Biomedical subjects

L A Henderson

Publications and source records attributed to L A Henderson.

At least 19 recordsLinked to original sources

PubMed2006

Somatotopic organization of the processing of muscle and cutaneous pain in the left and right insula cortex: a single-trial fMRI study.

The insula is involved in processing noxious information. It is consistently activated by acute noxious stimuli, can elicit pain on stimulation, and lesions encompassing the insula can alter pain perception. Anatomical tracing, electrophysiological and functional brain imaging investigations have suggested that the insula is somatotopically organized with respect to noxious cutaneous inputs. It has also recently been revealed that the anterior insula displays differential activation during cutaneous compared with muscle pain. Given this difference, it is important to determine if an insula somatotopy also exists for muscle pain. Using high-resolution functional magnetic resonance imaging (fMRI) we compared insula activation patterns in 23 subjects during muscle and cutaneous pain induced in the right leg and forearm. Group and frequency analyses revealed somatotopically organized signal increases in the posterior contralateral (left) and ipsilateral (right) anterior insula. Within the posterior contralateral insula, signal increases during both cutaneous and muscle forearm pain were located lateral and anterior to those evoked by leg pain, whereas in the ipsilateral anterior insula the pattern was reversed. Furthermore, within the ipsilateral anterior insula, muscle pain activated a region anterior to that activated by cutaneous pain. This somatotopic organization may be crucial for pain localization or other aspects of the pain experience that differ depending on both stimulation site and type of tissue activated. This study reveals that the insula is organized somatopically with respect to muscle and cutaneous pain and that this organization is further separated according to the tissue in which the pain originates.

Adult↗

PubMed2006

An isoflurane- and alcohol-insensitive mutant GABA(A) receptor alpha(1) subunit with near-normal apparent affinity for GABA: characterization in heterologous systems and production of knockin mice.

Volatile anesthetics and alcohols enhance transmission mediated by gamma-aminobutyric acid type A receptors (GABA(A)Rs) in the central nervous system, an effect that may underlie some of the behavioral actions of these agents. Substituting a critical serine residue within the GABA(A)R alpha(1) subunit at position 270 with the larger residue histidine eliminated receptor modulation by isoflurane, but it also affected receptor gating (increased GABA sensitivity). To correct the shift in GABA sensitivity of this mutant, we mutated a second residue, leucine at position 277 to alanine. The double mutant alpha(1)(S270H,L277A)beta(2)gamma(2S) GABA(A)R was expressed in Xenopus laevis oocytes and human embryonic kidney (HEK)293 cells, and it had near-normal GABA sensitivity. However, rapid application of a brief GABA pulse to receptors expressed in HEK293 cells revealed that the deactivation was faster in double mutant than in wild-type receptors. In all heterologous systems, the enhancing effect of isoflurane and ethanol was greatly decreased in the double mutant receptor. Homozygous knockin mice harboring the double mutation were viable and presented no overt abnormality, except hyperactivity. This knockin mouse line should be useful in determining which behavioral actions of volatile anesthetics and ethanol are mediated by the GABA(A)Rs containing the alpha(1) subunit.

Animals↗

PubMed2006

Distinct forebrain activity patterns during deep versus superficial pain.

All pain is unpleasant, but different perceptual and emotional qualities are characteristic of pain originating in different structures. Pain of superficial (cutaneous) origin usually is sharp and restricted, whereas pain of deep origin (muscle/viscera) generally is dull and diffuse. Despite the differences it has been suggested previously that all pain is mediated by an invariant set ("neuromatrix") of brain structures. However, we report here, using functional magnetic resonance imaging (fMRI), that striking regional differences in brain activation patterns were the rule. Signal differences were found in regions implicated in emotion (perigenual cingulate cortex), stimulus localization and intensity (somatosensory cortex) and motor control (motor cortex, cingulate motor area). Further, most fMRI signal changes matched perceived changes in pain intensity. These findings clearly indicate that distinct neural activity patterns in distinct sets of brain structures are evoked by pain originating from different tissues of the body. Further, we suggest that these differences underlie the different perceptual and emotional reactions evoked by deep versus superficial pain.

