Heart rate variability. The International Federation of Clinical Neurophysiology.
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Electrocardiography, Ambulatory↗
Biomedical subjects
R Baron
Publications and source records attributed to R Baron.
Assessment of blood pressure regulation. The International Federation of Clinical Neurophysiology.
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Blood Pressure↗
Dissociation between bone resorption and bone formation in osteopenic transgenic mice.
Bone mass is maintained constant in vertebrates through bone remodeling (BR). BR is characterized by osteoclastic resorption of preexisting bone followed by de novo bone formation by osteoblasts. This sequence of events and the fact that bone mass remains constant in physiological situation lead to the assumption that resorption and formation are regulated by each other during BR. Recent evidence shows that cells of the osteoblastic lineage are involved in osteoclast differentiation. However, the existence of a functional link between the two activities, formation and resorption, has never been shown in vivo. To define the role of bone formation in the control of bone resorption, we generated an inducible osteoblast ablation mouse model. These mice developed a reversible osteopenia. Functional analyses showed that in the absence of bone formation, bone resorption continued to occur normally, leading to an osteoporosis of controllable severity, whose appearance could be prevented by an antiresorptive agent. This study establishes that bone formation and/or bone mass do not control the extent of bone resorption in vivo.
Animals↗
[Sympathetic nervous system and pain--some open questions].
BACKGROUND: Neuropathic pain syndromes may be treated by intervention at the sympathetic nervous system. The pain in these syndromes is therefore called sympathetically maintained pain (SMP). Typical disorders with a SMP component are complex regional pain syndromes (reflex sympathetic dystrophy and causalgia), traumatic neuralgias and herpes zoster. RESULTS: Open questions are how the efferent sympathetic nervous system is capable of influencing pain sensation and which mechanisms underly the autonomic dysregulation often observed in these syndromes.(1) Somatic afferents that project through the sympathetic trunk do not exist. Therefore, a pure sympathetic block does not block afferent information arising from the affected extremity. What alternatives are possible? Under pathophysiological conditions a functional interaction of efferent sympathetic fibers and afferent nociceptive fibers could be demonstrated in patients and animal studies. The intensity of this coupling varies considerably between individual patients and is not necessary for the diagnosis of the disorder. (2) Sympathetically maintained pain and signs of autonomic dysfunction are independent clinical and pathophysiological phenomena without any causal relation. However, it is possible to treat both the SMP and the autonomic dysfunction with sympathetic blocks.
English Abstract↗
The calcitonin receptor stimulates Shc tyrosine phosphorylation and Erk1/2 activation. Involvement of Gi, protein kinase C, and calcium.
While it is well established that adenylyl cyclase and phospholipase C-beta are two proximal signal effectors for the calcitonin receptor, the more distal signaling pathways are less well characterized. G protein-coupled receptors can activate Erk1/2 by Gs-, Gi-, or Gq-dependent signaling pathways, depending on the specific receptor and cell type examined. Since the calcitonin receptor can couple to all three of these G proteins, the ability of calcitonin to activate Erk1/2 was investigated. Calcitonin induced time- and concentration-dependent increases in Shc tyrosine phosphorylation, Shc-Grb2 association and Erk1/2 phosphorylation and activation in a HEK 293 cell line that stably expresses the rabbit calcitonin receptor C1a isoform. Pertussis toxin, which inactivates Gi, and calphostin C, a protein kinase C inhibitor, each partially inhibited calcitonin-induced Shc tyrosine phosphorylation, Shc-Grb2 association, and Erk1/2 phosphorylation. In contrast, neither forskolin nor H89, a protein kinase A inhibitor, had a significant effect on basal or calcitonin-stimulated Erk1/2 phosphorylation. Our results suggest that the calcitonin receptor induces Shc phosphorylation and Erk1/2 activation in HEK293 cells by parallel Gi- and PKC-dependent mechanisms. The calcitonin-induced elevation of cytosolic free Ca2+ was required for Erk1/2 phosphorylation, since preventing any change in cytosolic free Ca2+ by chelating both cytosolic and extracellular Ca2+ abolished the response. However, the change in Ca2+ that is induced by calcitonin is not sufficient to account for the calcitonin-induced Erk1/2 phosphorylation, since treatment with 100 nM ionomycin or 10 microM thapsigargin, each of which induced elevations of Ca2+ comparable to those induced by calcitonin, induced significantly less Erk1/2 phosphorylation than that induced by calcitonin. Erk1/2 may have important roles as downstream effectors mediating cellular responses to calcitonin stimulation.
