Biomedical subjects
Publications and source records attributed to D Young.
With their knowledge of local community, families and schools, general practitioners are the ideal providers of primary health care to young people; however, doctors sometimes find it difficult to communicate with adolescents. Adolescents are often anxious and reluctant to visit a doctor. This article outlines possible approaches to the adolescent in the medical consultation that may help start the therapeutic relationship in a positive manner.
Scrub typhus is a zoonotic disease, caused by Rickettsia tsutsugamushi, in which humans are accidental hosts. Although it is an acute febrile illness, severe complications of this disease are very rare since the introduction of specific antibiotic therapy. The authors report two cases of scrub typhus complicating acute respiratory distress syndrome. The first case progressed to multiple organ failure, and the patient expired. In the second case, the patient recovered and was discharged. These two cases were proved to be scrub typhus by their travel history or their having lived in endemic area, clinical manifestations, an eschar and indirect immunofluorescent antibody test. For a good prognosis, early diagnosis and early treatment of this disease are important.
We have isolated 16 independent Schizosaccharomyces pombe cDNA clones that suppress the temperature-sensitive (ts) phenotype of a Saccharomyces cerevisiae strain containing the dominant-negative RAS2val19ala22 allele. Fourteen of these cDNAs encode Sz. pombe Ras1. The other two clones encode the C-terminal region of a protein we have named Pka1. We have cloned the pka1 gene from a Sz. pombe genomic library. It contains an uninterrupted open reading frame encoding a 512-amino-acid (aa) protein. The C-terminal region (aa 200-512) of Pka1 is 51-63% identical to cAMP-dependent protein kinase (Pka) catalytic subunits from other eukaryotes. Production of Pka1 suppresses the ts phenotypes exhibited by Sa. cerevisiae ras1-ras2ts or cyr1ts strains. Furthermore, overproduction of Pka1 in Sz. pombe results in a sterile phenotype and an abnormal morphology similar to that exhibited by cells in which the cAMP pathway is constitutively activated. These observations suggest that pka1 encodes the Sz. pombe Pka catalytic subunit.
MUSCARINIC, NMDA and metabotropic glutamate receptor antagonists were tested for anticonvulsant effects in a continuous hippocampal stimulation model in rats in order to identify the receptors involved in the initiation of electrically induced status epilepticus (SE). Whereas the muscarinic receptor antagonists scopolamine and atropine and the metabotropic receptor antagonist L(+)-2-amino-3-phosphonopropionic acid (AP3) did not affect SE initiation, the N-methyl-D-aspartate (NMDA) antagonist dizocilpine (MK-801) (1 mg kg-1 i.p.) and the non-NMDA ionotropic receptor antagonist 2,3-dihydroxy-6-nitro-7-sulphamoylbenzo(F)-quinoxaline (NBQX) (two doses of 50 micrograms i.c.v.) prevented the induction of SE. It has been shown in a previous study that non-NMDA ionotropic receptors are involved in SE maintenance and it is now suggested that activation of NMDA receptors may principally initiate electrically induced SE, although non-NMDA ionotropic receptors may also be involved.
Hsp70-binding sites were mapped on three antigens, the 16-, 19- and 38-kDa proteins of Mycobacterium tuberculosis, using overlapping synthetic peptides in a competitive-binding assay. In each protein, two or three prominent hsp70-binding sites were identified when peptides 20-amino-acid long were used, predominantly in regions containing clusters of aliphatic amino acids. Although there was an overall concordance in the pattern of peptide binding to hsp70 from bacterial (M. tuberculosis) and mammalian sources (immunoglobulin heavy-chain-binding protein), some differences in the specificity of polypeptide binding and the effect of peptides on ATPase activity were observed.
UNLABELLED: Thrombomodulin is an endothelial surface receptor that binds thrombin and accelerates the activation of protein C. We compared the effects of a recombinant thrombomodulin analog (TME), recombinant hirudin (r-HIR), heparin sodium (HEP), and normal saline (Control) on thrombus formation, activated partial thromboplastin time (APTT), thrombin time (TT), platelet aggregation and tail transection bleeding time (BT) in a rat model of vena cava thrombosis. RESULTS: TME, r-HIR and HEP prevented venous thrombosis in this model in a dose-dependent manner. At the dose required to reduce vena cava thrombosis by 50% (ED50), TME did not prolong the APTT or TT as did HEP and r-HIR. Platelet aggregation in response to thrombin was not effected by TME but was inhibited by both r-HIR and HEP. BT did not differentiate the agents tested. CONCLUSION: TME inhibited venous thrombosis in a rat vena cava model with less effect on hemostatic variables than HEP or r-HIR.
