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Biomedical subjects

M Harris

Publications and source records attributed to M Harris.

At least 145 records · Page 8Linked to original sources
PubMed1999

Are there low-penetrance TP53 Alleles? evidence from childhood adrenocortical tumors.

We have analyzed a panel of 14 cases of childhood adrenocortical tumors unselected for family history and have identified germline TP53 mutations in >80%, making this the highest known incidence of a germline mutation in a tumor-suppressor gene in any cancer. The spectrum of germline TP53 mutations detected is remarkably limited. Analysis of tumor tissue for loss of constitutional heterozygosity, with respect to the germline mutant allele and the occurrence of other somatic TP53 mutations, indicates complex sequences of genetic events in a number of tumors. None of the families had cancer histories that conformed to the criteria for Li-Fraumeni syndrome, but, in some families, we were able to demonstrate that the mutation had been inherited. In these families there were gene carriers unaffected in their 40s and 50s, and there were others with relatively late-onset cancers. These data provide evidence that certain TP53 alleles confer relatively low penetrance for predisposition to the development of cancer, and they imply that deleterious TP53 mutations may be more frequent in the population than has been estimated previously. Our findings have considerable implications for the clinical management of children with andrenocortical tumors and their parents, in terms of both genetic testing and the early detection and treatment of tumors.

Adaptor Proteins, Signal Transducing↗
PubMed1999

Doctors, nurses, and parents are equally poor at estimating pediatric weights.

OBJECTIVE: To evaluate the relative accuracy of physicians, nurses, and parents in estimating the weight of children presenting to the emergency department. METHODS: One hundred pediatric patients between the ages of 0 and 8 years presenting to an urban teaching emergency department (40,000 patients per year) were enrolled over a 1-month period (September 1996). The parents, triage nurse, and examining physician were asked to estimate the patient's weight, each blinded to the others' estimates and the child's actual weight. RESULTS: Parents, nurses, and physicians all slightly underestimated patient weights (P < 0 .05), but these groups did not differ among themselves (P > 0 .05). The total range of estimates was broad in each group (parents +292% to -41%, nurses +30% to -36%, and physicians +43% to -56%). There was no significant relationship between estimates with regard to age, weight, or sex. Twenty-nine percent of physicians' estimates, 40% of nurses' estimates, and 16% of parents' estimates differed from the actual weight by more than 15%. CONCLUSION: Emergency department pediatric weight estimates by parents, nurses, and physicians are significantly and similarly unreliable.

Anthropometry↗
PubMed1999

Mechanisms of internalization of Staphylococcus aureus by cultured human osteoblasts.

Staphylococcus aureus is an important bone pathogen, and evidence shows that this organism is internalized by chick osteoblasts. Here we report that S. aureus is internalized by human osteoblasts. Internalization was inhibited by monodansylcadaverine and cytochalasin D and to a lesser extent by ouabain, monensin, colchicine, and nocodazole. We propose that internalization occurs via a receptor-mediated pathway, requiring the participation of cytoskeletal elements, principally actin.

Actins↗
PubMed1999

Modified nasopharyngeal tube for upper airway obstruction.

A modified nasopharyngeal tube is described that does not add airway dead space and resistance, is well tolerated, highly successful, and allows simultaneous use of oxygen prongs. This potentially reduces the need for surgical intervention to relieve high upper airway obstruction from Pierre-Robin syndrome and other causes.

Airway Obstruction↗
PubMed1999

Temperature conditioning of nasal air: effects of vasoactive agents and involvement of nitric oxide.

Nitric oxide (NO) is released into nasal air, but its function is unknown. We hypothesized that nasal vascular tone and/or flow influences temperature conditioning of nasal air and that NO participates in this process. We measured nasal air temperature (via a thermocouple) and exhaled nasal NO release (by chemiluminescence) in five humans and examined the effects of an aerosolized vasoconstrictor (oxymetazoline), a vasodilator (papaverine), N(G)-nitro-L-arginine methyl ester, an inhibitor of NO synthase, or saline (control). Compared with saline (which caused no changes in nasal air temperature or exhaled NO release), oxymetazoline (0.05%) reduced nasal air temperature and NO release (130.8 +/- 15.1 to 81.3 +/- 12.8 nl. min(-1). m(-2); P < 0.01). Papaverine (0.01 M) increased nasal air temperature and NO release (131.8 +/- 13.1 to 157.2 +/- 17.4 nl. min(-1). m(-2); P < 0.03). N(G)-nitro-L-arginine methyl ester reduced nasal air temperature and NO release (123.7 +/- 14.2 to 44.2 +/- 23.7 nl. min(-1). m(-2); P < 0.01). The results suggest that vascular tone and/or flow modulates temperature conditioning and that NO may participate in that function.

