Rivaroxaban and apixaban induce clotting factor Xa fibrinolytic activity.

Essentials Activated clotting factor X (FXa) acquires fibrinolytic cofactor function after cleavage by plasmin. FXa-mediated plasma fibrinolysis is enabled by active site modification blocking a second cleavage. FXa-directed oral anticoagulants (DOACs) alter FXa cleavage by plasmin. DOACs enhance FX-dependent fibrinolysis and plasmin generation by tissue plasminogen activator. BACKGROUND: When bound to an anionic phospholipid-containing membrane, activated clotting factor X (FXa) is sequentially cleaved by plasmin from the intact form, FXaα, to FXaß and then to Xa33/13. Tissue-type plasminogen activator (t-PA) produces plasmin and is the initiator of fibrinolysis. Both FXaß and Xa33/13 enhance t-PA-mediated plasminogen activation. Although stable in experiments using purified proteins, Xa33/13 rapidly loses t-PA cofactor function in plasma. Bypassing this inhibition, covalent modification of the FXaα active site prevents Xa33/13 formation by plasmin, and the persistent FXaß enhances plasma fibrinolysis. As the direct oral anticoagulants (DOACs) rivaroxaban and apixaban bind to the FXa active site, we hypothesized that they similarly modulate FXa fibrinolytic function. METHODS: DOAC effects on fibrinolysis and the t-PA cofactor function of FXa were studied in patient plasma, normal pooled plasma and purified protein experiments by the use of light scattering, chromogenic assays, and immunoblots. RESULTS: The plasma of patients taking rivaroxaban showed enhanced fibrinolysis correlating with FXaß. In normal pooled plasma, the addition of rivaroxaban or apixaban also shortened fibrinolysis times. This was related to the cleavage product, FXaß, which increased plasmin production by t-PA. It was confirmed that these results were not caused by DOACs affecting activated FXIII-mediated fibrin crosslinking, clot ultrastructure and thrombin-activatable fibrinolysis inhibitor activation in plasma. CONCLUSION: The current study suggests a previously unknown effect of DOACs on FXa in addition to their well-documented anticoagulant role. By enabling the t-PA cofactor function of FXaß in plasma, DOACs also enhance fibrinolysis. This effect may broaden their therapeutic indications.

Effect of teenage pregnancy on educational disabilities in kindergarten.

Teenage pregnancies have become a public health issue because of their observed negative effects on perinatal outcomes and long-term morbidity. The association of young maternal age and long-term morbidity is usually confounded, however, by the high prevalence of poverty, low level of education, and single marital status among teenage mothers. The authors assess the independent effect of teenage pregnancy on educational disabilities and educational problems in a total population of children who entered kindergarten in Florida in 1992--1994 and investigate how controlling for potentially confounding factors affects the relation between teenage pregnancies and poor outcome. When no other factors are taken into account, children of teenage mothers have significantly higher odds of placement in certain special education classes and significantly higher occurrence of milder education problems, but when maternal education, marital status, poverty level, and race are controlled, the detrimental effects disappear and even some protective effects are observed. Hence, the increased risk for educational problems and disabilities among children of teenage mothers is attributed not to the effect of young age but to the confounding influences of associated sociodemographic factors. In contrast to teen age, older maternal age has an adverse effect on a child's educational outcome regardless of whether other factors are controlled for or not.

The outcome in the United States after thoracoabdominal aortic aneurysm repair, renal artery bypass, and mesenteric revascularization.

