Juggling obligations.
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Burnout, Professional↗
Biomedical subjects
M Reis
Publications and source records attributed to M Reis.
Extra-adrenal phechromocytoma and renal cell carcinoma--an unusual case of tumour synchronism.
We report an unusual case of tumour synchronism combining an extra-adrenal pheochromocytoma and a renal cell carcinoma in a 48-year-old male. The most usual forms of presentation are described in accordance with their clinical significance. We emphasize the diagnostic importance of specific biochemical studies and the accurate anatomical localization of extra-adrenal chromaffin tissue by magnetic resonance imaging (MRI) and scintigraphy with 131 Iodine-methyliodobenzylguanidine (131I-MIBG). Surgical excision was the treatment of choice after the institution of adequate preoperative cardiovascular management. Pertinent features of the natural history of these tumours are described in accordance with their different embryological origin.
Carcinoma, Renal Cell↗
Fli-1, an Ets-related transcription factor, regulates erythropoietin-induced erythroid proliferation and differentiation: evidence for direct transcriptional repression of the Rb gene during differentiation.
Erythropoietin (Epo) is a major regulator of erythropoiesis that alters the survival, proliferation, and differentiation of erythroid progenitor cells. The mechanism by which these events are regulated has not yet been determined. Using HB60, a newly established erythroblastic cell line, we show here that Epo-induced terminal erythroid differentiation is associated with a transient downregulation in the expression of the Ets-related transcription factor Fli-1. Constitutive expression of Fli-1 in HB60 cells, similar to retroviral insertional activation of Fli-1 observed in Friend murine leukemia virus (F-MuLV)-induced erythroleukemia, blocks Epo-induced differentiation while promoting Epo-induced proliferation. These results suggest that Fli-1 modulates the response of erythroid cells to Epo. To understand the mechanism by which Fli-1 regulates erythropoiesis, we searched for downstream target genes whose expression is regulated by this transcription factor. Here we show that the retinoblastoma (Rb) gene, which was previously shown to be involved in the development of mature erythrocytes, contains a Fli-1 consensus binding site within its promoter. Fli-1 binds to this cryptic Ets consensus site within the Rb promoter and transcriptionally represses Rb expression. Both the expression level and the phosphorylation status of Rb are consistent with the response of HB60 cells to Epo-induced terminal differentiation. We suggest that the negative regulation of Rb by Fli-1 could be one of the critical determinants in erythroid progenitor cell differentiation that is specifically deregulated during F-MuLV-induced erythroleukemia.
Animals↗
Stem cell function and engraftment is not affected by "in vivo purging" with rituximab for autologous stem cell treatment for patients with low-grade non-Hodgkin's lymphoma.
The chimeric anti-CD20 monoclonal antibody rituximab (Rituxan; IDEC Pharmaceuticals, San Diego, CA, and Genentech, Inc, San Francisco, CA) has recently been approved by the US Food and Drug Administration as single-agent treatment of relapsed/refractory low-grade or follicular non-Hodgkin's lymphoma. Initial results from the pivotal clinical trial revealed that response rates to rituximab were higher in patients who previously had high-dose therapy and autologous stem cell transplantation. We have initiated a clinical trial that combines the use of rituximab with high-dose chemotherapy followed by autologous stem cell transplantation for patients with chemosensitive relapsed follicular small cleaved or mantle cell lymphoma. A unique feature of this study is that in addition to eight maintenance infusions of rituximab after autologous stem cell transplantation, patients also received rituximab 375 mg/m2 2 days before a granulocyte colony-stimulating factor-mobilized stem cell collection as "in vivo purge." We report on preliminary results demonstrating the safety and efficacy of the in vivo purge on 10 patients undergoing stem cell mobilization, nine of whom have already undergone transplantation. The peripheral blood CD34+ counts were 14.92 and 20 x 10(6)/L on day 4 and day 5, respectively, of the stem cell mobilization with granulocyte colony-stimulating factor. This compares with 11.7 and 11.8 x 10(6)/L, respectively, for the control population. The median CD34 stem cell yield in the graft collection was 3.7 x 10(6)/kg in patients receiving rituximab in vivo purge compared with 3.1 x 10(6)/kg in the control population. The target stem cell collection was successfully collected in six of 10 patients in a 1-day single large-volume leukapheresis collection, while two patients required 2 days and the last two patients required 3 days. Functional assays revealed the stem cell colony-forming unit-granulocyte monocyte and burst-forming unit-erythrocyte to be 55 and 44 colonies per plate, respectively, for the patients receiving the in vivo rituximab purge. This compares favorably with 37 and 38.5 colonies per plate, respectively, for the control population. Neutrophil engraftment took a median of 11 days for both cohorts; platelet independence was achieved in 8 days compared with 10 days for the control population. The median number of platelet transfusions was two for patients receiving rituximab and 2.5 for the control group. Assessment of serum cytokines immediately before the rituximab infusion during the stem cell mobilization and immediately after revealed a twofold to sevenfold increase in interleukin-1beta, tumor necrosis factor-alpha, and interleukin-6. The polymerase chain reaction analysis for minimal residual disease in stem cell collections and in peripheral blood and bone marrow samples of these patients will help to determine the efficacy of rituximab in vivo purge on disease progression.
