Blastic natural killer (NK)-cell lymphoma: report of an unusual CD4 negative case and review of the CD4 negative neoplasms with blastic features in the literature

Blastic Natural Killer (NK)-cell lymphoma is a relatively new entity which has been recently included in the WHO classification. CD4 expression is observed in most cases of blastic NK-cell lymphomas and has been related with skin tropism. We report an unusual CD4 negative blastic NK-cell lymphoma with primary presentation in the skin, subsequent infiltration of the bone marrow and aggressive behavior. It is emphasized that extensive immunophenotyping and EBER RNA in situ hybridization are required in order to establish the diagnosis of blastic NK-cell lymphoma. We also present a review of the literature with respect to the CD4 negative NK-cell lymphomas with blastic morphological features.     

Gene therapy progress and prospects: fetal gene therapy--first proofs of concept--some adverse effects

Somatic gene delivery in utero is a novel approach to gene therapy for genetic disease based on the hypothesis that prenatal intervention may avoid the development of severe manifestations of early-onset disease, allow targeting of otherwise inaccessible tissues including expanding stem cell populations, induce tolerance against the therapeutic transgenic protein and thereby provide permanent somatic gene correction. This approach is particularly relevant in relation to prenatal screening programmes for severe genetic diseases as it could offer prevention as a third option to families faced with the prenatal diagnosis of a genetically affected child. Most investigations towards in utero gene therapy have been performed on mice and sheep fetuses as model animals for human disease and for the application of clinically relevant intervention techniques such as vector delivery by minimally invasive ultrasound guidance. Other animals such as dogs may serve as particular disease models and primates have to be considered in immediate preparation for clinical trials. Proof of principle for the hypothesis of fetal gene therapy has been provided during the last 2 years in mouse models for Crigler Najjar Disease, Leber's congenital amaurosis, Pompe's disease and haemophilia B showing long-term postnatal therapeutic effects and tolerance of the transgenic protein after in utero gene delivery. However, recently we have also observed a high incidence of liver tumours after in utero application of an early form of third-generation equine infectious anaemia virus vectors with SIN configuration. These findings highlight the need for more investigations into the safety and the ethical aspects of in utero gene therapy as well as for science-based public information on risks and benefits of this preventive gene therapy approach before application in humans can be contemplated.     

Percutaneous ultrasound-guided injection of the trachea in fetal sheep: a novel technique to target the fetal airways

OBJECTIVE: To access the fetal airways percutaneously using ultrasound-guided injection of the fetal trachea in sheep. METHODS: Adenoviral gene therapy vectors and transduction-enhancing agents were delivered to the trachea via a needle inserted through the thorax or the neck of late-gestation (0.9 term, n = 3) or mid-gestation (0.5-0.8 term, n = 18) fetal sheep using ultrasound guidance. RESULTS: Injection of the trachea in the fetal thorax was successful in 16 out of 18 fetuses and achieved at the first attempt in 9 fetuses within 12 min [mean 7 min and 31 s +/- (SD) 3 min and 4 s]. Survival was 100%. Injecting the trachea in the neck was less successful. CONCLUSIONS: The fetal trachea of the sheep can be safely accessed by percutaneous ultrasound-guided injection to deliver vectors directly to the fetal airways for gene therapy. It may also enable tracheal occlusion for the antenatal treatment of congenital diaphragmatic hernia without the need for endoscopy or open surgery.     

Immunogenicity and safety of hepatitis A vaccine in children with chronic liver disease

BACKGROUND: Acute hepatitis A superimposed on chronic liver disease has been associated with a more severe course of disease and development of fulminant hepatitis. The aim of this study was to evaluate the immunogenicity and safety of an inactivated hepatitis A virus vaccine in children with chronic liver disease. PATIENTS AND METHODS: This was an open, prospective, and controlled trial with 89 anti-HAV negative children between 1 and 16 years of age studied at a pediatric liver disease and transplantation referral center. Inactivated HAV vaccine (Havrix), from GlaxoSmithKline Biologicals containing 720 Elisa units of alum-adsorbed hepatitis A antigen per 0.5 ml dose was used. Thirty-four pediatric patients with chronic liver disease (mean age: 7.0 +/- 4.86 years) and 55 healthy controls (mean age: 4.8 +/- 2.7 years) received two doses of Havrix vaccine in months zero and six. Seroconversion and anti-HAV titers expressed as geometric mean titers (GMT) in mIU/ml were measured at months one and seven, by a modified Hepatitis A virus antibodies (HAVAB) assay. RESULTS: Seroconversion rates at four weeks after primary immunization were 76% and 94% and the GMT 107.77 and 160.77 mIU/ml in the patient and control groups, respectively. One month after second dose the seroconversion rates were 97% and 100% in the groups with GMT of 812.40 and 2,344.90 mIU/ml. Both doses were well tolerated with no significant adverse events observed. Local injection-site symptoms were the most common reactions reported in both groups. CONCLUSION: Although GMTs were significantly lower in children with chronic liver disease compared to healthy controls, the overall seroconversion rates were not different. Hepatitis A virus vaccine was safe, well-tolerated, and immunogenic in children with chronic liver disease.     

