Biomedical subjects
Publications and source records attributed to J Waters.
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The inactive X (Xi) differs from its active homologue (Xa) in a number of ways, including increased methylation of CpG islands, replication late in S phase, underacetylation of histone H4 and association with XIST RNA. Global changes in DNA methylation occur relatively late in development, but the other properties all change during or shortly after the establishment of Xi and may play a role in the mechanism by which an inactive chromatin conformation spreads across most of the chromosome. In the present report, we use two human X;autosome translocation chromosomes to study the spreading of inactive X chromatin across X;autosome boundaries. In one of these chromosomes, t(X;6), Xp distal to p11.2 is replaced by 6p21.1-6pter and, in the other, ins(X;16), a small fragment derived from 16p13 is inserted into the distal third of Xq. In lymphoid cells from patients carrying these translocations in an unbalanced form, Xi was shown by HUMARA assay to be derived exclusively [t(X:6)] or predominantly [ins (X;16)] from the derived X chromosome. We used a combination of immunolabelling and RNA/DNA fluorescence in situ hybridization to define the distribution of XIST RNA, deacetylated H4 and late-replicating DNA across the two derived X chromosomes in inactive form. Within the limits of the cytogenetic techniques employed, the results show complete coincidence of these three parameters, with all three being excluded from the autosomal component of the derived X chromosome.
OBJECTIVE: To examine baseline renal screening practices and the effect of nurse case management of patients with diabetes in a group model health maintenance organization (HMO). RESEARCH DESIGN AND METHODS: We performed both 1-year retrospective and 1-year prospective studies of renal assessment practices and ACE inhibitor usage in a cohort of 133 diabetic patients enrolled in a randomized controlled trial of a diabetes nurse case management program in a group model HMO. In accordance with American Diabetes Association recommendations, urine dipstick and quantitative protein and microalbuminuria testing rates were calculated. RESULTS: At baseline, 77% of patients were screened for proteinuria with dipsticks or had quantitative urine testing. Of patients with negative dipstick findings, 30% had appropriate quantitative protein or microalbumin follow-up at baseline. Baseline ACE inhibitor usage was associated with decreased follow-up testing (relative risk = 0.47). Nurse case management was associated with increased quantitative protein or or microalbumin testing and increased follow-up testing (relative risk = 1.65 and 1.60, respectively). CONCLUSIONS: We found a higher degree of adherence to recommendations for renal testing than has been reported previously. Nurse case management intervention further increased renal screening rates. The inverse association between ACE inhibitor usage and microalbumin testing highlights a potentially ambiguous area of current clinical pathways.
BACKGROUND: Control of hyperglycemia delays or prevents complications of diabetes, but many persons with diabetes do not achieve optimal control. OBJECTIVE: To compare diabetes control in patients receiving nurse case management and patients receiving usual care. DESIGN: Randomized, controlled trial. SETTING: Primary care clinics in a group-model health maintenance organization (HMO). PATIENTS: 17 patients with type 1 diabetes mellitus and 121 patients with type 2 diabetes mellitus. INTERVENTION: The nurse case manager followed written management algorithms under the direction of a family physician and an endocrinologist. Changes in therapy were communicated to primary care physicians. All patients received ongoing care through their primary care physicians. MEASUREMENTS: The primary outcome, hemoglobin A1c (HbA1c) value, was measured at baseline and at 12 months. Fasting blood glucose levels, medication type and dose, body weight, blood pressure, lipid levels, patient-perceived health status, episodes of severe hypoglycemia, and emergency department and hospital admissions were also assessed. RESULTS: 72% of patients completed follow-up. Patients in the nurse case management group had mean decreases of 1.7 percentage points in HbA1c values and 43 mg/dL (2.38 mmol/L) in fasting glucose levels; patients in the usual care group had decreases of 0.6 percentage points in HbA1c values and 15 mg/dL (0.83 mmol/L) in fasting glucose levels (P < 0.01). Self-reported health status improved in the nurse case management group (P = 0.02). The nurse case management intervention was not associated with statistically significant changes in medication type or dose, body weight, blood pressure, or lipids or with adverse events. CONCLUSIONS: A nurse case manager with considerable management responsibility can, in association with primary care physicians and an endocrinologist, help improve glycemic control in diabetic patients in a group-model HMO.
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To determine the prevalence of activated protein C resistance and the factor V Leiden mutation (position 1691, arginine 506 to glutamine substitution) in children with thrombosis, plasma samples from children with thrombosis were tested for activated protein C resistance. DNA was analyzed for the factor V Leiden mutation. Five of 34 children (15%) had activated protein C resistance; each was heterozygous for the factor V Leiden mutation. All 5 children heterozygous for the factor V Leiden mutation suffered non-CNS venous thromboses comprising 21% of the group of children (5/24) with non-CNS venous thrombotic events. Each of these 5 children had a family history of thrombosis. In conclusion, children with non-CNS venous thrombosis should be evaluated for the factor V Leiden mutation. Children most likely affected are those with a family history of thrombosis.
