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At least 703 records · Page 39Linked to original sources
PubMed2000

IGF-II ameliorates the dystrophic phenotype and coordinately down-regulates programmed cell death.

Duchenne muscular dystrophy (DMD) is a fatal and crippling disease of skeletal muscle which displays increased fibre turnover and elevated levels of programmed cell death (PCD) in muscle stem cells. Previously we showed that this cell death is inhibited by the growth factor IGF-II. To determine the functional significance of PCD to the dystrophic phenotype, we used a transgene to over-express IGF-II in the mdx mouse. We found that ectopic expression of IGF-II inhibited the elevated PCD observed in skeletal muscles in the absence of functional dystrophin and significantly ameliorates the early gross histopathological changes in skeletal muscles characteristic of the dystrophic phenotype. Replacement of the dystrophin gene abolished abnormal skeletal muscle cell PCD levels in vivo in a dose-dependent manner and in dystrophic SMS cell lines cultured in vitro. Thus elevation of stem cell PCD in dystrophic skeletal muscle is a direct consequence of the loss of functional dystrophin. Together these data demonstrate that elevated skeletal muscle cell PCD is a critical component of dystrophic pathology and is inversely correlated with both dystrophin gene dosage and with muscle fibre pathology. Targeting PCD in dystrophic muscles reduces both PCD and the classical features of dystrophic pathology in the mdx mouse suggesting that IGF-II is a strong candidate for therapeutic intervention in the dystrophinopathies.

Animals↗
PubMed2003

Genetic manipulations of adenovirus type 5 fiber resulting in liver tropism attenuation.

The development of genetically modified adenoviral vectors capable of specifically transducing a given cell population requires the addition and functional presentation of particular tropism determinants within the virus capsid, together with the abrogation of the molecular determinants that dictate their natural tropism in vivo. The human adenovirus serotype 5 (Ad5) first attaches to the cell surface following high-affinity binding of the C-terminal knob of the fiber capsid protein to the coxsackie and adenovirus receptor (CAR). Here we have assessed whether genetic shortening of the fiber shaft (virus BS1), or replacing the Ad5 fiber shaft and knob with their Ad3 counterparts (virus DB6), could cripple this interaction in vitro and in vivo. A 10-fold decrease in the binding of the modified capsids to soluble CAR was evidenced, which correlated with a similar reduction of their ability to transduce CAR-positive cells in vitro. The ability of BS1 to interact with cellular integrins was also impaired, suggesting that the penton base and the short-shafted fiber when embedded in the capsid preclude each other from efficiently interacting with their cognate cell surface receptors (CAR and integrins respectively). BS1 and DB6 intravenous injections in mice further supported a profound impairment of the ability of the capsid-modified viruses to transduce the liver as demonstrated by a 10-fold reduction of intracellular viral DNA and transgene expression. Interestingly enough, the host humoral response was also specifically weakened in BS1- and DB6-inoculated animals. Taken together, these observations indicate that (i) fiber shortening and (ii) pseudo-typing of Ad5-based vectors with the shaft and knob from non-CAR-binding serotypes constitute two promising strategies to successfully attenuate their native tropism in vitro and most importantly in vivo.

Animals↗
PubMed1997

Quality control of glycosylphosphatidylinositol anchor attachment in mammalian cells: a biochemical study.

