Biomedical subjects
B Sadowski
Publications and source records attributed to B Sadowski.
Bone marrow side population (SP) cells are donor derived after allogeneic stem cell transplantation in humans.
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[Onset of bilateral blindness in the first year of life. Alström syndrome].
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Antidepressant-type effect of the NK3 tachykinin receptor agonist aminosenktide in mouse lines differing in endogenous opioid system activity.
The influence of the tachykinin NK3 receptor agonist, aminosenktide on the immobility in the forced swimming test was studied in mouse lines selectively bred for divergent magnitudes of stress-induced analgesia. The high analgesia (HA) line is known to display enhanced, and the low analgesia (LA) line displays reduced activity of the opioid system. Aminosenktide at doses of 125 microg/kg or 250 microg/kg intraperitoneally (IP) reduced, in naltrexone-reversible manner, the immobility more of opioid receptor-dense HA than of unselected mice, but was ineffective in the opioid receptor-deficient LA line. The effect of aminosenktide was quite similar to the antiimmobility action of desipramine (10 mg/kg IP), a prototypic antidepressant agent. None of the compounds increased animals' locomotion as found with an open field test; therefore their antiimmobility effect cannot be attributed to a change in general motility. The results claim that aminosenktide causes an antidepressant effect, and endogenous opioids are involved in this process.
Acoustic startle and open-field behavior in mice bred for magnitude of swim analgesia.
Acoustic startle response (ASR) and open-field activity was examined in the 46th generation of mice that have been selectively bred for high analgesia (HA) and for low analgesia (LA) induced by 3-min swimming in 20 degrees C water. These lines were earlier found to differ in brain opioid receptor density and in the expression of opioid-mediated phenomena, as analgesic sensitivity to opiates and reversibility of swim stress-induced analgesia (SSIA) by naloxone. For comparison, a randomly bred control (C) line was used. To measure the amplitude of ASR, the mice were exposed to 110-dB acoustic stimuli in a Coulbourn apparatus. In saline-injected mice, the ASR force was found significantly lower in the LA than in the HA, as well in the C line, but did not differ between the two last lines. Naltrexone hydrochloride (10 mg/kg IP 30 min before ASR testing) augmented the startle in the opioid receptor-dense HA line, but had no effect in the opioid receptor-deficient LA line, as well in the C line; therefore, the ASR magnitude in naltrexone-injected HA mice was significantly higher compared to the C line. HA mice displayed less activity in an open-field test; that is, they remained immobile longer in the center of the field, and thereafter performed less ambulation and less rearing against the wall compared to the LA line. Naltrexone failed to modify the open-field activity in any line. The results confirm that the pattern of ASR depends on the genetic makeup of the animals. The higher amplitude of ASR, taken together with the lower open-field activity of HA mice, can be interpreted in terms of higher anxiety level, compared to the LA line. It is suggested that the higher ASR in HA mice relies on a nonopioid mechanism, which is tonically inhibited by the opioid system.
[Reading ability and need for reading aids, inadequate management of a nursing home population].
INTRODUCTION: In our society people are getting older and often become handicapped and immobile. Reading then is one of their main passtime and very important for their social integration and independence. PATIENTS AND METHODS: Seventy-seven (6 males, 71 females) randomly chosen elderly people (age ranged from 77 to 94 years, mean: 85.5 years) staying in nursing homes were examined concerning their reading ability of newspaper print with their own reading equipment. Exclusion criteria were extensive organic diseases and impaired mental ability, such as dementia. Relevant anamnestic data, including ophthalmologic, family and social history were ascertained by questionnaire. Special attention was given to visual acuity for near distance, reading ability, motivation and personal reading aids. Further questions dealt with general diseases, medication, social contacts inside and outside the nursing homes and the former occupation of the patient. If reading of newspaper print with individual glasses was impossible, the effect of magnification was evaluated and the magnification factor was determined (Zeiss reading charts). RESULTS: Thirty-eight people (45%) were unable to read with their own reading glasses. 91% of them regained reading ability by magnification, they had inadequate visual aids. 77% of this group had a magnification requirement of 1 to 3 times, 14% needed 10 to 25 times of magnification and 9% more than 25 times. Only one person had an electronic magnifying reading system (CCTV). CONCLUSION: Reading aids of elderly people very frequently are insufficient. Magnification can be helpful in most cases and various magnification systems are available. With this support elderly people could regain their quality of life, their independence and socialization. Nursing costs could also be reduced.
