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Intact electrodermal skin conductance responses after bilateral amygdala damage.

Several lines of evidence have suggested that the amygdala is a crucial component of the anatomical network that mediates the skin conductance orienting response (SCOR). In this study, the electrodermal activity of a patient whose entire amygdaloid complex had been destroyed bilaterally, and of 7 age- and gender-matched controls, was recorded under the same experimental conditions. The results indicate unequivocally that the subject could generate normal skin conductance and SCORs, in response to stimuli of different sensory modalities and configurations. This suggests that the amygdala is not a necessary component of the neural network underlying SCORs and that there are alternate neural units and pathways that link sensory cortices to autonomic effectors.

Aged↗

Origin of galanin-immunoreactive nerve fibers in the rat paracervical autonomic ganglia and uterine cervix.

Retrograde axonal tracing with fluorogold in conjunction with immunohistochemistry was used to examine the source of galanin-immunoreactive nerve fibers in the paracervical ganglia and uterine cervix of the female rat. Immunohistochemistry revealed galanin-immunoreactive neuron somata in lumbosacral dorsal root ganglia and around the central canal of the lumbosacral spinal cord (lamina X). Injection of fluorogold into the paracervical ganglia resulted in labelled cells in dorsal root ganglia and the sacral parasympathetic nucleus of the spinal cord; but fluorogold-labelled, galanin-immunoreactive cells were found only in dorsal root ganglia. Injection of the tracer in the cervix resulted in labelled cells in the paracervical ganglia and dorsal root ganglia; however, fluorogold-labelled, galanin-immunoreactive cells were again evident only in dorsal root ganglia. It is suggested that the galanin-immunoreactive nerve fibers and varicosities in the paracervical ganglia and uterine cervix are sensory fibers from spinal dorsal root ganglia. The galanin-immunoreactive varicosities in the ganglia could play a role in the modulation of pelvic visceral activity, while those in the musculature of the cervix could influence contractility.

Animals↗

How are tonic and phasic cardiovascular changes related to central motor command?

We examined the influence of central motor command on heart rate, respiration, and peripheral vascular activity. Central command was enhanced or reduced using tendon vibration. Muscle tension was held constant permitting the examination of variation in central command. Experiment 1 demonstrated in 13 college-aged males an enhancement of heart rate and vascular responses to an isometric, extensor contraction when vibration of the flexor tendon was added. Experiment 2 asked whether changes in central command interacted with phasic cardiovascular changes such as stimulus-linked anticipatory cardiac deceleration. Twenty college-aged males performed either an isometric flexor or extensor contraction with or without flexor tendon vibration. As expected, vibration enhanced cardiovascular change with extensor contraction more than with flexor contraction. Relative to control contractions, however, the flexor change was not an absolute decrease in cardiovascular change. More importantly, tendon vibration failed to alter phasic cardiovascular changes. Force and central commands for force induce cardiovascular change, but this change seems independent of phasic changes induced by the anticipation and processing of environmental stimuli.

Adolescent↗

Cell fate decisions and patterning in the vertebrate retina: the importance of timing, asymmetry, polarity and waves.

The differentiation of distinct cell populations in the retina is a multi-step process that involves cell cycle exit, migration, and dramatic changes of cell morphology. All these steps are tightly controlled by multiple regulatory pathways, which involve both cell-autonomous networks of transcription factors and cell-cell signaling events. Additional regulatory inputs into cell fate decisions have been recently suggested: accumulating evidence shows that the timing of cell cycle exit, the orientation of the mitotic spindle during the last cell division, and the polarity of neuronal progenitor cells could play important roles in cell fate determination.

Animals↗

Retinoic-acid-induced apoptosis in leukemia cells.

Retinoic acid (RA) cures more than 75% of patients with acute promyelocytic leukemia (APL). Here, we review the various anti-cancer activities of retinoids and rexinoids, alone and in combination with other drugs, with emphasis on the RA-dependent induction of a cancer-cell-selective apoptosis signaling pathway to which multiple anti-cancer signals converge. These findings identify the TRAIL (tumor-necrosis-factor-related apoptosis-inducing ligand) pathway as a central cell-autonomous anti-cancer weapon that can act independently of the immune system.

Apoptosis↗

Altered cardiovascular responses to chronic angiotensin II infusion in aged rats.

