Cognitive abilities, behaviour and quality of life in children after liver transplantation.

AIMS: We investigated interrelations between cognitive abilities, behavioural problems, quality of life and disease-related variables of children after LTX. METHODS: Our sample consisted of 25 children. They were 8.5/2.8 (M/SD) years old and had received the transplant 5.5/3.1 years previously. For assessment we used well-established instruments. RESULTS: Liver transplanted children scored below the population mean on the cognitive as well as on the behavioural instrument and showed scores below average in the scales Self-esteem, Friends and Total Score regarding QoL. Behavioural problems were associated with poorer cognitive performance (r=-0.38 to -0.63). QoL regarding physical well-being was correlated with sequential processing (r=0.41). Lower sequential processing scores were associated with lower QoL. Also between behavioural parameters and QoL correlations could be determined. Children with more behavioural problems experienced lower QoL (r=-0.40 to r=-0.76). Age at onset of disease showed correlations with behavioural and QoL parameters (r=-0.49 resp. r=0.44). Cognitive functioning was associated with medical complications (r=-0.44). CONCLUSIONS: High interrelations between cognitive functioning, behavioural deficits and QoL were obtained. Especially noticeable are correlations between sequential processing and internalized behavioural functions as both are associated with left lateralized brain functioning. This relationship could indicate differential effects on brain development during the preoperative phase.

Cellular and molecular mechanisms of cancer cell invasion.

Cancer malignancy is characterized by cancer cell invasion within local and distant ecosystems. Data from our laboratory are reviewed with a focus on cross-signaling between cancer cells and host cells such as myofibroblasts, mesenchymal stem cells and adipocytes. Invasion-associated cellular activities, namely epithelial to mesenchymal transition, homotypic and heterotypic cell-cell adhesion, cell-matrix adhesion, migration, proteolysis and vesicle exocytosis, depend on branching networks of signal transduction pathways including activation of trimeric G proteins, phosphoinositide 3-kinase, src, signal transducer and activator of transcription and the Rab, Rac and Rho family of small GTPases. The role of proteolysis in invasion is not limited to breakdown of extracellular matrix but also causes cleavage of pro-angiogenic fragments from cell surface glycoproteins. Some cell types or molecules implicated in invasion-associated activities may serve as prognostic biomarker or as target for patient-tailored therapy.

Agalactia in mares fed with grain contaminated with Claviceps purpurea.

This article reports an outbreak of intoxication of female horses with Claviceps purpurea in southern Brazil. The outbreak affected twelve pregnant mares which were fed with black oat (Avena strigosa) during the pre-delivery period. Underdevelopment of the mammary gland in the pre-delivery period resulting in post-delivery agalactia was the most pronounced finding. These mares delivered weak and unviable foals, which showed no suckling reflex and died within a few hours of birth. Laboratory analysis of oat samples fed to the animals resulted in the identification of Claviceps purpurea sclerotia. The fungus was identified in 0.22% of the examined seeds.

Saethre-Chotzen syndrome and hyper IgE syndrome in a patient with a novel 11 bp deletion of the TWIST gene.

Molecular genetic studies in a seven-year-old boy and his mother demonstrated a novel 11 bp deletion in the TWIST gene (127del11), causing Saethre-Chotzen syndrome. The mother had rather mild signs of the Saethre-Chotzen syndrome; however, her son presented with marked acrocephalosyndactyly type 3, leading to craniotomy at three years. He also had recurrent infections and laboratory findings comparable with the hyper IgE syndrome, a rare primary immunodeficiency disorder. It is likely that the 11bp deletion caused the Saethre-Chotzen syndrome in the patient and his mother, and another, not yet identified genetic defect, seen in the patient but not in the mother, is responsible for the hyper IgE phenotype. A combination of these two congenital conditions has not been described to date.

The mitosis of fibroblasts in cell culture is enhanced by binding GP IIb-IIIa of activated platelets on fibrinogen.

