Showing papers by "Johns Hopkins University published in 1987"

Asymptotic Properties of Maximum Likelihood Estimators and Likelihood Ratio Tests under Nonstandard Conditions

Abstract: Large sample properties of the likelihood function when the true parameter value may be on the boundary of the parameter space are described. Specifically, the asymptotic distribution of maximum likelihood estimators and likelihood ratio statistics are derived. These results generalize the work of Moran (1971), Chant (1974), and Chernoff (1954). Some of Chant's results are shown to be incorrect. The approach used in deriving these results follows from comments made by Moran and Chant. The problem is shown to be asymptotically equivalent to the problem of estimating the restricted mean of a multivariate Gaussian distribution from a sample of size 1. In this representation the Gaussian random variable corresponds to the limit of the normalized score statistic and the estimate of the mean corresponds to the limit of the normalized maximum likelihood estimator. Thus the limiting distribution of the maximum likelihood estimator is the same as the distribution of the projection of the Gaussian random v...

Prevalence of ras gene mutations in human colorectal cancers

Abstract: A combination of DNA hybridization analyses and tissue sectioning techniques demonstrate that ras gene mutations occur in over a third of human colorectal cancers, that most of the mutations are at codon 12 of the c-Ki-ras gene and that the mutations usually precede the development of malignancy.

Supercoiling of the DNA template during transcription.

Abstract: Transcription of a right-handed double-helical DNA requires a relative rotation of the RNA polymerase and its nascent RNA around the DNA. We describe conditions under which the resistance to the rotational motion of the transcription ensemble around the DNA can be large. In such cases, the advancing polymerase generates positive supercoils in the DNA template ahead of it and negative supercoils behind it. Mutual annihilation of the positively and negatively supercoiled regions may be prevented by anchoring points on the DNA to a large structure, or, in the case of an unanchored plasmid, by the presence of two oppositely oriented transcription units. In prokaryotes, DNA topoisomerase I preferentially removes negative supercoils and DNA gyrase (topoisomerase II) removes positive ones. Our model thus provides an explanation for the experimentally observed high degree of negative or positive supercoiling of intracellular pBR322 DNA when DNA topoisomerase I or gyrase is respectively inhibited. We discuss the implications of our model in terms of supercoiling regulation, DNA conformational transitions, and gene regulation in both prokaryotes and eukaryotes.

Art gallery theorems and algorithms

Abstract: Polygon partitions Orthogonal polygons Mobile guards Miscellaneous shapes Holes Exterior visibility Visibility groups Visibility algorithms Minimal guard covers Three-dimensions and miscellany.

The multicenter aids cohort study: rationale, organization, and selected characteristics of the participants

Abstract: The Multicenter AIDS Cohort Study was designed to elucidate the natural history of the infection causing acquired immunodeficiency syndrome (AIDS), identify risk factors for occurrence and clinical expression of the infection, and establish a repository of biologic specimens for future study. A variety of recruitment techniques, including special assurance of confidentiality, were used to enroll participants. Nearly 5,000 homosexual men volunteered for semiannual interview, physical examination, and laboratory testing in four metropolitan areas. A significant majority of these men in each center (69-83%) reported having 50 or more lifetime sexual partners, and over 80% had engaged in receptive anal intercourse with at least some of their partners in the previous two years. By the time of the participants' initial evaluation (April 1984-April 1985), infection with the human immunodeficiency virus (HIV) had occurred in higher proportions of men in Los Angeles (51%) and Chicago (43%) than in Baltimore/Washington, DC (31%) and Pittsburgh (21%), presumably as a result of the higher number of partners and proportion with whom these men had engaged in high-risk practices (e.g., receptive anal intercourse). Follow-up evaluations are underway in this comprehensive longitudinal investigation of HIV infection.

Direct measurement of free radical generation following reperfusion of ischemic myocardium