In this work we determined by telemetry the cardiovascular effects produced by Ang II infusion on blood pressure (BP) and heart rate (HR) in aged rats. Male Wistar aged (48-52 weeks) and young (12 weeks) rats were used. Ang II (6 microg/h, young, n=6; aged, n=6) or vehicle (0.9% NaCl 1 microl/h, young, n=4; aged, n=5) were infused subcutaneously for 7 days, using osmotic mini-pump. The basal diurnal and nocturnal BP values were higher in aged rats (day: 98+/-0.3 mm Hg, night: 104+/-0.4 mm Hg) than in the young rats (day: 92+/-0.2 mm Hg, night: 99+/-0.2 mm Hg). In contrast, the basal diurnal and nocturnal HR values were significantly smaller in the aged rats. Ang II infusion produced a greater increase in the diurnal BP in the aged rats (Delta MAP=37+/-1.8 mm Hg) compared to the young ones (Delta MAP=30+/-3.5 mm Hg). In contrast, the nocturnal MAP increase was similar in both groups (young rats; Delta MAP=22+/-3.0 mm Hg, aged rats; Delta MAP=24+/-2.6 mm Hg). During Ang II infusion HR decreased transiently in the young rats. An opposite trend was observed in the aged rats. Ang II infusion also inverted the BP circadian rhythm, in both groups. No changes in HR circadian rhythm were observed. These differences suggest that the aging process alters in a different way Ang II-sensitive neural pathways involved in the control of autonomic activity.

Aging↗

Thoracoscopic splanchnicectomy for "small duct" chronic pancreatitis: case selection by differential epidural analgesia.

Management of patients with intractable pain from "small duct" chronic pancreatitis has been difficult, often resulting in narcotic addiction and/or malnutrition from major pancreatic resection. Recently, denervation of sympathetic pain afferents from the pancreas by surgical splanchnicectomy has shown promise in relieving pain while preserving residual pancreatic function. However, results from surgical splanchnicectomy have been mixed in large part because of patient selection. Differentiating actual pancreatic pain from "pancreatic" pain caused by drug-seeking behavior, psychogenic diseases, or various somatically innervated conditions is clinically challenging at best. Between 1992 and 1996, twenty-two patients with 20 prior pancreatic operations, "small duct" chronic pancreatitis, and "pancreatic" pain requiring narcotics were evaluated. Each underwent differential epidural analgesia (DEA) using the following standard techniques: placebo, low-dose (sympathetic), and high-dose (somatic) blocks. Pain perceptions were recorded before and after DEA using a visual analogue scale (VAS). Six demonstrated a greater than 50% decrease in VAS pain after placebo injection and were eliminated from further study. In the remaining 16 patients, pain relief only occurred with sympathetic or somatic blockade. Greater and lesser splanchnicectomy (surgical splanchnicectomy) was performed 27 times in these 16 patients (11 bilateral, 6 synchronous) (5 unilateral; 2 right and 3 left) using thoracoscopic techniques in 14 patients and open thoracotomy in two. No significant surgical or anesthetic complications were encountered. Surgical splanchnicectomy resulted in an overall significant reduction in preoperative VAS scores (8.25 to 4.18; P <0.05). Ten of 13 patients with DEA-predicted sympathetic pain experienced a greater than 50% decrease in VAS after surgical splanchnicectomy, but only two had complete relief. None of the three patients with DEA-predicted somatic pain were benefited by splanchnicectomy. During an average follow-up of 23.3 months, initial good results from surgical splanchnicectomy were maintained in 8 of 10 patients. The following conclusions were reached: (1) surgical splanchnicectomy is a safe, often effective technique for amelioration of intractable pain from "small duct" chronic pancreatitis and (2) DEA is a promising approach for identifying patients most likely to respond to surgical splanchnicectomy.

Adult↗

Spinal cord stimulation does not change peripheral skin blood flow in patients with neuropathic pain.

BACKGROUND AND OBJECTIVE: Spinal cord stimulation has been used successfully for many years in the management of neuropathic pain. Nociceptive pathways are closely integrated into many autonomic reflexes. The aim was to test the hypothesis that pain relief caused by spinal cord stimulation is related to changes in peripheral skin blood flow. METHODS: Twelve patients with spinal cord stimulators implanted as a treatment for neuropathic pain were entered into the study. Laser Doppler perfusion scanning was used as a direct method for selective measurement of changes in skin (peripheral) blood flow. Measurements were taken before and after the onset of spinal cord stimulation over the site of its sensory projection. The degree of pain relief due to spinal cord stimulation and the skin temperature of each patient were also recorded. RESULTS: Apart from one patient, spinal cord stimulation did not change skin blood flow in a statistically significant manner. CONCLUSIONS: Pain relief due to spinal cord stimulation is not related to changes of skin blood flow.

Adult↗

Gibberellin response mutants identified by luciferase imaging.

