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8040254
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Cell type-specific gene expression in the neuroendocrine system. A neuroendocrine-specific regulatory element in the promoter of chromogranin A, a ubiquitous secretory granule core protein.
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The acidic secretory protein chromogranin A universally occurs in amine and peptide hormone and neurotransmitter storage granules throughout the neuroendocrine system. What factors govern the activity of the chromogranin A gene, to yield such a widespread yet neuroendocrine-selective pattern of expression? To address this question, we isolated the mouse chromogranin A gene promoter. The promoter conferred cell type-specific expression in several neuroendocrine cell types (adrenal medullary chromaffin cells, anterior pituitary corticotropes, and anterior pituitary somatolactotropes) but not in control (fibroblast or kidney) cells. In neuroendocrine cells, analysis of promoter deletions established both positive and negative transcriptional regulatory domains. A distal positive domain (-4.8/-2.2 kbp) was discovered, as well as negative (-258/-181 bp) and positive (-147/-61 bp) domains in the proximate promoter. The proximate promoter contained a minimal neuroendocrine-specific element between -77 and -61 bp. Sequence alignment of the mouse promoter with corresponding regions in rat and bovine clones indicated that the mouse sequence shares over 85% homology with rat and 52% with bovine promoters. DNaseI footprinting and electrophoretic gel mobility shift assays demonstrated the presence of nuclear factors in neuroendocrine cells that recognized the proximate promoter. We conclude that the chromogranin A promoter contains both positive and negative domains governing its cell type-specific pattern of transcription, and that a small proximate region of the promoter, containing novel as well as previously described elements, interacts specifically with neuroendocrine nuclear proteins, and is thereby sufficient to ensure widespread neuroendocrine expression of the gene.
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8040253
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Nonenzymatic glycosylation in vitro and in bovine endothelial cells alters basic fibroblast growth factor activity. A model for intracellular glycosylation in diabetes.
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Intracellular sugars are more reactive glycosylating agents than glucose. In vitro nonezymatic glycosylation of basic fibroblast growth factor (bFGF) by fructose, glucose-6-phosphate (G6P), or glyceraldehyde-3-phosphate (G3P) reduced high affinity heparin-binding activity of recombinant bFGF by 73, 77, and 89%, respectively. Mitogenic activity was reduced 40, 50, and 90%. To investigate the effects of bFGF glycosylation in GM7373 endothelial cells, we first demonstrated that GLUT-1 transporters were not downregulated by increased glucose concentration. In 30 mM glucose, the rate of glucose transport increased 11.6-fold, and the intracellular glucose concentration increased sixfold at 24 h and fivefold at 168 h. The level of total cytosolic protein modified by advanced glycosylation end-products (AGEs) was increased 13.8-fold at 168 h. Under these conditions, mitogenic activity of endothelial cell cytosol was reduced 70%. Anti-bFGF antibody completely neutralized the mitogenic activity at both 5 and 30 nM glucose, demonstrating that all the mitogenic activity was due to bFGF. Immunoblotting and ELISA showed that 30 mM glucose did not decrease detectable bFGF protein, suggesting that the marked decrease in bFGF mitogenic activity resulted from posttranslational modification of bFGF induced by elevated glucose concentration. Cytosolic AGE-bFGF was increased 6.1-fold at 168 h. These data are consistent with the hypothesis that nonenzymatic glycosylation of intracellular protein alters vascular cell function.
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8040252
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Homologies between T cell receptor junctional sequences unique to multiple sclerosis and T cells mediating experimental allergic encephalomyelitis.
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The selection of T cell clones with mutations in the hypoxanthine guanine phosphoribosyltransferase (hprt) gene has been used to isolate T cells reactive to myelin basic protein (MBP) in patients with multiple sclerosis (MS). These T cell clones are activated in vivo, and are not found in healthy individuals. The third complementarity determining regions (CDR3) of the T cell receptor (TCR) alpha and beta chains are the putative contact sites for peptide fragments of MBP bound in the groove of the HLA molecule. The TCR V gene usage and CDR3s of these MBP-reactive hprt-T cell clones are homologous to TCRs from other T cells relevant to MS, including T cells causing experimental allergic encephalomyelitis (EAE) and T cells found in brain lesions and in the cerebrospinal fluid (CSF) of MS patients. In vivo activated MBP-reactive T cells in MS patients may be critical in the pathogenesis of MS.
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8040226
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Patterns of fantasy play engagement across the transition to becoming a sibling.
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Patterns of spontaneous dyadic fantasy play among 30 3- to 5-year-old first-born children who were becoming siblings were evaluated at two pre- and three post-birth intervals for its length, thematic content and social quality. Children who interacted more positively with their sibling played longer, engaged in fantasy play that was thematically relevant to becoming a sibling and had more positive interactions with best friends than low-sibling acceptance children. High-sibling acceptance children also experienced a suppression in fantasy immediately following their sibling's birth; thus, a temporary disruption in fantasy play may indicate adaptive coping.
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8040225
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An observational study of mothers with eating disorders and their infants.
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Two groups of primiparous mothers and their infants were observed at home during play and at a mealtime when the infants were 12-24 months old. The index group consisted of mothers who had experienced an eating disorder during the postnatal year while the control group had been free from such psychopathology. The main findings were that, when compared to controls, the index mothers were more intrusive with their infants during both mealtimes and play; and that they expressed more negative emotion towards their infants during mealtimes but not during play. There were, however, no differences between the groups in their positive expressed emotion. The index infants' emotional tone was generally more negative and their mealtimes more conflictual compared to controls. Furthermore, the index infants tended to be lighter than controls and infant weight was found to be independently and inversely related to both the amount of conflict during mealtimes and the extent of the mother's concern about her own body shape.
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8040224
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Effects of sudden infant death on bereaved siblings: a comparative study.
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This study investigated behavioural problems (as rated by mothers) in 38 children who had been suddenly bereaved of an infant sibling between 3 and 27 months previously. These children were compared with 40 children matched on age, gender, family composition and social background. Bereaved siblings were reported to have a prolonged and significantly elevated rate of non-specific behavioural problems. It is argued that, either the bereaved children's problems were real, or bereaved mothers' perceptions of their surviving children were significantly distorted. In either case, there is serious cause for concern about the welfare of children in families bereaved by Sudden Infant Death Syndrome.
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8040223
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Children's behavioral adaptation early in psychiatric hospitalization.
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Behavioral patterns over time were assessed during the first 24 days of hospitalization for 98 child psychiatric inpatients. Staff completed daily behavioral monitoring and ratings. Patients were categorized as improved, unchanged or deteriorated during this time. Thirty-four percent of patients initially exhibited well-controlled behavior, but then significantly worsened after a period averaging 6.8 days. This result empirically supports the "honeymoon" phenomenon. Other patients showed either improvement during the initial period (15%), no change (30%), or could not be reliably classified (21%). Therefore, many child inpatients show rapid symptom stabilization after admission, but a large number then worsen. Clinical, scientific and administrative implications of these results are discussed.
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8040222
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Night-waking at five years of age: predictors and prognosis.
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A statistical study was made of reported night-waking in a national cohort of British 5-year-olds in order to explore long-term associations with physical, behavioural and mental development. After adjusting for the most likely confounders, reported night-waking at five was found to be linked at 10 years of age to certain chronic medical conditions and some symptoms of emotional distress. No convincing relationships existed between night-waking at five and selected measures of later physical development or intellectual ability.
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8040221
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Susceptibility to social influence in adults with Asperger's syndrome: a research note.
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Asch's line judgement task was used to compare the susceptibility to social influence of adults with Asperger's syndrome with that of two groups of controls one of which was matched on verbal IQ. There was no overall difference between the three groups' mean rate of conformity but in contrast to both groups of controls, the subjects with Asperger's syndrome were significantly more likely to adopt a consistently conforming or nonconforming strategy. There were also significant differences between the groups in their interaction with the other participants. The implications of the findings are discussed in the context of current theories of autistic social dysfunction.
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8040219
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Epidemiology of suicidal behavior among Korean adolescents.
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The purpose of this study was to estimate the prevalence of suicidal behaviors and their relation to background characteristics, social integration, academic stress, psychological distress, and substance use in a stratified random sample of 9886 high school students in Korea. In a multiple logistic regression, we found that depression was the strongest predictor of suicidal behaviors. The other factors significantly associated with suicidal behaviors were gender, academic stress, hostility and substance use. These results indicate that early identification of risk factors for suicidal behaviors may have potential for reducing possible future suicides.
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8040220
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Eating attitudes and weight preoccupation among female high school students in Japan.
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Eating disorder tendencies in 197 eleventh grade Japanese girls were examined to ascertain whether or not the reported correlates of eating disorder tendencies in North America would be replicated in Japan. The 26-item Eating Attitudes Test was administered along with a set of supplementary questions. As hypothesized, higher levels of eating disturbances were found in the students who: (1) perceived themselves as being overweight, (2) had been encouraged to diet, (3) reported engaging in frequent conversations with their mother about food and dieting. Implications for future cross-cultural research are discussed.
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8040218
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Practitioner review: early developmental language delay: what, if anything, should the clinician do about it?
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Early developmental language delay is characterized by slow development of language in preschoolers. The condition is frequent among two- and three-year-olds, causes concern among parents, and generates differences of opinion as to significance among informed professionals. Poorer long-term outcomes are much more likely if language delay persists until the later preschool years, and if the delay is not specific to language and/or includes problems in understanding. Specific language delay in the preschool period is better characterized as a risk factor than a disorder; most children with specific language delay recover to the normal range by five years of age.
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8040213
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Identification of an American hiker.
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The skeletonized remains of an American hitch-hiker were recovered from a forest near Knysna in the Cape. There were no recognizable features except the presence of dental restorations. The use of the "fax" to transmit dental records while being a speedy means of communication does have its limitations. Electrical faults on the telephone line can cause the document to become illegible and subsequent duplication of this document aggravates the problem. An appeal is made to standardize the notation of teeth by using the FDI code and to adopt a 2 digit code for restoration morphology.
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8040211
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Denture marking. A study of temperature resistance of different metal bands for ID-marking.
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Dentures are not always marked. In Sweden legislation now exists to enforce it. This study was undertaken to establish the frequency of marked dentures, the incidence of edentulousness and a temperature resistance test of three possible marking bands. Patients from two long-term units were included in the study (n = 58). Observation of the dental status included absence of teeth, some teeth present and influence of dentures, complete, partial, upper or lower. Marking of the dentures was also recorded. Three different types of steel bands (Jasch; Remanit; ID-band) were exposed to temperature levels of 1100, 1200 and 1300 degrees C. Of a total of 58 patients 64% were edentulous and only 17 of the patients could be identified by means of the denture markings. None of the metal bands had readable markings at 1200 and 1300 degrees C, but at 1100 degrees C the ID-band and the Jasch band were readable, but not the Remanit band.
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8040212
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Accuracy among dentists experienced in forensic odontology in establishing identity.
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The aim of this study was to investigate the accuracy of 17 forensic odontologists identifying individuals from two sets of radiographs, one regarded as ante- and the other as postmortem. Each case was observed twice and only one pair out of 31 did not match. The observers were asked to comment about each case, classifying it as easy, moderate or difficult. The results show that one observer was totally correct in the first analysis while four observers made no errors the second time. In the first evaluation 14 observers made between one and seven errors and two observers made 11 errors each. In the second evaluation 12 observers made between one and seven errors and one observer made 13 errors. At the first evaluation, the observers judged 18 of the cases as easy, eight as medium and five as difficult. At the second evaluation, the observers pronounced 13 of the cases as easy, 13 as medium and five as difficult. The corresponding values for the authors were 6, 12 and 13. Most of the mistakes were made on the cases with no restorations and the incorrect answers were found mostly among the difficult cases. In practical forensic work however additional dental chart information is usually available to the forensic odontologist.
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8040210
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Distraction method for chronic dorsal fracture dislocation of the proximal interphalangeal joint.