Adult↗
Is there a dural wall between the cavernous sinus and the pituitary fossa? Anatomical and MRI findings.
We compared MRI studies of the sellar area and embryological and adult histological studies of the cavernous sinuses and pituitary fossa. MRI studies were performed in 50 normal subjects with coronal sections using a fast inversion-recovery sequence to demonstrate the dural walls of the cavernous sinus and pituitary fossa. With this sequence, dura mater appears as a high-signal linear structure. The lateral and superior walls of the cavernous sinus was easily identified on all studies, but demonstration of a dural wall separating the cavernous sinus from the pituitary fossa was not possible. These results correlated well with embryological and adult histological studies obtained from 14 specimens. The absence of a strong separation between the pituitary fossa and the cavernous sinus explains the high incidence of extension of pituitary tumours to the cavernous sinuses and vice versa.
Adult↗
High signal in the adenohypophysis on T1-weighted images presumably due to manganese deposits in patients on long-term parenteral nutrition.
Hypermanganesaemia is reported in patients on long-term parenteral nutrition. Deposition of manganese, giving high signal on T1-weighted images, may involve the basal ganglia. MRI in nine patients (mean age 51 years, range 31-75 years) on long-term parenteral nutrition (mean duration 30 months, range 6-126 months), demonstrated high signal in the anterior pituitary gland on T1-weighted sagittal and coronal images. The gland appeared normal on T2-weighted images. Signal intensity in the basal ganglia on T1-weighted images was increased in all patients. Endocrine assessment showed no significant abnormality. Neurological examination showed a mild parkinsonian movement disorder in one patient. Hypermanganaesemia was present in all nine (1.3-2.8 micromol/l, mean 1.87 micromol/l). The high signal in the anterior pituitary gland was probably related to deposition of paramagnetic substances, especially manganese.
Adult↗
Anatomy and embryology of the lateral sellar compartment (cavernous sinus) medial wall.
In order to study the microanatomy of the lateral sellar compartment (cavernous sinus) medial wall, serial histological sections of human fetuses and adults, as well as dissections under operative microscope, were performed. The results were compared to high resolution Magnetic Resonance Images in human, to microdissections and to serial histological sections in adult nonhuman primates (Papio Cynocephalus anubis). We were able to show that the sellar compartment and both lateral sellar osteodural compartments are not separated from each other by a dural wall, but by a more or less dense, interrupted, fibrous tissue which derived from the mesenchyme surrounding the hypophysis, carotid artery, cranial nerves and venous channels. In the human fetus, the previous mentioned structures are located in a unique interperiosteodural space. Histoarchitecture of the superior and lateral wall dura-mater was different from the underlying mesenchyme derived connective tissue and was easily distinguished through histological examination. These findings correspond to MRI data. We conclude that there is no medial dural wall limiting the lateral sellar compartment (cavernous sinus), both parasellar and the hypophyseal compartment should be considered as a unique extradural space. The only dense connective tissue surrounding the pituitary gland is its own glandular capsule and the periosteum.
