Caregiver Perspectives on Pain Sensitivity and Pain Experience in Rett Syndrome.

Background: Although delayed or decreased responses to pain are commonly reported among caregivers of individuals with Rett syndrome (RTT), previous studies in relatively small samples have documented that caregivers are concerned about pain, particularly due to gastrointestinal and musculoskeletal conditions. Aims: The purpose of the current study was to investigate in detail caregivers' perceptions of pain sensitivity, as well as the types, severity, and effect of pain experienced by individuals with RTT in a larger sample than previous studies. Methods: A total of 51 caregivers (mostly mothers) participated in the study, which involved standardized questionnaires and interviews. The individuals with RTT ranged in age from 2 to 52 years of age, and most (n = 46; 90%) met criteria for classic RTT. Results: Across the sample, 84% of caregivers reported that they believed that their child was less sensitive to pain compared to her typically developing peers. Despite this perception, 63% of caregivers reported that their child had experienced at least one form of pain in the previous 7 days, and 57% reported their child experienced at least one form of chronic pain. On average, caregivers reported that their child's pain was of moderate severity and interfered with at least one activity of daily living. Conclusions: The results suggest that pain is a substantial concern among caregivers of individuals with RTT and indicate that additional research is needed to understand the apparent paradox of frequently reported pain experiences despite widespread perceptions of decreased pain sensitivity.

Contexte: Bien que des réponses tardives ou diminuées à la douleur soient fréquemment signalées par les soignants de personnes atteintes du syndrome de Rett (RTT), des études antérieures dans des échantillons relativement petits ont documenté que les soignants étaient préoccupés par la douleur, en particulier en raison de troubles gastro-intestinaux et d'affections musculosquelettiques.Objectifs: Le but de la présente étude était d'étudier en détail les perceptions de la sensibilité à la douleur par les soignants ainsi que les types, la gravité et l'effet de la douleur ressentie par les personnes atteintes de RTT dans un échantillon plus important que les études précédentes.Méthodes: Au total, 51 soignants (principalement des mères) ont participé à l'étude, qui a eu recours à des questionnaires et à des entretiens standardisés. Les personnes atteintes de RTT étaient âgées de 2 à 52 ans, et la plupart (n = 46 ; 90 %) répondaient aux critères de la RTT classique.Résultats: Dans l'échantillon, 84 % des soignants ont déclaré qu'ils croyaient que leur enfant était moins sensible à la douleur par rapport à ses pairs qui se développent normalement. Malgré cette perception, 63 % des soignants ont signalé que leur enfant avait ressenti au moins une forme de douleur au cours des sept jours précédents, et 57 % ont déclaré que leur enfant avait souffert d'au moins une forme de douleur chronique. En moyenne, les soignants ont signalé que la douleur de leur enfant était d'intensité modérée et interférait avec au moins une activité de la vie quotidienne.Conclusions: Les résultats indiquent que la douleur est une préoccupation importante chez les soignants des personnes atteintes de RTT et que des études supplémentaires sont nécessaires pour comprendre le paradoxe apparent voulant que des expériences douloureuses soient fréquemment rapportées bien que la perception d'une diminution de la sensibilité à la douleur soit largement répandue.

Peptide Binding Glucose Regulated Protein 78 Improves Type 1 Diabetes by Preventing Pancreatic ß Cell Apoptosis.

BACKGROUND AND OBJECTIVES: Diabetes Type 1 is characterized by hyperglycemia due to reduced insulin secretion that results from the death of pancreatic ß cells. It was suggested that endoplasmic reticulum (ER) stress is associated with the autoimmune-mediated ß cell destruction. Glucose regulated protein 78 (GRP78) functions as a key regulator to maintain the ER function. Under stress conditions GRP78 is up-regulated and expressed on the cell surface serving as a signaling receptor. Our first objective was to examine the effects of peptide binding cell surface GRP78 to reduce the deleterious effects of diabetes induced by streptozotocin. The second objective was to demonstrate the ability of the peptide to protect the pancreatic ß cells from apoptosis. METHODS: The effect of ADoPep on weight loss, HbA1c levels and anti GRP78 antibody titers was evaluated in a diabetes mouse model. The effect of ADoPep on the pancreatic ß Ins1E cell apoptosis was determined by FACS analysis. RESULTS: The administration of ADoPep to diabetic mice retained the weight loss and reduced HbA1c significantly in 60% of mice. Titers of anti GRP78 antibodies increased in 70% of the treated mice. Apoptosis was significantly inhibited in stressed pancreatic ß Ins 1E cells. CONCLUSIONS: We demonstrate that administration of the peptide ADoPep to diabetic mice improved type 1 diabetes by preventing pancreatic ß cell apoptosis.

