[Welcome, thought, pitfall and grief].
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Adolescent↗
Biomedical subjects
M David
Publications and source records attributed to M David.
Conversion of normal rats into SCID-like animals by means of bone marrow transplantation from SCID donors allows engraftment of human peripheral blood mononuclear cells.
We have recently shown that lethally irradiated normal strains of mice, radioprotected with SCID bone marrow, can be engrafted with human peripheral blood mononuclear cells (PBMC). We now demonstrate that lethally irradiated Lewis rats can also be radioprotected with a transplant of SCID bone marrow cells, administered 1 day after total body irradiation. Split chimerism was found in PBMC, 30 days after transplantation, with predominance of SCID donor-type cells. The average percentages of CD4 and CD8 T cells, of mouse or rat origin, were < 1%. This chimerism status could be maintained for over 3 months. When human PBMC (300-1000 x 10(6) cells) were transplanted intraperitoneally 1 day after the administration of SCID bone marrow, prompt engraftment of human CD4 and human CD8 T cells, as well as human CD20 B cells, was found in the peritoneum and in internal organ (such as liver, lung, spleen, thymus, and lymph nodes). T cell activation was high: about 50% of the cells expressed HLA-DR and almost all expressed CD45RO. High titers of human Ig (> 1 mg/ml) were initially found after 2 weeks; these levels were similar to those found in the irradiated mouse model and in the SCID model. Likewise, marked human anti-tetanus response, predominantly of the IgG type, was recorded 2 weeks after the immunization, reaching maximal levels at 4 weeks. The triple-chimeric SCID-like rats, which accept as much as 1000 x 10(6) human PBMC, can potentially be used to elicit both antibody responses and T cell responses against specific antigens, with the advantages of a larger animal.
Animals↗
Requirement for MAP kinase (ERK2) activity in interferon alpha- and interferon beta-stimulated gene expression through STAT proteins.
Activation of early response genes by interferons (IFNs) requires tyrosine phosphorylation of STAT (signal transducers and activators of transcription) proteins. It was found that the serine-threonine kinase mitogen-activated protein kinase (MAPK) [specifically, the 42-kilodalton MAPK or extracellular signal-regulated kinase 2 (ERK2)] interacted with the alpha subunit of IFN-alpha/beta receptor in vitro and in vivo. Treatment of cells with IFN-beta induced tyrosine phosphorylation and activation of MAPK and caused MAPK and Stat1 alpha to coimmunoprecipitate. Furthermore, expression of dominant negative MAPK inhibited IFN-beta-induced transcription. Therefore, MAPK appears to regulate IFN-alpha and IFN-beta activation of early response genes by modifying the Jak-STAT signaling cascade.
Binding Sites↗
Human/mouse radiation chimera are capable of mounting a human primary humoral response.
Lubin et al recently described a new approach that enables the generation of human/mouse chimera by adoptive transfer of human peripheral blood mononuclear cells (PBMC) into lethally irradiated normal strains of mice, radioprotected with bone marrow (BM) from donors with severe combined immune deficiency (SCID). In the present study, we demonstrate in such human/mouse chimera a marked humoral response to recall antigen, such as tetanus toxoid (TT) or hepatitis B surface antigen (HBsAg), as well as a significant primary response to keyhole limpet hemocyanin (KLH). Maximal anti-KLH response in human/Balb chimera was attained 2 to 4 weeks after the immunization and declined thereafter. One week after transplantation, the predominant anti-KLH subtype was IgM, while after 2 weeks, the dominance had shifted to IgG. Similar primary antibody response was also demonstrated against the human immunodeficiency virus (HIV) Nef protein. Comparison between human/Balb and human/SCID chimera showed a major difference in their ability to mount a primary response against KLH. In Balb/c recipients, more than half of the mice exhibited marked IgM titers against KLH, while there was hardly any anti-KLH IgM response in the SCID recipients. From the earliest time point onwards, when anti-KLH antibodies were found in the latter chimera, they were predominantly of the IgG type. We have previously shown that in human/Balb chimera, unlike in SCID recipients, dissemination of transplanted PBMC into the spleen and other internal organs occurs within 24 hours. Therefore, it is likely that the early seeding in the appropriate microenvironment of the lymphoid tissues, is crucial for the maintenance of virgin human B cells.
Animals↗
Amniocentesis rate and the detection of Down syndrome and other chromosomal anomalies in Israel.
