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PubMed2000

[Physiopathology and molecular diagnosis for prion diseases].

Prion diseases, including Creutzfeldt-Jakob disease (CJD), are infectious neurodegenerative disorders. The etiological agent, prion, is postulated to consist mainly of a proteinase K-resistant isoform of prion protein (PrPSc) which is generated by post-translational conversion from the proteinase K-sensitive normal version (PrPC) physiologically expressed on the surface of neuronal and glial cells. The constitutive conversion results in the tremendous accumulation of PrPSc in the prion-infected brain. Homozygous disruption of the Prnp gene encoding PrPC renders mice resistant to prion, and the animals are no longer capable of generating PrPSc, indicating an essential role for PrPSc in the pathogenesis of prion diseases. The PrP-null mice (Ngsk Prnp0/0) revealed progressive ataxia due to the degeneration of cellebellar Purkinje cells at old ages. Successful rescue of Ngsk Prnp0/0 mice from neurodegeneration by a transgene encoding the normal mouse PrPC has indicated that the functional loss of PrPC is essential for this phenotype. Moreover, we detected aberrant mRNAs chimeric between Prnp exon 1-2 and a novel gene encoding PrP-like protein (PrPLP). These results suggested that, in addition to the functional loss of PrPC, ectopic expression of the PrPLP in the brain of Ngsk Prnp0/0 mice could be associated with Purkinje cell degeneration.

Animals↗

PubMed1989

Developmental loss of functional laminin receptors on retinal ganglion cells is regulated by their target tissue, the optic tectum.

The ability of chick retinal ganglion cells (RGCs) to extend neurites on tissue culture substrata of the extra-cellular matrix protein laminin is lost during embryonic development. In order to establish the mechanism responsible for the loss of response, the number of high affinity (KD 10(-9) M) laminin receptors on both the cell bodies and neurites of RGCs were determined throughout this period by a ligand binding assay using radio-labelled laminin. It was found that the loss of response paralleled a decrease in receptor numbers on both the cell bodies and the neurites of the RGCs. Bilateral tectal ablation at embryonic day 6 resulted in the subsequent maintenance of laminin-stimulated neurite outgrowth, together with a partial inhibition of the loss of laminin receptors. Thus, the loss of response of the RGCs to laminin reflects a decrease in the numbers of laminin receptors on these neurons, and furthermore, this down-regulation is in turn dependent on innervation of the target tissue.

Animals↗

PubMed2002

Functional disability and quality of life in patients with ankylosing spondylitis.

The aim of this study was to evaluate functional disability and quality of life (QOL) in patients with ankylosing spondylitis (AS) and determine the relationship between functional status and measures of clinical condition including QOL. Fifty-one AS patients (45 male, six female) with a mean age of 37.2+/-10.8 years were included. The demographic data of the patients were recorded. Their clinical status was assessed using the Bath Ankylosing Spondylitis Metrology Index (BASMI), Bath Ankylosing Spondylitis Radiology Index (BASRI), and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). Global pain of the patients was determined with a visual analog scale (VAS), and QOL status was evaluated with the Nottingham Health Profile (NHP). Twenty-seven patients (52.9%) had peripheral articular involvement. Sixty percent had mild-to-moderate and 25.4% of the patients had severe functional disability, while 5.8% did not report any functional loss. A significant change in the mean scores of all clinical measures except BASRI was observed between patients with and without peripheral arthritis. The clinical measures of disease (BASRI, BASMI, and BASDAI) were all correlated with each other and with laboratory variables. The strongest factors correlating with functional loss were BASMI and BASDAI. The scores of all sections of the NHP were significantly higher, indicating a poor quality of life in AS patients. Peripheral joint involvement had a significant role in the deterioration of QOL. Physical domains of NHP such as pain and physical activity had highest correlations with functional disability, whereas psychosocial domains of NHP were found to correlate more highly with BASDAI and VAS pain scores. These results show the effect of AS, especially when the disease is active and associated with peripheral involvement. In conclusion, current management strategies should focus on decreasing pain, maintaining physical activity, and efforts to improve psychosocial health aspects for increasing QOL in patients suffering from AS.

