PubMed Health⌕ Search

Biomedical subjects

B Klein

Publications and source records attributed to B Klein.

At least 37 records · Page 2Linked to original sources
PubMed2001

Reduced intensity conditioning: enhanced graft-versus-tumor effect following dose-reduced conditioning and allogeneic transplantation for refractory lymphoid malignancies after high-dose therapy.

Non-myeloablative regimens have been proven to allow engraftment following allogeneic stem cells transplantation (allo-SCT) with minimal procedure-related toxicity. Conventional allo-SCT may produce remissions in patients with relapsed and refractory lymphoid malignancies (LM) but these good results may be achieved at the cost of high treatment-related morbidity and mortality. Application of allo-SCT using less intensive regimens may temper the frequency of these complications, allowing a potent graft-versus-tumor effect (GVT). We present our data on 11 patients with LM receiving allo-SCT with a reduced regimen. Ten patients had received previous high-dose therapy, and were at high risk for toxicity, thus precluding the use of allo-SCT. A fludarabine and low-dose busulfan combination facilitated engraftment while exerting GVT. Hematological recovery was quick, and full donor T cell chimerism preceded acute GVHD. GVHD and infections were the major problems. Spontaneous acute GVHD occurred in eight patients (72%). Five patients (45%) achieved complete remission, and the GVT effect was closely associated with GVHD. These results support the concept that GVT is effective against LM in patients who have been heavily pretreated. Further studies are needed to investigate strategies to generate more specific alloreactive effects providing optimal GVT and an acceptable risk of GVHD and infections.

Acute Disease↗
PubMed2001

Growth and immortalization of human myeloma cells in immunodeficient severe combined immunodeficiency mice: a preclinical model.

Human multiple myeloma (MM) purified tumour cells readily undergo apoptosis in vitro. Interleukin 6 (IL-6), a main growth factor of tumour cells, has enabled the development of IL-6-dependent MM cell lines. Recently, we developed anti-gp130 monoclonal antibodies (mAbs), two of which (B1 + I2) were able to dimerize gp130 and replace IL-6 in vitro. We show here that the injection of B1 + I2 IL-6 agonistic mAbs via the inguinal subcutaneous (SC) route efficiently produced tumours in severe combined immunodeficiency (SCID) mice grafted with IL-6-dependent myeloma cell lines compared with either the intraperitoneal (IP) or abdominal surgical bursa (SB) routes. The SC tumour graft, together with Matrigel and vascular endothelial growth factor (VEGF), leads to a strong vascularization and early detection of serum human immunoglobulins (huIgs). SCID mice treated with B1 + I2 mAbs were injected with fresh MM cells from five patients, four of whom had consistent levels of huIgs, and tumour growth was present in two. For one patient, tumour plasma cells that were passed several times subcutaneously in new SCID mice, still expressed their initial markers after several months. They remained unable to grow in vitro in the presence of B1 + I2 or IL-6. The nature of the SCID factors involved and the triggered genes are under investigation.

Animals↗
PubMed2001

Neonatal platelet activation in preeclampsia.

Preeclampsia is associated with an increased platelet activation; however, there are few studies concerning platelet activation of the newborn. The aim of our study was to compare platelet activation in newborns of preeclamptic mothers to newborns of healthy mothers by using whole blood flow cytometry. Blood samples were obtained from 20 newborns (10 healthy controls, 10 cases of preeclampsia/HELLP [hemolysis, elevated liver enzymes, and low platelet count] syndrome) during cesarean section. Antibodies against the following antigens were used as markers for platelet activation: CD 41, CD62P, CD 63, and platelet-bound fibrinogen. In addition to the basal platelet activation, the ability of platelets to undergo activation as a result of in vitro incubation with a weak agonist (adenosine diphosphate) was evaluated. A significant difference between the groups concerning basal platelet activation could only be seen for platelet-bound fibrinogen; the control group showed a higher extent of platelet activation (16.6 +/- 11.3 vs. 6.1 +/- 4.9; p = 0.03). Incubation with adenosine diphosphate in the control group resulted in minor increases of platelet activation, which was significant only for platelet-bound fibrinogen (16.6 +/- 11.3 vs. 42.5 +/- 22.1; p = 0.02). However, the preeclamptic group showed significantly increased levels of platelet activation for all used markers after in vitro activation (CD 41: 115.6 +/- 18.2 vs. 163.2 +/- 29.6; p = 0.002; CD62P: 2.4 +/- 0.4 vs. 3.9 +/- 0.3; p < 0.001; CD 63: 2.7 +/- 0.5 vs. 3.7 +/- 0.6; p = 0.002; platelet-bound fibrinogen: 6.1 +/- 4.9 vs. 55.1 +/- 9.1; p < 0.001). Preeclampsia or HELLP syndrome is therefore associated with an increased susceptibility to neonatal platelets, even against weak activators such as adenosine diphosphate. Whether this results from peculiarities in the fetal vascular environment or maternal influences is yet uncertain.

