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Biomedical subjects

J Altman

Publications and source records attributed to J Altman.

At least 91 records · Page 5Linked to original sources
PubMed1985

Embryonic development of the rat cerebellum. I. Delineation of the cerebellar primordium and early cell movements.

Short-survival and long-survival thymidine radiograms, and methacrylate-embedded tissue from normal and X-irradiated rat embryos were used to delineate the neuroepithelial source of the cerebellum and trace the earliest cell movements. The cerebellar anlage, crescent shaped, is demarcated by two ventricular landmarks, the anterior extension of the tela choroidea of the fourth ventricle and the embryonic cerebellar fissure. The cerebellar tela choroidea extends from the medullary fourth ventricle posteromedially to the lateral recess of the pontine fourth ventricle anterolaterally. The embryonic cerebellar fissure begins caudally as a single midline incision beneath the fused posterior cerebellar primordium, then splits to follow the unfused cerebellar halves, first separating each from the isthmus then from the pons. The cerebellar primordium is divided into three parts. The lateral cerebellar primordium caps the lateral recess of the fourth ventricle; it is contiguous with the pons medially and separated ventrally from the anlage of the cochlear nuclei by the tela choroidea. The subisthmal cerebellar primordium is situated beneath the isthmus, medially lining the isthmus canal. Laterally and posteriorly, it is continuous with the lateral and postisthmal primordia. The postisthmal cerebellar primordium caps the postisthmal recess of the fourth ventricle and extends to the medullary fourth ventricle. As we shall describe later, each of these primordia is a source of different components of the developing cerebellum. Most cells of the superficially located nuclear transitory zone are labeled with 3H-thymidine administered on day E14 but not thereafter. A high proportion of the cells of the deeper cortical transitory zone could still be labeled on day E15. This supports the assumption made earlier that the first is composed of differentiating deep neurons, the second of Purkinje cells. The cells of the nuclear transitory zone originate in the lateral cerebellar primordium near the junction with the tela choroidea prior to the formation of the germinal trigone and migrate in a superficial position medially. Beginning on day E16, the nuclear transitory zone splits into two components. One has transversely oriented cells that seem to be the source of a decussating fiber tract, presumably the hook bundle of Russell. The other is composed of longitudinally oriented cells that apparently contribute fibers to the ipsilateral superior cerebellar peduncle. The translocation of the cells of the nuclear transitory zone from the cerebellar surface to its depth, to form the deep nuclei, and the radial migration of the cells of the cortical transitory zone to the surfa

Animals↗
PubMed1985

Embryonic development of the rat cerebellum. II. Translocation and regional distribution of the deep neurons.

In thymidine radiograms and plastic-embedded sections, the migration of cerebellar deep neurons was traced from their germinal source to their final settling sites. The route proved to be roundabout and three developmental events could be distinguished during the process. First, between days E14 and E16, transversely oriented cells of the nuclear transitory zone move in an arc from the ventrolateral neuroepithelium of the lateral cerebellar primordium in a medial direction. Second, between days E16 and E18, the cells of the rostral component of the nuclear transitory zone assume a longitudinal orientation. We postulated that this is the period of axonogenesis, the longitudinally oriented cells issuing efferents that join the superior cerebellar peduncle ipsilaterally and the transversely oriented cells (representing the neurons of the caudal fastigial nucleus) sending decussating fibers to the uncinate fasciculus (the hook bundle of Russell). Third, between days E18 and E21, the earlier-produced superficial cells of the nuclear transitory zone and the later-produced deep cells of the cortical transitory zone (the young Purkinje cells) exchange positions. The descent of the deep neurons is in the direction of the fibers of the inferior cerebellar peduncle, which becomes distributed throughout the cerebellum on day E17. The ascent of the Purkinje cells is in the direction of the external germinal layer, which begins to spread from caudal to rostral on day E17. The three deep nuclei, the lateral (dentate), interpositus, and medial (fastigial), can be distinguished before their descent into the depth of the cerebellum, and by day E22 a small-celled and a large-celled subdivision is identifiable in each nucleus.

Animals↗
PubMed1985

Embryonic development of the rat cerebellum. III. Regional differences in the time of origin, migration, and settling of Purkinje cells.