Adolescent↗

PubMed1981

Smoking and lung function.

In a cross-sectional survey of 3 separate communities, we studied the white residents 7 year of age and older in order to determine the relation between cigarette smoking and lung function. We identified 2,817 nonsmokers, 664 ex-smokers, and 1,209 smokers who were further classified as light smokers (1 to 20 cigarettes per day) and heavy smokers (greater than 20 cigarettes per day). Residual lung function (observed-predicted) was examined in these groups for forced expiratory volume in one second (rFEV1) and for maximal expiratory flow rates at 50% and 25% of the vital capacity (rVmax50% and rVmax 25%). Mean residuals by sex, age, and smoking category were compared and revealed an increasing progression of lung function loss with advancing age in males and females in all smoking categories. These age-related trends were due primarily to the amount smoked by persons in each group. The age of onset of these abnormalities was found to be as early as the age group 15 to 24 yr. Abnormalities were greater in smokers than ex-smokers, even when the amount smoked was taken into account. This is suggested improvement in lung function after cessation of smoking. Men and women were found to experience the same relative degree of gain. Also, the contribution of the various smoking habits to lung function loss was assessed using regression analyses and accounted for no more than 15% of the variation of the residual lung function. Combinations of variables were found to explain only slightly more variation than a single variable. The two most important variables were duration of smoking and pack-years. Inhalation and use of filters were not significant. Although the same amount of variation explained by the smoking variables after accounting for age, height, weight, and sex was small, this variation accounted for almost all of the decrease, over age, in residual lung function for smokers and ex-smokers.

Adolescent↗

PubMed1997

Loss-of-function mutations in the maize homeobox gene, knotted1, are defective in shoot meristem maintenance.

The product of the maize homeobox gene, knotted1 (kn1), localizes to the nuclei of cells in shoot meristems, but is absent from portions of the meristem where leaf primordia or floral organs initiate. Recessive mutant alleles of kn1 were obtained by screening for loss of the dominant leaf phenotype in maize. Mutant kn1 alleles carrying nonsense, splicing and frame shift mutations cause severe inflorescence and floral defects. Mutant tassels produce fewer branches and spikelets. Ears are often absent, and when present, are small with few spikelets. In addition, extra carpels form in female florets and ovule tissue proliferates abnormally. Less frequently, extra leaves form in the axils of vegetative leaves. These mutations reveal a role for kn1 in meristem maintenance, particularly as it affects branching and lateral organ formation.

Alleles↗

PubMed2003

A robust subspace algorithm for principal component analysis.

We present a noise robust PCA algorithm which is an extension of the Oja subspace algorithm and allows tuning the noise sensitivity. We derive a loss function which is minimized by this algorithm and interpret it in a noisy PCA setting. Results on the local stability analysis of this algorithm are given and it is shown that the locally stable equilibria are those which minimize the loss function.

Algorithms↗

PubMed2001

Psychophysical measurement of glaucomatous damage.

Within the past twenty years, a number of new psychophysical test procedures have been adapted for use in perimetry and visual field testing. These procedures are designed to measure the functional properties of different types of retinal ganglion cell subpopulations. Although many of these new procedures exhibit better performance characteristics than standard automated perimetry, no single test procedure appears to be decidedly superior to all others. Comparison of multiple functions in patients with early glaucomatous damage suggests that visual function losses are not selective for specific retinal ganglion cell subpopulations in all patients. For evaluation of the efficacy of neuroprotective agents in glaucoma, one of the challenges facing the development of new psychophysical tests is to be able to distinguish visual function losses that are due to ganglion cell drop-out ("dead" cells) from those that are due to malfunctioning retinal nerve fibers ("sick" cells).

