Clinical manifestation of heparin-induced thrombocytopenia type II.
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Aged↗
Biomedical subjects
M Bauer
Publications and source records attributed to M Bauer.
Deficient T cell fate specification in mice with an induced inactivation of Notch1.
Notch proteins are cell surface receptors that mediate developmental cell specification events. To explore the function of murine Notch1, an essential portion of the gene was flanked with loxP sites and inactivation induced via interferon-regulated Cre recombinase. Mice with a neonatally induced loss of Notch1 function were transiently growth retarded and had a severe deficiency in thymocyte development. Competitive repopulation of lethally irradiated wild-type hosts with wild-type- and Notch1-deficient bone marrow revealed a cell autonomous blockage in T cell development at an early stage, before expression of T cell lineage markers. Notch1-deficient bone marrow did, however, contribute normally to all other hematopoietic lineages. These findings suggest that Notch1 plays an obligatory and selective role in T cell lineage induction.
Animals↗
DNA activates human immune cells through a CpG sequence-dependent manner.
While bacterial DNA and cytosine-guanosine-dinucleotide-containing oligonucleotides (CpG ODN) are well described activators of murine immune cells, their effect on human cells is inconclusive. We investigated their properties on human peripheral blood mononuclear cells (PBMC) and subsets thereof, such as purified monocytes, T and B cells. Here we demonstrate that bacterial DNA and CpG ODN induce proliferation of B cells, while other subpopulations, such as monocytes and T cells, did not proliferate. PBMC mixed cell cultures, as well as purified monocytes, produced interleukin-6 (IL-6), IL-12 and tumour necrosis factor-alpha upon stimulation with bacterial DNA; however, only IL-6 and IL-12 secretion became induced upon CpG ODN stimulation. We conclude that monocytes, but not B or T cells, represent the prime source of cytokines. Monocytes up-regulated expression of antigen-presenting, major histocompatibility complex class I and class II molecules in response to CpG DNA. In addition, both monocytes and B cells up-regulate costimulatory CD86 and CD40 molecules. The activation by CpG ODN depended on sequence motifs containing the core dinucleotide CG since destruction of the motif strongly reduced immunostimulatory potential.
Antigens, Surface↗
Hepatocyte growth factor in human osteoarthritic cartilage.
OBJECTIVE: Hepatocyte growth factor/scatter factor is a potent mitogen, morphogen and motogen for a variety of mainly epithelial cells. Hepatocyte growth factor is synthesized by mesenchymal cells and can be found in various tissues. The objective of this study was to investigate the expression and distribution patterns of this pleiotropic growth factor and its receptor, the product of the proto-oncogene c-met in normal and osteoarthritic human knee cartilage. METHODS: Five normal and 14 osteoarthritic human cartilage samples graded histomorphologically by Mankin Score, were studied by radioactive in-situ hybridization and immunohistochemistry for the expression of Hepatocyte growth factor and the c-met receptor. RESULTS: Hepatocyte growth factor could be found by immunohistochemistry in the territorial matrix surrounding the chondrocytes of calcified cartilage and within the deep zone of normal cartilage. Chondrocytes of these cartilage zones showed also positive c-met receptor-staining. Moreover, a small number of chondrocytes in the superficial and intermediate zone showed c-met staining. In accordance with the increased hepatocyte growth factor staining of osteoarthritic cartilage, an enhanced expression of hepatocyte growth factor-RNA by chondrocytes of the deep zone as well as the deeper mid zone was observed. Contrary to normal cartilage, c-met was identified immunohistochemically in osteoarthritic chondrocytes of all cartilage zones. CONCLUSION: These results indicate that hepatocyte growth factor seems to be acting in an autocrine/paracrine manner in normal and osteoarthritic cartilage. The ubiquitous presence of the HGF/HGF-receptor complex in osteoarthritic chondrocytes suggests that hepatocyte growth factor may contribute to the altered metabolism in osteoarthritic cartilage.