Adaptor Proteins, Signal Transducing↗
[Quantitative thermotest - investigations of thermal and nociceptive afferents in neuropathy. Is a multicentric approach useful to investigate rare painful neuropathies?].
Disturbances of small afferent nerve fibres play an important role in painful neuropathies. Quantitative thermotest offers a possibility to quantify these disturbances that can not be detected by conventional electrophysiology. It is a psychophysical method to investigate thermal and nociceptive afferents by determining thermal thresholds. Former experiences have shown that quantitative thermotest can be a helpful tool not only in daily routine but also for research work concerning pathophysiological mechanisms of neuropathy. Therefore a multicentric approach to investigate rare painful neuropathies seems to be useful.
English Abstract↗
Cloning and initial characterization of mouse meltrin beta and analysis of the expression of four metalloprotease-disintegrins in bone cells.
Here we report the cloning and initial biochemical characterization of the mouse metalloprotease/disintegrin/cysteine-rich (MDC) protein meltrin beta and the analysis of the mRNA expression of four MDC genes (meltrin alpha, meltrin beta, mdc9, and mdc15) in bone cells, including osteoclasts and osteoblasts. Like most other MDC proteins, the predicted meltrin beta protein consists of a signal sequence, prodomain, metalloprotease domain with a predicted catalytic site, disintegrin domain, cysteine-rich region, epidermal growth factor repeat, transmembrane domain, and cytoplasmic domain with putative signaling motifs, such as potential SH3 ligand domains. Northern blot analysis indicates that meltrin beta is widely expressed, with the highest expression in bone, heart, and lung. RNase protection studies revealed expression of all four MDC genes analyzed here in osteoblasts, whereas only mdc9 and mdc15 mRNAs were detectable in osteoclast-like cells generated in vitro. Treatment of primary osteoblasts with 10 nM calcitriol increased meltrin beta expression more than 3-fold, and both meltrin alpha and meltrin beta expression is apparently regulated in a differentiation-associated manner in a mouse osteoblastic cell line, MC3T3E1. Collectively, these results suggest that meltrin alpha and meltrin beta may play a role in osteoblast differentiation and/or function but are not likely to be involved in osteoclast fusion.
ADAM Proteins↗
Postherpetic neuralgia: irritable nociceptors and deafferentation.
Postherpetic neuralgia (PHN) is a common and often devastatingly painful condition. It is also one of the most extensively investigated of the neuropathic pains. Patients with PHN have been studied using quantitative testing of primary afferent function, skin biopsies, and controlled treatment trials. Together with insights drawn from an extensive and growing literature on experimental models of neuropathic pain these patient studies have provided a preliminary glimpse of the pain-generating mechanisms in PHN. It is clear that both peripheral and central pathophysiological mechanisms contribute to PHN pain. Some PHN patients have abnormal sensitization of unmyelinated cutaneous nociceptors (irritable nociceptors). Such patients characteristically have minimal sensory loss. Other patients have pain associated with small fiber deafferentation. In such patients pain and temperature sensation are profoundly impaired but light moving mechanical stimuli can often produce severe pain (allodynia). In these patients, allodynia may be due to the formation of new connections between nonnociceptive large diameter primary afferents and central pain transmission neurons. Other deafferentation patients have severe spontaneous pain without hyperalgesia or allodynia and presumably have lost both large and small diameter fibers. In this group the pain is likely due to increased spontaneous activity in deafferented central neurons and/or reorganization of central connections. These three types of mechanism may coexist in individual patients and each offers the possibility for developing new therapeutic interventions.
