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D F Andrews

Publications and source records attributed to D F Andrews.

53 records · Page 3Linked to original sources
PubMed1989

Rare occurrence of N-ras point mutations in Philadelphia chromosome positive chronic myeloid leukemia.

Point mutations of the N-ras oncogene are relatively common in acute myelogenous leukemia (AML) cells, occurring in some 25% to 50% of patient samples. We used a technique involving the direct nucleotide sequencing of in vitro amplified N-ras genomic fragments to determine the frequency of N-ras point mutations in chronic myeloid leukemia (CML) cells at various stages of the disease. This approach will detect N-ras point mutations in a mixed population of cells if the mutation is present in 25% or more of the cells. We could not demonstrate any point mutation at N-ras codons 12,13 or 59-63 in any of the 44 CML cases analyzed, which included 21 blast crisis samples. In contrast with AML N-ras point mutations are exceedingly rare in CML.

Gene Rearrangement↗
PubMed1987

Effect of recombinant alpha-interferon on the expression of the bcr-abl fusion gene in human chronic myelogenous human leukemia cell lines.

Recent investigations have shown a therapeutic and cytogenetic response in chronic myelogenous leukemia (CML) patients treated with recombinant alpha 2-interferon (IFN alpha 2). Philadelphia chromosome-positive (and many Ph1-negative) chronic myelogenous leukemia cells transcribe a novel bcr-abl fusion mRNA which may confer a growth advantage upon these cells. We investigated the effect of IFN alpha 2 on the levels of bcr-abl transcript expression in three Ph1-positive CML cell lines, EM2, KCL22, and K562. Although IFN alpha 2 inhibited cell proliferation in all three CML cell lines, IFN alpha 2 had no effect on the level of bcr-abl mRNA expression in any of the CML cell lines. In contrast, IFN alpha 2 increased the expression of class I HLA gene products. We conclude that while the bcr-abl fusion gene and its transcript undoubtedly play key roles in the pathogenesis of CML, the antiproliferative effect of IFN alpha 2 in CML cell lines relies upon genetic mechanisms other than modulation of bcr-abl expression.

Cell Division↗
PubMed1987

Making the most of multiple measurements in estimating carrier probability in Duchenne muscular dystrophy: the Bayesian incorporation of repeated measurements using logistic discrimination.

In carrier detection studies, females-at-risk are usually tested several times if the results are ambiguous, whereas subjects in the control and obligate carrier reference groups may not be tested as often. The question is how to incorporate the multiple measurements most effectively with information in the family pedigree into combined carrier risks. Sets of measurements on individuals are not independent, but are related with the correlation coefficient 0 less than rho less than 1. We have developed a procedure for incorporating repeated measurements on individuals and their a priori chance of having the disease into logistic models. This procedure utilizes the set of measurements and an estimate of rho. We describe application of this procedure to carrier detection in Duchenne muscular dystrophy (DMD) using serum creatine kinase (CK) measurements as the biochemical indicator of carrier status. Estimates of rho for controls and obligate DMD carriers did not differ significantly from 0.5. Repeated testing with use of rho = 0.5 significantly decreased the median logistic carrier probability for controls and increased it for carriers. In some cases four to six rather than the three CK tests conventionally used in genetic counseling were necessary to obtain a stable logistic carrier probability for a subject.

Creatine Kinase↗
PubMed1987

Comparison of surgical and conservative management in 208 patients with acute spinal cord injury.

The role of surgery in the management of acute spinal cord or cauda equina injuries remains controversial. The present study analyzed ten admission features and three outcome variables in 208 patients treated in an Acute Spinal Cord Injury Unit, 116 (56%) of whom underwent at least one spinal operation. The surgical and non-surgical groups showed no significant differences in the following seven clinical features: age, sex, distance travelled to the Unit, time interval between trauma and admission, type of accident, severity of injuries to the spinal cord, and severity of associated injuries. However, the two groups showed significant differences in level and type of vertebral column injury, and in the frequency of pre-existing spinal abnormalities. These differences were due to management policies which selected certain injuries for surgical or non-surgical treatment. One-third of the operative procedures were performed primarily for neural decompression, one-third primarily for reduction of bony structures and one-third for fusion. However, 95% of the operative patients had a fusion at the initial operation. Operative treatment was associated with a lower overall mortality rate (6.1%) than non-operative (15.2%), despite a higher frequency of thrombo-embolic complications in the surgical group. Overall, there was no difference between operated and non-operated patients in length of stay or neurological recovery. Surgical management of patients with acute spinal cord injury appears safe in terms of mortality rate and neurological recovery, but it has not been proven to improve the latter.

