We survey the theory of local models of Shimura varieties. In particular, we discuss their defini... more We survey the theory of local models of Shimura varieties. In particular, we discuss their definition and illustrate it by examples. We give an overview of the results on their geometry and combinatorics obtained in the last 15 years. We also exhibit their connections to other classes of algebraic varieties such as nilpotent orbit closures, affine Schubert varieties, quiver Grassmannians and wonderful completions of symmetric spaces.
The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry, 2005
Authors assessed temporal changes in mental health-related drug utilization and costs in an older... more Authors assessed temporal changes in mental health-related drug utilization and costs in an older population. This was a population-based, cross-sectional time-series analysis of more than 1.4 million residents of Ontario, Canada, age 65 years or older. The study examined mental health-related drug utilization and costs, as derived from administrative databases from 1993 through 2002. They assessed use of antidepressants, antipsychotics, mood stabilizers, benzodiazepines, and acetylcholinesterase inhibitors (AChEIs), assessing trends over time. The prevalence of mental health-related drug use increased from 21.3% of the older population in the beginning of 1993 to 23.8% by the end of 2002. The proportion of benzodiazepine prescriptions was the highest of all such drugs, but declined from approximately 67% of prescriptions, in 1993, to 38%, in 2002. Significant temporal increases were observed for use of antidepressants (5.6%, in 1993, to 10.9%, in 2002), antipsychotics (1.9% in 1993...
Patients with end-stage renal failure suffer from severe plasma trace metal deficiency that is no... more Patients with end-stage renal failure suffer from severe plasma trace metal deficiency that is not corrected by dialysis. Trace metals, including Zn(2+), are critical for cell differentiation and replication. Zn(2+)also plays important role in cell apoptosis. Both processes are known to be impaired in uremia. The present study was undertaken to evaluate the effect of Zn(2+) supplementation on apoptosis of cultured peripheral blood mononuclear cells (PBMC) from patients on chronic hemodialysis versus those from healthy control subjects, concomitantly with assessment of mitogen-induced cell proliferation. The results showed that (1) basal total cell-associated Zn(2+) was elevated in uremic PBMC, compared to normal controls (23.9 +/- 5.64 v 10.5 +/- 2.64 micromol/L/mg protein). The gap persisted following incubation in Zn(2+)-enriched medium (63.3 +/- 26.12 v 81.6 +/- 13.4 micromol/L/mg protein, P <.005). (2) Basal proliferative response to phytohemagglutinin (PHA) was significantly...
Acute inflammatory myopathy with severe subcutaneous edema is extremely rare and has been reporte... more Acute inflammatory myopathy with severe subcutaneous edema is extremely rare and has been reported in only a handful of cases. We describe two similar patients presenting with this disorder and generalized rash. Unlike the five previously reported cases, the clinical and histologic features of our two patients are more suggestive of dermatomyositis than polymyositis. Nevertheless, scrutinizing all seven reported patients, a number of specific characteristics could be defined. All patients were adult males. Dysphagia was present in four. In six patients, acute inflammatory myopathy was idiopathic while malignancy was present in one. Two patients died despite intensive therapy, three improved on corticosteroid treatment, and two recovered spontaneously. In all patients, limb involvement with marked subcutaneous edema was present, clinically mimicking deep vein thrombosis in both our patients. The presence of severe subcutaneous edema may be a hallmark of a distinctive variant of acute inflammatory myopathy. More cases are needed to discern subtypes of this general entity and to establish guidelines for treatment and prognosis.
