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Biomedical subjects

E M Wong

Publications and source records attributed to E M Wong.

14 recordsLinked to original sources
PubMed2005

Genetic, functional, and histopathological evaluation of two C-terminal BRCA1 missense variants.

BACKGROUND: The vast majority of BRCA1 missense sequence variants remain uncharacterized for their possible effect on protein expression and function, and therefore are unclassified in terms of their pathogenicity. BRCA1 plays diverse cellular roles and it is unlikely that any single functional assay will accurately reflect the total cellular implications of missense mutations in this gene. OBJECTIVE: To elucidate the effect of two BRCA1 variants, 5236G>C (G1706A) and 5242C>A (A1708E) on BRCA1 function, and to survey the relative usefulness of several assays to direct the characterisation of other unclassified variants in BRCA genes. METHODS AND RESULTS: Data from a range of bioinformatic, genetic, and histopathological analyses, and in vitro functional assays indicated that the 1708E variant was associated with the disruption of different cellular functions of BRCA1. In transient transfection experiments in T47D and 293T cells, the 1708E product was mislocalised to the cytoplasm and induced centrosome amplification in 293T cells. The 1708E variant also failed to transactivate transcription of reporter constructs in mammalian transcriptional transactivation assays. In contrast, the 1706A variant displayed a phenotype comparable to wildtype BRCA1 in these assays. Consistent with functional data, tumours from 1708E carriers showed typical BRCA1 pathology, while tumour material from 1706A carriers displayed few histopathological features associated with BRCA1 related tumours. CONCLUSIONS: A comprehensive range of genetic, bioinformatic, and functional analyses have been combined for the characterisation of BRCA1 unclassified sequence variants. Consistent with the functional analyses, the combined odds of causality calculated for the 1706A variant after multifactorial likelihood analysis (1:142) indicates a definitive classification of this variant as "benign". In contrast, functional assays of the 1708E variant indicate that it is pathogenic, possibly through subcellular mislocalisation. However, the combined odds of 262:1 in favour of causality of this variant does not meet the minimal ratio of 1000:1 for classification as pathogenic, and A1708E remains formally designated as unclassified. Our findings highlight the importance of comprehensive genetic information, together with detailed functional analysis for the definitive categorisation of unclassified sequence variants. This combination of analyses may have direct application to the characterisation of other unclassified variants in BRCA1 and BRCA2.

Adult↗
PubMed2005

Molecular characterization and cancer risk associated with BRCA1 and BRCA2 splice site variants identified in multiple-case breast cancer families.

Genetic screening of women from multiple-case breast cancer families and other research-based endeavors have identified an extensive collection of germline variations of BRCA1 and BRCA2 that can be classified as deleterious and have clinical relevance. For some variants, such as those in the conserved intronic splice site regions which are highly likely to alter splicing, it is not possible to classify them based on the identified DNA sequence variation alone. We studied 11 multiple-case breast cancer families carrying seven distinct splice site region genetic alterations in BRCA1 or BRCA2 (BRCA1, c.IVS6-2delA, c.IVS9-2A>C, c.IVS4-1G>T, c.IVS20+1G>A and BRCA2, c.IVS17-1G>C, c.IVS20+1G>A, c.IVS7-1G>A) and applied SpliceSiteFinder to predict possible changes in efficiency of splice donor and acceptor sites, characterized the transcripts, and estimated the average age-specific cumulative risk (penetrance) using a modified segregation analysis. SpliceSiteFinder predicted and we identified transcipts that illustrated that all variants caused exon skipping, and all but two led to frameshifts. The risks of breast cancer to age 70 yrs, averaged over all variants, over BRCA1 variants alone, and over BRCA2 variants alone, were 73% (95% confidence interval 47-93), 64% (95%CI 28-96) and 79% (95%CI 48-98) respectively (all P<0.0001). Therefore five of these seven consensus splice site variants of BRCA1 and BRCA2 produce a transcript similar to that of other previously described deleterious exonic variants and are associated with similar high lifetime risks.

Alternative Splicing↗
PubMed2001

Clinical determinants of the outcome of manual stretching in the treatment of congenital muscular torticollis in infants. A prospective study of eight hundred and twenty-one cases.

