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Biomedical subjects

A Newman

Publications and source records attributed to A Newman.

At least 19 recordsLinked to original sources
PubMed1999

Slow deformation and lower seismic hazard at the new madrid seismic zone

Global Positioning System (GPS) measurements across the New Madrid seismic zone (NMSZ) in the central United States show little, if any, motion. These data are consistent with platewide continuous GPS data away from the NMSZ, which show no motion within uncertainties. Both these data and the frequency-magnitude relation for seismicity imply that had the largest shocks in the series of earthquakes that occurred in 1811 and 1812 been magnitude 8, their recurrence interval should well exceed 2500 years, longer than has been assumed. Alternatively, the largest 1811 and 1812 earthquakes and those in the paleoseismic record may have been much smaller than typically assumed. Hence, the hazard posed by great earthquakes in the NMSZ appears to be overestimated.

Journal Article↗
PubMed1999

Involvement of protein kinase C and protein kinase A in the muscarinic receptor signalling pathways mediating phospholipase C activation, arachidonic acid release and calcium mobilisation.

The involvement of protein kinase C (PKC) and protein kinase A (PKA) in cholinergic signalling in CHO cells expressing the M3 subtype of the muscarinic acetylcholine receptor was examined. Muscarinic signalling was assessed by measuring carbachol-induced activation of phospholipase C (PLC), arachidonic acid release, and calcium mobilisation. Carbachol activation of PLC was not altered by inhibition of PKC with chelerythrine chloride, bisindolylmaleimide or chronic treatment with phorbol myristate acetate (PMA). Activation of PKC by acute treatment with PMA was similarly without effect. In contrast, inhibition of PKC blocked carbachol stimulation of arachidonic acid release. Likewise, PKC inhibition resulted in a decreased ability of carbachol to mobilise calcium, whereas PKC activation potentiated calcium mobilisation. Inhibition of PKA with H89 or Rp-cAMP did not alter the ability of carbachol to activate PLC. Similarly, PKA activation with Sp-cAMP or forskolin had no effect on PLC stimulation by carbachol. Carbachol-mediated release of arachidonic acid was decreased by H89 but only slightly increased by forskolin. Forskolin also increased calcium mobilisation by carbachol. These results suggest a function for PKC and PKA in M3 stimulation of arachidonic acid release and calcium mobilisation but not in PLC activation.

Animals↗
PubMed1999

BIRICODAR (VX-710; Incel): an effective chemosensitizer in neuroblastoma.

Clinical studies have suggested that both MDR1 and MRP may play a significant role in the chemosensitivity and outcome of neuroblastoma. To clarify the nature of multidrug resistance (MDR) in this tumour a series of six neuroblastoma cell lines have been characterized with regard to P-glycoprotein, MRP and LRP expression using immunocytochemistry and expression of MDR1, MRP, LRP and topoisomerase II genes using reverse transcription polymerase chain reaction (RT-PCR). By RT-PCR, all lines expressed MRP, five expressed LRP and four expressed MDR1, but protein levels of each of these were variable. Chemosensitization to a range of MDR-associated drugs (vincristine, doxorubicin, etoposide, taxotere, topotecan) and non-MDR-associated drugs (cisplatin, melphalan) by three modulating agents, cyclosporin A, PSC 833 and the novel Biricodar (VX-710; Incel), was evaluated using a colourimetric cytotoxicity assay (MTS). Alteration of daunorubicin efflux by these agents was evaluated using FACS analysis. Clonogenic assay was used to study the influence of these chemosensitizers on vincristine cytotoxicity. Marked sensitization to vincristine was observed in MDR1-positive lines, and a similar but less consistent effect was seen with taxotere, doxorubicin and etoposide. With MRP-positive, MDR-negative lines, only VX-710 caused consistent sensitization. These data confirm MDR1 and MRP expression as contributory factors in chemoresistance in neuroblastoma and indicate that VX-710 may be a useful modulator of both mechanisms and worthy of clinical evaluation in this tumour.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1998

Dorsal striatal size, shape, and metabolic rate in never-medicated and previously medicated schizophrenics performing a verbal learning task.

