Correction: In-school eyecare in special education settings has measurable benefits for children's vision and behaviour.

[This corrects the article DOI: 10.1371/journal.pone.0220480.].

In-school eyecare in special education settings has measurable benefits for children's vision and behaviour.

OBJECTIVES: To determine whether implementation of comprehensive in-school eyecare results in measurable benefits for children and young people in terms of visual status, classroom behaviours and how well their visual needs are met. DESIGN: School-based observational study. PARTICIPANTS & METHODS: 200 pupils [mean age 10 years 9 months, 70% male, majority moderate (40%) or severe (35%) learning difficulty] of a special education school in the UK. A sector-agreed in-school eyecare framework including full eye examination and cycloplegic refraction, dispensing of spectacles (as appropriate) and written reporting of outcomes to parents/teachers was applied. Classroom behaviours were observed and recorded prior to, and after, the in-school eyecare. Surveys were employed to obtain visual histories from parents/teachers. School records and statutory documents were reviewed for diagnostic and learning disability classifications. Visual function and ocular health were profiled at baseline and significant visual deficits identified. Where such deficits were previously unrecognised, untreated or not compensated for (e.g. correction of refractive error, enlargement of educational material) they were recorded as 'unmet visual need'. At follow-up, 2-5 months after initial (baseline) measures, eye examinations, parent/teacher surveys and behaviour observations were repeated. Follow-up measures were used to determine if measurable improvements were evident in visual function, ocular health, the level of unmet need and classroom behaviour following implementation of in-school eyecare. RESULTS: 199 participants completed baseline and follow-up measures. 122 (61%) participants presented with at least one significant visual or ocular health deficit and 90 (45%) participants had at least one unmet visual need. Younger pupils and those with no previous history of eyecare were more likely to demonstrate unmet visual needs at baseline (OR 1.12 95% CI 1.03 to 1.21) p = 0.012; (OR 4.44 95% CI 1.38 to 14.29 p = 0.007 respectively). On follow-up, the number of pupils with unmet visual needs dropped significantly to 36 (18%) (McNemar's test p<0.001). Visual and behavioural metrics of participants without significant visual deficits or whose visual needs were adequately addressed at baseline remained relatively unchanged between baseline and follow-up (Wilcoxon signed rank p>0.05). Where significant refractive deficits were corrected at follow-up, near visual acuity improved significantly (Wilcoxon signed rank p = 0.013), however, poor spectacle compliance was a persistent cause of unmet visual need. Off-task behaviour reduced significantly after actions to address unmet visual needs were communicated to parents and teachers (Wilcoxon signed rank p = 0.035). CONCLUSIONS: The present study demonstrates for the first time measurable visual and behaviour benefits to children in special education settings when they receive comprehensive in-school eye examinations, on-site spectacle dispensing and jargon-free reporting of outcomes to teachers and parents.

Dynamic deformability of sickle red blood cells in microphysiological flow.

In sickle cell disease (SCD), hemoglobin molecules polymerize intracellularly and lead to a cascade of events resulting in decreased deformability and increased adhesion of red blood cells (RBCs). Decreased deformability and increased adhesion of sickle RBCs lead to blood vessel occlusion (vaso-occlusion) in SCD patients. Here, we present a microfluidic approach integrated with a cell dimensioning algorithm to analyze dynamic deformability of adhered RBC at the single-cell level in controlled microphysiological flow. We measured and compared dynamic deformability and adhesion of healthy hemoglobin A (HbA) and homozygous sickle hemoglobin (HbS) containing RBCs in blood samples obtained from 24 subjects. We introduce a new parameter to assess deformability of RBCs: the dynamic deformability index (DDI), which is defined as the time-dependent change of the cell's aspect ratio in response to fluid flow shear stress. Our results show that DDI of HbS-containing RBCs were significantly lower compared to that of HbA-containing RBCs. Moreover, we observed subpopulations of HbS containing RBCs in terms of their dynamic deformability characteristics: deformable and non-deformable RBCs. Then, we tested blood samples from SCD patients and analyzed RBC adhesion and deformability at physiological and above physiological flow shear stresses. We observed significantly greater number of adhered non-deformable sickle RBCs than deformable sickle RBCs at flow shear stresses well above the physiological range, suggesting an interplay between dynamic deformability and increased adhesion of RBCs in vaso-occlusive events.

