Immunologic defenses against metastases: impairment by excision of an allotransplanted lymphoma.

Hamsters grafted with an allotransplantable lymphoma that does not metastasize develop a state of concomitant immunity which renders them refractory to reinoculation with cells of the same tumor. Removal of the tumor 7 days after transplantation rapidly leads to a decrease in immunity, the production of enhancing antibodies, and the appearance of metastatic deposits which are probably derived from preexisting tumor cells in the blood and lymphoid tissuces.

Aphasia and speech organization in children.

A long-standing controversy concerns whether lateralized cerebral specialization for speech and language is present at the time of language origins (developmental invariance) or whether it gradually develops from initial bilaterality (developmental progression). Thus controversy is complicated by conflicting reports of the incidence of childhood aphasia. The discrepancies are largely due to one early study. When methods for estimating speech organization distributions are applied to later studies, the developmental invariance position is supported.

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.

Cull rates of dairy cattle with antibodies to bovine leukemia virus.

The relationship of cull rate to age was investigated retrospectively in dairy cows with and without antibodies to bovine leukemia virus (BLV). Banked sera from eight annual herd tests on one 200-cow herd were tested for presence of BLV antibodies by agar-gel immunodiffusion using the Mr 51,000 glycoprotein antigen of BLV. Age-specific cull rates were computed for BLV-antibody-positive and antibody-negative cows yearly from 2 to 7 years of age. Cull rates, transformed by the Arc-sin square root, were analyzed by weighted regression. Transformed cull rates increased significantly as BLV-antibody-positive cows aged (one-tailed P = 0.023) but not as antibody-negative cows aged (one-tailed P = 0.59). A Mantel-Byar survival analysis showed significantly longer survival beyond 3.5 years of age among antibody-negative cows than among antibody-positive cows (P = 0.008).

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.

Crossed and uncrossed projections to cat sacrocaudal spinal cord: II. Axons from muscle spindle primary endings.

The terminal fields of primary afferent fibers from tail muscle spindle primary endings were mapped within cat sacrocaudal spinal cord (S3-Ca7), using intra-axonal recording and horseradish peroxidase staining techniques. We sought to determine the ipsilateral and contralateral projection patterns and to relate these to the fibers' muscles of origin. Fifty-three group Ia fibers were successfully stained. Segmental collaterals originated from either the ascending or descending branch within the dorsal columns. Collaterals coursed rostromedially within the dorsal columns and traversed the medial aspect of the dorsal horn. Ipsilateral terminations were similar for all fibers. Within the ventral horn, boutons were consistently observed in the medial or central portions of lamina VII. In lamina VIII, a variable number of boutons was seen on fine branches emerging from larger fibers coursing ventrally. Clusters of terminals were plentiful in the regions of motoneurons, i.e., lamina IX and the nucleus commissuralis. Terminals were found in the adjacent white matter. In addition to ipsilateral terminations, some group Ia fibers (20 of 53) had collateral branches that crossed ventrally to the central canal, terminating within the midline ventral gray commissure and/or the contralateral ventral horn. Crossed projections always originated in medial (dorsal or ventral), but not lateral, muscles of the tail. These data suggest that ipsilateral projections of group Ia fibers make connections on sacrocaudal motoneurons, on neurons mediating segmental reflex functions and on neurons conveying ascending information. It is speculated that crossed and uncrossed connections between group Ia fibers from medial muscles and bilateral dendritic trees of motoneurons subserve synchronized co-contraction of synergistic muscles located on the two sides of the body, such as with dorsal or ventral flexion of the tail. Group Ia projections from lateral muscles, that are entirely ipsilateral, would be involved with lateral movements of the tail.

Radical neck dissections for squamous carcinomas: pathological findings and their clinical implications with particular reference to transcapsular spread.