BACKGROUND: Magnetic resonance imaging and positron emission tomography were used to study the size and metabolic rate of the caudate and the putamen in 18 patients with schizophrenia (n=16) or schizo-affective disorder (n=2) and 24 age- and sex-matched control subjects. METHODS: The patients were either never medicated (n=7) or drug free (n=11) for a median of 3 weeks. During uptake of fludeoxyglucose F 18, all patients performed a serial verbal learning test. Positron emission tomographic and magnetic resonance imaging scans were coregistered, and the caudate and the putamen were traced on the magnetic resonance image. RESULTS: The striatum had a significantly lower relative metabolic rate in schizophrenics than in controls. Never-medicated patients had lower metabolic rates in the right putamen (ventral part of the dorsal striatum) than previously medicated patients. The caudate was significantly smaller in never-medicated patients than in controls and largest in previously medicated patients. Patients with higher relative metabolic rates in the putamen scored higher on the Abnormal Involuntary Movements Scale. CONCLUSIONS: The findings are consistent with reports of striatal enlargement in previously medicated patients and size increases after neuroleptic treatment. Never-medicated patients, in contrast, had ventral striatal structures that were smaller and less active than those observed in controls and previously medicated patients.

Adolescent↗
PubMed1998

Motion detection and directional tuning.

A random dot pattern was presented which made two jumps in various directions with a variable delay between them. The jumps occurred at the frame transitions of a 3-frame apparent motion sequence. The variation in detectability with the directional difference and the temporal separation of the jumps allows us to make inferences about directional tuning and the temporal response of the motion detection mechanism. The detectability of a pair of jumps was highest when the delay between the jumps was short and the difference in the jump directions was small. In all cases the data were well fitted with a vector version of the speed energy model earlier proposed by Simpson. The model supposes that the two input vectors are temporally filtered, squared and integrated. Using the model, the autocorrelation function of the motion system's temporal impulse response can be found. This function shows the filter to be lowpass. According to the model, the shape of the threshold or d' locus as a function of the difference in the directions of the two jumps does not show the tuning of a motion mechanism. A tuned mechanism will respond well to a jump in its preferred direction, but less well to any other jump. Instead we show that the apparent tuning evident in the threshold and d' loci is due to the way in which the two jump vectors, each fully recovered, are combined in a vector sum.

Humans↗
PubMed1998

Inhibitory effect of simvastatin on the proliferation of human myeloid leukaemia cells in severe combined immunodeficient (SCID) mice.

SCID mice were inoculated intravenously with cells from the human HL60 myeloblastic leukaemia cell line and then treated with the 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitor, simvastatin, by subcutaneous continuous infusion. The effect of the drug was measured by subsequent colony formation of surviving HL60 cells in vitro and flow cytometry. The number of clonogenic HL60 cells was reduced in the bone marrow of mice that received simvastatin compared with control mice by 65% and 68% in two separate experiments. The number of clonogenic, normal, murine, bone marrow progenitor cells concomitantly exposed to simvastatin in vivo, was not affected in either experiment. Flow cytometric analysis of bone marrow and spleen cells confirmed these results by showing that simvastatin had reduced the percentage of human leukaemia cells in these tissues by 70% and 88% respectively. The data show that the reported selective effect of simvastatin against acute myeloid leukaemia cells in vitro, can be extended to this in vivo model. HL60 bears an N-ras mutation. In further in vitro studies, ketoconazole, an inhibitor of cholesterol biosynthesis post farnesyl pyrophosphate synthesis, had a similar effect to simvastatin on HL60 colony development. Furthermore, the clonogenicity of a population of N-ras mutated, primary acute myeloid leukaemia (AML) cells was no more sensitive to simvastatin than a population without the mutation. The data suggest that the inhibition of AML cell proliferation by simvastatin may be independent of the RAS signalling pathway.

Acute Disease↗
PubMed1998

Aspirin use and incident stroke in the cardiovascular health study. CHS Collaborative Research Group.