OBJECTIVES: The purpose of this study was to determine outcome and identify predictors of death after thoracoabdominal aortic aneurysm (TAA) repair, renal artery bypass (RAB), and revascularization for chronic mesenteric ischemia (CMI). PATIENTS AND METHODS: In this retrospective analysis, data were obtained from the Nationwide Inpatient Sample, a 20% all-payer stratified sample of hospitals in the United States during 1993 to 1997. Patients were identified by the presence of a diagnostic or procedure code from the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM). The main outcomes we examined were death, ICD-9-CM -based complications, length of stay, hospital charges, and disposition. A multivariate model was constructed to predict death. RESULTS: A total of 2934 patients were identified (TAA, 540; RAB, 2058; CMI, 336) in the database. The mean age was comparable (TAA, 69 +/- 9 years; RAB, 66 +/- 12 years; CMI, 66 +/- 11 years), but the breakdown between the sexes varied by procedure (male: TAA, 53%; RAB, 55%; CMI, 24%). The mortality rate (TAA, 20.3%; RAB, 7.1%; CMI, 14.7%), complication rate (TAA, 62.2%; RAB, 37.4%; CMI, 44.6%), and the percentage of patients discharged to another institution (TAA, 21.2%; RAB, 9.3%; CMI, 12.0%) were clinically significant for all procedures. The mortality rate for RAB was greater when performed concomitant with an aortic reconstruction (4.4% vs 8.3%). All three procedures were resource intensive as reflected by the median length of stay (TAA, 14 days; RAB, 9 days; CMI, 14 days) and median hospital charges (TAA, $64,493; RAB, $36,830; CMI, $47,390). The multivariate model identified several variables for each procedure that had an impact on the predicted mortality rate (TAA, 14%-76%; RAB, < 1%-46%; CMI, < 2%-87%). CONCLUSIONS: The operative mortality rates across the United States for patients undergoing TAA repair and RAB are greater than commonly reported in the literature and mandate reexamining the treatment strategies for these complex vascular problems.

Extragenic suppressors of the nimX2(cdc2) mutation of Aspergillus nidulans affect nuclear division, septation and conidiation.

The Aspergillus nidulans NIMX(CDC2) protein kinase has been shown to be required for both the G(2)/M and G(1)/S transitions, and recent evidence has implicated a role for NIMX(CDC2) in septation and conidiation. While much is understood of its G(2)/M function, little is known about the functions of NIMX(CDC2) during G(1)/S, septation, and conidiophore development. In an attempt to better understand how NIMX(CDC2) is involved in these processes, we have isolated four extragenic suppressors of the A. nidulans nimX2(cdc2) temperature-sensitive mutation. Mutation of these suppressor genes, designated snxA-snxD for suppressor of nimX, affects nuclear division, septation, and conidiation. The cold-sensitive snxA1 mutation leads to arrest of nuclear division during G(1) or early S. snxB1 causes hyperseptation in the hyphae and sensitivity to hydroxyurea, while snxC1 causes septation in the conidiophore stalk and aberrant conidiophore structure. snxD1 leads to slight septation defects and hydroxyurea sensitivity. The additional phenotypes that result from the suppressor mutations provide genetic evidence that NIMX(CDC2) affects septation and conidiation in addition to nuclear division, and cloning and biochemical analysis of these will allow a better understanding of the role of NIMX(CDC2) in these processes.

Raman spectra of the double-anion salts M3ZnCl4NO3 (M+ = K+, Rb+, NH4).

Recently characterized K3ZnCl4NO3 and (NH4)3ZnCl4NO3, and newly prepared Rb3ZnCl4NO3 constitute a limited series of isomorphous double-anion salts (space group Pnma, Z = 4). Room-temperature (295 K) Raman spectra from polycrystalline samples of the compounds are reported and interpreted on the basis of the Cs site symmetry of the ZnCl4(2-) and NO3- ions with reference to the D2h factor group of the unit cell. The spectra are compared with Raman spectra of the corresponding M2ZnCl4 and MNO3 single-anion salts. Relative positions and frequencies of the ZnCl4(2-) modes vary considerably among the M3ZnCl4NO3 compounds, despite the isomorphism. The NO3- modes are more similar in all three compounds. The NO3- doubly degenerate v3 and V4 modes are split into two distinct bands as a result of the decent in symmetry from D3h for the free ion to Cs at the crystallographic site. The unequal intensities of the v3 bands observed for K3ZnCl4NO3 and Rb3ZnCl4NO3 and the equal intensities of the v4 bands observed for all three compounds suggest the same factor-group assignments as the high-temperature phase NH4NO3(III). The free-ion Raman-inactive planar deformation mode, v2, is evident in all three compounds, but with lesser intensity than its overtone 2v2. In K3ZnCl4NO3 and Rb3ZnCl4NO3, the symmetric stretching band, in addition to the very strong component for v1, shows a weak, low-frequency band found in many ionic nitrates, which has been attributed to thermally disordered nitrate ions or hot bands. This feature is not found in the spectrum of (NH4)3ZnCl4NO3. The 12 NH4+ ions in the unit cell of (NH4)3ZnCl4NO3, which occupy C1 and Cs sites in a 2:1 ratio, give rise to extremely broad bands that show no evidence of the individual symmetry distinctions of the cations. The broad band from NH4+ v4 obscures the region in which NO3- v3 bands are expected, but the NO3- overtone 2v2 is evident as a sharp peak above a similarly broad band from NH4+ v2.