BACKGROUND: The natural history of congenital muscular torticollis and the outcome of different treatment modalities have been poorly investigated, and the results of treatment have varied considerably. METHODS: The main objective of this prospective study was to evaluate the outcomes of 821 consecutive patients with congenital muscular torticollis who were first seen when they were less than one year old, were treated with a standardized program of manual stretching, and were followed for a mean of 4.5 years. Before treatment, the patients were classified into one of three clinical groups: (1) palpable sternomastoid tumor, (2) muscular torticollis (thickening and tightness of the sternocleidomastoid muscle), and (3) postural torticollis (torticollis but no tightness or tumor). RESULTS: Of the 821 patients, 452 (55%) had a sternomastoid tumor; 276 (34%), muscular torticollis; and ninety-three (11%), postural torticollis. Multivariate analysis of the outcomes showed that (1) the duration of treatment was significantly associated with the clinical group (p < 0.0001), a passive rotation deficit of the neck (p < 0.0001), involvement of the right side (p < 0.0001), difficulties with the birth (p < 0.009), and age at presentation (p < 0.0001); (2) the overall final assessment score was associated with the rotation deficit (p = 0.02), age at presentation (p = 0.014), and duration of treatment (p < 0.0001); and (3) subsequent surgical treatment was required by 8% (thirty-four) of the 452 patients in the sternomastoid tumor group compared with 3% (eight) of the 276 patients in the muscular torticollis group and 0% (none) of the ninety-three patients in the postural torticollis group. CONCLUSIONS: This large prospective study demonstrated that controlled manual stretching is safe and effective in the treatment of congenital muscular torticollis when a patient is seen before the age of one year. The most important factors that predict the outcome of manual stretching are the clinical group, the initial deficit in rotation of the neck, and the age of the patient at presentation. Surgical treatment is indicated when a patient has undergone at least six months of controlled manual stretching and has residual head tilt, deficits of passive rotation and lateral bending of the neck of >15 degrees, a tight muscular band or tumor, and a poor outcome according to our special assessment chart.

Age Factors↗
PubMed2001

Effects of blood-processing protocols on fetal and total DNA quantification in maternal plasma.

BACKGROUND: Recently, apoptotic cells have been found in plasma obtained by centrifugation of blood from pregnant women, raising the question of what constitutes plasma and whether plasma is truly cell free. We compared the effects of different blood-processing protocols on the quantification, DNA composition, and day-to-day fluctuation of fetal and total DNA in maternal plasma. METHODS: Blood samples were collected from healthy pregnant women. The blood sample from each individual was simultaneously processed by different means, including the following: Percoll separation, centrifugation, microcentrifugation, and filtration. The resulting plasma aliquots were subjected to real-time quantitative amplification of the beta-globin (for total DNA) and SRY (for fetal DNA) genes. The differences in the beta-globin and SRY DNA concentrations and the degree of variation between the various plasma aliquots were assessed statistically. RESULTS: Different protocols of blood processing significantly affected the quantification and the day-to-day fluctuation of total (P <0.001), but not fetal (quantification, P = 0.336; fluctuation, P = 0.206), DNA in maternal plasma. The quantitative difference could be attributed to the fact that efficacies of different protocols for generating cell-free plasma vary. Processing blood samples by centrifugation followed by filtration or microcentrifugation is effective in producing cell-free plasma. CONCLUSIONS: Standardization in plasma-processing protocols is needed for maternal plasma DNA analysis, especially for quantification of total DNA in maternal plasma. Such preanalytic factors may also affect other applications of plasma DNA analysis.

Blood Specimen Collection↗
PubMed2000

Longitudinal changes in trunkal balance after selective fusion of King II curves in adolescent idiopathic scoliosis.

STUDY DESIGN: A retrospective study was performed on the longitudinal changes of the trunkal balance in King II curves treated with selective posterior fusion of the thoracic curve. OBJECTIVES: To determine the effect of selective fusion on the coronal and sagittal plane balance in King II adolescent idiopathic scoliosis by analyzing the changes in shoulder level, pelvic tilt, trunk shift, centering of fusion mass, changes in the T11-L1 sagittal angle, and behavior of the unfused lumbar curve and its correlation with the end level of fusion. SUMMARY OF BACKGROUND DATA: It has been shown that selective fusion of the thoracic curve in a King II curve is associated with good results and arrest of lumbar curve progression in selected cases. Detailed quantitative analysis of the longitudinal changes and correlation between various clinical and radiologic parameters was not readily available in the literature. METHODS: This study investigated 24 patients with King II adolescent idiopathic scoliosis treated with Harrington rod and segmental spinous processes wiring in a 10-year period with follow-up periods of 3 to 8 years. Clinical and radiologic parameters were analyzed longitudinally during the preoperative and immediate postoperative period, then at 6 months, 1 year, 3 years, and final follow-up assessment. RESULTS: Progressive improvement in the trunk shift to within 2 cm of the center sacral line together with progressive leveling and stabilization of the shoulder and pelvic tilt was noted during the first year after surgery. Gradual movement of the Harrington rod toward the center sacral line assuming a "straight rod sign" with a rod to center line distance of less than 1 cm was found in 90% of the cases. Improvement of the sagittal alignment with no significant residual junctional kyphosis also was found. The unfused lumbar curve improved in both the coronal and sagittal plane and did not show any further progression. Patients whose lower end level of fusion was at T12 had a better percentage of lumbar curve correction than those that ended at L1. CONCLUSIONS: Selective thoracic fusion for King II idiopathic scoliosis curve can achieve acceptable coronal and sagittal plane balance of the spine. The rod to centersacral line distance is a helpful parameter in assessing the results and prognosis of surgically treated patients.