Afferent Pathways↗
[Pain syndromes with causal participation of the sympathetic nervous system].
The efferent sympathetic nervous system is organized into subsystems that innervate and regulate via separate peripheral sympathic pathways the different autonomic target organs. This review discusses mechanisms through which this efferent system may be causally involved in the generation of pain. Clinical pain syndromes in which this may be the case are "complex regional pain syndromes" (CRPS) type I (previously reflex sympathetic dystrophy) and type II (recently causalgia). The "sympathetically maintained pain" (SMP) is a symptom (and not a clinical entity) that can principally also be present in other pain syndromes. An explanatory hypothesis, which may explain the clinical phenomenology of CRPS (different types of pain, swelling, autonomic, motor and trophic changes) and the mechanisms involved, is described and discussed. This hypothesis consists of different components that either have been tested and verified experimentally or which are still hypothetical. The hypothesis consists of changes in the primary afferent (nociceptive and non-nociceptive) neurones (sensitization, ectopic impulse generation) and of the neurones in the spinal cord (preferentially in the dorsal horn) which are secondary consequences of the changes in the primary afferent neurones ("central sensitization"). These changes are not specific for SMP. The centerpiece of the hypothesis is a positive feedback circuit that consists of the primary afferent neurones, spinal cord neurones, sympathic neurones and the pathologic sympathetic-afferent coupling. This coupling can occur directly via noradrenaline (or possibly another substance) at different sites of the afferent neurone (at the lesion site, remote from the lesion site in the periphery and in the spinal ganglion). The direct coupling requires that the afferent neurone expresses adrenoceptors. Indirect coupling can occur via the vascular bed or otherwise, e.g. by changes of the neurovascular transmission. The activity in the sympathetic neurones to the affected extremity can change. This change does not consist of a generalized increase of sympathetic activity but of a change of the reflexes (e.g., thermoregulatory and nociceptive reflexes). From this follows that the pathophysiologal processes operating in CRPS may occur at four levels of integration that interact with each other: effector organ, peripheral afferent and sympathetic neurone, spinal cord, supraspinal centres. Recent experimental investigations on rats show that the sympathetic nervous system is possibly also causally involved in the generation of inflammation and inflammatory pain. The mechanisms by which this occurs are different from those operating in SMP during CRPS.
Animals↗
Color vision in two observers with highly biased LWS/MWS cone ratios.
Two sisters, heterozygous carriers for congenital X-linked protanopia, were diagnosed as normal trichromats by the Rayleigh match on the anomaloscope. The heterozygous state was established by molecular analysis of their visual pigment genes. The normal color match establishes that the spectral sensitivities of their long-wavelength-sensitive (LWS) and middle-wavelength-sensitive (MWS) cone visual photopigments are within normal variability. Their FM 100-hue test error scores were low, demonstrating superior chromatic discrimination. Heterochromatic flicker photometric (HEP) spectral sensitivities were like those of protanopes. The estimated LWS/MWS cone ratios from the HFP data were 0.09/1 and 0.03/1, compared with ratios in the range of 0.6/1 to 10/1 for typical normal trichromats. Measurements of chromatic grating acuity on chromatically selective backgrounds were performed to study the cone mosaic. The data were consistent with a sparsity of LWS cones. Both protan carriers showed normal spectral sensitivities for all three cone types under cone isolating chromatic adaptation and normal three-peaked curves for increment thresholds on a white pedestal. Hue estimation, run on one carrier was normal. The equilibrium yellow locus was measured in the other carrier and was in the range of normal trichromats. The data indicate that normal color vision can occur even when the LWS/MWS cone ratio is quite abnormal.
