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PubMed1999

Catalytic activity of antibodies against factor VIII in patients with hemophilia A.

Hemophilia A is an X chromosome-linked recessive disorder resulting in defective or deficient factor VIII (FVIII) molecules, which, in its severe form, is a life-threatening and crippling hemorrhagic disease. Infusion of homologous FVIII to patients with severe hemophilia A results, in 25% of patients, in the emergence of alloantibodies against FVIII (inhibitors)( ref. 1) that inhibit FVIII procoagulant activity by steric hindrance of the interaction of FVIII either with stabilizing molecules, with molecules essential for its activity or with activating molecules. Here, we report on the proteolysis of FVIII by alloantibodies of two patients with severe hemophilia A, demonstrating a previously unknown mechanism by which FVIII inhibitors may prevent the pro-coagulant function of FVIII. The kinetic parameters of FVIII hydrolysis indicate a functional role for the catalytic immune response in the inactivation of FVIII in vivo. The characterization of alloantibodies against FVIII as site-specific proteases may provide new approaches to the treatment of FVIII inhibitors.

Antibodies, Catalytic↗

PubMedDate not supplied

Capacity of purified Lyt-2+ T cells to mount primary proliferative and cytotoxic responses to Ia- tumour cells.

Allogeneic gene products of the major histocompatibility complex, the HLA complex in man and the H-2 complex in mice, induce T lymphocytes to exert powerful mixed lymphocyte reactions (MLR) and cell-mediated lympholysis (CML). In mice, the subset of T cells carrying the L3T4 surface antigen but lacking the Lyt-2 antigen responds predominantly to H-2 class II (Ia) differences whereas the L3T4- Lyt-2+ subset reacts to class I (K/D) differences. For primary responses the stimulus for MLR and CML appears to be controlled by Ia+ cells of the macrophage/dendritic cell lineages, for both L3T4+ and Lyt-2+ cells. The finding that Ia+ cells are required for responses involving Lyt-2+ cells has been taken to imply that triggering of these cells is controlled by Ia-restricted L3T4+ cells. Lyt-2+ cells have thus come to be regarded as crippled cells which are heavily dependent on 'help' from other T cells. This well-entrenched view is challenged by evidence presented here that purified Lyt-2+ cells can give high primary responses to certain Ia- tumour cells in vitro.

Animals↗

PubMed1988

Unresponsiveness to a foreign antigen can be caused by self-tolerance.

In mice, two sets of genes govern the immune response to the synthetic antigen GT. One maps to the major histocompatibility complex and behaves like a typical immune response gene. The second is a background gene encoding a cell surface structure found on B cells. Mice which express, and are therefore tolerant of, one form of this structure do not respond to GT. Thus, tolerance of self generates holes in the T-cell repertoire, partially crippling the immune system.

Animals↗

PubMed1999

Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand.

Bone remodelling and bone loss are controlled by a balance between the tumour necrosis factor family molecule osteoprotegerin ligand (OPGL) and its decoy receptor osteoprotegerin (OPG). In addition, OPGL regulates lymph node organogenesis, lymphocyte development and interactions between T cells and dendritic cells in the immune system. The OPGL receptor, RANK, is expressed on chondrocytes, osteoclast precursors and mature osteoclasts. OPGL expression in T cells is induced by antigen receptor engagement, which suggests that activated T cells may influence bone metabolism through OPGL and RANK. Here we report that activated T cells can directly trigger osteoclastogenesis through OPGL. Systemic activation of T cells in vivo leads to an OPGL-mediated increase in osteoclastogenesis and bone loss. In a T-cell-dependent model of rat adjuvant arthritis characterized by severe joint inflammation, bone and cartilage destruction and crippling, blocking of OPGL through osteoprotegerin treatment at the onset of disease prevents bone and cartilage destruction but not inflammation. These results show that both systemic and local T-cell activation can lead to OPGL production and subsequent bone loss, and they provide a novel paradigm for T cells as regulators of bone physiology.

Animals↗

PubMed2001

An antisense-based functional genomics approach for identification of genes critical for growth of Candida albicans.