Adolescent↗
PubMed2000

The clinical presentation and outcome of treatment of congenital muscular torticollis in infants--a study of 1,086 cases.

BACKGROUND/PURPOSE: The main objectives of this study were to define the clinical patterns and characteristics of congenital muscular torticollis (CMT) presented in the first year of life and to study the outcome of different treatment methods. METHODS: This is a prospective study of all CMT patients seen in 1 center over a 12-year period with uniform recording system, assessment methods, and treatment protocol. RESULTS: From a total of 1,086 CMT infants, 3 clinical subgroups of sternomastoid tumor (SMT; 42.7%), muscular torticollis (MT; 30.6%), and postural torticollis (POST; 22.1%) were identified. The SMT group was found to present earlier within the first 3 months and was associated with higher incidence of breech presentation (19.5%), difficult labor (56%), and hip dysplasia (6.81%). Severity of limitation of passive neck rotation range (ROTGp) was found to correlate significantly with the presence of SMT, bigger tumor size, hip dysplasia, degree of head tilt, and craniofacial asymmetry. CONCLUSIONS: A total of 24.5% of the patients with initial deficits of passive rotation of less than 10 degrees showed excellent and good outcome with active home positioning and stimulation program. The remaining cases with rotation deficits of over 10 degrees and treated with manual stretching program showed an overall excellent to good results in 91.1% with 5.1% requiring subsequent surgical treatment. The most important prognostic factors for the necessity of surgical treatment were the clinical subgroup, the ROTGp, and the age at presentation (P < .001).

Age Factors↗
PubMed1999

Derivation of a prediction rule for post-traumatic acute lung injury.

The purpose of this study was to derive an early, highly sensitive and specific prediction rule for the development of post-traumatic acute lung injury (ALI). In a prospective, non-interventional study a convenience sample of 92 adults admitted to the resuscitation room following blunt trauma was studied in order to derive this prediction rule. The study was conducted in the emergency department of a university hospital in the New Territories of Hong Kong. One emergency physician assessed each patient for 25 variables, which might predict post-traumatic ALI, and the primary outcome measure was the presence or absence of ALI 48 h post-injury. Eleven variables associated with ALI were entered into a classification and regression tree (CART) in order to derive models predictive of ALI. Two models were developed and used to derive the decision rule. Acute lung injury was likely if either: (1) the patient had an ISS > 27 and a haematocrit < 0.37, or (2) the patient had a haematocrit < 0.36 and a total leucocyte count > 15. The first guideline had a classification rate of 96.7% (95% confidence interval (CI), 90.8-99.3%), a sensitivity of 100% (CI 65.2-100%) and a specificity of 96.5% (CI 90.0-99.3%). The second guideline had a classification rate of 96.7% (CI 90.8-99.3%), a sensitivity of 85.7% (CI 42.1-99.6%) and a specificity of 97.7% (CI 91.8-99.7%). Practical highly sensitive and specific prediction guidelines for post-traumatic acute lung injury have been derived and now require prospective validation.

Adult↗
PubMed1998

Effects of blood transfusion on left ventricular output in premature babies.

OBJECTIVE: To investigate the acute effects of red blood cell transfusion on haemodynamics in preterm babies. SETTING: A neonatal unit in a University Hospital. PATIENTS: Preterm babies whose postnatal age was less than four weeks and who required red blood cell transfusion. MEASUREMENT: Cardiac output and left ventricular systolic function was determined using Doppler echocardiography before, one hour and 24 h after red blood cell transfusion. Blood pressure and haematocrit were also recorded at the same time. Mixed-effects regression model was used to analyse the effect of blood transfusion on left ventricular function and cardiac output. RESULTS: 57 preterm babies were recruited. Univariate analysis showed that cardiac index decreased significantly 24 h after transfusion (P<0.05). Systemic red cell transport increased by an average of 11.1% 24 h after transfusion (P<0.05). Multivariate analysis showed that the cardiac index was negatively associated with haematocrit and the index was higher in male babies. CONCLUSION: There was a significant drop in cardiac index and an increase in systemic red cell transport 24 h after transfusion in premature babies.

Analysis of Variance↗
PubMed1998

Risk factors for Enterobacter septicemia in a neonatal unit: case-control study.

