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PubMed1999

Knockout Corner.

Serotonin (5-hydroxytryptamine, 5-HT) is a neurotransmitter involved in a number of physiological functions including sleep, appetite, pain perception, and sexual activity. Several pathological states such as migraine, depression, and anxiety have been linked to the serotonergic system, and serotonergic drugs have been used to treat these disorders. To date, there are 14 known serotonin receptor subtypes through which serotonin exerts its multiple actions. The classic pharmacological approach to study how these individual receptor subtypes contribute to various behaviours has been to use selective drugs that either block or activate certain receptor subtypes, and then study the effects of these compounds on physiology and behaviour. A complementary genetic approach is the technique of gene targeting. Using this technology, we and others have begun to examine the contribution of several serotonin receptor subtypes to complex behaviours through the generation of knockout mice that lack the genes encoding these receptors. In this review, we will describe what we have learned about the serotonergic system and the function of the 5-HT(1B) receptor by the analysis of 5-HT(1B) receptor knockout mice. Furthermore, we will discuss the implications of these findings and our plans for future studies.

Journal Article↗

PubMed2005

Regional and subtype selective changes of neurotransmitter receptor density in a rat transgenic for the Huntington's disease mutation.

Huntington's disease (HD) is an autosomal dominantly inherited progressive neurodegenerative disorder caused by a CAG/polyglutamine repeat expansion in the gene encoding the huntingtin protein. We have recently generated a rat model transgenic for HD, which displays a slowly progressive phenotype resembling the human adult-onset type of disease. In this study we systematically assessed the distribution and density of 17 transmitter receptors in the brains of 2-year-old rats using quantitative multi-tracer autoradiography and high-resolution positron emission tomography. Heterozygous animals expressed increased densities of M(2) acetylcholine (increase of 148 +/- 16% of controls; p > 0.001; n = 7), nicotine (increase of 149 +/- 16% of controls; p > 0.01; n = 6), and alpha(2) noradrenergic receptors (increase of 141 +/- 15% of controls; p > 0.001; n = 6), respectively. Densities of these receptors were decreased in homozygous animals. Decreases of receptor density in both hetero- and homozygous animals were found for M1 acetylcholine, 5-HT 2A serotonin, A 2A adenosine, D1 and D2 dopamine, and GABA(A) receptors, respectively. Other investigated receptor systems showed small changes or were not affected. The present data suggest that the moderate increase of CAG/polyglutamine repeat expansions in the present rat model of Huntington's disease is characterized by subtype-selective and region-specific changes of neuroreceptor densities. In particular, there is evidence for a contribution of predominantly presynaptically localized cholinergic and noradrenergic receptors in the response to Huntington's disease pathology.

Animals↗

PubMed2005

[Vascular endothelial progenitor cells and cytokines related to hematopoietic regulation--review].

Endothelial progenitor cell (EPC) is a subtype of progenitor cells that can circulate, proliferate and have the ability to differentiate into mature endothelial cells. Exploration of EPC have significance to understand the vascular forming process of adults physiologically and pathologically. Cytokines, especially haematopoiesis-related cytokines, cellular stimulating factors in the body also influence EPC. In this review, the advances of research on the relationship between EPC and some cytokines related with haematopoiesis (G-CSF, EPO, HAPO and IL-18) and the potential signal transduction pathway were summarised.

Cytokines↗

PubMedDate not supplied

Clinical data and therapeutic approach in elderly patients with Hodgkin's disease.

The present study was undertaken to investigate the clinico pathologic features of Hodgkin's disease in a series of 114 elderly patients (age greater than 60 yrs), with particular reference to prognosis and treatment. Mixed cellularity (63.2%) was the most frequent histologic subtype. Clinical presentation was characterized by superficial lymphadenopathy (92%) and the presence of general symptoms (40.4%); mediastinal involvement was observed in 16.6% of cases; 17.5% of patients had a primitive infradiaphragmatic presentation. Thirty-eight patients were treated with radiotherapy alone (33.4%), 69 with chemotherapy alone (60.5%), while 7 received combined treatment. Complete remission was obtained in 85 patients (74.6%), 25 of whom relapsed. Elderly patients had an overall 5-year survival rate of 61.8% (considering only disease progression as a cause of death). Proportional-hazard multi variate statistics showed that survival was strongly influenced by the achievement of complete remission (P less than 0.001) and stage (P = 0.011). The achievement of complete remission was also significantly linked to the presence of constitutional symptoms, advanced stage and age greater than 70 yrs, as demonstrated by discriminant statistical analysis. The actuarial incidence of second cancer (28.7% at 15 yrs) was slightly higher than that previously reported in younger patients. Overall, our data indicate that the treatment of elderly patients with Hodgkin's disease should be aimed at achieving a cure, using the same therapeutic modalities commonly employed in younger subjects.