The time of origin, site of origin, migratory path and settling pattern of the Purkinje cells of the cerebellar hemispheres, anterior vermis, and posterior vermis were investigated in thymidine radiograms and plastic-embedded materials from rat embryos ranging in age from 15 to 22 days. In the hemispheres there is a rostral-to-caudal cytogenetic gradient: the Purkinje cells of lobulus simplex, crus I, and crus II are produced earlier than the Purkinje cells of the paramedian lobule and paraflocculus, followed by the Purkinje cells of the flocculus. The Purkinje cells of the vermis, in general, are generated later than those of the hemispheres, and with a reverse gradient from caudal to rostral: the Purkinje cells of the posterior vermis (lobules X-VI) being produced ahead of the Purkinje cells of the anterior posteriorly directed wedge of early-produced Purkinje cells through the vermis. Evidence was obtained that the Purkinje cells of the hemispheres derive from the lateral cerebellar primordium capping the lateral recess of the fourth ventricle anteriorly. The Purkinje cells of the anterior vermis originate from the subisthmal cerebellar primordium medially lining the isthmal canal. The Purkinje cells of the posterior vermis originate in the postisthmal cerebellar primordium overlying the tela choroidea caudally. The young Purkinje cells migrate from the neuroepithelium to the surface of the cerebellum in a strictly caudal-to-rostral order, paralleling the spread of the EGL superficially from posteroventral to anterodorsal. This pattern is independent of the time of origin of Purkinje cells. In the posterior vermis the earliest-settling Purkinje cells of the uvula follow a short radial course, and a discrete Purkinje layer is formed 3 days after they are generated. In the anterior vermis the Purkinje cells of lobulus centralis, which follow an anterodorsal migratory course, are still settling on day E22, 7 days after their production, presumably awaiting the fusion of the cerebellar base anteriorly. The fissura prima forms medially at the interface region of Purkinje cells derived from the postisthmal and subisthmal cerebellar primordia. For 1-2 days after their settling, the Purkinje cells of the newly forming lobules can be distinguished by certain cytological criteria from the Purkinje cells in the more caudally-situated, earlier-settled lobules.

Animals↗
PubMed1985

Stimulation of in vitro human skin collagenase expression by platelet-derived growth factor.

Platelet-derived growth factor (PDGF) is both chemoattractant and mitogenic for stromal cells. Here, we examined the effects of PDGF on collagenase expression by normal human skin fibroblasts. Culturing cells for 24 hr in the presence of PDGF at 0-180 ng/ml resulted in a dose-dependent, saturable increase in collagenase activity in the culture medium that was paralleled by equal increases in immunoreactive collagenase protein, suggesting enhanced synthesis of a catalytically unaltered enzyme. The specificity of this effect was demonstrated by comparing the collagenase-stimulatory effect with that on total protein synthesis and DNA synthesis. Under in vitro conditions that produced a 2.5-fold increase in collagenase synthesis, there was an approximately equal to 20% increase in total protein synthesis and no change in DNA synthesis. In addition, platelet factor 4, another platelet-derived protein, caused a less than 20% increase in collagenase expression. In time-course studies, stimulation of collagenase synthesis was first observed 8-10 hr after exposure to the growth factor. Conversely, when cells were primed with PDGF for approximately equal to 24 hr and the stimulator was then removed, an increased rate of synthesis was seen for an additional approximately equal to 6 hr, after which the rate reverted to control levels. Since the kinetic data suggested a possible pretranslational effect, fibroblasts cultured with PDGF were used to prepare mRNA. In cell-free translation, total protein synthesis was essentially unaltered; however, the growth factor caused a greater than 2-fold increase in translatable collagenase mRNA. The data suggest that PDGF specifically modulates collagenase synthesis, possibly through a series of events that lead to increased transcription or preferential translation of collagenase mRNA.

Cells, Cultured↗
PubMed1984

Synthesis of pyridine derivatives of L-phenylalanine as antisickling reagents.

Several bicyclic agents composed of L-phenylalanine coupled to various pyridines were synthesized: 2-, 3-, and 4-(L- phenylalanylamino )pyridine. All three compounds at 3 mM gave positive morphological antisickling effects on homozygous SS cells under reduced O2 tension. Studies on two of these compounds, 2- and 3-(L- phenylalanylamino )pyridine, showed that these agents increase the deoxy-HbS solubility ratio, Cs/ Cs0 , by 14% at 20 mM. Observed changes in the mean corpuscular hemoglobin concentration (MCHC) values of treated cells ranged from 4% at 1.3 mM to 15% at 5.6 mM in compound concentration. Very minor lytic activity was found for treated cells, indicating water uptake is responsible for changes in the MCHC. Further, exposure of sickle cells to a 3 mM concentration of these agents also increased by 6- to 7-fold cellular deformability of a treated erythrocyte population as compared to an untreated one at the same total O2 saturation of 47%. These agents demonstrate the potential of bicyclic compounds composed of a common constituent, L-Phe, in the development toward a viable therapeutic agent.