The spin trap 5,5-dimethyl-1-pyrroline-1-oxide (DMPO) alone, as well as DMPO or N-tert-butyl-alpha-phenylnitrone (PBN) in the presence of excess dimethyl sulfoxide (Me2SO), have been used as spin trapping systems for the detection of hydroxyl radical. However, the instability of DMPO and many of its corresponding spin-trapped adducts has limited the usefulness of this spin trap, particularly in biological systems. Spin trapping of multiple free radicals by the PBN/Me2SO system may undermine the sensitivity of this method to detect small, yet biologically significant amounts of hydroxyl radical. The present study was undertaken to select a spin trapping system with greater sensitivity and selectivity toward.OH than DMPO, DMPO/Me2SO, or PBN/Me2SO. We report that alpha-hydroxyethyl radical, resulting from the reaction of photolytically generated.OH with excess ethanol is spin trapped by 4-pyridyl-1-oxide-N-tert-butylnitrone (4-POBN) with a second-order rate constant nearly 10-fold greater than that for DMPO or PBN. In contrast to DMPO spin-trapped adducts, the alpha-hydroxyethyl radical adduct of 4-POBN, 4-POBN-CH(CH3)OH, is resistant to reduction by superoxide, even in the presence of cysteine. The efficiency of spin trapping and the marked stability of the resulting spin-trapped adduct confer a high degree of sensitivity and demonstrate the potential application of 4-POBN/ETOH toward the detection of hydroxyl radical in biological systems.
The iron-dependent superoxide dismutase from Mycobacterium tuberculosis has been crystallized by the hanging drop method. The crystals belong to the P2(1) space group and have unit cell dimensions of a = 68.5 A, b = 85.6 A, c = 66.5 A, beta = 99.8 degrees. There are four molecules per asymmetric unit which, from analysis of data to 2.5 A, appear to be related by non-crystallographic 222 symmetry.
To determine the effect of aggressive regional therapy for liver metastasis from breast cancer, we retrospectively reviewed data on 74 patients identified with liver metastases. Forty had only liver metastases. In this group of 40 patients, 18 were treated with regional therapy only, i.e., surgical resection and/or regional chemotherapy via hepatic artery or portal vein catheters whereas 22 patients had systemic chemotherapy. The two groups were comparable. The regional chemotherapy regimen was 5-FU, Adriamycin, methotrexate, and cytoxan. Median survival (27 months) for those patients treated with regional therapy (N = 18) was significantly longer than for those (N = 22) treated with systemic therapy (5 months) (P = 0.001). Only 45% of the regional treatment group failed in the liver. Our data, although retrospective and selective, suggest that certain subgroups of breast cancer patients with metastatic liver disease may benefit from aggressive regional therapy.
We defined the pharmacokinetics of paclitaxel after i.v., i.p., p.o., and s.c. administration of 22.5 mg/kg to CD2F1 mice. Additional mice were studied after i.v. bolus dosing at 11.25 mg/kg or 3-h continuous i.v. infusions delivered at 43.24 micrograms kg-1 min-1. Plasma was sampled between 5 min and 40 h after dosing. Brains, hearts, lungs, livers, kidneys, skeletal muscles, and, where applicable, testicles were sampled after i.v. dosing at 22.5 mg/kg. Liquid-liquid extraction followed by isocratic high-performance liquid chromatography (HPLC) with UV detection was used to determine paclitaxel concentrations in plasma and tissues. After i.v. administration to male mice, paclitaxel clearance (CLtb) was 3.25 ml min-1 kg-1 and the terminal half-life (t1/2) was 69 min. After i.v. administration to female mice, paclitaxel CLtb was 4.54 ml min-1 kg-1 and the terminal t1/2 was 43 min. The bioavailability of paclitaxel was approximately 10%, 0, and 0 after i.p., p.o., and s.c. administration, respectively. Paclitaxel bioavailability after i.p. administration was the same when the drug was delivered in a small volume to mimic the delivery method used to evaluate in vivo antitumor efficacy or when it was delivered in a large volume to simulate clinical protocols using i.p. regional therapy. Paclitaxel was not detected in the plasma of mice after i.p. delivery of the drug as a suspension in Klucel: Tween 80. Pharmacokinetic parameters were similar after i.v. delivery of paclitaxel at 22.5 and 11.25 mg/kg; however, the CLtb calculated in these studies was much lower than that associated with 3-h continuous i.v. infusions. After i.v. administration, paclitaxel was distributed extensively to all tissues but the brain and testicle. These data are useful in interpreting preclinical efficacy studies of paclitaxel and predicting human pharmacokinetics through scaling techniques.
This paper describes a general procedure for the two-step purification of recombinant proteins as antibody-antigen complexes in which there is no uncomplexed antibody or antigen. In this way, immune complexes containing the p17, p27, vpr and vpx proteins of simian immunodeficiency virus (SIV) have been purified. Antibody-antigen complexes are more immunogenic than antigen when administered either alone or with alum. The significance of the work is that this general method could be modified for the manufacture of immune complexes for incorporation into multivalent vaccines.