Abstract: Electron paramagnetic resonance spectroscopy was used to directly measure free radical generation in perfused rabbit hearts. Hearts were freeze-clamped at 77 degrees K during control perfusion, after 10 min of normothermic global ischemia (no coronary flow), or following post-ischemic reperfusion with oxygenated perfusate. The spectra of these hearts exhibited three different signals with different power saturation and temperature stability: signal A was isotropic with g = 2.004; signal B was anisotropic with axial symmetry with g parallel = 2.033 and g perpendicular = 2.005; signal C was an isotropic triplet with g = 2.000 and hyperfine splitting an = 24 G (1 G = 0.1 mT). The g values, linewidth, power saturation, and temperature stability of signal A are identical to those of a carbon-centered semiquinone, whereas those of signal B are similar to alkyl peroxyl or superoxide oxygen-centered free radicals; signal C is most likely a nitrogen-centered free radical. In the control heart samples signal A predominated, whereas in ischemic hearts signal A decreased in intensity, and signals B and C became more intense; with reperfusion all three signals markedly increased. Free radical concentrations derived from the intensities of the B and C signals peaked 10 sec after initiation of reflow. At this time the oxygen-centered free radical concentration derived from the intensity of signal B was increased over six times the concentration measured in control hearts and over two times the concentration measured in ischemic hearts. Hypoxic reperfusion did not increase any of the free radical signals over the levels observed during ischemia. These experiments directly demonstrate that reactive oxygen-centered free radicals are generated in hearts during ischemia and that a burst of oxygen radical generation occurs within moments of reperfusion.

Ability Grouping and Student Achievement in Elementary Schools: A Best-Evidence Synthesis

Abstract: This article reviews research on the effects of between- and within-class ability grouping on the achievement of elementary school students. The review technique—best-evidence synthesis—combines features of meta-analytic and narrative reviews. Overall, evidence does not support assignment of students to self-contained classes according to ability (median effect size [ES] = .00), but grouping plans involving cross-grade assignment for selected subjects can increase student achievement. Research particularly supports the Joplin Plan, cross-grade ability grouping for reading only (median ES = +.45). Within-class ability grouping in mathematics is also found to be instructionally effective (median ES = +.34). Analysis of effects of alternative grouping methods suggests that ability grouping is maximally effective when done for only one or two subjects, with students remaining in heterogeneous classes most of the day; when it greatly reduces student heterogeneity in a specific skill; when group assignments are...

Increased expression of the epidermal growth factor receptor gene in malignant gliomas is invariably associated with gene amplification.

Abstract: Primary malignant gliomas from 63 patients were analyzed to determine the relationship between amplification of the gene encoding the epidermal growth factor receptor (EGFR) and expression of the corresponding mRNA. Twenty-four tumors were found to have amplified the EGFR gene and amplification of other genes occurred in three additional tumors. Hybridization with synthetic RNA probes was used to quantitate mRNA levels in situ. All 24 tumors with amplification of the EGFR gene had high levels of expression of this gene, while none of the 39 tumors without amplification had increased levels. This shows that, in human gliomas, large increases in the expression of the EGFR gene are invariably associated with alterations in gene structure.

Increased Risk of Cancer in the Peutz–Jeghers Syndrome

Abstract: The Peutz-Jeghers syndrome is an autosomal dominant hereditary disease characterized by hamartomatous polyps of the gastrointestinal tract and by mucocutaneous melanin deposits. The frequency of cancer in this syndrome has not been studied extensively. Therefore, we investigated 31 patients with the Peutz-Jeghers syndrome who were followed from 1973 to 1985. All cases of cancer were verified by histopathological review. Cancer developed in 15 of the 31 patients (48 percent)--gastrointestinal carcinomas in 4, nongastrointestinal carcinomas in 10, and multiple myeloma in 1. In addition, adenomatous polyps of the stomach and colon occurred in three other patients. The cancers were diagnosed when the patients were relatively young, but after the Peutz-Jeghers syndrome had been diagnosed (interval between diagnoses, 25 +/- 20 years; range, 1 to 64). According to relative-risk analysis, the observed development of cancer in the patients with the syndrome was 18 times greater than expected in the general population (P less than 0.0001). Our results suggest that patients with the Peutz-Jeghers syndrome have an increased risk for the development of cancer at gastrointestinal and nongastrointestinal sites.

Venoocclusive disease of the liver following bone marrow transplantation

Abstract: Review of 235 consecutive patients undergoing bone marrow transplantation was performed in order to define the clinical syndrome of venoocclusive disease of the liver (VOD) in these patients. Analysis of all patients with histologically proven VOD revealed a consistent clinical syndrome of liver dysfunction occurring within the first 3 weeks after marrow infusion. This was characterized by hyperbilirubinemia peaking at greater than or equal to 2 mg/dl with at least 2 of 3 other findings: hepatomegaly, ascites, and 5% or greater weight gain. VOD developed in 22% (52 of 235). A persistently elevated aspartate aminotransferase (SGOT) prior to transplant was associated with an increased risk of developing VOD by multivariate analysis (P = 0.0003), and acute leukemia in first remission was associated with a decreased risk (P = 0.02). Neither the preparative regimen (busulfan and cyclophosphamide versus cyclophosphamide and total body irradiation) nor the type of graft (allogeneic versus autologous) influenced the occurrence. Twenty-four of these 52 patients (47%) died with VOD (10% of the entire group). This makes VOD the third leading cause of death in our allogeneic graft recipients, and the second leading cause in our patients receiving autologous transplants. VOD is a common complication of bone marrow transplantation and has a specific clinical presentation, which usually allows diagnosis without the need of liver biopsy.

