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Biomedical subjects

D Horn

Publications and source records attributed to D Horn.

At least 19 recordsLinked to original sources
PubMed1996

Identification of a novel bone/calcium metabolism-regulating factor in porcine pancreas.

We purified from porcine pancreas a hypocalcemic peptide clearly distinguishable from other pancreatic osteotropic factors such as amylin, calcitonin, and glucagon. Porcine pancreas was processed by acetone extraction, anion exchange chromatography, isoelectric focusing, and reverse-phase high performance liquid chromatography. Fractions were assayed for their inhibitory effects on bone resorption in vitro. Amino acid sequence of a homogeneous 28-kDa protein revealed 92% homology to a human elastase IIIB in the N terminus. Recombinant human elastase IIIB (rhEIIIB) inhibited bone resorption in organ culture stimulated by 1,25-dihydroxyvitamin D3 at concentrations as low as 75 ng/ml. Antibodies to rhEIIIB recognized purified pancreatic factor in Western blots and blocked its inhibitory effect on bone resorption. This antiresorptive activity was abolished by phenylmethylsulfonyl fluoride, suggesting the importance of elastase proteolytic activity for inhibition of bone resorption. In vivo, rhEIIIB and purified pancreatic factor significantly decreased recombinant human interleukin-1alpha-induced hypercalcemia. In conclusion, a novel naturally occurring inhibitor of bone resorption and calcium-lowering peptide has been identified in porcine pancreas. Because this pancreatic peptide has systemic effects on bone resorption and blood ionized calcium at low concentrations, it may represent a physiological regulator of normal bone remodeling and calcium homeostasis.

Amino Acid Sequence↗
PubMed1996

Neuronal-based synaptic compensation: a computational study in Alzheimer's disease.

In the framework of an associative memory model, we study the interplay between synaptic deletion and compensation, and memory deterioration, a clinical hallmark of Alzheimer's disease. Our study is motivated by experimental evidence that there are regulatory mechanisms that take part in the homeostasis of neuronal activity and act on the neuronal level. We show that following synaptic deletion, synaptic compensation can be carried out efficiently by a local, dynamic mechanism, where each neuron maintains the profile of its incoming post-synaptic current. Our results open up the possibility that the primary factor in the pathogenesis of cognitive deficiencies in Alzheimer's disease (AD) is the failure of local neuronal regulatory mechanisms. Allowing for neuronal death, we observe two pathological routes in AD, leading to different correlations between the levels of structural damage and functional decline.

Alzheimer Disease↗
PubMed1996

Temporal segmentation in a neural dynamic system.

Oscillatory attractor neural networks can perform temporal segmentation, i.e., separate the joint inputs they receive, through the formation of staggered oscillations. This property, which may be basic to many perceptual functions, is investigated here in the context of a symmetric dynamic system. The fully segmented mode is one type of limit cycle that this system can develop. It can be sustained for only a limited number n of oscillators. This limitation to a small number of segments is a basic phenomenon in such systems. Within our model we can explain it in terms of the limited range of narrow subharmonic solutions of the single nonlinear oscillator. Moreover, this point of view allows us to understand the dominance of three leading amplitudes in solutions of partial segmentation, which are obtained for high n. The latter are also abundant when we replace the common input with a graded one, allowing for different inputs to different oscillators. Switching to an input with fluctuating components, we obtain segmentation dominance for small systems and quite irregular waveforms for large systems.

Electrophysiology↗
PubMed1996

Pathogenesis of schizophrenic delusions and hallucinations: a neural model.

We implement and study a computational model of Stevens' theory of the pathogenesis of schizophrenia. This theory hypothesizes that the onset of schizophrenia is associated with reactive synaptic regeneration in brain regions that receive degenerating temporal lobe projections. Concentrating on one such area, the frontal cortex, we model a frontal module as an associative memory neural network whose input synapses represent incoming temporal projections. Modeling Stevens' hypothesized pathological synaptic changes in this framework results in adverse side effects similar to hallucinations and delusions seen in schizophrenia: spontaneous, stimulus-independent retrieval of stored memories focused on just a few of the stored patterns. These could account for the delusions and hallucinations that occur in schizophrenia without any apparent external trigger and for their tendency to concentrate on a few central cognitive and perceptual themes. The model explains why the positive symptoms of schizophrenia tend to wane as the disease progresses, why delayed therapeutic intervention leads to a much slower response, and why delusions and hallucinations may persist for a long time when they do occur.

Brain↗
PubMed1995

A developmentally regulated position effect at a telomeric locus in Trypanosoma brucei.

Trypanosoma brucei undergoes antigenic variation in the mammalian host. This can be achieved by activation and inactivation of telomeric variant-specific surface glycoprotein genes (vsg). In procyclic (insect midgut stage) cells, Vsg is not expressed. The mechanisms that regulate transcription of vsg expression sites (ESs) are unknown. Here we demonstrate that transcription from three different promoters was repressed when they were inserted at a transcriptionally silent telomere-proximal locus in bloodstream-form cells. This position effect was stable and heritable. Only transcription from an ES promoter was repressed in procyclic cells. The observed position effect and the promoter-specific developmental regulation suggest that these phenomena reflect the mechanisms that regulate vsg expression.