Traffic Light: prognosis-based eligibility for clinical trials of hematopoietic SCT in adults with sickle cell anemia.

Estimating prognosis in sickle cell anemia (SCA) assumes greater importance as intensive treatments, such as hematopoietic SCT (HSCT), are being tested. Here we estimate the mortality risk from the walk-PHaSST (Sildenafil Therapy for Pulmonary Hypertension and Sickle Cell Disease) trial of homozygous SCA patients with suspected pulmonary hypertension (19/468 deaths; 10 centers in the US and UK). Parallel investigations were also undertaken in the Cooperative Study of Sickle Cell Disease (CSCCD) and a contemporary urban sickle cell disease population (Case Western Reserve University-University Hospitals (CWRU-UH), Cleveland, OH, USA). One- and two-value positive predictive values for 2-year mortality (from study entry) are calculated using factors that include demographics, laboratory values and clinical evaluations. We define high-, intermediate-, and low-risk SCA as > 15%, 10-15% and < 10% 2-year mortality. In walk-PHaSST, no single factor qualifies as high-risk SCA, although several combinations of two factors (that is, both age > 35 years and history of chronic transfusion) do. Either elevated white blood cell count (> 13.5 × 10(3) cells/mcL, 7/70 deaths) or elevated Tricuspid Regurgitant Jet Velocity (⩾ 3.0 m/s, 8/67 deaths) was individually associated with intermediate-risk disease, as were many two-factor combinations. N-terminal pro-brain natriuretic peptide > 160 ng/L, lactate dehydrogenase > 600 IU/L, history of chronic transfusion, sepsis or age > 35 years are individually associated with low-risk SCA, as are many two-factor combinations. SCA risk was integrated with estimated donor type-associated risk from HSCT to form 'Traffic Light' eligibility criteria for clinical trials of HSCT. This method is adaptable to evolutions in clinical care.

A lack of vision: evidence for poor communication of visual problems and support needs in education statements/plans for children with SEN.

OBJECTIVE: Visual dysfunction is more common in children with neurological impairments and previous studies have recommended such children receive visual and refractive assessment. In the UK, children with neurological impairment often have educational statementing for Special Educational Needs (SEN) and the statement should detail all health care and support needs to ensure the child's needs are met during school life. STUDY DESIGN: This study examined the representation of visual information in statements of SEN and compared this to orthoptic visual information from school visual assessments for children in a special school in Northern Ireland, UK. METHODS: The parents of 115 school children in a special school were informed about the study via written information. Participation involved parents permitting the researchers to access their child's SEN educational statement and orthoptic clinical records. RESULTS: Statement information was accessed for 28 participants aged between four and 19 years; 25 contained visual information. Two participants were identified in their statements as having a certification of visual impairment. An additional 10 children had visual acuity ≥ 0.3 logMAR. This visual deficit was not reported in statements in eight out of these 12 cases (67%). 11 participants had significant refractive error and wore spectacles, but only five (45%) had this requirement recorded in their statement. Overall, 10 participants (55%) had either reduced visual acuity or significant refractive error which was not recorded in their statement. CONCLUSIONS: Despite additional visual needs being common, and described in clinical records, the majority of those with reduced vision and/or spectacle requirements did not have this information included in their statement. If visual limitations are not recognized by educational services, the child's needs may not be met during school life. More comprehensive eye care services, embedded with stakeholder communication and links to education are necessary to improve understanding of vision for children with neurological impairments.

Deforming a preoperative volume to represent the intraoperative scene.

