SEARCH · Search PubMed

Results for “CRIPPLES”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

SourceResearch connectionFrom yearThrough year

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 505 records · Page 28Linked to original sources

PubMed1999

Wild-type enzyme as a reporter of inhibitor binding by catalytically impaired mutant enzymes.

A method for the determination of inhibition constants for catalytically-debilitated mutant enzymes is described. The inhibitor is partitioned between the mutant and wild-type enzymes. Catalytic rates of the wild-type enzyme are used as the signal of inhibitor binding to the mutant enzyme. The method is validated with scytalone dehydratase, the Y50F mutant, and a potent inhibitor. The K(i) value for Y50F determined by this method is 0.49 +/- 0.10 nM. The K(i) value determined using the Y50F catalytic report for inhibitor binding in the absence of wild-type enzyme is 0.20 +/- 0.030 nM. The wild-type enzyme binds the inhibitor ten-fold less tightly, thus indicating that the hydrogen-bonding interaction between the Y50 hydroxyl group and the inhibitor (suggested by X-ray crystallography) is weak. The method is most useful when the catalytic activity of the wild-type enzyme is the most sensitive report of inhibitor binding and the mutant enzyme is greatly crippled in catalytic activity.

Amino Acid Substitution↗

PubMed1997

Alpha 6 beta 4 and alpha 6 beta 1 integrins associate with ErbB-2 in human carcinoma cell lines.

Growth factors modulate integrin-mediated cell adhesion and motility, and their receptors are thought to share proteins that mediate intracellular signaling with integrin receptors. The crosstalk between these receptors is thought to play a relevant role in transformation and tumor progression. To highlight possible interactions between growth factors and cell adhesion receptors we investigated whether integrins associate with tyrosine kinase receptors in tumor cells. By affinity chromatography and Western blot analyses of purified immune complexes, we studied the association of laminin receptors (alpha 6 beta 1 and alpha 6 beta 4) with ErbB-2 tyrosine kinase in human carcinoma cell lines. We demonstrated that the alpha 6 beta 4 and alpha 6 beta 1 integrins coprecipitated with ErbB-2 in lysates from carcinoma or NIH3T3 cells overexpressing ErbB-2. Integrin-mediated activation of ErbB-2 receptors suggested that this association is functionally meaningful. Indeed, carcinoma cells treated with a monoclonal antibody to the alpha 6 integrin subunit showed a ligand-dependent increase of ErbB-2-phosphorylated molecules coprecipitated with integrins and an increased DNA synthesis. The interaction between growth factor receptors and integrins was also studied in NIH3T3 cells overexpressing alpha 6 beta 4 receptors and ErbB-2 protein. We report that cells overexpressing both receptors, but not those overexpressing a crippled ErbB-2, showed enhanced proliferation rates and invasiveness, further suggesting that alpha 6 beta 4 integrin and ErbB-2 receptor interaction might contribute to generate a more malignant phenotype in carcinoma cells.

3T3 Cells↗

PubMed2001

Forest fires and environmental haze in Southeast Asia: using the 'stakeholder' approach to assign costs and responsibilities.

The 'seasonal haze' problem is one which afflicts large parts of Southeast Asia in years of drought. The major cause is forest, bush and field fires in the states of Kalimantan and Sumatra in Indonesia, and to a lesser extent in Sabah, Sarawak, and other parts of Malaysia. Almost all of these fires now seem preventable, since they are intentionally set to clear land for cultivation. Theoretically, the government authorities at central, provincial and local levels in these countries should be responsible for controlling activities in their territory. In practice, however, air pollution control through regulatory policies and practices is extraordinarily difficult to implement and maintain in a situation of this kind in developing countries, especially at a time of crippling economic setbacks. Moreover, the establishment of legal liability, through an international tribunal or otherwise, hardly seems a politically feasible course of action for the government of an affluent 'victim state' such as Singapore. Faith in the usual solutions--science, regulation, law and diplomacy--is weakened by one's sense of current realities. The purpose of this paper is to review the issues and suggested responses, the cost implications of each, the responsibilities as well as entitlements that might apply to the various stakeholders, and the special role of Singapore as an affluent 'victim state'. We also discuss the incentive mechanisms that would be needed to manage forest fires.