Anemia, Sickle Cell↗
PubMed1984

Potential use of biaromatic L-phenylalanyl derivatives as therapeutic agents in the treatment of sickle cell disease.

N-Phenylacetyl-L-phenylalanine (PAP) and L-phenylalanyl-3-aminopyridine ( PAPA ) are biaromatic agents with properties that make them suitable candidates for the development of a useful therapeutic agent for the treatment of sickle cell disease. PAP and PAPA are taken up by the erythrocyte to give intra-/extracellular concentration ratios of 2.2 and 1.5, respectively, after a 2-hr exposure period. The intracellular buildup of PAP and PAPA produces moderate decreases in the mean corpuscular hemoglobin concentration (MCHC) of 6 and 10%, respectively, at 3 mM and a further decline in MCHC with increased concentration. Both PAP and PAPA increase the deoxy-Hb S solubility, CS. If the solubility in the absence of the agent is COS, PAP and PAPA have CS/COS values of 1.21 and 1.14 at 20 mM, respectively, compared with a value of 1.06 for L-phenylalanine itself. Filterability assays of partially dexygenated homozygous sickle cells shows an increase in cell flexibility of 7 to 16 times more than that of untreated cells when these agents are present at 3-6 mM. These results are largely due to the reduction in the Hb S polymer content of the treated cells. At 3 mM or less, both PAP and PAPA delay the onset of gelation in reversible sickle cells for time periods that are likely to be therapeutically useful.

Anemia, Sickle Cell↗
PubMed1983

Genetic control of murine antibody-dependent cell-mediated cytotoxicity. Partial identity with the genetic control of NK activity.

We have observed that the intensity of the direct antibody-dependent cell-mediated cytotoxicity (ADCC) response after an inoculation of foreign tumour cells varies with the strain of mice studied. The inoculation of a human lymphoblastoid cell-line into CBA/J, BALB/c, or DBA/2 mice gives rise to a good cytotoxic response by the host K cells armed with specific antibodies. In contrast, A/J, B10.A, C57BL/6 and B10.S mice respond poorly under the same conditions. The high response is dominant in F1 hybrids between high and low responders and is also expressed among F2 backcrosses with the H-2 phenotype of low responders, suggesting that non-H-2 genes are also implicated in the regulation of ADCC. The genetic control is not exerted at the level of antibody secretion but at that of K-cell activity, since sera from high or low responders are equally effective in arming an ADCC reaction, whereas K cells from low-responder strains are less efficient than those from high-responder strains. The natural killer (NK) activity of the same strains has been screened. The results show a good correlation with some high- and low-responder strains, such as CBA and DBA/2 or A/J and SJL, respectively, but not with C57BL/6, B10.S or B10.A strains. Thus, in addition to common genes controlling both lytic functions, there are specific genetic factors influencing the balance between NK and K cells. These findings confirm the general view that NK and K cells represent only partially identical subsets.

Animals↗
PubMed1983

Sclerosteosis: neurogenetic and pathophysiologic analysis of an American kinship.

We studied an American kinship with sclerosteosis, an autosomal-recessive disorder of bone remodeling and bone overgrowth of the calvaria, skull base, and tubular bones. Unlike osteopetrosis, which is attributed to abnormal immune and osteoclast function as well as bone resorption, sclerosteosis appears to be primarily a disorder of osteoblast (bone formation) hyperactivity. Related to cranial vascular and neural foraminal narrowing and reduced intracranial volume, affected patients with sclerosteosis demonstrate frequent seventh nerve palsy, progressive optic and cranial neuropathies, mixed hearing loss, brainstem compression, intracranial hypertension with increased elastance, and sudden, premature death. Management should involve early childhood identification of homozygotes, monitoring and aggressive treatment of intracranial hypertension, and extensive bone removal from skull, posterior fossa, and cervical spine.

Adult↗
PubMed1982

The contribution of late-generated neurons to the callosal projection in rat: a study with prenatal x-irradiation.

Studies utilizing horseradish peroxidase tracing methods have suggested that there are species differences in the relative contribution of the different neocortical layers to the callosal projection. The present investigation utilized x-irradiation at different gestational ages to eliminate the late-generated neurons in the rat neocortex. The caudorostral gradient of reduction in the neuronal population of the supragranular layers is closely correlated with the gradient of reduction in the size of the corpus callosum. Furthermore, the callosal projection is absent in anteroposterior cortical segments in which the development of the supragranular layers was prevented without a reduction of the number of neurons in the infragranular layers of the neocortex. These results indicate that late-generated neurons residing primarily in the supragranular layers are essential for the formation of the corpus callosum.

Animals↗
PubMed1981

Lumbosacral skin lesions as markers of occult spinal dysraphism.

