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At least 433 records · Page 24Linked to original sources
PubMed1985

Progressive diaphyseal dysplasia: evaluation of corticosteroid therapy.

Progressive diaphyseal dysplasia is characterized clinically by crippling leg pain, fatigue, headache, poor appetite, muscle weakness, and waddling gait. Twelve affected patients, aged 2 years 4 months to 40 years, were treated with intermittent courses of low doses of prednisone given in a single dose on alternate mornings for periods ranging from 6 months to 10 years. The average initial dose of prednisone was 0.6 mg/kg/d, and average maintenance dose was 0.3 mg/kg/d. Relief of all crippling symptoms was achieved in all patients. No untoward serious side effects have been observed, and the growth of children was not slowed. However, corticosteroid therapy should be restricted to patients suffering from crippling pain. The mechanism through which steroids act remains undefined.

Adolescent↗
PubMed1997

[Genetic analysis of two cellular degenerations in filamentous fungus Podospora anserina].

The filamentous fungus Podopsora anserina presents an unavoidable arrest of vegetative growth (Senescence) determined by a cytoplasmic and infectious factor. Senescence is correlated with a disorganization of the mitochondrial DNA. This disorganization is caused by an event which is not the appearance of the first defective DNA molecules. These ones are generated constitutively and their accumulation during Senescence requires the presence of an additional factor. Life span of the strains is under nuclear and cytoplasmic genetic control. At least 600 nuclear genes influence longevity. Our analysis focuses on the role of the genes involved in cytosolic translation, since mutations in these genes seem to display the most drastic effects on longevity but also on the structure of the defective mitochondrial DNA molecules that accumulate during Senescence. We have detected in some Podospora anserina mutant strains (permissive strains) the presence of a novel cytoplasmic and infectious determinant that entails an easily discernible phenotype associated with a severe growth alteration (Crippled Growth). This growth alteration is not associated with mitochondrial DNA modifications. Only the strains that have an increased translational accuracy present Crippled Growth. However, the Crippled Growth Determinant is found in all the strains during the stationary phase; it is eliminated from the non permissive strains during the exit of the stationary phase. The mutants, that have an increased translational accuracy, probably lack a factor which is needed to eliminate the determinant when cells enter the growth phase.

Ascomycota↗
PubMed1992

What was wrong with Tiny Tim?

One of the most endearing characters in English literature is Tiny Tim, the crippled son of Ebenezer Scrooge's clerk, Bob Cratchit. Yet the nature of Tiny Tim's multifaceted and implicitly reversible illness is a mystery and open to debate and speculation. From details of the original manuscript and the eight film versions, it is possible to construct a differential diagnosis for Tim's short stature, asymmetric crippling disorder, and curious intermittent weakness that would lead to his death, if untreated, within a period of 1 year. Following the ghostly visitations, Scrooge vows to assist the struggling Cratchit family financially, thereby making available the best medical care money could buy. From review of pediatrics texts from 1830 to 1850, a recommended treatment plan would have included (1) general measures such as country air and exercise, and fish oils such as cod and halibut (vitamin D), and (2) specific treatments of tonics (containing combinations of belladonna, opium, sodium bicarbonate, sodium citrate, and potassium chloride) emphasizing alkalis, and splinting and bracing the limbs. Such treatments with vitamin D and alkalinization with sodium bicarbonate and sodium citrate suggest the plausible speculation that Tiny Tim had renal tubular acidosis (type I), a disorder that is characterized by growth failure and, if left untreated, complicated by osteomalacia with pathologic fractures, hypokalemic muscle weakness and periodic paralysis, nephrocalcinosis leading to renal failure, and death. I propose that Tiny Tim had distal renal tubular acidosis (type I).

Acidosis, Renal Tubular↗
PubMed2000

Inherited multicentric osteolysis with arthritis: a variant resembling Torg syndrome in a Saudi family.

The autosomal recessive multicentric osteolytic disorders of childhood-Torg, Winchester, and François syndromes-predominantly affect the carpal, tarsal, and interphalangeal joints, and their progressive bone loss and crippling arthritic deformities mimic severe juvenile rheumatoid arthritis. In a consanguineous Saudi Arabian family two affected sibs with facial anomalies and short stature displayed a distal arthropathy of the metacarpal, metatarsal, and interphalangeal joints starting in the first few months of life that eventually progressed to the proximal joints and resulted in crippling ankylosis and severe generalized osteopenia. Facial changes included proptosis, a narrow nasal bridge, bulbous nose, and micrognathia. In addition, they had large, painful fibrocollagenous palmar and plantar pads and mild body hirsutism. Affected individuals were of normal intelligence and had normal renal function. Routine hematologic, chemistry, and rheumatoid studies were within normal limits. Histologic examination of bone marrow and an interphalangeal joint biopsy were not informative. The autosomal recessive inheritance, clinical, and radiologic characteristics of the affected sibs suggested that they had a form of multicentric osteolysis most closely resembling the Torg syndrome, but with a unique facial appearance, fibrocollagenous pads, and body hirsutism not noted in the original description of the syndrome.