Adenosine Diphosphate↗
PubMed2001

[Relative study of soluble syndecan-1 and prognosis of patients with multiple myeloma].

OBJECTIVE: To investigate the role of soluble syndecan-1 in the pathogenesis of human multiple myeloma (MM). METHODS: Serum level of soluble syndecan-1 of patients with MM and plasma cell leukemia was determined by ELISA. RESULTS: (1) The median serum soluble syndecan-1 concentrations of MM patients and controls were 111 ng/ml (41 - 6,300 mg/L) and 63 mg/L (10 - 163 mg/L), respectively (P < 0.005). (2) For 47 myeloma patients, increased serum syndecan-1 concentrations at diagnosis were associated with a poor prognosis. Patients with serum syndecan-1 levels below or above 166 mg/L had significantly different survival times (median > 48 months or < 18 months, respectively, P < 0.0001). (3) Serum soluble syndecan-1 levels were correlated with beta-2 microglobulin concentrations and the percentage of plasma cell. CONCLUSION: Serum levels of circulating soluble syndecan-1 correlated with tumor mass and may exert pleiotropic effects on myeloma cell behavior.

Humans↗
PubMed2000

Cognitive outcome of children with epilepsy and malformations of cortical development.

OBJECTIVE: To assess intellectual functioning (IQ) in 54 children and adolescents with intractable epilepsy who later underwent cortical resection due to unilateral malformations of cortical development acquired in utero. METHODS: Lesion type was classified into circumscribed mass lesions and diffuse cortical dysplasia based on histopathologic analysis of surgical tissue. Cortical dysplastic lesions were further graded as mild, moderate, or severe according to specific microscopic features. Laterality of lesion was determined through neurologic examination and electrophysiologic and neuroradiologic procedures. Classification of lesion type was corroborated by its significant relationship with other disease-related variables known to be related to clinical severity (age at seizure onset, age at resection, and extent of lesion). RESULTS: Analyses of covariance revealed that circumscribed lesions had a less deleterious effect on nonverbal IQ than did diffuse cortical dysplasia, after controlling for age at seizure onset and extent of lesion. This effect was also found on verbal IQ measures, but only in subjects with right-sided lesions. Subjects with left-sided lesions performed significantly more poorly on verbal IQ measures than those with right-sided lesions. Additionally, younger age at onset and greater extent of lesion were associated with poorer cognitive outcome. CONCLUSIONS: Cortical dysplasia and early left hemisphere lesions have a significantly worse impact on cognitive functioning than circumscribed lesions or right hemisphere developmental lesions in children with epilepsy.

Adolescent↗
PubMed2000

Cell wall biogenesis of Blastomyces dermatitidis. Evidence for a novel mechanism of cell surface localization of a virulence-associated adhesin via extracellular release and reassociation with cell wall chitin.

Pathogenic yeast of Blastomyces dermatitidis express a surface protein adhesin, WI-1. Due to the crucial role of WI-1 in adherence and disease pathogenesis, we investigated how the protein localizes to the surface of B. dermatitidis. WI-1 released extracellularly by wild-type yeast coated the surfaces of co-cultured knockout yeast within 3 h of incubation, implying that secreted WI-1 provides a pathway for loading the protein onto the yeast cell wall. In radioligand binding assays, purified WI-1 bound saturably, specifically, and with high affinity (K(d) = 8.3 x 10(-9)) to the cell surface of knockout yeast devoid of WI-1. WI-1 added exogenously, in vitro, to knockout yeast was indistinguishable from native cell surface WI-1 by fluorescence staining and restored adhesivity to the knockout yeast in macrophage binding and phagocytosis assays. Analysis of interactions between WI-1 and elements of the yeast cell wall identified chitin as the anchor point for WI-1. This interaction was shown to hinge on the 24-amino acid tandem repeat sequence of WI-1. Efforts to extract surface WI-1 from the yeast demonstrated that it is fastened to the wall by non-covalent interactions and covalent links between cysteine residues. We conclude that the yeast cell surface adhesin WI-1 localizes to the cell wall, in part, through extracellular release followed by high affinity binding back onto exposed chitin fibrils. These findings point to a novel pathway of cell wall biogenesis in yeast and an unanticipated role for chitin in anchoring and displaying a surface adhesin and virulence determinant.