UNLABELLED: This study compared anxiety, fears, depression and behavioural problems as occurring in children with congenital heart disease, comparing them with samples of normal children. It further considered the influence of maternal anxiety, as well as analyzing a subgroup of children with cyanotic forms of congenital heart disease to determine if they were at higher risk than acyanotic children for the problems identified. METHOD: We recruited 40 consecutive children with congenital heart disease without obvious psychosocial problems from the Cardiology clinic at the Alberta Children's Hospital. Of the 40 children, 39 families consented to have the children participate, of which 24 were cyanotic and 15 acyanotic. Children completed the revised versions of the Fear Survey Scale-Revised and the Child Manifest Anxiety Scale as well as the Child Depression Inventory. Mothers completed the Child Behaviour Checklist, and the State Trait Anxiety Scale. RESULTS: Children with congenital heart diseases demonstrated more medical fears, and more physiological anxiety, than the normative samples. More specifically, children with cyanotic forms of congenital heart disease demonstrated more fears of the unknown, physiological anxiety, depression, and delinquent behaviors than the acyanotic children with congenital heart disease. Mothers of the children with cyanotic forms of congenital heart disease scored higher on both the state and trait scales, with higher maternal anxiety correlating with higher anxiety, medical fears and behavioral problems in the child. CONCLUSION: In a clinical setting, children with congenital heart diseases who do not present with psychological adjustment problems are still at risk for covert physiological anxiety, medical fears, depression and behavioral problems. The children with cyanotic malformations represent a subgroup at higher risk for these problems, which may be further exacerbated by increased maternal anxiety.
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Acute promyelocytic leukemia (APL) is typified by the reciprocal translocation, t(15; 17)(q22; q21), leading to the formation of PML-RARalpha and RARalpha-PML fusion genes. We have characterized 7 cases of morphologic APL found to lack the t(15; 17) on conventional cytogenetic assessment. In 6 of 7 cases, cryptic PML-RARalpha rearrangements were identified by reverse transcriptase-polymerase chain reaction and fluorescent in situ hybridization (FISH); whereas, in the remaining patient, APL was associated with the variant translocation, t(11; 17)(q23; q12-21), leading to the formation of PLZF-RARalpha and RARalpha-PLZF fusion genes. In each of the cases with cryptic PML-RARalpha rearrangements, PML-RARalpha transcripts were detected in the absence of RARalpha-PML, consistent with the concept that PML-RARalpha is the critical oncogenic fusion protein. In 4 of these cases with evaluable metaphase spreads, the occurrence of a nonreciprocal translocation was confirmed by FISH with sole formation of the PML-RARalpha fusion gene; in 3 cases with morphologically normal chromosomes 15 and 17, RARalpha was inserted into PML on 15q, whereas in the remaining patient the PML-RARalpha fusion arose due to insertion of 15q-derived material including PML into RARalpha on 17q. Immunofluorescence studies were performed using antibodies raised against PML and PIC 1, a ubiquitin-homology domain protein previously identified as an interaction partner of PML. In acute myeloid leukemia (AML) of subtypes other than M3, PIC 1 was localized to the nuclear membrane and colocalized with PML within discrete nuclear bodies. In APL cases with cryptic PML-RARalpha rearrangements, the characteristic microparticulate pattern of PML staining was detected with partial colocalization with PIC 1, indicative of disruption of the nuclear bodies; whereas in t(11; 17)-associated APL, PML and PIC 1 remained colocalized within discrete nuclear bodies, as observed in non-APL cases. Although deregulation of the putative growth suppressor PML and delocalization of other nuclear body constituents have been advocated to play a key role in the development of t(15; 17)-associated APL, the present study shows that disruption of PML nuclear bodies per se is not a prerequisite for the pathogenesis of APL.
The cellular localization of the precore/core and core proteins was studied by immunofluorescence following transfection of 143 thymidine kinase-negative (TK ) and Hep-G2 cells with expression constructs containing wild-type (hepatitis B e antigen [HBeAg]-positive) and precore mutant (HBeAg-negative) sequences. Precore/core constructs with the wild-type phenotype result in strong nuclear staining, while, in contrast, constructs expressing core antigen alone have strong cytoplasmic staining. These differences in the pattern of immunofluorescence staining may be caused by expression of the precore/core protein, some of which may be translocated into the nucleus, following removal of the signal peptide. In vitro translation experiments showed that the main protein products obtained in the presence of microsomal membranes were the precore/core protein and a truncated product representing the same protein without its signal peptide. Core protein expression from the precore mutant constructs was very much reduced, indicating that translational re-initiation was not very efficient. The significance of the precore/core protein being present in the nucleus is not clear, but suggests that it may be important in the replicative cycle of the virus. Finally, HBeAg produced by some of the constructs could not be detected because amino acid substitutions affected antibody-binding epitopes.