Aged↗

PubMed1982

[Hodgkin's lymphoma in the biopsy material. A retrospective analysis (author's transl)].

112 cases of Hodgkin's disease diagnosed between 1967 and 1976 at the Institute of Pathology and the Department of ENT, Medical Academy of Erfurt, GDR, were reclassified according to the Rye classification. Age and sex distribution as well as frequency and survival are presented. The most frequency subtype is "mixed cellularity" (43.8%) followed by "nodular sclerosis" (40.2%). The age distribution of all cases shows 3 peaks with only small differences between the subtypes. The cases are distributed among 71 males and 41 females. The most frequent subtype in males is "mixed cellularity" (50.7%) whereas in females it is "nodular sclerosis" (61.0%) The survival of cases with "lymphocyte predominance" and "nodular sclerosis" is significantly better than that of case with "mixed cellularity" and "lymphocyte depletion".

Adolescent↗

PubMed1994

[Pathological features of neuroleukemia. Changes and lessons].

Between 1971 and 1992 neuropathological examinations were performed in 316 patients having died of leukaemia. Among them 73 had acute lymphoid leukaemia, 134 acute myeloid leukaemia, 49 chronic lymphoid leukaemia and 60 chronic myeloid leukaemia. Meningeal leukaemia, which had been a frequent pathological complication at the beginning of the examination period, later had become rarer. The study made it possible to define further neurologic complications, the characteristic neuropathological changes of the different types and some subtypes of leukaemia and to draw clinical consequences. The incidence of cerebral "leukaemic nodules" was twelve times higher in the myeloid than in the lymphoid leukaemias, this may be the explanation for the fact that central nervous system haemorrhage was more frequent in the myeloid types. Subdural haematoma can primarily be expected in acute myeloid leukaemia. The neuropathologic features of chronic lymphoid leukaemia were particular, as no "leukaemic nodules" developed, and meningeal leukaemia was a rare event; at the same time, it was related with the highest incidence of infiltration of the dura mater and the sciatic nerve.

Adolescent↗

PubMed1996

An unusual presentation of telangiectatic osteosarcoma.

Telangiectatic osteosarcoma (TOS) is a rare subtype of osteosarcoma that accounts for approximately 2% of all osteosarcomas. Presented is a case of a sacral mass that was originally thought to be a chordoma and was treated surgically but on pathologic examination was diagnosed as a TOS. A review of the literature on other sacral lesions is provided. The intention for presenting this case is twofold: to make physicians aware of the differential diagnoses of sacral lesions and to report an unusual presentation of this rare tumor.

Adult↗

PubMed1996

Angiotensin receptors.

INTRODUCTION: The octapeptide angiotensin II, the potent effector molecule of the renin-angiotensin system, has been implicated in the pathology of hypertension, in cardiovascular diseases like cardiac left ventricular hypertrophy and in structural alterations of the heart such as post-infarct remodelling. ANGIOTENSIN RECEPTORS: The development of highly selective angiotensin II receptor ligands allowed the identification of angiotensin II receptor subtypes, designated AT1, AT2, AT3 and AT4. Most of the known effects of angiotensin II can be attributed to the AT1 receptor (e.g. vasoconstriction, aldosterone and vasopressin release and proliferative effects on vascular smooth muscle and other cells). The AT1 receptor is coupled to G-proteins and engages classical intracellular second messenger systems, for example activation of phospholipase C or inhibition of adenylate cyclase. In contrast, the function and the signal transduction pathways of the AT2 receptor, which exhibits only a 32-34% homology to the AT1 receptor, are so far not fully understood. Coupling of the AT2 receptor to phosphatases and inhibitory actions on AT1 receptor- and growth factor-mediated proliferation in endothelial and other cells as well as induction of neuronal outgrowth in PC12w cells have been demonstrated. Due to its wide distribution in fetal tissues including the central nervous system and its transient reappearance in the adult organism under pathological conditions (for instance after myocardial infarction) the AT2 receptor has been associated with cell differentiation and regeneration. RECEPTOR ANTAGONISTS: The application of orally active AT1 receptor antagonists as antihypertensive drugs has, compared to angiotensin converting enzyme inhibitors, the potential advantage of a more specific renin-angiotensin system inhibition. It is conceivable that the AT2 receptor, left unopposed by AT1 receptor antagonists, contributes to some of the actions of these drugs.