Adrenergic alpha-Agonists↗
PubMed1999

Systemic lupus erythematosus complicated by necrotizing fasciitis.

A case of necrotizing fasciitis (NF) is described in a 46-year-old woman with recent onset systemic lupus erythematosus (SLE). Deep-tissue infections are more common in SLE patients on high-dose corticosteroids, but, to our knowledge, this is the second case described in association with SLE. Although NF may initially be difficult to diagnose, the presence of marked systemic symptoms out of proportion to the local findings should suggest the correct diagnosis. NF diagnostic criteria, treatment and prognosis are discussed.

Fasciitis, Necrotizing↗
PubMed1999

Clinical presentation, course, and prognostic factors in lymphocyte-predominant Hodgkin's disease and lymphocyte-rich classical Hodgkin's disease: report from the European Task Force on Lymphoma Project on Lymphocyte-Predominant Hodgkin's Disease.

PURPOSE: Recent studies have suggested that lymphocyte-predominant Hodgkin's disease (LPHD) is both clinically and pathologically distinct from other forms of Hodgkin's disease, including classical Hodgkin's disease (CHD). However, large-scale clinical studies were lacking. This multicenter, retrospective study investigated the clinical characteristics and course of LPHD patients and lymphocyte-rich classical Hodgkin's disease (LRCHD) patients classified according to morphologic and immunophenotypic criteria. MATERIALS AND METHODS: Clinical data and biopsy material of all available cases initially submitted as LPHD were collected from 17 European and American centers, stained, and reclassified by expert pathologists. RESULTS: The 426 assessable cases were reclassified as LPHD (51%), LRCHD (27%), CHD (5%), non-Hodgkin's lymphoma (3%), and reactive lesion (3%); 11% of cases were not assessable. Patients with LPHD and LRCHD were predominantly male, with early-stage disease and few risk factors. Patients with LRCHD were significantly older. Survival and failure-free survival rates with adequate therapy were similar for patients with LPHD and LRCHD, and were stage-dependent and not significantly better than stage-comparable results for CHD (German trial data). Twenty-seven percent of relapsing LPHD patients had multiple relapses, which is significantly more than the 5% of relapsing LRCHD patients who had multiple relapses. Lymphocyte-predominant Hodgkin's disease patients had significantly superior survival after relapse compared with LRCHD or CHD patients; however, this was partly due to the younger average age of LPHD patients. CONCLUSION: The two subgroups of LPHD and LRCHD bore a close clinical resemblance that was distinct from CHD; the course was similar to that of comparable nodular sclerosis and mixed cellularity patients. Thorough staging is necessary to detect advanced disease in LPHD and LRCHD patients. The question of how to treat such patients, either by reducing treatment intensity or following a "watch and wait" approach, remains unanswered.

Adult↗
PubMed1999

Validation of computer-assisted manufacture of titanium plates for cranioplasty.

We have constructed 300 titanium cranioplasty plates, over 150 cases using a computerised technique, the remainder by external impression. The clinical follow-up of these cases over 8 years has shown consistently good results that justify our simple low-cost method of manufacturing these plates. Both techniques require the provision of a model on which to construct the plate. In the traditional technique, an approximate model is derived from the resected bone or a direct impression of the defect over the patient's scalp. Using the computerised technique, a more accurate model of the defect and the surrounding bone is milled in polyurethane foam from cross-sectional computerised tomographic (CT) scans. Sheet titanium is pressed to shape from a design outlined on a counterdie. The subsequent stages of the plate construction are then the same for both methods. This study describes the stages of the model manufacture, the validation of its accuracy and the plate construction that follows. Use of the computerised method has resulted in a reduction of errors, enabling the manufacture of a smaller plate than was possible previously. It has also enabled design changes through the achievement of greater accuracy in fit.

Bone Plates↗
PubMed1998

The ligamento-muscular stabilizing system of the spine.