Soft-tissue deformation can be a problem if a preoperative modality is used to help guide a surgical or interventional procedure. We present a method that can warp a preoperative CT image to represent the intraoperative scene shown by an interventional fluoroscopy image. The method is a novel combination of a 2D-3D image registration algorithm and a deformation algorithm that allows rigid bodies to be incorporated into a nonlinear deformation based on radial basis functions. The 2D-3D registration algorithm is used to obtain information on relative vertebral movements between preoperative and intraoperative images. The deformation algorithm uses this information to warp the preoperative image to represent the intraoperative scene more accurately. Images from an aortic stenting procedure were used. The observed deformation in our experiment was 5 degrees flexion and 5 mm lengthening of the lumbar spine over a distance of four vertebrae. The vertebral positions in the warped CT volume represent the intraoperative scene more accurately than in the preoperative CT volume. Although we had no gold standard with which to assess the registration accuracy of soft-tissue structures, the position of such structures within the warped CT volume appeared visually realistic.

Practical approach to determining costs and frequency of adverse drug events in a health care network.

The frequency, preventability, severity, root causes, and projected costs of adverse drug events (ADEs) occurring after or causing admission to a four-hospital integrated academic health network were studied. The sample included all admissions during a 53-day study period. Events were identified through daily record review of a random patient sample, computerized flags, and self-reporting. A case review committee validated the occurrence, classification, and root causes of the events. Additional length of stay and costs associated with ADEs were analyzed by using a case-control, multiple linear regression model. The estimated ADE rate during hospitalization was 4.2 events per 100 admissions, with a cost of $2162 per ADE. In addition, 3.2% of admissions were caused by ADEs, with an associated cost of $6685 per event. Fifteen percent of hospital ADEs and 76% of ADEs causing admission were judged preventable. The annual cost to the organization for events occurring during hospitalization was $1.7 million, and the cost of preventable ADEs was $260,000, while the projected costs of preventable ADEs causing admission were $3.8 million. The rate of admissions to the mental health center caused by ADEs was higher than for other settings at 13.6%, with a cost of preventable ADEs of $1.3 million. Patient noncompliance was judged to be the cause of the 69% of the ADEs causing admission. Seventy-one percent of the serious medication errors occurred at the prescribing stage of the medication-use process. ADEs were frequent, costly, and often preventable and resulted in many admissions to a mental health center.

The effect of age on radiocephalic fistula patency.

BACKGROUND: Inferior patency rates for radiocephalic fistulae in the elderly have been reported and may explain the increasing use of prosthetic grafts for vascular access. The aim of this study was to assess whether the patency rates of primary radiocephalic fistulae are affected by age. METHODS: A retrospective casenote review of 53 consecutive patients undergoing primary fistula formation between 1995 and 1998 under the care of a single consultant vascular surgeon. The setting was a specialist vascular surgical unit where the protocol is to offer all new patients a radiocephalic fistula. Fistula patency was defined as successful use for dialysis. RESULTS: Cumulative patency rates at 2 years were 60% in patients over 60 years (n=27), and 53% in patients under 60 years (n=26). The higher patency rates in the older age group were not significant on log rank testing (p=0.39). CONCLUSION: Age over 60 years did not influence patency rates of primary radiocephalic fistulae, which should remain the haemodialysis access procedure of choice at all ages.

Bleeding risk and platelet transfusion refractoriness in patients with acute myelogenous leukemia who undergo autologous stem cell transplantation.

Therapy for acute myelogenous leukemia can be complicated by alloimmunization to histocompatibility antigens (HLA), with resultant refractoriness to platelet transfusions. Autologous peripheral blood or bone marrow stem cell transplantation (referred here collectively as 'autoBMT') is emerging as a standard consolidative strategy in acute myelogenous leukemia (AML). We had noted life-threatening bleeding associated with platelet transfusion refractoriness following autoBMT; we therefore retrospectively analyzed 39 AML patients for this complication following BMT. All patients received high-dose chemoradiotherapy, followed by infusion of allogeneic sibling donor (n = 12, alloBMT) or autologous (n = 27, autoBMT) stem cells. HLA alloimmunization was assessed if patients were suspected of immune refractoriness to random donor platelet transfusions. Within 100 days of stem cell infusion, one of three alloBMT and six of 12 autoBMT recipients tested were HLA alloimmunized (not statistically significant, NS). Five of six HLA alloimmunized autoBMT patients experienced delayed bleeding, which contributed to their demise while still in remission (P < 0.001). Increased platelet requirements in HLA alloimmunized autoBMT recipients were observed between days 61 and 100 post-BMT, at a median of 211 platelet transfusions vs 0 in non-alloimmunized autoBMT patients (P < 0.01) and 17 in alloBMT patients. Our data suggest that platelet transfusion refractoriness, when associated with HLA alloimmunization, is a risk factor for increased platelet transfusion requirements, delayed bleeding, and poor outcome following autoBMT for AML.