Glaucoma↗

PubMed2004

Loss-of-function phenotype of hereditary neuropathy with liability to pressure palsies.

Hereditary neuropathy with liability to pressure palsies (HNPP) provides a human model to investigate the role of PMP22 in myelinated peripheral nerve, since the disease is caused by a deletion of one of the two PMP22 alleles. To systematically characterize the phenotype of HNPP, we prospectively evaluated the clinical features and electrophysiological findings in 17 genetically confirmed patients, 7 men and 10 women, ranging in age from 9 to 66 years (mean, 41 +/- 13). Fifteen symptomatic patients presented with episodes of transient focal weakness or sensory loss that were usually related to particular activities causing nerve compression, including stretching or minor repetitive focal trauma. No patient sought medical attention for symptoms of a symmetric polyneuropathy. Neurological examinations were either normal or mildly abnormal. Neither focal slowing of nerve conduction studies, nor reduction in compound muscle action potential (CMAP) or sensory nerve action potential (SNAP) amplitudes consistently predicted the site of symptoms. We conclude that the majority of patients with HNPP present with transient, recurrent, focal symptoms of weakness or sensory loss in the distribution of individual nerves or plexus, and that a diffuse symmetric sensorimotor polyneuropathy is an unusual presentation of HNPP. These studies suggest that the function of PMP22, at least in part, is to stabilize myelin so that it will be protected from injuries resulting from repetitive, minor trauma.

Adolescent↗

PubMedDate not supplied

Perception of horizontal head and trunk rotation in patients with loss of vestibular functions.

In patients with loss of vestibular functions, we studied psychophysically the self-motion perception for 'trunk in space' and 'head in space' during various combinations of horizontal head and trunk rotation in the dark. The results were compared to those of normal subjects. For their 'trunk in space' perception, the subjects relied on their internal image of space, derived from the vestibular receptors in the head, and referred their trunk to this as a reference by adding to it a nuchal trunk-to-head signal. The patients, by contrast, always considered the trunk as stationary. Obviously because they were devoid of any space cues, they abandoned or suppressed a neck contribution to their 'trunk in space' perception, which, in fact, would yield an erroneous perception in almost all conditions in the dark. Both the patients and the subjects based their 'head in space' perception on their internal representation of 'trunk in space' and added to this a nuchal head-to-trunk signal. However, the patients' head-to-trunk signal, unlike that of the subjects, was considerably larger than the actual head-to-trunk rotation at low stimulus frequency. We relate this finding to some unconscious modification of their neck muscle activity during passive head rotation. It appears that the patients' gain of the neck input per se is not increased, but rather that subsets of this input are modified according to the particular function they serve.

Adolescent↗

PubMed2001

Loss of functional caveolae during senescence of human fibroblasts.

Primary human fibroblasts have a finite replicative lifespan in culture that culminates in a unique state of growth arrest, termed senescence that is accompanied by distinct morphological and biochemical alterations. Senescent cell responses to extracellular stimuli are believed to be altered at a point after receptors are bound by ligand, leading to improper integration of the signals which initiate DNA replication. In this study we demonstrate that one of the key organizing membrane microdomains for receptor signaling, caveolae, are absent in senescent cells. A comparison of young and senescent cells indicated that senescent cells contained a higher total amount of caveolins 1 and 2 but had significantly less of both proteins in the caveolar fraction. Additionally, caveolar fractions from senescent cells completely lacked the tyrosine-kinase activity associated with functional caveolae. Furthermore, old cells had little caveolar protein exposed to the outer plasma membrane as estimated by using an in vivo biotinylation assay and no detectable caveolin 1 on the cell surface when processed for immunofluoresence and confocal microscopy. Together, these data suggest that a fundamental loss of signal integration at the plasma membrane of senescent cells is due to the loss of signaling competent caveolae.

Caveolae↗

PubMed2005

Bacillus endophthalmitis: roles of bacterial toxins and motility during infection.