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The authors used gradual ligamentous distraction for closed reduction of nine irreducible dorsal fracture dislocations of the PIP joint. The volar fragment size was equal to or less than 40% in five and more than 50% in four. The average follow up was 18 months. The sequence of treatment required distraction, translation, and joint flexion. Overdistraction by approximately 2 mm was necessary to get sufficient soft tissue lengthening. This allowed adequate joint flexion for concentric joint reduction. Distraction and simultaneous mobilization restored the final range of motion earlier than distraction and subsequent mobilization. The final range of motion of the PIP and DIP joints was from 12 degrees to 91 degrees and 0 to 45 degrees respectively.
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8040209
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The spectrum of sports-related interphalangeal joint injuries.
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Sports participation places the fingers at risk for injury, especially from end-on contact with many kinds of balls and other objects. Certain sports are likely to produce specific injuries. Joint sprains and dislocations are especially common, whether or not accompanied by articular fractures. Tendon ruptures in the digit may not be recognized until many days or weeks later. The athlete must be aware of the need for early, accurate diagnosis, precise treatment, and complete rehabilitation for these often apparently innocuous injuries.
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8040208
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Management of intra-articular fractures of the metacarpophalangeal joint.
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Displaced intra-articular fractures of the metacarpal head and of the proximal articular surface of the proximal phalanx often require open reduction and internal fixation, particularly if an articular step off is present. If secure internal fixation can be achieved, early motion may be instituted. Diagnosis may be facilitated by special views and tomography. Secondary reconstructive procedures may include tenolysis, osteotomy, arthroplasty, or tissue transfer from the foot.
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8040207
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Physeal and periphyseal injuries of the hand. Patterns of injury and results of treatment.
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To the authors' knowledge, this is the largest study assembled of finger fractures in children. Distribution of fractures according to location within the hand (see Fig. 1), location within the phalanges themselves, and the percent of epiphyseal fractures as well as the age distribution of the patients are all similar to what has previously been presented in smaller studies. Previously unreported synchronous and double epiphyseal injuries were identified. For the most part, thanks to the remodeling capacity and rapid healing of children's bone, treatment is short and complications are few. Nevertheless, as in other locations, there is a limited capacity to remodel angular deformity and no capacity to remodel rotational deformity. The clinical information in our study conflicts somewhat with previously described anatomic information about the insertion of ligaments with respect to the growth plate. Bogumill and Hankin and Janda have suggested that the ligaments insert primarily on the epiphysis in the proximal phalanx, and on the epiphysis and metaphysis in the middle and distal phalanges. Taken by itself, this information would suggest that a Salter-Harris III mechanism would be relatively more common at the MP joint, and the Salter-Harris II and IV mechanism (where the proximal fragment includes bone both proximal and distal to the growth plate at the point where the ligament is attached) would be relatively more common at the more distal levels. In fact, the opposite was true. The Salter-Harris II mechanism made up an overwhelming majority of the percentage of injuries of the MP joint, whereas the Salter-Harris III mechanism predominated at the PIP joint and was relatively common at the DIP joint as well. This would seem to suggest that either the contribution of ligament insertion distal to the growth plate of the PIP and DIP joints is not functionally important or that other factors are involved in the injury mechanism at both levels and play a role in producing these injuries. Further study will be required, possibly involving experimental fracture production to help elucidate this issue. Finally, it is critical to recognize and properly treat the four major categories of injury that constitute a small percentage of the total but a large percentage of the complications. The condylar and subcondylar fractures must be identified by obtaining a true lateral film by whatever means necessary. If undisplaced, they need to be adequately immobilized, possibly including the entire arm of a small child, and if displaced, they almost always require internal fixation.(ABSTRACT TRUNCATED AT 400 WORDS)
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8040206
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Fractures of the distal interphalangeal joint.
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Displaced fractures at the distal end of the middle phalanx require reduction if function is to be restored at the distal joint. Fractures at the base of the distal phalanx take on additional significance because of the insertions of the flexor and extensor tendons. The palmar articular fracture, when displaced, needs surgical replacement to restore flexor profundus function. In contrast, the displaced dorsal lip fracture, the mallet fracture, can be treated closed with the expectation of excellent results.
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8040205
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Interphalangeal joint arthrodesis.
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Interphalangeal joint fusion is a salvage procedure to achieve stability and pain relief and to correct deformity. The multiple fixation techniques for fusion are outlined. Paramount to successful arthrodesis are appropriate preparation of the joint surfaces and careful positioning and coaptation of the bone ends. If this is not accomplished, regardless of fixation technique, a pseudoarthrosis will ensue.
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8040204
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Flexible implant resection arthroplasty of the proximal interphalangeal joint.
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Flexible implant arthroplasty of the PIP joint in post-traumatic disorders can have very successful long-term results provided that the recommended surgical indications, operative techniques, and postoperative rehabilitation programs are carefully adhered to. Stability of the collateral ligament system and integrity of the extensor and flexor mechanism are essential prerequisites. A central slip splitting, central slip sparing, and palmar approach are described. The latter is preferred in post-traumatic conditions provided that the extensor mechanism is intact.
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8040203
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The volar plate reconstruction for fracture-dislocation of the proximal interphalangeal joint.
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This article discusses the volar plate arthroplasty utilized to resurface the proximal interphalangeal joint, for fracture subluxations involving the lower 60%. The procedure is effective when open reduction and internal fixation are not feasible because of excessive comminution or delay in treatment. The procedure has been used up to 2 years postinjury if certain conditions are met. The article also emphasizes the volar approach to the joint as an optimal exposure to fix these fractures.
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8040202
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Open reduction and internal fixation method for fractures at the proximal interphalangeal joint.
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When fragment size and mineralization permit, unstable and displaced proximal interphalangeal joint fractures can be secured in an anatomic position by any one of a number of direct (through the fragments) or indirect (buttress) pinning or screw fixation techniques. Transcutaneous or limited open reduction and fixation techniques are preferred in an effort to minimize additional soft tissue trauma and scarring. Plating is reserved for fractures otherwise difficult, if not impossible, to retain. The objectives of these internal fixation techniques are pain control and early active functional restoration.
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8040201
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Extension block splinting.
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Extension block splinting (EBS) at the proximal interphalangeal joints of the fingers is a common technique for both primary treatment of reduced dorsal dislocations/fracture-dislocations at that joint and as a rehabilitation method following open reduction of such injuries. It is seldom realized that the method is a classic example of two orthopedic principles: stable arc splinting and early protected motion. As a primary treatment technique, following reduction of the dislocation, EBS is exemplary for an ideal group of cases, competitive for a marginal group of cases, and often unsatisfactory for a questionable group of cases. Demarcation between the groups is made, and the technique of EBS is reviewed.
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8040200
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Mechanical requirements for application and modification of the dynamic force couple method.
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In 1987, Dr. John Agee described a method of holding reduction in unstable proximal interphalangeal fracture dislocations while allowing early motion. This method significantly improved the outcome of joint motion. This article explains Dr. Agee's method and the mechanics and physics necessary to use it. The limitations of the method and a modification of it for more complex fractures are also explained.
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8040199
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The physiologic basis of continuous passive motion for articular cartilage healing and regeneration.
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This article historically reviews the limited potential of articular cartilage to heal or regenerate, past emphasis on rest as opposed to motion, and the reasoning that led the author to create the biologic concept of continuous passive motion (CPM) in 1970. The basic premises and hypotheses of CPM are stated. A brief summary is provided of 19 scientific investigations of CPM in rabbits, with particular emphasis on the beneficial short-term and long-term effects of CPM in intra-articular fractures. The conclusions from the basic research are summarized. The clinical applications of CPM to the care of patients are discussed with respect to the indications and the results.
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8040198
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The therapist's management of intra-articular fractures.
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Fabrication of the dynamic traction splint is described in step-by-step fashion in order to aid surgeons to understand the principles of application of the method and to assist hand therapists to make the splint. The new 6-inch diameter arcuate hoop and the radial or ulnar gutter base splint are detailed. Modification of continuous passive motion machines is described for use in conjunction with dynamic traction. Alternative splint applications and post-dynamic traction splinting therapy methods are outlined.
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8040197
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The dynamic traction method. Combining movement and traction for intra-articular fractures of the phalanges.
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Dynamic traction is a new method of treatment of intra-articular fractures in the hand, combining the old idea of traction and the recent one of movement. Traction reduces fracture fragments through ligamentotaxis, and helps prevent joint ligament and periarticular contracture. Motion encourages cartilage regeneration and helps maintain mobility. Both early and long-term results have been excellent. The historical development of dynamic traction is detailed, and a summary given of the physiologic basis for the method's success.
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8040196
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Classification of fractures and dislocations of the proximal interphalangeal joint.
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Detailed categorization of fractures and fracture-dislocations of the proximal interphalangeal joint should be done for all patients with these injuries. Fractures of the proximal portion of the middle phalanx and fractures of the condyles of the proximal phalanx vary greatly in their presentation, severity, prognosis, and treatment. Fractures of the condyles can be categorized simply by noting whether they are unicondylar or bicondylar, and with or without displacement. For the middle phalanx, I propose the grading system listed in Table 1. Universal acceptance and application of this classification system will advance our understanding and treatment of these difficult fractures.
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8040195
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Anatomy of the proximal interphalangeal joint.
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The proximal interphalangeal joints (PIPs) of the fingers are crucial for normal digital and hand function. Studies of their anatomy reveal subtle bony differences that dictate the precise planes of motion allowed in the constrained joint. Soft tissue restraints guide the cartilaginous surfaces through permissible ranges of motion. Understanding these restraints and the precise orientation of other joint structures assists treatment of conditions affecting the PIP joint.
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8040194
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Paracrine Ca2+ signaling in vitro: serotonin-mediated cell-cell communication in mast cell/smooth muscle cocultures.
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Mast cells are tissue-resident immune cells that are capable of signaling many different cell types in vascularized tissue including epithelia and smooth muscle. We have developed an in vitro coculture system in which secretion of serotonin by a mucosal mast cell line (RBL-2H3) can be studied at a single cell level by measuring Ca2+ transients in fura-2 loaded mast cells and serotonin-sensitive A7r5 smooth muscle cells using fluorescence video microscopy and digital image processing. A7r5 cells elevate intracellular Ca2+ via 5HT2 receptors in response to bath-applied serotonin with an ED50 for serotonin of 550nM. Crosslinking IgE receptors with antigen caused Ca2+ transients in the mucosal mast cells. Ca2+ responses in the smooth muscle were detected approximately 30-240 sec after the initiation of the mast cell Ca2+ responses. Smooth muscle Ca2+ responses were dependent on preloading mast cells with serotonin and were blocked by the 5HT2 antagonist ketanserin. The timing and magnitude of the smooth muscle responses indicated that secretion from mast cells can lead to local concentrations of serotonin in the range of 300 nM within 1 min of antigen stimulation. This coculture technique has allowed the first direct demonstration of serotonin-mediated signaling between immune cells and vascular elements.
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8040193
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Proinflammatory cytokines (interleukin-1 beta and tumor necrosis factor-alpha) down regulate synthesis and secretion of thrombospondin by human endothelial cells.
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We examined the effects of proinflammatory cytokines on the expression of two extracellular matrix proteins, e.g., thrombospondin (TSP) and fibronectin (FN) b cultured human umbilical vein endothelial cells (HUVECs). Treatment of HUVECs with human recombinant interleukin-1 beta (IL-1 beta) or human tumor necrosis factor-alpha (TNF-alpha) caused a time-and dose-dependent decline in TSP production whereas FN production was not modified. At low concentrations, IL-1 beta and TNF-alpha in combination ha a greater effect than either agent alone. Interferon-gamma (IFN-gamma) was without effect. The decline in TSP synthesis resulted in a decreased secretion of this glycoprotein into the extracellular matrix. Endothelial cell monolayers cultured on porous filters were used to study the polarity of TSP secretion. Approximately two thirds of the synthesized protein was secreted to the apical side medium and one third to the basal side medium and both types of secretion were inhibited to a similar extent by cytokine treatment. Immunoprecipitation experiments revealed no apparent degradation of secreted TSP, either in the apical or in the basal compartment. Treatment of HUVECs with lL-1 beta, either alone or in combination with TNF-alpha, had no significant effect on the steady-state TSP mRNA levels, suggesting a posttranscriptional regulation. Our results indicate that IL-1 beta decreasing TSP deposition and suggest different regulatory mechanisms for the expression of various secreted proteins by endothelial cells.
