Biomedical subjects
Publications and source records attributed to J George.
Rosai-Dorfman disease is a rare entity predominantly affecting children and young adults, characterized in 83-95% of cases by painless bilateral cervical lymphadenopathy. We report the unusual case of a 41-year-old woman with Rosai-Dorfman disease that presented as a solitary lesion of the radius without other clinical manifestations.
OBJECTIVE: To develop consensus guidelines for management of delirium and to assess their effectiveness in improving the outcomes and process of care in delirium. METHOD: Guidelines for delirium were developed following a literature search and a formal multi-disciplinary consensus process using a two-stage Delphi technique. The process and outcomes of patients with delirium were then observed in a 'before' (211 patients) and an 'after' study (125 patients). Three levels of intervention were made in the 'after' study. (i) Feedback of baseline data only (low intensity intervention). (ii) As in (i), but also formal distribution of the guidelines to nurses and doctors (medium intensity intervention). (iii) As in (ii), but in addition the guidelines were reinforced with teaching sessions for the nurses and doctors (high intensity intervention). SETTING: Older people (aged over 65 years) with delirium admitted to acute medical or acute elderly care wards in five district general hospitals in England. RESULTS: Only in the high intervention group was there an improvement in process and outcome of care, but this failed to reach statistical significance. CONCLUSION: Delirium is a poorly managed condition in older people and guidelines alone fail to improve the process and outcomes of care.
Recent developments in the detection of pre-invasive lesions of the large airways by fluorescence bronchoscopy are reviewed and the clinical and biological implications discussed.
Insulin receptor substrates (IRS) are central integrators of hormone, cytokine, and growth factor signaling. IRS proteins can be phosphorylated by a number of signaling pathways critical to normal mammary gland development. Studies in transgenic mice that overexpress IGF-I in the mammary gland suggested that IRS expression is important in the regulation of normal postlactational mammary involution. The goal of these studies was to examine IRS expression in the mouse mammary gland and determine the importance of IRS-1 to mammary development in the virgin mouse. IRS-1 and -2 show distinct patterns of protein expression in the virgin mouse mammary gland, and protein abundance is dramatically increased during pregnancy and lactation, but rapidly lost during involution. Consistent with hormone regulation, IRS-1 protein levels are reduced by ovariectomy, induced by combined treatment with estrogen and progesterone, and vary considerably throughout the estrous cycle. These changes occur without similar changes in mRNA levels, suggesting posttranscriptional control. Mammary glands from IRS-1 null mice have smaller fat pads than wild-type controls, but this reduction is proportional to the overall reduction in body size. Development of the mammary duct (terminal endbuds and branch points) is not altered by the loss of IRS-1, and pregnancy-induced proliferation is not changed. These data indicate that IRS undergo complex developmental and hormonal regulation in the mammary gland, and that IRS-1 is more likely to regulate mammary function in lactating mice than in virgin or pregnant mice.
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The "Euro-Lupus Cohort" is composed by 1,000 patients with systemic lupus erythematosus (SLE) that have been followed prospectively since 1991. These patients have been gathered by a European consortium - the "Euro-Lupus Project Group". This consortium was originated as part of the network promoted by the "European Working Party on SLE", a working group created in 1990 in order to promote research in Europe on the different problems related to this disease. The "Euro-Lupus Cohort" provides an updated information on the SLE morbidity and mortality characteristics in the present decade as well as defines several clinical and immunological prognostic factors.
OBJECTIVES: The goal of this study was to test the hypothesis that induction of an immune response to heat shock protein (Hsp) 70 would increase intimal thickening in a rat carotid-injury model. BACKGROUND: Restenosis resulting from intimal thickening poses a major limitation to the long-term success of coronary angioplasty. Several studies have proposed that infectious agents increase restenosis. Heat shock proteins are highly conserved structures, produced by all cells in response to nonspecific forms of stress. Infectious agents are known to contain Hsp70, which is markedly immunogenic and can elicit a strong immune response. METHODS: To investigate whether Hsp70 immunity can affect neointimal thickening, we immunized rats with either Hsp70 (n = 11), bovine serum albumin ([BSA] n = 9) or with a control adjuvant (n = 10). Three weeks later, rats were boosted using the same regimen to achieve a sustained immune response to Hsp70 after which carotid injury was applied to all animals. RESULTS: Arterial injury was associated with upregulation of Hsp70, 3, 7 and 14 days after induction of the injury as evidenced by Western blotting and immunohistochemistry. Intimal area and intimal/medial ratio was significantly increased in Hsp70-immunized rats in comparison with BSA or control-injected rats. CONCLUSIONS: Our results imply that upregulation of Hsp70 in balloon-injured arteries can serve as a target for anti-Hsp70 immune response, thereby facilitating enhanced intimal thickening. These observations may provide a possible mechanism that explains the accelerated intimal thickening that has been associated with the occurrence of infectious pathogens.
