Defects in Bruton's tyrosine kinase (Btk) are responsible for X chromosome-linked agammaglobulinemia in patients. Mutations in each of the structural domains of Btk have been detected in patients, yet a mechanistic explanation for most of these mutant phenotypes is lacking. To understand the possible role of the unique pleckstrin homology and Tec homology (PHTH) module of Btk, we have compared the enzymatic properties of full-length Btk and a Btk mutant lacking the PHTH module (BtkDeltaPHTH). Here we show that Btk and BtkDeltaPHTH have similar basal catalytic activity but very different abilities to recognize protein substrates. Furthermore, the catalytic domain of Btk is inactive, in contrast to the catalytic domain of the prototypical Src tyrosine kinase that retains full catalytic ability. These data suggest that the PHTH module plays an important role in protein substrate recognition, that Btk and Src likely have different interdomain organizations and regulations, and that alterations in substrate recognition might play a role in X chromosome-linked agammaglobulinemia.

Agammaglobulinaemia Tyrosine Kinase↗

PubMed2001

Osteoporosis in primary biliary cirrhosis revisited.

BACKGROUND: Primary biliary cirrhosis (PBC) is increasingly being diagnosed in the earlier non-cholestatic stages of disease. Accepted wisdom has been that PBC is frequently complicated by osteoporosis. Whether this association holds true for the broader spectrum of PBC patients now recognised has not as yet been studied. AIMS: To examine the extent to which osteoporosis occurs more commonly in PBC patients than in normal individuals of the same age and sex. DESIGN: Retrospective review of a large cohort of well characterised PBC patients. PATIENTS: A total of 272 PBC patients with definite or probable PBC followed up for a mean of 10.1 years (total follow up 2726 patient years) who had at least one bone mineral density measurement (BMD). RESULTS: In this unselected group of PBC patients, mean Z scores (number of SDs from age and sex matched normal mean values) at the neck of femur (NOF) and lumbar spine (LS) at first BMD measurement (7 (6) years after PBC diagnosis) were -0.1 (1.4) and 0.1 (1.4), respectively. At first BMD measurement, 18 PBC patients had Z scores less than -2.0 and 85 had T scores less than -2.5. No factors predictive of osteoporosis were found in affected patients. A total of 957 BMD measurements were performed (0.35 per patient year of follow up); 220 patients had two or more measurements. No patient went on to develop de novo osteoporosis during follow up. In the 51 patients (who were clinically representative of the whole group) who received no PBC or bone related treatment during follow up, %BMD changes per year at the NOF and LS were -1.6 (3.2) and 0.1 (2.2), respectively. No variance in this "natural" rate of BMD measurement was seen in patients receiving PBC modulating agents (including prednisolone and UDCA) or osteoporosis prophylaxis/therapy. Significant improvement at the LS was seen in patients undergoing liver transplantation. CONCLUSIONS: Osteoporosis is not a specific complication of PBC.

Absorptiometry, Photon↗

PubMed2001

Multicentre investigations into uncertainty in neck of femur and total hip DXA measurements.

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Absorptiometry, Photon↗

PubMed1998

An IPSM sponsored intercomparison of surface contamination monitoring test results.

An intercomparison using two popular survey meters was arranged to assess the ability of participants to test surface contamination monitors in compliance with the requirements of the Ionising Radiations Regulations 1985. The instruments were circulated and the data returned were compared with the NRPB values. The major inconsistencies were caused by differences in the interpretation of what constitutes 1 Bq of 90Sr+ 90Y and in the conversion of the emission rate from (129)I plaques into a value of equivalent (125)I activity.

Iodine Radioisotopes↗

PubMed1996

The gene for gamma-glutamylcysteine synthetase from Thiobacillus ferrooxidans has low homology to its Escherichia coli equivalent and is linked to the gene for citrate synthase.

The gene for gamma-glutamylcysteine synthetase (gshA) from Thiobacillus ferrooxidans was isolated from a family of cosmids by its ability to complement an Escherichia coli gshA trxA double mutant which was unable to grow on minimal medium lacking glutathione. The predicted sequence of the gamma-glutamylcysteine synthetase was found to have only 18% amino acid sequence identity to the equivalent enzyme from E. coli. In spite of this low sequence homology, concentrations of GSH in a cell extract prepared from the E. coli gshA trxA mutant containing the cloned gene were almost as high as in a cell extract prepared from a wild-type E. coli strain. The gshA gene was found to be physically and transcriptionally linked to the T. ferrooxidans gene for citrate synthase (gltA). The T. ferrooxidans and E. coli citrate synthases shared 37% amino acid sequence identity and the cloned T. ferrooxidans citrate synthase gene was able to complement an E. coli gltA mutant.