Patients with end-stage renal failure suffer from severe plasma trace metal deficiency that is no... more Patients with end-stage renal failure suffer from severe plasma trace metal deficiency that is not corrected by dialysis. Trace metals, including Zn2+, are critical for cell differentiation and replication. Zn2+also plays important role in cell apoptosis. Both processes are known to be impaired in uremia. The present study was undertaken to evaluate the effect of Zn2+ supplementation on apoptosis of cultured peripheral blood mononuclear cells (PBMC) from patients on chronic hemodialysis versus those from healthy control subjects, concomitantly with assessment of mitogen-induced cell proliferation. The results showed that (1) basal total cell-associated Zn2+ was elevated in uremic PBMC, compared to normal controls (23.9 [plusmn] 5.64 v 10.5 [plusmn] 2.64 [mu ]mol/L/mg protein). The gap persisted following incubation in Zn2+-enriched medium (63.3 [plusmn] 26.12 v 81.6 [plusmn] 13.4 [mu ]mol/L/mg protein, P [lt ] .005). (2) Basal proliferative response to phytohemagglutinin (PHA) was significantly decreased in uremic PBMC compared to normal controls (12,000 [plusmn] 1,560 cpm v 16,600 [plusmn] 1,460 cpm, P [lt ] .01). Incubation of uremic PBMC in Zn2+-enriched medium improved their proliferative response to PHA, yielding counts per minute significantly higher compared to their normal counterparts (37,000 [plusmn] 7,500 cpm v 22,000 [plusmn] 3,000 cpm, P [lt ] .001). (3) Basal apoptosis rate in uremic PBMC was significantly elevated compared to normal control cells (7.6% v 2.6%, P [lt ] .05). Following incubation in Zn2+-enriched medium, apoptosis was increased both in normal and uremic PBMC. Percent apoptosis of uremic PBMC remained significantly elevated compared to control cells (11.7% v 5.7%). We conclude that uremic PBMC are more responsive to exogenous Zn2+ in culture than their normal counterparts. This, among other abnormalities, might reflect an abnormal regulation of Zn2+ transport by uremic mononuclear cell menbranes. The resultant increase in total cell-associated Zn2+ content improves poor proliferative responsiveness of uremic PBMC. On the other hand, increased total cell-associated Zn2+ stimulates enhanced apoptosis in uremic PBMC, which, probably by eliminating defective cells, contributes to the functional capability of the population as a whole. The net effect of the 2 processes is still augmentation of cell proliferation.
The cerebellum has traditionally been seen primarily to coordinate voluntary movement, but eviden... more The cerebellum has traditionally been seen primarily to coordinate voluntary movement, but evidence is accumulating that it may play a role in cognition and behavior as well. This is a selective review of studies assessing potential cognitive deficits and personality changes associated with cerebellar disease. Preliminary studies of the role of the cerebellum in schizophrenia, dementia, and other psychiatric disorders are also discussed. Efforts to understand the neurological substrates of behavior should consider the role of the cerebellum.
How senile plaques and neurofibrillary tangles are linked represents a major gap in our understan... more How senile plaques and neurofibrillary tangles are linked represents a major gap in our understanding of the pathophysiology of Alzheimer&#39;s disease (AD). We have previously shown that the addition of fibrillar beta-amyloid (Abeta) to mature hippocampal neurons results in progressive neuritic degeneration accompanied by the enhanced phosphorylation of adult tau isoforms. In the present study, we sought to obtain more direct evidence of the signal transduction pathway(s) activated by fibrillar Abeta leading to tau phosphorylation and the generation of dystrophic neurites. Our results indicated that fibrillar Abeta induced the progressive and sustained activation of the mitogen-activated protein kinase (MAPK) in mature hippocampal neurons. On the other hand, the specific inhibition of the MAPK signal transduction pathway by means of PD98059, a MAPK kinase (MEK) specific inhibitor, prevented the phosphorylation of tau (at Ser199/Ser202) induced by fibrillar Abeta. In addition, the inhibition of MAPK activation partially prevented neurite degeneration. Taken collectively, our results suggest that the sustained activation of the MAPK signal transduction pathway induced by fibrillar Abeta may lead to the abnormal phosphorylation of tau and the neuritic degeneration observed in AD.