Converting the complete genome sequence of Candida albicans into meaningful biological information will require comprehensive screens for identifying functional classes of genes. Most systems described so far are not applicable to C. albicans because of its difficulty with mating, its diploid nature, and the lack of functional random insertional mutagenesis methods. We examined artificial gene suppression as a means to identify gene products critical for growth of this pathogen; these represent new antifungal drug targets. To achieve gene suppression we combined antisense RNA inhibition and promoter interference. After cloning antisense complementary DNA (cDNA) fragments under control of an inducible GAL1 promoter, we transferred the resulting libraries to C. albicans. Over 2,000 transformant colonies were screened for a promoter-induced diminished-growth phenotype. After recovery of the plasmids, sequence determination of their inserts revealed the messenger RNA (mRNA) they inhibited or the gene they disrupted. Eighty-six genes critical for growth were identified, 45 with unknown function. When used in high-throughput screening for antifungals, the crippled C. albicans strains generated in this study showed enhanced sensitivity to specific drugs.

Antifungal Agents↗

PubMed2001

Mutation of the matrix metalloproteinase 2 gene (MMP2) causes a multicentric osteolysis and arthritis syndrome.

The inherited osteolyses or 'vanishing bone' syndromes are a group of rare disorders of unknown etiology characterized by destruction and resorption of affected bones. The multicentric osteolyses are notable for interphalangeal joint erosions that mimic severe juvenile rheumatoid arthritis (OMIMs 166300, 259600, 259610 and 277950). We recently described an autosomal recessive form of multicentric osteolysis with carpal and tarsal resorption, crippling arthritic changes, marked osteoporosis, palmar and plantar subcutaneous nodules and distinctive facies in a number of consanguineous Saudi Arabian families. We localized the disease gene to 16q12-21 by using members of these families for a genome-wide search for homozygous-by-descent microsatellite markers. Haplotype analysis narrowed the critical region to a 1.2-cM region that spans the gene encoding MMP-2 (gelatinase A, collagenase type IV; (ref. 3). We detected no MMP2 enzymatic activity in the serum or fibroblasts of affected family members. We identified two family-specific homoallelic MMP2 mutations: R101H and Y244X. The nonsense mutation effects a deletion of the substrate-binding and catalytic sites and the fibronectin type II-like and hemopexin/TIMP2 binding domains. Based on molecular modeling, the missense mutation disrupts hydrogen bond formation within the highly conserved prodomain adjacent to the catalytic zinc ion.

Amino Acid Sequence↗

PubMed1975

Enhancement of syngeneic murine tumour transplantability by whole body irradiation--a non-immunological phenomenon.

Experiments were undertaken to test the general validity of the assumption that potentiation of tumour transplantability by sublethal whole body irradiation (WBI) implies some degree of immunological resistance in the intact host. A transplantable carcinoma of spontaneous origin in CBA mice which exhibits a large WBI effect was assayed quantitatively in mice which had been immunologically crippled in terms of allograft acceptance by depletion of thymus derived lymphocytes. The mean number of tumour cells required for 50% successful takes (TD50) in these mice was found to be not significantly different from that in normal controls but highly significantly greater than in WBI mice. On the other hand, in mice which underwent laparotomy immediately before assay, the TD50 was reduced significantly though not to the same extent as in WBI mice. It was concluded that WBI effect was not due to impaired host immunity but possibly to physiological changes resulting from acute stress. The hypothesis that hyperfibrinogenaemia which occurs after both WBI and laparotomy might increase tumour transplantability was rejected because of the lack of correlation between TD50 and fibrinogen levels at different times after each procedure. From this and other work it is apparent that TD50 data, in themselves, give no reliable indication of host immunity.

Adenocarcinoma↗

PubMed1990

Anterior ischaemic optic neuropathy. Differentiation of arteritic from non-arteritic type and its management.

Anterior ischaemic optic neuropathy (AION), a common, visually crippling disorder, is discussed, with particular emphasis on differentiating AION due to giant cell arteritis (arteritic AION) from that not due to it (non-arteritic AION). Giant cell arteritis is an ophthalmic emergency because of imminent danger of bilateral total blindness, which is almost always preventable if the disease is quickly identified and treated urgently and aggressively. My studies have revealed that the best means of differentiating arteritic from non-arteritic AION is a combination of information from the following: systemic and visual symptoms of giant cell arteritis, high erythrocyte sedimentation rate and C-reactive protein, early massive visual loss, chalky-white optic disc swelling, associated cilio-retinal artery occlusion, massive non-filling of the choroid on fluorescein fundus angiography and temporal artery biopsy. Management of giant cell arteritis and of arteritic AION is discussed. Current misconceptions about AION are pointed out.