A fibroblast cell culture model enables us to measure the mitogenic ability mediated by growth factors released from stimulated platelets under different conditions. Simultaneously the growth factors secreted in the culture medium were determined. Cell mitotic rate was measured by incorporation of 3H-thymidine on days 3, 5 and 7 of culture. PDGF, TGF-beta, EGF and IGF-I were determined by Western blot. When fibroblasts were grown on surfaces precoated with a mixture of fibrinogen and thrombin-stimulated platelets, the 3H-thymidine uptake (196,645 +/- 56,864 cpm/ml) was increased, in comparison to fibroblasts grown on uncoated surfaces, in medium supplemented with FBS (28,855 +/- 7329 cpm/ml). Neither thrombin-stimulated platelets without fibrinogen nor fibrinogen alone had positive effects on the mitogenic activity of fibroblast. Growth factors were identified only in a culture medium in which the cells were grown on surfaces precoated with fibrinogen and thrombin-stimulated platelets. Blocking the platelet integrin GP IIb-IIIa inhibited the release of growth factors from thrombin-stimulated platelets and consecutively the stimulation of mitosis by fibrinogen and activated platelets was absent. Antibodies against the growth factors added to the medium suppressed the stimulation of cell mitosis. These results show that delivery of growth factors from platelets' secretory granules is dependent on binding of fibrinogen to GP IIb-IIIa.

Effect of highly active antiretroviral therapy and thymic transplantation on immunoreconstitution in HIV infection.

The purpose of this study was to determine whether thymic transplantation in addition to highly active antiretroviral therapy (HAART) will restore T cell function in HIV infection. Eight treatment-naive HIV-infected patients with CD4+ T cell counts of 200-500/mm3 were randomized into thymic transplantation and control arms. All patients received HAART (zidovudine, lamivudine, and ritonavir) for 6 weeks prior to transplantation. Thymic transplantation was done without immunosuppression, using postnatal HLA-unmatched cultured allogeneic thymus tissue. Patients were immunized every 6 months with the neoantigen keyhole limpet hemocyanin (KLH) and the recall antigen tetanus toxoid (TT). T cell phenotype and function and T cell receptor rearrangement excision circles (TRECs) were assessed. Thymic allografts were biopsied at 2 months. Six HIV-infected patients completed the study. Four patients received cultured allogeneic postnatal thymic grafts, two others were controls. CD4+ T cell counts increased and T cell-proliferative responses to Candida antigen and TT normalized in all patients. Proliferative responses to KLH developed in three of four transplant recipients and one of two controls. Patients responding to KLH after secondary immunization had greater TREC increases compared with the patients who did not respond. All thymic allografts were rejected within 2 months. In summary, four of six patients developed T cell-proliferative responses to the neoantigen KLH over the first 2 years of HAART. The transplanted thymus tissue, however, was rejected. There was no clear difference in restoration of T cell function in the transplant recipients compared with the controls. Increases in TRECs after initiation of HAART may correlate with improved immune function.

Transplantation of thymus tissue in complete DiGeorge syndrome.

BACKGROUND: The DiGeorge syndrome is a congenital disorder that affects the heart, parathyroid glands, and thymus. In complete DiGeorge syndrome, patients have severely reduced T-cell function. METHODS: We treated five infants (age, one to four months) with complete DiGeorge syndrome by transplantation of cultured postnatal thymus tissue. Follow-up evaluations included immune phenotyping and proliferative studies of peripheral-blood mononuclear cells plus biopsy of the thymus allograft. Thymic production of new T cells was assessed in peripheral blood by tests for T-cell-receptor recombination excision circles, which are formed from excised DNA during the rearrangement of T-cell-receptor genes. RESULTS: After the transplantation of thymus tissue, T-cell proliferative responses to mitogens developed in four of the five patients. Two of the patients survived with restoration of immune function; three patients died from infection or abnormalities unrelated to transplantation. Biopsies of grafted thymus in the surviving patients showed normal morphologic features and active T-cell production. In three patients, donor T cells could be detected about four weeks after transplantation, although there was no evidence of graft-versus-host disease on biopsy or at autopsy. In one patient, the T-cell development within the graft was demonstrated to accompany the appearance of recently developed T cells in the periphery and coincided with the onset of normal T-cell function. In one patient, there was evidence of thymus function and CD45RA+CD62L+ T cells more than five years after transplantation. CONCLUSIONS: In some infants with profound immunodeficiency and complete DiGeorge syndrome, the transplantation of thymus tissue can restore normal immune function. Early thymus transplantation - before the development of infectious complications - may promote successful immune reconstitution.