Inflammatory bowel disease (IBD) comprises primarily the two disorders - ulcerative colitis and C... more Inflammatory bowel disease (IBD) comprises primarily the two disorders - ulcerative colitis and Crohn&#39;s disease - that involve deregulated T cell responses. The ever-increasing incidence rate of Crohn&#39;s disease and ulcerative colitis during recent decades, combined with the limited efficacy and potential adverse effects of current treatments, explain the real need for seeking more specific and selective methods for treating these diseases. To investigate the ability of interleukin 2 (IL2)-caspase 3 chimeric protein, designed to target activated T lymphocytes that express the high-affinity IL2 receptor, to ameliorate the clinical symptoms of acute murine experimental colitis, using a mouse model of dextran sodium sulfate (DSS)-induced colitis. Mice with DSS-induced colitis were treated with IL2-caspase 3 for 7 days and disease severity was assessed in parallel to control, non-treated mice, receiving only daily injections of phosphate-buffered saline. IL2-caspase 3 was tested both for its ability to prevent the development of colitis, and for its therapeutic potential to cure on-going, active acute disease. In addition, colon tissue samples were used for myeloperoxidase assays and RNA isolation followed by polymerase chain reaction to determine mRNA expression levels of specific genes. Treatment with IL2-caspase 3 dose-dependently ameliorated the disease activity index (DAI) of mice colitis. We achieved up to 78% improvement in DAI with intravenous injections of 15 microg/mouse/day. Furthermore, IL2-caspase 3 decreased neutrophil and macrophage infiltration to the inflamed tissue by up to 57%. IL2-caspase 3 was proven as a therapeutic reagent in another model, where treatment begins only after disease onset. Here we demonstrated a 70% decrease in DAI when compared to non-treated sick mice. A reduction in mRNA expression levels of both IL1 beta and tumour necrosis factor alpha was found in lysates of total colon tissue of treated mice, as compared to sick, untreated mice. We also found that expression levels of Bcl2 were significantly decreased after treatment, while Bax was upregulated in comparison to non-treated mice. Moreover, the Bcl2/Bax ratio, which is elevated in both experimental colitis and in human Crohn&#39;s disease, decreased dramatically after treatment. IL2-caspase 3 chimeric protein may provide a novel approach to the therapy of human IBD, and a possible suggested treatment for other pathological conditions that involve uncontrolled expansion of activated T cells.
We survey the theory of local models of Shimura varieties. In particular, we discuss their defini... more We survey the theory of local models of Shimura varieties. In particular, we discuss their definition and illustrate it by examples. We give an overview of the results on their geometry and combinatorics obtained in the last 15 years. We also exhibit their connections to other classes of algebraic varieties such as nilpotent orbit closures, affine Schubert varieties, quiver Grassmannians and wonderful completions of symmetric spaces.
The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry, 2005
Authors assessed temporal changes in mental health-related drug utilization and costs in an older... more Authors assessed temporal changes in mental health-related drug utilization and costs in an older population. This was a population-based, cross-sectional time-series analysis of more than 1.4 million residents of Ontario, Canada, age 65 years or older. The study examined mental health-related drug utilization and costs, as derived from administrative databases from 1993 through 2002. They assessed use of antidepressants, antipsychotics, mood stabilizers, benzodiazepines, and acetylcholinesterase inhibitors (AChEIs), assessing trends over time. The prevalence of mental health-related drug use increased from 21.3% of the older population in the beginning of 1993 to 23.8% by the end of 2002. The proportion of benzodiazepine prescriptions was the highest of all such drugs, but declined from approximately 67% of prescriptions, in 1993, to 38%, in 2002. Significant temporal increases were observed for use of antidepressants (5.6%, in 1993, to 10.9%, in 2002), antipsychotics (1.9% in 1993...
Patients with end-stage renal failure suffer from severe plasma trace metal deficiency that is no... more Patients with end-stage renal failure suffer from severe plasma trace metal deficiency that is not corrected by dialysis. Trace metals, including Zn(2+), are critical for cell differentiation and replication. Zn(2+)also plays important role in cell apoptosis. Both processes are known to be impaired in uremia. The present study was undertaken to evaluate the effect of Zn(2+) supplementation on apoptosis of cultured peripheral blood mononuclear cells (PBMC) from patients on chronic hemodialysis versus those from healthy control subjects, concomitantly with assessment of mitogen-induced cell proliferation. The results showed that (1) basal total cell-associated Zn(2+) was elevated in uremic PBMC, compared to normal controls (23.9 +/- 5.64 v 10.5 +/- 2.64 micromol/L/mg protein). The gap persisted following incubation in Zn(2+)-enriched medium (63.3 +/- 26.12 v 81.6 +/- 13.4 micromol/L/mg protein, P <.005). (2) Basal proliferative response to phytohemagglutinin (PHA) was significantly...
