected for both vaccines, meeting all the criteria of the Committee for Medical Products for Human Use. After Beyer's correction for prevaccination status, Fluad exhibited better immunogenicity than Agrippal, as shown from the analysis of the geometric mean titers, with significant differences for some virus strains; however, no definitive conclusions on the clinical significance of such results can be drawn, because the method used to estimate antibody response is currently nonstandard for influenza virus vaccines. Significant induction of an antigen-specific CD4+ T-lymphocyte proliferative response was detected at all time points after immunization, for both the vaccines, among HIV-1-seronegative subjects. This was different from what was observed for HIV-1-infected individuals. In this group, significance was not reached at 30 days postvaccination (T30) for those immunized with Agrippal. Also when data were compared between treatment groups, a clear difference in the response at T30 was observed in favor of Fluad (P = 0.0002). The safety profiles of both vaccines were excellent. For HIV-1-infected individuals, no significant changes either in viremia or in the CD4+ cell count were observed at any time point. The results showed good safety and immunogenicity for both vaccines under study for both uninfected and HIV-1-infected adults, confirming current recommendations for immunization of this high-risk category.

MF59 is a safe and potent vaccine adjuvant for flu vaccines in humans: what did we learn during its development?

The MF59 adjuvant has been included in a licensed influenza vaccine for a decade. Hence, we have a significant amount of clinical data to establish its potency and safety. We can now reassess our early preclinical studies and determine whether or not they were useful to predict human responses. The main lesson learned is that mouse models can be valuable, but one must ask the right questions and the models must be used appropriately.

Experience with the clinical development of influenza vaccines for potential pandemics.

During normal interpandemic influenza seasons, immune responses to vaccines are quite predictable and meet the licensing criteria of the European Union (EU) Committee for Proprietary Medicinal Products (CPMP). In a pandemic situation, large sections, if not all of the community will be immunologically naïve and therefore new immunisation strategies will be needed. In 1976 and 1977 H1N1 vaccines were prepared and tested clinically. To stimulate 'protective' antibody responses, two doses of vaccine were needed in people below the age of 24 years (no previous experience of H1N1 virus), whereas one conventional dose was adequate in older people. In 1997, the highly pathogenic avian influenza H5N1 virus caused widespread concern when it infected man, with lethal effects. Due to safety concerns it was necessary to adopt new strategies for vaccine development and one such strategy was to produce vaccine from an avirulent H5N3 virus, A/Duck/Singapore-Q/F119-2/97. Clinical trials of a subunit vaccine prepared from A/Duck/Sing/97 virus revealed that even two doses of twice the normal vaccine concentration (i.e. 30 micro g haemagglutinin) were poorly immunogenic, whereas an H5N3 vaccine adjuvanted with microfluidised emulsion (MF) 59 stimulated antibody levels that complied with CPMP criteria after two half strength doses (i.e. 7.5 micro g haemagglutinin).

What are the limits of adjuvanticity?

Vaccines developed traditionally following empirical approaches have often limited problems of immunogenicity, probably due to the low level of purity of the active component(s) they contain. The application of new technologies to vaccine development is leading to the production of purer (e.g. recombinant) antigens which, however, tend to have a poorer immunogenicity as compared to vaccines of the previous generation. The search for new vaccine adjuvants involves issues related to their potential limits. Since the introduction of aluminium salts as vaccine adjuvants more than 70 years ago, only one adjuvant has been licensed for human use. The development of some of these new vaccine adjuvants has been hampered by their inacceptable reactogenicity. In addition, some adjuvants work strongly with some antigens but not with others, thus, limiting their potentially widespread use. The need to deliver vaccines via alternative routes of administration (e.g. the mucosal routes) in order to enhance their efficacy and compliance has set new requirements in basic and applied research to evaluate their efficacy and safety. Cholera toxin (CT) and labile enterotoxin (LT) mutants given along with intranasal or oral vaccines are strong candidates as mucosal adjuvants. Their potential reactogenicity is still matter of discussions, although available data support the notion that the effects due to their binding to the cells and those due to the enzymatic activity can be kept separated. Finally, adjuvanticity is more often evaluated in terms of antigen-specific antibody titers induced after parenteral immunization. It is known that, in many instances, antigen-specific antibody titers do not correlate with protection. In addition, very little is known on parameters of cell-mediated immunity which could be considered as surrogates of protection. Tailoring of new adjuvants for the development of vaccines with improved immunogenicity/efficacy and reduced reactogenicity will represent one of the major challenges of the ongoing vaccine-oriented research.