Cartilage, Articular↗
Early mycological treatment failure in AIDS-associated cryptococcal meningitis.
Cryptococcal meningitis causes significant morbidity and mortality in persons with AIDS. Of 236 AIDS patients treated with amphotericin B plus flucytosine, 29 (12%) died within 2 weeks and 62 (26%) died before 10 weeks. Just 129 (55%) of 236 patients were alive with negative cerebrospinal fluid (CSF) cultures at 10 weeks. Multivariate analyses identified that titer of cryptococcal antigen in CSF, serum albumin level, and CD4 cell count, together with dose of amphotericin B, had the strongest joint association with failure to achieve negative CSF cultures by day 14. Among patients with similar CSF cryptococcal antigen titers, CD4 cell counts, and serum albumin levels, the odds of failure at week 10 for those without negative CSF cultures by day 14 was five times that for those with negative CSF cultures by day 14 (odds ratio, 5.0; 95% confidence interval, 2.2-10.9). Prognosis is dismal for patients with AIDS-related cryptococcal meningitis. Multivariate analyses identified three components that, along with initial treatment, have the strongest joint association with early outcome. Clearly, more effective initial therapy and patient management strategies that address immune function and nutritional status are needed to improve outcomes of this disease.
AIDS-Related Opportunistic Infections↗
Differential expression pattern of heme oxygenase-1/heat shock protein 32 and nitric oxide synthase-II and their impact on liver injury in a rat model of hemorrhage and resuscitation.
OBJECTIVE: To investigate the role of the vasodilator systems heme oxygenase-1/heat shock protein 32 (HO-1/HSP32) and nitric oxide synthase-II (NOS-II), generating carbon monoxide and nitric oxide respectively, as modulators of liver injury in an experimental model of reversible hemorrhagic shock. DESIGN: Prospective controlled laboratory study. SETTING: University research laboratory. SUBJECTS: Male Sprague-Dawley rats weighing 250-350 g. INTERVENTIONS: Animals were anesthetized and assigned to a hemorrhagic shock (mean arterial pressure, 35-40 mmHg for 60 mins) or a sham protocol. On the basis of the time course of gene expression, HO-1/HSP32 or NOS-II was blocked 5 hrs after onset of resuscitation. To assess the role of the antioxidative properties of the heme oxygenase (HO) pathway in additional experiments, Trolox, a potent antioxidant, was administered at the time of blockade of HO. Liver injury was assessed morphometrically and by plasma alpha-glutathione-S-transferase (alpha-GST) release 11 hours after onset of resuscitation. MEASUREMENTS AND MAIN RESULTS: Hemorrhage and resuscitation increased HO-1/HSP32 messenger RNA and protein primarily in parenchymal cells, and a faint induction of NOS-II, restricted to nonparenchymal cells, was observed. Inhibition of the HO pathway with tin protoporphyrin-IX (SnPP-IX) increased the incidence of pericentral necrosis (intact acini: shock/vehicle 68.8%; shock/SnPP-IX 42.6%) and alpha-GST levels (sham 94+/-24 microg/L; shock/vehicle 377+/-139 microg/L; shock/SnPP-IX 1708+/-833 microg/L), whereas blockade of NOS-II with S-methylisothiourea did not affect liver injury. Coadministration of Trolox failed to attenuate the aggravation of necrosis associated with blockade of HO, whereas alpha-GST levels were reduced (intact acini: shock/vehicle/Trolox 82.1%, shock/SnPP-IX/Trolox 42.7%; alpha-GST: shock/vehicle/Trolox 202+/-55 microg/L; shock/SnPP-IX/Trolox 236+/-61 microg/L). CONCLUSIONS: These data suggest that HO-1/HSP32, but not the alternative cyclic guanosine monophosphate-generating enzyme NOS-II, is induced after hemorrhage and resuscitation and protects against hepatocellular injury. Both metabolites generated by the heme oxygenase pathway, e.g., carbon monoxide (a vasodilator) and biliverdin (an antioxidant) seem to contribute to the salutary effects of induction of HO-1/HSP32.