The gibberellin (GA) 20-oxidase encoded by Arabidopsis GA5 catalyzes the synthesis of active GAs. GA5 is a regulatory step in GA biosynthesis as GA5 mRNA levels are negatively regulated by its bioactive GA products. A fusion between the GA5 promoter and the firefly luciferase reporter (GA5-LUC) was shown to be similarly regulated, indicating GA feedback of GA5 occurs at the transcriptional level. The fidelity of the GA5-LUC reporter permitted a fusion genetic screen to identify mutants altered in transgene expression. This bioimaging screen identified two types of recessive mutants with increased LUC activity and apparent GA-related growth phenotypes, a dwarf (lue1) and two late flowering mutants (fpa1-3 and fpa1-4). Mutant progeny exhibited altered levels of LUC and of endogenous GA5 and other GA-regulated mRNAs. SSLP-based mapping localized lue1 to chromosome I near the ga2 locus, although complementation analyzes showed that lue1 is not allelic to ga2. Mapping and complementation analyzes showed that the late flowering mutants are allelic to fpa1. This provides genetic evidence for crosstalk between the autonomous and gibberellin-dependent flowering pathways.

Arabidopsis↗

Activation of expression of hedgehog target genes in basal cell carcinomas.

Mutations in hedgehog signaling pathway genes, especially PTC1 and SMO, are pivotal to the development of basal cell carcinomas. The study of basal cell carcinoma gene expression not only may elucidate mechanisms by which hedgehog signaling abnormalities produce aberrant tumor cell behavior but also can provide data on in vivo hedgehog target gene control in humans. We have found, in comparison with normal skin, that basal cell carcinomas have increased levels of mRNA for PTC1, GLI1, HIP, WNT2B, and WNT5a; decreased levels of mRNA for c-MYC, c-FOS, and WNT4; and unchanged levels of mRNA for PTC2, GLI2, WNT7B, and BMP2 and 4. These findings suggest that mutations in hedgehog signaling pathway genes may exert both cell autonomous and indirect effects and indicate that basal cell carcinoma tumor cells have a phenotype that at least in some aspects resembles that of epidermal stem cells.

Basal Cell Carcinoma↗

Differential requirement for Rel/nuclear factor kappa B family members in natural killer T cell development.

Natural killer T (NKT) cells have been implicated in diverse immune responses ranging from suppression of autoimmunity to tumor rejection. Thymus-dependent NKT cells are positively selected by the major histocompatibility complex class I-like molecule CD1d, but the molecular events downstream of CD1d are still poorly understood. Here, we show that distinct members of the Rel/nuclear factor (NF)-kappa B family of transcription factors were required in both hematopoietic and nonhematopoietic cells for normal development of thymic NKT cells. Activation of NF-kappa B via the classical I kappa B alpha-regulated pathway was required in a cell autonomous manner for the transition of NK-1.1-negative precursors that express the TCR V alpha 14-J alpha 18 chain to mature NK-1.1-positive NKT cells. The Rel/NF-kappa B family member RelB, on the other hand, had to be expressed in radiation resistant thymic stromal cells for the generation of early NK-1.1-negative NKT precursors. Moreover, NF-kappa B-inducing kinase (NIK) was required for both constitutive thymic DNA binding of RelB and the specific induction of RelB complexes in vitro. Thus, distinct Rel/NF-kappa B family members in hematopoietic and nonhematopoietic cells regulate NKT cell development with a unique requirement for NIK-mediated activation of RelB in thymic stroma.

Animals↗

The C. elegans sex-determining gene fem-2 encodes a putative protein phosphatase.

The genetic and molecular analysis of genes involved in the regulation of sex determination in Caenorhabditis elegans suggests that the gene fem-2 plays an important role in regulating a pathway transducing a non-cell-autonomous signal to a nuclear transcription factor. The wild-type fem-2 gene was cloned by identifying sequences from the C. elegans physical map that could restore normal Fem-2 function to homozygous mutant fem-2 transgenic animals. cDNA sequences mapping to the minimal rescuing region correspond to an open reading frame with a sequence similar to protein phosphatase 2C enzymes from systems as diverse as yeast, humans, and plants, but the alignments suggest that FEM-2 falls into a separate class of proteins than the canonical homologues. Several fem-2 mutant alleles were sequenced, and the mutations are predicted to cause protein changes consistent with their observed phenotypes, such as missense mutations in conditional alleles, and a nonsense mutation in a predicted null allele. This is the first evidence implicating phosphorylation and/or dephosphorylation as a control mechanism in C. elegans sex determination.

Alleles↗

Endogenous opioid analgesia in hemorrhagic shock.