A two-dose combined vaccine against hepatitis A and hepatitis B in healthy children and adolescents compared to the corresponding monovalent vaccines

BACKGROUND: Immunization against hepatitis A and B has been available for some time, protecting against both infections. With a view to achieving further reduction in the number of interventions and increasing convenience of the vaccinee, we investigated the reactogenicity and immunogenicity of a combined hepatitis A and B vaccine in healthy 4- to 20-year-old subjects at a 0, 6-month schedule. METHODS: Two hundred forty-eight study subjects were allocated to two study groups and received either two doses of the combined hepatitis A and B vaccine (68% of subjects) or the corresponding monovalent hepatitis A and hepatitis B vaccines (32% of subjects) concomitantly in opposite arms. Reactogenicity was assessed via diary cards after each vaccination. Serum samples were analyzed at months 1, 2, 6, and 7. RESULTS: All vaccines were well tolerated and very few symptoms were scored as severe. All but one subject seroconverted for anti-hepatitis A virus (anti-HAV) antibodies (98.6%) and 100% of subjects seroconverted for anti-hepatitis B (HBs) antibodies, with respective seroprotection rates of 98.7% for the combined vaccine group and 95.9% for the concomitant vaccine group (p >0.05), respectively. Geometric mean titers were higher in the group receiving the combined vaccine: 6,635 mIU/mL vs. 2,728 mIU/mL (p = 0.0001) for anti-HAV and 3,362 mIU/mL vs. 1,724 mIU/mL (p = 0.0205) for anti-HBs, respectively. Younger subjects had a stronger immune response compared to older subjects. CONCLUSIONS: The combined hepatitis A and B vaccine was well tolerated at this two-dose schedule. The combined vaccine had higher immunogenicity, probably explained by a adjuvant effect of the antigens. Vaccination programs requiring fewer injections will most likely have a positive impact on compliance rate and comfort of the vaccinee.     

The CC chemokine ligand, CCL2/MCP1, participates in macrophage fusion and foreign body giant cell formation

The foreign body reaction (FBR) develops in response to the implantation of almost all biomaterials and can be detrimental to their function. The formation of foreign body giant cells (FBGC), which damage the surface of biomaterials, is considered a hallmark of this reaction. FBGC derive from blood-borne monocytes that enter the implantation site after surgery in response to the release of chemotactic signals. In this study, we implanted biomaterials subcutaneous (s.c.) in mice that lack the monocyte chemoattractant CC chemokine ligand 2 (CCL2) and found that biomaterials were encapsulated despite reduced FBGC formation. The latter was due to compromised macrophage fusion rather than migration. Consistent with the reduction in FBGC formation, biodegradable biomaterials sustained reduced damage in CCL2-null mice. Furthermore, blockade of CCL2 function by localized gene delivery in wild-type mice hindered FBGC formation, despite normal monocyte recruitment. The requirement for CCL2 in fusion was confirmed by the ability of both a CCL2 inhibitory peptide and an anti-CCL2 Ab to reduce FBGC formation from peripheral blood monocytes in an in vitro assay. Our findings demonstrate a previously unreported involvement of CCL2 in FBGC formation, and suggest that FBGC are not the primary determinants of capsule formation in the FBR.     

Chronic functional constipation in adolescents: clinical findings and motility studies

OBJECTIVE: To evaluate the clinical findings and colonic transit time in adolescents with chronic functional constipation. METHODS: Forty-eight consecutive adolescents with chronic functional constipation referred to the Gastroenterology Service at the Hospital de Clínicas de Porto Alegre, Brazil were studied. Clinical parameters were assessed using a questionnaire. Total and segmental colonic transit time were measured with radiopaque markers. RESULTS: Mean age at first visit was 14 +/- 2 years, and age at onset of constipation was 6 +/- 4 years; 90% of patients depended on laxatives, and 86% on intermittent enemas; 76% had a family history of constipation. There was no statistical difference in the amount of daily fiber ingested by patients and controls. Measurements of colonic transit time revealed that 60% of patients had slow transit constipation, 13% had pelvic floor dysfunction, 10% had slow transit constipation associated with pelvic floor dysfunction, and 17% had a normal colonic transit time. Decreased frequency of evacuation and palpable abdominal fecal mass were significantly associated with slow transit constipation. CONCLUSIONS: Functional constipation in adolescence consists of a heterogeneous group of colonic functional disorders. The identification of these different functional disorders in adolescents will guide specific treatment, which may prevent the progression of this symptom into adult life.