Pentasomy X and hyper IgE syndrome: co-existence of two distinct genetic disorders.

We describe a 10-year-old girl with features of a penta-X syndrome. Cytogenetic analysis revealed a 49,XXXXX karyotype and molecular analysis of X-linked polymorphic markers showed that this aneuploidy arose by successive maternal non disjunctions. Apart from these features the patient has a lifelong history of eczema, recurrent pneumonia, and staphylococcal abscesses. Together with consistently increased serum IgE levels, low antibody responses, and low levels of serum IgA and IgG2, these findings are characteristic for the hyper IgE syndrome. While pentasomy X may be due to sequential non disjunctions in meiosis I and meiosis II in the mother, the underlying pathomechanism in hyper IgE syndrome remains unclear. This case is the first with co-existence of pentasomy X and hyper IgE syndromes.

Possible extrathymic development of nonfunctional T cells in a patient with complete DiGeorge syndrome.

Complete DiGeorge syndrome is characterized by the clinical triad of cardiac malformation, hypocalcemia, and T cell immunodeficiency due to congenital athymia. We describe an infant with complete DiGeorge syndrome who at presentation had no circulating T cells detectable by flow cytometry. The patient spontaneously developed circulating T cells but these cells did not proliferate in response to mitogens. The T cell receptor Vbeta repertoire was severely restricted. All T cells were host, not maternal, as assessed by fluorescent in situ hybridization evaluation of 22q11 hemizygosity. At autopsy, this patient had no grossly detectable thymus tissue and no microscopic evidence for thymopoiesis. These findings suggest that appearance of T cells in infants with complete DiGeorge syndrome may represent oligoclonal expansions of a small number of T cells that may have matured extrathymically and which do not respond in vitro to mitogen stimulation.

Gastroesophageal reflux and severe combined immunodeficiency.

BACKGROUND: Gastrointestinal and respiratory symptoms and failure to thrive not associated with infections or medications were noted in patients with severe combined immunodeficiency. OBJECTIVE: The aim of our study was to determine the frequency of gastroesophageal reflux in patients with severe combined immunodeficiency. METHODS: We studied the case histories of 73 pediatric patients who had been treated at Duke University Medical Center for severe combined immunodeficiency between 1982 and 1995. Charts were reviewed for documentation of gastroesophageal reflux on the basis of clinical course and results of barium swallow, esophageal pH probe monitoring, or endoscopy. To compare the incidence of gastroesophageal reflux in patients with severe combined immunodeficiency to known high-risk populations, we additionally tabulated the underlying diagnoses in an age-matched group of patients who underwent Nissen fundoplication from 1990 to 1995. RESULTS: We found clinically significant gastroesophageal reflux in 15 of the 73 patients (20.5%), much higher than has been reported in the normal population (0.1% to 0.3%, p < 0.001). Of patients treated between 1990 and the present, 10 of 36 (27.7%) had significant gastroesophageal reflux compared with five of 37 patients (13.5%) in the previous years. Thus with greater recognition and improved methods for diagnosis, the observed incidence of gastroesophageal reflux has increased greatly. The clinical presentations were not different from those of patients with other well-documented underlying diagnoses. Seven of the 15 patients (46.6%) did not respond to medical treatment with antacids, H2-blockers, and prokinetic agents and underwent surgical treatment. Indications for surgery included persistent esophagitis, vomiting, pneumonia, and growth failure. CONCLUSIONS: The reason for the high incidence of gastroesophageal reflux in patients with severe T-cell disorders remains unclear. Considering the frequency of this association, early recognition and treatment is important to enable adequate nutrition and prevent damage to the esophagus and lungs.