Improved outcome in children with advanced stage B-cell non-Hodgkin's lymphoma (B-NHL): results of the United Kingdom Children Cancer Study Group (UKCCSG) 9002 protocol.

From July 1990 to March 1996, 112 children with stage III or IV B-cell non-Hodgkin's lymphoma (B-NHL) with up to 70% FAB L3-type blasts (n = 42) in the bone marrow without central nervous system (CNS) disease were treated on the United Kingdom Children Cancer Study Group (UKCCSG) 9002 protocol (identical to the French LMB 84). The median age was 8.3 years. There were 81 boys and 31 girls. According to the extent of the primary disease, patients were sub-staged into three groups: IIIA with unresectable abdominal tumour (n = 39); IIIB with abdominal multiorgan involvement (n = 57) and IIIX with extra-abdominal primary lymphoma often presenting as pleural effusion (n = 16). Univariate and multivariate analyses were carried out to evaluate the prognostic significance of lactate dehydrogenase (LDH) level at diagnosis, the sub-stage and the time to achieve complete remission (CR). With a median follow up of 48 months (range 12-92), the overall and event free survival (EFS) is 87% (95% confidence interval (CI) 79.2-92.1 %) and 83.7% (95% CI 76.3-89.2%) respectively. Six patients (5.4%) never achieved CR, of whom one is alive following high-dose therapy. Eight patients (7.1%) relapsed after achieving CR, three are alive after second-line therapy. There were three early toxic deaths (2.7%), mainly from infection, and one late death from a second cancer. There was no significant difference in EFS according to LDH level at diagnosis, the sub-stage or the time to CR. This study confirms the overall good prognosis and low rate of toxic deaths in patients with advanced B-NHL treated with this intensive regimen. No significant difference in EFS according to the sub-stage, the time to achieve CR or LDH level at diagnosis making it difficult to identify a group that should not receive intensive therapy.

Effect of pollution on genetic diversity in the bay mussel Mytilus galloprovincialis and the acorn barnacle Balanus glandula.

To test if environmental contamination acts as a selection force affecting genetic diversity at the population level, two intertidal invertebrate species, Mytilus galloprovincialis and Balanus glandula, were collected from seven different bay sites in southern California. Collections were made at three relatively pristine 'clean' sites and four 'impacted' sites exposed to heavy industrial or boating activity, and which had previously been identified as having measurable levels of pollution. Genetic diversity at each site was assessed by comparing fragment polymorphisms generated from genomic DNA by randomly amplified polymorphic DNA-polymerase chain reaction (RAPD-PCR). All populations retained a large amount of genetic diversity and were genetically similar to each other. However, several different measures of diversity indicated that, for most primers, the populations of both species from impacted sites had lower genetic diversity compared to those populations from clean sites. Individuals at impacted sites were more likely to share the same haplotypes than were those from clean sites. Few bands seen in the clean sites were absent from the impacted sites or vice versa, but a number of bands in the clean site populations were significantly less common in the impacted populations, while a few bands uncommon in clean site populations were more common at impacted sites. Together, these results suggest that pollution at the impacted sites may reduce genetic diversity among the resident invertebrate populations.

The impact of low birth weight, perinatal conditions, and sociodemographic factors on educational outcome in kindergarten.