We investigated the contribution of different screening criteria to the prenatal detection of Down syndrome (DS) as well as other chromosomal anomalies in the Jewish population in Israel during 1990 and 1992. There was a significant decrease (P < 0.03) in the incidence of DS live-births during 1992 (40:78 442) compared with 1990 (69:73 751) which paralleled a marked increase in total prenatal testing and in DS cases detected prenatally. Private laboratories, which perform amniocenteses mostly for women with a low risk of DS and without genetic counselling, had a significantly lower detection rate (1:917) compared with that of the genetic institutes, which following genetic counselling test both women > or = 37 years of age (1:91) and women younger than 37 years (1:113). The detection of chromosomal anomalies other than DS was less affected by the reason for amniocentesis. Amniocentesis indicated by maternal serum marker screening of women younger than 37 years identified a greater number of chromosomal anomalies other than DS than amniocentesis based on age (> or = 37 years) alone (111:9604 versus 94:9810; P < 0.06). Prenatal detection of DS is most effective when the indication for amniocentesis follows genetic counselling. The increasing use of maternal serum marker screening leads to a significant improvement in the positive detection rate of chromosomal anomalies other than DS in young women.
Adult↗
A clinical screening cooperative group phase II evaluation of lobaplatin (ASTA D-19466) in advanced head and neck cancer.
We evaluated the efficacy and tolerability of lobaplatin, a new platinum compound, given at the dose of 50 mg/m2 by i.v. bolus every 4 weeks, in 49 patients with advanced and/or metastatic squamous cell carcinoma of the head and neck (SCCHN). One complete and 2 partial responses were observed in 43 eligible patients for an overall response rate of 7% (95% confidence interval: 1-19%). The duration of responses was 11, 16 and 32 weeks. Toxicities of WHO grade > or = 3 were hematologic: thrombocytopenia in 26%, granulocytopenia in 12% and anemia in 12% of patients. There was no therapy-related death. Nausea/vomiting, diarrhoea and paresthesia were mild and rare. In conclusion, lobaplatin was well tolerated, but its efficacy in advanced SCCHN at the presented dose and schedule, was marginal.
Adult↗
Transcription factors in interferon signaling.
Interferons (IFNs) comprise a family of polypeptides that exhibit diverse biological effects such as inhibition of cell growth and protection against viral infection. These activities are based mainly on the transcriptional induction of cellular genes by both type I (IFN-alpha and IFN-beta) and type II (IFN-gamma) interferons. Several of these IFN-induced early response genes have been cloned and common elements within their promoters defined. Transcription factors, such as interferon-stimulated gene factor-3, IFN-gamma activation factor and FcRF gamma, that bind to these enhancers subsequently have been isolated and their components identified. This review shall provide an overview of the DNA response elements, the components of the IFN-induced transcription factors and their mechanism of action.
Base Sequence↗
[Cutaneovisceral leishmaniasis following severe nervous depression].
Leishmania is considered an opportunistic agent during cellular immunodeficiency. The authors report the case of a patient living in the south of France presenting visceral leishmaniasis with cutaneous manifestations in the course of a severe nervous depression. This case report illustrates the possible relationships between stress and immunity.
Adult↗
Treatment of purpura fulminans in meningococcemia with protein C concentrate.
OBJECTIVE: To evaluate the clinical and laboratory effects of protein C concentrate as an adjunct to conventional therapy in the treatment of meningococcemia with purpura fulminans. DESIGN: Case series (pilot study). SETTING: Intensive care unit in a tertiary care pediatric hospital. PATIENTS: Four children (aged 3 months to 15 years) requiring intensive treatment for meningococcemia with shock, disseminated intravascular coagulation, and purpura fulminans. INTERVENTION: Intravenous administration of a protein C concentrate (100 IU/kg every 6 hours). MAIN OUTCOME MEASURES: Plasma protein C amidolytic activity, fibrinogen, and D-dimers; evolution of skin and limb lesions. RESULTS: Treatment with protein C concentrate led to a rise in plasma protein C activity levels to within normal limits in all patients, associated with an increase in plasma fibrinogen and a bimodal decrease in D-dimers. No adverse effects were noted. All patients had reversal of organ dysfunction despite the severity of the initial illness. Two patients recovered completely with no sequelae; two required amputations. CONCLUSIONS: These encouraging clinical and laboratory results and the absence of side effects warrant the initiation of a double-blind, randomized controlled multicenter trial to determine the role of protein C replacement in the treatment of meningococcemia-associated purpura fulminans.
Adolescent↗
Quality of care in adult heart surgery: proposal for a self-assessment approach based on a French multicenter study.