Animals↗

PubMed1992

Dementia in cerebral amyloid angiopathy: a clinicopathological study.

Dementia is in addition to cerebral haemorrhage major symptom of cerebral amyloid angiopathy (CAa). In order to explore the pathological basis for dementia in CAa-related conditions, we made a clinicopathological analysis of CAa, with special attention to dementia. Among 150 patients (mean age 78.6 years) with autopsy-proven intracranial haemorrhage in Tokyo Metropolitan Geriatric Medical Center, CAa with cerebral haemorrhage accounted for 8.0% (12 cases), associated with hypertension and metastatic brain tumour. Among 38 patients with lobar haemorrhage, CAa represented the second most common cause (21.1%) of intracranial haemorrhage after hypertension. A total of 20 patients with CAa (mean age 82.5 years) were studies clinically and pathologically. Hypertension was present in 50%. Thirteen had a history of stroke and others had either ill-defined or no strokes. The average number of strokes 2.9. Fifteen patients (75%) had dementia. Based on the clinicopathological grounds for dementia, CAa-related conditions could be divided into three subtypes: "haemorrhagic", "dementia-haemorrhagic" and "dementia" type. Haemorrhagic type (30%, 6 cases) showed multiple recurrent lobar haemorrhages caused by CAa. Hypertension was present in only 1 patient. The incidence of senile plaques and neurofibrillary tangles was generally correlated with age. Only 1 patient had dementia. The dementia-haemorrhagic type (40%, 8 patients) had recurrent strokes with cerebral haemorrhage after preceding dementia. There were two different neuropathological subsets: CAa with atypical senile dementia of Alzheimer type (SDAT) and CAa with diffuse leucoencephalopathy. Patients with CAa with atypical SDAT had multiple cerebral haemorrhages caused by CAa combined with atypical Alzheimer-type pathology. Patients with CAa with diffuse leucoencephalopathy had cerebral haemorrhages in combination with diffuse white matter damage like Binswanger's subcortical vascular encephalopathy (BSVE). The incidence of senile changes correlated with age. Patients with the dementia type (30%, 6 patients) showed progressive dementia with or without haemorrhage. All had hypertension. They had a combined condition of Alzheimer-type pathology with conspicuous CAa with BSVE. Dementia in CAa-related conditions may be responsible for multiple factors including not Alzheimer-type degeneration, but also diffuse leucoencephalopathy like Binswanger's disease. We also found an asymptomatic type, an ischaemic type, a vasculitis type and an hereditary type in this condition.

Aged↗

PubMed1991

5-Hydroxytryptamine and the pathophysiology of migraine.

5-Hydroxytryptamine (5-HT; serotonin) has long been implicated in the aetiology of migraine but the evidence remains circumstantial and certainly not definitive. Numerous papers have reviewed the background which is briefly outlined here. Although the continued belief in the primary involvement of 5-HT in the genesis of a migraine attack has recently been questioned, many antimigraine drugs undeniably interact potently with 5-HT receptors. It can be argued, however, that their modest clinical benefit results from their pharmacological effects, be they mediated through 5-HT receptors or otherwise, independently of any pathophysiological involvement of endogenous 5-HT. Nevertheless, there seems convincing evidence that central release of 5-HT by various drug mechanisms causes migraine-like headache in migraineurs. It remains to be seen whether these drugs mimic the pathological event initiating the spontaneous migraine attack. Regardless of these considerations, the focus of research on 5-HT and migraine has proved to be enormously profitable over several decades, culminating recently in the identification of a novel, potentially important, antimigraine drug for the treatment of the acute attack. This drug, sumatriptan, is a selective cranial vasoconstrictor which mediates this effect by specifically activating a particular 5-HT1 receptor subtype. Undoubtedly a precise understanding of its clinical mechanism of action, which is currently being studied by a number of groups, will lead to a better understanding of the pathogenesis of migraine. Perhaps this in turn will help in finally determining whether migraine is a vascular disease and whether or not a disturbance of 5-HT is just epiphenomenal or is truly the primary initiating pathological event.

Cerebrovascular Disorders↗

PubMed2006

Transitional cell carcinoma of the ovary.