Acute inflammatory myopathy with severe subcutaneous edema is extremely rare and has been reporte... more Acute inflammatory myopathy with severe subcutaneous edema is extremely rare and has been reported in only a handful of cases. We describe two similar patients presenting with this disorder and generalized rash. Unlike the five previously reported cases, the clinical and histologic features of our two patients are more suggestive of dermatomyositis than polymyositis. Nevertheless, scrutinizing all seven reported patients, a number of specific characteristics could be defined. All patients were adult males. Dysphagia was present in four. In six patients, acute inflammatory myopathy was idiopathic while malignancy was present in one. Two patients died despite intensive therapy, three improved on corticosteroid treatment, and two recovered spontaneously. In all patients, limb involvement with marked subcutaneous edema was present, clinically mimicking deep vein thrombosis in both our patients. The presence of severe subcutaneous edema may be a hallmark of a distinctive variant of acute inflammatory myopathy. More cases are needed to discern subtypes of this general entity and to establish guidelines for treatment and prognosis.
Patients with end-stage renal failure suffer from severe plasma trace metal deficiency that is no... more Patients with end-stage renal failure suffer from severe plasma trace metal deficiency that is not corrected by dialysis. Trace metals, including Zn2+, are critical for cell differentiation and replication. Zn2+also plays important role in cell apoptosis. Both processes are known to be impaired in uremia. The present study was undertaken to evaluate the effect of Zn2+ supplementation on apoptosis of cultured peripheral blood mononuclear cells (PBMC) from patients on chronic hemodialysis versus those from healthy control subjects, concomitantly with assessment of mitogen-induced cell proliferation. The results showed that (1) basal total cell-associated Zn2+ was elevated in uremic PBMC, compared to normal controls (23.9 [plusmn] 5.64 v 10.5 [plusmn] 2.64 [mu ]mol/L/mg protein). The gap persisted following incubation in Zn2+-enriched medium (63.3 [plusmn] 26.12 v 81.6 [plusmn] 13.4 [mu ]mol/L/mg protein, P [lt ] .005). (2) Basal proliferative response to phytohemagglutinin (PHA) was significantly decreased in uremic PBMC compared to normal controls (12,000 [plusmn] 1,560 cpm v 16,600 [plusmn] 1,460 cpm, P [lt ] .01). Incubation of uremic PBMC in Zn2+-enriched medium improved their proliferative response to PHA, yielding counts per minute significantly higher compared to their normal counterparts (37,000 [plusmn] 7,500 cpm v 22,000 [plusmn] 3,000 cpm, P [lt ] .001). (3) Basal apoptosis rate in uremic PBMC was significantly elevated compared to normal control cells (7.6% v 2.6%, P [lt ] .05). Following incubation in Zn2+-enriched medium, apoptosis was increased both in normal and uremic PBMC. Percent apoptosis of uremic PBMC remained significantly elevated compared to control cells (11.7% v 5.7%). We conclude that uremic PBMC are more responsive to exogenous Zn2+ in culture than their normal counterparts. This, among other abnormalities, might reflect an abnormal regulation of Zn2+ transport by uremic mononuclear cell menbranes. The resultant increase in total cell-associated Zn2+ content improves poor proliferative responsiveness of uremic PBMC. On the other hand, increased total cell-associated Zn2+ stimulates enhanced apoptosis in uremic PBMC, which, probably by eliminating defective cells, contributes to the functional capability of the population as a whole. The net effect of the 2 processes is still augmentation of cell proliferation.
