Targeted delivery of mutant Raf kinase to neovessels causes tumor regression.
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Animals↗
Biomedical subjects
J D Hood
Publications and source records attributed to J D Hood.
Selective requirement for Src kinases during VEGF-induced angiogenesis and vascular permeability.
Src kinase activity was found to protect endothelial cells from apoptosis during vascular endothelial growth factor (VEGF)-, but not basic fibroblast growth factor (bFGF)-, mediated angiogenesis in chick embryos and mice. In fact, retroviral targeting of kinase-deleted Src to tumor-associated blood vessels suppressed angiogenesis and the growth of a VEGF-producing tumor. Although mice lacking individual Src family kinases (SFKs) showed normal angiogenesis, mice deficient in pp60c-src or pp62c-yes showed no VEGF-induced vascular permeability (VP), yet fyn-/- mice displayed normal VP. In contrast, inflammation-mediated VP appeared normal in Src-deficient mice. Therefore, VEGF-, but not bFGF-, mediated angiogenesis requires SFK activity in general, whereas the VP activity of VEGF specifically depends on the SFKs, Src, or Yes.
Animals↗
Nitric oxide is an upstream signal of vascular endothelial growth factor-induced extracellular signal-regulated kinase1/2 activation in postcapillary endothelium.
We recently demonstrated that nitric oxide (NO) significantly contributes to the mitogenic effect of vascular endothelial growth factor (VEGF), suggesting a role for the NO pathway in the signaling cascade following kinase-derivative receptor activation in vascular endothelium. The aim of this study was to investigate the intracellular pathways linked to VEGF/NO-induced endothelial cell proliferation. We assessed the activity of the mitogen-activated protein kinase (MAPK) that is specifically activated by growth factors, extracellular-regulated kinase (ERK1/2), on cultured microvascular endothelium isolated from coronary postcapillary venules. ERK1/2 was immunoprecipitated, and its activity was assessed with an immunocomplex kinase assay. In endothelial cells exposed for 5 min to the NO donor drug sodium nitroprusside at a concentration of 100 microM, ERK1/2 activity significantly increased. VEGF produced a time- and concentration-dependent activation of ERK1/2. Maximal activity was obtained after 5 min of stimulation at a concentration of 10 ng/ml. The specific MAPK kinase inhibitor PD 98059 abolished ERK1/2 activation and endothelial cell proliferation in a concentration-dependent manner in response to VEGF and sodium nitroprusside. The NO synthase inhibitor Nomega-monomethyl-L-arginine, as well as the guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, blocked the activation of ERK1/2 induced by VEGF, suggesting that NO and cGMP contributed to the VEGF-dependent ERK1/2 activation. These results demonstrate for the first time that kinase-derivative receptor activation triggers the NO synthase/guanylate cyclase pathway to activate the MAPK cascade and substantiates the hypothesis that the activation of ERK1/2 is necessary for VEGF-induced endothelial cell proliferation.
Calcium↗
VEGF upregulates ecNOS message, protein, and NO production in human endothelial cells.
Vascular endothelial growth factor (VEGF) is an endothelium-specific secreted protein that potently stimulates vasodilation, microvascular hyperpermeability, and angiogenesis. Nitric oxide (NO) is also reported to modulate vascular tone, permeability, and capillary growth. Therefore, we hypothesized that VEGF might regulate endothelial production of NO. The production of nitrogen oxides by human umbilical vein endothelial cells (HUVECs) was measured after 1, 12, 24, and 48 h of incubation with VEGF. VEGF treatment resulted in both an acute (1 h) and chronic (> 24 h) stimulation of NO production. Furthermore, Western and Northern blotting revealed a VEGF-elicited, dose-dependent increase in the cellular content of endothelial cell nitric oxide synthase (ecNOS) message and protein that may account for the chronic upregulation of NO production elicited by VEGF. Finally, endothelial cells pretreated with VEGF for 24 h and subsequently exposed to A-23187 for 1 h produced NO at approximately twice the rate of cells that were not pretreated with VEGF. We conclude that VEGF upregulates ecNOS enzyme and elicits a biphasic stimulation of endothelial NO production.
Calcium↗
The interaction of angular and linear optokinetic stimuli with an angular vestibular stimulus.
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Darkness↗
Stretch-activated single-channel and whole cell currents in vascular smooth muscle cells.
Mechanosensitive ion channels may play a key role in transducing vascular smooth muscle (VSM) stretch into active force development. To test this hypothesis, we recorded single-channel and macroscopic currents during mechanical stimulation of enzymatically dispersed vascular smooth muscle cells. Patch pipette suction activated a nonselective cation channel that was permeable to K+, Na+, and Ca2+. Whole cell stretch was accomplished using two patch-type micropipettes attached to the cell ends with suction. Stretch elicited a sustained depolarization with a magnitude similar to that observed in pressurized arteries. Under whole cell voltage clamp, stretch activated an inward current with a reversal potential near -15 mV. In another series of experiments, whole cell stretch failed to modify the current-voltage relationship for voltage-gated calcium currents. Thus, in VSM, both single-channel and whole cell data are consistent with activation of a nonselective cation channel by stretch. This mechanism may, in part, account for pressure-induced activation of intact blood vessels.