Abnormalities, Multiple↗
PubMed2006

Molecular biology of Hodgkin's and Reed/Sternberg cells in Hodgkin's lymphoma.

Hodgkin's and Reed/Sternberg (HRS) cells, the tumour cells in classical Hodgkin's lymphoma (HL), represent transformed B cells in nearly all cases. The detection of destructive somatic mutations in the rearranged immunoglobulin (Ig) genes of HRS cells in classical HL indicated that they originate from preapoptotic germinal centre (GC) B cells that lost the capacity to express a high-affinity B-cell receptor (BCR). Several aberrantly activated signalling pathways and transcription factors have been identified that contribute to the rescue of HRS cells from apoptosis. Among the deregulated signalling pathways, activation of multiple receptor tyrosine kinases in HRS cells appears to be a specific feature of HL. In about 40% of cases of classical HL the HRS cells are infected by Epstein-Barr virus (EBV), indicating an important role of EBV in HL pathogenesis. Interestingly, nearly all cases of HL with destructive Ig gene mutations eliminating BCR expression (e.g. nonsense mutations) are EBV-positive, suggesting that EBV-encoded genes have a particular function to prevent apoptosis of HRS-cell precursors that acquired such crippling mutations. This idea is further supported by the recent demonstration that isolated human GC B cells harbouring crippled Ig genes can be rescued by EBV from cell death, giving rise to lymphoblastoid cell lines. The molecular analysis of composite Hodgkin's and non-Hodgkin's lymphomas indicated that many cases develop from a common GC B-cell precursor in a multistep transformation process with both shared and distinct oncogenic events.

B-Lymphocytes↗
PubMed2007

Suppression of fibroblast metalloproteinases by ajulemic acid, a nonpsychoactive cannabinoid acid.

Production of matrix metalloproteinases (MMP) in joint tissue of patients with inflammatory arthritis facilitates cartilage degradation and bone erosion, and leads to joint deformities and crippling. Thus, MMPs are important targets for agents designed to treat inflammatory arthritis. Oral administration of ajulemic acid (AjA), a synthetic, nonpsychoactive cannabinoid acid, prevents joint tissue injury in rats with adjuvant arthritis. AjA binds to and activates PPARgamma directly. Therefore, we investigated the influence of AjA on MMP production in human fibroblast-like synovial cells (FLS), and examined the role of PPARgamma in the mechanism of action of AjA. FLS, treated or not with a PPARgamma antagonist, were treated with AjA then stimulated with TNFalpha or IL-1alpha. Release of MMPs-1, 3, and 9 was measured by ELISA. The influence of AjA on MMP-3 release from stimulated PPARgamma positive (PPAR+/-) and PPARgamma null (PPAR-/-) mouse embryonic fibroblasts (MEF) was also examined. Addition of AjA to FLS suppressed production of MMPs whether or not PPARgamma activation was blocked. Secretion of MMP-3 was also suppressed by AjA in both TNFalpha- and IL-1alpha-stimulated PPARgamma+/- and PPARgamma-/- MEF. Suppression of MMP secretion from FLS by AjA appears to be PPARgamma independent. Prevention by AjA of joint tissue injury and crippling in the rat adjuvant arthritis model may be explained in large part by inhibition of MMPs. These results suggest that AjA may be useful for treatment of patients with rheumatoid arthritis and osteoarthritis.

Animals↗
PubMed1986

Club-foot through the centuries.

