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R J Hardy

Publications and source records attributed to R J Hardy.

At least 37 records · Page 2Linked to original sources
PubMed1999

A novel rat tetraspan protein in cells of the oligodendrocyte lineage.

The tetraspanin/transmembrane 4 superfamily gene superfamily encodes proteins that span the plasma membrane four times. Tetraspan proteins are implicated in proliferation, motility, and differentiation in various cell types, and in some cells they may link plasma membrane proteins into signalling complexes. Using a subtractive cDNA library prepared from oligodendrocytes and their progenitor cells, we have identified Tspan-2 as a member of this superfamily. In situ hybridization analysis revealed robust expression in cells of the oligodendrocyte lineage in comparison with the Plp gene, a well-characterized marker for myelin-forming glia in the CNS. Rat Tspan-2 mRNA is restricted to the nervous system and is detectable by northern blot shortly after birth in the CNS. Subsequently the gene is up-regulated strongly between postnatal day 3 and 10, and expression levels continue to rise up to postnatal day 22. These data indicate that Tspan-2 is likely to play a role in signalling in oligodendrocytes in the early stages of their terminal differentiation into myelin-forming glia and may also function in stabilizing the mature sheath.

Amino Acid Sequence↗
PubMed1999

Potential gains in life expectancy or years of potential life lost: impact of competing risks of death.

BACKGROUND: Measuring the impact of competing risks of death on society is important for setting public health policy and allocating resources. However, various indicators may result in inconsistent conclusions. The potential gains in life expectancy (PGLE) by elimination of deaths from HIV/AIDS, diseases of the heart and malignant neoplasms were compared to the years of potential life lost (YPLL) due to these causes in measuring the impact of premature death for the US population of working age (15-64 years). METHODS: The PGLE and the YPLL were computed from mortality reports (1987-1992) by race and gender group for deaths from HIV/AIDS, diseases of the heart and malignant neoplasms for the US population of working age. RESULTS: The YPLL overestimated the importance of premature deaths from HIV/AIDS compared to the PGLE. For the total US population and total US white population of working age, the YPLL were about 20-30% higher than the PGLE. However, the YPLL were about 20-30% lower than the PGLE for the US black population of working age. Furthermore the relative importance of the impact of death from various diseases may be interchanged by these two indicators. For example, for US black males of working age, the impact of deaths from HIV/AIDS by PGLE in 1992 was higher than that from malignant neoplasms and lower than that from diseases of the heart, but by using YPLL, the impact of premature deaths from HIV/AIDS was higher than that from both diseases of the heart and malignant neoplasms. CONCLUSIONS: The PGLE by elimination of deaths from diseases takes into account the competing risks on the population and it can be compared easily across populations. The YPLL is an index that does not take into account competing risks and it is also heavily influenced by the age structure and total population size. Although there are several standardization techniques proposed to improve the comparability of the YPLL across different populations, the YPLL fails to address the central issue of competing risks operating on the population. For this reason, we prefer the PGLE to the YPLL in measuring the impact of premature deaths on a population.

Acquired Immunodeficiency Syndrome↗
PubMed1999

Serum glucose level and diabetes predict tissue plasminogen activator-related intracerebral hemorrhage in acute ischemic stroke.