Adult↗
Validation of the indicators of abuse (IOA) screen.
It is important to enable social service agency practitioners to identify cases in which seniors are abused by their caregivers. The Indicators of Abuse (IOA) screening measure provides an abuse screening tool, based on abuse indicators, for use by practitioners. The study (N = 341) supports the validity of the 29-item set of indicators of the IOA, which discriminates abuse cases (84.4% of the time) from nonabuse cases (99.2% of the time). An abuse-indicator model evolving from the IOA suggests three main types of abuse signals: (a) caregiver personal problems/issues; (b) caregiver interpersonal problems/ issues; (c) care receiver social support shortages and past abuse.
Aged↗
[Spontaneous hyperintensity of the anterior pituitary gland in MRI T1-weighted images related to manganese deposits in a patient undergoing prolonged parenteral nutrition].
The signal abnormalities found on MRI in the basal ganglia in patients with an increased plasmatic level of manganese are well known. We report a case with a hyperintense signal in a patient with a high plasmatic level of manganese due to long term parenteral nutrition. The normal signal intensity of T2-weighted imaging in the anterior pituitary gland helps to differentiate the increased signal intensity of T1 weighted imaging due to deposition of manganese from hemorrhagic or fatty lesions.
Adult↗
Suppression of bladder hyperreflexia by intravesical resiniferatoxin.
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Administration, Intravesical↗
Identification and characterization of two novel SH2 domain-containing proteins from a yeast two hybrid screen with the ABL tyrosine kinase.
To further our understanding of the molecular mechanism of Bcr-Abl mediated transformation, a yeast two hybrid screen was used to identify proteins binding to the Abl tyrosine kinase. Two partial cDNAs encoding novel SH2 domain-containing proteins were cloned and designated Shd and She. Both have homology to Shb, a previously reported SH2 domain-containing protein. Northern blot analysis showed that She is expressed in heart, lung, brain, and skeletal muscle, while expression of Shd is restricted to the brain. The deduced amino acid sequence of the full length mouse Shd cDNA contains an amino-terminal proline-rich region, and a carboxyterminal SH2 domain. A bacterially expressed Shd domain bound multiple tyrosine-phosphorylated proteins with relative molecular weights of 200, 170, 130, 100, 90, 78, 72 and 32 kDa from K562 cell lysates. Shd contains five YXXP motifs, a substrate sequence preferred by Abl tyrosine kinases. Shd was tyrosine phosphorylated in COS-7 cells co-transfected with Shd and c-Abl or Bcr-Abl. These results suggest that Shd may be a physiological substrate of c-Abl and may function as an adapter protein in the central nervous system.
Adaptor Proteins, Signal Transducing↗
Human T cell responses against the major cysteine proteinase (cruzipain) of Trypanosoma cruzi: role of the multifunctional alpha 2-macroglobulin receptor in antigen presentation by monocytes.
Chagas' disease patients (CDP) develop both humoral and cellular immune responses against the major cysteine proteinase (cruzipain) from Trypanosoma cruzi. Here we demonstrate that complexes formed by cruzipain and alpha 2-macroglobulin (alpha 2M) are efficiently internalized by human monocytes, and that this process results in enhanced presentation of cruzipain peptides to CD4+ T cells from CDP. Purified or serum alpha 2M binds to polymorphic cruzipains, but only a fraction of the proteinases become covalently linked. Once bound to alpha 2M, fluorescein-labeled cruzipain (FITC-cruzipain) or [125I]cruzipain were more efficiently internalized by normal peripheral blood mononuclear cells (PBMC) or monocytes; this effect was abolished by (I) pre-treating the cells with receptor-associated protein (rRAP), a known antagonist the of alpha 2M receptor (alpha 2MR/LRP), and (II) inactivating [125I]cruzipain's active site prior to the reaction with alpha 2M, indicating that the exposure of receptor binding sites on alpha 2M complexes required bait region cleavage. We then sought to determine if the alpha 2MR/LRP-dependent uptake of alpha 2M:cruzipain by monocytes resulted in increased CD4+ T cell responses of PBMC-CDP (n = 13). These effects were only revealed after depletion of CD19+ B lymphocytes from PBMC-CDP; the threshold of T cell stimulation was far lower in cultures stimulated with alpha 2M:cruzipain, as compared to antigen alone. Myocardial specimens from CDP with chronic myocardiopathy (three necropsies) were analyzed by immunohistochemistry with mAb anti-cruzipain or anti-alpha 2MR/LRP (CD81+). Extracellular depots of cruzipain were localized amidst inflammatory mononuclear infiltrates, part of which contained CD91+ macrophage-like cells. Ongoing studies should clarify if T. cruzi cysteinyl proteinases play a role in the pathogenesis of Chagas' heart disease.