OBJECTIVE: To assess the relative effects and the impact of perinatal and sociodemographic risk factors on long-term morbidity within a total birth population in Florida. METHODS: School records for 339 171 children entering kindergarten in Florida public schools in the 1992-1993, 1993-1994, or 1994-1995 academic years were matched with Florida birth records from 1985 to 1990. Effects on long-term morbidity were assessed through a multivariate analysis of an educational outcome variable, defined as placement into 9 mutually exclusive categories in kindergarten. Of those categories, 7 were special education (SE) classifications determined by statewide standardized eligibility criteria, 1 was academic problems, and the reference category was regular classroom. Generalized logistic regression was used to simultaneously estimate the odds of placement in SE and academic problems. The impact of all risk factors was assessed via estimated attributable excess/deficit numbers, based on the multivariate analysis. RESULTS: Educational outcome was significantly influenced by both perinatal and sociodemographic factors. Perinatal factors had greater adverse effects on the most severe SE types, with birth weight <1000 g having the greatest effect. Sociodemographic predictors had greater effects on the mild educational disabilities. Because of their greater prevalence, the impact attributable to each of the factors (poverty, male gender, low maternal education, or non-white race) was between 5 and 10 times greater than that of low birth weight and >10 times greater than that of very low birth weight, presence of a congenital anomaly, or prenatal care. CONCLUSIONS: Results are consistent with the hypothesis that adverse perinatal conditions result in severe educational disabilities, whereas less severe outcomes are influenced by sociodemographic factors. Overall, sociodemographic factors have a greater total impact on adverse educational outcomes than perinatal factors.

Effect of reproductive status on feline renal size.

Renal length and width dimensions were determined from survey radiography and excretory urography in 28 cats of various sex and reproductive status. Renal dimensions were expressed as a ratio to the length of the second lumbar vertebra. Renal dimensions were not significantly different when males were compared to females. However, significant differences in renal dimensions between intact and neutered cats were identified. Renal length ratios for neutered cats were: left kidney 2.22 +/- 0.14 (mean +/- standard deviation), right kidney 2.29 +/- 0.14. In intact cats, renal length ratios were: left kidney 2.60 +/- 0.19, right kidney 2.65 +/- 0.24. The mean renal length ratios for neutered cats was smaller than previously reported normal values. Thus, reproductive status should be considered when evaluating feline kidneys for alterations in size. Based on this study, normal feline renal length ratios range from 1.9 to 2.6 for neutered cats and 2.1 to 3.2 for intact cats.

Synthesis, opioid receptor binding, and biological activities of naltrexone-derived pyrido- and pyrimidomorphinans.

A series of pyrido- and pyrimidomorphinans (6a-h and 7a-g) were synthesized from naltrexone and evaluated for binding and biological activity at the opioid receptors. The unsubstituted pyridine 6a displayed high affinities at opioid delta, mu, and kappa receptors with K(i) values of 0.78, 1.5, and 8.8 nM, respectively. Compound 6a was devoid of agonist activity in the mouse vas deferens (MVD) and guinea pig ileum (GPI) preparations but was found to display moderate to weak antagonist activity in the MVD and GPI with K(e) values of 37 and 164 nM, respectively. The pyrimidomorphinans in general displayed lower binding potencies and delta receptor binding selectivities than their pyridine counterparts. Incorporation of aryl groups as putative delta address mimics on the pyrido- and pyrimidomorphinan framework gave ligands with significant differences in binding affinity and intrinsic activity. Attachment of a phenyl group at the 4'-position of 6a or the equivalent 6'-position of 7a led to dramatic reduction in binding potencies at all the three opioid receptors, indicating the existence of a somewhat similar steric constraint at the ligand binding sites of delta, mu, and kappa receptors. In contrast, the introduction of a phenyl group at the 5'-position of 6a did not cause any reduction in the binding affinity at the delta receptor. In comparison to the unsubstituted pyridine 6a, the 5'-phenylpyridine 6c showed improvements in mu/delta and kappa/delta binding selectivity ratios as well as in the delta antagonist potency in the MVD. Interestingly, introduction of a chlorine atom at the para position of the pendant 5'-phenyl group of 6c not only provided further improvements in delta antagonist potency in the MVD but also shifted the intrinsic activity profile of 6c from an antagonist to that of a mu agonist in the GPI. Compound 6d thus possesses the characteristics of a nonpeptide mu agonist/delta antagonist ligand with high affinity at the delta receptor (K(i) = 2.2 nM), high antagonist potency in the MVD (K(e) = 0.66 nM), and moderate agonist potency in the GPI (IC(50) = 163 nM). Antinociceptive evaluations in mice showed that intracerebroventricular (icv) injections of 6d produced a partial agonist effect in the 55 degrees C tail-flick assay and a full agonist effect in the acetic acid writhing assay (A(50) = 7.5 nmol). No signs of overt toxicity were observed with this compound in the dose ranges tested. Moreover, repeated icv injections of an A(90) dose did not induce any significant development of antinociceptive tolerance in the acetic acid writhing assay. The potent delta antagonist component of this mixed mu agonist/delta antagonist may be responsible for the diminished propensity to produce tolerance that this compound displays.