BACKGROUND: Human 15-lipoxygenase (LO) and its murine analogue 12/15-LO are capable of directly oxidizing esterified fatty acids in lipoproteins and phospholipids. Because these oxidized products possess atherogenic properties, it was suggested that LOs may be involved in enhancing atherogenesis. Previous in vivo tests of the role of LOs in atherogenesis animal models, however, have yielded conflicting results. METHODS AND RESULTS: Aiming to study the role of the 12/15-LO in murine atherogenesis, we crossed LDL-receptor-deficient mice (LDL-R(-/-)) with 12/15-LO-knockout mice and evaluated plaque formation 3 to 18 weeks after initiation of a high-fat diet. Atherosclerotic lesions were considerably reduced in the LDL-R/12/15-LO-double-knockout mice compared with LDL-R(-/-) mice at 3, 9, 12, and 18 weeks, at the aortic root as well as throughout the aorta. The cellular composition of plaques from mice deficient in 12/15-LO did not differ with respect to macrophage and T-lymphocyte content compared with plaques from 12/15-LO littermates. CONCLUSIONS: 12/15-LO plays a dominant role in promoting atherogenesis in LDL-R(-/-) mice.
One lot of a nationally distributed diphtheria and tetanus toxoids and acellular pertussis (DTaP) vaccine was recalled in January 1999 because of a subpotent diphtheria toxoid component. To evaluate vaccine immunogenicity, children who had received the recalled lot for at least 2 of the 3 doses of their primary series were identified. Diphtheria antitoxin (DAT) levels were then prospectively assessed before and after dose 4 of (fully potent) DTaP vaccine. Of the 105 children evaluated, 84% had prevaccination DAT levels <0.10 IU/mL, which is the level generally accepted as protective. DAT levels rose a mean of 92-fold after dose 4; 100% of subjects had DAT levels >or=0.10 IU/mL, and 69% had DAT levels >or=1.0 IU/mL. These results indicate that diphtheria potency testing can identify vaccine that is less immunogenic when administered during the primary series. The booster response to dose 4, although reduced, was sufficient to confer adequate protection in the interval before receipt of the fifth dose of DTaP.
Dimethylnitrosamine (DMN) is a potent hepatotoxin that can cause fibrosis of the liver. It's ability to provide a suitable rapid experimental murine model for early human cirrhosis was examined. The drug was administered to adult male albino rats in order to document sequential pathological and biochemical alterations. Injury was produced by intraperitoneal injections of DMN on three consecutive days of each week over a 3-week period. A rapid increase in collagen content was documented, with linear increases occurring from days 7 to 21. Livers were examined for histopathological changes on days 7, 14 and 21 following the beginning of exposure. Severe centrilobular congestion and haemorrhagic necrosis could be observed on day 7. Centrilobular necrosis and intense neutrophilic infiltration were observed on day 14. By day 21, collagen fiber deposition could be observed, together with severe centrilobular necrosis, with focal fatty changes, bile duct proliferation, bridging necrosis and fibrosis surrounding the central veins. A decrease in total protein and increase in DNA were also documented. DMN-induced liver injury in rats appears to be a potential animal model for early human cirrhosis and the rapid deposition of collagen, and may serve as a convenient procedure for screening antifibrotic agents.
The application of brief periods of heat stress prior to induction of various forms of tissue injury (ischemia-reperfusion, myocardial infarction, endothelial denudation) has been shown to result in preconditioning and attenuation of subsequent damage. Atherosclerosis represents a state of heightened response to injury at the level of the vessel wall, involving endothelial cells, smooth muscle cells, and macrophages. In the current study, we studied the effects of whole body hyperthermia (WBH) on diet-induced atherosclerosis in a murine model. Low-density lipoprotein receptor deficient mice were either exposed to a 30-min WBH (n = 10) or nontreated (n = 7). Animals were given a high-fat ("Paigen"-type) diet to speed the progression of atherosclerosis immediately following WBH for 6 weeks. Aortic and plaque heat shock protein (HSP) 70, suggested to mediate thermotolerance, was assessed by immunohistochemisry and Western blot at different time points following induction of WBH. Aortic sinus plaque formation was significantly accelerated in WBH-treated mice (275,800 +/- 19,540 microm(2) ) in comparison with their control litters (152,100 +/- 18,200 microm(2); P = 0.0004). Plaque composition was also influenced by WBH as lesions were more mature and had an increased proportion of lipid core/fibrous cap accompanied by increased numbers of apoptotic cells. Total cholesterol and triglyceride levels were not affected significantly by WBH. HSP70 protein expression in the aortas was increased 30 min and 6 and 12 h following WBH induction. Thus, induction of WBH, which affords protection in models of arterial injury, appears to have a proatherogenic role in murine atherosclerosis, despite its upregulatory influence on the expression of HSP70.