Animals↗
PubMed2000

Hypochondriasis and its relationship to obsessive-compulsive disorder.

Hypochondriasis is a heterogeneous disorder. This was well demonstrated in the study by Kellner et al, which showed that patients with high levels of disease fear tended to be more anxious or phobic, whereas patients with high levels of disease conviction tended to have more and more severe somatic symptoms. Little comorbidity exists to support the statement that hypochondriasis is an obsessive-compulsive spectrum disorder. Although patients exist whose hypochondriac concerns are identical in quality to the intrusive thoughts of patients with OCD, as a group, patients with hypochondriasis do not share a comorbidity profile comparable with that of patients with OCD. The data support a closer relationship between hypochondriasis and somatization disorder than between hypochondriasis and OCD. The family history data is limited by the lack of adequate studies. Using comparable methods of the family history approach, Black's study reported a higher frequency of GAD but not OCD among the relatives of OCD patients--a finding similar to what Noyes found among the relatives of hypochondriac patients; however, using the direct interview method, somatization disorder was the only statistically more common disorder, among relatives of female hypochondriac patients. Therefore, although the parallel in overlap with GAD is suggestive of a commonality between OCD, GAD, and hypochondriasis, the finding of a greater frequency of somatization disorder leans against the hypothesis that hypochondriasis is best considered an OCD spectrum disorder. The pharmacologic treatment data are the one type of biologic evidence that supports a bridge to OCD. The pharmacologic studies suggest that for patients with general hypochondriasis, TCAs are not effective and that higher dosages and longer trials of the SRIs are needed. These pharmacologic observations are comparable with the ones made for patients with OCD but dissimilar to the observations made for depression. The benefit of imipramine among patients with illness phobia must be assessed in placebo-controlled trials among illness phobics and among hypochondriacs. Even more valuable would be a direct comparison of a TCA (e.g., imipramine or desipramine) and a selective SRI (e.g., fluoxetine) to determine whether the response to selective SRIs is greater. Although the pharmacologic data are compelling in supporting the hypothesis that hypochondriasis is an obsessive-compulsive spectrum disorder, the comorbidity data are equally compelling in dispelling that hypothesis. Perhaps future studies clarify the subtypes of hypochondriasis, be they "phobic, obsessive, and depressive," "chronic and episodic," "early onset versus late onset" or some other as yet undetermined subtype. Such clarification may be aided by better instruments to assess the obsessive-compulsive and hypochondria spectrums within individuals and families and by neuropsychological or pharmacologic challenge and neuroimaging studies.

Adult↗
PubMed2000

Regulation of Bcl-2-family proteins in myeloma cells by three myeloma survival factors: interleukin-6, interferon-alpha and insulin-like growth factor 1.

As survival regulation is a key process in multiple myeloma biology, we have studied the Bcl-2 family proteins that can be regulated by three myeloma cell survival factors: interleukin-6 (IL-6), interferon-alpha (IFN-alpha) and insulin-like growth factor (IGF-1). Eleven myeloma cell lines, whose survival and proliferation are dependent on addition of IL-6, variably expressed 10 anti-apoptotic or pro-apoptotic proteins of the Bcl-2-family. When myeloma cells from four cell lines were IL-6 starved and activated with IL-6 or IFN-alpha, we observed that only Mcl-1 expression was up-regulated with myeloma cell survival induction. Nor was obvious regulation of these 10 pro-apoptotic or anti-apoptotic proteins found with IGF-1, another potent myeloma cell survival factor. Our results indicate that the myeloma cell survival activity of IL-6 linked to Bcl-xL regulation cannot be generalized and emphasize that Mcl-1 is the main target of IL-6 and IFN-alpha stimulation. However, other changes in the activity of the Bcl-2 protein family or other apoptosis regulators must be identified to elucidate the IGF-1 action mechanism. Cell Death and Differentiation (2000) 7, 1244 - 1252.