hGHDAF28 is a chimaeric protein consisting of human growth hormone fused to a crippled signal sequence for glycosylphosphatidylinositol (GPI)-anchor addition from decay-accelerating factor, and serves as a model for quality control of GPI-anchor addition. hGHDAF28 is retained in a pre-Golgi compartment and degraded intracellularly by a mechanism with similarity to that for other endoplasmic reticulum (ER)-retained proteins (Field, Moran, Lee, Keller and Caras (1994) J. Biol. Chem. 269, 10830-10837). We have studied the specific pathway of degradation for hGHDAF28 using a number of compounds which affect protein folding and trafficking pathways in eukaryotic cells. We found that high concentrations of dithiothreitol (DTT) accelerated loss of hGHDAF28 by degradation from cell lysates, without promoting secretion or alteration of disulphide-bond distribution, in contrast to a number of other examples of ER-retained proteins where DTT alters disulphide-bond formation. Additionally, degradation of hGHDAF28 was sensitive to pH, being promoted at pH 6.0 and inhibited at pH 8.0; however, the latter effect was transient, indicating incomplete blockade. Degradation was also partially enhanced by depletion of ER calcium with thapsigargin, but this was again a partial and transient effect. Furthermore, degradation was temperature sensitive, with a gradual decrease in rate observed at lower temperatures. However, a sharp decrease in turnover between 15 degrees C and 20 degrees C, indicative of a requirement for transport to a post-ER compartment, was not observed. Degradation of hGHDAF28 was insensitive to treatment with nocodozole or compounds preventing cytoplasmic autophagy, suggesting that ER degradation is independent of classical autophagy and microtubule-dependent processes. In addition, disruption of N-glycosylation with tunicamycin, or inhibition of processing of immature N-glycan chains with castanospermine or deoxynojirimycin, had little effect on the stability of hGHDAF28, suggesting that disruption of the BiP/calnexin quality-control system by bulk cellular secretory proteins does not influence the ER-degradation pathway of hGHDAF28. Intermolecular hGHDAF28 cysteine bonds result in the formation of aggregates which are probably important in the retention of the molecule. The insensitivity of this structure to reduction in vivo, together with the enhanced degradation rate, indicates that DTT mediates its effect on stability via a molecule involved in degradation of hGHDAF28, possibly a thiol-sensitive protease.

Animals↗
PubMed1998

Proteasome and thiol involvement in quality control of glycosylphosphatidylinositol anchor addition.

Improperly processed secretory proteins are degraded by a hydrolytic system that is associated with the endoplasmic reticulum (ER) and appears to involve re-export of lumenal proteins into the cytoplasm for ultimate degradation by the proteasome. The chimaeric protein hGHDAF28, which contains a crippled glycosylphosphatidylinositol (GPI) C-terminal signal peptide, is degraded by a pathway highly similar to that for other ER-retained proteins and is characterized by formation of disulphide-linked aggregates, failure to reach the Golgi complex and intracellular degradation with a half life of approximately 2 h. Here we show that N-acetyl-leucinal-leucinal-norleucinal, MG-132 and lactacystin, all inhibitors of the proteasome, protect hGHDAF28; hGHDAF28 is still proteolytically cleaved in the presence of lactacystin or MG-132, by the removal of approximately 2 kDa, but the truncated fragment is not processed further. We demonstrate that the ubiquitination system accelerates ER-degradation of hGHDAF28, but is not essential to the process. Overall, these findings indicate that GPI quality control is mediated by the cytoplasmic proteasome. We also show that the presence of a cysteine residue in the GPI signal of hGHDAF28 is required for retention and degradation, as mutation of this residue to serine results in secretion of the fusion protein, implicating thiol-mediated retention as a mechanism for quality control of some GPI signals. Removal of the cysteine also prevents inclusion of hGHDAF28 in disulphide-linked aggregates, indicating that aggregate formation is an additional retention mechanism for this class of protein. Therefore our data suggest that an unpaired terminal cysteine is the retention motif of the hGHDAF28 GPI-processing signal and that additional information may be required for efficient engagement of ER quality control systems by the majority of GPI signals which lack cysteine residues.

Acetylcysteine↗
PubMed2002

An unbalanced translocation involving chromosome 14 is the probable cause for loss of potentially functional rearranged immunoglobulin heavy chain genes in the Epstein-Barr virus-positive Hodgkin's lymphoma-derived cell line L591.

In the vast majority of cases, Hodgkin-Reed Sternberg (H-RS) cells, the malignant cells in Hodgkin's lymphoma (HL), are derived from germinal centre B cells. In some cases, somatic mutations within the rearranged immunoglobulin heavy (IgH) chain genes were detected, rendering potentially functional gene rearrangements non-functional. In these H-RS cells the expression of high-affinity B-cell receptors (BCR) was prevented. As in other cases only one non-productive IgH chain gene rearrangement was amplified from H-RS cells, it was speculated whether, in these cases, the functionally rearranged IgH chain genes were lost. An alternative explanation might be that the rearranged genes could not be amplified owing to a high load of somatic mutations within the primer binding sites. Here, we showed that, in the HL-derived Epstein-Barr virus (EBV)-positive cell line L591, only one non-functional somatically mutated IgH gene rearrangement could be detected. The other potentially functional IgH gene rearrangement was lost as a result of an unbalanced translocation affecting the long arm of chromosome 14. Moreover, L591 cells express the EBV latent membrane proteins LMP1 and LMP2A, which might have contributed to the 'escape' of these cells from apoptosis within the germinal centre. We conclude that, apart from the introduction of 'crippling mutations' into the rearranged VDJ genes rearrangement, deletions of the IGH locus may be regarded as another mechanism to prevent the expression of a BCR in H-RS cells.

