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Biomedical subjects

R Harris

Publications and source records attributed to R Harris.

At least 37 records · Page 2Linked to original sources

Variation of benefits and harms of breast cancer screening with age.

The critical issue in deciding whether to recommend breast cancer screening for women in their forties is to determine whether potential benefits are substantially greater than potential harms. Recent evidence from randomized clinical trials makes it likely that, after 10-12 years of follow-up, there is a real benefit from screening women ages 40-49, on the order of a 15-20% reduction in the relative risk of breast cancer death. This relative risk reduction translates into an absolute risk reduction of 1-2 women whose lives are extended from screening 1,000 women in their forties annually for 10 years (i.e., about one life extended per 5,000 mammograms). The absolute benefit of screening increases with age. Evidence about potential harms is less well established, but it is compelling that there are 15-40 times as many false positive as true positive mammograms (depending on the patient's age), and that at least some of the women with false positive mammograms have ongoing psychological distress as a result. Some 30% of all women who are screened annually during their forties will have at least one false positive mammogram and this probability likely decreases with advancing age. If the balance between benefits and harms is judged to be a "close call" for women in their forties, a blanket recommendation for all is inappropriate. Instead, each woman in her forties should be helped to understand the pros and cons of screening, to clarify her own values, and to consider with her primary care physician what decision would be best for her.

Adult

Antecedent circumstances surrounding neural tube defect births in 1990-1991. The Steering Committee of the National Confidential Enquiry into Counselling for Genetic Disorders.

OBJECTIVE: To investigate births with neural tube defects at a time when most districts were screening for the condition. The objective was to document the circumstances surrounding each affected birth and assess the care provided against given standards. DESIGN: Retrospective review of antenatal casenotes by the obstetric team. POPULATION: Three hundred and eight births in England and Wales in 1990 to 1991 were reported to the Office of Population Census Survey (OPCS) to involve neural tube defects. Sufficient information was available to identify both the woman and the obstetrician in 213 pregnancies. Details were obtained from a questionnaire completed by the obstetric team for 168 (79%). In 20/168 cases either the reported outcome was not a live birth/stillbirth or the pregnancy did not involve a neural tube defect: eight resulted in a 'normal' infant, eight were terminated and in four the abnormality was not a neural tube defect. Thus 148 eligible cases were available for analysis. RESULTS: Of the 148 births, the anomaly was not detected prenatally or detected later than 25 weeks of gestation in 98 cases (66%), diagnosed in a multiple pregnancy in 24 (16%) and diagnosed prenatally but the woman chose to continue the pregnancy in 26 (18%). Of the 98 births not detected prenatally or detected late during pregnancy, the surrounding circumstances were that screening was declined in six cases (4%), screening was not offered due to late booking in 30 (20%), serum alpha-fetoprotein screening gave a false negative result in eight (5%), ultrasound screening gave a false negative result in 29 (20%), both screening methods gave false negative results in 17 (11%) and other reasons in eight (5%). The estimated sensitivity of ultrasound screening for anencephaly was 100%. For spina bifida the estimated sensitivity for singleton pregnancies is higher for serum alpha-fetoprotein screening, 84% to 92%, than ultrasound screening, 70% to 84%, for a range of assumptions regarding the degree of under-reporting to OPCS of live births and terminations. CONCLUSIONS: Late booking precluded the offer of screening tests in a substantial proportion (22%) of cases. The presence of multiple fetuses including one or more with a neural tube defect was a serious additional complication in prenatal screening, diagnosis and counselling. Screening for neural tube defects was widespread in 1990 to 1991, although variations in the services provided were documented. Ultrasound scanning was a major component but was associated with a lower sensitivity than maternal serum alpha-fetoprotein screening for neural tube defects other than anencephaly.

Anencephaly

Outcome of pregnancy in women with Marfan's syndrome.

