1. Unitary synaptic potentials evoked by the activity of single vestibulocollic neurones were recorded by means of spike-triggered signal averaging in neck extensor motoneurones of decerebrate cats. Properties of the vestibulocollic neurones which produced the potentials were examined.2. Vestibulocollic neurones were first identified as projecting to the C3 grey matter by antidromic microstimulation within the C3 extensor motoneurone pool. The spontaneous or glutamate-driven activity of the vestibulocollic neurones was then used to trigger the averaging computer. In this way ten inhibitory and two excitatory neurones were identified (20% of neurones tested).3. Action potentials in local branches of vestibulocollic neurones were usually recorded in the vicinity of motoneurones. Mean orthodromic conduction time from the foot of the extracellular spike, recorded in the vestibular nuclei, that triggered the averager was 0.72 msec. Mean synaptic delay was 0.4 msec.4. I.p.s.p.s had a mean time to peak of 0.81 msec and were readily reversed by injection of hyperpolarizing current. These data, together with the shape indices of i.p.s.p.s indicate that they are generated proximally on motoneurones.5. All vestibulocollic neurones making synapses with motoneurones were monosynaptically driven by stimulation of the ipsilateral vestibular nerve. Four out of seven tested were inhibited by stimulation of the contralateral vestibular nerve (commissural inhibition).6. Two excitatory neurones were located in Deiters' nucleus or on the Deiters'-descending border. Inhibitory neurones were found relatively medially in the vestibular complex in the medial, descending and Deiters' nuclei.7. Vestibulocollic neurones acting on motoneurones were tested for axon branching to more caudal levels of the spinal cord with electrodes placed at C5-7. Both of the excitatory and two out of nine inhibitory neurones branched. 相似文献
1. Vestibular neurones projecting to the upper cervical grey matter (vestibulocollic neurones) were identified by localized microstimulation in the C3 segment of the cat spinal cord.
2. The neurones were found in the lateral (Deiters'), medial and descending nuclei bilaterally and projected to the spinal cord in the lateral and medial vestibulospinal tracts (LVST and MVST). Ipsilateral axons of Deiters' neurones were mostly in the LVST, axons of medial and descending neurones in the MVST; a few Deiters' neurones had axons in the MVST; some descending neurones had axons in the LVST. Most axons of contralateral neurones were in the MVST.
3. The axons of 62% of ipsilateral vestibulocollic Deiters' neurones not only gave off a collateral to C3, but also extended as far as the cervical enlargement (`branching'); some of these neurones projected as far as the upper thoracic cord, almost none to the lumbar cord. Ipsilateral descending nucleus neurones branch in the same fashion, but there is no branching in the relatively small medial nucleus population.
4. A large majority of vestibulocollic neurones receive monosynaptic excitation from the ipsilateral labyrinth and a number are inhibited by stimulation of the contralateral labyrinth (commissural inhibition). It is possible that commissural inhibition acts on a broad population of vestibular neurones involved in the control of eye, head and trunk movement.
5. Vestibulocollic neurones do not make up a homogeneous population acting only on the neck. Instead it is likely that subpopulations, for example branching and non-branching neurones, have different functions.
Warfarin is a mainstay of therapy for conditions associated with an increased risk of thromboembolic events. However, the use of this common agent is fraught with complications and little is known regarding inter‐individual variation in warfarin response.
Objective
We tested for association between single nucleotide polymorphisms (SNPs) in VKORC1 and CYP2C9 and average weekly warfarin dose required to maintain patients at their desired anticoagulation target.
Methods
The sample consisted of 93 European‐American patients from anticoagulation clinics at the University of North Carolina at Chapel Hill. Data on mean weekly warfarin dose were collected over a mean treatment period of 20.6 months. ANCOVA models were used and haplotype analysis was performed.
Results
Three of six VKORC1 SNPs were found to be very strongly associated with the average warfarin dose required to achieve the target international normalised ratio (INR; p<0.0001). The mean weekly dose by genotype ranged from approximately 27 to 47 mg. There was no evidence for an association between either of the two CYP2C9 polymorphisms studied, CYP2C9*2 and CYP2C9*3. CYP2C9*3 was significantly (p = 0.05) associated with average warfarin dosage after adjustment for VKORC1*1173.