Two hundred fifty radical neck dissections, undertaken for mucosal squamous carcinomas of the head and neck, were reviewed with reference to pathological findings and their clinical implications. No major differences in descriptive surgical pathology were established between irradiated and non-irradiated resections. In general, irradiated dissections had lower total node counts and somewhat fewer nodal metastases involving a smaller number of different nodal groups. The topography of nodal deposits was similar in irradiated and non-irradiated resections. Palpable keratin granulomas (without intact tumor) were almost confined to irradiated patients. Transcapsular spread of tumor from involved lymph nodes was common: it was demonstrated in 160/188 'positive' dissections (85%) and was subclassified as 'macroscopic' in 90 and 'microscopic' in 70. The incidence and extent of transcapsular spread was similar in irradiated and nonirradiated resections. It was more frequently observed in association with large nodal masses but it was also regularly found with small nodal deposits less than 3 cm in diameter. Statistical analyses showed strong associations (p less than 0.0005) between the presence and/or extent of transcapsular spread and subsequent recurrence in the operated neck and overall survival. The predictive value of other clinical and pathological features vis-a-vis local neck recurrence such as numbers of involved nodal groups was weaker. Macroscopic transcapsulr spread emerges as the major prognostic factor for recurrent disease in the neck (p less than 0.0001). Attention is drawn to the advantages of accurate descriptive categories ('macroscopic', 'microscopic') for this critical prognostic feature.

Results of a prospective study evaluating the effects of mantle irradiation on pulmonary function.

Thirty patients with Stages I-III Hodgkin's disease receiving mantle irradiation were prospectively evaluated prior to therapy with spirometry, lung volumes, and tests of diffusing capacity (DLCO). Follow-up examinations were performed at 3, 6, and 12 months and then yearly. Sixteen patients had Hodgkin's disease involving the mediastinum at presentation, 10 were smokers, and 16 received either preirradiation or postirradiation chemotherapy. Mantle doses ranged between 2300 cGy and 4000 cGy (mode of 3750 cGy) given at 150 cGy to 170 cGy tumor dose per day with split-course technique. Pulmonary function test results were translated to percent change from predicted values obtained from normal standards for each age, sex, race, and height. These percent changes were then analyzed as a linear function of time. Twenty patients have been tested greater than or equal to 4 years after treatment with a median time from treatment to last pulmonary function test of 8 years. Changes over time in spirometry included an early, mild decrease in both forced vital capacity (FVC) and forced expiratory volume at 1 second (FEV1), which returned to baseline by 2 years and then gradually decreased to a 10-15% deficit as compared with predicted values at 6-10 years. Additionally, there was a very slight decrease in FEV1/FVC beginning at 1 year and gradually increasing to an 8% deficit at 6-10 years. Changes over time in lung volumes included a mild nadir of total lung capacity (TLC) and functional residual capacity (FRC) at 6 months to a year, which returned to baseline at 2-4 years and then gradually dropped to a 5-10% deficit at 6-10 years. Mean DLCO for the study group was 20% below predicted values prior to treatment and dropped to a low of 30% below predicted at 6 months following treatment, then gradually returned to baseline by 4 years and showed continued improvement to an overall deficit of approximately 10% at 6-10 years. With the exception of FEV1/FVC, the changes noted in spirometry and lung volumes were of insufficient degree to be classified as abnormal. The decrease in FEV1/FVC is indicative of a significant and progressive obstructive ventilatory defect. The effects on pulmonary function tests of smoking, the presence of mediastinal involvement by Hodgkin's disease, and exposure to chemotherapy were assessed by statistical analysis. No subsets of patients demonstrated consistent evidence of a restrictive ventilatory defect expected after irradiation.(ABSTRACT TRUNCATED AT 400 WORDS)

Studies on synthesis and anticancer activity of selected N-(2-fluoroethyl)-N-nitrosoureas.