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8040190
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TGF beta alters growth and differentiation related gene expression in proliferating osteoblasts in vitro, preventing development of the mature bone phenotype.
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This study examines the mechanism by which TGF-beta 1, an important mediator of cell growth and differentiation, blocks the differentiation of normal rat diploid fetal osteoblasts in vitro. We have established that the inability for pre-osteoblasts to differentiate is associated with changes in the expression of cell growth, matrix forming, and bone related genes. These include histone, jun B, c-fos, collagen, fibronectin, osteocalcin, alkaline phosphatase, and osteopontin. Morphologically, the TGF-beta 1-treated osteoblasts exhibit an elongated, spread shape as opposed to the characteristic cuboidal appearance during the early stages of growth. This is followed by a decrease in the number of bone nodules formed and the amount of calcium deposition. These effects on differentiation can occur without dramatic changes in cell growth if TGF-beta 1 is given for a short time early in the proliferative phase. However, continuous exposure to TGF-beta 1 leads to a bifunctional growth response from a negative effect during the proliferative phase to a positive growth effect during the later matrix maturation and mineralization phases of the osteoblast developmental sequence. Extracellular matrix genes, fibronectin, osteopontin and alpha 1(I) collagen, are altered in their expression pattern which may provide an aberrant matrix environment for mineralization and osteoblast maturation and potentiate the TGF-beta 1 response throughout the course of osteoblast differentiation. The initiation of a TGF-beta 1 effect on cell growth and differentiation is restricted to the proliferative phase of the culture before the cells express the mature osteoblastic phenotype. Second passage cells that are accelerated to differentiate by the addition of dexamethasone or by seeding cultures at a high density are refractory to TGF-beta 1. These in vitro results indicate that TGF-beta 1 exerts irreversible effects at a specific stage of osteoblast phenotype development resulting in a potent inhibition of osteoblast differentiation at concentrations from 0.1 ng/ml.
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8040192
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Cultured rat hepatocytes adapt their cellular glycolytic activity and adenylate energy status to tissue oxygen tension: influences of extracellular matrix components, insulin and glucagon.
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The influence of extracellular matrix components, insulin, and glucagon on the cellular response to periportal- or pericentral-equivalent tissue oxygen tension was investigated in freshly isolated rat hepatocytes cultured at 13% O2 or 4% O2 in Teflon membrane dishes. With extended culture time, significant increases in lactate release and cellular lactate content were observed in cultures at 4% O2 compared with 13% O2. This shift toward glycolysis was detectable when hepatocytes were cultured on dishes coated with rat liver crude membrane fraction (CMF/COL) but not in collagen type I-coated dishes. This indicates that extracellular matrix components are involved in the process of adaptation. ATP and total adenylate content in cells cultured at 4% O2 were up to 40% lower than in cells cultured at 13% O2. However, the adenylate energy charge was not affected, suggesting that an adequate energy supply was maintained also in hepatocytes cultured at pericentral-equivalent oxygen tension. This adaptation was reversible. When hepatocytes were transferred either from 4% to 13% O2 or from 13% to 4% O2, they adapted the corresponding metabolic profile to the new oxygen tension within 2 days. This demonstrates that hepatocytes are not fully unidirectionally programmed. The modulation of the glycolytic activity by insulin and glucagon was effective in cultures at pericentral-equivalent oxygen tension (4% O2) only. Insulin (0.1-100 nM) shifted cellular metabolism toward the glycolytic pathway and glucagon (1-100 nM) counteracted the effect of insulin in a dose-dependent manner. Clearly, oxygen tension is the principal regulator in the hepatic glycolytic activity, whereas the hormones (insulin and glucagon) act as secondary modulators.
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8040191
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Hormonal regulation of some steps of thyroglobulin synthesis and secretion in bicameral cell culture.
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Porcine thyroid cells were cultured for 15 days on porous bottom chambers with or without different mixtures of hormones added to serum-free basal medium. Assays with 10% serum were also performed for comparison with previously published results. The effects of the hormones, particularly insulin, TSH and hydrocortisone, were studied on total RNA content, thyroglobulin mRNA level, the amount of thyroglobulin secreted into the apical medium and on glycosylation. Insulin and TSH similarly increased the total RNA content, and their effects were additive. Thyroglobulin mRNA content was increased twofold by insulin and threefold by TSH. When they were added simultaneously, the maximal level of thyroglobulin mRNA was reached, showing that TSH and insulin effects on thyroglobulin gene expression were additive. Hydrocortisone alone did not modify total RNA or thyroglobulin mRNA content but the hormone amplified total RNA when insulin and TSH were present together. The basal level of thyroglobulin secreted into the apical medium was increased threefold by insulin and fourfold by TSH. The effects of these two hormones added together appeared to be additive. Hydrocortisone had no effect alone or even when combined with insulin or TSH. However, when the three hormones were added together, the hormonal response was amplified. TSH effect and insulin effect on the incorporation of 3H-mannose into thyroglobulin as well as on the anionic residue content of the molecule were additive.
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8040189
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Changes in promoter utilization in human and mouse c-myc genes upon transformation induction in temperature-sensitive cell lines.
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We have previously reported accelerated transcription and rapid accumulation of c-myc mRNAs upon induction of transformation in a temperature-sensitive mouse cell line (Gallant et al., 1989, Oncogene Res., 4:39-46). Here we have used both mouse and human cell lines transformed with a temperature-sensitive mutant of the Simian virus 40 (SV40) virus to investigate whether a shift in promoter utilization within the c-myc gene locus is part of a general mechanism that deregulates c-myc expression during transformation induction. We devised a simple and sensitive method using reverse transcription followed by radioactive polymerase chain reaction (RT-PCR) to measure the relative change in c-myc mRNAs arising from each of the four known promoters. We show that a three to fivefold increase in c-myc transcripts from the P1 and P3 promoters occurs in both human and mouse cell lines within 30 min of the shift to the permissive temperature. The major P2-initiated transcripts are not significantly effected. However, exon 3-containing RNAs increase more gradually up to 24 h postinduction and P1 and P3 transcripts, while remaining elevated, still contribute relatively little to the total c-myc RNA population. These and other results, demonstrating a transient activation of P1 and P3 promoters, suggest an indirect role of the minor transcripts in the deregulated expression of the c-myc gene in transformed cells.
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8040188
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Platelet-derived growth factor isoforms prevent cell death during starvation of AKR-2B fibroblasts.
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Confluent AKR-2B fibroblasts rapidly desintegrate upon removal of serum until a final density of approximately 50% of the initial value was reached after 12 h. This density remained unchanged for at least 48 h. Platelet-derived growth factor (PDGF)-BB stimulated more than 95% of these cells to divide. PDGF-AB or -BB added immediately after serum removal caused complete survival of the cells, but did not stimulate cell division as demonstrated by two-dimensional DNA flow cytometry. PDGF-AA was less effective leading to approximately 75% of the initial cell density. This effect could be augmented by the addition of ocadaic acid, a potent phosphatase inhibitor, suggesting that protein phosphorylation plays a role in this process. By using tyrphostin AG807 it was demonstrated that the signaling mechanism for survival requires receptor tyrosine autophosphorylation.
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8040187
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Regulation of gamma-actin gene expression by insulin.
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Insulin exerts rapid effects on cellular metabolism and can cause morphological changes by inducing rearrangements of cytoskeletal components. The regulation of specific cytoskeletal genes by insulin, however, has not been studied extensively. In the present work insulin was found to rapidly, but transiently, increase transcription of the cytoskeletal gamma-actin gene in rat H4IIE (H4) hepatoma cells. Insulin-induced transcription of the gamma-actin gene was evident within 5 min and was maximal by 15 min at 10-fold above control levels. The stimulation of transcription was transient, with a return towards basal levels by 120 min. Transcription of gamma-actin was increased at insulin concentrations as low as 1 x 10(-11) M and was maximal at 1 x 10(-9) to 1 x 10(-8) M. Transcription of several control genes (skeletal and cardiac alpha-actin and beta-tubulin) were unaltered by insulin administration. Messenger RNA (mRNA) levels for the gamma-actin gene increased, but to a lesser degree than transcription. Since the gamma-actin message is an abundant and stable mRNA, its levels would not be expected to change dramatically from a transient induction of transcription. Like insulin, phorbol esters transiently increased transcription of the gamma-actin gene. In addition, pretreatment of cells with phorbol esters for 24 h reduced the ability of insulin to induce gamma-actin transcription. These data support our hypothesis that insulin and phorbol esters share intracellular signalling pathways in the control of transcription of specific genes.
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8040186
|
Differential effects of warfarin on mRNA levels of developmentally regulated vitamin K dependent proteins, osteocalcin, and matrix GLA protein in vitro.
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The role of the vitamin K dependent proteins, osteocalcin which is bone specific and matrix Gla protein (MGP) found in many tissues, has been studied by inhibition of synthesis of their characteristic amino acid, gamma-carboxyglutamic acid (Gla) with the anticoagulant sodium warfarin. The effect of sodium warfarin on expression of these proteins, and other phenotypic markers of bone and cartilage during cellular differentiation and development of tissue extracellular matrix, was examined in several model systems. Parameters assayed include cell growth (reflected by histone gene expression) and collagen types I and II, osteopontin, alkaline phosphatase, and mineralization. Studies were carried out in calvarial bone organ cultures, normal diploid rat osteoblast and chondrocyte cultures, and rat osteosarcoma cell lines ROS 17/2.8 and 25/1. In normal diploid cells, warfarin consistently stimulated cell proliferation (twofold). In osteoblast cultures, MGP mRNA levels were generally increased (three to tenfold). Notably, MGP mRNA levels were not affected in chondrocyte cultures, either with chronic or acute warfarin treatments. Osteocalcin mRNA levels and synthesis were decreased up to 50% in ROS 17/2.8 cells and in chronically treated (1 and 5 micrograms/ml sodium warfarin) rat osteoblast cultures after 22 days. Early stages of osteoblast phenotype development from the proliferation period to initial tissue formation (nodules) appeared unaffected; while after day 14, further growth and mineralization of the nodule areas were significantly decreased in warfarin-treated cultures. In summary, warfarin has opposing effects on the expression of two vitamin K dependent proteins, MGP and osteocalcin, in osteoblast cultures and MGP is regulated differently between cartilage and bone as reflected by cellular mRNA levels. Additionally, warfarin effects expression of nonvitamin K dependent proteins which may reflect the influence of warfarin on endoplasmic reticulum associated enzymes.
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8040185
|
Formation of tight junctions and desmosomes protects MDCK cells against hyperthermic killing.
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Cell density is known to modify the survival of mammalian cells exposed to elevated temperatures. We have examined the role that cell-cell contact plays in this phenomenon. The formation of cell-cell contact is carried out by cells' junctional complex, i.e., tight junctions, desmosomes, and gap junctions. Lack of formation of tight junctions and desmosomes, or their opening, could interfere with the functions and structures of cell membrane. Membrane damage is at least partially responsible for cell death at elevated temperatures. MDCK cells with high density plated in low calcium medium form confluent monolayers devoid of the formation of tight junctions and desmosomes but quickly assemble them after Ca2+ restoration. We used MDCK cells and the calcium switch technique to investigate effects of cell-cell contact and, independently, of cell density on hyperthermic cell killing. We found that MDCK cells that formed tight junctions and desmosomes were more resistant to hyperthermic treatment than those that did not. Blocking the formation pathway of tight junctions made cells sensitive to heat. Cells growing at lowdensity showed almost the same survival as did cells at high density in the absence of the formation of tight junctions and desmosomes. The results suggest that the formation of tight junctions and desmosomes play a more important role in determining hyperthermic response than does density per se. The formation of tight junctions and desmosomes appears to protect cells modestly against hyperthermic killing.
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8040184
|
Characterization of rat aortic smooth muscle cells resistant to the antiproliferative activity of heparin following long-term heparin treatment.