The effect of growth hormone secretagogues and neuropeptide Y on hypothalamic hormone release from acute rat hypothalamic explants.

Growth hormone (GH) secretagogues (GH-releasing peptides and their non-peptide analogues) stimulate growth hormone release via specific G-protein coupled receptors both directly from the pituitary gland and through stimulation of the hypothalamus. The exact mechanism of action in the hypothalamus is not known. The presence of endogenous GH releasing hormone (GHRH) seems to be necessary for the in-vivo actions of growth hormone secretagogues (GHSs), but data suggest that further factors must be involved as well. The effect of GHSs is not entirely specific for the GH axis; they release prolactin and stimulate the hypothalamo-pituitary-adrenal axis causing elevations in circulating ACTH and cortisol levels in both animal and human studies. Recently, it has also been suggested that GHSs stimulate hypothalamic neuropeptide Y (NPY) neurones. In the present study, we have therefore investigated the direct effect of several GHSs (GHRP-6, hexarelin and the non-peptide analogues L-692, 429 and L-692, 585) on GHRH, somatostatin (SS), corticotrophin-releasing hormone (CRH) and arginine vasopressin (AVP) release in vitro in an acute rat hypothalamic incubation system. We also assessed the effect of NPY on GHRH, SS and AVP release. Freshly removed hypothalami were incubated in control media for 20 min and then in 1-4 consecutive 20-min periods in each of the test substances at different concentrations. There was no significant change in either the basal or potassium-stimulated release of GHRH or SS at low concentrations of any of the secretagogues; however, at millimolar doses a paradoxical inhibition of GHRH was observed with GHRP-6, hexarelin and L-692 585 (data are expressed as the ratio of treated to preceding basal release; at 20 min control group: 0.97+/-0.02, GHRP-6: 0.55+/-0.04, P<0.001 compared to control group; hexarelin: 0. 56+/-0.06, P<0.001, L-692,585: 0.70+/-0.03, P<0.001), while SS was stimulated after 60 or 80 min (at 80 min control: 0.80+/-0.03, hexarelin: 1.23+/-0.07, P<0.05 and L-692,585: 1.37+/-0.11, P<0.05). GHSs stimulated hypothalamic AVP release (at 20 min control: 0. 99+/-0.06 ratio to basal release, 10-4 M concentration of GHRP-6: 6. 31+/-1, P<0.001, hexarelin: 1.88+/-0.4, P<0.01, L-692,429: 1.90+/-0. 5, P<0.05 and L-692,585: 2.34+/-0.96, P<0.01), while no stimulatory effect was found on CRH release. NPY significantly stimulated SS and inhibited basal and potassium-stimulated GHRH release, while potentiating potassium-evoked AVP secretion. The Y1 receptor antagonist BIBP 3226 did not inhibit the effects of NPY on SS, GHRH or AVP release. We therefore conclude that, in this in-vitro rat hypothalamic incubation model, growth hormone secretagogues stimulate the release of AVP but have no effect on either GHRH, SS or CRH at low doses; at high doses paradoxically they inhibit the hypothalamic GH axis similar to in-vivo data in the rat. We speculate that these effects might be mediated by NPY.

The prevalence of hyperlipidemia in women and its association with use of oral contraceptives, sex hormone replacement therapy and nonlipid coronary artery disease risk factors. Canadian Heart Health Surveys Research Group.