OBJECTIVE: To improve life expectancy and prevent premature mortality in women with Marfan's syndrome. METHODS: During the development of a regional genetic register for Marfan's Syndrome the outcome of 91 pregnancies in 36 women with this condition was established retrospectively and the cardiovascular and obstetric complications documented. RESULTS: No patient had a significant cardiovascular abnormality limiting function before her pregnancy. Of 36 women, four had an aortic dissection relating to pregnancy and two others required aortic surgery following delivery. Thirty women had uncomplicated gestational histories. The incidence of obstetric complications did not exceed expectation. CONCLUSIONS: Women with Marfan's syndrome are at significant risk of aortic dissection in pregnancy even in the absence of preconceptional cardiovascular abnormality. Aortic root dilatation may be a predictor of risk but dissection may occur without significant dilatation. Guidelines for obstetric care are suggested and preconceptional assessment recommended.

Adult

Evolving phenotype of Marfan's syndrome.

AIM: To examine evolution of the physical characteristics of Marfan's syndrome throughout childhood. METHODS: 40 children were ascertained during the development of a regional register for Marfan's syndrome. Evolution of the clinical characteristics was determined by repeat evaluation of 10 patients with sporadic Marfan's syndrome and 30 with a family history of the condition. DNA marker studies were used to facilitate diagnosis in those with the familial condition. RESULTS: Musculoskeletal features predominated and evolved throughout childhood. Gene tracking enabled early diagnosis in children with familial Marfan's syndrome. CONCLUSIONS: These observations may aid the clinical diagnosis of Marfan's syndrome in childhood, especially in those with the sporadic condition. Gene tracking has a role in the early diagnosis of familial Marfan's syndrome, allowing appropriate follow up and preventive care.

Adolescent

Confidential inquiry into families with two siblings with cystic fibrosis.

OBJECTIVE: To audit the care that had been provided to couples before the birth of a child with cystic fibrosis where a sibling had been previously diagnosed. DESIGN: Retrospective review of case notes. SAMPLE: Families where at least one affected child had been born between 1 January 1991 and 30 June 1995 and the diagnosis in the first child was made before the second affected pregnancy reached 20 weeks. The combination of information on these families with data from the prenatal diagnosis register allowed the reconstruction of a cohort of pregnancies in women with a previous affected child. MAIN RESULTS: Forty six eligible families with a second affected child were identified. Details from the paediatrician who had diagnosed the first affected child were obtained in 43 cases: all 43 couples were offered genetic counselling, but where provided by a paediatrician this was difficult to assess as no couple was sent a summary letter. Details were obtained from the obstetrician in the subsequent affected pregnancy in 42 cases: prenatal diagnosis was not offered in 10 (24%), offered and declined in 24 (57%), offered and accepted but termination declined in eight (19%). In the overall cohort of at risk pregnancies, the estimated rate of prenatal diagnosis offer was 97%, prenatal diagnosis uptake 86%, false negative prenatal diagnosis rate 0%, and uptake of termination 95%. CONCLUSIONS: (1) Parental choice was an important determinant of second affected births. (2) Despite widespread availability, prenatal diagnosis was not offered in an estimated 3% of at risk pregnancies. (3) There were shortcomings in counselling documentation, in particular failure to send a summary letter to counselled couples.

Abortion, Legal

The uptake and acceptability to patients of cystic fibrosis carrier testing offered in pregnancy by the GP.