Early treatment of occult spinal dysraphism may prevent progressive neurological deficits. However, diagnosis is often delayed until the onset of irreversible neurological damage. A review of data from the literature and patients at Johns Hopkins Hospital suggests that lumbosacral skin abnormalities such as tufts of hair, hemangiomas, lipomas, skin tags, or pigmented nevi should alert the physician to search for occult spinal dysraphism. In the asymptomatic patient with a skin lesion, roentgenography of the lumbosacral spine is a useful screening procedure for identifying treatable underlying problems.

Adolescent↗
PubMed1981

Development of the brain stem in the rat. V. Thymidine-radiographic study of the time of origin of neurons in the midbrain tegmentum.

Groups of pregnant rats were injected with two successive daily doses of 3H-thymidine from gestational day E12 and 13 (E12 j3) until the day before parturition (E21 k2) in order to label in their embryos the proliferating precursors of neurons. At 60 days of age the proportion of neurons generated (no longer labeled) on specific embryonic days was determined quantitatively in 18 regions of the midbrain tegmentum. The neurons of the oculomotor and trochlear nuclei are generated concurrently on days E12 and 13. There was a mirror image cytogenetic gradient in these nuclei and this was interpreted as the dispersal of neurons derived from a common neuroepithelial source to the medial longitudinal fasciculus. Neurons in three other components of the tegmental visual system are produced in rapid succession after the motor nuclei. In the nucleus of Darkschewitsch peak production time was on day E12 and 13, extending to day E15; in the Edinger-Westphal nucleus the time span was the same but with a pronounced between days E13; finally, the neurons of the parabigeminal nucleus were produced between days E13 and E15 with a peak on day E14. The neurons of the periaqueductal gray were generated between days E13 and 17 with a pronounced ventral-to-lateral and lateral-to-dorsal gradient. In the red nucleus the neurons were produced on days E13 and E14 with a caudal-to-rostral gradient: the cells of the magnocellular division preceding slightly but significantly the cells of the parvocellular division. The neurons of the interpeduncular nucleus originated between days E13 and E15; the peak in its ventral portion was on day E13, in its dorsal portion on days E14 and E15. A ventral-to-dorsal gradient was seen also in both the dorsal and the median raphe nuclei in which neuron production occurred between days E13 and E15. The neurons of the pars compacta and pars reticulate of the substantia nigra were both produced between days E13 and E15 with a modified lateral-to-medial gradient. This gradient extended to the ventral tegmental area where neurons of the pars medialis were produced between days E14 and E16. With the exception of the central gray, neuron production was rapid and relatively early in the structures situated ventral to the midbrain tectum. A comparison of the cytogenetic gradients in the raphe nuclei of the lower and upper medulla, the pontine region, and the midbrain suggests that they originate from at least three separate neuroepithelial sources.

Animals↗
PubMed1981

Time of origin of neurons of the rat inferior colliculus and the relations between cytogenesis and tonotopic order in the auditory pathway.

Groups of pregnant rats were injected with two successive daily doses of 3H-thymidine from gestational day 12 and 13 (E12+13) until the day before parturition (E21+22) in order to label in their embryos the proliferating precursors of neurons. At 60 days of age the proportion of neurons generated (or no longer labelled) on specific embryonic days was determined quantitatively in six vertical strips of the inferior colliculus. It was established that the neurons of the inferior colliculus are produced between days E14 and the perinatal period in an orderly sequence: the earliest generated cells are situated rostrally, laterally and ventrally in the principal nucleus, the latest generated cells are situated caudally, medially and dorsally in the pericentral nucleus. This cytogenetic gradient suggested that the cells are produced dorsally in the caudal recess of the embryonic aqueduct and are deployed in an "outside-in" pattern. This study has brought to a conclusion our datings of neuron production in the central auditory pathway of the rat. The results revealed that in those structures in which a cytogenetic gradient could be recognized, the orientation of this gradient and the regional tonotopic order (demonstrated mostly in species other than the rat) tended to be aligned. Moreover, with the exception of the medial trapezoid nucleus and the dorsal nucleus of the lateral lemniscus (which receive contralateral input from the cochlear nuclei), sites with early-produced neurons correlated with units responding preferentially to high frequency tones and vice versa. This suggested that the orderly production of neurons within different components of the auditory system is a factor in their subsequent topographic organization. A comparison of the temporal order of neuron production in different components of the auditory pathway suggested that the establishment of orderly topographic relations between some of the structures (e.g., the medial geniculate body and the primary auditory cortex) takes place before this spatial relationship could be specified as a cochleotopic order.

Animals↗