Mu and delta opioid receptor analgesia, binding density, and mRNA levels in mice selectively bred for high and low analgesia.
The present study examined mu and delta opioid analgesia, receptor binding, and receptor mRNA levels in lines of mice from two selective breeding projects of relevance to opioid analgesia. Large differences were observed in the analgesic potency of [d-Ala2, NMPhe4, Gly-ol]enkephalin (DAMGO), [d-Pen2,5]enkephalin (DPDPE), and [d-Ala2]deltorphin II (DELT), selective mu, delta1, and delta2 opioid receptor agonists, respectively, in mice selectively bred for high (HA) and low (LA) swim stress-induced analgesia (SIA). HAR and LAR mice, selectively bred for high and low levorphanol analgesia, respectively, display equally large differences in their analgesic sensitivity to DAMGO, modest differences in sensitivity to DPDPE, and no differences in sensitivity to DELT. These sizable genotypic differences in analgesic potency were accompanied by HA/LA and HAR/LAR differences in whole-brain homogenate [3H]DPDPE and/or [3H]DELT, but paradoxically not [3H]DAMGO, binding. Solution hybridization of mRNA extracts encoding mu (MOR-1) or delta (DOR-1) opioid receptors indicated some regional differences in gene expression between high and low lines. Surprisingly, differences in these in vitro markers were often in the direction of LAR>HAR. The present data indicate that selection for either SSIA or levorphanol analgesia produces differential effects on mu and delta opioid analgesia that are accompanied by alterations on in vitro assays, the significance of which remains to be determined. The data are discussed with regard to the utility of in vitro biological markers and genetic models of analgesia.
Analgesia in selectively bred mice exposed to cold in helium/oxygen atmosphere.
In order to evaluate the stressing role of swim hypothermia in producing swim stress-induced analgesia (SSIA), we examined whether a mere decrease in the animals' core temperature without swimming would be sufficient to elicit analgesia. The subjects were Swiss-Webster mice selectively bred for 37 and 40 generations for divergent magnitudes of SSIA. High (HA) and low analgesia (LA) mice were exposed for 15 min to temperatures in the range between -5 and +20 degrees C in 79% He/21% O2 (Heliox) atmosphere. The Heliox exposure produced ambient temperature-dependent hypothermia and analgesia, as assessed with a hot-plate test (56 degrees C). The post-Heliox analgesia was of much higher magnitude in HA than in LA mice. The steeper slope of regression of the magnitude of analgesia upon hypothermia in HA mice indicates that these mice are far more sensitive to the analgesic effect of hypothermia than LA mice. Naltrexone HCl (10 mg/kg i.p.) attenuated analgesia in ambient temperature-dependent manner in HA, but not in LA mice. In view of the apparent similarity of Heliox-induced analgesia and SSIA we suggest that hypothermia is a powerful component of swim stress to induce SSIA in the mouse.
Alterations of brain monoamine levels in pigs exposed to acute immobilization stress.