Amino Acid Sequence↗
PubMed2003

Human immunodeficiency virus-1 envelope glycoproteins and anti-CD4 antibodies inhibit interleukin-2-induced Jak/STAT signalling in human CD4 T lymphocytes.

Human immunodeficiency virus (HIV) infection leads to a profound T cell dysfunction well before the clinical onset of acquired immunodeficiency syndrome (AIDS). We have been accumulating evidence that one of the mechanisms responsible for this T cell deficiency may be the dysregulation of signal transduction via the interleukin (IL)-2/IL-2 receptor (R) complex. In CD4 T cells, we have observed previously that viral envelope (env) glycoproteins induce IL-2 unresponsiveness and the down-regulation of the three chains making up the IL-2R (alpha, beta, gamma) in vitro. We have now established further that this disruption of the IL-2/IL-2R system manifests itself in defective signal propagation via the Janus kinase (Jak)/signal transducer and activator of transcription (STAT) pathway in response to IL-2. The treatment of CD4 T cells with HIV env or surface ligation of CD4 with anti-CD4 monoclonal antibodies inhibited the IL-2-induced activation of Jak-1 and Jak-3, as well as their targets, STAT5a and STAT5b. This Jak/STAT deficiency may contribute to the crippling of CD4 T cell responses to a cytokine central to the immune response by HIV.

Antibodies, Monoclonal↗
PubMed2001

Coconut palm-related injuries in the Pacific Islands.

INTRODUCTION: Coconut palms are an integral part of life in the Solomon Islands, given the widespread dependence of subsistence agriculture. Injuries related to the coconut palm are thus inevitable. Hospital records from the Central Referral Hospital were reviewed to identify (i) how commonly the coconut palm is implicated in injuries referred to the surgery department; (ii) which patients are being injured; and (iii) the type of injuries sustained. METHODS: The present study reviews all patients referred to the Department of Surgery and Orthopaedics between January 1994 and December 1999 who had a coconut palm-related injury. This was possible due to the trauma epidemiology form, which records the patient details, cause of injury, fracture details and other injury information. RESULTS: A total of 3.4% of all injuries presenting to the surgical department was related to the coconut palm. Eighty-five patients fell from the coconut palm, 16 patients had a coconut fruit fall on them, three patients had a coconut palm fall on them and one patient kicked a coconut palm. The majority of patients who were injured by falling from a coconut palm were young (aged 6-25 years). Eleven of the 16 patients struck by falling fruit were under 25 years of age. The majority of injuries sustained were fractures. Patients falling from coconut palms sustained mainly upper limb fractures (60.1% of all fractures) or spinal fractures (16.3%). Patients injured by falling fruit sustained skull or upper limb fractures. All skull fractures occurred in patients under the age of 10 years. CONCLUSION: This is the largest review of coconut palm-related injuries. It highlights some epidemiological facts that raise considerations for preventative health measures in the Solomon Islands. Parents and young children must be warned of the dangers of playing beneath coconut trees. Boy and girls should be warned of the dangers of collecting fruit. With an increasing amount of schooling becoming available the Solomon Islands is an ideal place to direct an education programme about the dangers of coconut palms as well as many other primary health issues. Because subsistence farming plays a crucial role in the life of most Solomon Islanders, injuries that result in loss of function are crippling both to the patient and the village. Any preventative measure to reduce the rates of injury will be important.

Accidental Falls↗
PubMed1999

Botulinum toxin A versus fixed cast stretching for dynamic calf tightness in cerebral palsy.