Angiogenic peptides improve blood flow and promote capillary growth in a diabetic and ischaemic mouse model.

OBJECTIVES: It is a common clinical observation that collateral vessel development is impaired in diabetic patients with ischaemic vascular diseases. Consequently, alternative revascularisation strategies in diabetic patients are needed. This study presents the effect and mechanism of new peptide therapeutic angiogenesis in an ischaemic and diabetic mouse model. DESIGN: Streptozocin-injected mice that had undergone hind-limb ischaemia were treated with angiogenic peptides. Blood flow restoration was calculated by laser Doppler imager and corroborated by histological section. For the mechanism study, endothelial cells were exposed to hypoxia and high glucose concentrations to study the effect of the peptides on proliferation and anti-apoptosis. RESULTS: The peptides significantly restored blood perfusion 21 days after surgery in the diabetic mice (p < 0.01) by neo-vascularisation, corroborated by an increase in capillary density. In addition, the peptides induced the proliferation of hypoxic endothelial cells (p < 0.01) and protected the cells from apoptosis in high glucose cultures. CONCLUSIONS: This is the first approach for treatment of ischaemic vascular disease with peptides in a diabetic mouse model.

Treatment with BAT monoclonal antibody decreases tumor burden in a murine model of leukemia/lymphoma.

BAT is a monoclonal antibody produced against membranes of Daudi cells that induces anti-tumor activity in mice against a variety of solid murine and human tumors, mediated by its immune stimulatory properties on murine and human lymphocytes. The present study analyzes the effect of BAT on leukemia/lymphoma using the BCL1 model of leukemia/lymphoma in BALB/C mice. BAT antibody binds to BCL1 leukemia cells and recognizes a 48 kDa protein similar to the antigen on Daudi cells. Mice inoculated with leukemia cells were treated either by direct BAT injections or by adoptive transfer of lymphocytes from BAT-injected mice. Administration of BAT monoclonal antibody was either once, on day 14, or daily on days 10-13 post tumor inoculation. A single injection of BAT resulted in reduction of peripheral blood tumor cells, however additional injections further decreased the tumor cell number reaching a 95-fold reduction on day 20 post tumor inoculation. Anti-tumor effect was also obtained when animals were injected with splenocytes from BAT-treated donor mice. A significant prolongation of survival of BAT-treated mice was observed although with no cure. The results of this study indicate that BAT might be used for reducing the tumor burden in leukemia for immunotherapy and in combination with other treatment modalities.

Effect of exogenous thyroid-stimulating hormone on thyroid papillary carcinoma cells in tissue culture.

BACKGROUND: To determine the prognostic value of thyroid suppression therapy in patients with thyroid carcinoma, we studied the effect of thyroid-stimulating hormone (TSH) on the morphology, proliferation rate, and the T3, T4 production rate of primary thyroid carcinoma cells in culture. METHODS: From August 1997 to February 1998 tissues were collected for immediate culture from 13 patients undergoing surgery for thyroid cancer. Cells were incubated for 48 h with TSH in different concentrations. T3 and T4 production was measured by radioimmunoassay; cell proliferation was measured in a radioactive counter. Morphology was determined by cytologic examination. RESULTS: Ten samples were eligible for analysis. Changes in TSH affected T3 and T4 levels. The proliferation rate was not influenced by TSH levels. CONCLUSIONS: Thyroid papillary carcinoma cells grown in culture maintain their T3 and T4 synthesis ability. This ability is TSH-dependent and correlates with TSH concentration. The morphology of the cells is also maintained. However, their proliferation is not TSH-dependent, placing the current postthyroidectomy treatment policy in question.

CD4+ T lymphocytes as a primary cellular target for BAT mAb stimulation.