A prospective study was carried out from January to April 1993 in 42 centers to assess the quality of care in adult heart surgery in France. One hundred eight parameters were collected (i.e., risk factors, surgery, postoperative course) for 7181 patients. Eight simple, objective factors were selected using a multivariate analysis. Point weighting was assigned to each factor. A simple cumulative score was thereby established to classify patients within four incremental risk groups (respective distribution of patients and mortality were 38.6%, 26.5%, 21.3%, 13.5% and 2%, 3.9%, 6.1%, 21.4%). This score was highly predictive for mortality and severe morbidity. Objectivity and independence of the observer, coupled with a reliable score, are needed for meaningful assessment of the quality of care. Administrative supervision and/or comparison of raw center results therefore remain controversial. A national data base was developed as a part of this study, that includes anonymous information from two-thirds of all cardiac surgery cases. Nation-wide results for France allow each center freely to assess its results. This self-assessment approach is, in our view, the most accurate way of quality of care assessment. A pan-European system using a similar approach should be developed.
Adult↗
Replacement therapy with a monoclonal antibody purified protein C concentrate in newborns with severe congenital protein C deficiency.
Protein C replacement therapy with a monoclonal antibody purified, virus inactivated protein C concentrate was carried out in nine infants (three male, six female) with severe congenital protein C deficiency and life-threatening purpura fulminans and/or thrombosis associated with disseminated intravascular coagulation (DIC). Eight infants were homozygous for protein C deficiency; one was a compound heterozygote. The treatment period varied from 22 days to three years. The half-life of protein C was found to be as short as two to three hours during activation of the coagulation system, increasing to approximately ten hours after stabilization. During the acute phase, protein C levels of 0.10 to 0.25 IU/mL were associated with elevated markers of coagulation activation indicating DIC, while protein C levels greater than 0.25 were associated with normalization of coagulation markers. No product-related side effects were reported. Episodes of bleeding or purpura recurred in all patients who were switched to oral anticoagulant therapy, necessitating reinstatement of protein C replacement therapy, either as needed to control symptoms, or on a long-term prophylactic schedule, alone or in addition to oral anticoagulation. Home treatment with protein C concentrate allowed a near-normal life-style for patients who otherwise would be hospitalized for long periods of time.
Antibodies, Monoclonal↗
[Occurrence of suspicious changes in cervix cytology in women after liver transplantation].
After transplantation the necessary immunosuppressive therapy predisposes to the development of de novo cancers. From January 1989 to April 1994 we collected PAR smears of 98 women before and repeatedly after liver transplantation. After surgery all women received as immunosuppressive agents either Cyclosporin A or FK 506 as long-term medication. In seven patients (8.5%) who had a normal cervical cytology before transplantation a suspicious PAP smear was found on average 11 months after transplantation. In five cases a histological verification (exploratory excision, coning of the cervix) was made. In two cases we found a CIN III. Possible causes for the higher incidence of dysplasia of the cervix observed in the transplant patients are discussed. Similar to kidney transplant recipients female liver transplant recipients are at higher risk of developing cervical dysplasias and neoplasias. Accelerated development of malignancy seems likely. The influence on the cervical cells of both immunosuppressive drugs Cyclosporin A and FK 506 seems to be of a similar nature. Recommendations for the gynaecological care of female liver transplant recipients treated with immunosuppressive therapy are given.
Adult↗
Acute myocardial infarction related to myocardial bridging.
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Adult↗
Flow cytometric DNA analysis of classic and steroid-induced Kaposi's sarcoma.
Flow cytometric DNA analysis of various tumours has indicated a correlation between the degree of malignancy and ploidy; results which could have clinical significance. We analysed the ploidy of Kaposi's sarcoma (KS) tumours, and classified the results according to clinical history and histological findings. We found that patients on steroid treatment had an aneuploid pattern, and most of the patients with classic-type KS had a diploid pattern on flow cytometry.
Aged↗
Adrenarche does not occur in treated patients with congenital adrenal hyperplasia resulting from 21-hydroxylase deficiency.