Expression of a set of growth-related immediate early genes in BALB/c 3T3 cells: coordinate regulation with c-fos or c-myc

Abstract: We have previously identified by cDNA cloning 5 mRNAs that appear in resting BALB/c 3T3 cells soon after growth stimulation by serum or platelet-derived growth factor. Five additional mRNAs of this class are described in this report. The mRNAs reached peak levels between 40 and 120 min after serum addition and rapidly decayed thereafter. All 10 RNAs were superinduced in the presence of cycloheximide. Nuclear run-on experiments indicated that the increase in the mRNAs is the result of rapid transcriptional activation of their genes on stimulation by serum or platelet-derived growth factor. Superinducibility by cycloheximide is due to two effects: prolonged transcription and stabilization of mRNAs. This overall pattern of regulation is similar to that of the c-fos or c-myc protooncogenes reported previously. We hypothesize that these newly identified "immediate early" genes play a role in the proliferative response induced by growth factors.

Neurofilament gene expression: a major determinant of axonal caliber.

Abstract: Within the wide spectrum of axonal diameters occurring in mammalian nerve fibers, each class of neurons has a relatively restricted range of axonal calibers. The control of caliber has functional significance because diameter is the principal determinant of conduction velocity in myelinated nerve fibers. Previous observations support the hypothesis that neurofilaments (NF) are major intrinsic determinants of axonal caliber in large myelinated nerve fibers. Following interruption of axons (axotomy) by crushing or cutting a peripheral nerve, caliber is reduced in the proximal axonal stumps, which extend from the cell bodies to the site of axotomy. (The distal axonal stumps, which are disconnected from the cell bodies, degenerate and are replaced by the outgrowth of regenerating axonal sprouts arising from the proximal stump). This reduction in axonal caliber in the proximal stumps is associated with a selective diminution in the amount of NF protein undergoing slow axonal transport in these axons, with a decrease in axonal NF content, and with reduced conduction velocity. The present report demonstrates that changes in axonal caliber after axotomy correlate with a selective alteration in NF gene expression. Hybridization with specific cDNAs was used to measure levels of mRNA encoding the 68-kDa neurofilament protein (NF68), beta-tubulin, and actin in lumbar sensory neurons of rat at various times after crushing the sciatic nerve. Between 4 and 42 days after axotomy by nerve crush, the levels of NF68 mRNA were reduced 2- to 3-fold. At the same times, the levels of tubulin and actin mRNAs were increased several-fold. These findings support the hypothesis that the expression of a single set of neuron-specific genes (encoding NF) directly determines axonal caliber, a feature of neuronal morphology with important consequences for physiology and behavior.

Of Market Failure, Voluntary Failure, and Third-Party Government: Toward a Theory of Government-Nonprofit Relations in the Modern Welfare State

Abstract: Despite the fact that gouernment in the United States relies more heavily on nonprofit organizations than on its own instrumentalities to deliver government- funded human services, and that nonprof...

Identification of an Amplified, Highly Expressed Gene in a Human Glioma

Abstract: A gene, termed gli, was identified that is amplified more than 50-fold in a malignant glioma. The gene is expressed at high levels in the original tumor and its derived cell line and is located at chromosome 12 position (q13 to q14.3). The gli gene is a member of a select group of cellular genes that are genetically altered in primary human tumors.

Improved hospital morbidity, mortality, and survival after the Whipple procedure.