Animals↗
PubMed1995

Reduced neurofibromin content but normal GAP activity in a patient with neurofibromatosis type 1 caused by a five base pair duplication in exon 12b of the NF1 gene.

We screened a total of 87 unrelated patients with neurofibromatosis type 1 (NF1) for mutations in exons 11, 12a, and 12b of the NF1 gene using temperature gradient gel electrophoresis (TGGE). A novel mutation (1998insCCTCT) was found in exon 12b. The 5-bp duplication comprising nucleotides 1994 to 1998 is predicted to lead to a truncated protein product lacking three quarters of its C-terminal sequence including the entire GTPase-activating protein-(GAP)-related domain. This mutation is associated with a reduction by 50% of the detectable amount of neurofibromin found in this patient. Despite the reduced level of neurofibromin cellular GAP activity was normal, which suggests that defects in other functions of the neurofibromin molecule may be important in the pathogenesis of NF1.

Base Composition↗
PubMed1995

Identification of denatured double-stranded DNA by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry.

We created double-stranded DNA (dsDNA) by annealing synthetic oligonucleotides and used matrix-assisted laser desorption/ionization time-of-flight mass spectrometry to measure the difference in molecular weight of the complementary strands after denaturation. Refined sample preparation and deliberate rectilinear construction at a linear mass spectrometer produced a mass resolution exceeding 1000 for single-stranded DNA. We present methodologies and demonstrate the potential for analysing dsDNA by determining the mass of the complementary strands.

Base Sequence↗
PubMed1995

Pallister-Killian syndrome: normal karyotype in prenatal chorionic villi, in postnatal lymphocytes, and in slowly growing epidermal cells, but mosaic tetrasomy 12p in skin fibroblasts.

We report on two patients with Pallister-Killian syndrome: an 18 month old male infant followed since the neonatal period and a 4 year old boy. Prenatal diagnosis by chorionic villi sampling (CVS) in the first case showed a normal karyotype without mosaicism. Chromosome analysis on peripheral lymphocytes of the newborn also showed a normal karyotype. The clinical diagnosis of Pallister-Killian syndrome was made after the first year of life because of the typical facial dysmorphism and other characteristic clinical features, such as frontotemporal alopecia, depigmented area of the skin, sensorineural hearing loss, and severe psychomotor retardation. Chromosome analysis from skin fibroblasts now showed an isochromosome 12p mosaicism. The origin of the extra chromosome was confirmed by in situ hybridisation using a chromosome 12 specific library. In the second case chromosomal analysis from peripheral lymphocytes at the age of 19 months showed a normal karyotype 46,XY. Following the clinical diagnosis of Pallister-Killian syndrome a superficial skin biopsy was performed which showed very poor and slow growth of cells and a normal karyotype. Because of the typical symptoms a larger and deeper skin biopsy was performed from which there was rapid growth of fibroblasts. Now the diagnosis was established on the basis of the presence of an i(12p) extra chromosome in 69% of the metaphases.

Abnormalities, Multiple↗
PubMed1995

Oto-palato-digital syndrome with features of type I and II in brothers.

We report on the oto-palato-digital syndrome (OPD) in two sons of a mother showing minimal signs of the condition. The index patient, a 10-year-old boy, presents typical symptoms of OPD type I together with bowing of the long bones and abnormalities of the thorax and spinal column. During the following pregnancy ultrasonographic studies of the male fetus in the 16th week of gestation revealed severe micrognathia, short and wide thumbs, and big toes, and bowed tibiae. After termination of the pregnancy further features were observed which fulfilled the diagnostic criteria of both OPD I and II. A possible explanation of these findings is that OPD type I and II and the features in the described cases are part of a continuous clinical spectrum of the same underlying mutation, or that several different alleles are involved in the OPD type I, type II, and mixed phenotypes.

Abnormalities, Multiple↗
PubMed1995

Perspectives for the control of tuberculosis.

The control of tuberculosis has become more elusive with the increased incidence of HIV, and the continued selection of multidrug-resistant organisms. The intracellular pathogenesis of, and host-response to Mycobacterium tuberculosis present challenges to both classical chemotherapeutic and vaccination approaches, with the organism able to replicate in an unrestricted manner in lung but not other tissues. Adequate control of this pathogen, that has evolved so successfully for its symbiotic exploitation of man, will require complex approaches including additional chemotherapeutics of more acceptable toxicity and efficacy, vaccination and commitment to public health measures. In this review, the worldwide scope of the disease is outlined, and its direct and indirect costs considered. The organism enjoys the protective advantages of a slow replication and of a specialized phagolysosomal intracellular niche, requiring a host-response capable of breaching these cellular barriers. The challenges of current vaccine approaches, including live vaccines, target antigen selection and the antigen delivery and adjuventation necessary to elicit adequate pulmonary responses are discussed. Our current understanding is inadequate to control TB and the rekindling of fundamental experimental approaches to the organism, and the host response it evokes, are essential to generate the preventative and therapeutic means necessary for its worldwide control.