Increased immunogenicity of the MF59-adjuvanted influenza vaccine compared to a conventional subunit vaccine in elderly subjects.

Three-hundred and eight outpatient elderly subjects (> or = 65 years) were randomly assigned to receive the MF59-adjuvanted influenza vaccine (FLU-AD; n = 204) or a conventional subunit influenza vaccine (AGRIPPAL S1; n = 104) in order to compare the safety and immunogenicity of the two vaccines. Although mild pain at the injection site was reported more frequently by subjects immunised with the adjuvanted vaccine, both vaccines were shown to be safe and well tolerated. The adjuvanted vaccine was more immunogenic as indicated by higher post-immunisation geometric mean titres (GMTs) and by higher proportions of subjects with post-immunisation > or = four fold increases of antibody titres or subjects with > or = 1/160 post-immunisation HI titres. These differences, statistically significant for all three strains after immunisation, indicated that, by addition of the MF59 adjuvant emulsion, conventional subunit influenza antigens acquire an enhanced immunogenicity without any clinically significant increase of their reactogenicity.

Safety and antigenicity of non-adjuvanted and MF59-adjuvanted influenza A/Duck/Singapore/97 (H5N3) vaccine: a randomised trial of two potential vaccines against H5N1 influenza.

BACKGROUND: In 1997, pathogenic avian influenza A/Hong Kong/97 (H5N1) viruses emerged as a pandemic threat to human beings. A non-pathogenic variant, influenza A/Duck/Singapore/97 (H5N3), was identified as a leading vaccine candidate. We did an observer-blind, phase I, randomised trial in healthy volunteers to assess safety, tolerability, and antigenicity of MF59-adjuvanted and non-adjuvanted vaccines. METHODS: 32 participants were randomly assigned MF59, and 33 non-adjuvanted vaccine. Two doses were given 3 weeks apart, of 7.5, 15, or 30 microg haemagglutinin surface-antigen influenza A H5N3 vaccine. Antibody responses were measured by haemagglutination inhibition, microneutralisation, and single radial haemolysis (SRH). The primary outcome was geometric mean antibody titre 21 days after vaccination. FINDINGS: The A/Duck/SIngapore vaccines were safe and well tolerated. Antibody response to non-adjuvanted vaccine was poor, the best response occurring after two 30 microgram doses: one, four, four, and one person of eleven seroconverted by haemagglutination inhibition, microneutralisation, H5N3 SRH, and H5N1 SRH, respectively. The geometric mean titres of antibody, and seroconversion rates, were significantly higher after MF59 adjuvanted vaccine. Two 7.5 microg doses of MF59 adjuvanted vaccine gave the highest seroconversion rates: haemagglutination inhibition, six of ten; microneutralisation, eight of ten; H5N3 SRH, ten of ten; H5N1 SRH, nine of ten. Geometric mean titre of antibody to the pathogenic virus, A/Hong Kong/489/97 (H5N1), was about half that to A/Duck/Singapore virus. INTERPRETATION: Non-adjuvanted A/Duck/Singapore/97 (H5N3) vaccines are poorly immunogenic and doses of 7.5-30 microg haemagglutinin alone are unlikely to give protection from A/Hong Kong/97 (H5N1) virus. Addition of MF59 to A/Duck/Singapore/97 vaccines boost the antibody response to protection levels. Our findings have implications for development and assessment of vaccines for future pandemics.