An activated carbamate, 2-nitrophenyl (2-fluoroethyl)nitrosocarbamate (3), was used to advantage in the synthesis of the water-soluble (2-fluoroethyl)nitrosoureas 6a--d from 2-aminoethanol, (1 alpha, 2 beta, 3 alpha)-2-amino-1,3-cyclohexanediol, cis-2-hydroxycyclohexanol, and 2-amino-2-deoxy-D-glucose. In a variation of this method, 2,4,5-trichlorophenyl (2-fluoroethyl)carbamate (4) was used to prepare the urea from which the essentially water-insoluble N-(2,6-dioxo-3-piperidinyl)-N-(2-fluoroethyl)-N-nitrosourea (6e) was derived. The anticancer activity of these nitrosoureas was determined against the murine tumors B16 melanoma and Lewis lung carcinoma and found to be significant and comparable to their chloroethyl counterparts. On the basis of results from both systems, the dihydroxycyclohexyl derivative 6b may be the most effective.

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.

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.

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.

Prospective pricing system for tertiary neonatal intensive care.

This study assessed the potential impact of the federal neonatal diagnosis-related group (DRG) pricing system upon reimbursement to a state neonatal intensive care program. Data for length of intensive care unit stay, procedures, hospital charges, and audited cost reports from the state of Florida's ten regional neonatal intensive care centers were analyzed for 8,492 neonates whose charges totaled $118 million. Mean lengths of stay in these tertiary care centers were substantially longer than those reported for the federal DRGs, which were based on community hospital data. If federal DRG-based reimbursement to hospitals were implemented in Florida's perinatal intensive care program, compensation would range from 9% to 56% of actual hospital care charges. Federal DRG price rates were not predictive of hospital charges. Only 16% of the total variation in hospital charges was explained by differences among federal DRG rates (R2 = .16). Analysis of data by major determinants of resource consumption provided groups more homogeneous with respect to hospital charges and, hence, cost. Therefore, we developed a prospective pricing system that used modifications of federal newborn DRG system. These modifications resulted in a threefold increase in R2 (.52). Our proposed system permits prediction of cost and reimbursement for infants by three criteria: birth weight, need for mechanical ventilation and/or major surgery, and survival status and length of survival for those who die.

Prospective pricing model for neonatologists and obstetricians in tertiary care centers.

According to the new federal diagnosis-related group (DRG) system, hospitals are reimbursed fixed sums based on discharge diagnoses, rather than variable sums that depend on specific goods and services consumed and number of days hospitalized. The government is now exploring DRGs as a potential mechanism for reimbursing physicians. In Florida, two DRG-type reimbursement systems were developed for neonatal and obstetrical hospitalizations in tertiary care settings, as departures from the federal DRG system. Called neonatal care groups (NCGs) and obstetrical care groups (OBCGs), both classification systems predicted hospital charges in these settings more accurately than did federal DRGs. The feasibility of a prospective pricing system for neonatologists and obstetricians based on NCGs and OBCGs was investigated. The data showed that neonatologists' charges had a high correlation with hospital charges (r = .90) and that increasing levels of intensity of care as defined by the NCGs were reflected by consistent increases in reimbursement to neonatologists. If the NCG system were to be applied, neonatologists would receive compensation equivalent to that which they currently earn according to the fee-for-service system. In contrast, obstetricians' charges bore almost no relationship to hospital charges. However, modest differences in obstetrician's charges did emerge as a reflection of number of complications, which are incorporated into the OBCG categories; this suggests that a reimbursement system based on hospital OBCG categories might be applied to obstetricians.

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.

Educational outcome of neonatal intensive care graduates.

Studies of developmental outcome of neonatal intensive care unit graduates have generally been limited to the first 2 to 3 years of life, with outcome determined by psychometric tests. This study followed neonatal intensive care unit graduates born 1975 through 1983 (n = 457) into the public school system and compared their educational outcomes with those of newborn nursery graduates (n = 656). Outcomes were evaluated by placement in four academic categories: regular classroom, academic problems, speech/language impairment, and major impairment. Educational outcomes for children of both groups were essentially the same. Their placement in the four academic categories were equally affected by nonmedical variables, primarily income (below/above poverty level), race, and sex. Seventy percent of poverty-level children were in one of the three problem categories, compared with 40% of children above poverty level. Neither neonatal intensive care unit treatment nor low birth weight were major predictors of educational outcome. The only clear-cut neonatal intensive care unit effect occurred among children born with sensory or physical impairments. Therefore, in order to reduce poor educational outcomes, follow-up and intervention programs should be targeted primarily to children with diagnosable handicaps and from minority, low-income families.