OBJECTIVE: To report the prevalence of lipid and nonlipid coronary artery disease risk factors in women classified by use of oral contraceptives or sex hormone replacement therapy. DESIGN, SETTING AND PARTICIPANTS: A population-based cross-sectional survey in nine Canadian provinces (not including Nova Scotia) between 1988 and 1992 invited 13,506 women aged 18 to 74 years to participate. During a clinic visit after a home interview, a blood sample was obtained following a fast of 8 h or more from 8637 women. OUTCOME MEASURES: Fasting plasma total cholesterol, triglycerides, low density lipoprotein (LDL) cholesterol, high density lipoprotein (HDL) cholesterol, blood pressure, smoking status, self-reported diabetes, and self-reported use of oral contraceptive or sex hormone replacement therapy pills. MAIN RESULTS: The prevalence of oral contraceptive use was 41% for women 18 to 24 years old and 20% for women 25 to 34 years old. The prevalence of sex hormone replacement therapy was 4% for women 35 to 44 years old, 20% for women 45 to 64 years old and 11% for women 65 to 74 years old. Users of sex hormone replacement therapy aged 35 to 44 years had slightly higher mean LDL cholesterol than nonusers (3.04 versus 2.89 mmol/L). Users and nonusers aged 45 to 54 years had similar LDL cholesterol levels, and users aged 55 to 64 and 65 to 74 years had lower LDL cholesterol and higher HDL cholesterol levels, respectively, than nonusers. Triglyceride levels were higher in oral contraceptive users and in younger women on sex hormone replacement therapy than in nonusers. In the general population of Canada the use of oral contraceptives in women less than age 35 years had only a marginal effect on the prevalence of lipid and nonlipid risk factors. Women aged 18 to 24 years using oral contraceptives had a higher mean LDL cholesterol level of 2.73 versus 2.35 mmol/L for nonusers. The prevalence of lipid and nonlipid risk factors in women using sex hormone replacement therapy increased slightly for those aged 35 to 54 years and decreased in women aged 55 to 74 years. A lower percentage of women using sex hormone replacement therapy, aged 55 to 74 years, had high risk LDL cholesterol levels (21% versus 36% for nonusers). A larger percentage of women using sex hormone replacement therapy had low risk HDL cholesterol levels (54% versus 29% for nonusers). The nonlipid risk factor profile for women aged 35 to 54 years on sex hormone replacement therapy was less favourable than for nonusers: obesity was more common (36% versus 28%, respectively), hypertension was higher (22% versus 12%, respectively), and the proportion of women with one or more nonlipid risk factors was higher. The nonlipid risk factor profile for women 55 to 74 years of age who were using sex hormone replacement therapy was more favourable than for nonusers: obesity was lower (31% versus 47%, respectively), smoking was lower (7% versus 16%, respectively), sedentary behaviour was lower (28% versus 37%, respectively), and fewer women had two or more of these risk factors (31% versus 52%, respectively). CONCLUSION: The findings suggest that women at higher risk for coronary artery disease tend to have a lower prevalence of use of sex hormone replacement therapy.

Prevalence of high plasma triglyceride combined with low HDL-C levels and its association with smoking, hypertension, obesity, diabetes, sedentariness and LDL-C levels in the Canadian population. Canadian Heart Health Surveys Research Group.

OBJECTIVE: To report the associations of plasma triglyceride, high density lipoprotein cholesterol (HDL-C) and low density lipoprotein cholesterol (LDL-C) with nonlipid coronary artery disease risk factors. In particular, the associations for persons with high triglyceride and low HDL-C levels were examined. DESIGN: A stratified random probability sample of 29,855 men and women aged 18 to 74 years from the Canadian Heart Health Surveys (1986 to 1992) in 10 provinces. Blood samples were obtained from 18,555 participants who had fasted for 8 h or more. Plasma lipids were determined at the J Alick Little Lipid Research Laboratory, Toronto, Ontario, with standardization of the Centers for Disease Control Lipid Standardization Program, Atlanta. OUTCOME MEASURES: Fasting plasma total cholesterol, triglyceride, LDL-C and HDL-C levels. MAIN RESULTS: The prevalence of men with triglyceride levels above 1.7 mmol/L and HDL-C levels below 0.9 mmol/L was 10%, compared with 3% for men with triglyceride levels below 1.7 mmol/L and HDL-C levels below 0.9 mmol/L. The prevalence of women with triglyceride levels above 1.7 mmol/L and HDL-C levels below 0.9 mmol/L was 3% compared with a prevalence of less than 1% for women with triglyceride levels below 1.7 mmol/L and HDL-C levels below 0.9 mmol/L. Even when plasma LDL-C was low at less than 3.4 mmol/L, there was an age trend for increasing prevalences of the combination of triglyceride levels 2.3 mmol/L or greater and HDL-C levels less than 0.9 mmol/L in both sexes. The prevalence of a triglyceride levels 2.3 mmol/L or greater combined with an HDL-C level below 0.9 mmol/L was increased in groups who were cigarette smokers, diabetic, hypertensive, obese or sedentary, or who had higher LDL-C levels in both sexes, and the increase was even greater in the presence of two or more of these other risk factors. CONCLUSIONS: Among men or women with low HDL-C and high triglyceride levels, smoking, diabetes, sedentariness, hypertension and obesity were much more prevalent than among those at low risk with high HDL-C and low triglyceride levels.