BACKGROUND AND PURPOSE: Five pretreatment variables (P<0.1 univariate analysis), including serum glucose (>300 mg/dL), predicted symptomatic intracerebral hemorrhage (ICH) in the National Institute of Neurological Disorders and Stroke rtPA trial. We retrospectively studied stroke patients treated <3 hours from onset with intravenous rtPA at 2 institutions to evaluate the role of these variables in predicting ICH. METHODS: Baseline characteristics, including 5 prespecified variables (age, baseline glucose, smoking status, National Institutes of Health Stroke Scale [NIHSS] score, and CT changes [>33% middle cerebral artery territory hypodensity]), were reviewed in 138 consecutive patients. Variables were evaluated by logistic regression as predictors of all hemorrhage (including hemorrhagic transformation) and symptomatic hemorrhage on follow-up CT scan. Variables significant at P<0.25 level were included in a multivariate analysis. Diabetes was substituted for glucose in a repeat analysis. RESULTS: Symptomatic hemorrhage rate was 9% (13 of 138). Any hemorrhage rate was 30% (42 of 138). Baseline serum glucose (5.5-mmol/L increments) was the only independent predictor of both symptomatic hemorrhage [OR, 2.26 (CI, 1.05 to 4.83), P=0.03] and all hemorrhage [OR, 2.26 (CI, 1.07 to 4.69), P=0.04]. Serum glucose >11.1 mmol/L was associated with a 25% symptomatic hemorrhage rate. Baseline NIHSS (5-point increments) was an independent predictor of all hemorrhage only [OR, 12.42 (CI, 1.64 to 94.3), P=0.01]. Univariate analysis demonstrated a trend for nonsmoking as a predictor of all hemorrhage [OR, 0.45 (CI, 0.19 to 1. 08), P=0.07]. Diabetes was also an independent predictor of ICH when substituted for glucose in repeat analysis. CONCLUSIONS: Serum glucose and diabetes were predictors of ICH in rtPA-treated patients. This novel association requires confirmation in a larger cohort.

Acute Disease↗
PubMed1999

Loss of p27Kip1 function results in increased proliferative capacity of oligodendrocyte progenitors but unaltered timing of differentiation.

In many tissues, progenitor cells permanently withdraw from the cell cycle prior to commitment towards a differentiated phenotype. In the oligodendrocyte lineage a counting mechanism has been proposed, linking the number of cell divisions to growth arrest and differentiation. A direct prediction of this model is that an increase in the number of cell divisions would result in a delayed onset of differentiation. Since the cell cycle inhibitor p27Kip1 is an essential component of the machinery leading to oligodendrocyte progenitor growth arrest, we examined the temporal relationship between cell cycle withdrawal and expression of late differentiation markers in vivo, in mice carrying a targeted deletion in the p27Kip1 gene. Using bromodeoxyuridine to label proliferating cells, quaking (QKI) to identify embryonic glial progenitors, NG2 to identify neonatal oligodendrocyte progenitors, and myelin basic protein to label differentiated oligodendrocytes, we found an increased number of proliferating QKI- and NG2-positive cells in germinal zones of p27Kip1(-/-) mice at the peak of gliogenesis. However, no delay was observed in these mice in the appearance of the late differentiation marker myelin basic protein in the developing corpus callosum and cerebellum. Significantly, a decrease in cyclin E levels was observed in the brain of p27Kip1 null mice coincident with oligodendrocyte growth arrest. We conclude that two distinct modalities of growth arrest occur in the oligodendrocyte lineage: a p27Kip1-dependent mechanism of growth arrest affecting proliferation in early phases of gliogenesis, and a p27Kip1-independent event leading to withdrawal from the cell cycle and differentiation.

Animals↗
PubMed1999

Interobserver agreement for grating acuity and letter acuity assessment in 1- to 5.5-year-olds with severe retinopathy of prematurity.

PURPOSE: To evaluate interobserver test-retest reliability of the Teller Acuity Card procedure for assessment of grating acuity at ages 1, 2, 3.5, 4.5, and 5.5 years, for HOTV letter acuity at 3.5 and 4.5 years, and for Early-Treatment Diabetic Retinopathy Study (ETDRS) letter acuity at 5.5 years in the multicenter study of Cryotherapy for Retinopathy of Prematurity (CRYO-ROP). METHODS: Subjects were the 73 participants in the CRYO-ROP study who had acuity assessed at one or more ages by two of the seven study visual acuity testers as part of a quality control procedure. All subjects had birth weights of less than 1251 g, and all had severe (threshold) ROP in one or both eyes. RESULTS: For sighted eyes, interobserver agreement for grating acuity (across all five test ages) was 0.5 octave or better in 57% of eyes and 1.0 octave or better in 85% of eyes. Interobserver agreement for letter acuity (3.5-, 4.5-, and 5.5-year test ages) was 0.5 octave or better in 71% of eyes and 1.0 octave or better in 93% of eyes. For all eyes (sighted and blind), Kendall rank correlation coefficients (Tau) were 0.86, 0.83, and 0.94 for grating, HOTV, and ETDRS acuity, respectively. Kappa statistics on data from all eyes indicated excellent interobserver agreement for grating, HOTV, and ETDRS acuity (0.73, 0.80, and 0.84, respectively). Interobserver agreement was not related to age or to severity of retinal residua of ROP. CONCLUSIONS: Excellent interobserver agreement for grating acuity measurements and for letter acuity measurements was obtained. Results suggest that with careful training and implementation of quality control procedures, high reliability of visual acuity results is possible in clinical populations of young children.