OBJECTIVE: There have been few studies of adrenarche in patients with congenital adrenal hyperplasia (CAH). We have therefore sought to detect the onset of adrenarche in CAH patients and to investigate whether its evolution was influenced by the severity of the disease, the age at the onset of substitution therapy, or both. DESIGN AND PATIENTS: Sixteen female CAH patients were studied longitudinally for 4-11 years. They were all given substitution therapy and treatments were well controlled as judged by repeated hormonal evaluations. The patients were divided into two groups: group A consisted of 10 girls with a severe classic (congenital) form, while group B included 6 girls presenting with a non-classic form. MEASUREMENTS: Circulating levels of dehydroepiandrosterone sulphate (DHEAS), were determined as an indicator of adrenarche. Hormonal assessments included measurements of 17-hydroxyprogesterone (17-OHP), testosterone, ACTH and plasma renin activity. All were estimated by conventional specific assays. RESULTS: Mean levels were analysed in consecutive two-year age periods. In group A, DHEAS levels were significantly lower at any age than in control subjects, and lower than in patients with non-classic CAH. DHEAS levels showed no increment with age. In group B, plasma DHEAS levels were surprisingly high for the age at the time of diagnosis, declining gradually on substitution therapy, although they remained somewhat higher than in group A. CONCLUSIONS: The high DHEAS levels observed in untreated girls of group B are probably the result of chronic hypersecretion of ACTH. Under well controlled, non-suppressive substitution therapy, patients with congenital adrenal hyperplasia showed no rise in DHEAS levels at the physiological age of adrenarche whatever the degree of the enzyme defect and whatever the age at onset of therapy.
17-alpha-Hydroxyprogesterone↗
Susceptibility of llamas (Lama glama) to infection with foot-and-mouth-disease virus.
An experimental trial was conducted to evaluate the ability of foot-and-mouth-disease (FMD) virus (serotypes A79, C3, O1) to infect susceptible llamas exposed either directly to affected livestock, or indirectly to llamas that had been directly exposed to affected livestock. In addition, susceptible livestock species (cattle, pigs, goats, and sheep) were exposed to those llamas that had been both directly and indirectly exposed to the FMD virus to further look at potential transmission possibilities. Of 30 llamas directly exposed to the FMD virus, only three (3/30) showed evidence of infection, and of those, only two (2/30) had mild clinical signs. No FMD virus was isolated from either oesophageal-pharyngeal (OP) fluid or blood samples collected from the infected llamas beyond 14 days post-exposure. There was no evidence of virus transmission between the directly exposed and indirectly exposed llamas or between both groups of llamas and susceptible domestic livestock, as determined by the lack of clinical signs, by virus isolation, and by serology results. These results provide further evidence that llamas are resistant to FMD infection, and that they play a minor role, if any, in transmitting the virus to domestic livestock.
Animals↗
Differential regulation of the alpha/beta interferon-stimulated Jak/Stat pathway by the SH2 domain-containing tyrosine phosphatase SHPTP1.
Interferons (IFNs) induce early-response genes by stimulating Janus family (Jak) tyrosine kinases, leading to tyrosine phosphorylation of Stat transcription factors. Previous studies implicated protein-tyrosine phosphatase (PTP) activity in the control of IFN-regulated Jak/Stat signaling, but the specific PTPs responsible remained unidentified. We have found that SH2 domain-containing PTP1 (SHPTP1; also called PTP1C, HCP, or SHP) reversibly associates with the IFN-alpha receptor complex upon IFN addition. Compared with macrophages from normal littermate controls, macrophages from motheaten mice, which lack SHPTP1, show dramatically increased Jak1 and Stat1 alpha tyrosine phosphorylation, whereas Tyk2 and Stat2 activation is largely unaffected. These findings correlate with selectively increased complex formation on a gamma response element, but not an IFN-stimulated response element, in motheaten macrophages. Our results establish that SHPTP1 selectively regulates distinct components of Jak/Stat signal transduction pathways in vivo.
Animals↗
Aortic valve regurgitation caused by blunt chest injury.
Aortic valve regurgitation is an uncommon consequence of closed chest injury. It is caused by damage to the valve apparatus (ruptured cusp) or when subadventitial rupture of the ascending aorta causes prolapse of a subjacent valve cusp. Aortic valve regurgitation was detected in 4 patients (2 men and 2 women, 30 to 65 years old) who had sustained multiple injuries in road accidents 1 week to 30 years before. Three had subadventitial rupture of the ascending aorta and one had isolated rupture of the noncoronary cusp of the aortic valve. The mechanism responsible for the damage was believed to be a consequence of multiple chest lesions (right costal flap, sternal fracture, pulmonary contusion). It is difficult to diagnose and treat aortic regurgitation in patients with multiple injuries. Three patients had repair operations and the remaining patient needed valve replacement. If aortic regurgitation is haemodynamically well tolerated, the operation should be postponed until the patients have recovered from their other injuries. The results in these 4 patients and in other reported cases indicate that operations can be performed soon after the acute phase.
Adult↗