Conclusions
These results are of considerable clinical interest and confirm recently published results regarding the role of these two genes in modifying warfarin metabolism and maintenance dosage. The consistent findings regarding the role of VKORC1 and CYP2C9 in warfarin metabolism and maintenance dosage represent a clinically useful proof of principal for the use of pharmacogenomic information in medicine and may lead to improved understanding of warfarin''s actions. 相似文献
Inhibiting nitric oxide (NO) synthesis during learning that food is inedible in Aplysia blocks subsequent memory formation. To gain insight into the function of NO transmission during learning we tested whether blocking NO synthesis affects aspects of feeding that are expressed both in a nonlearning context and during learning. Inhibiting NO synthesis with L-NAME and blocking guanylyl cyclase with methylene blue decreased the efficacy of ad libitum feeding. D-NAME had no effect. L-NAME also decreased rejection responses frequency, but did not affect rejection amplitude. The effect of L-NAME was explained by a decreased signaling that efforts to swallow are not successful, leading to a decreased rejection rate, and a decreased ability to reposition and subsequently consume food in ad libitum feeding. Signaling that animals have made an effort to swallow is a critical component of learning that food is inedible. Stimulation of the lips with food alone did not produce memory, but stimulation combined with the NO donor SNAP did produce memory. Exogenous NO at a concentration causing memory also excited a key neuron responding to NO, the MCC. Block of the cGMP second-messenger cascade during training by methylene blue also blocked memory formation after learning. Our data indicate that memory arises from the contingency of three events during learning that food is inedible. One of the events is efforts to swallow, which are signaled by NO by cGMP. 相似文献
The incomplete penetrance of mutations in BRCA1 and BRCA2 suggests that some combination of environmental and genetic factors modifies the risk of breast cancer in mutation carriers. This study sought to identify possible interactions between established breast cancer risk factors and BRCA1 or BRCA2 mutations using a case-only study design. Breast cancer cases that had been tested for BRCA1 and BRCA2 mutations were identified from 11 collaborating centers. Comparisons of reproductive and lifestyle risk factors were made between women with breast cancer who were positive for BRCA1 mutations (n = 283), BRCA2 mutations (n = 204), or negative for both BRCA1 and BRCA2 mutations (n = 894). Interaction risk ratios (IRRs) were calculated using multinominal logistic regression models. Compared with non-carriers, statistically significant IRRs were observed for later age at menarche among BRCA2 mutation carriers, for a greater number of pregnancies among both BRCA1 and BRCA2 mutation carriers, and for alcohol use among BRCA1 mutation carriers. Our data suggest that the risk for breast cancer among BRCA1 or BRCA2 carriers may be modified by reproductive characteristics and alcohol use. However, our results should be interpreted cautiously given the overall inconsistency in the epidemiologic literature on modifiers of BRCA1 and BRCA2.相似文献
Objective To explore the characteristics of arrhythmogenic right ventricular cardiomyopathy (ARVC). Methods Seven patients with arrhythmogenic right ventricular cardiomyopathy and 34 members of three families were studied. All patients and family members underwent history collection, clinical examination, electrocardiogram (ECG), two-dimensional echocardiography (2-DE) and a signal averaging electrocardiogram. Programmed ventricular stimulation was performed in five patients. Results All patients and family members had normal morphologic characteristics and normal function of the left ventricular by 2-DE. Fourteen persons had abnormal findings indicating ARVC. Five had enlargement of the right ventricular with diffused hypocontractility, eight had thin and systolic bulging in the focal anterior wall with hypokinesia and one had bulging of the inferior wall. Twenty-five persons (seven patients and 18 family members) had abnormal findings in ECG. Positive ventricular late potential was recorded in 13 persons (six patients). Two to three monomorphic ventricular tachycardia (VT) with left bundle branch block (LBBB) configurations were induced in five patients. Ventricular fibrillation was induced in two patients during the electrophysiologic study (EPS). Five patients had very high pacing threshold and/or ineffective pacing in one or many regions of the right ventricle. Two members of one family died suddenly. One member was a dwarf with ARVC. Spontaneous VT with a left bundle branch block (LBBB) configuration was recorded in five patients, polymorphic VT with extremely short coupling interval in one, and premature ventricular complexes with LBBB configuration in 12 (six patients). Conclusion Our familial study strongly suggests that ARVC may be a hereditary disease and it is helpful in the diagnosis and detection of ARVC. The most common manifestations were abnormal structure and function of the right ventricle and abnormal ECG of repolarization and ventricular arrhythmia which originates from the right ventricle. 相似文献
The neuronal basis of pharyngeal ingestion and peristalsis was studied in the gastropod Navanax inermis. Radially and circumferentially oriented muscles produced expansion and constriction of the pharynx. Motor fields of 11 identified radial motoneurons and 13 identified circumferential motoneurons were determined with respect to circumferential and longitudinal muscle band coordinates by muscle movements, electromyography, antidromic stimulation and axonal anatomy. Activation of these identified motoneurons can account for all the elemental pharyngeal movements observed during feeding. Four motoneurons, each innervating most of radial muscle, can mediate ingestion. Three radial motoneurons with anterior motor fields can mediate anterior expansion during sealing of the pharyngeal lips around prey and during regurgitation. Ten circumferential motoneurons have small arciform motor fields, the distributions of which correspond to the regional specializations in circumferential band organization. Arciform constriction can center eccentric ingested prey within the pharyngeal lumen during peristalsis. Arciform constrictions could combine to form an annular constriction in peristalsis. Small, non-overlapping, circumferential motor fields maximize the number of independent annular units available to produce a fine peristaltic wave. Sphincters have more circumferential motoneurons with smaller motor fields; this innervation permits finer motor control. Radial motoneurons with posterior motor fields can produce expansion caudal to a circumferential constriction during peristalsis. Motor fields of regional radial motoneurons show greater interanimal variability than circumferential motor fields, which is correlated with a less essential role of radial motoneurons in peristalsis. Two circumferential motoneurons with giant posterior pharyngeal motor fields can mediate pharyngeal emptying either in swallowing or in regurgitation. 相似文献