Acute Disease↗
PubMed1987

Reproducibility of noninvasive vascular laboratory measurements of the peripheral circulation.

This study reports the reproducibility of noninvasive vascular laboratory measurements for the diagnosis of peripheral arterial occlusive disease and compares their variability to other clinical measurements, including pulse rate, hemoglobin, white blood cell count, blood urea nitrogen, and creatinine. To study the reproducibility of these measurements, we considered three components that affect the repeatability; the variation associated with the measurement process, the variation associated with transient changing characteristics of the patients with time, and the variation among the patients. It is useful to consider the variation of each component relative to the variation among the patients, measured in units of standard deviation. The variation associated with the measurement process (expressed as the relative precision) was determined by repeating the measurements in pairs at random times throughout the study period. The relative precision was 0.3% for the measurements of ankle-arm systolic blood pressure ratio and treadmill walking time, 2.7% for pulsatility index, and 1.2% to 4.2% for the other clinical, hematologic, and biochemical measurements. The temporal variations were determined by repeating the measurements over a 6-week period in 15 patients. The normalized long-term fluctuation was 1.7% for ankle-arm systolic pressure ratio, 3.2% for treadmill walking time, 7.5% for pulsatility index, and 1.3% to 5.5% for the other measurements. For each test, the 95% confidence interval for an individual patient's measurements and the values above which the difference between two successive measurements can be considered significantly different (95%) have been calculated. It is concluded that the reproducibility of standard vascular laboratory measurements compares favorably to the other clinical, hematologic, and biochemical measurements evaluated in this study.

Aged↗
PubMed1987

Heterogeneity in expression of the bcr-abl fusion transcript in CML blast crisis.

The 9;22 Philadelphia chromosome translocation in chronic myelogenous leukemia (CML) generates a bcr-abl fusion gene which codes for an aberrant 8-kb bcr-abl hybrid message. CML blast crisis cell lines display enhanced in vitro expression of this aberrant bcr-abl transcript when compared with fresh CML chronic phase cells. We directly compared in fresh patient samples the level of expression of the bcr-abl transcript in CML blast crisis versus chronic phase cells. All chronic phase patients displayed relatively low amounts of this aberrant transcript, while four of 10 blast crisis patients expressed this transcript at significantly higher levels. The remaining six blast crisis samples exhibited low levels of the aberrant transcript comparable to chronic phase cells. The two patients displaying the highest levels of the bcr-abl transcript did not harbor amplified copies of the bcr-abl fusion gene. This heterogeneity in the level of expression of the bcr-abl transcript in CML blast crisis indicates that enhanced expression of this aberrant transcript is not an absolutely necessary condition for blast transformation.

Adult↗
PubMed1986

DUCHEN: an interactive computer program for calculating heterozygosity (carrier) risks in X-linked recessive lethal diseases, and its application in Duchenne muscular dystrophy.