Analysis of Variance↗
Paroxetine and amitriptyline augmentation of lithium in the treatment of major depression: a double-blind study.
To study the efficacy and safety of antidepressant augmentation of ongoing lithium therapy, lithium-maintained patients suffering from an breakthrough episode of major depression were randomly assigned under double-blind conditions to receive paroxetine 20 mg/day (N = 19) or amitriptyline 75 mg/day (N = 23). The initial dosages could be increased after 2 weeks to 40 mg/day and 150 mg/day, respectively, and the patients were treated for a total of 6 weeks. Efficacy was assessed weekly with the 21-item Hamilton Rating Scale for Depression (HAM-D) and the Clinical Global Impression Scale (CGI), and safety was assessed with the Dosage Record and Treatment Emergent Symptom Scale. After 4 weeks, a significantly greater proportion of patients in the paroxetine group had achieved a 50% reduction in baseline HAM-D scores, and the mean improvement in CGI severity of illness was significantly greater in the paroxetine group at weeks 3 and 5. The type and number of emergent events occurring during study treatment corresponded to the known side effect profiles of paroxetine and amitriptyline. Serum lithium levels were not affected by either antidepressant. The authors proposed that the more rapid improvement demonstrated by the group receiving the combination of lithium and paroxetine may be due to the synergistic serotonergic effects of these two medications.
Adult↗
Lithium augmentation in treatment-resistant depression: meta-analysis of placebo-controlled studies.
The addition of lithium to the treatment regimens of previously nonresponding depressed patients has been repeatedly investigated in controlled studies. The authors undertook this meta-analysis to investigate the efficacy of lithium augmentation of conventional antidepressants. An attempt was made to identify all placebo-controlled trials of lithium augmentation in refractory depression. Only double-blind studies that involved participants who had been treated with lithium or placebo addition after not responding to conventional antidepressants were to be included in the meta-analysis. Further inclusion criteria were the use of accepted diagnostic criteria for depression and the use of response criteria based on the acceptable measurement of depression as an outcome variable. Studies were located by a search of the MEDLINE database, a search in the Cochrane Library, and an intensive search by hand of reviews on lithium augmentation. Nine of 11 placebo-controlled, double-blind studies were included in this meta-analysis. Aggregating three studies with a total of 110 patients that used a minimum lithium dose of 800 mg/day, or a dose sufficient to reach lithium serum levels of > or = 0.5 mEq/L, and a minimum treatment duration of 2 weeks, the authors found that the pooled odds ratio of response during lithium augmentation compared with the response during placebo treatment was 3.31 (95% confidence interval, 1.46-7.53). The corresponding relative response rate was 2.14 (95% confidence interval, 1.23-3.70), the absolute improvement in response rate was 27% (95% confidence interval, 9.8%-44.2%), and the number of patients needed to be treated to obtain one more responder was 3.7. Inclusion of six more studies that fulfilled inclusion criteria but which treated subjects with additional lithium for less than 2 weeks or with a lower lithium dose (total, 234 patients) resulted in even higher estimates. Lithium augmentation seems to be the treatment strategy in refractory depression that has been investigated most frequently in placebo-controlled, double-blind studies. The authors conclude from this meta-analysis that with respect to efficacy, lithium augmentation is the first-choice treatment procedure for depressed patients who fail to respond to antidepressant monotherapy.
Antidepressive Agents↗
Role of reactive oxygen species for hepatocellular injury and heme oxygenase-1 gene expression after hemorrhage and resuscitation.