Amino Acid Sequence↗

PubMed1996

A questionnaire for the measurement of paranoia/suspiciousness.

A 47-item Paranoia/Suspiciousness Questionnaire was developed on a non-psychiatric sample using modified items from several established scales of paranoia and related concepts. Factor analysis of the questionnaire identified five moderately correlated subscales labelled Interpersonal Suspiciousness/Hostility, Negative Mood/Withdrawal, Anger/Impulsiveness, Mistrust/Wariness and Perceived Hardship/Resentment. There were no significant difference between males and females on the questionnaire or any of the subscales. The full questionnaire and the subscales showed satisfactory internal consistency and test-retest reliability. Further research is needed to establish the scale as a useful diagnostic tool.

Adolescent↗

PubMed1993

Cerebral perfusion abnormalities in children with central nervous system manifestations of lupus detected by single photon emission computed tomography.

OBJECTIVE: Central nervous system (CNS) abnormalities have been reported in 30-60% of children with systemic lupus erythematosus (SLE) during the course of the disease. Unlike most other manifestations of childhood lupus, few laboratory studies and imaging modalities aid in the documentation of CNS lupus. Single photon emission computed tomography (SPECT) provides a means of assessing cerebral blood flow and may reveal subtle areas of decreased perfusion or loss of functioning brain parenchyma. METHODS: We evaluated 5 children with clinical signs of CNS lupus using SPECT, lumbar puncture, electroencephalogram (EEG), computerized tomogram (CT) and magnetic resonance imaging (MRI), as well as autoantibody and complement serologic testing. All patients fulfilled classification criteria for SLE and within one year of onset presented with the following CNS manifestations: grand mal seizures with encephalopathy or psychosis (2) and transverse myelitis (1), focal seizure and depression (1), and severe headache and ophthalmitis (1). RESULTS: Four patients had anticardiolipin (aCL) antibodies. One girl with positive aCL had a concurrent ischemic event involving both parietal lobes and another had a CNS bleed. Both of these children had abnormal EEG, CT and MRI scans. All children had normal cerebral spinal fluid analyses. No correlation was found between serologic variables and CNS disease. All 5 children had abnormal SPECT perfusion studies. CT and MRI failed to demonstrate abnormalities in 3 children. Although CT and MRI documented parietal lobe infarcts in one child and focal hemorrhage in another, poor perfusion found with SPECT extended beyond these abnormalities and into areas which appeared intact using the conventional imaging techniques. All children improved clinically and 4/5 had additional SPECT studies. In all 4, the perfusion abnormalities improved but did not resolve. One of these patients had a recurrence of hallucinations and worsening of SPECT findings which improved again after the patient stabilized. CONCLUSIONS: We conclude that the cerebral perfusion SPECT scan is a sensitive tool and may prove useful in the documentation of CNS lupus in children.

Adolescent↗

PubMed1989

Early CT reevaluation after empiric praziquantel therapy in neurocysticercosis.

Neurocysticercosis can be difficult to diagnose in patients with negative serologic studies and single parenchymal cysts. To avoid surgical intervention, we empirically administered praziquantel to 2 children with isolated cysts and observed complete resolution of the lesions within 1 month after treatment. Early CT reevaluation following empiric praziquantel therapy can be an effective tool in the diagnosis of neurocysticercosis in patients with single parenchymal lesions.

Brain↗

PubMed1983

Intussusception associated with Yersinia enterocolitica gastroenteritis.

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Clindamycin↗

PubMed1976

Evaluation of a new spirometer based on a fluidistor technique.

Using a mechanical model and human subjects a new spirometer based on fluidistor principles was evaluated. At normal minute volumes the fluidistor was accurate to within +/-5% when compared with a Bernstein spirometer. It underread at low volumes and overread at high. Prolonged expiratory time constant as well as the use of gas with low density increased the error. The instrument was somewhat sensitive to variation in breathing frequency and gas flow pattern but insensitive to moisture. The resistance to gas flow of the instrument itself was fairly high. The fluidistor is based on a sound and simple principle (no movable parts). It proved to be stable and easy to handle and accurate enough for clinical use in anaesthesia and intensive care. The tendency of the spirometer to underread at low flow and to overread at high flow could possibly be substantially reduced if the instrument was provided with several flow heads so that the oscillation volume could be individually adapted to the gas flow rate to be studied.

Airway Resistance↗