The program DUCHEN calculates the probability that a woman is a carrier of an X-linked, lethal recessive disease on the basis of information in the woman's family and any available biochemical data. It is easily used by persons without computer knowledge or experience. The present version can accommodate families consisting of up to 100 people in seven generations. Risks may be estimated on the basis of pedigree information only, or with the inclusion of one or more types of biochemical test results. Biochemical data are incorporated with pedigree information into final risks using the powerful statistical technique of logistic discrimination, a procedure particularly suited for the separation of non-normal populations on the basis of overlapping quantitative characteristics. Mutation rates are specified separately for males and females. DUCHEN is available in FORTRAN 77, IBM BASIC, and Applesoft BASIC, and may be used on a variety of mainframe or microcomputers. The model was used to calculate risks for 375 girls and women in 46 families with Duchenne muscular dystrophy (DMD); serum creatine kinase tests had been carried out on 167 of these subjects who were of reproductive age. Carrier probabilities equal to or lower than the population risk (0.0004) were obtained for 21% of the aunts and 43% of the cousins of affected boys from families with an isolated case of DMD and for 14% of the cousins of affected boys from families with a known DMD history. DUCHEN should assist counsellors in determining which members of large families should be further examined using either standard biochemical carrier detection methods or DNA marker studies.(ABSTRACT TRUNCATED AT 250 WORDS)

Creatine Kinase↗
PubMed1984

Serum myoglobin in Duchenne muscular dystrophy carrier detection: a comparison with creatine kinase and hemopexin using logistic discrimination.

Logistic discrimination was used to assess the effectiveness of serum myoglobin (Mb), creatine kinase (CK), and hemopexin (H) measurements in identifying Duchenne muscular dystrophy (DMD) carriers. Subjects included 36 obligate carriers, 46 age-matched control women, 30 mothers of isolated cases, and 14 DMD patients. The percentages of obligate carriers with logistic carrier probabilities exceeding the upper normal 95th centile (or 97.5th centile) were: CK alone, 63% (50%); Mb alone, 65% (62%); CK and Mb, 66% (62%); CK and H, 78% (65%); CK H and Mb, 72% (65%). In this study, Mb identified more carriers than CK at the 97.5% level, but there was no advantage in using Mb measurements with CK. CK provided slightly better overall separation of the control and carrier groups than Mb. CK, Mb, and H in combination provided significantly better separation than CK and H, or CK alone.

Adult↗
PubMed1984

The University of Toronto head injury treatment study: a prospective, randomized comparison of pentobarbital and mannitol.

Fifty-nine patients were treated in a prospective, randomized comparison of pentobarbital and mannitol for the control of intracranial hypertension resulting from head injury. Patients with elevated intracranial pressure (ICP) after evacuation of intracranial hematomas were randomized to one of two treatment groups; mannitol initially or pentobarbital initially, followed by the second drug as required by further elevation of ICP. Similarly, patients with raised ICP but without hematomas requiring evacuation were randomly assigned to two treatment groups in an identical paradigm. Those with ICP elevation and no hematoma treated with pentobarbital as initial therapy had a 77% mortality compared to a 41% mortality for those with mannitol as initial treatment. Patients with evacuated hematomas had mortalities of 40% and 43% (no significant difference) for pentobarbital and mannitol respectively. In both no-hematoma and hematoma streams pentobarbital was less effective than mannitol for control of raised ICP. Multivariable statistical analysis indicates that pentobarbital coma is not better than mannitol for the treatment of intracranial hypertension and may be harmful in no-hematoma patients with intracranial hypertension after head injury.

Adult↗
PubMed1982

Duchenne muscular dystrophy carrier detection using logistic discrimination: serum creatine kinase, hemopexin, pyruvate kinase, and lactate dehydrogenase in combination.

In the absence of an unambiguous test for identifying Duchenne muscular dystrophy (DMD) heterozygotes, methods are needed for combination of the results of individually equivocal tests as effectively and rationally as possible. Tw used logistic discrimination to assess the effectiveness of measurements of serum creatine kinase, hemopexin, pyruvate kinase, and lactate dehydrogenase alone and in various combinations in identifying DMD carriers. We analyzed 127 serum samples from 63 normal female controls (20-40 years old) and 67 from 38 obligate DMD carriers. The best two tests to use in combination were creatine kinase and hemopexin, and these two, with lactate dehydrogenase, were the best three. t the 95% level (with 5% of controls misclassified), 54% of the carriers were identified by CK alone, whereas 88% were identified by means of the four tests. Although a small proportion of known carriers still cannot be identified, application of the four tests to a group of 45 possible carrier mothers of isolated cases of DMD resolves the population into fairly discrete "normal" and "abnormal" subgroups. Thus, if bias of selection can be eliminated, application of logistic discrimination may permit a direct estimate of the proportion of mothers of affected boys who are homozygous normal.