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Vascular smooth muscle cells (SMC) do not represent a homogeneous population (Schwartz et al., 1990, Am. J. Pathol. 136: 1417-1428). Cellular clones resistant to the antiproliferative activity of heparin were isolated from rat aortic SMC cultures (Pukac et al., 1990, Cell Regul., 1:435-443; San Antonio et al., 1993, Arterioscler. Thromb., 13:748-757) and from explant of human arterial restenotic lesions (Chan et al., 1993, Lancet, 341:341-342). We have shown in the present study that long-term treatment (growth medium supplemented with 200 micrograms/ml heparin, from the second to the tenth passage) of rat aortic SMC, without cell cloning, resulted in a significant loss of sensitivity to the growth inhibition by heparin and its derivatives. The heparin resistance was stable after growing cells for two passages in heparin-free medium, suggesting the selection of a particular phenotype. We tried to characterize these cells and to determine the causes of the resistance to the growth inhibition by heparin. Heparin-treated SMC (HT-SMC) were smaller than their control culture at the same passage, expressed less alpha-SM actin, and did not overgrow after reaching confluence. As in the heparin-resistant clones (San Antonio et al., 1993, Cell Regul., 1:435-443) expression of alpha-SM actin could be increased in HT-SMC by heparin addition before Western blotting. Heparin resistance was associated with a tenfold decrease in [3H]-heparin binding capacity (Bmax = 1.9 x 10(6) sites per cell) compared to control cultures (Bmax = 1.7 x 10(7) sites per cell), which was irreversible after growing the cells for two additional passages in heparin-free medium. We also investigated protein kinase C (PKC) in HT-SMC in terms of both enzymatic activity and protein expression (evaluated by [3H]-staurosporine and [3H]-phorbol-12,13-dibutyrate binding). We found that HT-SMC had only half the PKC activity and expression as control SMC. Therefore, long-term treatment of rat aortic SMC with heparin allowed the selection of a less differentiated subpopulation of cells, exhibiting low sensitivity to the growth inhibition by heparin, which could be related to the low capacity of binding heparin and to a lower PKC activity and/or expression.
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8040183
|
Hematopoietic progenitor cells of transgenic mice with increased copper/zinc-superoxide dismutase activity are resistant to tumor necrosis factor.
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The mechanism of growth inhibition mediated by tumor necrosis factor (TNF) is unclear. Since recent data strongly suggested that generation of superoxide is a key step in cytotoxicity of TNF, we reasoned that cells expressing high levels of enzymes that degrade superoxide radicals would be resistant to TNF. Therefore, we examined the TNF-sensitivity of bone marrow progenitor cells of transgenic mice that expressed the gene for human copper zinc-superoxide dismutase (CuZn-SOD). The CuZn-SOD is a key enzyme in the metabolism of superoxide radicals. Heterozygous and homozygous transgenic mice had 3- and 5-fold increased levels of CuZn-SOD activity, respectively. Bone marrow cells of transgenic and nontransgenic mice were plated in soft gel culture with TNF (0.01-100 ng/ml). TNF inhibited myeloid colony formation supported by either granulocyte-macrophage colony-stimulating factor (GM-CSF) or G-CSF from nontransgenic mice in a dose-dependent manner. In contrast, the myeloid clonal growth of homozygote transgenic mice was not inhibited by TNF at concentrations up to 100 ng/ml. As expected, the effects of TNF on erythroid clonogenic cells, which do not produce superoxide, and the action of transforming growth factor-beta on myeloid progenitor cells, were similar in both transgenic and nontransgenic mice. These results suggest that the mechanism of TNF-mediated growth inhibition of hematopoietic cells occurs through production of superoxide.
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8040182
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EGF modulates phosphoinositide levels in ovarian granulosa cells stimulated by luteinizing hormone.
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Hamster granulosa cells were exposed to epidermal growth factor (EGF) and luteinizing hormone (LH) to study cross-talk between second messenger pathways involving tyrosine kinase, cAMP, and phosphoinositides. Granulosa cells from ovarian preovulatory follicles of PMSG-primed hamsters were incubated with various additives in serum-free medium. LH, but not EGF, stimulated inositol phosphate (IP) accumulation; however, when combined with LH, EGF inhibited IP accumulation in a manner that was concentration dependent for both LH and EGF. The inhibitory effects of EGF were significantly reduced by the tyrosine kinase inhibitor genistein and by pertussis toxin suggesting a role for tyrosine kinase and an inhibitory G-protein (Gi) in this system. EGF stimulated an increase in cAMP, but it does not appear to modulate LH-stimulated IP levels via cAMP.
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8040179
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Bronchoscopy findings and early treatment of patients with blunt tracheo-bronchial trauma.
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Five of 238 patients who suffered blunt chest trauna required surgery to repair a tracheobronchial injury. All patients were injured in a motor vehicle accident. The site of the injury was within 2.5 cm of the carina in four patients and 5.5 cm proximal to the carina in one. Pre-, intra-, and post-operative respiratory management was facilitated by the insertion of a Univent tube, an endotracheal tube with movable blocker capable of excluding one lung. The Univent tube prevented aspiration of blood by the healthy lung and the development of acute respiratory failure. Improved control over ventilation has the secondary benefit of allowing the surgeon to assess other injuries under less duress in patients with multiple trauma.
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8040180
|
Pretreatment natural history of small cell lung cancer presenting as a solitary pulmonary nodule.
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Small cell lung cancer (SCLC) occasionally presents as an asymptomatic solitary pulmonary nodule (SPN) on chest radiography. This group of SCLC patients appears to have different tumor growth properties and greater potential for cure than most SCLC patients. Some investigators have hypothesized that SCLC presenting as a SPN represents a biologically unique subset of SCLC. To provide support for this hypothesis, uncontrolled but infrequently obtainable natural history observations are reported. A retrospective radiograph review of selected patients with SCLC presenting as a SPN was done. Teaching hospital. Three patients with delay in treatment of SCLC were reviewed. Slow growth of SPNs was documented over a 14, 27, and 40 month period in these patients. No lymph node or systemic metastases were found. Radiographic observations were made retrospectively; delayed treatment of the SPNs was not intentional. SCLC was diagnosed by pulmonary resection in two patients and fine needle aspiration cytology in one patient. The hypothesis that SCLC presenting as a SPN is a biologically unique subset of SCLC, with relatively slow growth and potential for cure, is supported by these uncontrolled observations.
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8040178
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Primary malignant pericardial mesothelioma: a case report and review.
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Primary malignant pericardial mesothelioma is a rare tumor of unknown etiology. The prognosis is extremely poor due to generally late presentation, inability to completely eradicate it surgically and its poor response to radiotherapy or chemotherapy. An unusual case of pericardial mesothelioma which presented as constrictive pericarditis is described. A comprehensive review of the 140 cases reported in the literature so far is presented to assist the readers in the management and prognosis of this rare, pathological tumor.
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8040177
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Successful management of hemorrhage from the pulmonary artery stump after lobectomy for bronchogenic carcinoma.
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Pulmonary bleeding from the arterial stump following lung resection is a life-threatening complication requiring immediate surgical correction. Predisposing conditions are almost always represented by bronchopleural fistula and empyema. The operation often represents a major challenge to the thoracic surgeon, because of the choice of the most appropriate surgical access, the optimal technique to control the bleeding, as well as to treat the associated bronchopleural fistula. We present a case of successful treatment of hemorrhage from the pulmonary artery stump associated with BPF and empyema following lobectomy for bronchogenic carcinoma. A standard postero-lateral thoracotomy using the previous incision was used with adequate exposure of the source of bleeding and the bronchopleural fistula.
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8040176
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Lung cancer found in a patient with absence of the inferior vena cava associated with a left superior vena cava.
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A patients with anomalies of the main systemic veins developed lung cancer. In this patient, the large hemiazygos vein emptied into the left superior vena cava which communicated with the right atrium through the coronary sinus. The cancer was located in the right upper lobe and directly invaded the mediastinum. Fortunately, because of the absence of a right superior vena cava in the normal position, the tumor was completely resected by sleeve upper lobectomy without necessitating angioplastic procedures.
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8040175
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Acute laryngeal oedema following carotid endarterectomy.
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Two cases of acute laryngeal oedema are reported following carotid endarterectomy. Although the mechanisms of development of oedema differ in each case they both illustrate a potentially lethal complication of any form of neck surgery. The requirement for careful haemostasis and airway observation of patients for the first 24 hour after neck surgery is emphasised.
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8040174
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Singular case of tardive anastomotic disjunction in a Dacron R vascular graft.
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We investigated a case of anastomotic disjunction of the termino-lateral insertion of a bifurcate aortic graft in the right external iliac artery. The graft in woven Dacron R n. 19, was implanted in 1977 and the left femoral insertion became infected shortly after surgery. The infection was treated according to standard procedures with removal of the infected branch, reconstruction with the transobturatory by-pass and antibiotics. For antibiotic treatment of local and general sepsis the approach was completely new as regards dose regimen and duration. In 1993 a pseudoaneurysm developed through weakening of the right iliac anastomosis. In view of the anamnesis we were surprised to find that the origin was of a mechanical nature.
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8040173
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A rare association of fibromuscular dysplasia of the femoral artery with aneurysm and occlusion treated alternatively.
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A unique case of fibromuscular dysplasia of the femoral artery with aneurysm and occlusion of the superficial femoral artery component is presented. This aneurysm was treated by dacron wrap. External dacron grafts have been previously reported and used with success in a variety of arterial aneurysms. The authors present their rationale and indication for its use in this unusual arterial problem.
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8040172
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Technique for management of an axilloaxillary by-pass graft complicating a median sternotomy.
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A technique is presented for intraoperative management of an axilloaxillary by-pass graft when performing a median sternotomy for myocardial revascularization. This method allows continual perfusion of both upper extremities during the operation thereby preventing the potential complications of upper extremity or cerebral ischemia.
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8040171
|
Long-term follow-up of different therapy procedures in spontaneous pneumothorax.
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The objective of this follow-up study was to evaluate the success rate of different therapy procedures in spontaneous pneumothorax. In order to achieve comparable conditions the study was restricted to those patients who were treated because of a first episode (n = 96) in the time between January 1978 and December 1987. Seventy-one were males and 25 females, ratio 3:1. The right side to left side ratio was 3:2. Both sides were affected in 11% (n = 11). All patients received an intercostal tube drainage with a permanent suction. In case of treatment failure thoracoscopy, pleurodesis or an operation were performed. The follow-up investigations was performed in January 1990 thus to further evaluate the outcome of 79 patients (82%) after 2 to 12 years after treatment. Among the patients, 33 patients presented a persistence or an early recurrence, 26 of them were operated during their first stay in hospital. A further 25 patients presented a late recurrence, of whom 14 underwent a later thoracotomy. Consequently the drainage therapy had a failure rate of 61% (n = 58). The frequency of operation was 42% (n = 40). The results after thoracotomy (n = 26) were as follows: slight complications, which did not require surgical treatment occurred in 8% (n = 2). The long-term results after surgical intervention (lung apex resection and/or parietal pleurectomy) were excellent concerning the rate of late recurrences (0% within the follow-up group) and the general condition (96% free or almost free of symptoms) regardless the method of operation.(ABSTRACT TRUNCATED AT 250 WORDS)
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8040170
|
Efficacy of pre-emptive analgesia and continuous extrapleural intercostal nerve block on post-thoracotomy pain and pulmonary mechanics.
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Thoracotomy results in severe pain and deleterious changes in pulmonary physiology. The literature suggests that these alterations in pulmonary mechanics are inevitable and can only be minimised but not prevented by effective analgesia. We have re-evaluated this concept and assessed the efficacy of pre-emptive analgesia [preincisional afferent block, premedication with opiate and/or non-steroidal anti-inflammatory drug (NSAID)] in conjunction with postoperative extrapleural continuous intercostal nerve block on postoperative pain and pulmonary function. A prospective randomized study was conducted on 56 patients undergoing elective thoracotomy. Subjective pain relief was assessed on a linear visual analogue scale. Pulmonary function was measured on the day before operation and 12 hourly for 48 hours after operation. There were seven patients in each of the eight groups. The balanced analgesia group comprising preincisional block and premedication with opiate and NSAID (Group 1) had significantly better analgesia, needed less postoperative supplementary analgesics and maintained their preoperative pulmonary function postoperatively irrespective of the nature of the operation. The ranking of importance of the three components of the pre-emptive analgesia as assessed in this study are preincisional block, opiate premedication and premedication with NSAID's. No significant change in plasma levels of cortisol or glucose occurred in Group 1 patients from prior to induction of anaesthesia to 24 hours postoperatively, suggesting effective somatic and sympathetic afferent blockade had been achieved in these patients. There were no complications related to the infusion or the use of NSAID's. We conclude that a balanced analgesic regime comprising preoperative pain prophylaxis and postoperative maintenance analgesia by NSAID and continuous extrapleural intercostal nerve block will minimise and even reverse the expected decline in lung function after thoracotomy. The postoperative decline in lung function is not obligatory but primarily due to incisional pain and thus is preventable by effective analgesia. An ideal balanced pre-emptive analgesic regime should include preincisional local anaesthetic afferent block and premedication with opiates and a NSAID:
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8040169
|
Acute renal failure following pulmonary surgery.