Child↗
PubMed1999

Agreement between grating acuity at age 1 year and Snellen acuity at age 5.5 years in the preterm child. Cryotherapy for Retinopathy of Prematurity Cooperative Group.

PURPOSE: To examine the relation between grating acuity at age 1 year and Snellen acuity and grating acuity at 5.5 years, in preterm children with birth weights less than 1251 g. METHODS: Subjects were participants in the multicenter study of Cryotherapy for Retinopathy of Prematurity. The Teller acuity card (TAC; Vistech Consultants, Dayton, OH) procedure was used to measure monocular grating acuity in children at ages 1 and 5.5 years. Early-treatment diabetic retinopathy study (ETDRS) charts were used to measure the childrens' monocular recognition (Snellen) acuity at age 5.5 years. Data are presented for 575 eyes with measurable TAC grating acuity at 1 year and 111 eyes that had no measurable acuity at 1 year. RESULTS: Among eyes with normal acuity at 1 year, 86.8% showed normal Snellen acuity, and 94.3% showed normal grating acuity at 5.5 years. Among eyes that were blind (i.e., had no measurable TAC grating acuity) at 1 year, 96.8% showed no quantifiable Snellen acuity, and 89.2% showed no quantifiable grating acuity at 5.5 years. Only 2.4% of eyes had acuity in the range between normal and blind at 1 year (i.e., measurable grating acuity <1.6 cyc/deg); thus, the predictive value of acuity scores in this range could not be determined. Correlation analysis indicated that the relative position within the normal range of an eye's grating acuity score at 1 year was not predictive of the relative position within the normal range of that eye's acuity score at 5.5 years. CONCLUSIONS: Among a large population of low-birth-weight infants, eyes with normal grating acuity at age 1 year generally showed normal Snellen and grating acuity at age 5.5 years, and eyes that had no quantifiable acuity at 1 year remained blind at 5.5 years. Relative position of an eye's acuity score within the normal range was not predictive of the relative position of that eye's later acuity score.

Blindness↗
PubMed1998

QKI expression is regulated during neuron-glial cell fate decisions.

QKI proteins are expressed by differentiated glia and have been implicated as regulators of myelination, but are also thought to function during early neural development. This study shows that QKI proteins are expressed in neural progenitors of the ventricular zone (vz) during murine CNS development, but that their expression is down-regulated during neuronal differentiation. By contrast, neural progenitors located in specific subdomains of the vz maintain expression of QKI proteins as they differentiate and migrate away into the emerging nervous system. These QKI+ cells have characteristics consistent with the acquisition of a glial rather than neuronal fate; they express nestin, incorporate BrdU, fail to express neuronal markers, and similar QKI+ cells are found in the postnatal subventricular zone, a known area of gliogenesis. In vitro, neural progenitor cells also down-regulate QKI expression as they differentiate into neurons, but not if they differentiate into glia. Furthermore, neural progenitors in strictly delineated subdomains of the vz dramatically up-regulate expression of the QKI-5 isoform prior to the emergence of QKI+ cells from these regions. Taken together, these data indicate that (1) glia are generated from subsets of neural progenitors found in specific, identifiable subdomains of the vz (2) QKI expression is regulated as neural progenitors undergo the neuron-glial cell fate decision and (3) QKI expression is a characteristic of glial progenitors.

Animals↗
PubMed1998

Lack of efficacy of light reduction in preventing retinopathy of prematurity. Light Reduction in Retinopathy of Prematurity (LIGHT-ROP) Cooperative Group.