The inhibitory neuromodulator adenosine is an endogenous anticonvulsant that terminates brief seizures in the brain and it has been proposed that loss of adenosine or adenosine-mediating systems may play a major role in the development of status epilepticus, a seizure condition characterized by prolonged and/or recurrent seizures that last by definition, at least 20 min. In this study, the effect of specific A1-adenosine agonists and antagonists were tested for their ability to prevent and cause status epilepticus in two electrical stimulation models in rats. In a recurrent electrical stimulation model, whereas no vehicle-treated animals developed status epilepticus after 20 recurrent electrical stimulations, rats injected with 10 mg/kg of the specific A1-adenosine antagonist 8-cyclopentyl-1,3-dimethylxanthine intraperitoneally developed status epilepticus after stimulation. 8-(p-Sulphophenyl)-theophylline, which has limited penetrability into the brain when administered peripherally, did not cause status epilepticus when injected intraperitoneally. However, when 200 micrograms of 8-(p-sulphophenyl)-theophylline were administered intracerebroventricularly, status epilepticus developed in all animals, suggesting status epilepticus developed as a result of central adenosine receptor antagonism. In the second study, whereas all vehicle-treated animals developed status epilepticus after constant electrical stimulation, administration of N6-cyclohexyladenosine and N6-cyclopentyladenosine prior to stimulation suppressed the development of status epilepticus. N6-Cyclohexyladenosine was also effective in terminating status epilepticus after it had progressed for 20 min. The effects of a selective A2-agonist was also tested on both stimulation models and had no anticonvulsant effects. An electrical stimulus given to rats pretreated three days prior to stimulation with pertussis toxin, a compound which inactivates Gi-proteins, also resulted in generalized status epilepticus, suggesting that impairment of G-protein-linked receptors is involved in the development of status epilepticus. The effects of a GABAB antagonist, phaclofen, and a GABAB agonist, baclofen, were also tested in the recurrent stimulation model, as GABAB receptors are also coupled to the same subset of K+ channels as the A1-receptor. Rats given phaclofen did not develop status epilepticus after recurrent electrical stimulation, although baclofen was effective at preventing the induction of status epilepticus in the constant stimulation model. These results, together with some preliminary data obtained showing that the GABAA antagonist picrotoxin did not cause status epilepticus after recurrent stimulation, suggest that loss of GABAergic inhibition only has a minor role in status epilepticus development in our models. Brains from all animals were also assessed for brain injury.(ABSTRACT TRUNCATED AT 400 WORDS)
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Tuberculosis (TB) is the single largest killer among infectious diseases. The recent resurgence of TB together with outbreaks of multidrug resistant tuberculosis has focused attention on understanding the mechanisms of such drug resistance. Because of the relative neglect of TB research in the past and late arrival of mycobacterial genetic tools, the molecular mechanisms of drug resistance in TB remained largely unknown until very recently. In this paper we review recent progress on the mechanisms of resistance to three major anti-TB drugs; isoniazid, rifampicin and streptomycin. While the resistance mechanisms for rifampicin and streptomycin are similar to those found in other bacteria, isoniazid susceptibility and resistance is unique to Mycobacterium tuberculosis. So far, mutations in two chromosomal loci, katG and inhA have been found to be involved in isoniazid resistance in TB. Identification and characterization of mutations responsible for resistance opens up new possibilities for rapid detection of drug resistant strains. Molecular understanding of drug resistance and drug action in M. tuberculosis may eventually lead to rational design of new anti-TB drugs.
A 70-year-old man presented with a keratotic lesion of the right buttock. Histologic examination revealed an endophytic cystic and papillary lesion of the dermis. The papillae were lined by two layers of cuboidal epithelial cells with a dense plasmacytic infiltrate of the stroma, consistent with syringocystadenoma papilliferum (SCAP). The overlying epidermis showed acanthosis, papillomatosis, and hyperkeratosis. There were multiple foci of prominent koilocytotic atypia. In situ DNA probes for HPV type 6/11 were positive in many epidermal nuclei. The concurrent occurrence of SCAP and CA may be coincidental; however, the occurrence of CA may be related to the environment at the surface of the SCAP. Syringocystadenoma papilliferum often occurs in association with nevus sebaceus (NS), but it has also been reported from most body sites. When it is not seen in association with NS, the epidermis overlying SCAP may be hyperkeratotic or verrucous. The verrucous changes in our case had features of condyloma acuminatum (CA), which were confirmed by in situ DNA probes.
Southern blot analysis of chromosomal DNA from clinical isolates of Mycobacterium tuberculosis using cosmid DNA probes revealed extensive strain variation in the katG region of the genome. In addition to deletion of the katG gene itself in some isoniazid-resistant strains, adjacent DNA fragments were missing or altered in a range of drug-sensitive and drug-resistant isolates. A species-specific 2kb Kpnl fragment located 10kb upstream of katG in M. tuberculosis H37Rv hybridized to fragments of differing size in different clinical isolates and was characterized in detail. Sequence analysis of this fragment in detail. Sequence analysis of this fragment showed that it comprised three tandem copies of a novel 75 bp repeat element flanked by multiple copies of the previously described 10 bp major polymorphic tandem repeat of M. tuberculosis (MPTR). The copy number of the 75 bp repeat was found to vary between strains, allowing application of a polymerase chain reaction amplification strategy for strain differentiation. These results indicate that the katG region of the M. tuberculosis genome is highly variable and unstable. The presence of repetitive sequences may contribute to instability in this region of the genome.
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