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At least 973 records · Page 54Linked to original sources
PubMed1981

[Isolated loss of function of the flexor pollicis longus muscles in moderate polyneuropathy].

A 60 year old female patient was referred to us with the diagnosis of a traumatic rupture of the flexor pollicis longus tendon. Because of disturbances in sensitivity in the superficial branch of the radial nerve, we carried out a neurological examination. A mild polyneuropathy was found, but there was no evidence against the presence of a trauma-induced rupture of the flexor pollicis longus tendon. In the surgical revision, a rupture could not be detected. However, the musculature of the flexor pollicis longus differed markedly in color and consistency from the other flexors and the histological examination showed atrophy patterns of the muscle fibers which are typical for polyneuropathy of the distal type.

Female↗
PubMed1997

Apc gene mutation is associated with a dominant-negative effect upon intestinal cell migration.

Apc-associated intestinal tumor formation appears to require functional loss of both Apc alleles. Apc has, therefore, been classified as a tumor suppressor gene. Loss of APC protein function results in increased intracellular beta-catenin, a molecule important to both cell-cell adhesion and regulation of cellular growth. In mice bearing a germ-line Apc mutation, we found that enterocyte beta-catenin expression was also increased in histologically normal intestinal mucosa. Enterocyte crypt-villus migration was decreased by 25%, and treatment of Min/+ animals with sulindac sulfide normalized both beta-catenin expression and enterocyte migration. Our data suggest that alterations in enterocyte migration occur in cells bearing a single mutant Apc allele, and that sulindac sulfide may normalize enterocyte growth in these cells.

Analysis of Variance↗
PubMed1998

Connexin32 mutations associated with X-linked Charcot-Marie-Tooth disease show two distinct behaviors: loss of function and altered gating properties.

The X-linked form of Charcot-Marie-Tooth disease (CMTX) is associated with mutations in the gene encoding connexin32 (Cx32), which is expressed in Schwann cells. We have compared the functional properties of 11 Cx32 mutations with those of the wild-type protein by testing their ability to form intercellular channels in the paired oocyte expression system. Although seven mutations were functionally incompetent, four others were able to generate intercellular currents of the same order of magnitude as those induced by wild-type Cx32 (Cx32wt). In homotypic oocyte pairs, CMTX mutations retaining functional activity induced the development of junctional currents that exhibited changes in the sensitivity and kinetics of voltage dependence with respect to that of Cx32wt. The four mutations were also capable of interacting in heterotypic configuration with the wild-type protein, and in one case the result was a marked rectification of junctional currents in response to voltage steps of opposite polarity. In addition, the functional CMTX mutations displayed the same selective pattern of compatibility as Cx32wt, interacting with Cx26, Cx46, and Cx50 but failing to do so with Cx40. Although the functional mutations exhibited sensitivity to cytoplasmic acidification, which induced a >/=80% decrease in junctional currents, both the rate and extent of channel closure were enhanced markedly for two of them. Together, these results indicate that the functional consequences of CMTX mutations of Cx32 are of two drastically distinct kinds. The presence of a functional group of mutations suggests that a selective deficit of Cx32 channels may be sufficient to impair the homeostasis of Schwann cells and lead to the development of CMTX.

Animals↗
PubMed1998

Loss of function of the homeobox gene Hoxa-9 perturbs early T-cell development and induces apoptosis in primitive thymocytes.

Hox homeobox genes play a crucial role in specifying the embryonic body pattern. However, a role for Hox genes in T-cell development has not been explored. The Hoxa-9 gene is expressed in normal adult and fetal thymuses. Fetal thymuses of mice homozygous for an interruption of the Hoxa-9 gene are one eighth normal size and have a 25-fold decrease in the number of primitive thymocytes expressing the interleukin-2 receptor (IL-2R, CD25). Progression to the double positive (CD4+CD8+) stage is dramatically retarded in fetal thymic organ cultures. This aberrant development is associated with decreased amounts of intracellular CD3 and T-cell receptor beta (TCRbeta) and reduced surface expression of IL-7R and E-cadherin. Mutant thymocytes show a significant increase in apoptotic cell death and premature downregulation of bcl-2 expression. A similar phenotype is seen in primitive thymocytes from adult Hoxa-9-/- mice and from mice transplanted with Hoxa-9-/- marrow. Hoxa-9 appears to play a previously unsuspected role in T-cell ontogeny by modulating cell survival of early thymocytes and by regulating their subsequent differentiation.