Plasma lipids and lipoprotein reference values, and the prevalence of dyslipoproteinemia in Canadian adults. Canadian Heart Health Surveys Research Group.

OBJECTIVE: To report reference values for plasma lipids and lipoproteins in Canadian adults and the prevalence in the population of various levels of risk for coronary artery disease from dyslipoproteinemia. DESIGN, SETTING AND PARTICIPANTS: Population- based provincial heart health cross-sectional surveys in 10 provinces between 1986 and 1992 invited 29,855 men and women aged 18 to 74 years to participate. During a clinic visit after a home interview a blood sample was obtained following a fast of 8 h or more from 18,555 people. Plasma lipid levels were determined at the J Alick Little Lipid Research Laboratory, Toronto, with standardization of the Centers for Disease Control Lipid Standardization Program, Atlanta. OUTCOME MEASURES: Fasting plasma total cholesterol, triglyceride, low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C) and non-HDL-C levels. MAIN RESULTS: Mean plasma total cholesterol, LDL-C, non-HDL-C and triglyceride levels increased with age in men to a peak at around age 54 years, while in women the increases were more gradual at a lower level until age 54 years, after which they increased appreciably eventually exceeding values for men. A high percentage of adults were at increased risk for coronary artery disease: 44% had elevated total cholesterol levels above 5.2 mmol/L; 14% had LDL-C levels above 4.1 mmol/L; 8% had HDL-C values below 0.9 mmol/L; and 14% had triglyceride levels above 2.3 mmol/L. Eleven per cent of adults had both total cholesterol level above 6.2 mmol/L and LDL-C level above 4.1 mmol/L. CONCLUSION: The high prevalence of Canadian adults at risk because of elevated plasma lipid levels strongly indicates the need for comprehensive public health programs to reduce plasma lipid levels in the population and the need to encourage physicians to treat those at high risk.

Impact of different blood lipid evaluation and treatment guidelines on the proportion of Canadians identified and treated for elevated blood cholesterol. Canadian Heart Health Surveys Research Group.

OBJECTIVE: To report on the impact of different blood lipid evaluation and treatment guidelines on the proportion of Canadians identified and treated for high blood cholesterol. DESIGN, SETTING AND PARTICIPANTS: The Canadian Heart Health Surveys were carried out in Canada between 1986 and 1991. The data used in this study were from cross-sectional probability samples of adults aged 18 to 74 years, gathered in four provincial health surveys (Quebec, Alberta, Manitoba and Ontario) between 1989 and 1992, which obtained information on family history of heart disease. Data reported are for 7238 subjects fasting 8 h or more and providing a blood sample. All blood lipid analysis were done at the J Alick Little Lipid Research Laboratory, University of Toronto, which is standardized according to the National Heart, Lung, and Blood Institute, Centers for Disease Control (Atlanta) Lipid Standardization Program. OUTCOME MEASURES: With respect to the four guidelines examined--the Canadian Consensus Conference on Cholesterol (CCCC), 1987; the Toronto Working Group on Cholesterol Policy (TWG), 1990; the Canadian Task Force on the Periodic Health Examination (PHE), 1993; and the National Cholesterol Education Program (NCEP), 1993, in the United States--a comparison of the proportion of individuals in the population for whom a lipid profile was constructed, and who were prescribed a diet and drug therapy under different assumptions of success with dietary therapy for each guideline. MAIN RESULTS: Major differences were observed in the impact of the various guidelines with respect to the percentage of subjects who were tested, provided with a lipid profile, and eligible for diet and/or drug therapy. In general the percentages in each group were higher for the CCCC and the NCEP guidelines than for the PHE and TWG guidelines. CONCLUSION: The divergent results obtained from the application of the various guidelines are cause for concern and explain in part the confusion that surrounds the topic of blood cholesterol in public health and clinical contexts. Public health policy in the area of cardiovascular disease prevention would benefit from explicit consideration of various types of criteria for formulation of identification and treatment guidelines.