This is a study of the history of club-foot from ancient times up to the present. It embraces not only the clinical aspects of the deformity but also its social implications, particularly of its early history when the attitude of society towards the lame and crippled in general and to foot deformities in particular is discussed. Relevant references from Greek mythology and also from the Old Testament are quoted. A close study is made of the old Chinese custom of foot-binding which produced club-foot like deformities which became a symbol of social standing. Inevitably, like most other medical conditions, club-foot has been well described by Hippocrates and it is a sobering thought that his concepts of causation and his principles of treatment are as valid today as they were 2300 years ago. This paper also briefly describes club-foot in history and art. Encouraged by society's compassionate approach towards the cripple, famous painters of the 17th century produced sympathetic portraits of the deformed and the club-footed. Well-known personalities who suffered from club-foot, such as Lord Byron and Sir Walter Scott, are mentioned and it is shown how the deformity affected them. The saga of the physician and surgeon W.J. Little, himself afflicted by club-foot, is unfolded. His life was dedicated to the study and relief of his own deformity and later he devoted his efforts towards the cure of his fellow sufferers. W.J. Little has done so much for the advancement of orthopaedic surgery that Sir Robert Jones called him the father of orthopaedic surgery; yet at heart W.J. Little was a physician! Another physician, Nicholas André, deserves the title of father of orthopaedic surgery. He coined the word 'orthopaedia' and laid down the principles of preventing and correcting deformities and he detailed the conservative management of club-foot. The treatment of the deformity came into the hands of bone setters and instrument makers and it was almost beneath the dignity of a surgeon to treat it. Yet, with the advent of tenotomy, popularised by Little, surgical treatment of the condition increased, aided by the development of antiseptic and aseptic technique and anaesthesia.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed2005

Braces, wheelchairs, and iron lungs: the paralyzed body and the machinery of rehabilitation in the polio epidemics.

The successful fund raising appeals of the March of Dimes employed images of cute crippled children standing on braces and forearm crutches, sitting in wheelchairs, or confined to iron lungs. Those who had to use these devices as a result of polio, however, were often stigmatized as cripples. American cultural antipathy to these assistive devices meant that polio survivors often had to overcome an emotional and psychological resistance to using them. Whatever their fears, polio survivors quickly discovered the functionality of braces and wheelchairs. By confronting the cultural stigma associated with these devices and in some sense embracing these mechanical "friends," polio survivors compensated for their paralyzed bodies and became active in the wider world of home, school and work.

Advertising↗
PubMed2000

Molecular control of bone remodeling and osteoporosis.

Osteoprotegerin ligand (OPGL, TNFS11) and its receptor RANK (TNFRS11A) are essential for the development and activation of osteoclasts and critical regulators of physiological bone remodeling and osteoporosis. Production of OPGL by activated T cells can directly regulate osteoclastogenesis and bone remodeling. This may explain why autoimmune diseases, cancers, leukemias, asthma and chronic viral infections such as hepatitis and HIV result in systemic and local bone loss. OPGL is also the pathogenetic factor that causes bone and cartilage destruction and clinical crippling in arthritis. Inhibition of OPGL binding to RANK via the natural decoy receptor osteoprotegerin (OPG) prevents bone loss in postmenopausal osteoporosis and cancer metastases and completely blocks crippling in a rat model of arthritis. Moreover, OPG expression is induced by estrogen which provides a molecular explanation of postmenopausal osteoporosis in women.

Animals↗
PubMed1998

Role of the [4Fe-4S] cluster in reductive activation of the cobalt center of the corrinoid iron-sulfur protein from Clostridium thermoaceticum during acetate biosynthesis.

The corrinoid iron-sulfur protein (CFeSP) from Clostridium thermoaceticum functions as a methyl carrier in the Wood-Ljungdahl pathway of acetyl-CoA synthesis. The small subunit (33 kDa) contains cobalt in a corrinoid cofactor, and the large subunit (55 kDa) contains a [4Fe-4S] cluster. The cobalt center is methylated by methyltetrahydrofolate (CH3-H4folate) to form a methylcobalt intermediate and, subsequently, is demethylated by carbon monoxide dehydrogenase/acetyl-CoA synthase (CODH/ACS). The work described here demonstrates that the [4Fe-4S] cluster is required to facilitate the reactivation of oxidatively inactivated Cob(II)amide to the active Co(I) state. Site-directed mutagenesis of the large subunit gene was used to change residue 20 from cysteine to alanine, which resulted in formation of a cluster with EPR and redox properties consistent with those of [3Fe-4S] clusters. The midpoint potential of the cluster in the C20A variant was approximately 500 mV more positive than that of the [4Fe-4S] cluster in the native enzyme. Accordingly, it was found that the Co center in the C20A mutant protein could be reduced artificially but was severely crippled in its ability to be reduced by physiological electron donors. This is probably because the reduced cluster of the C20A protein cannot provide the driving force needed to reduce Co(II) to Co(I), since the Co(II/I) midpoint potential is -504 mV. The C20A variant also was unable to catalyze the steady-state synthesis of acetyl-CoA when CH3-H4folate or methyl iodide were provided as methyl donors and CO and CODH/ACS as reductants. Addition of chemical reductants rescued the catalytically crippled variant form in both of these reactions. On the other hand, in single-turnover reactions, the methyl-Co state of the altered protein was fully active in methylating H4folate and in synthesizing acetyl-CoA in the presence of CO and CoA. The combined results strongly indicate that the FeS cluster of the CFeSP is necessary for reductive activation of Co(II) to Co(I) by physiological reductants but is not required for catalysis, e.g., demethylation of CH3-H4folate or methylation of CODH/ACS. We propose that, during reductive activation, electrons flow from the reduced electron-transfer protein (e.g., CODH/ACS or reduced ferredoxin (Fd)) to the FeS cluster which then directs electrons to the cobalt center for catalysis. These results also support earlier hypotheses that the methylation and demethylation reactions involving the CFeSP are SN2-type nucleophilic displacement reactions and do not involve radical chemistry.