OBJECTIVE: To compare botulinum toxin A injections with fixed plaster cast stretching in the management of cerebral palsied children with dynamic (i.e. non-fixed) calf tightness. METHODS: The settings were the Women's and Children's Hospital (WCH) and the Crippled Children's Association of South Australia (CCA), Adelaide, South Australia. Twenty children were selected by two paediatric rehabilitation specialists. A prospective, randomized, single-blind controlled study, was carried out, with 10 children in each arm. The clinicians were blinded as to the allocated interventions. The outcome measures for 6 months post intervention were clinical assessment, modified Ashworth Scale, Gross Motor Function Measure, 2 D-video ratings using a modified Physical Rating Scale and a global scoring scale and a parent satisfaction questionnaire. RESULTS AND CONCLUSION: Botulinum toxin A injections were of similar efficacy to serial fixed plaster casting in improving dynamic calf tightness in ambulant or partially ambulant children with cerebral palsy. The ease of outpatient administration, reduction of muscle tone and safety with botulinum toxin A was confirmed. Parents consistently favoured botulinum toxin A and highlighted the inconvenience of serial casting.

Botulinum Toxins, Type A↗
PubMed1998

HLA DR2 and DQ1 frequency among narcoleptic patients in Hong Kong Chinese.

Narcolepsy is a life-long crippling sleep disorder with significant physical and psychosocial impairments. Although its exact etiology and neuropathology is not clear, a strong association with specific human leucocyte antigen (HLA) subtype, particularly DR2 (DRw15) and DQw1 (DQw6), has been demonstrated across different ethnic groups including Caucasians and Japanese. The presence of 100% association with HLA DR2 in a series of Hong Kong Chinese narcoleptic patients has previously been reported. The report can now be extended, and as far as could be ascertained in the available subjects, all were HLA DQw1 (DQw6)-positive. This is concordant with the experiences of Japanese narcoleptic patients who are 100% HLA DR2- and DQw1-positive. However, the definitive account of the population prevalence of narcolepsy in Chinese could be determined only by a well-conducted epidemiological study with laboratory confirmation.

Adolescent↗
PubMed1997

Natural erection induced by prostaglandin-E1 in the diagnosis and treatment of congenital penile anomalies.

OBJECTIVE: To report the use of a natural erection induced by prostaglandin EI (PGE1) in the diagnosis and therapy of congenital penile anomalies as an alternative to artificial erection. PATIENTS AND METHODS: From February 1991 to December 1995 a natural erection was induced in 672 patients (mean age 5.7 years, range 12 months-47 years) to diagnose and treat congenital anomalies, e.g. simple penile curvature, chordee with and without hypospadias, epispadias, micropenis, cripple penis, etc. The dose injected intracavernosally was dependent on the patient's age, penile size and response, and ranged from 0.5 to 15 micrograms. RESULTS: A natural dilatation of erectile tissue was achieved in all forms of penile anomalies except in seven patients who did not respond. The mean duration of erection was 80 min, but a prolonged erection, for up to 6 h, occurred in two patients. CONCLUSION: The natural erection achieved by injecting PGE1 into the corpora cavernosa is a useful alternative to artificial erection in the diagnosis and treatment of congenital penile anomalies.

Adolescent↗
PubMedDate not supplied

Nursing and health in Russia.

There are over one million nurses in Russia, and they work in a crippled healthcare system facing a dramatic increase in infectious diseases. But nurses are valiantly coping with the country's health crisis and becoming a recognized profession.

Delivery of Health Care↗
PubMed2002

Contribution of SISCOM imaging in the presurgical evaluation of temporal lobe epilepsy related to dysembryoplastic neuroepithelial tumors.