Cell Survival↗
PubMed2000

Agonist anti-gp130 transducer monoclonal antibodies are human myeloma cell survival and growth factors.

We have previously reported obtaining two monoclonal antibodies (mAb) against the human gp130 interleukin-6 (IL-6) transducer which made possible the dimerization of gp130 and the activation of several IL-6-driven functions when used together. We report here that these mAb induce gp130-mediated signaling in human myeloma cells and support the survival and the long-term growth of five IL-6-dependent human myeloma cell lines. Their agonist activity is not affected by neutralizing antibodies to IL-6 or IL-6R. These mAb induce a transient proliferation of primary myeloma cells from most patients with multiple myeloma. Again, IL-6 inhibitors do not affect this agonist activity. By using highly purified primary myeloma cells, we found that these anti-gp130 mAb supported the long-term survival of primary myeloma cells from five patients with primary plasma cell leukemia but failed to induce their long-term growth. For patients with fulminant disease and secondary extramedullary proliferation, the antibodies supported a long-term survival and growth, and anti-gp130 mAb-dependent cell lines were obtained. For patients with medullary involvement only, a co-stimulatory signal is necessary, together with gp130 activation, to trigger cell survival and cycling. Leukemia (2000) 14, 188-197.

Antibodies, Monoclonal↗
PubMed2000

Extensive characterization of dendritic cells generated in serum-free conditions: regulation of soluble antigen uptake, apoptotic tumor cell phagocytosis, chemotaxis and T cell activation during maturation in vitro.

Dendritic cells (DC) play a key role in the initiation of primary immune response, and pilot clinical studies have demonstrated their ability to induce efficient antitumor immunity. However, the DC used in these clinical trials were generated with various serum sources and were poorly characterized. Obtaining fully characterized DC in controlled and reproducible culture conditions is thus of major interest. We demonstrate that X-VIVO 15 medium supplemented with 2% human albumin can be used to obtain DC. The phenotypic and functional characteristics of these clinical-grade DC were analyzed according to their differentiation stages. CD83 immature DC, obtained in the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin (IL)-4, were able to endocyte soluble antigens and internalize apoptotic tumor cells, and also expressed receptors for inflammatory chemokines. Tumor necrosis factor-alpha (TNF-alpha) induced irreversible DC maturation in association with a decreased ability to uptake antigens and an increased allostimulatory capacity. CD83+ mature DC became responsive to EBI1 ligand chemokine (ELC), a chemokine specifically expressed in secondary lymphoid organs. In addition, mature DC obtained with TNF-alpha produced IL-12 and some IL-10 in response to CD40 stimulation. In conclusion, we present well-defined culture conditions allowing the control of DC maturation for clinical or fundamental studies.

Antigens, Neoplasm↗
PubMed2000

JAK2 tyrosine kinase inhibitor tyrphostin AG490 downregulates the mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription (STAT) pathways and induces apoptosis in myeloma cells.

Cytokines of the interleukin 6 (IL-6) family, which activates the signal transducer gp130, are major survival and growth factors for human multiple myeloma (MM) cells. The signal transduction of gp130 involves the Janus tyrosine kinases (JAK) JAK1, JAK2 and Tyk2 and then the downstream effectors comprising the signal transducer and activator of transcription 3 (STAT3) and mitogen-activated protein kinase (MAPK) pathways. We evaluated the effects of the JAK2 inhibitor tyrphostin AG490 on MM cells. We found that AG490 suppressed cell proliferation and induced apoptosis in IL-6-dependent MM cell lines. JAK2 kinase activity, ERK2 and STAT3 phosphorylation were inhibited. These results suggest that the chemical blocking of the gp130 signalling pathway at the JAK level could be a relevant therapeutic approach to MM.

Antigens, CD↗
PubMed2000

Insulin-like growth factor induces the survival and proliferation of myeloma cells through an interleukin-6-independent transduction pathway.