Reactive oxygen species (ROS) generated during hemorrhage and subsequent resuscitation (H/R) may contribute to cellular injury but may also regulate an adaptive cellular response to stress. Heme oxygenase (HO)-1 has been recognized as an important stress-inducible gene conferring protection after H/R. The aim of this study was to determine the contribution of ROS to hepatocellular injury and to induction of HO-1 in parenchymal and nonparenchymal cells after H/R. Anesthetized Sprague-Dawley rats were subjected to reversible H/R with or without coadministration of the potent antioxidant Trolox (6 mg/kg body wt). HO-1 gene expression was determined at baseline, at the end of hemorrhagic hypotension, and after 1, 3, and 5 h of resuscitation on the messenger ribonucleic acid (mRNA) and protein level. Assessment of hepatocellular injury by alpha-glutathione-S-transferase serum levels showed a significant increase after H/R that was attenuated by Trolox (sham: 38 (26-42); H/R: 286 (150-696); Trolox: 14 (2-227) microg/L; median (25th/75th percentile) P<0.05). Injury correlated with induction of HO-1 mRNA (r2 = 0.97) on the whole organ level and with the expression pattern of HO-1-immunoreactive protein in pericentral hepatocytes after H/R. Trolox attenuated H/R-induced increase of HO-1 in hepatocytes. In contrast, nonparenchymal cells showed high constitutive levels of HO-1 mRNA and protein that were increased by sham operation and H/R to a similar extent. HO-1 steady-state transcripts in nonparenchymal cells were not modulated by Trolox. These results suggest a differential regulation of HO-1 gene expression in hepatocytes and nonparenchymal cells. ROS formation seems to contribute to early hepatocellular injury but also serves as an important trigger for HO-1 gene expression in parenchymal cells, which confers delayed protection after H/R.
Animals↗
Sendai virus infection induces apoptosis through activation of caspase-8 (FLICE) and caspase-3 (CPP32).
Sendai virus (SV) infection and replication lead to a strong cytopathic effect with subsequent death of host cells. We now show that SV infection triggers an apoptotic program in target cells. Incubation of infected cells with the peptide inhibitor z-VAD-fmk abrogated SV-induced apoptosis, indicating that proteases of the caspase family were involved. Moreover, proteolytic activation of two distinct caspases, CPP32/caspase-3 and, as shown for the first time in virus-infected cells, FLICE/caspase-8, could be detected. So far, activation of FLICE/caspase-8 has been described in apoptosis triggered by death receptors, including CD95 and tumor necrosis factor (TNF)-R1. In contrast, we could show that SV-induced apoptosis did not require TNF or CD95 ligand. We further found that apoptosis of infected cells did not influence the maturation and budding of SV progeny. In conclusion, SV-induced cell injury is mediated by CD95- and TNF-R1-independent activation of caspases, leading to the death of host cells without impairment of the viral life cycle.
Animals↗
Their only privacy is between their sheets. Privacy and the sexuality of elderly nursing home residents.
This study which was based on hermeneutic phenomenology, investigated how paid caregivers in two nursing homes experienced older residents' sexuality. Caregivers acknowledged there were obstacles to residents fulfilling their sexual desires. The medical model of care still largely determines the norms and values within nursing homes and governs the actions of staff. Sexuality within the current medical model is not considered to be part of the primary caregiving role because sexuality is not deemed to play a vital role in the maintenance of bodily functions. Because they are geared toward the demands of basic body care, nursing homes are not inclined to create an environment conductive to the fulfillment of sexual needs.
Aged↗
[Brachytherapy in the management of the initial stage of the mobile tongue carcinoma].