PURPOSE: Bacillus endophthalmitis is a highly explosive infection of the eye that commonly results in rapid inflammation and vision loss, if not loss of the eye itself, within a few days. Quorum-sensing-controlled toxins are essential to virulence during infection. Another unique characteristic of this disease is the ability of Bacillus to replicate rapidly and migrate to all parts of the eye. This study was conducted to determine the combined roles of toxins and motility during Bacillus endophthalmitis. METHODS: Rabbit eyes were injected intravitreally with approximately 100 cfu of wild type, nonmotile, or nonmotile/quorum-sensing-deficient Bacillus thuringiensis. Infection courses were analyzed by biomicroscopy, histology, electroretinography, and quantitation of bacteria and inflammatory cells. RESULTS: Infection with wild type B. thuringiensis resulted in complete retinal function loss by 18 hours after infection, whereas nonmotile B. thuringiensis infections required 30 hours to achieve a reduction of >90% in retinal function. Further attenuation of infection resulted from infection with the nonmotile/quorum-sensing-deficient B. thuringiensis strain, with approximately 90% retinal function loss occurring at 36 hours. Overall, the nonmotile and nonmotile/quorum-sensing-deficient mutants were significantly less virulent than wild-type B. thuringiensis. CONCLUSIONS: The results demonstrate that, in addition to quorum-sensing-controlled toxin production, bacterial migration within the eye contributed to the rapidly fulminant and destructive course of Bacillus endophthalmitis. Motility and quorum-sensing may therefore represent possible targets for the development of therapies designed to attenuate the devastating effects of Bacillus in the eye during endophthalmitis.

Animals↗

PubMedDate not supplied

Short-term hypothermic preservation of porcine hepatocyte spheroids using UW solution.

The feasibility of University of Wisconsin (UW) solution in short-term hypothermic preservation of porcine hepatocyte spheroids was investigated, because they have great potential in bioartificial liver (BAL) systems. Porcine hepatocyte spheroids preserved for 3 days expressed almost comparable levels of albumin secretion as those without preservation, during 8 subsequent days of recultivation in continuous rotational culture, whereas isolated single cells did not reorganize into spheroids and completely lost their function in recultivation. Although for 3-day-preserved spheroids, the albumin secretion was lowered immediately after recultivation (Days 0-2), it was completely restored to that of nonpreserved ones. The function was completely lost in recultivation for 7-day-preserved ones. These results demonstrate that reorganization into spheroids is effective in preventing the functional loss of porcine hepatocytes occurring in hypothermic preservation, and that spheroid formation should precede the preservation as long as spheroid culture is finally used in BAL systems. Also, porcine hepatocyte spheroids are shown to be satisfactory stored in UW solution up to 3 days without significant cellular or functional loss.

Adenosine↗

PubMed1997

Specificity of neurotrophin-3 determined by loss-of-function mutagenesis.

Neurotrophin-3 (NT-3) is a member of the family of neurotrophic factors, which also includes nerve growth factor (NGF) and which have specific activities on different subsets of vertebrate neurons. The aim of this study was to determine which residues in NT-3 direct its specificity to the cognate TrkC receptor. It was possible to replace 80% of the residues in NT-3 with NGF residues without loss of specific activity. Residues D72, Y85, R87, W101, S107, and A111, together with either the residues F12, V18, V20, M37, V42, F54, and K57 or the variable regions IV and V, accounted for the specificity of NT-3. It is concluded that NGF and NT-3 use overlapping as well as separated regions for determination of specificities for their cognate receptors TrkA and TrkC, respectively.

Amino Acid Sequence↗

PubMed1999

Walking after spinal cord injury: evaluation, treatment, and functional recovery.

