Biomedical subjects
N Jones
Publications and source records attributed to N Jones.
Lack of antigenicity of recombinant human thyrotropin after multiple injections in patients with differentiated thyroid cancer.
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Equivalence of ceftriaxone and rifampicin in eliminating nasopharyngeal carriage of serogroup B Neisseria meningitidis.
The efficacy of ceftriaxone in eliminating nasopharyngeal carriage of Neisseria meningitidis was compared with that of rifampicin during an epidemic of serogroup B meningococcal disease in Auckland, New Zealand. Household contacts of cases had a throat swab taken and were randomized to treatment. Carriers had a repeat swab taken 6 days later to determine efficacy of treatment. Ceftriaxone (98.2%) was equivalent to rifampicin (97.6%) in eliminating serogroup B N. meningitidis. It is cheaper than rifampicin and has the advantage of full compliance and fewer contraindications, but its acceptability by patients may limit its use as a first-line prophylactic agent.
Household crowding a major risk factor for epidemic meningococcal disease in Auckland children.
BACKGROUND: New Zealand is in its ninth year of a serogroup B meningococcal disease epidemic with annual rates of up to 16.9 cases per 100,000. The highest incidence is in Maori and Pacific Island children in the Auckland region. We conducted a case-control study to identify potentially modifiable risk factors for this disease. METHODS: A case-control study of 202 cases of confirmed and probable meningococcal disease in Auckland children younger than 8 years of age recruited from May, 1997, to March, 1999, was undertaken. Controls (313) were recruited door-to-door by a cluster sampling method based on starting points randomly distributed in the Auckland region. They were frequency matched with the expected distribution of age and ethnicity in the meningococcal disease cases. RESULTS: With the use of a multivariate model and controlling for age, ethnicity, season and socioeconomic factors, risk of disease was strongly associated with overcrowding as measured by the number of adolescent and adult (10 years or older) household members per room [odds ratio (OR), 10.7; 95% confidence interval (CI), 3.9 to 29.5]. This would result in a doubling of risk with the addition of 2 adolescents or adults to a 6-room house. Risk of disease was also associated with analgesic use by the child, which was thought to be a marker of recent illness (OR 2.4, CI 1.5 to 4.0); number of days at substantial social gatherings (10 or more people for > 4 h; OR 1.8, CI 1.2 to 2.6); number of smokers in the household (OR 1.4, CI 1.0 to 1.8); sharing an item of food, drink or a pacifier (OR 1.6, CI 1.0 to 2.7); and preceding symptoms of a respiratory infection (cough, "cold or flu," runny nose, sneezing) in a household member (OR 1.5, CI 1.0 to 2.5). CONCLUSION: Some of these identified risk factors for meningococcal disease are modifiable. Measures to reduce overcrowding could have a marked effect on reducing the incidence of this disease in Auckland children.
Effects of TNF-alpha on expression of ICAM-1 in human airway epithelial cells in vitro. Signaling pathways controlling surface and gene expression.
Signaling pathways associated with tumor necrosis factor (TNF)-alpha-induced intercellular adhesion molecule 1 (ICAM-1) surface and gene expression were investigated in well differentiated normal human bronchial epithelial (NHBE) cells in air-liquid interface primary culture. Cells were exposed to human recombinant TNF-alpha (hrTNF-alpha; 0.015 to 150 ng/ml [specific activity, 2.86 x 10(7) U/mg]). TNF-alpha enhanced ICAM-1 surface expression (measured by flow cytometry) and steady-state messenger RNA (mRNA) levels (assessed by Northern hybridization) in concentration- and time-dependent manners. TNF-alpha-induced ICAM-1 surface and gene expression were both blocked by the RNA polymerase II inhibitor actinomycin D (0.1 microg/ml), and surface expression was attenuated by a neutralizing monoclonal antibody directed against the TNF-alpha receptor p55 (TNF-RI). The intracellular signaling pathway leading to enhanced expression appeared to involve activation of a phospholipase C that hydrolyzes phosphatidylcholine (PC-PLC) because D609, a specific PC-PLC inhibitor, attenuated TNF-alpha-induced increases in production of diacyl-glycerol (DAG), a hydrolysis product of PC-PLC, and also attenuated TNF-alpha enhancement of ICAM-1 surface and gene expression. Because DAG formed by action of PC-PLC can activate protein kinase C (PKC), involvement of PKC was investigated. The specific PKC inhibitor calphostin C blocked both surface and gene expression of ICAM-1 in response to TNF-alpha in a concentration-dependent manner. Finally, TNF-alpha stimulated binding of p65 and/or c-rel complexes to the nuclear factor (NF)-kappaB consensus binding site found on the ICAM-1 promoter, and binding of these complexes was inhibited by D609. The results support the following pathway, whereby TNF-alpha enhances expression of ICAM-1 in NHBE cells: TNF-alpha --> TNF-RI --> PC-PLC --> DAG --> PKC --> (NF-kappaB?) --> ICAM-1 mRNA --> ICAM-1 surface expression.
Preventing psychological trauma in soldiers: the role of operational stress training and psychological debriefing.