Conservative management of follicular non-Hodgkin's lymphoma in childhood.

Among 447 children with non-Hodgkin's lymphoma (NHL) on the childhood U.K. registry, seven children with follicular (NHL) were identified. Four were male and their age ranged from 4.25 to 13.5 years (median 7.5); all had localized disease, Murphy's stage I (n = 4) and II (n = 3). Sites involved at presentation were cervical lymph nodes and tonsils (n = 5), ileum (n = 1) and parotid gland (n = 1). Three had complete surgical excision only and four had complete (n = 1) or incomplete excision (n= 3) followed by a short multi-agent chemotherapy regimen (UKCCSG 9001 protocol). With a median follow-up of 1.5 years (range 0.25-5 years) from diagnosis, six are alive in complete remission (CR) including three who had no chemotherapy. These results confirm previous reports that follicular lymphomas in children are rare (1.5%) and tend to be localized at presentation. Their rarity makes it difficult to produce guidelines about treatment, but in localized cases a period of non-intervention may be justified.

Educational disabilities of neonatal intensive care graduates.

OBJECTIVE: To determine the relationship between perinatal and sociodemographic factors in low birth weight and sick infants hospitalized at regional neonatal intensive care units (NICUs) and subsequent educational disabilities. METHOD: NICU graduates born between 1980 and 1987 at nine statewide regionalized level III centers were located in Florida elementary schools (kindergarten through third grade) during academic year 1992-1993 (n = 9943). Educational disability was operationalized as placement into eight mutually exclusive types of special education (SE) classifications determined by statewide standardized eligibility criteria: physically impaired, sensory impaired (SI), profoundly mentally handicapped, trainable mentally handicapped, educable mentally handicapped, specific learning disabilities, emotionally handicapped, and speech and language impaired (SLI). Logistic regression was used to estimate the odds of placement in SE for selected perinatal and sociodemographic variables. RESULTS: Placement into SE ranged from .8% for SI to 9.9% for SLI. Placement was related to four perinatal factors (birth weight, transport, medical conditions [congenital anomalies, seizures or intraventricular hemorrhage] and ventilation), and five sociodemographic factors (child's sex, mother's marital status, mother's race, mother's educational level, and family income). Perinatal factors primarily were associated with placement in physically impaired, SI, profoundly mentally handicapped, and trainable mentally handicapped. Perinatal and sociodemographic factors both were associated with placement in educable mentally handicapped and specific learning disabilities whereas sociodemographic factors primarily were associated with placement in emotionally handicapped and SLI. CONCLUSIONS: Educational disabilities of NICU graduates are influenced differently by perinatal and sociodemographic variables. Researchers must take into account both sets of these variables to ascertain the long-term risk of educational disability for NICU graduates. Birth weight alone should not be used to assess NICU morbidity outcomes.

Synthesis, opioid receptor binding, and bioassay of naltrindole analogues substituted in the indolic benzene moiety.