The aim of this study was to evaluate the efficacy of two experimental regimes of human intravenous immunoglobulins (IVIG) on the progression of experimental autoimmune myocarditis (EAM). EAM is induced by immunization against myosin and represents a T-cell-dependent disorder that progresses toward dilated cardiomyopathy similar to the human equivalent. No effective treatment is currently at hand for management of the disorder, as immunosuppressant drugs are associated with multiple side effects. Three groups of Lewis rats were induced to develop EAM by immunization with porcine myosin and sacrificed 21 days later. Group A received a 5-day regimen of IVIG (800 mg/kg) following induction of the disorder; Group B received a daily dose of IVIG (800 mg/kg) and group C was treated with PBS. IVIG given daily but not during the first 5 days significantly suppressed myocarditis score (0.81 +/- 0.26 and 1.14 +/- 0.42, respectively) in comparison with controls (mean score of 1.78 +/- 0.36). The effect was accompanied by a reduction in the cellular and humoral immune response of the respective animals toward myosin. IVIG was deposited within the extracellular matrix surrounding the damaged myocytes. TNF-alpha expression was reduced in both groups treated with IVIG, whereas iNOS expression paralleled the extent of myocardial inflammation regardless of treatment. IVIG at doses twice those applied for human disease are effective in ameliorating the progression of EAM. The effect may be mediated by suppression of the cellular and humoral response to myosin. IVIG may be found clinically feasible in humans as an adjuvant or single therapy for autoimmune myocarditis.
High-level microsatellite instability (MSI-H) is demonstrated in 10 to 15% of sporadic colorectal cancers and in most cancers presenting in the inherited condition hereditary nonpolyposis colorectal cancer (HNPCC). Distinction between these categories of MSI-H cancer is of clinical importance and the aim of this study was to assess clinical, pathological, and molecular features that might be discriminatory. One hundred and twelve MSI-H colorectal cancers from families fulfilling the Bethesda criteria were compared with 57 sporadic MSI-H colorectal cancers. HNPCC cancers presented at a lower age (P < 0.001) with no sporadic MSI-H cancer being diagnosed before the age of 57 years. MSI was less extensive in HNPCC cancers with 72% microsatellite markers showing band shifts compared with 87% in sporadic tumors (P < 0.001). Absent immunostaining for hMSH2 was only found in HNPCC tumors. Methylation of hMLH1 was observed in 87% of sporadic cancers but also in 55% of HNPCC tumors that showed loss of expression of hMLH1 (P = 0.02). HNPCC cancers were more frequently characterized by aberrant beta-catenin immunostaining as evidenced by nuclear positivity (P < 0.001). Aberrant p53 immunostaining was infrequent in both groups. There were no differences with respect to 5q loss of heterozygosity or codon 12 K-ras mutation, which were infrequent in both groups. Sporadic MSI-H cancers were more frequently heterogeneous (P < 0.001), poorly differentiated (P = 0.02), mucinous (P = 0.02), and proximally located (P = 0.04) than HNPCC tumors. In sporadic MSI-H cancers, contiguous adenomas were likely to be serrated whereas traditional adenomas were dominant in HNPCC. Lymphocytic infiltration was more pronounced in HNPCC but the results did not reach statistical significance. Overall, HNPCC cancers were more like common colorectal cancer in terms of morphology and expression of beta-catenin whereas sporadic MSI-H cancers displayed features consistent with a different morphogenesis. No individual feature was discriminatory for all HNPCC cancers. However, a model based on four features was able to classify 94.5% of tumors as sporadic or HNPCC. The finding of multiple differences between sporadic and familial MSI-H colorectal cancer with respect to both genotype and phenotype is consistent with tumorigenesis through parallel evolutionary pathways and emphasizes the importance of studying the two groups separately.