The cerebellum has traditionally been seen primarily to coordinate voluntary movement, but eviden... more The cerebellum has traditionally been seen primarily to coordinate voluntary movement, but evidence is accumulating that it may play a role in cognition and behavior as well. This is a selective review of studies assessing potential cognitive deficits and personality changes associated with cerebellar disease. Preliminary studies of the role of the cerebellum in schizophrenia, dementia, and other psychiatric disorders are also discussed. Efforts to understand the neurological substrates of behavior should consider the role of the cerebellum.
How senile plaques and neurofibrillary tangles are linked represents a major gap in our understan... more How senile plaques and neurofibrillary tangles are linked represents a major gap in our understanding of the pathophysiology of Alzheimer&#39;s disease (AD). We have previously shown that the addition of fibrillar beta-amyloid (Abeta) to mature hippocampal neurons results in progressive neuritic degeneration accompanied by the enhanced phosphorylation of adult tau isoforms. In the present study, we sought to obtain more direct evidence of the signal transduction pathway(s) activated by fibrillar Abeta leading to tau phosphorylation and the generation of dystrophic neurites. Our results indicated that fibrillar Abeta induced the progressive and sustained activation of the mitogen-activated protein kinase (MAPK) in mature hippocampal neurons. On the other hand, the specific inhibition of the MAPK signal transduction pathway by means of PD98059, a MAPK kinase (MEK) specific inhibitor, prevented the phosphorylation of tau (at Ser199/Ser202) induced by fibrillar Abeta. In addition, the inhibition of MAPK activation partially prevented neurite degeneration. Taken collectively, our results suggest that the sustained activation of the MAPK signal transduction pathway induced by fibrillar Abeta may lead to the abnormal phosphorylation of tau and the neuritic degeneration observed in AD.
Inflammatory bowel disease (IBD) comprises primarily the two disorders - ulcerative colitis and C... more Inflammatory bowel disease (IBD) comprises primarily the two disorders - ulcerative colitis and Crohn&#39;s disease - that involve deregulated T cell responses. The ever-increasing incidence rate of Crohn&#39;s disease and ulcerative colitis during recent decades, combined with the limited efficacy and potential adverse effects of current treatments, explain the real need for seeking more specific and selective methods for treating these diseases. To investigate the ability of interleukin 2 (IL2)-caspase 3 chimeric protein, designed to target activated T lymphocytes that express the high-affinity IL2 receptor, to ameliorate the clinical symptoms of acute murine experimental colitis, using a mouse model of dextran sodium sulfate (DSS)-induced colitis. Mice with DSS-induced colitis were treated with IL2-caspase 3 for 7 days and disease severity was assessed in parallel to control, non-treated mice, receiving only daily injections of phosphate-buffered saline. IL2-caspase 3 was tested both for its ability to prevent the development of colitis, and for its therapeutic potential to cure on-going, active acute disease. In addition, colon tissue samples were used for myeloperoxidase assays and RNA isolation followed by polymerase chain reaction to determine mRNA expression levels of specific genes. Treatment with IL2-caspase 3 dose-dependently ameliorated the disease activity index (DAI) of mice colitis. We achieved up to 78% improvement in DAI with intravenous injections of 15 microg/mouse/day. Furthermore, IL2-caspase 3 decreased neutrophil and macrophage infiltration to the inflamed tissue by up to 57%. IL2-caspase 3 was proven as a therapeutic reagent in another model, where treatment begins only after disease onset. Here we demonstrated a 70% decrease in DAI when compared to non-treated sick mice. A reduction in mRNA expression levels of both IL1 beta and tumour necrosis factor alpha was found in lysates of total colon tissue of treated mice, as compared to sick, untreated mice. We also found that expression levels of Bcl2 were significantly decreased after treatment, while Bax was upregulated in comparison to non-treated mice. Moreover, the Bcl2/Bax ratio, which is elevated in both experimental colitis and in human Crohn&#39;s disease, decreased dramatically after treatment. IL2-caspase 3 chimeric protein may provide a novel approach to the therapy of human IBD, and a possible suggested treatment for other pathological conditions that involve uncontrolled expansion of activated T cells.
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