OBJECTIVE: To present some recent developments and concepts emerging from both animal and human studies aimed at enhancing recovery of walking after spinal cord injury (SCI). DATA SOURCES: Researchers in the field of restoration of walking after SCI, as well as references extracted from searches in the Medline computerized database. STUDY SELECTION: Studies that reported outcome measures of walking for spinal cord injured persons with an incomplete motor function loss or cats with either a complete or incomplete spinal section. DATA EXTRACTION: Data were extracted and validity was assessed by the authors. DATA SYNTHESIS: This review shows that a multitude of interventions--mechanical, electrical, or pharmacologic--can increase the walking abilities of persons with SCI who have incomplete motor function loss. CONCLUSIONS: A comprehensive evaluation of walking behavior requires tasks involving the different control variables. This comprehensive evaluation can be used to characterize the process of recovery of walking as well as the effectiveness of various treatments.

Animals↗

PubMed1998

[The Vibrant Soundbridge System: a new kind of hearing aid for sensorineural hearing loss. 1: Function and initial clinical experiences].

INTRODUCTION: Patients suffering from moderate to severe cochlear hearing impairment can not be considered for cochlear implantation on account of their relatively good residual hearing. Conventional hearing aids, on the other hand, have considerable disadvantages which clearly limit the benefit for these patients, e.g. feedback, sound distortion, unfavorable conditions for frequency transfer, occlusion, and recurrent infections of the auditory canal. In addition, many patients complain about a poor speech intelligibility in noise. VIBRANT SOUNDBRIDGE HEARING PROSTHESIS: Implantable hearing aids offer a new approach for improved auditory rehabilitation. The Vibrant Soundbridge system is based on an electromagnetic system, which is linked directly to the intact ossicular chain. Due to the high sound quality and the high frequency characteristic this system is ideally suited for the above-mentioned patient group. The usual disadvantages of conventional hearing aids can be avoided. Externally visible is merely the audio processor, which is worn in the retroauricular area and covered by hair. This processor transfers data and power via magnetic attachment transcutaneously. PATIENT POOL: During a European multicenter clinical study, 19 patients were implanted at MHH since February 1997. No significant complications occurred. RESULTS: In all patients, postoperative unaided pure tone threshold was unaltered in comparison with the preoperative recordings. The use of the audio processor leads to a significant functional gain, particularly in the high frequencies. The patients report about undistorted hearing resulting in a better speech understanding even in situations with loud background noise. CONCLUSION: The preliminary results show a promising new approach to the use of hearing prostheses for patients suffering from moderate to severe sensorineural hearing loss.

Audiometry, Pure-Tone↗

PubMed1998

Hematopoietic malignancies demonstrate loss-of-function mutations of BAX.

The BCL-2 gene family regulates the susceptibility to apoptotic cell death in many cell types during embryonic development and normal tissue homeostasis. Deregulated expression of anti-apoptotic BCL-2 can be a primary aberration that promotes malignancy and also confers resistance to chemotherapeutic agents. Recently, studies of Bax-deficient mice have indicated that the pro-apoptotic BAX molecule can function as a tumor suppressor. Consequently, we examined human hematopoietic malignancies and found that approximately 21% of lines possessed mutations in BAX, perhaps most commonly in the acute lymphoblastic leukemia subset. Approximately half were nucleotide insertions or deletions within a deoxyguanosine (G8) tract, resulting in a proximal frame shift and loss of immunodetectable BAX protein. Other BAX mutants bore single amino acid substitutions within BH1 or BH3 domains, demonstrated altered patterns of protein dimerization, and had lost death-promoting activity. Thus, mutations in the pro-apoptotic molecule BAX that confer resistance to apoptosis are also found in malignancies.

Animals↗

PubMed1996

Loss of functional beta 2-microglobulin in metastatic melanomas from five patients receiving immunotherapy.