Adaptation, Ocular↗
Traumatic neuralgias: complex regional pain syndromes (reflex sympathetic dystrophy and causalgia): clinical characteristics, pathophysiological mechanisms and therapy.
Complex regional pain syndromes (CPRS) may develop as a disproportionate consequence of a trauma affecting the limbs without (CRPS I, reflex sympathetic dystrophy) or with (CRPS II, causalgia) obvious nerve lesions. The clinical picture of CRPS consists of asymmetrical distal extremity pain, swelling, and autonomic (sympathetic) and motor symptoms. Changes in the peripheral and central somatosensory, autonomic and motor processing, and a pathologic interaction of sympathetic and afferent systems are discussed as underlying pathophysiologic mechanisms. Therapeutic strategies include pharmacologic pain relief, sympatholytic interventions, and rehabilitation.
Analgesics↗
Complex Regional Pain Syndromes: guidelines for therapy.
This report aims to present an orderly approach to the treatment of Chronic Regional Pain Syndrome (CRPS) types I and II through an algorithm. The central theme is functional restoration: a coordinated but progressive approach that introduces each of the treatment modalities needed to achieve both remission and rehabilitation. Reaching objective and measurable rehabilitation goals is an essential element. Specific exercise therapy to reestablish function after musculoskeletal injury is central to this functional restoration. Its application to CRPS is more contingent on varying rates of progress that characterize the restoration of function in patients with CRPS. Also, the various modalities that may be used, including analgesia by pharmacologic means or regional anesthesia or the use of neuromodulation, behavioral management, and the qualitatively different approaches that are unique to the management of children with CRPS, are provided only to facilitate functional improvement in a stepwise but methodical manner. Patients with CRPS need an individual approach that requires extreme flexibility. This distinguishes the management of these conditions from other well-described medical conditions having a known pathophysiology. In particular, the special biopsychosocial factors that are critical to achieving a successful outcome are emphasized. This algorithm is a departure from the contemporary heterogeneous approach to treatment of patients with CRPS. The underlying principles are motivation, mobilization, and desensitization facilitated by the relief of pain and the use of pharmacologic and interventional procedures to treat specific signs and symptoms. Self-management techniques are emphasized, and functional rehabilitation is the key to the success of this algorithm.
Algorithms↗
Normalization of mineral ion homeostasis by dietary means prevents hyperparathyroidism, rickets, and osteomalacia, but not alopecia in vitamin D receptor-ablated mice.
1,25-Dihydroxyvitamin D3 plays a major role in intestinal calcium transport. To determine what phenotypic abnormalities observed in vitamin D receptor (VDR)-ablated mice are secondary to impaired intestinal calcium absorption rather than receptor deficiency, mineral ion levels were normalized by dietary means. VDR-ablated mice and control littermates were fed a diet that has been shown to prevent secondary hyperparathyroidism in vitamin D-deficient rats. This diet normalized growth and random serum ionized calcium levels in the VDR-ablated mice. The correction of ionized calcium levels prevented the development of parathyroid hyperplasia and the increases in PTH messenger RNA synthesis and in serum PTH levels. VDR-ablated animals fed this diet did not develop rickets or osteomalacia. However, alopecia was still observed in the VDR-ablated mice with normal mineral ions, suggesting that the VDR is required for normal hair growth. This study demonstrates that normalization of mineral ion homeostasis can prevent the development of hyperparathyroidism, osteomalacia, and rickets in the absence of the genomic actions of 1,25-dihydroxyvitamin D3.
Alopecia↗
Murine bone marrow stromally derived BMS2 adipocytes support differentiation and function of osteoclast-like cells in vitro.