BAT is a monoclonal antibody (mAb) produced against membranes of a human Burkitt lymphoma cell line (Daudi) that was selected for its ability to stimulate lymphocyte proliferation. BAT manifests anti-tumor properties in mice bearing a variety of murine tumors. BAT also induced regression of human tumors inoculated into SCID mice that had been engrafted with human lymphocytes. The anti-tumor activity of BAT was related to its immune stimulatory properties. Previous data indicated that T lymphocytes and NK cells mediate in vivo the anti-tumor activity. In order to define the primary target cell for BAT stimulatory activity, the in vitro stimulatory effect of BAT on purified lymphocyte subpopulations was investigated. Human CD4(+), CD8(+) T cells and CD56(+) NK cells were purified and their in vitro response to BAT was investigated. Results indicate that BAT selectively stimulated CD4(+) cells as assessed by proliferation and secretion of IFN-gamma. FACS analysis has also revealed a selective increase in BAT antigen on CD4(+) T cells that were cultured with BAT antibody. The effector cells that mediate BAT-induced tumor eradication may, however, be distinct from those that serve as the primary cellular target of the antibody. Cytokines such as IFN-gamma that are produced by CD4(+) cells may be involved in activation of additional cell types that may be involved in tumor destruction.

Activation of lymphocytes by BAT and anti CTLA-4: comparison of binding to T and B cells.

In this study we compare the binding and immune stimulatory properties of BAT and anti CTLA-4 monoclonal antibodies (mAbs). Both antibodies were previously shown to manifest effective immune responses against tumor cells. We have described that BAT antibody, produced against Daudi, a B lymphoblastoid cell line, binds and activates T cells. In this paper we demonstrate that anti CTLA-4, produced against the T-cell activation determinant CTLA-4, binds also to B lymphoblastoid cell lines like Daudi and Raji. Both antibodies do not bind resting B cells. BAT binds resting T lymphocytes as well as activated T lymphocytes, whereas anti CTLA-4 binds only activated T cells. Competitive binding experiments indicate that the binding sites of BAT and anti CTLA-4 on activated T cells are distinct. We have studied the in vitro stimulatory effect of BAT and anti CTLA-4 on lymphocytes cultured with or without tumor cells. In contrast to BAT that increased the proliferation of lymphocytes that have been cultured with tumor cells, anti CTLA-4 did not synergize with tumor cells to enhance lymphocyte proliferation.

A lymphocyte-activating monoclonal antibody induces regression of human tumors in severe combined immunodeficient mice.

Monoclonal antibodies were raised against Daudi B-lymphoblastoid cell line membranes. An mAb (BAT) was selected for its ability to stimulate human and murine lymphocyte proliferation. BAT induced cytotoxicity in human and murine lymphocytes against natural killer cell-sensitive and -resistant tumor cell lines. A single intravenous administration of BAT to mice that had been inoculated with various murine tumors (e.g., B16 melanoma, 3LL carcinoma, and methylcholanthrene fibrosarcoma) resulted in striking antitumor effects as manifested by complete tumor regression and prolonged survival of the treated mice. BAT exhibited a diminished but significant antitumor effect in athymic nude mice, which are deficient in T lymphocytes, and in beige mice, which are deficient in NK cells. Furthermore, selective depletion of T or NK cells in mice reduced the response to the antitumor effect of BAT. These data indicate a dual role for T and NK cells in mediating the antitumor activity of BAT. We report here on the antitumor activity of BAT mAb on human tumor xenografts in mice. BAT demonstrated an antitumor effect in nude mice bearing human colon carcinoma (HT29) xenografts. It failed, however, to inhibit established lung metastases in severe combined immunodeficient (SCID) mice that had been inoculated (i.v.) with SK28 human melanoma. Engraftment of human lymphocytes into SCID mice bearing human melanoma xenografts rendered them responsive to the antitumor effect of BAT. The efficacy of BAT in the regression of human tumors by activation of human lymphocytes indicates its potential clinical use.

Immune stimulatory and anti-tumor properties of anti-CD3 and BAT monoclonal antibodies: a comparative study.

A novel monoclonal antibody raised to Daudi cell membranes was found to exhibit immune stimulatory and anti-tumor properties. The activity of this antibody (BAT) which also binds T cells was compared to that of anti-CD3. Anti-CD3 reacts with the T cell receptor complex, induces cell proliferation, and cytolytic activity in vitro and also manifests in vivo anti-tumor effect against murine tumors. Comparison of the two antibodies demonstrates similar induction in vitro of splenocyte proliferation and cytolytic activity. Both BAT and anti-CD3 antibodies manifest anti-tumor activity in mice bearing B16 melanoma. They differ however in the timing of antibody administration post-tumor inoculation which is most effective in eliciting the anti-tumor effect. Whereas BAT is most effective when administered 10 to 14 days post-tumor inoculation, anti-CD3 is effective at an early time. Data also indicate that BAT synergises with tumor cells in eliciting cell proliferation in vitro. In contrast, this effect could not be demonstrated with anti-CD3. The properties of BAT may be of advantage in its potential clinical use.