Acetates↗
PubMed2001

Cell degeneration in the model system Podospora anserina.

Podospora anserina is a filamentous fungus used in many studies of fundamental cell biology, including cell ageing. In this organism, ageing is defined as a diminution of cell ability to proliferate and/or differentiate. This may or may not culminate with cell death. Two different ageing processes are intensively studied. The 'Senescence' phenomenon is present in all wild-type strains, results in cell death and is caused by a yet undefined cytoplasmic and infectious element. It is associated with extensive mitochondrial DNA modifications. Longevity of the strains is controlled by a highly complex network of genes. Among these, those involved in cytosolic translation and respiratory metabolism are of special importance. The 'Crippled Growth' phenomenon is present only in strains with elevated translational accuracy. It does not result in cell death but in a severe impairment of cell growth, an acceleration of Senescence and a diminution of differentiation potencies. No mitochondrial DNA modification is associated with Crippled Growth. Another cytoplasmic and infectious element with peculiar properties, C, is causally involved in the set up of this cell degeneration. The study of P. anserina degenerative processes provides a conceptual framework to understand ageing in more complex organisms. Especially, it emphasises the complex control exerted by genes on longevity, the multiplicity of degenerative processes that may occur to cells with identical genotype and the potential role of non-conventional infectious elements in cell ageing.

Animals↗
PubMed2005

Treating osteoporotic and neoplastic vertebral compression fractures with vertebroplasty and kyphoplasty.

BACKGROUND: Compression fractures are common in patients with osteoporosis and cancer. In particular, vertebral compression fractures are crippling, and pose an additional risk of cord compression. Although a number of nonmedical options such as bracing and exercise programs may help these patients, the combination of constant, severe pain and spinal instability was until recently almost invariably synonymous with painful gradual deterioration and a poor quality of life. Vertebroplasty, and more recently kyphoplasty, are minimally invasive procedures that aim at limiting or reversing painful collapse of the vertebrae, while providing stability to the treated segment of the spine. As these new options are highly effective and involve minimal risk, it is important that physicians be familiar with them. OBJECTIVE: This paper reviews the demographics of vertebral compression fractures, both osteoporotic and neoplastic, the technical aspects of vertebroplasty and kyphoplasty, and current results and outcomes. RESULTS: Pain relief rates in excess of 90% have been reported with both vertebroplasty and kyphoplasty in patients with vertebral compression fractures. Procedural complication rates should be very low, in the 1%-2% range at most with proper technique. CONCLUSIONS: Until the advent of vertebroplasty, almost no effective therapeutic option could be offered to patients suffering from neoplastic or osteoporotic vertebral compression fractures, which are relatively common and often crippling. The technical feasibility of these procedures is high, the risk low, and the effectiveness high. Therefore, it is important that physicians consider vertebroplasty and kyphoplasty as viable and strong options.

Fractures, Compression↗
PubMed2000

Treatment of bone diseases with bisphosphonates, excluding osteoporosis.