BACKGROUND: In a subset of patients with metastatic melanoma, T lymphocytes bearing the cell-surface marker CD8 (CD8+ T cells) can cause the regression of even large tumors. These antitumor CD8+ T cells recognize peptide antigens presented on the surface of tumor cells by major histocompatibility complex (MHC) class I molecules. The MHC class I molecule is a heterodimer composed of an integral membrane glycoprotein designated the alpha chain and a noncovalently associated, soluble protein called beta2-microglobulin (beta 2m). Loss of beta 2m generally eliminates antigen recognition by antitumor CD8+ T cells. PURPOSE: We studied the loss of beta 2m as a potential means of tumor escape from immune recognition in a cohort of patients receiving immunotherapy. METHODS: We successfully grew 13 independent tumor cell cultures from tumor specimens obtained from 13 patients in a cohort of 40 consecutive patients undergoing immunotherapy for metastatic melanoma and for whom tumor specimens were available. These cell lines, as well as another melanoma cell line (called 1074mel) that had been derived from tumor obtained from a patient in a cytokine-gene therapy study, were characterized in vitro cytofluorometrically for MHC class I expression and by northern and western blot analyses for messenger RNA (mRNA) and protein expression, respectively, and ex vivo by immunohistochemistry. RESULTS: After one melanoma cell line (1074mel) was found not to express functional beta 2m by cytofluorometric analysis, four (31%) of the 13 newly established melanoma cell lines were found to have an absolute lack of functional MHC class I expression. Northern blot analysis of RNA extracted from the five cell lines exhibiting no functional MHC class I expression showed that these cells contained normal levels of alpha-chain mRNA but variable levels of beta 2m mRNA. In addition, no immunoreactive beta 2m protein was detected by western blot analysis. When human beta 2m was transiently expressed with the use of a recombinant vaccinia virus, cell-surface MHC class I expression was reconstituted and the ability of these five cell lines to present endogenous antigens was restored. Immunohistochemical staining of tumor sections revealed a lack of immunoreactive MHC class I in vivo, supporting the notion that the in vitro observations were not artifactual. Furthermore, archival tumor sections obtained from patients prior to immunotherapy were available from three patients and were found to be beta 2m positive. This result was consistent with the hypothesis that loss of beta 2m resulted from immunotherapy. CONCLUSIONS: These data suggest that the loss of beta 2m may be a mechanism whereby tumor cells can acquire immunoresistance. This study represents the first characterization of a molecular route of escape of tumors from immune recognition in a cohort of patients being treated with immunotherapy.

Adult↗

PubMed2004

Loss of function of vascular smooth muscle cells by nitric oxide-dependent and -independent interactions with tumorigenic cells.

Little is known about the interaction of tumor cells with host vascular smooth muscle cells. In reconstitution experiments, tumorigenic cell lines (including the rat hepatocarcinoma Morris 7777 and human melanoma M-21) were cultured for 17 hr in the presence of rat aortic rings, subsequently evaluated in contractility assays (response to phenylephrine and KCl). An agonist-independent loss of contractility was observed in rings pre-incubated with either tumorigenic cell lines or their conditioned medium (CM). The depressing effect of Morris cells depends largely on the expression of inducible nitric oxide synthase (iNOS) in smooth muscle cells and was reversed by an inhibitor of this enzyme; iNOS immunoreactivity was verified in some muscular vessels at the periphery of tumors formed by the Morris cell line in rats. The M-21 melanoma produces cytotoxicity in rat aortic rings (presence of single stranded DNA, cleavage of PARP, in differentiated smooth muscle only), accounting for the irreversible loss of contractility. The cytotoxicity produced by M-21 CM is not dependent on NO. Gel filtration of CM suggests that both the iNOS- and cytotoxicity-inducing substances from Morris hepatoma cells or M-21 cells, respectively, are mainly of low molecular weight (1 kDa or less). Other cell lines derived from rat or human tumors produce minimal effects on the rat aorta smooth muscle (H4-II-E-C3) or an irreversible anergy (RBL, MDA-MB-231, HEP-3B, HEP G2). The results emphasize that inhibition of vascular smooth muscle is relevant to tumor biology both by modulation of tumoral hemodynamics and by influencing the state of vessel maturation.

Animals↗