Animals↗
An exploration of attachment styles and personality traits in caregiving for dementia patients.
The present study examined the influence of caregivers' Attachment Styles (Anxious-ambivalent and Avoidant factors) and personality traits (Neuroticism, Extraversion, Agreeableness, and Conscientiousness) on their experiences of caring for dementia dependents. A total of 126 caregiver-dependent pairs participated in the study. Support was found for the contribution of the attachment style factors in explaining aspects of caregiver experiences. Those who chose to institutionalize dependents were higher on the Avoidance factor than those choosing to maintain them in the community. Less Anxious-ambivalent caregivers reported larger social support networks, and more satisfaction with the support received than those lower on this factor. The caregiver Anxious/ambivalence and Neuroticism dimensions seemed to function as generalized responses reflected in perceptions and appraisals of the stressful situation.
Adaptation, Psychological↗
Desensitization of bladder sensory fibers by intravesical capsaicin has long lasting clinical and urodynamic effects in patients with hyperactive or hypersensitive bladder dysfunction.
PURPOSE: Capsaicin was used to treat symptomatic patients with hyperactive or hypersensitive bladders. MATERIALS AND METHODS: Capsaicin solution (1 mM.) was instilled into the bladder of 16 patients with spinal hyperreflexia, bladder instability or hypersensibility. RESULTS: Frequency decreased in 14 patients and continence was achieved in 10 of 14 incontinent cases. Mean first desire to void and maximal cystometric capacity increased significantly. These effects lasted for 6 to 12 months and were renewed following repeat treatment. CONCLUSIONS: Bladder afferent desensitization with capsaicin is promising in patients with motor or sensory bladder dysfunction, although initial pungency might limit its use.
Administration, Intravesical↗
Immunity to lantibiotics.
Bacteria producing bacteriocins have to be protected from being killed by themselves. This mechanism of self-protection or immunity is especially important if the bacteriocin does not need a specific receptor for its action, as is the case for the type A lantibiotics forming pores in the cytoplasmic membrane. At least two different systems of immunity have evolved in this group of bacteriocins containing modified amino acids as a result of posttranslational modification. The immunity mechanism of Pep5 in Staphylococcus epidermidis is based on inhibition of pore formation by a small 69-amino acid protein weakly associated with the outer surface of the cytoplasmic membrane. In Lactococcus lactis and Bacillus subtilis the putative immunity lipoproteins NisI and SpaI, respectively, are also located at the outer surface of the cytoplasmic membrane, suggesting that a similar mechanism might be utilized by the producers of nisin and subtilin. In addition an ABC-transport system consisting of two membrane proteins, (NisEG, SpaG and the hydrophobic domain of SpaF, and EpiEG) and a cytoplasmic protein (NisF, the cytoplasmic domain of SpaF, and EpiF) play a role in immunity of nisin, subtilin and epidermin by import, export or inhibition of pore formation by the membrane components of the transport systems. Almost nothing is known of the immunity determinants of newly described and other type of lantibiotics.
ATP-Binding Cassette Transporters↗
Inhibition of glutamate uptake and proton pumping in synaptic vesicles by S-nitrosylation.