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To determine incidence, predisposing factors, and outcome of acute renal failure complicating pulmonary surgery. Retrospective review. Tertiary cancer hospital. Patients undergoing pulmonary resection over a 25-year period. Morbidity and mortality of postoperative acute renal failure. Six of 1595 (0.4%) patients developed acute renal failure. All 6 patients had advanced thoracic malignancies that required extensive resections. No patient undergoing simple lobectomy, or lesser pulmonary resection, developed acute renal failure. Sepsis and respiratory failure were present in all 6 patients prior to onset of acute renal failure. All patients died of multiple organ failure. The incidence of acute renal failure following pulmonary surgery is very low. Management strategies developed for other surgical patients may not be appropriate in the setting of pulmonary surgery. Specific perioperative preventive measures, such as intravenous fluid loading, are not warranted and may be harmful. Acute renal failure after pulmonary surgery has a very high mortality. Associated post-operative complications, such as sepsis and respiratory failure. are largely responsible for this high mortality. Treatment of acute renal failure in pulmonary surgery patients consists of maintenance of tissue oxygenation, elimination of sepsis, nutritional support, and dialysis or hemofiltration.
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8040168
|
Aortopulmonary septal defects. A review of the literature and report of ten cases.
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From 1981 to 1992, 10 infants with aortopulmonary septal defect (APSD) underwent surgical repair. The mean age at operation was 5.6 +/- 5.5 months, and the mean weight 4.6 +/- 2 kg. Intracardiac associated anomalies were as follows: ventricular septal defects (7 cases), tetralogy of Fallot (2 cases), aortic valve stenosis (2 cases), atrial septal defect (3 cases), patent ductus arteriosus (3 cases), pulmonary valve stenosis (1 case). Cardiac catheterization was performed in 8 out of 10 patients. Eight patients had type I (proximal) defect, 1 had type II (distal) defect and 1 had type III (absent aortopulmonary septation) defect. A variety of surgical procedure was employed. APSD closure with hemoclip was feasible in 3 cases with small window. In 6 patients, during a period of cardiopulmonary by-pass, a side biting clamp was positioned on the ascending aorta close the defect; the border of the window was divided leaving a flap of pulmonary wall on the left side to close the aortic defect; the pulmonary artery was repaired by an autologous pericardial patch. In the patient with type III APSD, aortopulmonary septation was carried out through a transwindow approach. Associated anomalies were repaired in all infants except one. Hospital mortality was 10% (1 case). No late deaths occurred. At a mean follow-up of 47 +/- 35 months 8 patients are asymptomatic and 1 is awaiting for repair of associated anomalies. Conclusions. APSD is a rare but nonetheless well identifiable anomaly. Surgery is indicated as soon as the diagnosis is established, regardless of the patient's age.(ABSTRACT TRUNCATED AT 250 WORDS)
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8040167
|
Measurement of myosin light chain I and troponin T as markers of myocardial damage after cardiac surgery.
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The purpose of the study was to test cardiac myosin light chain I (CMLCI) and troponin T (TNT) as markers on myocardial damage after heart surgery. Forty-three patients undergoing cardiac surgery were arbitrarily divided into two groups according to creatine kinase MB isoenzyme (CK-MB) levels and postoperative electrocardiogram (ECG) changes. Group 1: CK-MB > 100 micrograms/L or ECG changes (extensive myocardial damage, 42%); Group 2: CK-MB < 100 micrograms/L and no ECG changes (minimal myocardial damage, 58%). Group 1 was divided into 2 groups (Infarction and Injury groups). CMLCI levels showed strong correlations with TNT levels after the operation. The peak CMLCI and TNT levels in group 1 were significantly higher than in group 2. The peak CMLCI in the Infarction group was significantly higher than in the Injury group. TNT showed different patterns in the Infarction and Injury groups. This study showed that CMLCI and TNT estimation could evaluate myocardial damage over several postoperative days. TNT estimation could identify myocardial damage earlier than CMLCI, however CMLCI could discriminate perioperative infarction better than TNT.
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8040166
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Performance of indirect embolectomy aided by a new developed flush-suction catheter system. Forty-seven experimental embolectomy procedures in test animals.
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Embolectomy by means of the Fogarty catheter is the therapy of choice in the event of acute occlusions of limb arteries. However, less invasive catheter procedures have become established means to perform embolectomies lately. In order to improve the results after using the above mentioned methods, we have developed a new embolectomy procedure. The system applied consists of a flush-suction catheter as well as a high pressure pump. There is a jet-suction unit on the head of the tubular two-lumen catheter to gather thromboembolic material from the circumference of the head, to erode the collected material and evacuate it. The flushing pressure is generated by the pump. For the experimental testing of the system, the flush-suction embolectomy has been performed in 19 pigs after 47 artificial produced extremities embolism. Angiographically and angioscopically it could be proved that even older thrombotic material could be removed completely and without significant trauma of the vessel. At the pathologic investigation of the vessel in which embolectomy had been performed in no case an essential vessel-wall damage could be found. In almost each case the embolic material was removed completely. Only in 5 cases (10.6%) we have distal microembolism. Due to the experimental tests, the system turns out to be reliable as far as the technique is concerned. In addition, in the event of clinical application, the system allows the expectation of a reduction of the time interval between diagnosis and therapy, as well as a percutaneous application.
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8040165
|
Local thrombolysis for occluded arterial grafts: is the yield worth the effort?
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This study reports the results and complications of local thrombolytic therapy of 50 recently occluded grafts. These occurred in 41 patients with acute severe but still reversible ischemia. The majority were infra-inguinal synthetic grafts. Thrombolysis was induced with urokinase (n = 1), streptokinase (n = 11) or alteplase (n = 38) via an intra-arterial catheter. Complete angiographical lysis was obtained in 36 grafts (72%) and partial lysis in 6 (12%). The highest lysis rate was obtained with alteplase (32/36; 89%). Complementary endovascular and/or surgical intervention was needed in 17 patients to correct an underlying stenosis and/or to save the limb. Fifteen complications occurred (30%) of which distal embolization (n = 4) and bleeding (n = 8 of which 3 fatal) were the most frequent. Six of the bleeding episodes occurred in patients on chronic aspirin intake. The late results were poor. At six months, the primary patency of successfully lysed grafts dropped to 19% and the limb salvage rate to 64%. Thrombolytic therapy is far from the ideal management of thrombosed grafts: maintenance of restored patency is the challenge.
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8040161
|
Prime number identification in idiots savants: can they calculate them?
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Several idiots savants who were able to identify prime numbers have been reported. This ability requires complex calculations, because no simple algorithms are known for determining primes. Many savants, however, who demonstrate this ability, do not possess the arithmetical skills to perform such calculations. Explanations offered for the feats of idiots savants are reviewed in the light of their applicability to the cases of prime identification. Existing models cannot fully explain prime number identification for savants with weak arithmetical skills. The author shows that through the natural tendency of visual perception to be organized symmetrically, a distinction between prime and nonprime numbers can be made. This process could both explain the origin of the interest and the ability to identify prime numbers in mathematically weak savants.
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8040160
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Why and when do some language-impaired children seem talkative? A study of initiation in conversations of children with semantic-pragmatic disorder.
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Six language-impaired children fitting the clinical picture of semantic-pragmatic disorder (mean age 11 years) engaged in conversations with adults in four situations varying in terms of familiarity of the interlocutor (familiar or unfamiliar) and type of setting (interview or toy exploration). These children did not produce more utterances or longer utterances than normally developing children of similar age or ability, but they were more likely to produce utterances that served the conversational function of initiating, rather than responding or acknowledging. This tendency was most pronounced in the toy setting. There was a nonsignificant trend for control children to initiate more with a familiar than with an unfamiliar adult, but no such tendency in the semantic-pragmatic group. A high rate of initiations in children with semantic-pragmatic disorder cannot be regarded as an unusual behavior provoked by the demands of the interview setting, as it is even more apparent during toy exploration, where the child is under less pressure to respond to adult questions.
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8040159
|
I, you, me, and autism: an experimental study.
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The nature of autistic individuals' abnormalities in the use of personal pronouns has been a topic of considerable speculation but little systematic investigation. We tested groups of CA- and verbal MA-matched autistic and nonautistic mentally retarded children and young adults on a series of tasks that involved the comprehension and use of the personal pronouns "I," "you," and "me." All subjects were able to comprehend these pronouns within the test situations, and there were few instances of pronoun reversal. However, autistic subjects were significantly less likely to employ the pronoun "me" in a visual perspective-taking task (when instead they tended to say: 'I can see the . . .'), and lower ability subjects were more likely to use their own proper names rather than personal pronouns in certain photograph-naming tasks. There were also circumstances in which autistic subjects were less likely than controls to employ the pronoun "you" to refer to the experimenter. A high proportion of these autistic subjects were reported to have current difficulties with personal pronouns in their everyday life, and we discuss some alternative interpretations of the results.
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8040158
|
An advanced test of theory of mind: understanding of story characters' thoughts and feelings by able autistic, mentally handicapped, and normal children and adults.
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Research has suggested that the core handicaps of autism result from a specific impairment in theory of mind (ToM). However, this account has been challenged by the finding that a minority of autistic subjects pass 1st- and even 2nd-order ToM tests while remaining socially handicapped. In the present study, able autistic subjects who failed ToM tasks, those who passed 1st-order, and those who passed 2nd-order tasks were tested with a battery of more naturalistic and complex stories. Autistic subjects were impaired at providing context-appropriate mental state explanations for the story characters' nonliteral utterances, compared to normal and mentally handicapped controls. Performance on the stories was closely related to performance on standard ToM tasks, but even those autistic subjects who passed all ToM tests showed impairments on the more naturalistic story materials relative to normal adult controls.
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8040157
|
Domains of the Childhood Autism Rating Scale: relevance for diagnosis and treatment.
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The Childhood Autism Rating Scale (CARS) was factor analyzed. Three factors emerged: Social Impairment (SI), Negative Emotionality (NE), and Distorted Sensory Response (DSR). Unit-weight factor scales showed moderate-to-good internal consistency. Cross-sectional analyses demonstrated that autistic (AUT) subjects were distinguished from subjects with pervasive developmental disorders (PDD) and nonpervasive developmental disorders (NPDD) by higher scores on SI. An SI cutoff score of 26 classified individuals as autistic vs. nonautistic with 78% accuracy. Longitudinal analyses showed that DSR was stable over 6 months of treatment, with little indication of symptom reduction. SI decreased over time across the diagnostic groups, but still showed significant continuity over the period. NE was most malleable and apparently sensitive to the effects of treatment.
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8040155
|
Nocturnal asthma symptoms may be more prevalent than we think.
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We evaluated the prevalence of nocturnal asthma in our subspecialty allergy clinic to see whether it was significantly different than the prevalence in a previous study (3). A questionnaire was sent to 1258 patients, and there were 325 responses. Of the 325, 304 patients had asthma. A total of 204 (67%) of these had nocturnal symptoms of asthma. Eleven percent of the total population awakened every night, 16% awakened three to six nights per week, 20% one or two nights per week, 20% one night per month, and 33% not at all. We discovered that patients had a rather nonchalant view of their asthma and frequently did not report nocturnal symptoms to their doctors. We conclude that even in a specialty allergy and asthma practice, nocturnal asthma symptoms may be more prevalent than suspected. The reason for this is unclear but may be related to a problem with patient perception and possibly to a lack of diligence in physician history taking.
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8040154
|
Asthma-related symptoms and lung function in primary school children.