A comparison of similarity measures for use in 2-D-3-D medical image registration.

A comparison of six similarity measures for use in intensity-based two-dimensional-three-dimensional (2-D-3-D) image registration is presented. The accuracy of the similarity measures are compared to a "gold-standard" registration which has been accurately calculated using fiducial markers. The similarity measures are used to register a computed tomography (CT) scan of a spine phantom to a fluoroscopy image of the phantom. The registration is carried out within a region-of-interest in the fluoroscopy image which is user defined to contain a single vertebra. Many of the problems involved in this type of registration are caused by features which were not modeled by a phantom image alone. More realistic "gold-standard" data sets were simulated using the phantom image with clinical image features overlaid. Results show that the introduction of soft-tissue structures and interventional instruments into the phantom image can have a large effect on the performance of some similarity measures previously applied to 2-D-3-D image registration. Two measures were able to register accurately and robustly even when soft-tissue structures and interventional instruments were present as differences between the images. These measures were pattern intensity and gradient difference. Their registration accuracy, for all the rigid-body parameters except for the source to film translation, was within a root-mean-square (rms) error of 0.54 mm or degrees to the "gold-standard" values. No failures occurred while registering using these measures.

Elevated LDL triglyceride concentrations in subjects heterozygous for the hepatic lipase S267F variant.

Although naturally occurring loss-of-function mutations in human hepatic lipase (HL) have been described, the biochemical phenotype of heterozygous HL deficiency remains ill defined. This may be due to the relatively small numbers of heterozygous adult carriers of HL mutations in index kindreds. We have identified several new heterozygotes for the catalytically inactive, nonsecreted HL variant S267F in the kindred that was originally ascertained because of hypertriglyceridemia due to the mutant, secreted, circulating apolipoprotein (apo) CII variant apo CII-T. Pairwise comparisons with family controls showed that only the plasma low density lipoprotein triglycerides (LDL TGs) were higher in 11 simple heterozygotes for HL S267F (P=0.002). In contrast, both plasma total TGs and LDL TGs were significantly higher in 12 simple heterozygotes for apo CII-T than in family-matched control subjects (P=0.005 and 0.009, respectively). These findings suggest that the TG content of LDL is increased by heterozygosity for 2 different mutations that affect different proteins involved in lipolysis. However, the mechanisms underlying this compositional change in LDL appear to be different for the 2 mutations, because the total TGs are also elevated in subjects heterozygous for apo CII-T but not in subjects heterozygous for HL S267F.

Silencing and activation of embryonic globin gene expression.

An understanding of the mechanisms that control developmental stage-specific transcription of globin genes offers the promise of successful therapeutic activation of fetal or embryonic beta-type genes in beta-thalassemia syndromes. A large body of evidence supports the notion of conservation of such mechanisms across vertebrate species and validates the use of pre-clinical studies of silencing and activation of fetal or embryonic globin genes in animals. Using globin gene transfections into primary avian erythroid cells and cultured murine erythroleukemia cells, we have studied mechanisms involved in stage-specific embryonic beta-type globin gene silencing and activation. These studies show that 1) methylation of the exact CpG nucleotides that are methylated in normal adult erythroid cells in vivo is capable of blocking transcription of a transfected embryonic globin gene promoter via binding of a methyl DNA binding protein in primary erythroid cells. 2) Activation of embryonic beta-type globin gene transcription in adult erythroid cells by short chain fatty acids is mediated through specific DNA sequences both in the promoter and downstream of the promoter.