Abstract: Between 1969 and 1986, 88 patients had a Whipple resection for adenocarcinoma of the pancreas (N = 50), ampulla (N = 19), distal bile duct (N = 10), and duodenum (N = 9) Forty-nine patients were men, 39 were women, and the mean age was 58 years (range: 34-84 years) The patients were divided into two groups on the basis of two different time periods: those operated on from 1969 to 1980 (N = 41) and those operated on from 1981 to 1986 (N = 47) There were no significant differences between the two groups in terms of mean age, sex distribution, duration of symptoms before presentation, or mean weight loss Likewise, preoperative laboratory data were similar for both groups of patients In addition, mean tumor size for patients with pancreatic cancer (35 cm vs 32 cm) and patients with nonpancreatic periampullary cancer (19 cm vs 22 cm) was similar in both groups, as was the incidence of positive lymph nodes Among the 41 patients operated on during the first period, hospital morbidity and mortality rates were 59% and 24%, respectively In contrast, hospital morbidity and mortality rates were 36% and 2%, respectively, among the 47 patients operated on during the recent period During the recent period, more Whipple procedures were performed each year (78 vs 34) and by fewer surgeons (34 operations/surgeon vs 19 operations/surgeon) In addition, between 1981 and 1986, there were fewer total pancreatectomies (9% vs 39%), fewer vagotomies (26% vs 76%), and more pyloric-preserving procedures (30% vs 0) performed compared with the earlier period During the recent period, mean operative time (78 vs 90 hours), mean estimated blood loss (1694 vs 3271 mL), and mean intraoperative blood replacement (36 vs 63 units) were all significantly less than in the earlier period These findings suggest that the recent decline in operative morbidity and mortality may be due to fewer surgeons performing more Whipple resections in less time and with less blood loss The actuarial 5-year survival rate for the 38 patients with nonpancreatic periampullary cancer was 34% Surprisingly, the actuarial 5-year survival rate among the 50 patients with pancreatic cancer was 18% Moreover, in the absence of positive lymph node involvement, the 5-year actuarial survival rate among patients with pancreatic cancer was 48% No explanation is obvious for the improvement in survival among patients with pancreatic cancer

Clonal analysis of human colorectal tumors

Abstract: The clonal composition of human colorectal tumors was studied by means of restriction fragment length polymorphisms (RFLPs). First, X-linked RFLPs were used to examine the pattern of X chromosome inactivation in colorectal tumors of females. All 50 tumors examined showed monoclonal patterns of X chromosome inactivation; these tumors included 20 carcinomas as well as 30 adenomas of either familial or spontaneous type. Second, RFLPs of autosomes were used as clonal markers to detect the somatic loss or gain of specific chromosomal sequences in colorectal tumors. Among other changes, it was found that somatic loss of chromosome 17p sequences occurred in over 75 percent of the carcinomas examined, but such loss was rare in adenomas. These data support a monoclonal origin for colorectal neoplasms, and suggest that a gene on the short arm of chromosome 17 may be associated with progression from the benign to the malignant state.

Loss of the neural integrator of the oculomotor system from brain stem lesions in monkey.

Abstract: Eye movement were recorded from four juvenile rhesus monkeys (Macaca mulatta) before and after the injection of neurotoxins (kainate or ibotenate) in the region of the medial vestibular and prepositus hypoglossi nuclei, an area hypothesized to be the locus of the neural integrator for horizontal eye movement commands. Eye movements were measured in the head-restrained animal by the magnetic field/eye-coil method. The monkeys were trained to follow visual targets. A chamber implanted over a trephine hole in the skull permitted recordings to be made in the brain stem with metal microelectrodes. The abducens nuclei were located and used as a reference point for subsequent neurotoxin injections through cannulas. The effects of these lesions on fixation, vestibuloocular and optokinetic responses, and smooth pursuit were compared with predicted oculomotor anomalies caused by a loss of the neural integrator. Kainate and ibotenate did not create permanent lesions in this region of the brain stem. All the eye movements returned toward normal over the course of a few days to 2 wk. Histological examination revealed that the cannula tips were mainly located between the vestibular and prepositus hypoglossi nuclei, in their rostral 2 mm, bordered rostrally by the abducens nuclei. Dense gliosis clearly demarcated the cannula tracks, but for most injections there were no surrounding regions of neuronal loss. Thus the eye movement disorders were due to a reversible, not a permanent, lesion. The time constant for the neural integrator was determined from the velocity of the centripetal drift of the eyes just after an eccentric saccade in total darkness. For intact animals this time constant was greater than 20 s. Shortly after bilateral injections of neurotoxin, the time constant began to decrease and reached a minimum of 200 ms; every horizontal saccade was followed by a rapid centripetal drift with a time constant of approximately 200 ms. For vertical eye movements, in this acute phase, the time constant was approximately 2.5 s. The vestibuloocular reflex (VOR) was drastically changed by the lesions. A step of constant head velocity in total darkness evoked a step change in eye position rather than in velocity. In the absence of the neural integrator, the step velocity command from the canal afferents was not integrated to produce a ramp of eye position (normal slow phases); rather this signal was relayed directly to the motoneurons and caused a step in eye position. The per- and postrotatory decay of the head velocity signal was decreased to 5-6 s indicating that vestibular velocity storage was also impaired.(ABSTRACT TRUNCATED AT 400 WORDS)

Predictors of the acquired immunodeficiency syndrome developing in a cohort of seropositive homosexual men.