OBJECTIVE: Transitional cell carcinoma (TCC) of the ovary is a rare, recently recognized, subtype of ovarian surface epithelial cancer. We present a case of TCC of the ovary, managed by staging operation and followed by postoperative chemotherapy with carboplatin and cyclophosphamide. CASE REPORT: A 67-year-old postmenopausal woman presented with a 2-year history of progressive enlargement of an abdominal mass. Pelvic sonography and abdominal computed tomography showed a pelvic mass measuring 210 x 165 x 203 mm. The serum CA-125 titer was also elevated (65.01 U/mL). A staging operation with total abdominal hysterectomy, bilateral salpingo-oophorectomy, infracolic omentectomy and pelvic lymph node dissection was performed. After surgery, the pathologic report of the left ovarian tumor was TCC, grade 2-3, stage IA. The patient then underwent four cycles of postoperative chemotherapy with carboplatin and cyclophosphamide. CA-125 levels declined to within the normal range after the first cycle of chemotherapy. CONCLUSION: TCC of the ovary is a rare subtype of epithelial ovarian cancer. It differs from malignant Brenner tumor by the absence of a benign or borderline Brenner component. Surgical resection is the primary therapeutic approach, and patient outcomes after chemotherapy are better than for other types of common epithelial ovarian cancers.

Aged↗

PubMed2000

Levodopa-induced dyskinesia: a pathological form of striatal synaptic plasticity?

The pathogenesis of the alterations in motor response that complicate levodopa therapy of Parkinson's disease remains obscure. Several experimental and clinical observations strongly suggest that changes in striatal activity may be crucial for this physiopathological condition. Accordingly, it has been postulated that dyskinesia might be due to abnormal activity of the corticostriatal pathway. Here, we review the physiological and pharmacological mechanisms underlying glutamatergic regulation of striatal neurons by the corticostriatal projection. In particular, we discuss the role of both (RS)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) glutamate receptors in the control of the short- and long-term efficacy of corticostriatal transmission. Indeed, repetitive cortical activation can generate either long-term depression or long-term potentiation (LTP) at corticostriatal synapses depending on the subtype of glutamate receptor activated during the induction phase of these forms of synaptic plasticity. Dopamine plays an important function in the regulation of both forms of synaptic plasticity. Dopamine denervation abolishes the physiological corticostriatal plasticity by producing biochemical and morphological changes within the striatum. We have recently observed a 'pathological' form of LTP at the corticostriatal synapse during energy deprivation. We speculate that this 'pathological' LTP, depending on the activation of NMDA glutamate receptors located on spiny striatal neurons, might play a role in the generation of levodopa-induced dyskinesia.

Dopamine Agents↗

PubMed2003

Contribution of angiotensin-(1-7) to cardiovascular physiology and pathology.

Increased understanding of the contribution of angiotensin peptides to the physiologic control of arterial pressure and cardiovascular regulation has been made possible with the introduction of agents that either inhibit the activity of angiotensins forming enzymes or block the action of the peptides at their specific receptor subtypes. This review highlights some of the lessons that have been learned from the study of the actions of angiotensin-(1-7) and its inter-relationship with other vasodilator mechanisms that modulate the control systems that determine blood pressure and tissue perfusion. The studies suggest that the renin-angiotensin system acts as a humoral mechanism for blood pressure control through the generation of several distinct forms of angiotensin peptides that may bind to diverse receptor subtypes.

Angiotensin I↗

PubMedDate not supplied

Involvement of the bone marrow by non-Hodgkin's lymphomas: incidence, histology and pathologic correlations.

The Lukes and Collins system of classification was applied to 151 cases of non-Hodgkin's lymphoma who had bone marrow biopsies taken immediately after histologic diagnosis. Incidence and histologic pattern of bone marrow involvement at the time of initial diagnosis were determined for each subtype of lymphoma. Thirty-three patients (21.8%) had bone marrow involvement. The frequency of bone marrow involvement was high for undefined and convoluted lymphocyte lymphomas (66.6%) and low to intermediate for follicular centre cell (20.3%) and small lymphocyte lymphomas (20.0%). Within the FCC lymphomas the non-cleaved cell type had a higher incidence of marrow involvement than the cleaved cell type (41.6% vs 8.9%). The follicular and diffuse histologic patterns in the diagnostic node did influence the incidence of marrow invasion in the non-cleaved cell type (75% vs 25%). A low incidence of marrow involvement was observed for the immunoblastic lymphomas (14.2%); evidence of marrow infiltration was never observed in patients with true histiocytic lymphomas.

Adolescent↗

PubMed1988

[Pathological classification of malignant lymphoma].