A series of analogues of the delta opioid receptor antagonist naltrindole (1) possessing a phenyl, phenoxy, or benzyloxy group at the 4'-, 5'-, 6'-, or - 7'-positions (4-15) and a 2-(2-pyridinyl)ethenyl group at the 5'-position (16) on the indolic benzene ring were synthesized through Fischer indolization of naltrexone. Compounds 4-16 were evaluated for their affinities in opioid receptor binding assays in rat or guinea pig brain membranes and for their opioid antagonist and agonist activities in vitro on the guinea pig ileum (GPI) and mouse vas deferens (MVD) preparations. All of the compounds displayed delta selectivity in binding to the delta, mu, and kappa opioid receptors. The binding potencies of most of the compounds at the delta, mu, and kappa sites, however, were lower than that of 1. Among positional isomers, the 7'-substituted compounds in general had higher affinities than 6'-, 5'-, or 4'-substituted analogues, indicating that bulky groups are tolerated better at the 7'-position than at other positions. The affinity of the compounds were also determined at putative subtypes of the delta and kappa receptors: deltacx-1 (mu-like), deltacx-2 (delta-like), and the kappa2b site in an attempt to identify subtype selective agents. Although none were identified, the data revealed a different rank-order of potency beteween mu vs deltacx-1, deltacx-2 vs delta, and the kappa2b vs mu, delta, and kappa1. The antagonist potencies of the compounds in the MVD were in agreement with their binding affinities at the delta site in rat brain membrane. The most potent member of the series, the 7'-phenoxy compound 14, binds to the delta site with a Ki of 0.71 nM, shows >40-fold delta over mu and delta over kappa binding selectivity, and exhibits delta receptor antagonist potency in the MVD with a Ke of 0.25 nM, properties which are comparable to the delta receptor affinity and antagonist potency of naltrindole (Ki = 0.29 nM, Ke = 0. 49 nM). Interestingly, many members of the series were found to possess significant partial to full agonist activities in the MVD (6, 9, 10, 13, 16) or GPI (6, 11, 14, 15). Among the compounds studied, the highest agonist activity in the MVD was displayed by 16 (IC50 = 220 nM), and the highest agonist activity in the GPI was displayed by 14 (IC50 = 450 nM). The overall affinity and activity profile of compound 14 is, therefore, that of a nonpeptide ligand possessing mixed mu agonist/delta antagonist properties. Recently there has been considerable interest in such compounds possessing mu agonist/delta antagonist activities because of their potential therapeutic usefulness as analgesics with low propensity to produce tolerance and dependence side effects. The results of the present study suggest that morphinan derivatives related to 16 and 14 may provide useful leads for the development of potent nonpeptide ligands possessing delta agonist or mixed delta antagonist/mu agonist activities.

An assessment of the operation of an external quality assessment (EQA) scheme in histopathology in the South Thames (West) region: 1995-1998.

AIMS: To describe the design and organisation of a voluntary regional external quality assessment (EQA) scheme in histopathology, and to record the results obtained over a three year period. METHODS: A protocol is presented in which circulation of EQA slides alternated with teaching sessions. Procedures for the choice of suitable cases, evaluation of submitted diagnoses, and feedback of results to participants are described. The use of teaching sessions, complementary to the slide circulations, and dealing with current diagnostic problems is also outlined. RESULTS: Participation rates in the nine slide circulations varied between 66% and 89%, mean 85%. Overall scores were predictably high but 4% of returns, from 10 pathologists, were unsatisfactory. These low scores were typically isolated or intermittent and none of the participants fulfilled agreed criteria for chronic poor performers. CONCLUSIONS: This scheme has been well supported and overall performances have been satisfactory. The design was sufficiently discriminatory to reveal a few low scores which are analysed in detail. Prompt feedback of results to participants with identification of all "incomplete" and "wrong" diagnoses is essential. Involvement of local histopathologists in designing, running, and monitoring such schemes is important.

Loss of heterozygosity at 5q21 in non-small cell lung cancer: a frequent event but without evidence of apc mutation.