The main biologic action of bisphosphonates consists of the inhibition of osteoclastic bone resorption, and, at least, for the drugs introduced after etidronate, without any significant inhibition of bone mineralization. Bisphosphonates therefore play a major role in conditions that are characterized, at least partly, by an increased bone resorption. Primary and secondary osteoporosis by far constitute the most widespread indications for bisphosphonates, mostly because recent published trials have demonstrated their ability to prevent fractures. Potentially crippling conditions such as symptomatic Paget disease of bone remain a major therapeutic challenge for bisphosphonates, but the prevention of the major complications such as sarcoma has still to be proven. The availability of more potent bisphosphonates, less toxic for bones, has certainly widened the therapeutic interventions to asymptomatic patients, bearing in mind the various potential troublesome complications. Fibrous dysplasia resembles, in certain aspects, Paget disease; it is therefore not surprising that bisphosphonate therapy has been proposed in this indication. With the aging of world populations, more and more cancers will be diagnosed. For those with a bone metastatic propensity or malignant hematologic condition, such as multiple myeloma, the most recent generation of more potent bisphosphonates may bring more comfort to crippled patients and even, hopefully, have a direct antitumoral activity, if used synergistically with the armamentarium already available to the clinician. New indications for bisphosphonates include osteogenesis imperfecta both in children and adults. In the future, they might be used in the prevention of erosions in rheumatoid arthritis and of loosening of joint prostheses, as well as possibly in osteoarthritis. Now that the fear of theoretically freezing bone remodeling has been reasonably dismissed, potential uses for bisphosphonates might be considered nearly infinite.

Abnormalities, Drug-Induced↗
PubMedDate not supplied

The evolution of orthopaedic nursing at the Hospital for Special Surgery: the first orthopaedic institution in the United States.

The history of nursing began in London in the late 1800s with the reform of unsanitary conditions by Florence Nightingale. During the same period, the United States was bitterly fighting the Civil War. Nursing had not developed as a profession, and most of the duties performed by nurses were conducted by men. Casualties of war required rehabilitation and care. Crippled children were left to die because they were considered a burden to society. Dr. James Knight founded the Hospital for the Ruptured and Crippled in his home on Second Avenue. This would later become a world-renowned orthopaedic institution with exceptional nursing care. A historical analysis of nursing education and practice are reviewed, along with the evolution of the first orthopaedic hospital in the United States.

Education, Nursing↗
PubMed2000

The characteristics of Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphoma: comparison between EBV(+) and EBV(-) cases in Japanese population.

We have investigated 114 cases with diffuse large B-cell lymphoma (DLBCL) to clarify the characteristics of DLBCL with Epstein-Barr virus (EBV) infection. Thirteen cases (11.4%) showed EBV-encoded RNA 1 (EBER1) signals by RNA in situ hybridization. EBV-encoded latent membrane protein 1 (LMP1) and EBV-encoded nuclear antigen 2 (EBNA2) were expressed in 11 and 4 cases, respectively. Expression of CD30, Bcl-6 and immunoglobulin (Ig) was found in 92%, 31% and 23% with EBV(+) DLBCL, and in 15%, 79% and 82% with EBV(-) DLBCL, respectively. The sequence of rearranged Ig heavy chain (IgH) variable (V) region gene was analyzed in 5 cases with EBV(+) DLBCL and 61 cases with EBV(-) DLBCL. Somatic mutation was found in all cases except one with EBV(-) DLBCL. Average mutation frequency was 9.6% in EBV(+) DLBCL vs. 11.5% in EBV(-) DLBCL. The rates of replacement mutation vs. silent mutation (R / S values) in complementarity determining region II and framework region III were 2.7 and 1.5 in EBV(+) DLBCL, 2.6 and 1.4 in EBV(-) DLBCL. Crippling mutation generating a stop codon was found in 2 of 5 cases (40%) with EBV(+) DLBCL, but none of 61 cases (0%) with EBV(-) DLBCL. These findings suggest that EBV(+) DLBCL and EBV(-) DLBCL were both derived from germinal center (GC) or post-GC B cells, and EBV(+) DLBCL frequently have a non-functional IgH gene owing to crippling mutation.

Adolescent↗
PubMed2007

Role of the coronavirus E viroporin protein transmembrane domain in virus assembly.

Coronavirus envelope (E) proteins are small (approximately 75- to 110-amino-acid) membrane proteins that have a short hydrophilic amino terminus, a relatively long hydrophobic membrane domain, and a long hydrophilic carboxy-terminal domain. The protein is a minor virion structural component that plays an important, not fully understood role in virus production. It was recently demonstrated that the protein forms ion channels. We investigated the importance of the hydrophobic domain of the mouse hepatitis coronavirus (MHV) A59 E protein. Alanine scanning insertion mutagenesis was used to examine the effect of disruption of the domain on virus production in the context of the virus genome by using a MHV A59 infectious clone. Mutant viruses exhibited smaller plaque phenotypes, and virus production was significantly crippled. Analysis of recovered viruses suggested that the structure of the presumed alpha-helical structure and positioning of polar hydrophilic residues within the predicted transmembrane domain are important for virus production. Generation of viruses with restored wild-type helical pitch resulted in increased virus production, but some exhibited decreased virus release. Viruses with the restored helical pitch were more sensitive to treatment with the ion channel inhibitor hexamethylene amiloride than were the more crippled parental viruses with the single alanine insertions, suggesting that disruption of the transmembrane domain affects the functional activity of the protein. Overall the results indicate that the transmembrane domain plays a crucial role during biogenesis of virions.