Air Pollution↗

PubMed2002

A functional role for a flexible loop containing Glu182 in the class II fructose-1,6-bisphosphate aldolase from Escherichia coli.

Class II fructose 1,6-bisphosphate aldolases (FBP-aldolases) catalyse the zinc-dependent, reversible aldol condensation of dihydroxyacetone phosphate (DHAP) and glyceraldehyde 3-phosphate (G3P) to form fructose 1,6-bisphosphate (FBP). Analysis of the structure of the enzyme from Escherichia coli in complex with a transition state analogue (phosphoglycolohydroxamate, PGH) suggested that substrate binding caused a conformational change in the beta5-alpha7 loop of the enzyme and that this caused the relocation of two glutamate residues (Glu181 and Glu182) into the proximity of the active site. Site-directed mutagenesis of these two glutamate residues (E181A and E182A) along with another active site glutamate (Glu174) was carried out and the mutant enzymes characterised using steady-state kinetics. Mutation of Glu174 (E174A) resulted in an enzyme which was severely crippled in catalysis, in agreement with its position as a zinc ligand in the enzyme's structure. The E181A mutant showed the same properties as the wild-type enzyme indicating that the residue played no major role in substrate binding or enzyme catalysis. In contrast, mutation of Glu182 (E182A) demonstrated that Glu182 is important in the catalytic cycle of the enzyme. Furthermore, the measurement of deuterium kinetic isotope effects using [1(S)-(2)H]DHAP showed that, for the wild-type enzyme, proton abstraction was not the rate determining step, whereas in the case of the E182A mutant this step had become rate limiting, providing evidence for the role of Glu182 in abstraction of the C1 proton from DHAP in the condensation direction of the reaction. Glu182 lies in a loop of polypeptide which contains four glycine residues (Gly176, Gly179, Gly180 and Gly184) and a quadruple mutant (where each glycine was converted to alanine) showed that flexibility of this loop was important for the correct functioning of the enzyme, probably to change the microenvironment of Glu182 in order to perturb its pK(a) to a value suitable for its role in proton abstraction. These results highlight the need for further studies of the dynamics of the enzyme in order to fully understand the complexities of loop closure and catalysis in this enzyme.

Amino Acid Substitution↗

PubMed1998

What does palaeontology contribute to systematics in a molecular world?

Palaeontology provides the only direct record for morphological and genetic change through time and uniquely contributes to systematics in two ways: by providing access to denser taxon sampling than is otherwise possible and by dating divergence times. Claims that ancient DNA has survived millions of years in certain fossils suggested the possibility that palaeontology could contribute directly to molecular systematic studies. Unfortunately, none of the supposed geologically ancient DNA records stands up to detailed scrutiny and fossils therefore contribute primarily through the morphological information they preserve. Denser taxon sampling can improve the accuracy of phylogenetic estimates primarily through allowing better discrimination of homoplasy from homology. This in turn leads to more accurate hypotheses of character transformation. Denser taxon sampling also offers the opportunity for more accurate rooting, since more characters can be polarized by reference to a stem-group taxon than to an extant sister-group taxon. Missing data can be a problem for fossils, but is not crippling. Finally the temporal order of clade appearances in the fossil record can provide ancillary evidence for selecting a working phylogeny from among a number of equally most parsimonious cladograms.

Animals↗

PubMed1997

In vitro selection for different mutational patterns in the HIV-1 reverse transcriptase using high and low selective pressure of the nonnucleoside reverse transcriptase inhibitor HBY 097.

In vitro resistance of HIV-1 against high levels of HBY 097 ((S)-4-isopropoxycarbonyl-6-methoxy-3-(methylthiomethyl)-3, 4-dihydro-quinoxaline-2(1H)-thione) and other quinoxaline nonnucleoside reverse transcriptase inhibitors (NNRTIs) is characterized by a specific amino acid substitution in the reverse transcriptase (RT), Gly 190Glu. This change results in decreased RT polymerase activity and in reduced growth properties of the corresponding viral variant. Here we show that the appearance of the crippling mutation at codon 190 can be prevented by lowering the selective pressure exerted by HBY 097. Under low selective pressure an accumulation of other NNRTI-specific mutations is observed. Up to five NNRTI-specific substitutions were detected in some of these virus lineages. In addition, we report novel RT amino acid changes which were not observed previously, including Val106lle, Val106Leu, and Gly190Thr. HBY 097 selects for different mutational patterns under high and low selective pressure conditions, respectively. Thus, the type of mutations which appear in HIV-infected patients undergoing therapy may be determined by the levels of the selecting drug.