Diabetes mellitus is one of the major risk factors for atherosclerosis. In recent years several murine models have been developed in an attempt to reproduce the accelerated atherosclerosis by combining induced hyperglycemia with hyperlipidemia. In the present study we wished to examine the effect of spontaneous hyperglycemia and hyperlipidemia induced by high fat diet on atherosclerosis development and on markers of the immune system in diabetes prone NOD mice. We tested two high fat dietary regimens (with or without cholate supplementation) in female NOD mice that either developed or did not develop diabetes. Plasma fasting glucose, lipid profile, antibodies to oxidized-LDL and glycated-LDL were assessed. The spleens from both groups were evaluated for their proliferative response. The extent of atherosclerosis was assessed at the aortic sinus. It was found that the two high fat dietary regimens were insufficient to elicit atherosclerosis in the diabetic and non-diabetic NOD mice. The diabetic hyperlipidemic NOD mice displayed an increased cellular immune response to glycated-LDL in comparison with their non-diabetic littermates. The immune response towards copper oxidized LDL was similar in both groups despite an increased susceptibility of LDL extracted from diabetic hyperlipidemic mice to undergo copper induced oxidation. We conclude that the NOD mouse is highly resistant to atherosclerosis even in the presence of hyperglycemia-hyperlipidemia and increased susceptibility to copper induced LDL oxidation.
Inflammatory mechanisms appear to influence the progression of intimal thickening in experimental models of arterial injury. Intravenous immunoglobulin (IVIG) is a polyspecific preparation of human immunoglobulin (Ig)G employed for treatment of autoimmune disorders. In this study, we sought to investigate whether treatment with IVIG could influence intimal thickening in a model of murine arterial injury. Intimal thickening was induced by placement of a periadventitial cuff over the right femoral artery of male C57BL/6 mice. In the first experiment, IVIG or human serum albumin (HSA) (10 mg/mouse) were administered intraperitoneally for five consecutive days starting 1 day prior to cuff placement. In the second experiment, IVIG or HSA treatment were delivered similarly, but initiated 3 days following induction of arterial injury. Neointimal area and intimal/medial ratio were significantly reduced in mice treated with IVIG prior to cuff placement as compared with HSA treatment. No differences were noted with regard to neointimal area or intimal/medial ratio, between IVIG- and HSA-treated mice when the treatment was commenced 3 days following induction of injury. IVIG treatment reduced the proliferative capacity of splenocytes to the non-specific mitogen Con-A. Treatment with IVIG was associated with a significantly enhanced secretion of interleukin (IL)-10) by the respective splenocytes in comparison with HSA-treated mice. No effect of IVIG was evident on the secretion of IL-4 or IFN-gamma. Thus, IVIG has proven beneficial in ameliorating intimal thickening in a mouse model of arterial injury. The effect could be mediated by upregulation of T-cell secretion of the anti-inflammatory cytokine IL-10.
OBJECTIVES: This study was designed to determine the role of cellular and humoral immune responses to heat shock protein 65 (HSP65) in murine atherosclerosis. BACKGROUND: Inflammatory processes appear to influence the progression of atherosclerosis. Immunization with HSP65 was previously shown to induce arteriosclerosis in rabbits and to enhance fatty-streak formation in mice. However, it has not been demonstrated directly whether HSP65-reactive antibodies and lymphocytes are separately capable of influencing lesion formation. METHODS: Low density lipoprotein-receptor deficient (LDL-RD) mice were immunized with HSP65 or control bovine serum albumin (BSA). Lymph-node cells, splenocytes and immunoglobulin G (IgG) were obtained from the immunized mice and transferred separately to six groups of syngenic LDL-RD mice. RESULTS: Adoptive transfer of HSP65-reactive lymph node cells increased fatty-streak formation in comparison with mice treated with BSA-primed cells. Similarly, transfer of splenocytes reactive with HSP65 led to enhanced fatty-streak generation compared with mice injected with BSA-sensitized splenocytes. Repeated intraperitoneal administration of IgG from serum of HSP65-immunized mice (every 10 days) enhanced fatty-streak formation in mice in comparison with their anti-BSA-IgG injected littermates. CONCLUSIONS: Antibodies and lymphocytes reactive to HSP65 promote fatty-streak formation in mice, providing direct evidence for the proatherogenic properties of cellular and humoral immunity to HSP65.
Indirect data coming from animal studies and in vitro observations support the contention that the mere presence of antiphospholipid antibodies may be sufficient to increase atheroma development, regardless of other predisposing factors. It seems that humoral and cellular immune responses to beta 2-glycoprotein I can play an important role in mediating the increased propensity to atherosclerosis.
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