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The aim of the present study was to determine the prevalence of asthma-related symptoms in a group of primary school children, by means of a questionnaire completed by their parents, and their lung function using spirometry and the forced oscillation technique (FOT). Also investigated were diagnostic labeling and medical prescription. We approached 535 children, from two primary schools in Maastricht, the Netherlands. Completed questionnaires were received from 482 children (90%). Valid lung function values were obtained in 470 of these children (98%). The lifetime prevalence of wheeze and attacks of shortness of breath with wheeze was 29% and 19%, respectively. The period prevalence of wheeze was 15%, 13% reported chronic cough, and 10% attacks of shortness of breath with wheeze. The doctor-diagnosed asthma and bronchitis prevalence was 6% and 19%, respectively. Of the children diagnosed as having asthma, 69% used antiasthma medication; none of the children diagnosed as having bronchitis used antiasthma medication. A symptom-based asthma prevalence of 11% was calculated. Statistically significant differences in spirometric and FOT indices were found between the children with and without complaints. In conclusion, among the 482 investigated children a relatively high prevalence of unrecognized or misclassified, and therefore undertreated, asthma-related symptoms was found. These observations were confirmed by the lung function data, in that we found significant differences in spirometric and FOT indices between children with and without complaints.
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8040153
|
Mortality from airways disorders in Alberta, 1927-1987: an expanding epidemic of COPD, but asthma shows little change.
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Mortality from asthma has been reported to be increasing in recent years in many countries, including Canada. Alberta, and the prairie provinces generally, appear to have an excess of deaths from asthma compared to other provinces. We studied mortality from asthma and from chronic obstructive pulmonary disease (COPD) generally in Alberta between 1927 and 1987 using a data set compiled and recorded from Alberta Vital Statistics to describe birth cohorts' age-specific mortality rates. We also present the distribution of deaths in the years since 1987. There was a clear and sustained increase in mortality from COPD since 1950 after age 40 but no evidence to support the proposition that deaths from asthma were increasing in recent years; more recent data from Alberta Vital Statistics show no sustained increase since 1987, either. There was great variability from year to year and sporadically increased rates in a given year that were not sustained. These transient increases were observed particularly among females aged 10-14, 15-19, and 25-29 and among males aged 15-19, 25-29, and 80-84; however, there were also comparable decreases in asthma mortality of similar magnitude during the same time period in different age groups or in the other sex in the age group 10-14. We conclude that there is no excess of deaths from asthma over those expected by historical trends in Alberta at the present time but that the smoking-related epidemic of deaths from COPD continues unabated. The "smoothness" and consistency of the mortality trends suggest that physicians certifying deaths from these causes are using implicit diagnostic criteria that have not changed abruptly.
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8040152
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Educating teachers about asthma.
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The objectives of this project were to investigate teachers' knowledge of asthma and to evaluate the effectiveness of an information session similar to the asthma programs for schools developed and offered by an organization charged with educating the community about asthma. A questionnaire consisting of 24 multiple-choice questions on asthma and its management was created for this project. There were no significant differences in knowledge of asthma between teachers who attended an information session about asthma and teachers who did not. Teachers with asthma had more knowledge of asthma than nonasthmatic teachers, but knowing someone with asthma made no significant difference to teachers' knowledge. There were no significant differences between teachers who had or had not received training in asthma from some other source prior to our intervention. Ninety-three percent of teachers indicated they wanted more information on asthma prior to the intervention session. Seventy-nine percent of teachers wanted further information after the intervention session. Methods of improving the effectiveness of the transmission of information concerning asthma and its management are explored.
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8040151
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Influence of asthma or allergies on the utilization of health care resources and quality of life of college students.
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The objectives of this study were to describe the treatment regimens of college students with asthma or allergies, to determine how asthma or allergies affect the lives of college students, and to evaluate the health care resources utilized by college students with asthma or allergies. A mail survey was sent to 275 students who received treatment for asthma or allergies at the Thomson Student Health Center at The University of South Carolina (TSHC-USC) during the fall 1991 semester. This survey, consisting of 46 questions, covered three key areas: current asthma or allergy management, class and work days missed, and utilization of health care resources. Students with "asthma and allergy" missed on average 2.4 days of class during the fall semester, whereas those with "asthma only" and "allergy only" missed on average 0.8 day and 1.5 days of class, respectively. Students with "allergy only" appeared to have a greater interference in their daily class and academic activities than students with "asthma and allergy" and "asthma only." In conclusion, students reported interference in their college activities and reported missing days of work and school because of asthma or allergies. This study also showed that a majority of these college students have not received asthma or allergy patient education nor utilized appropriate asthma or allergy management skills.
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8040150
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Occupational asthma following kapok exposure.
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Whether a distinct kapok allergen exists or whether the fiber's allergenicity is due to contamination by other allergens has never been resolved. Several years ago, we evaluated a patient who appeared to develop occupational asthma to kapok. We performed an environmental assessment, cross-shift spirometric testing of the patient's co-workers, and the first reported bronchoprovocation challenge with kapok. The disappearance of the patient's asthma following cessation of kapok exposure, with now 7 years of follow-up, our inability to incriminate any other agent, and the patient's positive specific bronchoprovocation challenge strengthen the evidence, but do not prove definitively, that kapok fiber itself is allergenic.
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8040147
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Liposomal anthracyclines.
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Preclinical experiments with liposome-encapsulated anthracyclines indicate that this form of delivery may be effective in decreasing the cardiotoxic effect of these drugs. The tumor drug levels and the antitumor efficacy of anthracyclines in a number of mouse models are significantly enhanced by delivery in long-circulating liposomes. Drastic changes in the clinical pharmacokinetics of doxorubicin have been observed using liposomal delivery. Clinical trials with liposomal anthracycline preparations are ongoing to determine whether the pharmacokinetic changes are translated in a superior therapeutic index of this important group of chemotherapeutic agents.
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8040146
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Platinum resistance. Experimental and clinical status.
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It has become clear that multiple mechanisms of cellular resistance to platinum compounds exist; however, the knowledge that platinum resistance can not only be explained by processes such as reduced drug accumulation, and increased detoxification, has shifted the attention of researchers to more molecular mechanisms. The introduction of new techniques, such as the PCR technique for example, has opened the possibility to monitor genes involved in antitumor responses and may provide molecular information on the emergency of resistance.
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8040145
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Purine metabolism of lymphocytes. Targets for chemotherapy drug development.
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The unique metabolic profile that renders lymphoid cells sensitive to purine deoxynucleosides also accounts for the response of chronic lymphoid malignancies to purine analogues. Consistent with earlier observations in children with adenosine deaminase deficiency, a profound and relatively selective lymphocyte depletion results from treatment with drugs that elevate or mimic deoxyadenosine. Three such agents available for clinical use are 2-chlorodeoxyadenosine, 2'-deoxycoformycin, and fludarabine phosphate. In addition to a review of the relevant biochemistry and cellular pharmacology of these agents in target lymphoid cells, this article reviews the current clinical response data in leukemias and lymphoma.
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8040144
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Topoisomerase I inhibitors. An overview of the camptothecin analogs.
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The topoisomerase I inhibitors are an exciting new class of antineoplastic agents currently under clinical development. Analogues of camptothecin with improved toxicity profiles and antitumor activity included CPT-11 and topotecan. CPT-11 has demonstrated activity against a variety of tumor types, particularly colon and lung cancer. Early results with topotecan against ovarian and lung cancer are also encouraging. Combination trials with other antineoplastic agents including cisplatin and etoposide, and early clinical trials with new topoisomerase I inhibitors, such as 9-aminocamptothecin, are underway.
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8040143
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New drugs in clinical development in the United States.
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Over the past few years, a number of new antineoplastic agents have reached the clinical arena. These agents have demonstrated activity in a wide variety of preclinical tumor models and many have been found to have novel mechanisms of action. Some of these new agents are now in Phase I and Phase II trials demonstrating antitumor activity and unique toxicity profiles. In this article, the authors review some of the new agents in clinical development in the United States.
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8040142
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New drugs in clinical development in Europe.
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This article deals with new antitumor agents currently in Phase I or II evaluation in various European centers. Drugs reviewed in this article include Taxotere, Camptothecin analogues, CPT-11, and Topotecan. Rhizoxin, D1694, and Bryostatin are among other agents reviewed in this article.
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8040141
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New anticancer drugs under clinical trials in Japan.
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A total of 16 drugs developed in Japan are currently under Phase I or II trials. This article reviews results of some studies of these drugs. Studies included in the article are of SM-5887, MX-2, DWA2114R, and CPT-11.
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8040140
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Pharmacologically based phase I trials in cancer chemotherapy.
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Recent developments in Phase I trial methodology are reviewed. Preclinical pharmacological studies can be used in Phase I trials to improve patient selection, starting dose identification, and dose escalation. Establishing pharmacokinetic-pharmacodynamic relationships is also an important new aspect of Phase I trial methodology; these relationships can be exploited in subsequent efficacy studies. Finally, the inclusion of molecular pharmacodynamic studies in Phase I trials is increasing with a view to identifying the mechanism of action of a new agent in patients.
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8040124
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A controlled trial of the tolerance of amphotericin B infused in dextrose or in Intralipid in patients with haematological malignancies.
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Patients with haematological malignancies requiring an antifungal therapy were randomly assigned to receive amphotericin B diluted in either 5% dextrose or in fat emulsion (Intralipid). Twenty-one patients were included in each group. Mean duration of amphotericin B therapy was 8.4 days in the dextrose group and 12.8 days in the Intralipid group. Amphotericin B infusion induced chills in 16 of 21 patients in the dextrose group and in 5 of 21 in the Intralipid group (P = 0.0008). Serum creatinine increased > 75% from baseline in ten patients in the dextrose group compared with only two in the Intralipid group (P = 0.007). A > or = 50% decrease of creatinine clearance was observed in 14 of 21 patients in the dextrose group compared with seven of 21 patients in the Intralipid group (P = 0.025). No difference was found between the two groups with regard to potassium and sodium requirement. Among patients who did not receive magnesium before antifungal therapy, magnesium supplementation was required more frequently in the dextrose group (8/12 vs 2/11; P = 0.02). Concomitant amikacin dosage reduction was more frequent in the dextrose group due to nephrotoxicity (7/19 vs 2/20; P = 0.045). A similar difference in vancomycin dosage reduction was observed between the two groups (12/20 vs 5/19; P = 0.03).
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8040123
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Mucosal concentration and excretion of clindamycin by the human stomach.
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Each of 12 patients undergoing routine diagnostic upper gastrointestinal endoscopy received a single iv infusion of clindamycin phosphate 300 mg over 10 min. During the endoscopy, mucosal biopsies of the gastric antrum and fundus were obtained at varying times following the infusion. The clindamycin concentrations in the biopsies and in serum samples also taken after the infusion were determined. In addition, six healthy volunteers participated in a cross-over study on two different days. On both days, each subject received a single iv infusion of clindamycin phosphate 300 mg, immediately after which, gastric secretion was stimulated by iv pentagastrin (2 micrograms/kg/h) which was infused continuously over 150 min. On one of the study days, acid secretion by the stomach was inhibited by a slow iv infusion of ranitidine 50 mg. Clindamycin concentrations in gastric aspirates and serum samples collected after the infusion were determined. Concentrations of clindamycin in the fundal mucosa were significantly higher than the simultaneous serum concentrations (median ratio of tissue concentration to serum concentration, 2.0; P < 0.005) while concentrations in the antral mucosa were similar to those in serum (median ratio, 1.2; P = 0.65). Ranitidine significantly inhibited pentagastrin-stimulated acid secretion as demonstrated by a decrease in the volume of gastric aspirate when ranitidine was administered compared with when it was not administered (P < 0.01). Clindamycin concentrations in gastric juice were approximately one and one-half times higher than those in serum samples obtained simultaneously, both during stimulation of gastric acid secretion with pentagastrin and during inhibition of pentagastrin-stimulated acid secretion with ranitidine. Gastric juice concentrations of clindamycin were significantly higher following administration of ranitidine than after stimulation of gastric secretion by pentagastrin alone. Fundal mucosal and gastric juice concentrations of clindamycin exceeded the hypothetical maximum serum concentrations, indicating that accumulation in the stomach occurred against a concentration gradient.