PURPOSE: Dysembryoplastic neuroepithelial tumors (DNTs) are a group of glioneuronal supratentorial and intracortical lesions often associated with the early onset of intractable and crippling partial seizures. They are characterized by their location, multinodular architecture, and heterogeneous cell composition, with a specific glioneuronal element in the specific form. Foci of cortical dysplasia may be associated with the tumoral lesion, and identifying the presence and the extent of cortical dysplasia is not always easy on magnetic resonance images (MRIs). The purpose of this article is to evaluate, retrospectively, the usefulness of ictal single-photon emission computed tomography (SPECT) imaging to assess the presence and the extent of cortical dysplasia associated with DNTs in nine patients with intractable temporal lobe epilepsy related to histopathologically confirmed DNTs. METHODS: The results of the subtraction of ictal and interictal SPECT coregistered to MRI (SISCOM) were compared with the results of the examinations of pathological material after surgery. RESULTS: SISCOM showed a strongly hyperperfused area corresponding anatomically to electroclinical abnormalities and to the location of DNTs on MRI. A circumscribed hyperperfusion was present in DNTs without cortical dysplasia, limited to the location of the tumor on MRI. In cases of associated cortical dysplasia, a widespread hyperperfusion including areas corresponding to normal perilesional regions on MRI was found. CONCLUSIONS: SISCOM, used among presurgical investigations, contributes to detecting cortical dysplasia associated with DNTs. Concordance between the symptomatogenic zone (defined from the medical history and electroclinical data), MRI scans, SISCOM pattern, and complete resection of the epileptic zone was predictive of a good postsurgical outcome.

Adolescent↗
PubMed2006

Reemergence of an unusual disease: the chikungunya epidemic.

Since the beginning of 2006, a crippling mosquito-borne disease has shown an explosive emergence in nations in the Indian Ocean area. By March 7, 2006, 157,000 people had been infected in the French island La Réunion, and the disease had spread to the islands of Seychelles, Mauritius, and Mayotte (French). Subsequently, the disease appeared in India, China, and European countries. The World Health Organization is taking measures to assist in fighting the epidemic. This article describes the disease, its recent emergence, and the current epidemic.

Aedes↗
PubMedDate not supplied

Severe carpometacarpal osteoarthritis in older Arabian horses.

OBJECTIVE: To report a severe form of carpometacarpal osteoarthritis (CMC-OA) affecting primarily older Arabian horses. STUDY DESIGN: Retrospective study. ANIMALS: Thirty-one horses with CMC-OA. METHODS: Carpal radiographs (405 sets) from 3 hospitals were evaluated to identify horses with marked osteoproliferative reaction across the medial aspect of the CMC joint. Owners were contacted to obtain detailed histories and status updates. Necropsy specimens of the CMC joint were evaluated at 2 hospitals to determine the prevalence of 2 variations in the articulation between the proximal second and third metacarpal bones. RESULTS: Thirty-one horses were identified as having marked osteoproliferative reaction at the CMC joint. Twenty-three (74%) were Arabian horses. Of the Arabian horses, the average age at admission was 14.4 years. Eight (34.8%) Arabian horses had a known history of trauma. Most were no longer rideable at presentation. Ten of the horses were subsequently euthanatized because of lameness. The dorsal and palmar articulations between the second and third metacarpal bones were examined in 177 horses. The palmar articulation was absent in 48% of Arabian horses and 12.5% of non-Arabian horses at 1 center, including 4 horses with CMC-OA. At the second center, the palmar articulation was present in 8 of 8 Arabian horses but was absent in 22 of 92 (24%) non-Arabian horses. CONCLUSIONS: An increased frequency of this crippling form of OA was observed in Arabian horses. It may reflect an increased prevalence, in some geographical regions, of an absent palmar articulation between the second and third metacarpal bones. CLINICAL RELEVANCE: Carpal trauma in some Arabian horses may result in unexpectedly severe carpometacarpal osteoarthritis.

Animals↗
PubMed2004

Alkaptonuria, ochronosis, and ochronotic arthropathy.