OBJECTIVE: To determine the effect of third-trimester calcium supplementation on maternal hemodynamic function. METHODS: Pregnant women were randomized to receive either 1.5 g of elemental calcium or placebo for 6 weeks during the third trimester. Using Doppler technique, maternal hemodynamic characteristics were measured at baseline, at 2 hours after the first dose of study drug, and at the completion of 6 weeks. Serum, dietary, and urinary calcium levels were also assessed. Power calculation indicated the need to study ten subjects in each group to detect a 1.2 L (20%) difference in cardiac output between groups, assuming a mean of 6.2 +/- 1.0 L/minute. Data were analyzed by analysis of variance for repeated measures, Student t test, Mann-Whitney U test, and Fisher exact test. RESULTS: Twenty-three women enrolled, and 18 completed the study. There were no statistically significant differences in demographic characteristics or in serum, dietary, or urinary calcium levels between the two groups. There were also no statistically significant differences in hemodynamic function over time within the calcium supplementation or placebo group (P > .05; analysis of variance for repeated measures). After 6 weeks, there were no significant differences between the calcium- and placebo-treated subjects in any hemodynamic measurement. Specifically, there was not a statistically significant difference in cardiac output (7.3 +/- 1.2 L/minute versus 8.0 +/- 0.9 L/minute; P = .09) between the calcium- and placebo-treated groups. CONCLUSION: These findings suggest that third-trimester calcium supplementation does not significantly alter cardiac output. The mechanism by which calcium supplementation lowers blood pressure remains to be elucidated.
A factor V506 Arg-Gln mutation is the most common inherited cause of thrombophilia in adults. To date, there are no data regarding the detection of this mutation in neonatal blood or the relationship of this dysfunctional factor V to neonatal thrombosis. This study compared a modified activated protein C resistance functional assay with the PCR-based DNA assay for the factor V mutation in 115 prospectively collected umbilical cord blood samples. The incidence of activated protein C resistance in cord blood was 6%. The sensitivity and specificity of the modified assay for the factor V Leiden mutation was 100%.
A criminal defendant must be competent to stand trial (CST) to safeguard the fundamental right to a fair trial. If there is a question as to a defendant's ability to assist in his or her own defense, a mental health professional is asked to perform a CST evaluation. Forensic assessment is a growing field, and CST is the most frequent evaluation requested. Over the years, forensic examiners' reports to the courts have been criticized for lack of relevance, insufficiency, and invading the province of the judge. If mental health professionals wish to advance the field of forensic assessment and respond to these criticisms, research on current practice with suggestions for advancement are necessary. A total of 66 CST reports conducted within the last five years in two states were compared to a proposed model for CST assessment. Results indicated that although forensic examiners are maintaining legal relevance, some CST reports may lack thoroughness and/or provide information that exceeds their role responsibilities. The findings support the need for the development of a standardized method of conducting and writing CST evaluations that should improve the quality of such reports.
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The trisomy 16 mouse (Ts16) is a general accepted animal model for both Downs syndrome (DS) and Alzheimer's Disease (AD). However, the efficacy of this model is severely hampered by the fact that Ts16 is lethal after about 18-20 days of gestation. Chimeras, long-term tissue culture and neural transplantation of Ts16 material have previously been used to overcome this limitation presented by death in utero of the Ts16. In this paper we describe a new strategy to overcome this limitation, i.e. immortalization of primary cells from Ts16 mice with retrovirus-mediated gene transfer of a temperature sensitive immortalizing oncogene. By this method we have obtained a total of 21 stable cell lines from Ts16 hippocampus, Ts16 cortex, normal hippocampus, and normal cortex. So far, two of the cell lines have been karyotyped and as expected, the cell line immortalized from Ts16 embryos has retained three copies of chromosome 16. We are currently characterizing these cell lines with respect to expression of APP, T-antigen, Nestin, GFAP, NF and Map-2. Moreover, the processing and secretion of APP fragments are being investigated by immunoblotting. In summary, we have immortalized CNS cells from Ts16 mice and we expect that these cell lines will be useful as in vitro and in vivo models for studying various aspects of the pathology of Alzheimer's disease.