Animals↗
Linear and angular optokinetic nystagmus in labyrinthine and central nervous system lesions.
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Adult↗
Visual control of balance in cerebellar and parkinsonian syndromes.
The role of vision in the control of balance in patients with Parkinson's disease (PD) and cerebellar disease (CD) was studied by measuring body sway with eyes open, closed, and in response to visual stimuli generated by discrete lateral displacements of a moveable room which enclosed the subjects. In response to room movement, normal subjects swayed by an amount intermediate between sway with eyes open and eyes closed and their response attenuated on repetition of the movement, a process depending on shifting from predominantly visual to proprioceptive control. CD patients swayed more than controls with eyes open or closed and as shown by high 'Romberg quotients' (eyes closed/eyes open sway ratio) were able to use visual information to control much of their unsteadiness. CD patients had a normal attenuation of response to repetition of the room movement. PD patients had normal sway with eyes open or closed but their responses to room movement were abnormal, being proportionately larger and failing to attenuate during successive stimuli. The results indicate that cerebellar lesions seem largely to spare the visuopostural loop and also spare the ability to shift from a visual to a proprioceptive control of postural sway. In contrast, the findings in PD suggest that the visuopostural loop is hyperactive and that its influence cannot easily be de-emphasized when visual information is misleading. The latter finding suggests that basal ganglia participation in posture is concerned with the reweighting of the various sensorimotor loops controlling posture in the process of adapting to novel situations.
Adaptation, Physiological↗
Effect of simulated bilateral cochlear distortion on speech discrimination in normal subjects.
Bilateral sensorineural hearing loss may introduce grossly dissimilar cochlear distortion at the two ears, causing abnormal demands to be made upon the cortical analytical centres which normally receive congruent information. As a result, the prescription of binaural hearing aids may be a handicap rather than a help. In order to explore this possibility, 10 normal subjects were presented with simulated, dissimilar cochlear distortion at the two ears. Discrimination scores with binaural presentation were poorer than the best monaural score and there were clear indications that in the former, subjects selectively attended to one ear and neglected the other. In contrast, binaural presentation of the same simulated distortion resulted in a significant improvement, compared with the monaural discrimination score. Inability of the cortex to contend with discongruent speech input from the two ears may be a factor contributing to the rejection of binaural hearing aids in some individuals.
Adolescent↗
The functional significance of auditory adaptation.
If a short duration pulse is added periodically every 30 s to a continuous tone, then the loudness of the continuous tone, which would otherwise remain unchanged, appears to undergo a progressive decline over a period of 3 min. The question at issue is whether the loss of loudness is actually induced by the pulse or merely made obvious. In support of the latter proposition a model has been developed which indicates how the loudness difference between the pulsed and continuous tone will increase as a result of adaptation. However, the model also predicts that a loudness loss should, in addition, be apparent in the pulsed tone itself. This has been confirmed by balancing the loudness in one ear of a 10 dB increment to a continuous tone of 60 dB at 1 kHz with an intermittent pulsed tone of the same frequency in the other. The magnitude of the loudness loss (of the order of 5 dB) accords well with the model prediction. The functional implications are that adaptation of continuous background noise should serve to reduce its masking effect upon speech and other transitory auditory stimuli rendering them more easily detectable.
Adaptation, Physiological↗
The pattern of consonant and vowel errors in patients with conductive and cochlear hearing loss.
An analysis was carried out of the pattern of errors in those words which were incorrectly perceived by patients during the course of routine speech audiometric tests using consonant-vowel-consonant words. Responses were examined from 20 patients with conductive hearing loss, and 20 with cochlear hearing loss due to Ménière's disease. Word errors result from misinterpretations of a single consonant in 70% of the conductive group and 56% of the Ménière group. The latter make slightly more errors involving both consonants. Errors in vowels alone are rare in both groups and, even in combination, with one or other consonant, never exceed 25%. Word recognition appears to fail for the same reason in the two groups.
Hearing Loss↗
A novel series of milbemycin antibiotics from Streptomyces strain E225. II. Isolation, characterization, structure elucidation and solution conformations.
A novel series of milbemycin antibiotics were isolated from the fermentation broth of a Streptomyces species designated E225. The structures of the four main metabolites VM 44857 (1), VM 44864 (2), VM 44865 (3) and VM 44866 (4) were determined by NMR techniques. In addition we describe the solution conformations of the major metabolite VM 44857 (1).
Animals↗
Observations bearing upon semi-circular canal dynamics.