Adult↗

PubMed2005

Neural sites involved in the sustained increase in muscle sympathetic nerve activity induced by inspiratory capacity apnea: a fMRI study.

A maximal inspiratory breath hold (inspiratory capacity apnea) against a closed glottis evokes a large and sustained increase in muscle sympathetic nerve activity (MSNA). Because of its dependence on a high intrathoracic pressure, it has been suggested that this maneuver causes unloading of the low-pressure baroreceptors, known to increase MSNA. To determine the central origins of this sympathoexcitation, we used functional magnetic resonance imaging to define the loci and time course of activation of different brain areas. We hypothesized that, as previously shown for the Valsalvsa maneuver, discrete but widespread regions of the brain would be involved. In 15 healthy human subjects, a series of 90 gradient echo echo-planar image sets was collected during three consecutive 40-s inspiratory capacity apneas using a 3-T scanner. Global signal intensity changes were calculated and subsequently removed by using a detrending technique, which eliminates the global signal component from each voxel's signal intensity change. Whole brain correlations between changes in signal intensity and the known pattern of MSNA during the maneuver were performed on a voxel-by-voxel basis, and significant changes were determined by using a random-effects analysis procedure (P < 0.01, uncorrected). Significant signal increases emerged in multiple areas, including the rostral lateral medulla, cerebellar nuclei, anterior insula, dorsomedial hypothalamus, anterior cingulate, and lateral prefrontal cortexes. Decreases in signal intensity occurred in the dorsomedial and caudal lateral medulla, cerebellar cortex, hippocampus, and posterior cingulate cortex. Given that many of these sites have roles in cardiovascular control, the sustained increase in MSNA during an inspiratory capacity apnea is likely to originate from a distributed set of discrete areas.

Adult↗

PubMed2003

Functional magnetic resonance imaging responses to expiratory loading in obstructive sleep apnea.

Obstructive sleep apnea (OSA) is characterized by diminished upper airway muscle phasic and tonic activation during sleep, but enhanced activity during waking. We evaluated neural mechanisms underlying these patterns with functional magnetic resonance imaging procedures during baseline and expiratory loading conditions in nine medication-free OSA and 16 control subjects. Both groups developed similar expiratory loading pressures, but appropriate autonomic responses did not emerge in OSA cases. Reduced neural signals emerged in OSA cases within the frontal cortex, anterior cingulate, cerebellar dentate nucleus, dorsal pons, anterior insula and lentiform nuclei. Signal increases in OSA over control subjects developed in the dorsal midbrain, hippocampus, quadrangular cerebellar lobule, ventral midbrain and ventral pons. Fastigial nuclei and the amygdala showed substantially increased variability in OSA subjects. No group differences were found in the thalamus. OSA patients show aberrant responses in multiple brain areas and inappropriate cardiovascular responses to expiratory loading, perhaps as a consequence of previously-demonstrated limbic, cerebellar and motor area gray matter loss.

Adult↗

PubMed2002

Noxious activation of spinal or vagal afferents evokes distinct patterns of fos-like immunoreactivity in the ventrolateral periaqueductal gray of unanaesthetised rats.

The consequences of a severe traumatic injury--deep pain and haemorrhage--usually evoke a passive emotional coping reaction characterised by: quiescence and immobility, decreased vigilance, hypotension and bradycardia. Results of studies utilising microinjections of excitatory amino acids suggest that passive coping reactions are mediated, at least in part, by activation of the midbrain, ventrolateral periaqueductal gray (vlPAG) region. Further, experiments in anaesthetised rats, using the expression of the immediate-early gene, c-fos, as a marker of neuronal activation, report that pain arising from muscles, joints or viscera selectively activates the vlPAG. Anaesthesia alone, however, evokes substantial Fos-like immunoreactivity (IR) within the vlPAG and this may have obscured any differences in patterns of Fos expression following noxious deep somatic versus noxious visceral activation. In these experiments, in unanaesthetised rats, the effects of noxious spinal versus noxious vagal primary afferent activation were re-examined and distinct rostrocaudal patterns of Fos-expression were observed. Specifically: (i) injection of algesic substances into muscle, which preferentially activates spinal afferents, evoked Fos expression predominantly within the caudal vlPAG; whereas, (ii) noxious manipulations whose effects are mediated by (cardiopulmonary) vagal activation evoked preferential Fos-expression within the rostral vlPAG. On the other hand, hypotensive haemorrhage evoked substantial Fos expression along the entire rostrocaudal extent of the vlPAG, a finding which fits with suggestions that haemorrhagic shock is triggered by a combination of: (i) spinally-relayed nociceptive signals originating from ischaemic tissue, and (ii) vagally-relayed signals reflecting poor cardiac filling.