STUDY DESIGN: Electrical and mechanical stimulation of the lumbar supraspinous ligament of three patients with L4-L5 spinal deficits and of the feline model, respectively, was applied while recording electromyography on the multifidus muscles. OBJECTIVES: To determine if mechanoreceptors in the human spine can reflexively recruit muscle force to stabilize the lumbar spine, and to demonstrate, in the feline model, that such ligamento-muscular synergy is elicited by mechanical deformation of the lumbar supraspinous ligament (and possibly of other spinal ligaments), the facet joint capsule, and the disc. SUMMARY OF BACKGROUND DATA: The literature repeatedly confirms that ligaments have only a minor mechanical role in maintaining spine stability, and that muscular co-contraction of anterior and posterior muscles is the major stabilizing mechanism of the spine. The literature also points out that various sensory receptors are present in spinal ligaments, and that the ligaments are innervated by spinal and autonomic nerves. Data that describe how ligaments and muscles interact to provide stability to the spine were not found. METHODS: The supraspinous ligament at L2-L3 and L3-L4 was electrically stimulated in three patients undergoing surgery to correct deficits at L4-L5. Electromyography was performed from the multifidus muscles at L2-L3 and L3-L4, bilaterally. In 12 cats, the supraspinous ligaments from L1-L2 to L6-L7 were mechanically deformed, sequentially, while electromyography was performed from the multifidus muscles of the six levels. Loading of the ligament was applied before and after each of the two vertebrae were externally fixed to prevent motion. RESULTS: Electromyograms were recorded from the multifidus muscles, bilaterally, in the two of the three patients, demonstrating a direct relationship to receptors in the supraspinous ligament. Electromyograms were recorded from the feline multifidus muscle with mechanical loading of the supraspinal ligament at each of the L1-L2 to L6-L7 motion segments. In the free-spine condition the largest electromyographic discharge was present in the level of ligament deformation, and lower electromyographic discharge was recorded in two rostral and caudal segments. After immobilizing any two vertebrae, loading of the ligament resulted in electromyographic discharge in the muscles of the same level and at least one level above and/or below. CONCLUSIONS: Deformation or stress in the supraspinous ligament, and possibly in other spinal ligaments, recruits multifidus muscle force to stiffen one to three lumbar motion segments and prevent instability. Strong muscular activity is seen when loads that can cause permanent damage to the ligament are applied, indicating that spastic muscle activity and possibly pain can be caused by ligament overloading.

Animals↗
PubMed1998

Estimates of the virological benefit of antiretroviral therapy are both assay- and analysis-dependent.

OBJECTIVE: To assess the potential discrepancies in reported changes in plasma viral load (PVL) depending on how values below the detection limit of the assay are handled in the data analysis phase of a randomized controlled clinical trial. DESIGN: Data from a recently completed clinical trial comparing combinations of zidovudine, didanosine and nevirapine were analysed. In this trial, PVL was measured using an assay with a lower quantification limit of 400 HIV-1 RNA copies/ml initially. All PVL values less than 500 copies/ml were retested with a more sensitive assay with a lower quantification limit of 20 copies/ml. METHODS: Several summary measures for assessing change in PVL were calculated using three different methods to adjust for PVL values less than the quantification limit of the assay. The differences between these measures were evaluated. RESULTS: We found that the magnitude of the discrepancy between summary measures used to report changes in PVL depended on the proportion of subjects with PVL less than the quantification limit of the assay, how those observations were handled in the data analysis, and the relative difference between the quantification limits of the conventional and more sensitive assay. CONCLUSION: The lack of consensus in reporting of PVL data in the literature makes the interpretation of published trial results difficult. In the absence of agreement on the most appropriate summary measure of PVL data, we recommend that all summaries include information on the quantification limit of the assay used, the proportion of observations at or below the quantification limit and how these observations were handled in the data analysis.

Analysis of Variance↗
PubMed1998

Suppression of plasma viral load below 20 copies/ml is required to achieve a long-term response to therapy.