OBJECTIVE: To determine the uptake and acceptability of cystic fibrosis (CF) carrier testing when offered to women at the first antenatal booking appointment by their general practitioner. SETTING: Eight-general practices in the north west region with a combined patient list size of 42000. DESIGN: Offer of carrier screening at first antenatal booking appointment to pregnant women below 14 weeks' gestation; women accepting were alternately allocated to either couple testing (with full disclosure) or stepwise testing: SUBJECTS: Six hundred and twenty three women were offered CF carrier testing. MAIN OUTCOME MEASURES: (1) Acceptance of the offer of CF carrier testing. (2) Acceptability of the test to women following screening, evaluated through (i) postal questionnaire, (ii) semistructured interview. RESULTS: Five hundred and twenty-nine (84.9%) women accepted the test; the level of uptake varied across the eight practices (range 11-99%). In 26/249 (10%) couple tests no paternal sample was provided. When asked what had influenced their decision to be tested, 59/377 (16%) women did not refer to CF in their answers and six (2%) said that they did not feel they could refuse the test. After receiving their results, 368/379 (97%) women felt that they had made the right decision to be tested, but two carriers and three non-carriers had felt unhappy about testing. Couple testing with full disclosure was associated with lower anxiety levels two weeks after receiving the result for the pregnancy than stepwise testing and 82/278 (29%) non-carriers believed that they had no residual risk in relation to CF. CONCLUSIONS: The response from women accepting CF carrier testing was largely positive but a minority of women expressed concern about the test and the way it was offered and a substantial proportion of women were falsely reassured by their "negative" result. Higher levels of acceptance tended to occur in the practices which offered the test there and then rather than giving couples more time to decide about testing. Some women appeared to have accepted the test because of a belief in the importance of testing in pregnancy rather than because of the disease in question.

Adolescent

Acute neurologic dysfunction associated with high-dose chemotherapy and autologous bone marrow rescue for primary malignant brain tumors.

UNLABELLED: Acute neurologic complications occurred 103 times in 50 (54%) of 92 patients (primarily children) treated with high-dose chemotherapy and autologous bone marrow rescue for primary central nervous tumors. Different types of neurologic compromise occurred during the chemotherapy infusion as compared to the first 100 days after the chemotherapy and the greater-than-100-day time period. The causes of the neurologic compromise were also time sensitive. BACKGROUND: Results of treatment for children with primary brain tumors using high-dose chemotherapy with autologous marrow rescue (ABMR) have been encouraging. However, the neurotoxicity associated with this technique remains a major concern. We reviewed the records of 92 patients who underwent ABMR for malignant brain tumors between 1986 and 1992 for the occurrence and timing of acute neurologic dysfunction (AND). METHODS: Individual investigators at the participating institutions retrospectively completed standardized forms on each patient. The manner in which the distribution of AND versus time of treatment emerged led to the establishment of distinct time periods for data analysis and discussion. The pre-ABMR period included those events that occurred during the chemotherapy infusion, the early posttreatment period included the first 100 days following bone marrow rescue, and the late posttreatment period was greater than 100 days following bone marrow rescue. RESULTS: Fifty patients (54%) had 103 episodes of AND. AND included encephalopathies with or without hallucinations or coma (32), seizures (23), headaches (9), ataxia-tremor-dysarthria syndrome (7), anorexia and nausea syndrome (7) and others (25). During the chemotherapy infusion, encephalopathies and seizures were most common. Hallucinations occurred primarily related to drug infusion, while encephalopathies without hallucinations were usually due to demonstrable dysmetabolic states. In the 100 days following ABMR, dysmetabolic states and iatrogenic factors caused 45% and progressive disease caused 33% of AND. Greater than 100 days from ABMR, progressive disease caused 55% of AND; 7 patients were noted to develop chronic anorexia and nausea of unclear etiology. The occurrence of neurologic compromise was not related to the chemotherapy regimens, tumor histology, tumor location, patient age, prior treatment, or the amount of tumor at time of treatment. Dexamethasone use was the only clinical factor associated with AND (p < 0.004). CONCLUSIONS: The cause of AND was definable for 95% of instances that occurred within 100 days of ABMR. Early AND was often iatrogenic and reversible. The greater the time from ABMR the more likely AND was due to progressive disease. Clinical factors could not predict the occurrence of AND as only the concurrent use of dexamethasone at the time of treatment proved significant. Although frequent, AND should not be considered a limiting toxicity of this approach or preclude the use of this technique.

Acute Disease

Outcome of unrelated donor bone marrow transplantation in 40 children with Hurler syndrome.