From 1986 to 1994, 61 patients with oral tongue epidermoid carcinoma were treated using low dose rate iridium brachytherapy. Eleven patients treated with combined external beam and brachytherapy and 8 with nodal metastases at presentation were excluded from the study. The results in 42 fully evaluable and regularly followed patients here retrospectively reviewed. In 22 cases clinical stage was T1 greater than 1 cm and in the remaining 20 T2, N0 M0; all were cases of epidermoid carcinoma. The patients received definitive brachytherapy to the primary site using plastic tube technique at a dose of 5067 Gy (median 60 Gy) at reference isodose. The dose rate ranged from 35 cGy/h to 80 cGy/h (median 53 cGy/h). Elective neck dissection was performed in 24 patients, whereas a surveillance protocol was adopted in the remaining 18 cases. After an average follow-up of 40 months, 5 year absolute and disease specific survival (Kaplan Meier) was 61% and 88% respectively. Two patients failed at the primary site (local control probability 96%). Nodal metastases were found in 6 of 24 electively dissected patients and developed subsequently in 3 of 18 pN0 cases and in 4 of 18 non dissected patients. Four patients died of uncontrolled neck disease (regional control probability 76%). A severe necrosis developed in 9 patients (soft tissue in 4 and bone in 5 patients), but only 3 cases required surgery. This study confirms brachytherapy as an effective treatment modality for the early stage of oral tongue carcinoma.
Adult↗
Differential effect of anti-TNF-alpha antibody on proinflammatory cytokine release by Kupffer cells following liver ischemia and reperfusion.
To study the role of tumor necrosis factor-alpha (TNF-alpha) for induction of the proinflammatory cytokine cascade after liver ischemia and reperfusion (I/R), rats were injected intraperitoneally with anti-TNF-alpha monoclonal antibodies (mAb) or placebo (IgG1) 30 min prior to global hepatic ischemia. Blood levels of TNF-alpha, interleukin (IL)-1alpha and -6 were determined. In addition, Kupffer cells (KC) were harvested after 60 min of reperfusion and spontaneous cytokine release was measured. Sham-operated animals were used as controls. Levels of proinflammatory cytokines in serum and KC supernatants were detected using specific bioassays and ELISA. Liver I/R resulted in increased (p < .01) serum levels of TNF-alpha, IL-1alpha, and IL-6, which was associated with an enhanced (p < .05) release of these cytokines by KC. In vivo pretreatment with anti-TNF-alpha mAb led to complete neutralization of TNF-alpha serum levels and decreased (p < .01) IL-6 levels (-62%). Moreover, anti-TNF-alpha mAb markedly (p < .05) decreased the release of TNF-alpha (-69%) and IL-6 (-56%) by KC, while IL-1alpha was not affected. These data indicate that TNF-alpha produced early after liver I/R triggers both its own secretion as well as IL-6 release by KC during reperfusion while the release of IL-1alpha occurs independent from TNF-alpha.
Animals↗
Detection of epithelial cells in dried blood stains by reverse transcriptase-polymerase chain reaction.
The identification of menstrual blood stains can be improved by detection of messenger ribonucleic acid (mRNA) specific for epithelial (endometrial) cells. RNA molecules, however, are believed to be unstable and require careful sample processing. In this study, we have investigated the extraction of RNA suitable for reverse transcriptase-polymerase chain reaction (RT-PCR) from dried blood stains stored for up to six months. With a modified RNA isolation protocol, it was possible to obtain RNA from dried blood stains with at least 5 x 10(2) leukocytes. In an additional experiment, we evaluated the RNA isolation from mixed stains composed of leukocytes and T47D cells, a breast cancer-derived cell line with epithelial origin. Detection of 10(2) T47D cells in a total number of 10(5) leukocytes was possible by amplification of cytokeratin 19 mRNA and progesterone receptor-mRNA specific for hormonally regulated epithelial cells. In both experiments amplification results were not dependent on storage time with similar data from one day to six months. Furthermore, it was possible to identify dried menstrual blood samples by showing the presence of mRNA specific for epithelial cells. These results demonstrate for the first time, that RNA suitable for RT-PCR, can be isolated from forensic specimens stored up to at least six months, and that a small number of epithelial (endometrial) cells can be identified in dried blood specimens. Using this method, it will be possible to identify the origin of small and partially degraded blood samples which can be especially useful in forensic evaluation of cases with sexual offense.