Animals↗
PubMed1998

Coexpression of erythropoietin and vascular endothelial growth factor in nervous system tumors associated with von Hippel-Lindau tumor suppressor gene loss of function.

Hemangioblastomas are highly vascular tumors of the central nervous system that overexpress the hypoxia-inducible gene, vascular endothelial growth factor (VEGF), as a consequence of mutational inactivation of the von Hippel-Lindau tumor suppressor gene (VHL). Previous reports showed that hemangioblastomas can also express erythropoietin (Epo), which is also hypoxia-inducible. However, Epo expression in hemangioblastomas was observed only in individual cases, and the analyses were mainly based on indirect determination of erythropoiesis-stimulating activity. Therefore, we analyzed a series of 11 hemangioblastomas for Epo, VEGF, and VHL expression by Northern blot analysis and compared the results with normal brain and glioblastomas. Surprisingly, we observed Epo mRNA expression in all hemangioblastoma specimens analyzed, but in none of four glioblastomas. In contrast, VEGF mRNA was expressed in all hemangioblastomas and all glioblastomas. In situ hybridization revealed neoplastic stromal cells as Epo- and VEGF-producing cells in hemangioblastomas. These results suggest that in the nonhypoxic microenvironment of hemangioblastoma, Epo, similar to VEGF, might be negatively regulated by the VHL gene product.

Adult↗
PubMed1998

Phantom loss of function in traumatic brain injury.

Despite appearing normal, survivors of TBI typically experience residual effects that significantly impact their daily functioning. Informed that they have a mild, transient brain injury which is expected to resolve rapidly, they encounter marked psychological difficulties when their cognitive dysfunction persists. Left undiagnosed and untreated, patients with TBI are at risk of developing serious psychiatric disorders. Early identification and referral to specialists in neuropsychology can head off this adverse clinical course through appropriate assessment and intervention.

Activities of Daily Living↗
PubMed2006

Mineral formation in joints caused by complete or joint-specific loss of ANK function.

UNLABELLED: To reveal the ANK complete loss of function phenotype in mice, we generated conditional and null alleles. Mice homozygous for the null allele exhibited widespread joint mineralization, similar in severity to animals harboring the original ank allele. A delayed yet similar phenotype was observed in mice with joint-specific loss of ANK function. INTRODUCTION: The ANK pyrophosphate regulator was originally identified and proposed to play a key role in articular cartilage maintenance based on a single spontaneous mouse mutation (ank) that causes severe generalized arthritis. A number of human mutations have subsequently been reported in the human ortholog (ANKH), some of which produce skull and long bone defects with no apparent defects in joints or articular cartilage. None of the currently known mouse or human mutations clearly eliminate the function of the endogenous gene. MATERIALS AND METHODS: Two new Ank alleles were generated using homologous recombination in mouse embryonic stem (ES) cells. Joint range of motion assays and muCT studies were used to quantitatively assess phenotypic severity in wildtype, heterozygous, and homozygous mice carrying either the null (Anknull) or original (Ankank) allele. A Gdf5-Cre expressing line was crossed to mice harboring the conditional (Ankfloxp) allele to eliminate ANK function specifically in the joints. Histological stains and beta-galactosidase (LACZ) activity were used to determine the correlation between local loss of ANK function and defective joint phenotypes. RESULTS: Anknull/Anknull mice develop severe ectopic postnatal crystal deposition in almost every joint of the body, leading to eventual joint fusion and loss of mobility. The severity of phenotype in these mice is indistinguishable from that of Ankank/Ankank mice. In addition, despite the widespread expression of Ank in many tissues, the specific deletion of Ank in joints also produces joint mineralization and ankylosis. CONCLUSIONS: These studies show that ANK function is required locally in joints to inhibit mineral formation and that the Ank gene plays a key role in postnatal maintenance of joint mobility and function.