Antiviral Agents↗

PubMed2003

Role of the RB tumor suppressor in cancer.

Apart from their coordinated inactivation by DNA tumor viral oncoproteins, the pRB and p53 tumor suppressor pathways were not known to be connected ten years ago. Within the last decade, our appreciation of how these pathways are interconnected has grown substantially. The checks and balances that exist between pRB and p53 involve the regulation of the G1/S transition and its checkpoints, and much of this is under the control of the E2F transcription factor family. Following DNA damage, the p53-dependent induction of p21CIP1 regulates cyclin E/Cdk2 and cyclin A/Cdk2 complexes both of which phosphorylate pRB, leading to E2F-mediated activation. Similarly, E2F1-dependent induction of p19ARF antagonizes the ability of mdm2 to degrade p53, leading to p53 stabilization and potentially p53-mediated apoptosis or cell cycle arrest. From the existing mouse models discussed above, we also know that proliferation, cell death and differentiation of distinct tissues are also intimately linked through entrance and exit from the cell cycle, and thus through pRB and p53 pathways. Virtually all human tumors deregulate either the pRB or p53 pathway, and often times both pathways simultaneously, which is critical for crippling cellular defense against neoplasia. The next decade of cancer research will likely see these two tumor suppressor pathways only merge even more.

Animals↗

PubMed1980

Indications and ethical considerations of deep brain stimulation.

Electrical impulses through chronically implanted electrodes in the human brain are used today in the relief of chronic crippling pain, motor movement disorders and behavior disturbances. A great number of reports from animal studies and several descriptions of the results produced by human stimulation seem to suggest that pain can often be adequately controlled. However, the perspectives of such methods raise many ethical problems and ask for caution. Nervous tissue damage after long-term stimulation, biochemical modifications, electrode migration and long-term follow-up of its clinical value are still under study and are the factors which might limit for the time being the indications. A restrictive role for this procedure is advocated for: 1. cases of chronic facial pain, 2. cases of chronic pain in other locations where other neurosurgical operations have failed and where the patient is not too young and is not suffering from pain of benign origin.

Brain↗

PubMed1994

Effect of high-dose intramuscular triamcinolone in older adults with severe, chronic asthma.

Life threatening asthma is a serious condition that is often difficult to treat. Often, despite maximal medical therapies, these patients remain functionally crippled. In addition, older patients are even more susceptible to asthma as they are less able to adapt to or tolerate the symptoms. In this paper we report the effectiveness of a new treatment regimen of high-dose intramuscular triamcinolone (360 mg) in 7 elderly patients with severe, chronic, steroid-dependent asthma. Each patient was given one intramuscular injection of 360 mg of triamcinolone (Kenalog) after maximizing traditional medicines. All 7 patients experienced resolution of their asthma symptoms within 1 week of receiving this injection. They showed marked functional improvement in their activities of daily living, and independence. Six of seven progressed from being homebound to walking, shopping, and grooming without restriction. All had a corresponding rise in peak expiratory flow rates ranging between 25 and 93%. In addition, all were able to stop taking their daily oral prednisone. Response durations ranged from 3 to 24 months. In the 6 patients who experienced relapse, all requested and received a second injection, with similar positive outcomes. Some experienced transient weakness and diabetes during the first week of the therapy but all elected to receive additional shots when they experienced break-through wheezing. Thus, we feel that high-dose intramuscular triamcinolone should be considered as a therapeutic option for a highly select group of older steroid-dependent asthma patients.

Activities of Daily Living↗

PubMed1994

Progressive pseudorheumatoid chondrodysplasia: a report of nine cases in three families.