Long-term survival and improved neuropsychological function have occurred in selected children with Hurler syndrome (MPS I H) after successful engraftment with genotypically matched sibling bone marrow transplantation (BMT). However, because few children have HLA-identical siblings, the feasibility of unrelated donor (URD) BMT as a vehicle for adoptive enzyme therapy was evaluated in this retrospective study. Forty consecutive children (median, 1.7 years; range, 0.9 to 3.2 years) with MPS I H received high-dose chemotherapy with or without radiation followed by BMT between January 27, 1989 and May 13, 1994. Twenty-five of the 40 patients initially engrafted. An estimated 49% of patients are alive at 2 years, 63% alloengrafted and 37% autoengrafted. The probability of grade II to IV acute graft-versus-host disease (GVHD) was 30%, and the probability of extensive chronic GVHD was 18%. Eleven patients received a second URD BMT because of graft rejection or failure. Of the 20 survivors, 13 children have complete donor engraftment, two children have mixed chimeric grafts, and five children have autologous marrow recovery. The BM cell dose was correlated with both donor engraftment and survival. Thirteen of 27 evaluable patients were engrafted at 1 year following URD BMT. Neither T-lymphocyte depletion (TLD) of the bone marrow nor irradiation appeared to influence the likelihood of engraftment. Ten of 16 patients alive at 1 year who received a BM cell dose greater than or equal to 3.5 x 10(8) cells/kg engrafted, and 62% are estimated to be alive at 3 years. In contrast, only 3 of 11 patients receiving less than 3.5 x 10(8) cells/kg engrafted, and 24% are estimated to be alive at 3 years (P = .05). The mental developmental index (MDI) was assessed before BMT. Both baseline and post-BMT neuropsychological data were available for 11 engrafted survivors. Eight children with a baseline MDI greater than 70 have undergone URD BMT (median age, 1.5 years; range, 1.0 to 2.4 years). Of these, two children have had BMT too recently for developmental follow-up. Of the remaining six, none has shown any decline in age equivalent scores. Four children are acquiring skills at a pace equal to or slightly below their same age peers; two children have shown a plateau in learning or extreme slowing in their learning process. For children with a baseline MDI less than 70 (median age, 2.5 years; range, 0.9 to 2.9 years), post-BMT follow-up indicated that two children have shown deterioration in their developmental skills. The remaining three children are maintaining their skills and are adding to them at a highly variable rate. We conclude that MPS I H patients with a baseline MDI greater than 70 who are engrafted survivors following URD BMT can achieve a favorable long-term outcome and improved cognitive function. Future protocols must address the high risk of graft rejection or failure and the impact of GVHD in this patient population.

Bone Marrow Transplantation

Genetic testing.

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Genetic Counseling

Hepatitis C in human immunodeficiency virus-coinfected patients: increased variability in the hypervariable envelope coding domain.

Patients coinfected with the hepatitis C virus (HCV) and the human immunodeficiency virus (HIV) were studied with regard to nucleotide sequence variability in the E2/NS1 first hypervariable region of the HCV genome. The nucleotide variability within individual patients was compared to patients infected only with HCV. The proportion of predicted synonymous and nonsynonymous amino acid changes, and the relationship to putative high-antigenicity sites, were evaluated in the hypervariable envelope domain. Ninety-one clones from 10 patients with HCV/HIV coinfection were sequenced, following polymerase chain reaction (PCR) amplification of the hypervariable region. The control HCV group included 53 clones from 7 patients. Sequence analysis encompassed the region coding for amino acids 384 to 414. Consensus sequences from each patient were used as the internal standard for nonsynonymous amino acid codon variability. Cumulative proportional comparison at each amino acid site revealed increased variability in HCV RNA from patients with HCV/HIV coinfection versus HCV alone (P < .05). The greatest variability was observed at amino acids 386, 397, 400, 402, 405, 407, and 414, with >l0 percent clonal variation at these sites. Jameson-Wolf plots were used to predict putative high-antigenicity domains. Nonsynonymous clonal variation resulted in alteration of putative antigenic sites within the hypervariable region. All clones had at least one high-probability site. Clones with unique predicted antigenic domains were observed more frequently in HIV/HCV coinfected patients, and, independent of viral titer, were consistent with increased sequence variability. These data suggest an accumulation of envelope variants in the HCV/HIV coinfected patients, which could be related to ineffective viral clearance, and may help explain prior reports of interferon (IFN) resistance in this patient group.