Alleles↗
PubMed1985

Shoulder function following the loss of the latissimus dorsi muscle.

A study of shoulder function was carried out in a group of 19 male patients who had their latissimus dorsi muscle removed as a free flap. A control group was examined to obtain data for the normal range of movement and power at the shoulder. Only a few patients had any subjective impairment of shoulder function; 13 of our 19 patients had a complete range of movement at the shoulder. There was no significant difference in power between the patient group and the control group when dominant and non-dominant sides were considered separately (p greater than 0.05). Patients who had surgery carried out more recently and patients with a scar contracture had a significantly higher disability score. The latter group also had a greater deficit in range of movement at the shoulder (p less than 0.05). Most patients encountered no difficulty whatever with their occupational and sporting activities. Our results support the view that the latissimus dorsi muscle is totally expendable and that there is no significant functional loss at the shoulder, either in casual or in forceful activities.

Adolescent↗
PubMedDate not supplied

[Progression of chronic renal insufficiency in chronic rejection: the role of chronic transplantation glomerulopathy].

Chronic rejection of kidney transplant is a chronic and progressive decline of kidney transplant function related to certain morphologic changes, such as obliterate vasculopathy, interstitial fibrosis, tubular atrophy, and transplant glomerulopathy [1]. The purpose of this study was to investigate the involvement of chronic transplant glomerulopathy in the progression of chronic renal failure. METHOD, PATIENTS: Of 16 transplant patients with histologic diagnosis of chronic kidney transplant rejection in biopsy specimens, 8 patients had chronic transplant glomerulopathy (ChR-1), and in the other 8 patients glomeruli were relatively preserved (ChR-2). Transplant biopsies were performed between the seventh and the 15th month in ChR-1, and between the ninth and the 34th month in ChR-2 group. Morphologic vasculopathy cv2 changes, tubular atrophy ct1 and ct2 in the half of each group, and interstitial fibrosis ci2, were graded according to the BANFF criteria [2]. During the follow up the patients received similar doses of prednisone, as well as of azathioprine and cyclosporine A. IMMUNOHISTOCHEMICAL INVESTIGATION: The expression of MHC I antigen, MHC II antigens, CD3, CD25, CD54 (ICAM-1) was analyzed by indirect immunoperoxidase technique of staining on the frozen sections, (DAKOPATTS). The immunoreactivity score was 0 to 3. BIOCHEMICAL INVESTIGATION: The renal function was expressed as reciprocal serum creatinine values (1/mumol/L) reflecting the mean monthly levels, over the period between the third and the 22nd month following the transplantation. In each patient a decline in kidney functioning was determined in two ways: 1. by the slope of the curve representing the function of regression of the reciprocal serum creatinine over time, started from the third month after the transplantation, 2. by the rate of regression (percent) of the reciprocal serum creatinine values at the sixth, the ninth, the 18th and the 22nd month, compared to the attained serum creatinine level at the third posttransplantation month. RESULTS AND DISCUSSION: Glomeruli with present chronic transplant glomerulopathy (patients of the ChR-1 group) had moderate expression of MHC I antigen [1-2], week expression of ICAM-1 (CD54), whereas DR antigens were almost absent. In cortical tubuli the expression of MHC I antigen was very low. The relatively preserved glomeruli in patients without chronic transplant glomerulopathy (ChR-2 group) showed high expression of MHC I antigen [2], moderate expression of ICAM-1, and low (up to 1) DR expression. The CD25 molecules were not detected in any analyzed glomeruli (62 in total), except a positive cellular crescent formation, seen in 3 patients with chronic transplant glomerulopathy. The regression slopes of reciprocal serum creatinine values according to months, over the third and the 22nd month were similar in both groups of patients, and the speculating mean graft survival time was 44 months, in both groups. However, 4 of 8 patients of the ChR-1 group, and only 1 of 8 patients of the ChR-2 group returned to the haemodialyses because of the graft functioning loss. Besides, the mean percentual rate of the decline in renal functioning, as the rate of decrease of serum reciprocal creatinine values in the chosen growing periods in time after the third month were higher in group ChR-1 with present chronic transplant glomerulopathy in biopsy specimens. The difference was of statistical significance at the end of the 18th month, t = 4.10, p less than 0.01. In this period proteinuria exceeding 3 grams a day was discovered in 6 patients of ChR-1 group, and in 4 patients in ChR-2 group. Our results suggest that the early appearance of chronic transplant glomerulopathy induces a slightly higher loss of function of the kidney transplant with chronic rejection, despite of the absence of the immune activation in the glomeruli with the present chronic transplant glomerulopathy. (ABSTRACT TRUNCATED)

Chronic Disease↗
PubMed1992

Diffuse loss of rod function in autosomal dominant retinitis pigmentosa with pro-347-leu mutation of rhodopsin.