BACKGROUND AND PURPOSE: Randomized clinical trials testing aspirin in relatively low-risk, middle-aged people have consistently shown small increases in stroke associated with aspirin use. We analyzed the relationship between the regular use of aspirin and incident ischemic and hemorrhagic stroke among people aged 65 years or older participating in the Cardiovascular Health Study. METHODS: We conducted a multivariate analysis of incident stroke rates in a prospectively assessed, observational cohort of 5011 elderly people followed for a mean of 4.2 years. RESULTS: Participants had a mean age of 72 years, and 58% were women. Twenty-three percent used aspirin frequently, and 17% used aspirin infrequently at study entry. Frequent aspirin use was associated with an increased rate of ischemic stroke compared with nonusers (relative risk= 1.6; 95% confidence interval [CI], 1.2 to 2.2; P=0.001). After adjustment for other stroke risk factors, women who used aspirin frequently or infrequently at study entry had a 1.8-fold (95% CI, 1.2 to 2.8) and 1.6-fold (95% CI, 0.9 to 3.0) increased risk of ischemic stroke, respectively (P<0.01, test for trend), compared with nonusers. In men, aspirin use was not statistically significantly associated with stroke risk. Findings were similar when aspirin use in the years before the incident stroke was used in the modeling. Aspirin use at entry was also associated with a 4-fold (95% CI, 1.6 to 10.0) increase in risk of hemorrhagic stroke for both infrequent and frequent users of aspirin (P=0.003). CONCLUSIONS: Aspirin use was associated with increased risks of ischemic stroke in women and hemorrhagic stroke overall in this elderly cohort, after adjustment for other stroke predictors. The possibility exists of confounding by reasons for aspirin use rather than cause and effect. Whether regular aspirin use increases stroke risk for elderly people without cardiovascular disease can only be determined by randomized clinical trials.

Aged↗
PubMed1997

RNA splicing: out of the loop.

Recent functional analysis of catalytic and exon-binding domains from group II autocatalytic introns has revealed haunting similarities with small nuclear RNA sequences in the spliceosome.

Introns↗
PubMed1997

G-CSF mobilization of haemopoietic cell populations in SCID mice engrafted with human leukaemia.

We have studied granulocyte colony-stimulating factor (G-CSF)-induced mobilization of haemopoietic cells in severe combined immune-deficient (SCID) mice engrafted with human leukaemia. Three leukaemia cell lines were investigated: the HL60 myeloblastic cell line, a chronic myeloid leukaemia (CML) xenograft cell line and an acute myeloid leukaemia (AML) xenograft line. Engraftment was detected using immunofluorescent staining of class I human leukocyte antigens and flow cytometry. All the tumours grew as disseminated disease with engraftment of bone marrow preceding involvement of peripheral blood (PB). After treatment with G-CSF (250 microg/kg/day) for 5 days, mobilization of haemopoietic progenitor cells (HPCs) was observed in non-engrafted SCID mice (40-fold) and in mice engrafted with human leukaemia (20-fold). G-CSF stimulated increases in PB HPCs and total numbers of host nucleated cells in leukaemia-bearing mice but did not induce rises in numbers of circulating HL60 colony-forming cells. Similarly, in mice engrafted with human CML or AML, G-CSF did not increase the number of malignant cells in the PB. These results provided evidence that the migration of normal and malignant haemopoietic cells into the PB are controlled by different mechanisms, and that contamination of PBSC harvests with leukaemic cells in SCID-human chimaeric mice is not enhanced by G-CSF-stimulated mobilization.

Animals↗
PubMed1997

Equivalent background speed in recovery from motion adaptation.

We measured, in the same observers, (1) the detectability, d, of a small rotational jump following adaptation to rotational motion and (2) the detectability of the same jump when superimposed on one of several background rotation speeds. Following 90 s of motion adaptation the detectability of the jump was impaired, and sensitivity slowly recovered over the course of 60 s. The detectability of the jump was also impaired by the background speed in a way consistent with a quadratic form of Weber's law. We propose that motion adaptation impairs the detectability of the small jump because it is as if an equivalent background speed has been superimposed on the display. We measured the equivalent background by finding the real background speed that produced the same d' at each instant in the recovery from motion adaptation. The equivalent background started at approximately one to two thirds the speed of the adapting motion, declined rapidly, rose to a small peak at 30 s, then disappeared by 60 s. Since the equivalent background speed corresponds to the speed of the motion aftereffect, we have measured the time course of the motion aftereffect with objective psychophysics.

Adaptation, Physiological↗
PubMed1997

A comparison of the effect of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors simvastatin, lovastatin and pravastatin on leukaemic and normal bone marrow progenitors.