The management of primary lymphoma of bone.

From October 1962 through April 1982, 21 patients with the diagnosis of primary lymphoma of bone (18 monostotic, stages IE and IIE; 3 polyostotic) were treated with curative intent. A combination of chemotherapy and radiation therapy was used in 11 patients, local treatment alone in 9 patients, and chemotherapy alone in one patient. Overall 5-year survival for the patients treated with curative intent was 56%. Standard work-up has changed over the 20-year study period. Five-year survival for the subset of eight stage I and II patients with full pretherapy staging was 83%. Prognosis was significantly correlated with extent of pretherapy staging. Treatment parameters that also seemed to predict outcome were the aggressiveness of chemotherapy and the use of irradiation or surgery for local-regional disease; the only local failure occurred in the patient who received chemotherapy alone. Complications of radiation therapy alone and in combination with chemotherapy are discussed and correlated with irradiation dose. Radiation therapy techniques are described, and a management approach is recommended.

Autoantibodies and immunoglobulins among atomic bomb survivors.

The purpose of this study was to determine if exposure to atomic bomb radiation affects immune responsiveness, such as the occurrence of autoantibodies and levels of immunoglobulins. Rheumatoid factor, antinuclear antibody, antithyroglobulin antibody, anti-thyroid-microsomal antibody and immunoglobulin levels (IgG, IgM, IgA and IgE) were measured among 2,061 individuals exposed to atomic bomb radiation in Hiroshima and Nagasaki whose estimated doses ranged from 0 to 5.6 Gy. The prevalence and titers of rheumatoid factor were found to be increased in the individuals exposed to higher radiation doses. The IgA level in females and the IgM level in both sexes increased as radiation dose increased, although the effects of radiation exposure were not large. No effect of radiation was found on the prevalence of antinuclear antibody, antithyroglobulin antibody and anti-thyroid-microsomal antibody or on the levels of IgG and IgE.

Monoclonal gammopathy in atomic bomb survivors.

An analysis of monoclonal gammopathy in relation to radiation exposure was conducted on atomic bomb survivors examined between October 1979 and September 1981 and between June 1985 and May 1987. There was no overall increase in the relative risk of monoclonal gammopathy and only a suggestive increase in benign monoclonal gammopathy in the second survey which did not achieve statistical significance (P = 0.17). Thirty-one cases were detected among 8796 individuals studied in the first survey, whereas 68 cases were found among 7350 people in the second survey. Among the 31 cases found in the first survey, 9 individuals (29%) died before the second survey: 4 of cancer, 4 of vascular disease, and 1 of infection. Among the 8 individuals with benign monoclonal gammopathy examined in both surveys, 4 developed suppression of residual immunoglobulin(s), suggesting the progression of monoclonal gammopathy. The overall relative risks of monoclonal gammopathy in atomic bomb survivors in the two surveys were not significantly increased with increasing radiation dose. Only benign monoclonal gammopathy in 1985-1987 showed a suggestive increase with radiation exposure. The relative risk of benign monoclonal gammopathy in 1985-1987 was 2.64 in the group exposed to 0.01-0.49 Gy and 2.14 in the > or = 0.50-Gy group (95% confidence intervals = 0.90-8.82 and 0.69-7.31, respectively).

Granulocyte changes in infectious mononucleosis.

Various changes in the granulocytes have been investigated in a large series of patients with infectious mononucleosis. A high proportion of cases regularly show a neutropenia with a shift to the left during the first three to four weeks of the disease; these changes, though transient, may be profound. The band cells present during the acute phase of the disease also show certain alterations in cytochemical staining and low alkaline phosphatase scores are common at this time. The maturation and release of leucocytes from the bone marrow is apparently normal. Theoretical mechanisms for the neutropenia are briefly discussed, including the possible role of excessive peripheral destruction.