There is considerable variety among the clinical features of autosomal dominant retinitis pigmentosa (ADRP). This is probably at least in part due to genetic heterogeneity. Recently, various mutations of the rhodopsin gene have been detected in some ADRP families. We report on six patients from two families with ADRP who were investigated by means of psychophysical and electrophysiological methods. All displayed the same rhodopsin gene mutation at codon 347, which exchanges the amino acid proline for leucine (pro-347-leu). The patients had early-onset night blindness and impaired side vision as of the end of their second life decade. They produced monophasic dark-adaptation curves, showing a lack of rod function and elevated cone thresholds. Dark-adapted two-color threshold perimetry using 500- and 650-nm stimuli revealed a diffuse loss of rod function and centrally preserved cone function. The electroretinogram was nonrecordable at the age of about 30 years. A certain variability of visual function loss was noted among patients in the overall severe course of the disease, but the clinical findings of this genotype corresponded to type 1 ADRP of Massof and Finkelstein in all cases.

Adult↗
PubMed2002

Loss of RecA function affects the ability of Escherichia coli to maintain recombinant plasmids containing a Ter site.

In the Escherichia coli chromosome, DNA replication forks arrested by a Tus-Ter complex or by DNA damage are reinitiated through pathways that involve RecA and numerous other recombination functions. To examine the role of recombination in the processing of replication forks arrested by a Tus-Ter complex, the requirements for recombination-associated gene products were assessed in cells carrying Ter plasmids, i.e., plasmids that contain a Ter site oriented to block DNA replication. Of the E. coli recombination functions tested, only loss of recA conferred an observable phenotype on cells containing a Ter plasmid, which was inefficient transformation and reduced ability to maintain a Ter plasmid when Tus was expressed. Given the current understanding of replication reinitiation, the simplest explanation for the restriction of Ter plasmid maintenance was a reduced ability to restart plasmid replication in a recA tus(+) background. However, we were unable to detect a difference in the efficiency of replication arrest by Tus in recA-proficient and recA-deficient cells, which suggests that the inability to restart arrested replication forks is not the cause of the restriction on growth, but is due to an additional function provided by RecA. Other explanations for restriction of Ter plasmid maintenance were examined, including plasmid multimerization, plasmid rearrangements, and copy number differences. The most likely cause of the restriction on Ter plasmid maintenance was a reduced copy number in recA cells that was detected when the copy number was measured in relation to an external control. Possibly, loss of RecA function leads to improper processing of replication forks arrested at a Ter site, leading to the generation of degradation-prone substrates.

DNA Replication↗
PubMed2003

Membrane topology of CLN3, the protein underlying Batten disease.

Juvenile neuronal ceroid lipofuscinosis, or Batten disease, is an autosomal recessive disorder characterized by progressive loss of motor and cognitive functions, loss of vision, progressively severe seizures, and death. The disease is associated with mutations in the gene CLN3, which encodes a novel 438 amino acid protein, the function of which is currently unknown. Protein secondary structure prediction programs suggest that the CLN3 protein has five to seven membrane-spanning domains (MSDs). To distinguish among a number of hypothetical models for the membrane topology of CLN3 we used in vitro translation of native, Flag epitope-labeled and glycosylation site-mutated CLN3 protein in the presence or absence of canine pancreatic microsomes. These were immunoprecipitated using antibodies specific for Flag or peptide sequences within CLN3 or left untreated. The results indicate that CLN3 contains five MSDs, an extracellular/intraluminal amino-terminus, and a cytoplasmic carboxy-terminus.

Glycosylation↗