Base Sequence↗
Fulminant liver failure in a young child following repeated acetaminophen overdosing.
Acetaminophen (paracetamol), a widely used analgetic drug, is well tolerated at therapeutic doses, but may cause severe hepatotoxicity when ingested in large overdose. Self-poisoning is still very popular in adults and accidental ingestion of one single overdose occurs occasionally in children. In contrast, lethal intoxication in children after repeated administration of therapeutic doses is a very rare event. This case report describes an iatrogenic acetaminophen overdosing in a 5-year-old child receiving 8.5 g acetaminophen in 48 h. Fulminant liver failure developed within 60 h. Autopsy findings included panlobular liver cell necrosis. Acetaminophen serum levels were rather low compared to cases with ingestion of one single overdose. Postmortem diagnosis of chronic acetaminophen intoxication as cause of death should include the clinical history as well as, if available, the calculated drug serum half-life.
Acetaminophen↗
Sequence motifs determine structure and Ca++-binding by EF-hand proteins.
Prediction of protein structural and functional characteristics based on specific motif interactions could serve as a powerful tool in many facets of the biological sciences. Such improvements in protein modeling will be instrumental in the enhancement of drug design. A new approach to a sequence description of EF-hand motifs with more than one EF-hand domain is presented here; this permits precise insight into the structural and functional properties of many members of the EF-hand superfamily of calcium-binding proteins. Three separate regular expressions, or signatures, are used to describe an EF-hand motif, and specific relationships must exist between the two sequence motifs for the two neighboring EF-hands in a given calcium-binding domain. Specifically, each of the sequence motifs has a conserved phenylalanine. These two phenylalanine residues are separated by 57+/-10 amino acid residues but interact closely with each other in the tertiary structure of the calcium-binding domain. Changes in conserved residues in the sequence motifs have been shown experimentally to decrease or eliminate the ability of the protein to bind calcium. This new approach of use of multiple sequence motifs, with motif interrelationships, yields a highly specific and robust tool for the prediction of structural and functional properties of new and novel proteins.
Amino Acid Motifs↗
On the role of the second coding exon of the HIV-1 Tat protein in virus replication and MHC class I downregulation.
Tat is an essential protein of human immunodeficiency virus type 1 (HIV-1) and activates transcription from the viral long terminal repeat (LTR) promoter. The tat gene is composed of two coding exons of which the first, corresponding to the N-terminal 72 amino acid residues, has been reported to be sufficient for its transcription function. We introduced a stop codon at the end of the first Tat-coding exon in an expression vector that produces a truncated 71-amino acid Tat protein. This Q72stop mutant displays reduced transcriptional activity of approximately 54% in transient LTR-CAT transfection assays. To test the contribution of the second Tat-coding exon to virus replication, the Q72stop mutation was also introduced in the infectious pLAI molecular clone. The effect on virus replication was analyzed in primary cells and in a transformed T cell line. The fitness of the mutant virus was calculated to be approximately 75% compared with the wild-type control. Thus, a small contribution of the C-terminal Tat domain to viral fitness was measured. It has been proposed that the second Tat-coding exon is involved in transcriptional downregulation of the MHC class I gene of the infected host cell. Cell surface expression of the MHC protein was analyzed in T cells infected with the wild-type LAI virus and the replication-competent Q72stop mutant. MHC expression was transiently reduced on infection with either virus, indicating that the second Tat-coding exon is not involved in this downregulation.
Animals↗
Identification of the autoantigen of celiac disease.
Tissue transglutaminase is demonstrated to be the unknown endomysial autoantigen by means of immunoprecipitations from a fibrosarcoma cell culture. A novel hypothesis for the pathogenesis of celiac disease is formulated: The mainly intracellular tissue transglutaminase is released from cells during wound healing where it aids in stabilizing the wound area by cross-linking a small set of extracellular matrix components.
Autoantibodies↗