Afferent Pathways↗

PubMed2001

A device for feline head positioning and stabilization during magnetic resonance imaging.

Minimization of head movement and reproduction of standard head positions are essential for reliable brain functional magnetic resonance imaging. Devices for stabilization and alignment of feline preparations are not available currently. We describe a system that involves minimal surgery, allows for both acute and chronic atraumatic positioning, and has the potential to be used for unanesthetized animals. The device uses non-metallic materials and stabilizes the head by means of an apparatus that fixes the head with nylon screws and dental cement in the frontal sinuses. Application of the head-stabilizing device decreases head movements by more than a factor of ten. Anatomical images show that this device provides 3 dimensional head placement at a precision comparable to that of a stereotactic frame, i.e. within 1 mm.

Animals↗

PubMed2000

Caudal midline medulla mediates behaviourally-coupled but not baroreceptor-mediated vasodepression.

Within the caudal medulla there are two regions whose activation leads to vasodepression and bradycardia, the caudal ventrolateral medulla and a discrete region of the caudal midline medulla. This study investigated, in the halothane anaesthetized rat, the contribution of these two vasodepressor regions to "homeostatic" and "behaviourally-coupled" cardiovascular regulation. In an initial set of experiments the contribution of each of these two regions to the hypotension and bradycardia evoked by acute hypovolaemia (15% haemorrhage) was investigated. It was found that inactivation of the caudal midline medulla significantly attenuated (cobalt chloride) or completely blunted (lignocaine) the hypotension and bradycardia evoked by acute hypovolaemia. In contrast, inactivation of the caudal ventrolateral medulla using cobalt chloride, although attenuating the magnitude of the hypotension and completely blocking the bradycardia, did not delay the onset of the hypotension evoked by acute hypovolaemia. The caudal ventrolateral medulla is known to be critical in homeostatic cardiovascular control through the expression of the "baroreceptor reflex" and the hypotension and bradycardia evoked by activation of cardiopulmonary afferents. In a second series of experiments we found inactivation of the caudal midline medulla played no role in baroreflex-evoked bradycardia (i.v. phenylephrine) or the hypotension and bradycardia evoked by cardiopulmonary afferent activation (i.v. 5-hydroxytryptamine). These data suggest that the caudal midline medulla and caudal ventrolateral medulla play different roles in cardiovascular control. The caudal ventrolateral medulla is involved in mediating cardiovascular changes associated with a variety of stimuli including "homeostatic" and "behaviourally-coupled" cardiovascular changes, whereas the caudal midline medulla is critical for mediating "behaviourally-coupled" changes in arterial pressure and heart rate.

Animals↗

PubMed1998

Hypotension following acute hypovolaemia depends on the caudal midline medulla.

Acute hypovolaemia evokes abrupt, life-threatening hypotension and bradycardia. Hypotension can be evoked also by excitation of the caudal midline medulla (CMM). This study investigated the possible contribution of the CMM depressor area to hypotension evoked by acute hypovolaemia. Inactivation of the CMM, with either lignocaine or cobalt chloride did not alter resting arterial pressure. However lignocaine injections blocked the fall in arterial pressure, and cobalt chloride injections delayed the onset and significantly attenuated the size of hypovolaemic-evoked hypotension. These findings suggest that the CMM is a key region triggering hypotension after blood loss, and that the brain areas mediating cardiovascular response to challenges such as acute hypovolaemia are not the same areas that regulate resting arterial pressure.