Four genetic polymorphisms in the APC and MCC genes at chromosome 5q21 were analysed for loss of heterozygosity (LOH) in 97 primary squamous carcinomas and adenocarcinomas of the lung. LOH was identified in at least two polymorphic loci in 41 percent of informative cases. There was no significant difference in the frequency of LOH between squamous carcinomas and adenocarcinomas. Within the adenocarcinoma group, however, LOH appeared to be more common in tumours having a bronchial origin (5/9; 56 per cent) than in parenchymal adenocarcinoma (6/21; 29 per cent). All 32 tumours showing LOH at one or more polymorphic sites were examined for mutations in the mutation cluster region (MCR) of APC by single-strand conformational polymorphism (SSCP) analysis. Mutations were not detected in any of these cases. We therefore propose that it is likely that a tumour suppressor gene on 5q other than APC is involved in the pathogenesis of lung cancer.

Correlation between systolic blood pressure and physical development in adolescence.

Although the close relation between blood pressure and physical development in adolescence has been established in cross-sectional and comparative cross-sectional studies, the entire trend of systolic blood pressure (SBP) during adolescence has not been elucidated in conjunction with physical development in a longitudinal study. Blood pressure (mmHg), body weight (kg), and body height (m) were measured annually for 418 subjects in Hiroshima and Nagasaki, Japan, from age 10 (1955 or 1956) through 18 years (1963 or 1964). The Gompertz growth model was used to determine the velocity of weight increase (VEL) during that age period. The relations between SBP from age 10 to 18 and VEL, weight, height, body mass index (BMI; weight/height2, kg/m2), and the age at which the measurements were made were investigated individually using random-coefficient growth-curve analysis. The SBP trend for the 10- to 18-year age period could be shown by the following prediction equations: for the 163 Hiroshima males, SBP = 82.38 + 0.89 VEL at age 1.15 years prior to the current examination (VEL (age - 1.15)) + 1.40 BMI; for the 57 Nagasaki males, SBP = 92.70 + 1.07 VEL (age - 1.15) + 0.79 BMI; for the 148 Hiroshima females, SBP = 104.88 + 1.63 VEL (age - 1.15) + 0.05 BMI; for the 50 Nagasaki females, SBP = 113.62 + 1.67 VEL (age - 1.15) - 0.59 BMI. VEL 1.15 years prior to the current examination was significantly and positively related to SBP in each city by sex group (p < 0.01), and current BMI was significantly related to SBP for males in Hiroshima (p < 0.01) and nearly so in Nagasaki (p = 0.06), but not for females in either city (p = 0.84 and 0.13, respectively). Because the plot of VEL was a convex curve, SBP peaked approximately 1-2 years after the peak in VEL and then decreased in both sexes. The entire SBP trend during adolescence can be expressed as an equation of VEL and BMI in males and of VEL in females. SBP does not increase linearly with age.

Lipophilic antifolates as agents against opportunistic infections. 1. Agents superior to trimetrexate and piritrexim against Toxoplasma gondii and Pneumocystis carinii in in vitro evaluations.