BACKGROUND: Hospital-nursery lighting has been suggested as a factor in causing retinopathy of prematurity. Despite ongoing debate, a causal relation has not been established. METHODS: We conducted a prospective, randomized, multicenter study of the effects of light reduction on 409 premature infants with birth weights of less than 1251 g and gestational ages of less than 31 weeks. Two hundred five infants were exposed to reduced light, and 204 to typical nursery lighting. The amount of light reaching the infants' eyes was reduced within 24 hours after birth by placing goggles on the infants that reduced visible-light exposure by 97 percent and ultraviolet-light exposure by 100 percent. The babies wore the goggles until 31 weeks' postconceptional age or 4 weeks after birth, whichever was longer. Once the goggles were removed, ophthalmologists masked to the treatment assignments assessed the infants for retinopathy of prematurity at least biweekly for up to 13 weeks. RESULTS: There were 188 infants in the group that wore goggles and 173 in the control group who survived and were available for follow-up. The mean birth weights were 906 g in the goggles group and 914 g in the control group; the mean gestational ages were 27.4 weeks and 27.2 weeks, respectively. The mean ambient-light level adjacent to the infants' faces was 399 lux for the goggles group and 447 lux for the control group. Retinopathy of prematurity was diagnosed in 102 infants (54 percent) in the goggles group and 100 (58 percent) in the control group (relative risk, 0.9; 95 percent confidence interval, 0.8 to 1.1; P=0.50). CONCLUSIONS: A reduction in ambient-light exposure does not alter the incidence of retinopathy of prematurity.

Eye Protective Devices↗
PubMed1998

Detecting and describing heterogeneity in meta-analysis.

The investigation of heterogeneity is a crucial part of any meta-analysis. While it has been stated that the test for heterogeneity has low power, this has not been well quantified. Moreover the assumptions of normality implicit in the standard methods of meta-analysis are often not scrutinized in practice. Here we simulate how the power of the test for heterogeneity depends on the number of studies included, the total information (that is total weight or inverse variance) available and the distribution of weights among the different studies. We show that the power increases with the total information available rather than simply the number of studies, and that it is substantially lowered if, as is quite common in practice, one study comprises a large proportion of the total information. We also describe normal plots that are useful in assessing whether the data conform to a fixed effect or random effects model, together with appropriate tests, and give an application to the analysis of a multi-centre trial of blood pressure reduction. We conclude that the test of heterogeneity should not be the sole determinant of model choice in meta-analysis, and inspection of relevant normal plots, as well as clinical insight, may be more relevant to both the investigation and modelling of heterogeneity.

Adult↗
PubMed1998

Molecular defects in the dysmyelinating mutant quaking.

The quaking [or quakingviable (qk[v])] mutant mouse, which exhibits severe dysmyelination of the central nervous system (CNS), has been studied extensively over the last 30 years. The genetic defect responsible for the dysmyelinating phenotype had remained elusive, however, until the recent cloning of a candidate gene, qkI (Ebersole et al.: Nature Genet 12:260-265, 1996). qkI encodes three proteins, QKI-5, QKI-6, and QKI-7, which are abundant in myelin-forming cells in wild-type mice but whose levels are severely reduced in myelin-forming cells of qk(v) mice, consistent with the notion that abnormalities of qkI expression underlie the qk(v) phenotype. This review discusses some of the known molecular defects in qk(v) in the context of this new information and the potential role of QKI proteins in myelinogenesis.

Animals↗
PubMed1998

Strabismus in premature infants in the first year of life. Cryotherapy for Retinopathy of Prematurity Cooperative Group.

OBJECTIVES: To present the 3- and 12-month strabismus data from 3030 premature infants with birth weights less than 1251 g enrolled in the Multicenter Trial of Cryotherapy for Retinopathy of Prematurity. DESIGN: Data from the 3- and 12-month examinations conducted at 23 regional study centers were tabulated for all infants. The main outcome measure, ocular motility, was compared with baseline demographic variables and retinopathy of prematurity severity for the worse eye. Findings at 3 months were compared with the incidence of strabismus at 12 months. RESULTS: At 3 months, 200 (6.6%) of the 3030 infants were strabismic. In the 2449 infants examined at both time points, 289 (11.8%) were found to have strabismus at 12 months. Retinopathy of prematurity was significant for strabismus at both 3 and 12 months (P<.001). The presence of strabismus at 3 months was found to be a highly significant predictor of strabismus at 12 months. Anisometropia, abnormal fixation, and unfavorable retinal structure also were significant predictors of strabismus at 1 year. The total prevalence of strabismus in the first year of life was 14.7%. CONCLUSION: The presence of acute-phase retinopathy of prematurity places the premature infant at increased risk for strabismus.