Acute Disease↗

PubMed1998

The ventrolateral periaqueductal gray projects to caudal brainstem depressor regions: a functional-anatomical and physiological study.

The reaction of shock, a precipitous, life-threatening fall in arterial pressure and heart rate, is evoked often by the combination of deep pain and blood loss following traumatic injury. A similar "shock-like" pattern of response can be evoked by excitation of the ventrolateral midbrain periaqueductal gray. Further, ventrolateral periaqueductal gray neurons are selectively activated by deep somatic or visceral pain and haemorrhage. The pathways mediating ventrolateral periaqueductal gray evoked hypotension and bradycardia are not known. In this study, the projections from the ventrolateral periaqueductal gray to "cardiovascular" regions in the caudal medulla of the rat were examined. Injections of the anterograde tracer, biotinylated dextran amine at physiologically-defined, ventrolateral periaqueductal gray depressor sites, revealed strong projections to the caudal midline medulla and to the depressor region of the caudal ventrolateral medulla. Injections of excitatory amino acids established that substantial falls in arterial pressure could be evoked from the ventrolateral periaqueductal gray-recipient parts of the caudal midline medulla. Injections of the retrograde tracer, cholera toxin subunit B at physiologically-defined, depressor sites in the caudal midline medulla and the caudal ventrolateral medulla confirmed the existence of substantial projections from the ventrolateral periaqueductal gray. Although previous studies have emphasized the importance of projections from the ventrolateral periaqueductal gray to the pressor region of the rostral ventrolateral medulla, this study has revealed the existence of strong ventrolateral periaqueductal gray projections to depressor regions within the caudal medulla (caudal midline medulla and caudal ventrolateral medulla) which likely contribute to ventrolateral periaqueductal gray-mediated hypotension and bradycardia.

Animals↗

PubMed1997

Cardiovascular effects of microinjections of opioid agonists into the 'Depressor Region' of the ventrolateral periaqueductal gray region.

Microinjections of excitatory amino acids made into the ventrolateral midbrain periaqueductal gray of the rat have revealed that neurons in this region integrate a reaction characterised by quiescence, hyporeactivity, hypotension and bradycardia. Microinjections of both excitatory amino acids and opioids into the ventrolateral periaqueductal gray have shown also that it is a key central site mediating analgesia. The effects of injections of opioids into the ventrolateral periaqueductal gray on arterial pressure and heart rate or behaviour are unknown. In this study we first mapped in the rat the extent of the ventrolateral periaqueductal gray hypotensive region as revealed by microinjections of excitatory amino acids. We found that ventrolateral periaqueductal gray depressor region extended more rostrally than previously thought into the tegmentum ventrolateral to the periaqueductal gray. Subsequently we studied for the first time, the effects of microinjections of mu-, delta-, and kappa-opioid agonists made into the ventrolateral periaqueductal grey depressor region. In contrast to the effects of excitatory amino acid injections, microinjections of the mu-opioid agonist ([D-Ala2,N-Me-Phe4,Gly-ol5]enkephalin) evoked hypertension and tachycardia at approximately 50% of sites. Similar to excitatory amino acid injections, microinjections of both the delta-opioid agonist ([D-Pen2,D-Pen5]enkephalin), and the kappa-opioid agonist ((5,7,8)-(+)-N-Methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-y l]-benzeneacetamide) evoked either a hypotension and bradycardia, or had no effect. These results indicate that different opiate receptor subtypes are present on a distinct population of ventrolateral periaqueductal gray neurons, or at different ventrolateral periaqueductal gray synaptic locations (pre- or post-synaptic).

Analgesics↗

PubMed1994

Changes in human papillomavirus typing of recurrent respiratory papillomatosis progressing to malignant neoplasm.

A patient with recurrent respiratory papillomatosis progressed spontaneously to carcinoma resulting in death. Serial biopsy specimens obtained during a 9-year course of this patient's disease were tested via polymerase-chain reaction and Southern hybridization to detect the human papillomavirus (HPV) types present during the patient's course of disease. Early biopsy specimens were positive for HPV types 6 and 11. As atypia progressed to carcinoma, HPV types 6 and 11 remained present, but the signal decreased and HPV 16 became increasingly positive. The significance of these findings will be discussed.