BACKGROUND: Hemorrhagic shock produces an immediate activation of the autonomic nervous system and endogenous opioid pathways. Our studies have demonstrated that endogenous opioid activation aggravates the hemodynamic and inflammatory responses to shock. However, it is unclear whether endogenous opioid activation is triggered by noxious stimuli and furthermore whether it produces analgesia. METHODS: Experiments were conducted in chronically catheterized, conscious, unrestrained, nonheparinized, male, Sprague-Dawley rats subjected to fixed pressure hemorrhage. Blood samples were obtained for determinations of circulating beta-endorphin and substance P. Analgesia was measured using the tail-flick response to a noxious stimulus before and during hemorrhage. The contribution of sensory neurons to eliciting the neuroendocrine, opioid, and inflammatory responses to hemorrhage was investigated in capsaicin-treated animals. RESULTS: Hemorrhagic shock produced marked naltrexone-sensitive analgesia without significant modulation of substance P. Peripheral sensory denervation did not alter the hemodynamic, neuroendocrine, or inflammatory responses to shock. CONCLUSION: Endogenous opioid activation during shock produces analgesia. Sensory neuron activation appears to have limited effect on shock-induced hemodynamic and proinflammatory responses. Furthermore, these results suggest that the activation of neuroendocrine and opioid pathways during shock is not likely to be a response to noxious stimuli.

Analgesics, Opioid↗

Reproducibility of transesophageal pacing in patients with Wolff-Parkinson-White syndrome.

The purpose of this study was to assess, in patients with ventricular preexcitation, the time dependent physiological variation of antegrade conduction properties in the AV node and in accessory pathways (Aps) as a function of autonomic tone variation induced by posture and physical effort, using noninvasive transesophageal atrial pacing. In 74 WPW patients (mean age 21.31 +/- 9.46 yrs), AV node and Kent antegrade effective refractory periods (at pacing cycle lengths 600, 400, and 320 ms), Wenckebach point, shortest preexcited RR intervals during sustained atrial fibrillation (AF) or atrial pacing, as well as the inducibility of AV reentry tachycardia (AVRT) and AF/flutter (AFL) were assessed. All measurements were carried out at rest, in supine and upright positions, and during effort. A second study was carried out approximately 3 months after the first study. The coefficient of variation (CVs) and reproducibility (CRs) were calculated. For each parameter, the differences between the mean of the two studies were not statistically significant. The CVs and CRs ranged between 0.4% and 4% and between 2 and 28 ms, respectively. AF was induced in 40 (54%) of 74 patients at the first study and in 30 (40.5%) of 74 patients at the second study. AVRT was induced in 33 (45%) of 74 patients at the first study and in 38 (51.3%) of 74 patients at the second study. The reproducibility was 45% for AF/AFL and 65% for reentry tachycardia. Transesophageal atrial pacing is a reliable method for noninvasive reproducible evaluation of antegrade electrophysiological properties of both the AV node and APs in WPW patients. However, the effect of autonomic balance variation has to be taken into account and precisely defined because it may significantly affect the inducibility of supraventricular arrhythmias and the estimation of the absolute values of the vulnerable parameters.

Adult↗

Efferent innervation of the small intestine by adrenergic neurons from the cervical sympathetic and stellate ganglia, studied by retrograde transport of peroxidase.

The nervous pathways between the small intestine of cat and guinea pig and various sympathetic ganglia were investigated by the retrograde horse-radish peroxidase (HRP) technique. HRP was injected at multiple sites in the wall of the duodenum and the first third of the jejunum. At 1--5 days after the injections, the HRP reaction product was searched for in various sympathetic ganglia. Not only the coeliac and nodose ganglia, but also the superior cervical, medial cervical, stellate and thoracic ganglia contained HRP-positive nerve cells. Crushing the cervical vagal nerve prevented the occurrence of HRP-reaction in the cervical ganglia, indicating that the HRP was transported from the gut to the cervical ganglia via axons in the vagal nerve. The results demonstrate that the sympathetic ganglia in the neck (sup, and med. cerv. ganglia and stellate ggl.) send efferent fibres to the small intestine.

Animals↗

Sympathetic nervous control of cerebrospinal fluid production from the choroid plexus.

The rabbit choroid plexus, responsible for the bulk production of cerebrospinal fluid, is well supplied by sympathetic nerves emanating in the superior cervical ganglia. Electrical stimulation of these nerves markedly reduces production of cerebrospinal fluid, measured by [14C] inulin dilution during ventricular perfusion, whereas sympathetic denervation enhances the rate of formation.

Adrenergic Fibers↗