Nine cases of progressive pseudorheumatoid chondrodysplasia in subjects aged 7-60 years are reported. Six of them were members of one large family with several consanguineous marriages. Evaluation of six generations of this family suggested an autosomal recessive mode of inheritance. The presentation of the disease was between the ages of 3 and 8 years with waddling gait and fusiform swelling of the interphalangeal joints of the hands, clinically resembling juvenile rheumatoid arthritis. Most of the other joints become progressively involved, with crippling disability. One of the patients had typical features of Blount disease at presentation.

Adolescent↗

PubMed1984

[Tuberculous osteoarthritis of the foot and ankle joint].

The authors have reviewed 26 cases of tuberculosis of the foot and 32 of the ankle, which they have treated personally. All the patients were adults and most presented with advanced destruction of bone and joints. Bacterial and histological confirmation of the diagnosis was obtained in 56 patients. All were treated by chemotherapy; the drugs and regime varied over the years. All responded well to this treatment, but one relapsed after 24 months. Orthopaedic problems were usually managed by immobilisation in plaster casts, but 6 patients required arthrodesis, 5 of the ankle and one triple fusion. The functional results of the standard treatment were generally good. Arthrodesis is seldom needed and should be performed only for permanent pain or crippling deformity.

Adolescent↗

PubMed1983

Spondyloepiphyseal dysplasia tarda with progressive arthropathy.

The clinical and roentgenographic manifestations of six cases suffering from spondyloepiphyseal dysplasia tarda with progressive arthropathy are presented. The roentgenographic features consist of generalized platyspondyly and varying degrees of epiphyseal involvement with conspicuous enlargement of both ends of the short tubular bones of the hands. This disorder appears at an earlier age, and is more crippling than the usual form of spondyloepiphyseal dysplasia tarda. It is suggested that orthopaedic measures are essential for all patients with this disorder, as profound disability may be expected by progressive involvement of the major joints.

Adolescent↗

PubMed1987

Effects of local irradiation and i.v. methotrexate on brain morphology in rabbits: early changes.

Brain damage following cranial radiation therapy can be crippling or even life-threatening and has been studied in both patients and animals. An additional toxic effect of chemotherapy has been found in children, who died following brain irradiation and systemic chemotherapy for the treatment of acute lymphoblastic leukemia. To study the interaction of radiation and drugs on brain tissue, we treated rabbits with brain irradiation and/or i.v. methotrexate. For a period of up to 3 months following radiation therapy, brain morphology was compared in seven treatment groups. Weekly doses of methotrexate administered i.v. produced no brain damage. Histological examination showed myelin swelling and beading 14 weeks after fractionated brain irradiation with 24 Gy. Combination of brain irradiation and methotrexate produced additional hypertrophy of microglia and pyknosis of adventitial cells. In none of these groups, even after doses of 48 Gy brain irradiation, was calcification or brain necrosis observed during the first 14 weeks following irradiation.

Animals↗

PubMed1984

The syndrome of the central L-3-herniated disc with special emphasis on motor involvement.

Literature about the clinical characteristics of herniation of the lumbar intervertebral disc is profuse. Due to their predominant frequency, attention was almost entirely devoted to the L-4 and L-5 prolapses. As clinical accuracy still remains a very important target, specially in departments where myelography is not used for the diagnosis of this entity, the authors thought it of interest to describe the clinical picture of the L-3-herniated disc. Special stress is placed on the motor involvement. Fourteen cases form this series. They were all central soft herniations. Cases of spondylotic narrow spinal canal were excluded. The special features were their predominance in people above 50 years old and the compromise of the hip abductors and internal rotator muscle groups making it impossible for the patient to stand on the affected limb (Trendelenburg sign). An abnormal knee jerk was a frequent accompaniment. Contrary to common knowledge the quadriceps muscle strength was almost unaffected. Sensory disturbances were not useful for location. The L-3 section of the lower lumbar spine is the narrowest explaining the reason why 3/4 of the patients had a more or less complete cauda equina syndrome. It was therefore a very dangerous herniation that crippled quickly, needing usually an emergency operation with all the risks involved in this older age group of patients.