Armed conflict is associated with significant long-term psychiatric morbidity. Interventions to reduce the incidence of psychiatric disorder following psychological trauma may be classified into three categories. Primary prevention includes the selection, preparation and training of individuals likely to be exposed to potentially traumatizing events. Secondary prevention comprises a variety of brief psychological techniques immediately or shortly after traumatizing life events, the best known of which is Psychological Debriefing. Tertiary interventions comprise the treatment of established PTSD and others. Psychiatric morbidity was studied in 106 British soldiers returning from UN peace-keeping duties in the former Republic of Yugoslavia. All 106 soldiers received an Operational Stress Training Package prior to their deployment and a randomly selected group also received a post-operational PD. Very low rates of PTSD and other psychopathology were found overall and the Operational Stress Training Package may have contributed to this. Elevated CAGE scores suggestive of significant alcohol misuse were observed in both groups and chemical avoidance behaviours arising from this may have masked psychopathology. CAGE scores diminished significantly in the debriefed group by the end of the follow-up period suggesting that PD may have been of benefit despite the apparent absence of PTSD. This study also demonstrates that a high incidence of psychiatric morbidity is not an inevitable consequence of military conflict.
Evaluation of 1,2-indanedione and 5,6-dimethoxy-1,2-indanedione for the detection of latent fingerprints on porous surfaces.
The ability of 1,2-indanedione and 5,6-dimethoxy-1,2-indanedione to detect latent prints on porous surfaces, as compared to DFO and ninhydrin, has been evaluated. Comparisons of prints developed under various conditions determined the optimum development conditions for the new reagents. The indanediones tested were found to have lower detection limits for glycine. The carrier solvent used was found to affect the quality of the prints developed. In Arklone, the new reagents developed prints that displayed superior luminescence to those developed with DFO. In HFE 7100, 1,2-indanedione and 5,6-dimethoxy-1,2-indanedione gave superior luminescence to DFO after zinc salt treatment and cooling with liquid nitrogen, both of which improve the luminescence of prints developed with 1,2-indanediones. 1,2-Indanediones could offer less expensive but effective alternatives to DFO. With further optimization, the new reagents may supersede DFO as the method of choice for the detection of latent fingerprints on porous surfaces.
Acute care of patients aged 95 to 99 years: experience in a community teaching hospital.
BACKGROUND: People older than 90 years represent an increasing segment of the US population, but little information exists on their hospitalization for acute illness. METHODS: We retrospectively analyzed the clinical characteristics of patients aged 95 through 99 years admitted during 1 year to a large teaching hospital. RESULTS: Of 43 patients admitted at least once, 14 were admitted twice, 6 were admitted three times, and 1 was admitted four times; 35 (81%) were women, and 8 (19%) were men. Patients admitted more than once took a mean of 6.8 +/- 3.3 drugs compared with 4.4 +/- 2.6 drugs for patients admitted only once. Routine laboratory values were typically normal or mildly abnormal. Mean hospitalization was 5.6 +/- 3.5 days. Only 2 patients (5%) died. All 11 patients with a recent fall were discharged to a long-term nursing facility, compared with only 18 of 30 patients without a recent fall. CONCLUSIONS: Patients aged 95 through 99 years generally have a favorable prognosis when hospitalized for an acute medical condition. However, patients with a recent fall are more likely to require placement in a long-term nursing facility, and patients taking six or more drugs on admission are more likely to be rehospitalized within 12 months.
Dexamethasone reduces nausea and vomiting after laparoscopy.
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Identification of Tek/Tie2 binding partners. Binding to a multifunctional docking site mediates cell survival and migration.
The Tek/Tie2 receptor tyrosine kinase plays a pivotal role in vascular and hematopoietic development. To study the signal transduction pathways that are mediated by this receptor, we have used the yeast two-hybrid system to identify signaling molecules that associate with the phosphorylated Tek receptor. Using this approach, we demonstrate that five molecules, Grb2, Grb7, Grb14, Shp2, and the p85 subunit of phosphatidylinositol 3-kinase can interact with Tek in a phosphotyrosine-dependent manner through their SH2 domains. Mapping of the binding sites of these molecules on Tek reveals the presence of a multisubstrate docking site in the carboxyl tail of Tek (Tyr(1100)). Mutation of this site abrogates binding of Grb2 and Grb7 to Tek in vivo, and this site is required for tyrosine phosphorylation of Grb7 and p85 in vivo. Furthermore, stimulation of Tek-expressing cells with Angiopoietin-1 results in phosphorylation of both Tek and p85 and in activation of endothelial cell migration and survival pathways that are dependent in part on phosphatidylinositol 3-kinase. Taken together, these results demonstrate that Angiopoietin-1-induced signaling from the Tek receptor is mediated by a multifunctional docking site that is responsible for activation of both cell migration and cell survival pathways.
Recruitment of Dok-R to the EGF receptor through its PTB domain is required for attenuation of Erk MAP kinase activation.