Stromal cells are required for in vitro osteoclast differentiation and maturation. The murine bone marrow stromally derived BMS2 cell line exhibits adipocytic and osteoblastic features as well as the ability to support lymphopoiesis and myelopoiesis. This work examined the ability of the BMS2 cell in either the preadipocyte or adipocyte state to support the formation of osteoclast-like cells. BMS2 cells can be induced to undergo adipogenic differentiation in response to treatment with glucocorticoids or thiazolidinedione compounds. Primary bone marrow cells, enriched for hematopoietic progenitors and depleted of their adherent stromal and macrophage populations, were stimulated with vitamin D3 (vitamin D; 10(-8) M) to undergo osteoclast differentiation and maturation when cocultured with BMS2 cells. In both preadipocyte and adipocyte-enriched BMS2 stromal layers, comparable numbers of tartrate-resistant acid phosphatase-positive osteoclast-like cells, characterized by their response to salmon calcitonin with an increase in cAMP and formation of resorption pits on bovine bone slices, were formed. The gene expression and protein levels of macrophage colony-stimulating factor produced by preadipocyte and adipocyte-rich BMS2 layers were comparable. However, adipocyte-rich stromal layers supported osteoclast-like cell formation longer in culture than preadipocytes, independent of the agent used to induce adipocyte differentiation. These studies demonstrate for the first time that fully differentiated adipocyte stromal cells can support osteoclast-like cell formation and function in vitro.
Acid Phosphatase↗
A new method to isolate large numbers of rabbit osteoclasts and osteoclast-like cells: application to the characterization of serum response element binding proteins during osteoclast differentiation.
We have developed a new method that allows the purification of large numbers of both authentic osteoclasts (OCs) and in vitro differentiated osteoclast-like cells (OCLs) from rabbits. We characterized the OCLs in terms of the expression of different phenotypic markers of OC differentiation and their ability to resorb bone. The method provides a system for performing biochemical and molecular studies of OC differentiation and function in a single species. We used this system to characterize the effect of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) on the expression of proteins that bind to the serum response element (SRE) of the c-fos promoter. We found that OCLs and OCs displayed similar SRE-binding activities, including the serum response factor (SRF). This pattern is established in a time-dependent and cell-specific manner in response to long-term treatment of rabbit bone marrow by 1,25(OH)2D3. Thus, 1,25(OH)2D3 can modulate SRF and/or SRF-related protein. This finding may contribute to understanding the role of c-Fos in the regulation of OC differentiation.
Animals↗
Optimal treatment of phantom limb pain in the elderly.
Phantom limb and stump pain is a common sequela of amputation. In geriatric patients with an amputated limb and multiple other illnesses, drug therapy may be problematic and invasive techniques may be risky. Interactions between pathophysiological mechanisms in the peripheral and central nervous systems may be responsible for the initiation and maintenance of chronic phantom limb and stump pain. These mechanisms include: (i) peripheral damage to nociceptive fibres and dorsal root ganglion cells, which acquire abnormal sensitivity to mechanical, thermal and chemical stimuli; (ii) the prolonged sensitisation of central nociceptive 'second order' neurons in the dorsal horn of the spinal cord, which become hyperexcitable and start responding to nonnoxious stimuli; and (iii) the degeneration of nociceptive neurons, which may trigger the anatomical sprouting of low threshold mechanosensitive terminals to form connections with central nociceptive neurons. This may subsequently induce functional synaptic reorganisation in the dorsal horn. The provision of a pain-free perioperative interval using regional anaesthetic techniques is likely to reduce the incidence of phantom limb pain. The therapy of manifest pain is difficult, and treatment should start as soon as possible to prevent chronic pain. In the acute state, the infusion of calcitonin and oral opioid analgesics have proven to be helpful, while established phantom limb pain may respond to antidepressants, anticonvulsants and drugs that mimic or enhance gamma-aminobutyric acid function. Pharmacological treatment should be combined with transcutaneous electrical nerve stimulation, sympathetic blockade and psychotherapy. In addition, new therapeutic strategies are now being tested; examples include capsaicin, new anticonvulsants and N-methyl-D-aspartate antagonists. Patients with severe pain should be referred to a pain specialist to ensure optimal and timely interventional pain management.