Blindness↗

PubMed1994

Inactivation of E2a in recombinant adenoviruses improves the prospect for gene therapy in cystic fibrosis.

Although first generation recombinant adenoviruses, deleted of sequences spanning E1a and E1b, have been useful for in vivo applications of gene therapy, expression of the recombinant gene has been transient and often associated with the development of inflammation. We show that with first generation adenovirus-mediated gene transfer to the mouse lung, viral proteins are expressed leading to destructive cellular immune responses and repopulation of the lung with nontransgene containing cells. Second generation E1 deleted viruses further crippled by a temperature sensitive mutation in the E2a gene were associated with substantially longer recombinant gene expression and less inflammation. Stable expression of human CF transmembrane conductance regulator has been achieved in lungs of CF mice instilled with a second generation virus.

Adenoviridae Infections↗

PubMed2004

Targeted inhibition of V(D)J recombination by a histone methyltransferase.

The tissue- and stage-specific assembly of antigen receptor genes by V(D)J recombination is regulated by changes in the chromatin accessibility of target gene segments. This dynamic remodeling process is coordinated by cis-acting promoters and enhancers, which function as accessibility control elements. The basic epigenetic mechanisms that activate or repress chromatin accessibility to V(D)J recombinase remain unclear. We now demonstrate that a histone methyltransferase overrides accessibility control element function and cripples V(D)J recombination of chromosomal gene segments. The recruited histone methyltransferase induces extensive revisions in the local chromatin environment, including altered histone modifications and de novo methylation of DNA. These findings indicate a key function for histone methyltransferases in the tissue- and stage-specific suppression of antigen receptor gene assembly during lymphocyte development.

Animals↗

PubMed2004

p47 GTPases: regulators of immunity to intracellular pathogens.

Activation of the innate immune system by interferon-gamma (IFN-gamma is crucial for host resistance to infection. IFN-gamma induces the expression of a wide range of mediators that undermine the ability of pathogens to survive in host cells, including a newly discovered family of 47-kDa GTPases. Elimination of different p47 GTPases in mice by gene targeting severely cripples IFN-gamma-regulated defence against Toxoplasma gondii, Listeria monocytogenes, Mycobacterium spp. and other pathogens. In this article, we review our understanding of the role of p47 GTPases in resistance to intracellular infection and discuss the present evidence concerning their mode of action.

Animals↗

PubMed2006

The electrostatic character of the ribosomal surface enables extraordinarily rapid target location by ribotoxins.

Alpha-sarcin ribotoxins comprise a unique family of ribonucleases that cripple the ribosome by catalyzing endoribonucleolytic cleavage of ribosomal RNA at a specific location in the sarcin/ricin loop (SRL). The SRL structure alone is cleaved site-specifically by the ribotoxin, but the ribosomal context enhances the reaction rate by several orders of magnitude. We show that, for the alpha-sarcin-like ribotoxin restrictocin, this catalytic advantage arises from favorable electrostatic interactions with the ribosome. Restrictocin binds at many sites on the ribosomal surface and under certain conditions cleaves the SRL with a second-order rate constant of 1.7 x 10(10) M(-1) s(-1), a value that matches the predicted frequency of random restrictocin-ribosome encounters. The results suggest a mechanism of target location whereby restrictocin encounters ribosomes randomly and diffuses within the ribosomal electrostatic field to the SRL. These studies show a role for electrostatics in protein-ribosome recognition.

Animals↗

PubMed2005

Solution structure of the HIV-1 integrase-binding domain in LEDGF/p75.

Lens epithelium-derived growth factor (LEDGF)/p75 is the dominant binding partner of HIV-1 integrase (IN) in human cells. We have determined the NMR structure of the integrase-binding domain (IBD) in LEDGF and identified amino acid residues essential for the interaction. The IBD is a compact right-handed bundle composed of five alpha-helices. Based on folding topology, the IBD is structurally related to a diverse family of alpha-helical proteins that includes eukaryotic translation initiation factor eIF4G and karyopherin-beta. LEDGF residues essential for the interaction with IN were localized to interhelical loop regions of the bundle structure. Interaction-defective IN mutants were previously shown to cripple replication although they retained catalytic function. The initial structure determination of a host cell factor that tightly binds to a retroviral enzyme lays the groundwork for understanding enzyme-host interactions important for viral replication.