The adjuvanted influenza vaccines with novel adjuvants: experience with the MF59-adjuvanted vaccine.

Elderly people and subjects with underlying chronic diseases are at increased risk for influenza and related complications. Conventional influenza vaccines provide only limited protection in the elderly population. In order to enhance the immune response to influenza vaccines, several adjuvants have been evaluated. Among these, an oil in water adjuvant emulsion containing squalene, MF59, has been combined with subunit influenza antigens and tested in clinical trials in comparison with non-adjuvanted conventional vaccines. Data from a clinical database of over 10000 elderly subjects immunised with this adjuvanted vaccine (Fluad, Chiron Vaccines, Siena, Italy) demonstrate that, although common postimmunisation reactions are more frequent in recipients of the adjuvanted vaccine, this vaccine is well tolerated, also after re-immunisation in subsequent influenza seasons. Immunogenicity analyses demonstrate a consistently higher immune response with statistically significant increases of postimmunisation geometric mean titres, and of seroconversion and seroprotection rates compared to non-adjuvanted subunit and split influenza vaccines, particularly for the A/H3N2 and the B strains. The higher immunogenicity profile of the MF59-adjuvanted vaccine is maintained also after subsequent immunisations. An even higher adjuvant effect was shown in subjects with low pre-immunisation titre and in those affected by chronic underlying diseases. In conclusion, the addition of MF59 to subunit influenza vaccines enhances significantly the immune response in elderly subjects without causing clinically important changes in the safety profile of the influenza vaccine.

Dose range evaluation of a new inactivated hepatitis A vaccine administered as a single dose followed by a booster.

A total of 242 healthy adults were immunised with a first dose of an investigational inactivated hepatitis A vaccine. Three concentrations (3, 6 and 12 EU [ELISA units]) of the experimental vaccine were used and compared to a licensed reference vaccine. The aim was to determine the antigenic concentration of the study vaccine inducing the highest seroconversion rate and anti-Hepatitis A virus (HAV) antibody response at 2 weeks after the primary immunisation. A booster dose was given at month 6. At 15 days after the primary immunisation the seroconversion rates in subjects vaccinated with the 6 and 12 EU vaccines were 78 and 94%, respectively. At 30 and 180 days after the primary immunisation the percentages of seropositivity were 100% for both groups. The antibody response to the 12 EU study vaccine was similar to that to the reference vaccine. The percentages of seropositivity at 15 and 180 days after the primary immunisation were 94 vs 93%, and 100 vs 93% in the experimental and reference vaccine respectively. Thus, because it induces early and lasting seroconversion, the 12 EU study vaccine seems to be the most effective as a high potency HAV vaccine.

Evidence of a role of endogenous estrogen in the modulation of autonomic nervous system.

We studied heart rate variability in 14 healthy women before and after oophorectomy compared with 14 matched women who underwent hysterectomy with ovarian conservation. Surgical menopause induced a decline in cardiac vagal modulation with a shift toward sympathetic hyperactivity. Recovery of the baseline condition after 3 months of estrogen replacement therapy in oophorectomized women suggests a role of estrogen in the autonomic nervous control of the cardiovascular system.

Safety and immunogenicity of MF59-adjuvanted influenza vaccine in the elderly.

Safety and immunogenicity of the influenza vaccine adjuvanted with MF59 (FLUAD) were compared to those of a non adjuvanted subunit vaccine in elderly subjects during three consecutive influenza seasons. Geometric mean titres and proportions of subjects with either a > or = four-fold increase in antibody titres or with an HI titre > or = 128 after immunisation were higher in FLUAD recipients. The adjuvant effect on the magnitude of the responses was most pronounced in subjects with pre-vaccination titres < or = 40. Although associated with more frequent mild local reactions, the adjuvanted vaccine was well tolerated. Thus, the addition of MF59 increased the immunogenicity of the subunit influenza vaccine in elderly persons with low pre-vaccination titres, who are at greatest risk of developing severe influenza disease and vaccine failure, without a clinically important increase in reactogenicity.