Concentrations of noradrenaline (NA), adrenaline (A), dopamine (DA) and 5-hydroxytryptamine (5-HT), as well as DA metabolites 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and the main 5HT metabolite, 5-hydroxyindole-3-acetic acid (5-HIAA), were measured using the HPLC technique in 15 brain areas of control and immobilized Duroc pigs. The animals were immobilized for 5, 15, 30 and 60 min in a prone position. Control pigs displayed patterns of regional distribution of brain monoamines similar to those described in other species, especially rats and dogs. However, absolute values of noradrenaline and adrenaline in the hypothalamus were much higher than in other species. Also, in most structures, the DOPAC/DA ratio was relatively high, in comparison to a relatively low HVA/DA ratio, which suggests a species-related difference in the turnover of dopamine. The most conspicuous changes produced by immobilization stress consisted of a substantial decrease in the hypothalamic levels of noradrenaline and adrenaline. Dopamine and 5-HT turnover was affected in the hippocampus (cornu Ammonis), and in the raphe nuclei. These structures are proposed to play a major role in the responsiveness of pigs to acute stress conditions.
Acute morphine dependence in mice selectively-bred for high and low analgesia.
Acute morphine dependence was compared in mice selectively-bred for high (HA) and low (LA) swim stress-induced analgesia and high (HAR) and low (LAR) levorphanol analgesia by counting the number of naloxone-precipitated jumps. Whereas LAR mice displayed greater acute morphine dependence than HAR mice, HA and LA mice did not differ. No genotypic differences were observed in non-dependent mice, discounting possible differences in basal naloxone sensitivity and/or opioid peptide levels. Thus, the two selection projects, while both producing lines exhibiting highly divergent sensitivity to morphine analgesia, have not had analogous effects on all opioid measures, supporting the notion of independent genetic mediation of opioid analgesia and dependence. Further, these data suggest that analgesic sensitivity may not predict sensitivity to morphine dependence.
["Oligocone" trichromasy, a rare form of incomplete achromatopsia].
PATIENTS AND METHODS: An 11-year-old girl presented because of reduced visual acuity while color vision was almost normal. Besides a general ophthalmological examination, special psychophysical tests, such as perimetry, color vision tests using pseudoisochromatic plates, arrangement tests, the Nagel anomaloscope and spectral sensitivity measurement, and electrophysiological tests (electroretinogram and electrooculogram) were conducted. RESULTS: The tests yielded the following: congenital nystagm, normal results at ophthalmoscopy, best visual acuity of 0.1 monocular and 0.2 binocular. Perimetry revealed a relatively central scotoma. All color vision tests showed only mild dysfunction of the blue-sensitive cones. Findings at photopic electroretinogram were almost completely lacking. There was no sign of progression in the last 6 years. CONCLUSION: Differential diagnosis includes all diseases associated with congenital nystagm, such as aniridia, diseases of the optic nerve, albinism and all forms of hereditary cone dysfunction, cone dystrophies and complete and incomplete congenital stationary monochromatism. In the present case the findings are most congruent with oligocone trichromasy.
Cone and rod function in cone degenerations.
Progressive cone dystrophy (CD) is usually marked in the initial stages by reduced visual acuity, color vision deficiency and alterations in the photopic electroretinogram, while morphological alterations can be very mild; in some forms rods are affected in a later stage as well. We examined 40 patients with progressive cone dystrophy to determine the extent of functional losses in the cone system with psychophysical tests. A great variety of visual acuity and fundus alterations was found. Myopia was present in 74% of the patients. An autosomal dominant pattern of inheritance predominated (32%). No prevalence of gender was found. The age of onset ranged between 10 and 30 yr. All patients had progression of their symptoms. The total error score in color arrangement tests, the saturated Farnsworth Panel D-15 and the Farnsworth-Munsell 100-hue test, was pathologic with a predominance of confusions along the tritan and scotopic axis. Especially if visual acuity was below 0.5, color vision defects increased, but color vision defects were also found in patients with normal visual acuity. A general decrease of sensitivity in all three cone mechanisms was observed in measurements of spectral sensitivity. Moreover, cone-cone interaction as tested by transient tritanopia measurements was usually disturbed. In the dark adaptation function the threshold of the cone branch was usually elevated. These tests provide a good means to ascertain the correct diagnosis in early stages of the disease and to monitor progression in patients suffering from cone dystrophy.