Adult↗
PubMed1982

Serum creatine kinase in the detection of Duchenne muscular dystrophy carriers: effects of season and multiple testing.

The usefulness of serum creatine kinase (CK) activity in the detection of Duchenne muscular dystrophy (DMD) carriers is dependent upon a reliable control distribution. In controls there is a small but reproducible seasonal variation in CK activity, with a statistically significant variation in the upper 95th percentile (78 IU/liter in May, 53 IU/liter in November, as compared with 67 IU/liter for the whole calendar year). Because CK values in DMD heterozygotes are higher in November than in May, the carrier detection rate may be highest in November. Failure to consider this seasonal variation in controls may cause misclassification of too many normal subjects. If tests are conducted throughout the year, however, the seasonal influence can be reduced by serial testing at intervals of several months. In this case, use of the highest of the results obtained in 3 tests compared with the normal range of single measurements misclassifies too many normal subjects. Use of the mean of 3 determinations provides more accurate classification.

Adult↗
PubMed1981

Duchenne muscular dystrophy carrier detection using logistic discrimination: serum creatine kinase and hemopexin in combination.

Creatine kinase (CK) activity and hemopexin concentration were measured in 208 serum samples from 104 normal females and 22 obligate carriers of Duchenne muscular dystrophy (DMD) 20-40 years old. Logistic discrimination was used to assess the effectiveness of the parameters alone or in combination in identifying DMD carriers. In this approach, a serum sample with particular CK, hemopexin, or a combination of CK and hemopexin values is given a probability that if drawn at random from a defined mixture of controls and carriers, it comes from a carrier. The carrier probability based on the biochemical tests can be directly combined with the carrier probability determined from a woman's pedigree to yield a final posterior probability that she is a carrier. When CK and hemopexin were considered individually, 65 and 27% of the carriers, respectively, could be distinguished from 95% of the controls. When the two tests were used in combination, 82% of the carriers could be distinguished from 95% of the controls. When the two-test method was applied to 93 possible carriers, 35 women were classified as carriers, whereas only 29 were identified using CK alone. This method can be extended to include other variables in order to further improve the identification of DMD carriers. It can also be applied to carrier detection in other genetic disorders.

Adolescent↗
PubMed1980

Pathologic rupture of the spleen in non-Hodgkin's lymphoma.

Pathologic rupture of the spleen was the signal event in the onset of diffuse histiocytic lymphoma in a young woman. The diagnosis of lymphoma was established only after one month of observation. In a review of clinical features of ten patients with pathologic rupture of the spleen due to lymphoma, spleen size was variable, and in four of ten patients a diagnosis of lymphoma had not been suspected previously. In addition to the patient described herein, only two of those previously described survived splenic rupture.

Adult↗
PubMedDate not supplied

Watershed imaging features and clinical vascular injury in cyclosporin A neurotoxicity.

PURPOSE: The purpose of our study was to assess whether the imaging and clinical features of cyclosporin A (CsA) neurotoxicity support a vascular "watershed" cause for the brain lesions observed. METHOD: Fourteen patients receiving CsA after allogeneic bone marrow transplantation or with marrow aplastic disorders developed neurotoxicity and MR or CT imaging abnormalities. The locations of brain lesions were analyzed, and clinical features, in particular bone marrow transplant thrombotic microangiopathy (BMT-TM), were assessed. RESULTS: Sixty-six lesions had consistent locations in watershed zones between major cerebral vessels or their main branches, including the parietal area (19), occipital poles (18), frontoparietal junction (15), inferior temporooccipital junction (10), and cerebellum (3). BMT-TM was identified in 10 of 10 marrow transplant patients studied. CONCLUSION: Vascular injury, suggested from watershed location and BMT-TM, likely establishes the location of the brain lesions in CsA neurotoxicity. Secondary toxicity in these vulnerable regions may cause the white matter lesions.

Adult↗