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8040122
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Paradoxical dose effect of continuously administered cloxacillin in treatment of tolerant Staphylococcus aureus endocarditis in rats.
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The efficacies of different doses of cloxacillin administered by continuous infusion were compared in the treatment of endocarditis in rats caused by a beta-lactam tolerant strain of Staphylococcus aureus and its non-tolerant variant. In-vitro killing of the tolerant strain was maximal at a concentration near the MIC, while at higher concentrations the rate of killing gradually decreased, a paradoxical effect, not found for the non-tolerant strain. During treatment of endocarditis caused by a tolerant strain, the reduction of bacterial numbers in the infected vegetations decreased significantly with increasing doses of cloxacillin. Thus for the tolerant strain a paradoxical dose effect was also apparent in vivo. For the non-tolerant strain this paradoxical effect was not found. Furthermore, continuous administration of cloxacillin was significantly less effective in reducing bacterial numbers in the vegetations for the tolerant strain than for the non-tolerant strain. The results of this study suggest that the phenomenon of tolerance, demonstrated in vitro, may have a significant influence on the outcome of treatment of S. aureus endocarditis with continuously administered cloxacillin, particularly when high doses of antibiotic are used.
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8040121
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Effect of elimination of phagocytic cells by liposomal dichloromethylene diphosphonate on aspergillosis virulence and toxicity of liposomal amphotericin B in mice.
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The role of macrophages in the toxicity and efficacy of liposomal amphotericin B (L-Amp B) was studied in a murine aspergillosis model infection. Macrophages and polymorphonuclear phagocytes (PMN cells) were depleted in the liver and spleen of mice by the administration of liposome encapsulated dichloromethylene diphosphonate. Macrophage depletion had no effect on the lethality of Fungizone, a commercial deoxycholate preparation of Amp B, but significantly increased the lethality of L-Amp B (P < 0.01). Macrophage depletion led to an increase in the fungal loads in the lung, liver and kidney (P < 0.05) and to an increase in the virulence of aspergillosis (P < 0.05). Tissue distribution analysis of L-Amp B revealed that in macrophage/PMN-depleted mice there was a decrease in the concentration of Amp B in the liver, with concomitant increases in the circulation, spleen and lung, both in the uninfected and in the infected conditions. The results clearly demonstrate that depletion of macrophage/PMN cells increases the virulence of aspergillosis, as well as the toxicity of L-Amp B. Moreover, L-Amp B treatment does not improve the survival rate of macrophage/PMN-depleted mice subjected to aspergillosis challenge.
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8040120
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Conditions for the emergence of resistance to cefpirome and ceftazidime in experimental endocarditis due to Pseudomonas aeruginosa.
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The conditions for the emergence of resistance to cefpirome and ceftazidime were studied in rabbits with experimental aortic endocarditis due to Pseudomonas aeruginosa. The MIC of cefpirome was 16 mg/L and that of ceftazidime was 4 mg/L. Resistant mutants with MICs of > or = 64 mg/L were obtained in vitro to cefpirome after a single passage and to ceftazidime after five passages. A single dose of 50 mg/kg intramuscularly gave mean peak serum concentrations of 110.0 +/- 31.7 mg/L for cefpirome compared with 67.7 +/- 21.4 mg/L for ceftazidime and the half-lives were 1.2 +/- 0.1 h and 2.1 +/- 0.4 h, respectively. After treating infected rabbits for 4 days with various dosing regimens, resistant strains were only detected in those animals in which the time that the serum concentration exceeded the MIC was less than half of the dosing interval. There was no evidence of emergent resistance when the serum concentrations exceeded the MIC for a longer period nor when amikican was combined with the cephalosporins on the first day of therapy. Moreover, once differences in MICs and pharmacokinetics were taken into account, both antibiotics had a similar propensity to induce resistance.
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8040119
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vanA-mediated vancomycin-resistant Enterococcus spp. in sewage.
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Three high-level vancomycin-resistant Enterococcus strains (two Enterococcus faecium and one Enterococcus durans) were recovered from three of eight sewage samples taken from the general sewage collector at Logroño (Northern Spain). The strains were present in the sewage samples at estimated concentrations of ten resistant bacteria/mL, corresponding to about 0.4% of the enterococcal population. The VanA protein was detected in each strain by immunoblotting of membrane extracts of the vancomycin-induced cells, and the vanA gene was demonstrated in the wild strains and their transconjugants by DNA-DNA hybridization. This is the first, confirmed report of vanA mediated vancomycin resistance in E. durans.
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8040118
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Efficacy of combinations of doxycycline and rifampicin in the therapy of experimental mouse brucellosis.
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Mice infected with Brucella melitensis were treated with doxycycline and rifampicin in daily dosages of: 1.5, 3 and 6 mg/kg separately and in combination, for a period of 14 days. Doxycycline alone in all dosages did not result in a cure rate superior to controls. A significant reduction in the viable count of B. melitensis recovered from the spleens of mice (which was the criterion for cure) was achieved with 6 and 3 mg/kg/day of doxycycline. Rifampicin at a dose of 6 mg/kg/day gave significantly better cure rates and reduction of mean viable counts of B. melitensis than untreated controls or doxycycline in similar doses. Low dose therapy with rifampicin (1.5 and 3 mg/kg) resulted in a further reduction in viable counts from spleens but with a cure rate no better than untreated animals. Rifampicin was more potent than doxycycline in all low dose regimens. When rifampicin was given in combination with doxycycline, the effect observed was similar to that of rifampicin alone. No synergy between rifampicin and doxycycline was demonstrable in the mouse model of brucellosis.
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8040117
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The activity of 2-substituted quinoline alkaloids in BALB/c mice infected with Leishmania donovani.
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Potent antileishmanial activity has recently been described in vivo when certain 2-substituted quinoline alkaloids are administered to mice with cutaneous leishmaniasis. We now report the antileishmanial activity of four 2-substituted quinoline alkaloids, namely chimanine D or 2-(1',2'-trans-epoxypropyl) quinoline (I), 2-n-propylquinoline (II), 2-styrylquinoline (III) and 2-(2'-hydroxypropyl) quinoline (IV), for experimental treatment of visceral leishmaniasis in infected BALB/c mice. Subcutaneous treatment with chimanine D for 10 days at 0.54 mmol/kg per day resulted in 86.6% parasite suppression in the liver. Oral administration of 0.54 mmol/kg of 2-n-propylquinoline once daily for 5 or 10 days to L. donovani-infected mice suppressed parasite burdens in liver by 87.8 and 99.9%, respectively. Cutaneous administration of meglumine antimonate for 10 days resulted in 97.4% parasite suppression in the liver. This study is, to our knowledge, the first to demonstrate the activity of 2-substituted quinoline alkaloids in experimental treatment of visceral leishmaniasis. Further biological and chemical studies of these products might yet prove helpful for the development of new antileishmanial drugs.
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8040116
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Investigation of dirithromycin and erythromycylamine uptake by human neutrophils in vitro.
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Dirithromycin, a new semisynthetic 14-membered-ring macrolide was avidly concentrated by human neutrophils in a time- but not concentration-dependent manner with mean cellular/extracellular, concentration ratios (C/E) of 9 within the first 5 min and up to 47 at 120 min. Erythromycylamine, the hydrolysis product of dirithromycin, was concentrated significantly less by neutrophils, reaching C/E values of 4 and 19 (at 5 and 120 min). A point of interest was the interindividual variability in the antibiotic uptake kinetics; in particular, 7 out of 47 neutrophil samples from different healthy volunteers displayed very slow uptake of both drugs (C/E values at 30 min: dirithromycin, 5.8; erythromycylamine, 4.6). The reason(s) for this is unknown. The uptake of both drugs was decreased at acidic pH and increased at basic pH. Chloroquine, an antimalarial drug which is concentrated in and alkalinizes azurophilic granules, reduced uptake by half. Metabolic inhibitors (2-4 dinitrophenol, sodium fluoride, potassium cyanide and sodium azide) did not impair the uptake of either drug but, interestingly, ouabain, an inhibitor of membrane Na+/K+ ATPase activity, impaired uptake by about 30%. Competitive inhibitors of some transport systems identified on neutrophil membrane (nucleosides, D-glucose and various aminoacids) did not alter the uptake of either drug. Dirithromycin and to a lesser extent, erythromycylamine, reached intracellular concentrations much higher than those required to inhibit the growth of sensitive microorganisms. Although the mechanism of uptake is not clear, one interesting hypothesis involves trapping by protonation into acidic compartments of neutrophils.
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8040115
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The uptake of ampicillin-loaded nanoparticles by murine macrophages infected with Salmonella typhimurium.
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The purpose of this study was to investigate the in-vitro interaction between [3H]ampicillin-loaded polyisohexylcyanoacrylate nanoparticles and murine macrophages (peritoneal and J774) infected with Salmonella typhimurium. The multiplicity of infection was ten bacteria to each macrophage and the mean (+/- S.D.) diameter of the nanoparticles was 220 (+/- 20 nm), corresponding to an ampicillin concentration of 2 g/L. The uptake of nanoparticle-bound [3H]ampicillin by non-infected J774 and peritoneal macrophages was six- and 24-fold greater respectively than that of free [3H]ampicillin. For infected cells, uptake by J774 and peritoneal macrophages was nine- and 20-fold greater respectively. However, there was no difference between nanoparticle-bound ampicillin and free ampicillin in terms of bactericidal activity against intracellular S. typhimurium. This unexpected observation might be accounted for by bacterium-induced inhibition of phagosome-lyosome fusion within the macrophages, thereby preventing contact between the bacteria in the phagosomes and the nanoparticles in the secondary lysosomes.
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8040114
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In-vitro evaluation of cefpodoxime.
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In-vitro antimicrobial activity of cefpodoxime was evaluated against several microbial species by both conventional tests and additional parameters which take into consideration some of the conditions likely to be encountered in infected tissues. MICs for 414 recent clinical isolates, including staphylococci, streptococci, Haemophilus influenzae, Moraxella catarrhalis, several Enterobacteriaceae, Aeromonas hydrophila and Campylobacter jejuni were determined. MIC values overall were similar to those observed for strains from other geographical areas. Inhibition of growth by cefpodoxime was virtually unaffected by the inoculum size, even using bacterial populations as large as 10(9) cfu of Staphylococcus aureus, Streptococcus pyogenes, Streptococcus pneumoniae, H. influenzae, beta-lactamase-negative M. catarrhalis, Escherichia coli, Klebsiella pneumoniae and Proteus mirabilis. Growth in the presence of human serum as the only source of nutrients did not significantly affect the inhibition exerted by cefpodoxime, even against large bacterial populations of S. aureus, S. pneumoniae, E. coli, and K. pneumoniae. For K. pneumoniae, E. coli, P. mirabilis and beta-lactamase-negative M. catarrhalis it was also found that sub-MIC concentrations of cefpodoxime were still able to inhibit the majority of cells in microbial populations as large as 10(9) cfu. Evaluation of bactericidal activity demonstrated that cefpodoxime concentrations comparable to those achievable in plasma or in the respiratory tract were able to kill rapidly large bacterial populations of S. pneumoniae and S. pyogenes. The bactericidal activity was apparently lower against M. catarrhalis, H. influenzae, S. aureus, E. coli, and K. pneumoniae.
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8040113
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Effects of different test conditions on the susceptibility of Mycobacterium fortuitum and Mycobacterium chelonae to amikacin.
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Eighteen rapidly growing mycobacteria were tested for susceptibility to amikacin by six different antibiotic susceptibility procedures to assess method variability and factor variation within a single method. Using amikacin MICs determined by the microdilution method as the reference standard, results for Mycobacterium chelonae were on average eight-fold higher by the macrodilution method and two-fold higher by the BACTEC, 1% standard proportion, and agar dilution methods. For Mycobacterium fortuitum, macrodilution MICs were on average four-fold higher than microdilution results; however, for this species, agar dilution, the 1% standard proportion method, and the BACTEC method showed good correlation with microdilution testing. The use of different test media and incubation in increased CO2 tension increased amikacin MICs for Mycobacterium chelonae. An inoculum effect was observed with both species, especially when the organism concentration increased from 10(5) cfu/mL to 10(6) cfu/mL for broth testing and 10(5) to 10(6) cfu per spot for agar dilution. These results indicate that different antibiotic susceptibility methods and test conditions markedly influence MICs of amikacin for these rapidly growing mycobacteria.