Cryotherapy↗
PubMed1998

Estimation of duration of separation, widowhood, and family life cycle.

This is the second of two reports on a study of the durations related to marriage. Divorce and death of one's spouse, the main causes of dissolution of marriage, are two of the most important events in a person's life. In the United States in 1994, 30.7 million, or 16.2%, of the adult population were either divorced or widowed. Among the widowed, the female to male ratio was 5 to 1! In this paper duration of separation due to divorce and duration of widowhood are the main variables under study. Algebraic formulas are derived and computer programs are written for estimating these durations for husbands and wives, and for living couples of any age. Relations with the duration of marriage, the expectation of life, and the family life cycle are also presented.

Adult↗
PubMed1998

Prevalence of myopia between 3 months and 5 1/2 years in preterm infants with and without retinopathy of prematurity. Cryotherapy for Retinopathy of Prematurity Cooperative Group.

PURPOSE: The purpose of the study was to examine spherical equivalent refractive errors, especially myopia, at six ages between 3 months and 5 1/2 years post-term in preterm children with birth weights of less than 1251 g. DESIGN: A cohort study. PARTICIPANTS: There were a total of 827 participants in the multicenter study of cryotherapy for retinopathy of prematurity (ROP). Approximately one third of the eyes did not develop ROP, whereas two thirds developed mild-to-severe ROP. None of the eyes underwent cryotherapy. INTERVENTION: Refractive error was measured at 3 months, 1 year, and 5 1/2 years term due date at the five long-term follow-up centers. In most eyes, refractive error also was measured at 2, 3 1/2, and 4 1/2 years. MAIN OUTCOME MEASURE: Myopia was defined as 0.25 diopter (D) or greater with high myopia as 5 D or greater. RESULTS: The proportion of eyes with myopia in this preterm population was increased compared to published data on full-term children and was related to severity of both acute-phase and cicatricial-phase ROP. The percentage of eyes with myopia varied little across ages, ranging from 21.2% at 1 year to 15.7% at 4 1/2 years. The percentage of eyes with high myopia doubled from 1.8% to 3.9% between 3 months and 1 year and remained stable thereafter. The distribution of refractive errors in eyes with mild acute-phase ROP was similar to that of eyes with no ROP. In contrast, eyes with moderate or severe acute-phase ROP showed an increased prevalence of high myopia. The distribution of refractive errors changed between 3 months and 1 year with little change after 1 year. This pattern of refractive development differs from that of full-term infants. Birth weight, severity of ROP, and degree of myopia at 3 months predicted the presence of myopia and high myopia at 5 1/2 years of age. CONCLUSIONS: The distribution of refractive errors in preterm infants from age 3 months to 5 1/2 years varies with severity of acute-phase ROP and cicatricial disease. Changes in refractive error distribution occur primarily between 3 months and 1 year and involve a decrease in the proportion of eyes with hyperopia and an increase in the proportion with high degrees of myopia.

Acute Disease↗
PubMed1997

Dorsoventral patterning and oligodendroglial specification in the developing central nervous system.

While the bulk of oligodendendrocytes are generated postnatally in rodents, it is now clear that the first oligodendrocytes are born during midembryonic development. Recent studies imply that the first oligodendrocytes to appear are specified concurrently with certain neuronal subtypes. In addition, patterning molecules known to confer positional information on neural tissues during development, such as sonic hedgehog and bone morphogenetic proteins, have also been implicated in the specification of glial fate. This review discusses some of the recent advances in our knowledge of how oligodendrocytes are generated and the mechanisms by which this might occur in the developing brain and spinal cord.

Aging↗
PubMed1997

The design and analysis of paired cluster randomized trials: an application of meta-analysis techniques.