The classification of malignant lymphoma is an important factor in treatment. Hodgkin's disease (HD) and non-Hodgkin's lymphoma (NHL) should be clearly differentiated from each other, since their clinical behavior and response to treatment are quite different. Although four histological subtypes of HD has been recognized, the subclassification is not so important clinically. Many classifications of NHL have been devised, but most of them are based on morphological features only and do not incorporate recent advances in understanding of origin, function and differentiation of lymphoma cells. Further improvement is necessary to establish a reproducible, histogenetically accurate and clinically meaningful classification.

B-Lymphocytes↗

PubMed1997

von Willebrand factor and factor VIII: C in acute cerebrovascular disease. Relationship to stroke subtype and mortality.

BACKGROUND: Elevated von Willebrand factor (vWF) is a risk factor in the development of acute myocardial infarction. The importance of vWF and factor VII:C in the pathogenesis of cerebrovascular disease (CVD) is poorly defined. METHODS AND RESULTS: We studied 208 cases of stroke whose pathological type was defined by cranial computed tomography. Cerebral infarcts were grouped according to the Oxfordshire Community Stroke Project (OCSP) clinical classification. The results in patients were compared with 184 healthy reference subjects. In patients, vWF and FVIII:C levels were determined initially and after three months. Patients were followed prospectively for six months or until death. Levels of vWF and FVIII:C were elevated initially (1.86 IU/ml and 2.20 U/ml respectively) and after 3 months (1.51 IU/ml and 1.90 U/ml) compared with a healthy reference population (1.26 IU/ml and 1.49 U/ml p = 0.0001). In the initial sample, vWF was associated with age (p = 0.01). FVIII:C was related to age (p = 0.04), gender (p = 0.007 higher for females) and a history of diabetes mellitus (2.56 U/ml vs. 2.16 U/ml in non-diabetics, p = 0.008). Initial vWF levels were higher in subjects with large vessel disease (TACI/PACI) group compared with the small vessel disease (LACI) group [2.12 IU/ml, (n = 112) vs. 1.48 IU/ml (n = 59) respectively, p = 0.0001] and similarly in initial FVIII:C levels (2.43 U/ml vs. 1.87 U/ml, p = 0.0001). Analysis of six-month case fatality, vWF levels were associated with risk of death [p = 0.01, OR 1.73 (1.12, 2.66) for an increase of I U/ml], even after allowing for stroke type. CONCLUSION: The relationship of vWF with stroke mortality has not previously been described. Although we have not demonstrated a causal role for vWF in the pathogenesis of CVD, elevated circulating levels of vWF may be associated with increased risk of death following stroke. A prospective study would be required to establish whether vWF is predictive for the development of CVD.

Acute Disease↗

PubMed1987

Histologic features relating to prognosis in synovial sarcoma.

Although the American Joint Commission has classified all synovial sarcomas as "high grade," histologic subtypes can be identified. By histologically subclassifying synovial sarcoma tumors according to percent glandularity and mitotic rates, the authors were able to define high-risk and low-risk patients. Charts and original pathologic slides were reviewed on 45 synovial sarcoma patients. With a 41-month median follow-up, the low-risk patients showed 100% survival, whereas the high-risk patients showed 37% survival.

Actuarial Analysis↗

PubMed1994

K-ras gene mutations: an unfavorable prognostic marker in stage I lung adenocarcinoma.

Activation of K-ras gene by point mutations, a common finding in lung adenocarcinomas, has been suggested to decrease patient survival. We investigated 109 lung adenocarcinomas, mostly small, peripheral, stage I tumours (81/109) for presence of K-ras gene mutations at codons 12 and 13. Mutations were detected by denaturing gradient gel electrophoresis analysis of specific sequences amplified by polymerase chain reaction from DNA extracted from archival pathological material. Thirty-three of 109 (30.3%) tumours showed mutations at codon 12 (28/33, 84.8%) or 13 (5/33, 15.2%) of the gene. Mutations and type of nucleotide substitutions were differently distributed among cytological subtypes, being more prevalent among less differentiated (G2 and G3) tumours and among bronchial than bronchiolo-alveolar type adenocarcinomas. Survival analysis showed an adverse effect of K-ras mutation on survival, restricted to stage I tumours. Median survival for 81 stage I patients was 30 months for non-mutated tumours versus 20 months for mutated tumours (p = 0.016). Multivariate analysis showed that age of patient (p = 0.001) and K-ras mutation status (p = 0.04) were the only independent factors influencing survival significantly. These data strengthen the hypothesis that K-ras gene mutations may be useful in identifying a subgroup of patients with poor outcome.

Adenocarcinoma↗