Metabolic correlates of selection for swim stress-induced analgesia in laboratory mice.
The upper limits of metabolic rates and the links between maximal and resting metabolic rates in vertebrates have recently received a lot of attention, mainly due to their possible relationship to the evolution of endothermy. We measured peak metabolic rates during 3 min swimming in 20 degrees C water (Vo2swim), maximal metabolic rate (Vo2max) in -2.5 degrees C Helox, and basal metabolic rate (BMR) in two lines of mice selected for high (HA) and low (LA) swim stress-induced analgesia (SSIA). We found that exercise combined with heat loss used for producing SSIA also acted as a selection agent, resulting in a 15% HA/LA line difference in Vo2swim. Core body temperature of HA mice (characterized by lower Vo2swim) was also on average 3.2 degrees C lower than that of LA mice. Furthermore, Vo2max of HA mice was lower than that of LA mice by 8% and accompanied by larger hypothermia. Thus mice with exceptionally high (or low) Vo2max tended to have exceptionally high (or low) Vo2swim, resulting in a positive correlation between Vo2swim and Vo2max. All these suggest that selection for SSIA produced genetically correlated responses in both Vo2swim and Vo2max. However, we did not observe HA/LA differences in BMR. Hence, changes in resting and maximum metabolic rates are not necessarily correlated. We hypothesize that the lack of such a correlation was partially due to the modulation of metabolic responses by SSIA.
The genetics of pain and pain inhibition.
The present review summarizes the current state of knowledge about the genetics of pain-related phenomena and illustrates the scope and power of genetic approaches to the study of pain. We focus on work performed in our laboratories in Jastrzebiec, Poland; Portland, OR; and Los Angeles, which we feel demonstrates the continuing usefulness of classical genetic approaches, especially when used in combination with newly available molecular genetic techniques.
Opioid and nonopioid swim stress-induced analgesia: a parametric analysis in mice.
Environmental stress causes the activation of two types of endogenous pain inhibitory systems in animals: opioid analgesia is antagonized by opiate receptor blockers (e.g., naloxone and naltrexone), whereas analgesia produced by nonopioid systems is insensitive to such antagonism. A large literature documents that the parameters of the laboratory stressor will determine the neurochemical identity of the resultant analgesia. In rats, low severity stressors produce opioid analgesia and higher severity stressors produce nonopioid analgesia. A recent parametric analysis of swim stress-induced analgesia (SSIA) in the female Quackenbush mouse, however, observed the opposite pattern. The present study is a parametric analysis of SSIA using a range of swim temperatures (15-38 degrees C), swim durations (45 s to 7 min), and genetic models [male Swiss-Webster mice, and mice selectively bred from this outbred strain for high (HA), low (LA), or control SSIA]. We find that in nonselected mice low severity swims (i.e., warm temperature, short duration) produce naloxone-sensitive opioid SSIA, whereas high severity swims (i.e., cold temperature, long duration) produce nonopioid SSIA. This pattern is also seen in HA mice displaying very high analgesic magnitudes, but not in LA mice displaying minimal SSIA. In the selectively bred mice, analgesia and hypothermia from forced swimming are positively correlated, but can be dissociated both genetically and neurochemically. Furthermore, swimming in body temperature (38 degrees C) water produces analgesia without concommitant hypothermia, and the increased magnitude of 38 degrees C SSIA displayed by HA mice over control levels is entirely opioid.
Differential sensitivity of mice bred for stress-induced analgesia to morphine and ACEA-1011 in the formalin test.