The statistical issues in clinical trials where clusters, communities or groups rather than individuals are randomized are often not fully appreciated. In this paper we discuss the design and analysis of trials in which pairs of clusters are randomized in the context of one recent trial, the British Family Heart Study. Both sample size calculations and the analysis strategy need to take account of the between-cluster component of variance. The analysis can be considered as a random effects meta-analysis across cluster pairs, and can usefully be presented as such. Techniques developed in the context of meta-analysis can then be used in the analysis, for example using a profile likelihood method to derive a confidence interval for the overall treatment effect which takes into account the variability in the estimate of the between-cluster variance. The methods presented here are contrasted with previously published methods for cluster randomized trials.

Adult↗
PubMed1997

Racial variation in retinopathy of prematurity. The Cryotherapy for Retinopathy of Prematurity Cooperative Group.

OBJECTIVES: To determine and compare the incidence of severe, vision-threatening retinopathy of prematurity (ROP) in black and white low-birth-weight infants. DESIGN: Prospective cohort study. SETTING: Seventy neonatal intensive care units in 23 US participating centers in the Multicenter Trial of Cryotherapy for Retinopathy of Prematurity. PATIENTS: A total of 4099 premature infants weighing less than 1251 g at birth were enrolled to evaluate the natural history of ROP. This 'Natural History' cohort included 2158 white infants and 1584 black infants who were followed up prospectively according to a Natural History protocol. MAIN OUTCOME MEASURES: Incidence and severity of acute ROP. RESULTS: While ROP occurred with similar frequency in all racial subgroups, severe ROP was less common in black infants. One hundred sixty (7.4%) of 2158 white infants reached threshold ROP (defined as at least 5 contiguous or 8 cumulative clock-hours of stage 3 retinopathy in zone 1 or zone 2 in the presence of "plus disease" [dilation and tortuosity of the posterior pole blood vessels]), but only 51 (3.2%) of 1584 black infants progressed to threshold ROP. Using multiple logistic regression analysis, race emerged as a highly significant factor (P < .001) in the development of threshold disease, even when birth weight, gestational age status at delivery, sex, multiple births, and transport status were considered. CONCLUSIONS: Severe, vision-threatening ROP occurs with greater frequency in low-birth-weight white infants than in low-birth-weight black infants who are seemingly at equivalent risk. The reason for this disparity is unknown. We speculate that differences in retinal pigmentation may confer relative protection against free radical-mediated phototoxic injury in black infants.

Birth Weight↗
PubMed1997

Outcome-based management of retinopathy of prematurity. Multicenter Trial of Cryotherapy for Retinopathy of prematurity Cooperative Group.

PURPOSE: A system is presented for sequentially computing the risk of progression of retinopathy of prematurity (ROP) for infants born weighing not more than 1250 gm. A personal computer program is used to monitor infants' risk of threshold ROP from first appearance of ROP, and the progression in severity is tracked with multiple logistic risk models developed from data in the Multicenter Trial of Cryotherapy for Retinopathy of Prematurity. METHODS: After entry of the infant's birth weight, gestational age, ethnicity, birth in the current hospital or elsewhere, single or multiple birth, and maturity zone of retinal vessels, risk of progression to threshold severity is calculated. New estimates of risk are computed at onset of ROP and prethreshold ROP (any zone I ROP, zone II stage 2+ or 3) according to the extent of retinal vascularization when ROP first appears, how rapidly ROP progresses, and how severe it is. When threshold ROP (8 total or 5 contiguous clock hours of stage 3+ in zone I or II) is reached,the system provides separate estimates of risk that the eye will have an unfavorable 3-month outcome if treated or not. RESULTS: Estimates of risk of progression to threshold disease among the 4099 patients in the Multicenter Trial of Cryotherapy for Retinopathy of Prematurity natural history study varied from less than 1% to more than 70%. For eyes with threshold disease, the risk of an unfavorable outcome at 3 months without treatment varied from less than 10% to more than 90%. CONCLUSION: This method of tracking identifies infants at high risk for severe ROP and poor structural outcome. It provides information about prognosis with a specificity heretofore impossible.

Algorithms↗