Female↗

PubMed1995

Use of intravenous immune globulin in the therapy of children with rheumatological diseases.

Traditional treatment of dermatomyositis often fails and is associated with severe side effects, especially in children. Similarly, some patients with systemic juvenile rheumatoid arthritis continue to develop crippling arthritis despite the currently used modalities of therapy. We have used monthly infusions of intravenous immune globulin (2 g/kg/month) in patients with dermatomyositis or systemic juvenile rheumatoid arthritis who have not responded to traditional treatment. We show that intravenous immune globulin is beneficial in improving muscle strength and skin manifestations of dermatomyositis. In a similar fashion, intravenous immune globulin infusions were very effective in ameliorating systemic manifestations of systemic juvenile rheumatoid arthritis but less effective in controlling long-lasting arthritis (more than 1 year). We established prognostic criteria early after disease onset which predict the development of severe joint disease and should help in patient selection for future studies.

Adolescent↗

PubMed1992

Targeted estrogen/progesterone replacement therapy for osteoporosis: calculation of health care cost savings.

Osteoporosis is a crippling affliction in which bone mass decreases, making it more susceptible to fracture. In postmenopausal women it presents most often as a hip, spinal, or forearm fracture. Adult women face a 15% lifetime risk of a hip fracture, and the annual costs of hip fractures alone are estimated at $7.3 billion in the United States. Since the 1970s, estrogen/progestogen therapy has been recognized as an effective intervention that reduces the risk of fractures. Recently, the development of methods for accurately determining bone mass and thus helping to predict bone fracture risk has made this intervention attractive for use in a targeted population. This report analyzes the health care costs and calculates the cost savings of coupling bone mineral density screening at the time of menopause with long-term estrogen/progestogen therapy for those most at risk for developing fractures. The model assumes that a cohort of 100,000 American white women, aged 50, are screened for bone mineral density and that 90% of the high-risk group (density less than 0.85 g/cm3) and 70% of the mid-risk group (density between 0.85 and 1.00 g/cm3) elect to take hormone replacement therapy for 15 years. Based on calculations of the costs of screening and hormone replacement therapy, and the savings in cost of treatment and lost productivity from reduced fractures, it is estimated that the present value of savings in cost of illness for this cohort over a 40-year period is $5.1 million.(ABSTRACT TRUNCATED AT 250 WORDS)

Bone Density↗

PubMed1993

The true meaning of 'exotic species' as a model for genetically engineered organisms.

The exotic or non-indigenous species model for deliberately introduced genetically engineered organisms (GEOs) has often been misunderstood or misrepresented. Yet proper comparisons of of ecologically competent GEOs to the patterns of adaptation of introduced species have been highly useful among scientists in attempting to determine how to apply biological theory to specific GEO risk issues, and in attempting to define the probabilities and scale of ecological risks with GEOs. In truth, the model predicts that most projects may be environmentally safe, but a significant minority may be very risky. The model includes a history of institutional follies that also should remind workers of the danger of oversimplifying biological issues, and warn against repeating the sorts of professional misjudgements that have too often been made in introducing organisms to new settings. We once expected that the non-indigenous species model would be refined by more analysis of species eruptions, ecological genetics, and the biology of select GEOs themselves, as outlined. But there has been political resistance to the effective regulation of GEOs, and a bureaucratic tendency to focus research agendas on narrow data collection. Thus there has been too little promotion by responsible agencies of studies to provide the broad conceptual base for truly science-based regulation. In its presently unrefined state, the non-indigenous species comparison would overestimate the risks of GEOs if it were (mis)applied to genetically disrupted, ecologically crippled GEOs, but in some cases of wild-type organisms with novel engineered traits, it could greatly underestimate the risks. Further analysis is urgently needed.

Bacterial Physiological Phenomena↗

PubMed1978

Influence of the thymus on the incidence of secondary and parabiotic disease.

The secondary disease in P leads to F1 strain combination depends upon the immune status of both partners. It is most clearly expressed if both donors and recipients are immunologically crippled by thymectomy and irradiation. Conspicuous reduction in the immune potential of parental parabionts induced by thymectomy and irradiation displayed their marked incidence of parabiotic death.

Animals↗