Dok (for downstream of tyrosine kinases) proteins are a newly identified family of docking molecules that are characterized by the presence of an amino-terminal pleckstrin homology (PH) domain, a central putative phosphotyrosine-binding (PTB) domain and numerous potential sites of tyrosine phosphorylation [1] [2] [3] [4] [5] [6]. Here, we explore the potential role of the Dok family member Dok-R (also known as p56(Dok2) or FRIP) in signaling pathways mediated by the epidermal growth factor (EGF) receptor. An intact PTB domain in Dok-R was critical for its association with two PTB-binding consensus sites on the EGF receptor and the PH domain further contributed to stable in vivo binding and tyrosine phosphorylation of Dok-R. Multiple sites on Dok-R were tyrosine-phosphorylated following EGF stimulation; phosphorylated Tyr276 and Tyr304 are proposed to dock the tandem Src homology 2 (SH2) domains of the p21(Ras) GTPase-activating protein rasGAP and Tyr351 mediates an association with the SH2 domain of the adapter protein Nck. Interestingly, we have found that Dok-R could attenuate EGF-stimulated mitogen-activated protein (MAP) kinase activation independently of its association with rasGAP. Together, these results suggest that Dok-R has an important role downstream of growth factor receptors as a potential negative regulator of signal transduction.
Modulation of p27(Kip1) levels by the cyclin encoded by Kaposi's sarcoma-associated herpesvirus.
DNA tumour viruses have evolved a number of mechanisms by which they deregulate normal cellular growth control. We have recently described the properties of a cyclin encoded by human herpesvirus 8 (also known as Kaposi's sarcoma-associated herpesvirus) which is able to resist the actions of p16(Ink4a), p21(Cip1) and p27(Kip1) cdk inhibitors. Here we investigate the mechanism involved in the subversion of a G1 blockade imposed by overexpression of p27(Kip1). We demonstrate that binding of K cyclin to cdk6 expands the substrate repertoire of this cdk to include a number of substrates phosphorylated by cyclin-cdk2 complexes but not cyclin D1-cdk6. Included amongst these substrates is p27(Kip1) which is phosphorylated on Thr187. Expression of K cyclin in mammalian cells leads to p27(Kip1) downregulation, this being consistent with previous studies indicating that phosphorylation of p27(Kip1) on Thr187 triggers its downregulation. K cyclin expression is not able to prevent a G1 arrest imposed by p27(Kip1) in which Thr187 is mutated to non-phosphorylatable Ala. These results imply that K cyclin is able to bypass a p27(Kip1)-imposed G1 arrest by facilitating phosphorylation and downregulation of p27(Kip1) to enable activation of endogenous cyclin-cdk2 complexes. The extension of the substrate repertoire of cdk6 by K cyclin is likely to contribute to the deregulation of cellular growth by this herpesvirus-encoded cyclin.
AP-1 transcription factors in yeast.
In the past two years, the completion of the Saccharomyces cerevisiae genome project and molecular analysis of other fungal species has resulted in the identification of a growing number of yeast AP-1 transcription factors. Characterisation of these factors indicates that, like their mammalian counterparts, they activate gene expression in response to a variety of extracellular stimuli. In particular, these factors are required for the response to oxidative stress and for surviving exposure to a variety of cytotoxic agents. Much progress has also been made in understanding how members of this family of proteins are regulated. These studies promise to further our awareness of eukaryotic stress responses and are likely to have implications for the study of mammalian AP-1.
Overcoming inhibitions: subversion of CKI function by viral cyclins.
DNA tumour viruses deregulate the mammalian cell cycle to provide a better environment for their replication. Studies of such deregulation have led to the identification of key regulatory steps that normally control the G1-S phase transition of the cell cycle. The balance between the activities of G1-specific cyclin-CDK complexes and their inhibitors is critical. Recent studies suggest that certain herpesviruses disrupt this balance: the viruses encode a cyclin that generates active complexes even in the presence of high inhibitor levels.
Photo quiz. Osteoarticular sporotrichosis.
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Cell cycle-regulated transcription in fission yeast: Cdc10-Res protein interactions during the cell cycle and domains required for regulated transcription.
In Schizosaccharomyces pombe the MBF (DSC1) complex mediates transcriptional activation at Start and is composed of a common subunit called Cdc10 in combination with two alternative DNA-binding partners, Res1 and Res2. It has been suggested that a high-activity MBF complex (at G1/S) is switched to a low-activity complex (in G2) by the incorporation of the negative regulatory subunit Res2. We have analyzed MBF protein-protein interactions and find that both Res proteins are associated with Cdc10 throughout the cell cycle, arguing against this model. Furthermore we demonstrate that Res2 is capable of interacting with a mutant form of Cdc10 that has high transcriptional activity. It has been shown previously that both Res proteins are required for periodic cell cycle-regulated transcription. Therefore a series of Res1-Res2 hybrid molecules was used to determine the domains that are specifically required to regulate periodic transcription. In Res2 the nature of the C-terminal region is critical, and in both Res1 and Res2, a domain overlapping the N-terminal ankyrin repeat and a recently identified activation domain is important for mediating cell cycle-regulated transcription.