Adult

Research in the community: recruiting and retaining practices.

Medical investigators increasingly attempt to demonstrate the effectiveness of treatments given in routine practice settings as well as in research settings. We identified and describe several key issues in practice-based research: identifying the appropriate population; drawing the sample; recruitment of physicians and patients; maintenance of the physician-researcher relationship; and data management. Three on-going practice-based projects are described from the perspective of these key issues. Two are practice-based randomized trials, one is a larger cohort study. Common characteristics are identified which contributed to the success of the three projects: direct recruitment of clinicians by clinicians; close liaison with local medical organizations; on-going personal contact with the practices; and recognition of the value of the practicing physician's time.

Community Medicine

commissureless controls growth cone guidance across the CNS midline in Drosophila and encodes a novel membrane protein.

The commissureless (comm) gene was identified previously in a large-scale screen for mutations that disrupt CNS axon pathways in Drosophila. The comm gene has a unique mutant phenotype: the complete absence of most axon commissures, while midline cells and other aspects of CNS fate and patterning are left unchanged. Here, we report on the molecular cloning, characterization, and expression of the comm gene. comm encodes a novel protein of 370 amino acids that lacks a signal sequence, has a transmembrane domain, and biochemically copurifies with membranes. COMM mRNA and COMM protein are dynamically expressed during embryogenesis, including by CNS midline glia during the formation of the axon commissures. Anti-COMM antibodies reveal strong staining of organelles likely to include the Golgi complex and endosomes and weaker staining of the cell surface. As commissural growth cones contact and traverse the CNS midline, COMM protein is apparently transferred from midline glia to commissural axons.

Animals

Guidance cues at the Drosophila CNS midline: identification and characterization of two Drosophila Netrin/UNC-6 homologs.

Netrins are chemotropic guidance signals that play important roles in circumferential axon guidance in C. elegans and in the developing vertebrate spinal cord. We have identified two Drosophila homologs of this protein family (Netrin-A and Netrin-B). Both Netrins are dynamically expressed throughout embryogenesis, including CNS midline expression at the time of commissure formation. Both Netrin genes map close to each other on the X chromosome, and embryos deficient for this region exhibit defects in commissure formation. This CNS phenotype can be rescued by expression of either Netrin at the CNS midline, confirming an important role for Drosophila Netrins in commissural growth cone guidance. A localized source of Netrin protein at the midline is apparently important for function, since ectopic expression of either Netrin throughout the CNS results in phenotypic defects similar to the loss-of-function phenotype.

Animals

Observation of albumin resonances in proton nuclear magnetic resonance spectra of human blood plasma: N-terminal assignments aided by use of modified recombinant albumin.

Two-dimensional total shift correlation spectroscopy (TOCSY) and double-quantum-filtered phase-sensitive homonuclear shift-correlated spectroscopy (DQF-COSY) 1H NMR spectra are used to assign peaks for about one sixth of the amino acids residues of isolated human serum albumin (67 kDa) to amino acid types. Sequential assignments are presented for 1H NMR resonances of the N-terminal residues Asp1, Ala2 and His3 of human serum albumin (HSA). These are based on pH-dependent chemical shifts reflecting the titrating N-terminal NH2 and the His3 imidazole ring, in addition to DQF-COSY and TOCSY experiments. Studies of variant recombinant human albumin with Asp1 deleted, rHA(2-585), aided the assignments. The structural nature of the N-and C-termini of HSA are discussed and pKa values of 7.9 and 6.3 were determined for the N-terminal amino group and His3 imidazole ring, respectively. About 20 spin systems for albumin, including those for the N-terminal amino acids, were assigned in 1H NMR spectra of blood plasma buy comparison with isolated albumin. Resonances for lipids within lipoproteins and also several low molecular mass components can also be assigned in 2D TOCSY 1H NMR spectra of plasma.

Amino Acid Sequence