Animals↗
PubMed1994

Decomposition of a mixture of signals in a model of the olfactory bulb.

We describe models for the olfactory bulb which perform separation and decomposition of mixed odor inputs from different sources. The odors are unknown to the system; hence this is an analog and extension of the engineering problem of blind separation of signals. The separation process makes use of the different temporal fluctuations of the input odors which occur under natural conditions. We discuss two possibilities, one relying on a specific architecture connecting modules with the same sensory inputs and the other assuming that the modules (e.g., glomeruli) have different receptive fields in odor space. We compare the implications of these models for the testing of mixed odors from a single source.

Animals↗
PubMed1993

Monocyte-mediated restoration of density-dependent growth control and induction of cell death in tumor cell populations.

It is shown in a serum-free system with human cells that during monocyte/tumor cell interactions signals are generated which restore the principles of density-dependent inhibition of growth in tumor cell populations. Tumor cells that fail to comply with these principles are induced to die. This cell death is an active process in target cells involving protein biosynthesis and tumor cell-derived signals.

Cell Death↗
PubMed1993

The cardiac form of the tissue-specific SmN protein is identical to the brain and embryonic forms of the protein.

The SmN protein is a component of small nuclear ribonucleoprotein particles and closely related to the ubiquitously expressed SmB and B' splicing proteins. However, SmN is only expressed in a limited range of tissues and cell types such as brain, heart and early embryonic cells. The isolation of cDNA clones derived from the mRNA encoding SmN in different cell types has indicated that the brain and embryonic forms of the protein are identical and are encoded by a distinct gene to that encoding SmB and B'. It has been suggested however, that the cardiac form of SmN is encoded by a distinct mRNA which is derived from a different gene from that encoding the brain and embryonic forms of SmN. By using the polymerase chain reaction as well as cDNA cloning we have shown that this is not the case and that the cardiac, brain and embryonic forms of the protein are identical and are translated from the same mRNA encoded by a single gene. The significance of this finding is discussed in terms of the complex expression pattern of this gene and the possible functional role of SmN.

Amino Acid Sequence↗
PubMed1992

Modulation of tumor cell susceptibility to cytokine-induced cell death by hormones, growth factors, and cell density.

The mechanisms controlling "spontaneous" cellular death rates in normal and tumorigenic tissues are largely unknown. An important parameter in this respect is the susceptibility of the target cell to induction of the lytic pathway by appropriate signals. In the present article it is demonstrated in a serum-free in vitro system that the susceptibility of human tumor cells (TC) to induction of lysis by cytokine signals generated during interaction of TC with elutriated human monocytes (MO) is a highly dynamic parameter subject to modulation by hormones, growth factors, and tumor cell density. It was found that growth stimulatory signals such as insulin, and especially epidermal growth factor (EGF), increase lytic susceptibility, whereas hydrocortisone, which does not exert significant growth modulatory effects in these examples, protects TC against the induction of lysis. Increasing TC density above confluence dramatically enhances lytic susceptibility, suggesting interactions between TC to be involved in the induction of their death. In conjunction with previous data demonstrating the insusceptibility of TC, which are forced out of the cell cycle into the quiescent state (G0), the hypothesis is put forward that growth stimulatory factors increase a TC's lytic susceptibility by preventing its transit from G1 to G0 in response to growth inhibitory signals generated during MO/TC interaction. The data support the concept that TC susceptibility to the induction of cell death is a consequence of simultaneously activated growth stimulatory and growth inhibitory signalling pathways.

Cell Communication↗
PubMed1992

Extra-pyramidal symptoms in Alzheimer's disease: a hypothesis.

Recent studies have shown that compensatory processes have an important role in counteracting the neurodegenerative changes underlining Alzheimer's disease (AD), much like their well known role in Parkinson's disease (PD). In the light of these reports, we review the findings of the positive correlation existing between the appearance of extra-pyramidal symptoms and an increased rate of progression in AD patients. We propose that this correlated symptomatology arises from the wasting of globally shared compensatory resources, manifested both in an increasing inability to compensate for persisting sub-clinical nigral lesions, and in enhanced AD deterioration rate. Our hypothesis gains support from various clinical reports and by the neural modeling of synaptic changes in AD.

Alzheimer Disease↗
PubMed1992

Absence of a gene dosage effect during bacteriophage T3- and T7-coded RNA polymerase synthesis.

The rates of synthesis of phage-coded RNA polymerase upon infection of Escherichia coli by bacteriophages T3 or T7 were measured at different MOIs under permissive and non-permissive conditions. At MOIs from 1 to 15, these rates did not vary appreciably, at MOIs of about 20 there was a slight depression in the synthesis rate. The reason for this absence of a positive gene dosage effect is unknown.

DNA-Directed RNA Polymerases↗