Indirect modulation of neuronal excitability and synaptic transmission in the hippocampus by activation of proteinase-activated receptor-2.

BACKGROUND AND PURPOSE: Proteinase-activated receptor-2 (PAR2) is widely expressed in the CNS under normal physiological conditions. However, its potential role in modulating neuronal excitability and synaptic transmission remains to be determined. Here, we have investigated whether PAR2 activation modulates synaptic activity in the hippocampus. EXPERIMENTAL APPROACH: PAR2 activation and its effect on the hippocampus were examined in rat primary cultures and acute slices using whole cell patch clamp and standard extracellular recordings, respectively. KEY RESULTS: PAR2 activation leads to a depolarization of hippocampal neurones and a paradoxical reduction in the occurrence of synaptically driven spontaneous action potentials (APs). PAR2-induced neuronal depolarization was abolished following either the inhibition of astrocytic function or antagonism of ionotropic glutamate receptors whilst the PAR2-induced decrease in AP frequency was also reduced when astrocytic function was inhibited. Furthermore, when examined in acute hippocampal slices, PAR2 activation induced a profound long-term depression of synaptic transmission that was dependent on NMDA receptor activation and was sensitive to disruption of astrocytic function. CONCLUSIONS AND IMPLICATIONS: These novel findings show that PAR2 activation indirectly inhibits hippocampal synaptic activity and indicate that these receptors may play an active role in modulating normal physiological CNS function, in addition to their role in pathophysiological disorders.

Cannabidiol inhibits synaptic transmission in rat hippocampal cultures and slices via multiple receptor pathways.

BACKGROUND AND PURPOSE: Cannabidiol (CBD) has emerged as an interesting compound with therapeutic potential in several CNS disorders. However, whether it can modulate synaptic activity in the CNS remains unclear. Here, we have investigated whether CBD modulates synaptic transmission in rat hippocampal cultures and acute slices. EXPERIMENTAL APPROACH: The effect of CBD on synaptic transmission was examined in rat hippocampal cultures and acute slices using whole cell patch clamp and standard extracellular recordings respectively. KEY RESULTS: Cannabidiol decreased synaptic activity in hippocampal cultures in a concentration-dependent and Pertussis toxin-sensitive manner. The effects of CBD in culture were significantly reduced in the presence of the cannabinoid receptor (CB(1) ) inverse agonist, LY320135 but were unaffected by the 5-HT(1A) receptor antagonist, WAY100135. In hippocampal slices, CBD inhibited basal synaptic transmission, an effect that was abolished by the proposed CB(1) receptor antagonist, AM251, in addition to LY320135 and WAY100135. CONCLUSIONS AND IMPLICATIONS: Cannabidiol reduces synaptic transmission in hippocampal in vitro preparations and we propose a role for both 5-HT(1A) and CB(1) receptors in these CBD-mediated effects. These data offer some mechanistic insights into the effects of CBD and emphasize that further investigations into the actions of CBD in the CNS are required in order to elucidate the full therapeutic potential of CBD.

Plasmapheresis. A therapeutic option in the management of heparin-associated thrombocytopenia with thrombosis.

Heparin-associated thrombocytopenia with thrombosis (HATT) is an uncommon syndrome that is estimated to occur in 1-5% of patients with heparin-induced thrombocytopenia. Early diagnosis requires careful clinical surveillance, and the management of these patients can be complex. Cessation of heparin therapy and substitution or addition of oral anticoagulants, antiplatelet agents, dextrans, and prostacyclin analogues have been advocated. The authors are aware of only two case reports in the literature that examine the use of plasmapheresis as a therapeutic alternative. The authors report a case of a 53-year-old white man who developed HATT after a single protamine-reversed exposure to heparin. Controlled platelet aggregation studies performed before and after apheresis sessions documented a dramatic response and rapid normalization of platelet number and function in the patient. The authors conclude that plasmapheresis could be a valuable adjunct in the successful management of patients with HATT. When done in conjunction with platelet aggregation studies, an objective measurement of therapeutic efficacy can be achieved.

Extraskeletal osteogenic sarcoma of the mediastinum.

This report describes the clinical and pathologic aspects of a mediastinal extraskeletal osteogenic sarcoma. This is a rare tumor that presented clinically as a thymoma. The literature on extraskeletal osteogenic sarcomas is reviewed with respect to location, age, sex, treatment, and course. The potential role of fine-needle aspiration biopsy in the diagnosis of this lesion is discussed.