Carcinoma, Squamous Cell↗

PubMed1993

A peptide inhibitor of human immunodeficiency virus infection binds to novel human cell surface polypeptides.

Putative cell surface human immunodeficiency virus (HIV) gp41 receptor proteins of 45 and 80 kDa (p45 and p80, respectively) were identified on human cells using a 17-amino acid peptide, referred to as CS3. In contrast, murine P815 cells expressed a peptide binding protein of 80 kDa only. A segment of 8 amino acids within CS3 contains the minimum sequence able to inhibit binding of radiolabeled CS3 to p80 and p45, as shown by competitive binding studies. Human p45 was purified from CD4+ RH9 cells by CS3 peptide affinity chromatography. Human p80 was partially purified from RH9 cell lysates by size exclusion chromatography followed by SDS-polyacrylamide gel electrophoresis; a rabbit polyclonal antibody was raised against this preparation. Anti-p80 antibody inhibited HIV infection in a dose-dependent manner. The CS3 region of gp41 has been been shown previously to be exposed on viral particles and envelope-expressing cells predominately after conformational changes in the HIV envelope occur due to the interaction of CD4 with gp120. These results, together with those from previous studies, suggest that following the interaction of gp120 with CD4, there may be a second receptor interaction necessary for virus entry/fusion.

Amino Acid Sequence↗

PubMed1992

The effect of brassica vegetable consumption on caffeine metabolism in humans.

Ten healthy volunteers were used in two studies investigating the effect of short-term Brassica consumption on caffeine metabolism. In the first study volunteers were given three Brassica-containing meals, the last one 3 h prior to caffeine administration. In the second study volunteers were given two Brassica-containing meals and then fasted overnight before caffeine administration. In both studies the mean plasma half-life of caffeine was reduced by approximately 20% following a Brassica diet, suggesting that Brassica vegetables stimulate caffeine metabolism. When caffeine was given 3 h after the last meal, plasma caffeine concentrations over 6 h, were increased by up to 27% on the Brassica diet compared to controls. This may be due to a transient increased permeability of the intestine to caffeine, immediately following Brassica consumption. This effect was not seen in the second study where there was a 12-h period between the last meal and caffeine administration. There was large interindividual variation in the effect of the Brassica diet on caffeine metabolism.

Administration, Oral↗

PubMed1991

Genetic destabilization of Candida albicans by hydroxyurea.

Candida albicans is a commensal component of the normal human microflora, but frequently causes infections in persons undergoing treatment for malignancies. The cytotoxicity and genotoxicity of the antineoplastic agent hydroxyurea (HU) for the yeast is demonstrated. Cultivation of the organism on defined complete medium in the presence of HU induced growth inhibition or cell death, gene mutations, segregations of heterozygous loci through reciprocal and nonreciprocal mitotic recombinations, and a special heritable system for high frequency switching between phenotypes reflecting cellular growth characteristics and susceptibilities to HU. Each of these responses is influenced differently by variations in drug concentration and temperature. The biochemical complexity underlying cytotoxic and genetic effects of HU, and the implications for the likelihood of HU induced changes occurring in indigenous yeast populations of persons undergoing therapy with the drug, are discussed.

Candida albicans↗

PubMed1990

Recombinagenicity of caffeine for Candida albicans.