Effects of acute administration of natural progesterone on peripheral vascular responsiveness in healthy postmenopausal women.

Peripheral vascular responses to acute administration of natural progesterone were studied in 12 postmenopausal women (mean +/- SD age 50.3 +/- 4.8 years) with no evidence of cardiovascular disease. According to a randomized, double-blind protocol, all subjects were given natural progesterone as a vaginal cream, able to produce a rapid peak and decay of plasma hormone concentrations, or matched placebo, with crossover after a 1-week washout period. Forearm blood flow and peak flow after ischemic stress (ml/100 ml/min), local vascular resistance (mm Hg/ml/100 ml/min), venous volume (ml/100 ml), and venous compliance (ml/100 ml/mm Hg) were measured by strain-gauge venous occlusion plethysmography at baseline and after progesterone or placebo administration. Plasma norepinephrine concentrations were determined by high-performance liquid chromatography with electrochemical detection. Progesterone sharply decreased forearm blood flow (p <0.01) through an increase in local vascular resistance (p <0.01). Measures of venous function remained unchanged. Although the hormone increased circulating norepinephrine concentrations (p <0.05), there were no significant changes in mean arterial pressure or heart rate. Furthermore, progesterone reduced the local vasodilator capacity, shown by a decrease in forearm delta flow (difference between peak flow and basal flow, p <0.05). Compared with the well-known effect of estrogen, progesterone exerted an opposite action on peripheral vascular responsiveness. Peripheral circulatory changes may be attributed to a direct activity of progesterone on the arterial wall and may in part reflect a modulation of the hormone on peripheral sympathetic tone. Consideration must be given to the hypothesis that the addition of progestin may attenuate the beneficial effects of unopposed estrogen replacement therapy in postmenopausal women.

CD30 overexpression enhances negative selection in the thymus and mediates programmed cell death via a Bcl-2-sensitive pathway.

The biological function of CD30 in the thymus has been only partially elucidated, although recent data indicate that it may be involved in negative selection. Because CD30 is expressed only by a small subpopulation of medullary thymocytes, we generated transgenic (Tg) mice overexpressing CD30 in T lymphocytes to further address its role in T cell development. CD30 Tg mice have normal thymic size with a normal number and subset distribution of thymocytes. In vitro, in the absence of CD30 ligation, thymocytes of CD30 Tg mice have normal survival and responses to apoptotic stimuli such as radiation, dexamethasone, and Fas. However, in contrast to controls, CD30 Tg thymocytes are induced to undergo programmed cell death (PCD) upon cross-linking of CD30, and the simultaneous engagement of TCR and CD30 results in a synergistic increase in thymic PCD. CD30-mediated PCD requires caspase 1 and caspase 3, is not associated with the activation of NF-kappaB or c-Jun, but is totally prevented by Bcl-2. Furthermore, CD30 overexpression enhances the deletion of CD4+/CD8+ thymocytes induced by staphylococcal enterotoxin B superantigen and specific peptide. These findings suggest that CD30 may act as a costimulatory molecule in thymic negative selection.

CD30 in normal and neoplastic cells.

In 1982 Stein and coworkers identified a new molecule, CD30 (Ki-1), which is expressed by Reed-Sternberg (RS) cells of Hodgkin's Disease (HD) (1). Although CD30 is not a specific RS cell marker, its characterization has assumed an important role not only in the differential diagnosis of HD, but also in the identification of a morphologically and clinically distinct type of large cell lymphoma, now designated as anaplastic large cell lymphoma (ALCL) (2). The cloning of human and murine CD30 and the utilization of genetically manipulated animal models have rapidly expanded our knowledge on its physiological role in lymphoid development and differentiation. The goal of this review is to present an overview of this rapidly evolving field and discuss the role of CD30 in normal and neoplastic lymphoid cells.