It can be shown that following an angular velocity step stimulus delivered in darkness, the nystagmic responses can be effectively 'dumped' after any interval in time by the application of an appropriate step decrement in velocity. In practise the null velocity is bracketed between those step decrements inducing just detectable nystagmus to left and right and can be determined within a range of +/- 1.5 degrees s-1. With test stimuli of 22, 44, and 64 degrees s-1 the 'dump' velocities have been established at varying intervals in time on four normal subjects. Contrary to expectations the dump velocity/time relations for all three test stimuli follow a convergent linear course. The dump velocities are unaffected by fixation suppression of the nystagmus induced by the test stimuli. The seeming irrelevance of nystagmus generation to dump velocity values is confirmed by the good correspondence with the results of a separate study using the oculogyral illusion as a guide in place of nystagmus. These findings are difficult to relate to conventional concepts of cupular dynamics.
Humans↗
A novel series of milbemycin antibiotics from Streptomyces strain E225. I. Discovery, fermentation and anthelmintic activity.
A novel series of milbemycin antibiotics were produced by soil isolate, strain E225 which was shown to be a Streptomyces species. The antibiotics displayed anthelmintic activity against Trichostrongylus colubriformis in the gerbil. Two of the compounds, VM 44857 and VM 44866 were shown to be potent anthelmintics against mixed nematode infections in sheep.
Animals↗
Hearing acuity and susceptibility to noise-induced hearing loss.
Above a critical level (CL) of fatiguing tone, temporary threshold shift (TTS) rises rapidly with intensity. Using a fatiguing tone of 1000 Hz, threshold shift following 1 min stimulation at varying intensities was measured at the same frequency in 55 normal subjects and the CL determined for each. In a second and more limited study, TTS was measured at a frequency half an octave above that of the fatiguing tone. A significant inverse correlation was established between hearing level (HL) and CL at the same frequency with a fall of 2.5 dB in the latter for every 10 dB rise in the former. CLs measured half an octave above the fatiguing tone frequency were appreciably lower by 5 to 11 dB. No correlation was apparent between TTS and HTL, implying that TTS and CL are subserved by differing physiological mechanisms. The findings have relevance to the topic of susceptibility to noise-induced hearing loss and the formulation of damage risk criteria.
Acoustic Stimulation↗
The cervico-ocular reflex in normal subjects and patients with absent vestibular function.
The role of the cervico-ocular reflex (COR) has been studied in 12 patients with absent vestibular function and 13 normal subjects. Ramp and sinusoidal displacement stimuli were applied with trunk on head and head on trunk movements. In all patients, trunk on head movements evoked a marked slow-phase compensatory COR while in normal subjects it was weak and variable in direction. Fast components of the COR induced gaze shifts in the direction of the relative head movement ('anticompensatory' direction) which could be suppressed by imagining an earth fixed targed. No tonic component could be identified instead, in the case of ramp stimuli, a residual eye deviation was noted which was significantly enhanced in the patients and resulted from activity dynamically generated during the course of the trunk movement and not from its final angular displacement. Head on trunk ramp displacements in the dark evoked initial anticompensatory saccades followed by slow compensatory components, a pattern of eye movements remarkably similar to that seen during active head-eye target seeking. Thus, in the absence of labyrinthine function, the COR appears to take on the role of the vestibulo-ocular reflex in head-eye coordination in the initiation of the anticompensatory saccade which takes the eyes in the direction of the target, and the generation of the subsequent slow compensatory eye movements. Central pre-programming, as revealed by comparing the effect of different instructions and active versus passive neck-induced eye movements, has a profound influence on COR functioning.
Adult↗
New perspectives in the investigation of disorders of balance.
It is a common misconception that all disorders of balance can be attributed to derangements of the vestibular system. In fact spatial orientation is dependent upon the proper coordination of a number of sensory inputs and each of these is susceptible to damage by disease or injury. A variety of new tests is described which have as their aim the indentification of balance disorders resulting specifically from derangements of visual processing, proprioception and the neck reflexes. In addition, attention is given to the differential impairment of linear and circular vection and to the possible clinical application of vestibular evoked potentials.
Diagnosis, Differential↗
Observations upon the evoked responses to natural vestibular stimulation.
Repetitive rotational stimuli simulating natural head movements have been applied to the study of the vestibular evoked response in normal subjects and 12 patients with complete loss of vestibular function. Special precautions were taken to eliminate all possible sources of artefacts, in particular, all eye movements were restrained by requiring the subject to fixate upon a target light attached to the rotating chair throughout the course of the test. With a stimulus of 2 sec duration the typical response took the form of a slow negative wave with a mean peak amplitude of approximately 24 microV and maximally recorded from the vertex. It was characteristically absent in the patient group. Occasionally, both in normal subjects and patients it was preceded by a long latency complex thought to be non-vestibular in origin. Tests carried out both in total darkness and in the light show a statistically significant increase in the potential in the latter condition indicating an influence of the optokinetic effect exerted by the visual surround. Further studies have explored the phase changes brought about by varying the amplitude and duration of the stimulus. These have revealed certain parallels in the results of recent animal experimental studies.
Adult↗