Simvastatin is an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and also selectively inhibits the growth of leukaemic progenitor cells. The antileukaemic action of simvastatin was compared in vitro with that of lovastatin and pravastatin, chemically related compounds which are also competitive inhibitors of HMG-CoA reductase. After 18 hours incubation with 2.5-20 microM of inhibitor, no effect was observed by any of the compounds on the subsequent clonogenic growth of normal bone marrow (BM) progenitor cells from 4 donors and BM cells from one patient in remission. However, simvastatin and lovastatin produced inhibition of acute myeloid leukaemia (AML) progenitor cell growth of between 25% and 100% in 5 populations tested (4 primary AMLs and the HL60 cell line). Pravastatin showed similar growth inhibitory effects to simvastatin and lovastatin in 2 out of 3 primary AMLs but was less active against one primary AML cell population and HL60 cells. These results indicate that, in addition to simvastatin, lovastatin and pravastatin are also selective inhibitors of leukaemic cell growth, however simvastatin was chosen for clinical trial in patients with leukaemia.

Acute Disease↗
PubMed1996

Clinical improvement of photoaged skin with 50% glycolic acid. A double-blind vehicle-controlled study.

BACKGROUND: Although there is increasing interest in the use of glycolic acid in the treatment of photoaged skin, to our knowledge, no controlled study has been done to assess the efficacy or the mode of this agent. OBJECTIVE: The purpose of this study was to determine whether 50% glycolic acid can improve photoaged skin and to study the histological basis for this improvement. METHODS: Forty-one volunteers were recruited into this double-blind vehicle-controlled study. Glycolic acid (50%) or vehicle was applied topically for 5 minutes to one side of the face, forearms, and hands, once weekly for 4 weeks. Punch biopsies were taken at pretherapy and at 5 weeks for histologic study. RESULTS: Significant improvement noted included decrease in rough texture and fine wrinkling, fewer solar keratoses, and a slight lightening of solar lentigines. Histology showed thinning of the stratum corneum, granular layer enhancement, and epidermal thickening. Some specimens showed an increase in collagen thickness in the dermis. CONCLUSION: The results of this study demonstrate that the application of 50% glycolic acid peels improves mild photoaging of the skin.

Adult↗
PubMed1996

Utility of new electrocardiographic models for left ventricular mass in older adults. The Cardiovascular Health Study Collaborative Research Group.

Several multivariate statistical models have recently been introduced for estimation of left ventricular mass from standard 12-lead electrocardiographic measurements. The validity of these algorithms has not been adequately evaluated. The objective of this investigation was to compare the associations between echocardiographic and electrocardiographic left ventricular mass values with clinical and subclinical indexes of coronary heart disease. The evaluation was performed with participants of the Cardiovascular Health Study, a population-based sample of 5201 men and women aged 65 years and older. Echocardiographic M-mode measurements of left ventricular mass were performed from videotape recordings with the use of a strictly standardized protocol. Electrocardiographic algorithms of the Novacode program and new algorithms derived from the Cardiovascular Health Study population were used for left ventricular mass prediction. Echocardiographic and electrocardiographic determinations of left ventricular mass were technically successful in 3410 (65.6%) and 5013 (96.4%) participants, respectively. The Novacode model overestimated echocardiographic left ventricular mass. Compared with the Novacode model, the new Cardiovascular Health Study electrocardiographic model, which includes adjustment for body weight, eliminated left ventricular mass prediction bias and improved the correlation between echocardiographic and electrocardiographic left ventricular mass from .33 to .54 in women and from .46 to .51 in men. Echocardiographic and electrocardiographic models both demonstrated similar and about equally strong associations with overt and subclinical disease and with risk factors for left ventricular hypertrophy. These observations demonstrate the potential utility of electrocardiographic models for left ventricular mass estimation.

Age Factors↗
PubMed1995

A murine antibody to Shigella dysenteriae type 1 employs V-genes that contain a rearranged codon for the lambda light chain.

The cDNA coding for a hybridoma anti Shigella dysenteriae type 1 antibody (3707 E9) has been cloned, and sequenced. Binding patterns with fragments of the bacterial polysaccharide antigen had already been studied in detail. The VH sequence utilizes the VH441 gene, first identified amongst beta-(1,6)galactan-binding antibodies, while the VL is closely related to the V lambda 1 gene. We found that the VL3707 E9 gene employed a VL-J combinatorial joining leading to a rare Trp-->Leu substitution at position L96.

Amino Acid Sequence↗