OBJECTIVES: To describe the clinical presentation and course of a relatively large group of Italian adult patients screened for mutation of the homogentisate dioxygenase gene causing alkaptonuria (AKU) and ochronosis, and to review typical and atypical facets of this condition. METHODS: We reviewed the medical records of 9 patients affected by ochronotic arthropathy who were observed in our institutions between 1979 and 2001. All patients were diagnosed as having AKU through a rapid urine test with alkali. Mutation screening was performed by single-strand conformation analysis of all homogentisate dioxygenase exons, followed by sequencing of altered conformers. RESULTS: Our 9 cases had similar clinical features and they reflected those described in the literature: a progressive degenerative arthropathy mainly affecting axial and weight-bearing joints associated with extraarticular manifestation. Musculoskeletal symptoms began in most of our patients around the age of 30 years with back pain and stiffness: involvement of the large peripheral joints usually occurred several years after spinal changes. Ochronotic peripheral arthropathy generally was degenerative, but joint inflammation was observed in some cases; this could be attributed to an inflammatory reaction of the ochronotic shard in the synovial membrane. CONCLUSIONS: Ochronosis is a model of arthropathy with known etiologic factors. Over time, AKU, the genetically determined metabolic defect, leads to the accumulation of pigment and the development of this crippling condition. Most of the clinical findings may be explained by inhibition of collagen crosslinks, but some require additional interpretation. For example, inflammatory features of the ochronotic joint only occur in a minority of cases, and may be attributable to ochronotic shards. Further studies are needed to establish the genotype-phenotype correlation to identify mutations that are predictive of severe disease. For this purpose, the Italian Study Group on Alkaptonuria (www.dfc.unifi.it/aku) is enrolling affected patients in an on-line database to characterize the molecular defects and their relationship to clinical data.

Aged↗
PubMed2000

Hypoglycemia in association with various organic and amino acid disorders.

A number of organic and amino acidemias, particularly those that involve the oxidation of fatty acids, cause hypoglycemia intermittently. This may be associated with distrubances of acid base equilibrium and accumulation of lactic acid and/or ketone bodies. When such diseases are not diagnosed rapidly, they might lead to neurological crippling and, at times, death. As a group, these disorders involve more than 1 organ and their phenotypic expression may include all or a single system. The symptoms may appear soon after birth or as late as 1 year of age. Their early recognition and rapid intervention provide rewarding clinical outcome. With the recent advances in diagnostic techniques, such as the introduction of tandem mass spectrometry (MS), screening for these diseases now can be performed because rapid identification on a large scale is possible. The phenotypes, mutations involved, pathognomonic laboratory findings, prognosis, and treatment procedures available have been reviewed for major diseases.

Amino Acid Metabolism, Inborn Errors↗
PubMed2002

Thomas Huckle Weller MD: Nobel Laureate and research pioneer in poliomyelitis, varicella-zoster virus, cytomegalovirus, rubella, and other infectious diseases.

In 1954, the Nobel Prize for Medicine was awarded to Drs John Enders, Thomas Weller, and Frederick Robbins for their watershed discovery that growth of poliomyelitis virus occurred in cultures of cells of extraneural origin, first reported in 1949. Their demonstration in 1949 that the Lansing type II strain of poliomyelitis could be grown in cultures of human embryonic tissue set into motion a race to develop a vaccine for the disease that had crippled countless thousands of individuals. The discovery and subsequent recognition were only the beginning of a prolific career for Thomas Huckle Weller, who made numerous contributions to the field of virology, including isolating the varicella-zoster virus (VZV) from cases of chickenpox and zoster, providing suggestive evidence that the same virus is responsible for both diseases; isolating the human cytomegalovirus (CMV) for the first time in tissue culture and suggesting the descriptive name now used for it; establishing Coxsackie viruses as the cause of epidemic pleurodynia: and first isolating rubella virus, the cause of German measles. This article presents a brief biography of Dr Thomas Huckle Weller, one of the field's most important figures, with primary focuses on his work on poliomyelitis, varicella-zoster virus, rubella virus, and cytomegalovirus.

Cytomegalovirus↗
PubMed2000

Haploid plants regenerated from androgenic cell cultures of Digitalis lanata.

Androgenic callus was obtained from cold treated anthers and pollen of Digitalis lanata. The callus was mixoploid and contained haploid, diploid and tetraploid cells as shown by impulse cytophotometry. Haploid cell lines were selected by colony cloning. They were unstable and selection had to be repeated every 1-2 months. Mixoploid shoot cultures were derived from embryogenic haploid cell lines via somatic embryos. Haploid shoots were selected by explanting shoot tips. The shoots showed wide variability in cardenolide content and profile. Rooting of the haploid shoots resulted in haploid plants. These plants were smaller in size than diploid plants. Often the flowers were morphologically abnormal and showed male sterility due to crippled anthers.

Androgens↗