Multiple myeloma (MM) is a B-cell neoplasia that is associated with an increased level of bone resorption. One important mediator of bone remodelling, insulin-like growth factor (IGF-I), has been shown to stimulate the proliferation of human myeloma cells. However, the mechanisms of action of IGF-I in these cells have not been determined. Using interleukin (IL)-6-dependent myeloma cell lines, we show IGF-I to be as potent a survival and proliferation factor as IL-6. We demonstrated that IGF-I functions independently of the IL-6 transducer gp130 and that these two cytokines have additive effects. Moreover, inhibition of the IGF-I pathway did not modulate the proliferative effect of IL-6. Accordingly, we found that IL-6 and IGF-I activated distinct downstream signalling molecules: IL-6 activated STAT3 phosphorylation, whereas IGF-I treatment resulted in the phosphorylation of IRS-1. Interestingly, these signalling pathways appear to converge as both cytokines activated the ras/MAPK pathway. Thus, IGF-I acts as a potent survival and proliferation factor for myeloma cells by stimulating an IL-6-independent signalling cascade. These data, together with the finding that, in vivo, IGF-I is normally expressed in close proximity to myeloma cells within the bone matrix, strongly suggest a role for this cytokine in the pathophysiology of multiple myeloma.

Apoptosis↗
PubMed2000

[Lethal osteochondrodysplasias: prenatal and postnatal differential diagnosis].

PURPOSE: Lethal osteochondrodysplasias show an abnormal maturation and a disturbed growth of cartilage and bones. They represent a heterogeneous group of rare genetic diseases. Their incidence is 1 to 3 in 10,000 births. MATERIAL AND METHODS: We report altogether 5 cases: two of thanatophoric dysplasia, one of achondrogenesis type II and two cases of the rare fibrochondrogenesis. The differential diagnosis in respect to ultrasonographic, morphologic, radiographic and histopathologic criteria of the most common of these diseases are discussed together with a review of the literature. RESULTS: On the basis of the ultrasound finding of the short-rib-syndrome, it is possible to differentiate between viable and lethal osteochondrodysplasias at 19 to 22 weeks of gestation. The short-rin-syndrome leads to pulmonary hypoplasia. CONCLUSIONS: It is essential to obtain an exact diagnosis postnatally by radiographic and histopathological examinations to counsel the parents concerning the risk of recurrency. The risk in this heterogeneous group of genetic diseases ranges between less than 1% up to 50% depending on the final diagnosis. Our two cases of fibrochondrogenesis in a consanguineous couple strongly suggest an autosomal recessive inheritance in this disease.

Adult↗
PubMed2000

Cognitive decline affects subject attrition in longitudinal research.

We evaluated prospectively 210 patients with idiopathic Parkinson's disease (PD) to determine whether cognitive deterioration and disease disability affect subject drop out. Subjects who refused to return for follow-up testing had a greater degree of bradykinesia and overall disability, more advanced disease, fewer years of education and greater depressive symptomatology. However, discriminant analysis indicated that performance on the neuropsychological measures, rather than PD severity, significantly predicted whether patients return for follow-up testing. Our findings indicate that cognitive impairment uniquely contributes to subject attrition, which may distort dementia estimates in PD.

Aged↗
PubMed2000

Academic and Social Benefits of a Co-enrollment Model of Inclusive Education for Deaf and Hard-of-Hearing Children.

Deaf and hard-of-hearing (d/hh) students are traditionally educated within self-contained programs at residential or special day schools, within self-contained or resource classrooms in public schools, or within regular education classrooms with support provided by an itinerant teacher. The co-enrollment model offers a promising alternative in which these students are educated within a regular education classroom composed of both d/hh and hearing students and team-taught by a teacher of the deaf and a regular education teacher. This article examines the development of one such program and the social and academic performance of the d/hh students within the program. Data on social interaction between d/hh and hearing classmates suggest that specific instructional strategies that promoted students' sign language development, identified d/hh students as "sign language specialists" and grouped d/hh and hearing students during academic activities resulted in increased interaction between these two groups of students. Stanford Achievement Test scores in the areas of reading vocabulary, reading comprehension, mathematical problem solving and procedures indicate that although d/hh students scored below the national normative hearing group, reading comprehension levels exceeded the national normative sample of d/hh students during both years two and three of the program. We discuss the challenges of implementing a co-enrollment program.

Journal Article↗