BACKGROUND: Current guidelines state that the goal of antiretroviral therapy for HIV-infected individuals is to suppress plasma viral load (pVL) to below 400 copies/ml. METHODS: Predictors of achieving and maintaining pVL suppression were examined in a randomized trial of combinations of zidovudine, nevirapine and didanosine in patients with CD4+ T cell counts of between 200 and 600 x 10(6) cells/l who were naive to antiretroviral therapy and AIDS-free at enrolment. RESULTS: One hundred and four patients had pVL > 500 copies/ml at baseline and a pVL nadir below 500 copies/ml. Of these, 77 patients experienced an increase in pVL above 500 copies/ml. The median number of days of pVL suppression to below 500 copies/ml was 285 (42) for patients with pVL nadir < or = (>) 20 copies/ml (P = 00.0001). The relative risk of an increase in pVL above 500 copies/ml associated with a pVL nadir below 20 copies/ml was 0.11 (P = 0.0001). The relative risks of an increase in pVL above 5000 copies/ml associated with a pVL nadir below 20 copies/ml or between 20 and 400 copies/ml were 0.05 [95% confidence interval (CI), 0.02-0.12] and 0.37 (95% CI, 0.23-0.61) respectively, compared with individuals with a pVL nadir > 400 copies/ml. Individuals with a pVL nadir < or = 20 copies/ml were at a significantly lower risk of virologic failure than individuals with a pVL nadir of between 21 and 400 copies/ml (P = 0.0001). CONCLUSIONS: Our results demonstrate that suppression of pVL below 20 copies/ml is necessary to achieve a long-term antiretroviral response. Our data support the need for a revision of current therapeutic guidelines for the management of HIV infection.

Anti-HIV Agents↗
PubMed1998

Cancer phenotype correlates with constitutional TP53 genotype in families with the Li-Fraumeni syndrome.

The Li-Fraumeni cancer predisposition syndrome is associated with germline TP53 mutations in the majority of families. We have investigated cancer incidence in 34 Li-Fraumeni families, according to their constitutional TP53 mutation status. Families with germline missense mutations in the core DNA binding domain showed a more highly penetrant cancer phenotype than families with other TP53 mutations or no mutation. Cancer phenotype in families carrying such mutations was characterized by a higher cancer incidence and earlier ages at diagnosis, especially of breast cancer and brain tumours, compared with families carrying protein truncating or other inactivating mutations (P=0.03 for all cancers, P=0.006 for breast cancers, P=0.05 for brain tumours). Proband cancers showed significantly younger ages at diagnosis in those with missense mutations in the DNA binding domain than in those with protein inactivating mutations (P=0.031). In individuals with the former type of mutation, there was a significantly lower proportion of tumours which showed loss of the wild-type TP53 allele (P=0.004). These results are consistent with observations in experimental systems which demonstrate that certain mutations exhibit gain of function and/or dominant-negative properties. Our results support an enhanced oncogenic potential for such mutations in human populations.

Adolescent↗
PubMed1998

The human immunodeficiency virus type 1 Nef protein binds the Src-related tyrosine kinase Lck SH2 domain through a novel phosphotyrosine independent mechanism.

Primate lentiviruses encode for an unique nef gene with an essential function in both viral replication and pathogenicity in the host. The molecular basis for this function remains however poorly defined. Several Nef-binding cellular proteins are thought to be instrumental in its function. Indeed, Nef contains a proline-rich motif implicated in the binding to the Src-like tyrosine kinase Hck and also to a Ser/Thr kinase of molecular weight 62 kDa. The disruption of this motif affects the binding to both these kinases as well as viral replication. Whereas Hck is expressed in the myeloid lineage and hence may account for the nef function in infected monocytes, we and others have reported previously that Nef also interacts with the T-lymphocyte Src-kinase Lck, leading to specific cell signaling impairment. This interaction occurs through the binding of Nef to both Lck SH2 and SH3 domains. Both the proline motif and phosphorylation of Nef on tyrosine residue were proposed to account for these interactions. Here, we investigate the mechanism of Lck SH2 binding by HIV-1 Nef. Using recombinant fusion proteins to precipitate lysates, we show that although SH2 binding is dependent on phosphorylation events, it occurs in a tyrosine independent manner because it requires neither tyrosine residues in Nef nor the phosphotyrosine binding pocket from the Lck SH2 domain, hence suggesting a role for a phosphoserine or a phosphothreonine residue. Further, we show that Hck SH2 does not interact with Nef, indicating that Hck SH3 binding is sufficient for Nef binding, whereas Lck SH2 cooperate together with SH3 to allow Nef binding to a level similar to Hck SH3. Together, our results establish different mechanisms for Hck and Lck binding by HIV-1 Nef protein, and identify a novel mechanism for Src-like tyrosine kinase targeting by a viral protein.

Gene Products, nef↗