2,4-Diaminopteridines (21 compounds) and 2,4-diamino-5-methyl-5-deazapteridines (34 compounds) along with three 2,4-diamino-5-unsubstituted-5-deazapteridines and four 2,4-diaminoquinazolines, each with an aryl groups attached to the 6-position of the heterocyclic moiety through a two-atom bridge (either CH2NH, CH2N(CH3),CH2S, or CH2CH2), were synthesized and evaluated as inhibitors of the growth of Toxoplasma gondii in culture and as inhibitors of dihydrofolate reductase enzymes from T. gondii, Pneumocystis carinii, and rat liver. Exceptionally high levels of combined potency and selectivity as growth inhibitors of T. gondii and as inhibitors of the microbial enzymes relative to the mammalian enzyme were found among the 5-methyl-5-deazapteridines but not for the other heterocyclic types. Thirty of the 34 5-methyl-5-deaza compounds gave growth inhibition IC50 values lower than that of pyrimethamine (0.4 microM) with 14 compounds below 0.1 microM, values that compare favorably with those for piritrexim and trimetrexate (both near 0.02 microM). As inhibitors of T gondii DHFR, all but three of the 34 5-methyl-5-deaza compounds gave IC50 values in the order of magnitude with those of piritrexim (0.017 microM) and trimetrexate (0.010 microM), and 17 compounds of this group gave IC50 values versus P. carinii DHFR similarly comparable with those of piritrexim (0.031 microM) and trimetrexate (0.042 microM). Thirteen of these congeners gave both T. gondii growth inhibition and DHFR inhibition IC50 values of 0.10 microM or less, thus indicating facile penetration of the cell membrane. Eleven of these inhibitors of both T. gondii growth and DHFR have selectivity ratios (IC50 rat liver divided by IC50 T. gondii) of 5 or greater for the parasite DHFR. The highest selectivity ratio of nearly 100 belongs to the 5-methyl-5-deaza compound whose 6-substituent is CH2CH2C6H3(OCH3)2-2,5. This compound is over 10(3)-fold more selective for T. gondii DHFR than bridge homologue piritrexim (selectivity ratio 0.088), a compound now in clinical trials. The candidate with CH2NHC6H3(CH3)2-2,5 in the 6-position gave the highest P. carinii DHFR selectivity ratio of 4.0, which is about 60-fold more selective than trimetrexate (0.071) and 80-fold more selective than piritrexim (0.048) toward this enzyme. The 10 best compounds with respect to potency and selectivity includes six compounds bearing 2,5-disubstituted phenyl groups in the side chain (with little, if any, difference in effects of methyl, methoxy, or ethoxy), two side chains bearing 1-naphthyl groups, and two with 5,6,7,8-tetrahydro-1-naphthyl groups. Bridge groups represented in the 10 choice compounds are CH2NH, CH2N(CH3), CH2CH2, and CH2S. The high levels of both potency and selectivity among these agents suggest that in vivo studies now underway may lead to agents that could replace trimetrexate and piritrexim in treatment of toxoplasmosis and P. carinii pneumonia.

Changes in survival patterns of very low-birth-weight infants from 1980 to 1993.

OBJECTIVE: To determine changes in survival patterns among very low-birth-weight ( < 1500 g) infants between 1980 and 1993. METHODS: The records of 12,960 infants treated in nine perinatal intensive care centers in Florida were analyzed on the basis of survival (discharged alive from hospital) according to four independent variables: birth weight, race, sex, and transport status. Survival curves were generated using log linear regression techniques for each race by sex by transport status group. RESULTS: Race, sex, and transport status correlated significantly with survival: survival percentages were higher among black infants, female infants, and infants transported to the perinatal intensive care centers than among white infants, male infants, and those admitted initially to the tertiary care centers. After 1985, 95% of neonates with birth weights between 1200 and 1500 g survived. In addition, survival of 500- to 500-g transported black male infants increased from zero to near 80% during the 13-year period; that of 500- to 550-g inborn white female infants rose from 35% to 70%. CONCLUSIONS: These results illustrate the value of taking into account race, sex, and transport status in efforts to understand the contribution that neonatal intensive care of extremely low-birth-weight infants makes to the lowering of infant mortality, and of using multivariable statistical procedures to generate predicted survival probabilities for different subpopulations. These probabilities can be applied to (1) predicting survival for specific subgroups of extremely low-birth-weight infants, and (2) helping physicians develop clinical guidelines for extending care to infants at the threshold of viability.

An index for early assessment of neonatal survival in low birthweight infants.

Since its development in the 1950s, the Apgar index has come into widespread use as a tool to evaluate neonatal condition, with predictive implications for mortality and morbidity. However, Apgar scores were validated in predominantly term infants and have questionable prognostic value for low birthweight infants. The purpose of this study was to develop a survival index applicable to premature infants. Thirty-six perinatal variables were evaluated initially, based on data from 441 neonates weighing 500 to 1800 g. A multifactorial index of nine variables was derived, each independently related to mortality. Sensitivity of the index was 95%, specificity was 68%, positive predictive value was 90%, and negative predictive value was 81%. This index provides the most accurate tool yet reported in the literature for predicting concurrent survival of premature infants. The tool is recommended for use as an index of neonatal condition for low birthweight infants. Its additional use, as a predictor of the likelihood of survival would require time and place specific validation.