Nitric oxide (NO; including NO-., NO+, and NO-) was found to inhibit glutamate uptake by isolated synaptic vesicles of rat brain. This was observed when two unrelated NO donors, S-nitrosogluthathione and S-nitroso-N-acetylpenicillamine, were used. The primary target of NO is the H(+)-ATPase found in the synaptic vesicles, which leads to dissipation of the electrochemical proton gradient and inhibition of glutamate uptake. Oxyhemoglobin (12 microM) and, to a much lesser extent, methemoglobin protected the vacuolar H(+)-ATPase from inhibition. Inhibition of H+ pumping by NO was reversed by addition of 0.5 mM dithiothreitol. The results indicate that the vacuolar H(+)-ATPase from synaptic vesicles is inhibited by NO by a mechanism that involves S-nitrosylation of critical sulfhydryl groups in the enzyme. The interaction of NO with synaptic vesicles might be of importance for the understanding of the multiple effects of NO in neuro-transmission.
Animals↗
Engraftment of human chronic lymphocytic leukemia cells in SCID mice: in vivo and in vitro studies.
Chronic lymphocytic leukemia (CLL) is a heterogeneous disease of the elderly which can present in one of three stages; benign, intermediate or advanced. The molecular events governing the progression of CLL are poorly understood. In order to develop model systems for predicting the aggressiveness of leukemic clones in CLL, in vivo transplantation of SCID mice with CLL cells, and the in vitro growth of CLL cells on mouse and human stromal layers, were investigated. Bone marrow or peripheral blood cells from 40 patients at different stages of CLL were transplanted into 172 immune-deficient SCID mice. Thirty-five percent of SCID mice injected with CLL cells were positive for the presence of human DNA by Southern blot or PCR analysis. The most frequently involved sites were the spleen, lung, kidney and bone marrow, at levels corresponding from 0.1 to 10 percent human DNA. Thrice-weekly intraperitoneal injections of IL-2, alone or in combination with IL-7, did not increase the level of human cell engraftment. SCID mice developed endogenous thymic lymphomas at an incidence of 10-33 percent, a rate that was not increased by CLL cell transplantation. In vitro, CLL cells were able to proliferate for 9 weeks on human stromal layers supplemented with CM (conditioned media from a culture of the human bladder carcinoma cell line 5637), but failed to thrive on the murine stromal cell line MTE cultured either in CM or autologous serum. FACS analysis revealed that 81 percent of proliferating cells on human stromal layers carried the CD5 cell surface marker, identifying them as CLL cells. Previously EBV-negative CLL cells became EBV-positive after 9 to 12 weeks in culture. The results of this study provide a firm foundation for the development of in vivo and in vitro model systems for the study of human CLL.
Animals↗
Nucleotide sequence of the lantibiotic Pep5 biosynthetic gene cluster and functional analysis of PepP and PepC. Evidence for a role of PepC in thioether formation.
The biosynthesis of Pep5, a lanthionine-containing antimicrobial peptide, is directed by the 20-kbp plasmid pED503. We identified a 7.9-kbp DNA-fragment within this plasmid which covers the information for Pep5 synthesis in the homologous host Staphylococcus epidermidis 5 which has been cured of pED503. This fragment contained, in addition to the previously described structural gene pepA and the immunity gene pepI [Reis, M., Eschbach-Bludau, M., Iglesias-Wind, M. I., Kupke, T. & Sahl, H.-G. (1994) Appl. Env. Microbiol. 60, 2876-2883], a gene pepT coding for a translocator of the ABC transporter family, a gene pepP coding for a serine protease and two genes pepB and pepC coding for putative modification enzymes; the gene arrangement is pepTIAPBC. We analyzed the biosynthetic genes with respect to their function in Pep5 biosynthesis. Deletion of PepT reduced Pep5 production to about 10%, indicating that it can be partially replaced by other host-encoded translocators. Inactivation of PepP by site-directed mutagenesis of the active-site His residue resulted in production of incorrectly processed Pep5 fragments with strongly reduced antimicrobial activity. Deletion of pepB and pepC leads to accumulation of Pep5 prepeptide in the cells without excretion of processed peptide. A pepC-deletion clone did not excrete correctly matured Pep5 but it did produce fragments from which serine and threonine were absent. Only one of these fragments contained a single lanthionine residue out of three expected while the remaining, unmodified cysteine residues could be detected by reaction with Ellman's reagent. These results demonstrate that PepC is a thioether-forming protein and strongly suggest that PepB is responsible for dehydration of serine and threonine.
ATP-Binding Cassette Transporters↗