Alanine↗
PubMed1990

Mutagenesis of the 3' nontranslated region of Sindbis virus RNA.

A cDNA clone from which infectious RNA can be transcribed was used to construct 42 site-specific mutations in the 3' nontranslated region of the Sindbis virus genome. The majority of these mutations were made in the 3'-terminal 19-nucleotide conserved sequence element and consisted of single nucleotide substitutions or of small (1 to 8) nucleotide deletions. An attempt was made to recover mutant viruses after transfection of SP6-transcribed RNA into chicken cells. In most cases, viable virus was recovered, but almost all mutants grew more poorly than wild-type virus when tested under a number of culture conditions. In the case of mutations having only a moderate effect, the virus grew as well as the wild type but was slightly delayed in growth. Mutations having a more severe effect led to lower virus yields. In many cases, virus growth was more severely impaired in mosquito cells than in chicken cells, but the opposite phenotype was also seen, in which the mutant grew as well as or better than the wild type in mosquito cells but more poorly in chicken cells. One substitution mutant, 3NT7C, was temperature sensitive for growth in chicken cells and severely crippled for growth in mosquito cells. Insertion mutations were also constructed which displaced the 19-nucleotide element by a few nucleotides relative to the poly(A) tail. These mutations had little effect on virus growth. Deletion of large regions (31 to 293 nucleotides long) of the 3' nontranslated region outside of the 19-nucleotide element resulted in viruses which were more severely crippled in mosquito cells than in chicken cells. From these results, the following principles emerge. (i) The entire 3' nontranslated region is important for efficient virus replication, although there is considerable plasticity in this region in that most nucleotide substitutions or deletions made resulted in viable virus and, in some cases, in virus that grew quite efficiently. Replication competence was particularly sensitive to changes involving the C at position 1, the A at position 7, and a stretch of 9 U residues punctuated by a G at position 14. (ii) The panel of mutants examined collectively deleted the entire 3' nontranslated region. Only mutants in which 8 nucleotides in the 3' terminal 19 nucleotides had been deleted or in which the 3' terminal C was deleted were nonviable. Although the 3' terminal C was essential for replication, it could be displaced by at least 7 nucleotides from its 3' terminal position adjacent to the poly(A) tract.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1992

Attenuation of Sindbis virus neurovirulence by using defined mutations in nontranslated regions of the genome RNA.

We examined a panel of Sindbis virus mutants containing defined mutations in the 5' nontranslated region of the genome RNA, in the 3' nontranslated region, or in both for their growth in cultured cells and virulence in newborn mice. In cultured cells, these viruses all had defects in RNA synthesis and displayed a wide range of growth rates. The growth properties of the mutants were often very different in mouse cells from those in chicken cells or in mosquito cells. We hypothesize that host factors, presumably proteins, interact with these nontranslated regions to promote viral replication and that the mammalian protein and the chicken or mosquito protein are sufficiently divergent that alterations in the viral RNA sequence can affect the interactions with these different host proteins in different ways. Some of the mutants were temperature sensitive for plaque formation, whereas one mutant was slightly cold sensitive in its growth in chicken cells. Upon inoculation into mice, viruses that grew well in cultured mouse cells retained their virulence, but mice that succumbed usually had extended survival times. One virulent mutant that grew slightly less well in cultured mouse cells than did the parental virus produced eight times as much virus in mouse brain following intracerebral inoculation, suggesting that changes in these regulatory regions may have tissue-specific as well as host-specific effects. Viruses that were severely crippled in their growth in mouse cells in culture were usually, but not always, attenuated in their virulence. In particular, temperature sensitivity was correlated with attenuation. The effect of two mutations was found to be cumulative, and double mutants that contained mutations in both the 5' and 3' nontranslated regions were more attenuated than was either single mutant. Three of four double mutants tested were severely crippled for virus production in cultured cells and were avirulent for mice, even when inoculated intracerebrally.

Animals↗