Amino Acid Sequence↗

PubMed1982

Social reintegration of paraplegics and tetraplegics in the Cape Province of the Republic of South Africa.

Rehabilitation of the disabled is a dynamic process which should start from the first day post-injury. Total rehabilitation should include, not only attaining maximum function, but also, satisfaction with life in one's own environment. The obstacles created by able-bodied society, are problems that face the disabled person. The right to participate in, and contribute to, all aspects of economic, social and political life is theirs too, as is the right to make decisions about the future. This should not be overlooked, as decision making sows the seeds of motivation. This in turn dictates the measure of success of social reintegration. Assistance is provided in South Africa by various organisations of central government, provincial and local authorities and private welfare organisations. The Cripple Care Association is a private welfare organisation which provides assistance and acts as a link with other relevant organisations. In the Western Cape the number of successfully rehabilitated persons increases and their presence in the community creates an awareness of their needs. This in turn initiates the process of positive change and action.

Adult↗

PubMed1990

Neurological complications of endemic skeletal fluorosis, with special emphasis on radiculo-myelopathy.

The results of surveys carried out between 1976 and 1985 in the fluorosis-endemic area of the Ethiopian Rift Valley is summarised, with emphasis on the neurological complications resulting from the crippling osteofluorosis. The neurological manifestations in the forms of myelopathy with and without radiculopathy (respectively 72% and 28%) occurred after exposure to high fluoride (greater than 4 ppm) for longer than 10 years. These deficits were clearly found to be a consequence of fluoride deposition in bones, resulting in generalised sclerosis and osteophytosis, with reduction in the diameter of the intervertebral foramina and of the spinal conal. Advanced osteosclerosis commonly causes severe spastic quadriparesis in flexion, accompanied by distressing spasms and urinary incontinence. The dilemma of these medical problems in relation to the agro-industrial economic developments of the Ethiopian Rift Valley is discussed.

Agriculture↗

PubMed1990

The Elephant Man. Part I.

Joseph Merrick was one of three children. His mother and younger sister were cripples, but their disease is unknown. Joseph's own swellings began to appear in early childhood and he rapidly became so grotesque, that he eventually sought a living as a freak. After an unhappy continental tour, he was given asylum in The London Hospital at the instigation of Mr Frederick Treves, and stayed there until he died. Books, a play and a film have featured his unique story, but each presented it with varying degrees of artistic license. However, contemporary accounts of his condition survive. Both bony abnormalities and substantial soft tissue masses contributed to his deformity. Features of these considered separately suggest neurofibromatosis as a diagnosis, but because the presentation is more extreme than seen in any other recorded patient, other diagnoses have been entertained. In the following three papers, the evidence which supports this diagnosis is reviewed, together with a consideration of the disease affecting his left hip and the manner of his death. This first article reviews the Elephant Man's life story.

History, 19th Century↗

PubMed1992

A new dental health project in Zambia.

In Zambia's population of 8 million, 69% are under 24 years of age. The country has a crippling foreign debt, and consequently public services are poorly funded. From March this year my wife and I have been working in Zambia. I have been asked to establish and develop a dental service based at Mukinge Hospital in the North Western Province. Zambia borders eight other countries on the central African plateau and lies at an altitude of between 3000 and 6000 feet.

Dental Health Services↗

PubMed2006

Treatment planning of the edentulous mandible.

Edentulism can be a debilitating handicap. Zarb described endentulous individuals who could not function as 'denture cripples'.(1) Most difficulty with complete denture prostheses arises from the inability to function with the mandibular prostheses. Factors that adversely affect successful use of a complete denture on the mandible include: 1) the mobility of the floor of the mouth, 2) thin mucosa lining the alveolar ridge, 3) reduced support area and 4) the motion of the mandible (Figs 1,2). These factors alone can explain the difficulty of wearing a denture on the mandibular arch compared to the maxillary arch. The maxilla exhibits much less mobility on the borders of the denture than the mandible, moreover having a stable palate with thick fibrous tissues available to support the prostheses and resist occlusal forces. These differences explain most of the reasons why patients experience difficulty with using a complete denture on the mandibular arch compared to the maxillary arch.

Dental Prosthesis, Implant-Supported↗