Amputation Stumps↗
The relationship between isokinetic quadriceps strength test and hop tests for distance and one-legged vertical jump test following anterior cruciate ligament reconstruction.
Isokinetic measurements and functional tests are often used to assess function following knee ligament reconstruction using the opposite limb as a control. However, the question of whether the uninvolved leg may serve as a reference on functional tests has not been adequately answered. In particular, the one-legged rebound vertical jump has not been used to assess functional levels following surgery of the cruciate ligament. The purposes of this study were: 1) to determine whether the uninvolved leg is within normal range of an age- and weight-matched group, 2) to determine differences between the involved and uninvolved leg in patients after anterior cruciate ligament reconstruction, 3) to examine the relationship between knee extensor strength and four functional performance tests, and 4) to determine if the one-legged rebound vertical jump yields more information in the assessment of knee function than the other functional tests with respect to two time-frames. Fifty healthy subjects (group A, mean age = 28.1 years) and 55 anterior cruciate ligament patients (groups B and C) participated in dynamometric measurement, one-legged and two-legged vertical jump, and the single- and the triple-hop test. Mean time for testing was 13 weeks following surgery for group B (N = 30, mean age = 27.8 years) and 54 weeks following surgery for group C (N = 25, mean age = 29.9 years). Pearson product moment correlation coefficients between peak torque and single and triple hop were r = .45, r = .48, r = .51, and r = .55 for groups B and C, respectively. Pearson product moment correlation coefficients between peak torque and the height of the vertical jump was r = .51 for group C. Results for group A revealed limb symmetry indices of 95% or more on all functional performance and isokinetic tests. In group B, all patients showed a limb symmetry index of less than 85% on all tests. In group C, the index for the vertical jump was the only functional test that fell below the level of 85%. Regardless of whether the dominant or nondominant leg is involved, the uninvolved leg can be used adequately as a reference guide for outcome from rehabilitation using these measurements. The one-legged vertical jump test is capable of detecting functional limitations of the lower limb following knee ligament reconstruction up to 54 weeks postoperatively.
Adult↗
[Prevention of postherpetic neuralgia: does it exist?].
THEORETICAL CONSIDERATIONS: Several pathophysiological mechanisms may be responsible for initiation and maintenance of chronic postherpetic pain. (1) Peripheral nociceptive fibers can develop abnormal sensitization. Secondary to this, central nociceptive "second-order" neurons in the spinal cord dorsal horn can also be sensitized, i.e. they become hyperexcitable and start responding to non-noxious stimuli. (2) Degeneration of nociceptive neurons may trigger anatomical sprouting of low-threshold mechanosensitive terminals to form connections with central nociceptive neurons and may subsequently induce functional synaptic reorganization in the dorsal horn. According to these mechanisms theoretical possibilities of therapeutical interventions to prevent postherpetic neuralgia are (1) adequate analgesia in the acute phase (analgesics, antidepressants, sympathetic blocks) and (2) prevention of C-fiber degeneration by reducing the inflammatory reaction (antiviral drugs, corticosteroids, neurotrophins). CLINICAL EXPERIENCE: The present clinical trials concerning prevention of postherpetic neuralgia were analyzed. Only for the antiviral drugs have valid clinical studies been performed. Using acyclovir a considerable reduction of acute pain and time to healing could clearly be demonstrated. However, there was no significant effect on prevention of postherpetic neuralgia. The second-generation antiviral drugs valaciclovir and famciclovir may be more effective when applied early in the disease course. Preliminary studies indicate that the early onset of therapy with the antidepressant agent amitriptyline may reduce the incidence of postherpetic neuralgia. These results need to be confirmed in further studies. CONCLUSION: Although there is no clear evidence in favor of a prevention of postherpetic neuralgia for any of the interventions, it is definitely reasonable to perform the best analgesia possible during the acute phase of herpes zoster.
English Abstract↗