Unifocal eosinophilic granuloma of the temporal lobe.

The clinical features, treatment, and two-year postoperative course of a 14-year-old boy with unifocal eosinophilic granuloma of the temporal lobe are presented. A literature review of unifocal eosinophilic granuloma of the brain revealed 11 additional cases, 9 of which involved the hypothalamus and 1 each the frontal and temporal lobes. Four of the 9 patients with involvement of the hypothalamus developed multifocal disease, whereas none of the 3 who had frontal or temporal lobe involvement developed multifocal lesions. Effective therapy for eosinophilic granuloma in a single resectable site in the brain appears to be total excision. Low-dose radiation has been used to eradicate locally recurrent disease.

Chronic endometritis: morphologic and clinical observations.

The histologic and clinical manifestations of chronic endometritis were reviewed in 99 women. The morphologic features found to be of value in diagnosing this condition were superficial stromal edema, increased stromal density, and pleomorphic stromal inflammatory infiltrate dominated by lymphocytes in the absence of premenstrual changes or any other significant pathologic endometrial lesions. When these changes were present, a plasma cell infiltrate was invariably found. Clinically, the major presenting complaint was vaginal bleeding in 94% of the patients. No correlation was found between the presenting clinical complaint and either the extent of the lesion or the number of plasma cells in the leukocyte infiltrate. On follow-up, the lesion appeared to be eradicated by biopsy or curettage in approximately 80% of the patients. The major predisposing conditions were found to be intrauterine leiomyomas and a recent endometrial biopsy or curettage. The limitations of the plasma cells criterion for recognition of the lesion are discussed.

Evaluation of the office endometrial biopsy in the detection of endometrial carcinoma and atypical hyperplasia.

The purpose of this study is to assess the accuracy and limitations of the outpatient endometrial biopsy in detection of endometrial carcinoma and atypical hyperplasia. This was done by reviewing all the endometrial material from the 891 women at this clinic whose first endometrial sample in 1974 was by the biopsy technique. The results of this material were correlated with subsequently available additional uterine samples obtained over a three year period by biopsy, dilatation and curettage, or hysterectomy. The detection rate by biopsy for the 21 cases of endometrial carcinoma proven by hysterectomy was 81%. There was a 5% false negative rate and no false positives. For the 25 cases of atypical hyperplasia proven by hysterectomy, the detection rate by biopsy was 68%. There was lack of hysterectomy confirmation in 33% and 24% false negatives. Insufficient material was obtained initially in 9% of the 891 women. Five percent of this group were found at hysterectomy to have either endometrial carcinoma or atypical hyperplasia. With an understanding of its limitations, the endometrial biopsy, although somewhat less accurate than the D & C, is considered to be a useful diagnostic tool for detection of these lesions.

Nemaline myopathy.

Nemaline myopathy occurred sporadically in a 59-year-old woman. She had slowly progressive weakness. A muscle biopsy specimen showed nemaline rods, increased variation in fiber size, apparent loss of Type IIb fiber differentiation, and a "moth-eaten" pattern of the intermyofibrillar network. At least 44 cases of this disorder have been reported. Clinically, they showed several different modes of onset, patterns of muscle group involvement, and rates of progression. There was a suggestion of familial involvement in at least half. In addition to the presence of nemaline rods, pathological abnormalities of muscle biopsy specimens were quite variable. Results of recent biochemical studies have shown abnormal myosin in a patient with rod myopathy. A hypothesis is proposed that relates the diverse clinical and histological features of this disease to a hereditary molecular abnormality of myosin synthesis.

The relation of adenomyosis uteri to coexistent endometrial carcinoma and endometrial hyperplasia.

The relation of adenomyosis uteri to endometrial carcinoma and endometrial hyperplasia has been the subject of only a few studies. These investigations have resulted in opposing conclusions on the association between the conditions. In this study of a 10-year period, all cases were retrieved from the surgical pathology laboratory files of adenomyosis uteri with either simultaneous endometrial carcinoma or endometrial hyperplasia. A control population was selected from patients who underwent hysterectomy for mechanical problems related to the uterus. Adenomyosis was found in association with endometrial carcinoma in 19.4% of 175 cases and in association with endometrial hyperplasia in 20.5% of 254 cases. The control series of 203 patients had a 16.7% incidence of adenomyosis. Statistical analysis showed no association between these conditions.