The antinociceptive effect of morphine, an opioid receptor agonist, and ACEA-1011, a novel NMDA receptor/glycine site antagonist, was examined in the formalin test in mice selectively bred for high (HA) and low (LA) swim stress-induced analgesia (SSIA). A subcutaneous (SC) injection of formalin produced a biphasic nociceptive response in both lines. HA mice spent more time licking the injected paw than the LA mice in both phases of the formalin test. Morphine was equally potent in the early phase in both lines, but it was more potent in HA mice than in LA mice in the tonic late phase of the formalin test. Similarly, ACEA-1011 produced an equally potent antinociceptive effect in the early phase in both lines; however, the compound was more potent in LA mice than in HA mice in the tonic late phase of the formalin test. These data suggest that in HA mice antinociception in the tonic late phase of the formalin test is mediated largely by an opioid-mediated mechanism, whereas in the opioid-deficient LA line at least a nonopioid-mediated mechanism involving the NMDA receptor is also implicated.
Differential genetic mediation of sensitivity to morphine in genetic models of opiate antinociception: influence of nociceptive assay.
Several genetic mouse models of opiate sensitivity have been identified or produced in an attempt to investigate mechanisms underlying individual variation in responses to opiate drugs like morphine. The major models in use presently are the DBA/2 (DBA) versus C57BL/6 (C57) inbred strains, the recombinantly inbred CXBK strain, and mouse lines selectively bred for high- and low-magnitude antinociception after swim stress (HA and LA lines, respectively) or levorphanol administration (HAR and LAR lines, respectively). The hot-plate test, an assay of acute, thermal nociception, was used in the selection of the HA/LA and HAR/LAR lines, and has largely been used to characterize the differential opiate sensitivity of the DBA (high) and C57 (low) strains and the deficient sensitivity of the CXBK strain. There exist, however, many other nociceptive assays used with murine subjects; the most common are the tail-flick/withdrawal test, the acetic acid abdominal constriction test and the formalin test. In the present experiment, baseline nociceptive sensitivities and morphine antinociceptive dose-response relationships (0.1-10 mg/kg i.p. or s.c.) were investigated in mice of all four genetic models and in all four major nociceptive assays, with identical parameters. Results indicate a high degree of dissociation between different genetic models, which suggests that these strains differ in their nociceptive and antinociceptive sensitivities due to the effects of very different genetic and physiological mechanisms. In addition, the present findings suggest that morphine inhibits different modalities of nociception via separate mechanisms that can be genetically dissociated and independently altered. Strikingly, in HA/LA and HAR/LAR mice, we find that an inverse relationship exists with respect to morphine antinociceptive sensitivity in the hot-plate and acetic acid abdominal constriction tests, respectively.
Oligogenic determination of morphine analgesic magnitude: a genetic analysis of selectively bred mouse lines.
Two ongoing selective breeding projects have produced mice that display divergent analgesic responses to morphine. These two projects have selected for similar phenotypes: high and low levorphanol analgesia (HAR/LAR lines; Portland, OR) and high and low swim stress-induced analgesia (HA/LA lines; Jastrzebiec, Poland). Evidence suggests genetic commonalities between mice of the two projects. Using a Mendelian breeding protocol, we have recently found that one or two genetic loci predominantly determine the high morphine analgesia exhibited by HA mice. In the present study we demonstrate that the differential morphine analgesia (5 mg/kg, i.p.) displayed by HAR and LAR mice is similarly oligogenic, predominantly determined by two unlinked loci. A complementation analysis, in which the analgesic responses to morphine of the recessive homozygotes of each project (HAR and HA) were compared to those of their hybrid offspring (HAR x HA), revealed that different genetic loci have been fixed in each project. An intriguing bimodal distribution was observed in the HAR x HA population: Some HAR x HA hybrids displayed greater morphine analgesia than either HAR or HA mice, whereas others displayed minimal analgesia. LAR x LA hybrids displayed less analgesia than either LAR or LA mice. The analgesic responses of HAR x LA and LAR x HA mice were comparable to those of their low-line parents. These findings indicate not only that different loci were responsible for producing high morphine responders in each selection project but that these distinct loci can interact synergistically to produce "superhigh" and "superlow" responders.