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8040112
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beta-Lactamase types amongst Staphylococcus aureus isolates in relation to susceptibility to beta-lactamase inhibitor combinations.
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Relationships between beta-lactamase type and antimicrobial susceptibility were investigated for Staphylococcus aureus isolates collected recently at UK and Irish hospitals, and for reference producers of types A, B, C and D enzymes. Producers of types A and C beta-lactamases predominated amongst the isolates. Tazobactam and clavulanate combinations were studied, as previous observation showed that these inhibitors incompletely reversed the in-vitro amoxycillin and piperacillin resistance of beta-lactamase-positive staphylococci. Further penicillins and cephalosporins served as controls. Organisms with type C beta-lactamase were less susceptible than those with type A enzyme to piperacillin/tazobactam and amoxycillin/tazobactam in disc and MIC tests, and to co-amoxiclav in disc tests only. Conversely, producers of type A enzyme were less susceptible to cephazolin than those with type C enzyme. Kinetic assays showed that type A enzymes bound piperacillin and amoxycillin less tightly than did type C enzyme (higher Kmapp), and were more susceptible to inhibition by clavulanate and tazobactam (lower I50s). However, the susceptibility to beta-lactamase inhibitor combinations for the few producers of types B and D enzymes tested could not be similarly explained by Kmapp and I50 data. It therefore seems that other factors besides beta-lactamase affinity co-determine the susceptibility of the staphylococci. Possible variables include the exact chemistry of the enzyme-inhibitor interaction, and the degree of beta-lactamase induction. Both tazobactam and clavulanate induced staphylococcal types A and C penicillinases.
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8040111
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Comparative in-vitro activity of biapenem against enterobacteria with beta-lactamase-mediated antibiotic resistance.
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The effects of enterobacterial beta-lactamases were studied for biapenem (L627), a new carbapenem. Susceptibility tests were performed for isogenic mutant series of Citrobacter freundii, Enterobacter cloacae, Morganella morganii, Serratia marcescens and Proteus vulgaris which varied only in chromosomal beta-lactamase expression. beta-Lactamase-derepressed organisms in these series were as susceptible as beta-lactamase-inducible strains to biapenem; beta-lactamase-basal mutants were up to eight-fold more susceptible. Similar patterns of relative activity against the different expression types were noted for imipenem and biapenem. These data were related to direct induction and hydrolysis assays: biapenem, like imipenem, was a strong inducer of several Class I enzymes and of the P. vulgaris cefuroximase and, like the other carbapenems, was only very slowly hydrolysed by these enzymes. Moreover, like meropenem, biapenem reversibly deactivated these beta-lactamases. Piperacillin and the cephalosporins, tested as comparators, were more labile than carbapenems to the Class I enzymes, were weak inducers below their MICs and lacked deactivator function. In consequence their MICs were higher for derepressed organisms than for those with inducible or basal beta-lactamase expression. Unlike the carbapenems, they selected derepressed mutants from inducible populations. Biapenem, like imipenem and meropenem, retained full activity against most transconjugants of Escherichia coli K-12 that produced plasmid-mediated beta-lactamases, including extended-spectrum TEM mutants. Only production of OXA-10 (previously PSE-2) enzyme gave a slight reduction in susceptibility to the new carbapenem. Biapenem resistance (MIC 16 mg/L) did, however, occur in S. marcescens S6, which produced a chromosomal carbapenemase. This enzyme hydrolysed biapenem. Overall, our findings indicate that biapenem shares the favourable properties of imipenem and meropenem in its interactions with the most important beta-lactamases of enterobacteria.
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8040110
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Effect of antibiotics on non-growing planktonic cells and biofilms of Escherichia coli.
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Several classes of antibiotics were assessed for activity against non-growing Escherichia coli and cells grown as a biofilm. Antibiotics which had activity against non-growing cells also showed some activity against biofilms. Cephamycins were more active than other cephalosporins, but the most effective antibiotics were imipenem and ciprofloxacin, which were also active against steady state biofilms. However, none of the antibiotics studied was capable of completely eradicating a biofilm. These results suggest that growth rate plays a role in mediating resistance of biofilms to antibiotics.
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8040109
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Binding of teicoplanin and vancomycin to polymer surfaces.
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Both teicoplanin and vancomycin were found to bind to a range of polymer surfaces. The binding of teicoplanin to specimen vessel surfaces was, on average, four times greater than that of vancomycin and was particularly marked with silconized polymers (5.2 micrograms/cm2). Pre-exposure of a polymer surface to human body fluids caused a 60% reduction in teicoplanin binding. Reduction of the negative surface charge on a polymer surface with ferric nitrate resulted in a ten-fold increase in teicoplanin binding. The accumulation of a strain of Staphylococcus epidermidis on silicone rubber catheter segments pre-exposed to glycopeptide antibiotics was examined. In phosphate buffered saline binding of bacteria to vancomycin-treated polymer was greater than to an unexposed control surface. In contrast, in human serum both antibiotics caused reductions in adherent growth. The binding of glycopeptide antibiotics, in particular teicoplanin, to polymer surfaces may interfere with the results of in-vitro assays. However, this phenomenon may be useful in the prevention of bacterial accumulation on the surfaces of medical devices.
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8040108
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Characterization of the genetic basis of antibiotic resistance in Clostridium difficile.
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By using dot blot hybridization, 69 of 102 Clostridium difficile isolates (68%) from the United States and other countries hybridized with at least one of nine DNA probes for erythromycin (Erm), tetracycline (Tet) or chloramphenicol (Cat) resistance determinants. The distribution of individual determinants in descending order of frequency was: Tet M, 32%; Erm Q, 25%; Erm FS, 18%; Tet P, 15%; Tet K, 15%; Cat P, 15%; Cat Q, 12%; Erm BP, 11%; Tet L, 7%. This is the first report of Tet P being carried by C. difficile and hitherto Erm FS has only been found within the genus Bacteriodes, while neither Tet K nor Tet L have been previously identified among the genus Clostridia. Eighteen percent of the hybridizing isolates carried multiple determinants coding for the same phenotype. A higher frequency of resistance genes was associated with prior exposure to antimicrobial agents, cytotoxin production and diarrhoea. Isolates recovered from bone marrow transplant patients carried significantly fewer antibiotic resistance genes than did those from immunocompetent general medicine patients. However, this may be due to the fact that each was located at a different site. Antibiotic resistance determinants may play a role in the virulence associated with C. difficile.
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8040107
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The fluoroquinolones as treatment for infections caused by gram-positive bacteria.
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The fluoroquinolones have become attractive options as treatment for a broad range of infections caused by Gram-negative bacteria. However, the value of these antibiotics to patients with infections caused by Gram-positive pathogens remains controversial. Experience with quinolones as therapy for skin and skin structure infections, osteomyelitis and peritonitis in patients receiving continuous ambulatory peritoneal dialysis suggests that the concerns which have been expressed about the use of these agents against methicillin-resistant Staphylococcus aureus (MRSA), Staphylococcus epidermidis and streptococci are justified; indeed, the frequent emergence of quinolone-resistant strains of MRSA and coagulase-negative staphylococci either during or following treatment is now well documented. The fluoroquinolones should be prescribed with caution to patients with community-acquired pneumonia or whenever severe infection of pneumococcal aetiology is proven or suspected. As prophylaxis for the granulocytopenic patient, quinolones such as norfloxacin and ciprofloxacin have been shown to be effective in reducing the incidence of morbidity attributable to Gram-negative bacteria, but they have not significantly affected the incidence of infection caused by Gram-positive bacteria. In the treatment of febrile episodes in the neutropenic patient, ciprofloxacin, the quinolone investigated most extensively in this clinical setting, produced high cure rates only when it was combined with an antibiotic which was predictably active against Gram-positive organisms. We review here the role of currently-available fluoroquinolones (norfloxacin, enoxacin, pefloxacin, ofloxacin and ciprofloxacin) as treatment for these and other infections.
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8040106
|
Hepatic side-effects of antibiotics.
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Although the liver is particularly exposed to drugs and their metabolites, hepatic side-effects of antibiotics are far less frequent than other adverse effects such as gastrointestinal disorders or cutaneous reactions. However, the potential severity of hepatic side-effects for some drugs is stressed. Antibiotic related liver injuries cover most of the clinical and pathological expressions of hepatic dysfunction, including cytotoxic hepatitis (isoniazid), intrahepatic cholestasis (macrolides, penicillins, clavulanic acid), mixed hepatitis (sulphonamides), chronic active hepatitis (nitrofurantoin), or microvesicular steatosis (tetracycline). In most cases, toxicity is idiosyncratic, reactions occurring only in some susceptible individuals. The mechanisms underlying toxicity may be primarily metabolite-dependent (isoniazid), hypersensitivity-mediated (beta-lactams), or result from both processes (sulphonamides, erythromycin derivatives). In some cases, the liver is not the primary target organ for toxicity but appears to mediate the clinical expression of some adverse effects induced by antibiotics. The most significant example of this is hypoprothrombinaemia due to the inhibition of hepatic gamma-carboxylation of vitamin K-dependent clotting factors by sulphydryl group-containing cephalosporins. Inhibition of bilirubin conjugation or transport by rifampicin or fusidic acid may also be viewed as hepatic side-effects of antibiotics. Ascertaining the casual relationship of a given drug to an hepatic adverse effect may prove particularly difficult, because of the potential contribution of host status and concurrent medications. Diagnosis is based mainly on circumstantial evidence, i.e. the temporal relationship between drug administration (or withdrawal) and the time-course of liver dysfunction. Improving morbidity related to drug hepatotoxicity relies on a free flow of information between manufacturers and practitioners in order to optimize detection of potentially serious liver damage, and advances in pharmacogenetics toward a better identification of those at particular risk for developing drug-related liver toxicity.
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8040103
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Binaural processing after corrected congenital unilateral conductive hearing loss.
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Binaural processing was measured in a series of tests in patients before and after surgery to correct congenital unilateral conductive hearing losses. Data are presented from 19 patients between the ages of 6 and 33 years that had an abnormal external and/or middle ear on one side but normal hearing in the other ear. Surgery improved thresholds an average of 36 dB HL (from 56 to 20 dB HL). Patients were tested pre- and postoperatively for interaural temporal difference limens, alternate and simultaneous loudness balances, sound localization, binaural detection thresholds, and speech perception in noise. There was statistically significant improvement after surgery in all tests, and the amount of improvement varied along a continuum that appears to be related to the simplicity of the task. For example, most postoperative patients had normal or near-normal performance in a test of interaural temporal difference limens, while almost all had difficulty localizing sounds. Neither binaural performance (before or after surgery) nor the improvement in performance was correlated with age, pure-tone thresholds, or asymmetry. Limited available data show no significant changes in performance from four weeks to over 24 weeks after surgery. In conclusion, binaural ability following corrective surgery exists in varying degrees in these tasks, suggesting different effects of abnormal early experience on different aspects of binaural hearing.
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8040102
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Effects of endolymphatic and perilymphatic application of salicylate in the pigeon. II: Fine structure of auditory hair cells.
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Large doses of salicylate are known to cause reversible ototoxic effects including fine structural alterations of the auditory hair cells in mammals. To investigate possible fine structural correlates of salicylate effects on pigeon auditory hair cells, the basilar papillae following perilymphatic or endolymphatic application of salicylate were fixed and processed for transmission electron microscopy. The pigeon auditory hair cells possessed organelles typically described in avians. A single or multi-layered array of cisternae along the cytoplasmic side of the lateral plasma membrane, i.e. subsurface cisternae that are characteristic for mammalian outer hair cells, was not seen. The most prominent fine structural alterations of hair cells after salicylate application were an increase in the luminal width of smooth and rough endoplasmic reticulum as well as the frequent occurrence of prominent single-membrane-bound vesicles filled with electron-dense bodies. Based on the assumption that subsurface cisternae represent a specialized form of endoplasmic reticulum, the present findings indicate that the structural correlates of salicylate toxicity are similar in mammalian and avian auditory hair cells.
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