Caffeine at concentrations of 0.5 x 10(-2) M or higher inhibited cell replication and induced gene segregations in Candida albicans cultured on defined complete medium. Both responses increased incrementally with increasing caffeine concentrations, and were more severe during incubation at 37 degrees C than 25 degrees C; at 37 degrees C, caffeine levels above 1.5 x 10(-2) M caused cellular inactivation. Caffeine effects occurred only under conditions permitting cell growth, and their magnitudes were greater for unbudded than budding cells, were influenced by cellular genetic backgrounds, and were unaffected by the presence of adenine in the medium. Evaluations of segregations for recessive auxotrophic markers of a four member linkage group carried heterozygously in a cis arrangement in treated cells established that induced segregants arise through either reciprocal or nonreciprocal recombinations. The frequency distributions of classes of reciprocal and nonreciprocal recombinants for these markers conformed with those previously obtained following induction by ultraviolet radiation, indicating that the probabilities of recombinational events within the chromosomal regions defined by the markers are not biased by the differences in kinds of initial DNA lesions caused by the two recombinagens. A panel of four protoplast fusion hybrids considered deficient for DNA repair because of enhanced susceptibilities to UV induced cellular inactivation and mitotic recombination exhibited corresponding increased sensitivities to caffeine, signifying that DNA damage induced by caffeine is subject to repair. Caffeine did not affect behavior of a variant strain exhibiting high frequency phenotypic switching between minute smooth and large rough colonial forms, and no evidence for mutagenicity of the drug was obtained with systems for detection of forward or reverse mutations. The mechanism of caffeine's recombinagenicity, and the implications of that property for genetic studies of C. albicans are discussed.

Adenine↗

PubMed1990

Characterization of a putative cellular receptor for HIV-1 transmembrane glycoprotein using synthetic peptides.

The transmembrane glycoprotein (gp41 or TM) of HIV-1 contains limited sequence similarity to TM of some immunosuppressive animal retroviruses. A specific HIV-1 TM sequence, denoted CS3, inhibits T-cell activation in vitro and antibody specific to CS3 has been linked to the absence of disease. CS3, when conjugated to human serum albumin (HSA) and labeled with fluorescein, binds specifically to CD4+ cell lines. Cross-linking of CS3-HSA to its binding activity on the CD4+ cell line RH9 reveals a putative subunit size of approximately 44 kD. Incubation of RH9 cells with CS3-HSA prior to addition of HIV-1 prevented HIV-1-mediated cell lysis and inhibited infection. These results suggest that the CS3 region of TM plays an important role in the pathogenesis of the AIDS virus, HIV-1.

Acquired Immunodeficiency Syndrome↗

PubMed1988

Nonspecific and Candida-specific immune responses in mice suppressed by chronic administration of anti-mu.

CBA/J mice were immunosuppressed by repeated administration of goat antibody specific for mu chain of immunoglobulin M (IgM) and tested for nonspecific and Candida albicans-specific immune responses. Immunosuppression was demonstrated by a dramatic reduction in the number of antibody-forming cells in the spleens of anti-mu-treated mice when immunized with sheep erythrocytes, by greatly reduced in vitro responsiveness of both spleen and lymph node lymphocytes from anti-mu-treated mice to lipopolysaccharide, and by a large reduction in the number of splenic IgM-positive cells. T cell function, on the other hand, appeared to be relatively unaltered in anti-mu-treated animals, in the cytotoxic T lymphocyte activity against an allogeneic target was similar in splenocyte cultures from anti-mu- and mock-treated animals, and splenic and lymph node lymphocytes proliferated in response to concanavalin A in a lymphocyte stimulation assay. Moreover, Candida-specific delayed hypersensitivity to two different Candida antigens, one cell wall-derived (GP) and the other cell membrane-derived (BEX), was of comparable intensity in immunosuppressed and normal animals. When anti-mu- and mock-treated mice were immunized by the cutaneous inoculation of viable C. albicans blastospores and then challenged intravenously to assess the development of protective immunity, only mock-treated animals, male and female, had significant (p less than or equal to 0.05) protective responses demonstrable by reduction in the number of colony-forming units cultured from their kidneys 28 days after intravenous challenge. If consideration was given to the number of animals which had cleared Candida completely from the kidney, however, there appeared to be protective responses operative in the female anti-mu-treated animals as well. Neither anti-mu-treated males nor females, when immunized and challenged with C. albicans, produced Candida-specific antibody detectable by counterimmunoelectrophoresis, whereas all immunized and challenged mock-treated animals produced antibody. The data are consistent with the hypothesis that anti-mu treatment has little effect on multiple cellular immune functions, including those specific for C. albicans, and the combination of antibody, cell-mediated immunity and innate defenses are responsible for solid systemic defense against the fungus.

Animals↗