Thirty cases of Enterobacter aerogenes or Enterobacter cloacae septicemia diagnosed over a 32-month period in a tertiary care neonatal unit were enrolled in a case-control study. Each case patient was matched with two controls (patients occupying the cots nearest the case patient when the latter developed septicemia). Of the 32 perinatal characteristics evaluated, 11 were identified by univariate analysis to be significantly associated with the infection. These included parents being residents of the Vietnamese refugee camps, respiratory distress syndrome, necrotizing enterocolitis, umbilical arterial catheterization, umbilical venous catheterization, bladder catheterization, mechanical ventilation, antibiotic treatment, peripheral venous catheterization, nasogastric intubation, and parenteral nutrition. Multivariate analysis, however, showed that preceding bladder catheterization and ongoing parenteral nutrition were the only independent risk factors for enterobacter septicemia. Strict aseptic technique in the preparation of parenteral nutrition fluid and avoidance of bladder catheterization are measures that may reduce the risk of enterobacter sepsis for newborns.

Bacteremia↗
PubMed1985

Alternative conformations of the ColE1 replication primer modulate its interaction with RNA I.

Replication of the ColE1 plasmid is regulated by the interaction of its primer RNA with a small countertranscript (RNA I) that acts as a repressor of functional primer formation. The interaction is dependent on the specific conformations of the complementary RNA molecules. Early in its synthesis, primer adopts an "anti-RNA I" configuration. As transcription proceeds, it is preempted by formation of an alternative domain designated stem-loop IV. This conformational transition has a significant effect on the rate of association of RNA I with the primer in vitro. Nascent primer in the "anti-RNA I" conformation (135 nucleotides) interacts with RNA I 6-fold faster than primer in the stem-loop IV conformation (241 nucleotides), and 35-fold faster than a 567 nucleotide primer precursor. We propose that a conformation-dependent "window of susceptibility" of primer to RNA I exists during primer transcription, and that altered conformations play a role in modulating the rate of functional primer formation.

Bacteriocin Plasmids↗
PubMed1982

Temperature-sensitive copy number mutants of CoIE1 are located in an untranslated region of the plasmid genome.

We have isolated two mutant plasmid derivatives of ColE1 that exhibit temperature-sensitive replication properties. Both mutants have a normal copy number at 30 degrees C but increase their copy number 30- to 40-fold after a shift in temperature to 42 degrees C. A plasmid-encoded enzyme, beta-lactamase (penicillinase, EC 3.5.2.6), undergoes a 30- to 40-fold increase in specific activity concomitant with the increase in plasmid copy number. The copts phenotype of these mutants is not due to the synthesis of a temperature-sensitive polypeptide. Both mutations are located in an untranslated region of the plasmid genome encoding two overlapping transcripts involved in plasmid replication: a small transcript known as RNA I that acts as a negative control element in replication and a large transcript that has been characterized as the replication primer in vitro. The mutations alter the sequence encoding the primer but lie immediately 5' to the initiating nucleotide of RNA I, in the RNA I promoter region. The possibility that the temperature-dependent plasmid DNA amplification is a consequence of a temperature-sensitive RNA I promoter was tested by inserting the RNA I promoters from the wild-type and mutant plasmids into a plasmid in which galactokinase expression is dependent upon an exogenous promoter. These experiments demonstrate that the mutant promoters are not temperature-sensitive. Rather, the mutations may affect the secondary structure of the replication primer in a region important for RNA I interaction.

Bacterial Proteins↗
PubMed1981

Antihypertensive pyrrolo[1,2-c]quinazolines and pyrrolo[1,2-c]quinazolinones.

The synthesis of a variety of pyrrolo[1,2-c]quinazolines and pyrrolo[1,2-c]quinazolinones is described. Several of these compounds have exhibited antihypertensive properties in the spontaneously hypertensive rat (SHR). Structure-activity comparisons have indicated that optimal activity is obtained in both the 2-carbethoxydihydroquinazoline series (C) and 2-carbethoxyquinazolinone series (D) when there is either a carbethoxy or cyanoethyl group at position 6 and no substitution in the benzene ring, while optimal activity is obtained in the 2-methyl-quinazolinone series (D) when both position 6 and the benzene ring are unsubstituted.

Animals↗
PubMedDate not supplied

Colour but not form patterns combine between the eyes.

PURPOSE: A visual pattern was broken into patches, some of which were shown to one eye and the remainder of which were shown to the other eye. Our aim was to find the conditions under which the subject could combine the information given to the two eyes separately to reconstruct the original pattern. METHODS: One green and four red patches were presented to one eye. Five patches were presented to the other eye at corresponding locations but with red substituted for green and green for red. RESULTS: When the chromatic contrasts were appropriately adjusted, subjects saw five patches of a single colour for most of the viewing time. Intermixed horizontal and vertical gratings did not separate into coherent percepts in the same way. CONCLUSIONS: This result indicates cooperation between the responses to colour patches presented to different eyes, a finding that may be of use in testing for normal binocular vision.

Color Perception↗