Abstract: In a cohort of 1835 homosexual men who were seropositive for human immunodeficiency virus (HIV) on entry into a prospective study, the acquired immunodeficiency syndrome (AIDS) developed in 59 during a median follow-up of 15 months. We matched 5 seropositive controls to each case according to study center and date of enrollment and performed a case-control analysis to determine factors predictive of AIDS. In a multivariate analysis, a decreased number of T helper lymphocytes, an increased number of T suppressor lymphocytes, a low level of antibody to HIV, a high titer of cytomegalovirus antibody, and a history of sex with someone in whom AIDS developed were independently associated with subsequent AIDS. Separate analyses of risk factors for Kaposi's sarcoma and opportunistic infections failed to support previously reported associations between the use of nitrites or an elevated cytomegalovirus-antibody titer and Kaposi's sarcoma. These variables may be markers rather than determinants of disease progression. A vigorous antibody response to HIV infection may confer at least temporary protection against the progression of immunodeficiency to AIDS, or a low level of antibody to HIV may reflect a later stage of infection. The increased risk associated with a history of sex with someone in whom AIDS developed may indicate earlier infection in cases or infection with a more virulent strain of HIV. These results may be useful in counseling HIV-seropositive persons and in designing studies of clinical interventions.

Dolomitization; a critical view of some current views

Abstract: The principal models in vogue today for dolomitization are the mixing zone and the sabkha models. Despite the wide acceptance of these models, there has been little critical assessment of their validity. Such an assessment is the objective of the present paper. A close look at the "Dorag" mixing-zone model (Badiozamani 1973) reveals several serious weaknesses: 1) the range of freshwater-seawater mixtures that meet the Dorag requirement for dolomitization shrinks to a small "window" if the geologically more realistic disordered dolomite is used in the calculations instead of the ordered dolomite on which the model is based; 2) in none of the known modern coastal mixing zones in limestone or lime sediments has replacement by dolomite been observed; 3) in a number of dolomites interpreted to be of mixing-zone origin, dolomite has precipitated without dissolution of the calcite substrate, evidence that negates the fundamental premise of the Dorag model. In addition to these weaknesses, isotope and trace-element data used to identify mixed-water dolomite are inadmissible because 1) isotopic fractionation factors for dolomites remain unresolved; 2) isotope values (uncorrected for temperature) for a host of dolomites, interpreted to be of different origins, overlap; 3) nonisomorphous trace elements, such as Na, in dolomite cannot, on theoretical grounds, be relied on to identify dolomitizing fluids. Similar overall objections can be brought against Folk and Land9s (1975) "schizohaline" version of mixing-zone dolomitization. In summary, mixing-zone models have such weak underpinnings that they should be questioned as viable explanations for massive dolomitization. Contemporaneous dolomite formation in modern sabkhas is well documented, but the important question of whether the mechanism of dolomite formation is replacement or direct precipitation remains to be resolved. In the well-studied sabkha at Abu Dhabi, brine chemistry changes have been used as evidence of a replacement origin for the dolomite, but it is shown here that this evidence is far from unequivocal. An alternative origin of direct precipitation of dolomite is offered, an origin in keeping with dolomite precipitation known from other modern sabkhas and saline lakes, and in line with our laboratory experience with dolomite synthesis. Moreover, it is suggested here that, in general, contemporaneous dolomite will form at low temperatures only by direct precipitation, a mechanism that requires special conditions of highly super-saturated waters of high Mg/Ca ratio and elevated CO 3 -HCO 3 concentrations. This may explain why modern dolomite is mainly restricted to evaporitic environments, a bias not shared by ancient dolomites. In contrast, replacement dolomite appears to require, at low temperatures, long reaction times > or = 10 4 yr?), a requirement that is mainly to be met in large, regional groundwater-flow systems, both marine and nonmarine. A third dolomitization model considered here is that of Baker and Kastner (1981), based on the experimental finding that sulfate ions inhibit or retard dolomitization. A number of modern sedimentary dolomites are not in accord with this model in that they are forming from brines with large sulfate concentrations, 2 to 70 times that of seawater. Thus, the Baker-Kastner model should be held in abeyance until these serious contradictions are resolved. The current emphasis on mixing-zone and sabkha dolomitization has diverted attention from other promising avenues of approach to the dolomite problem. Four of these avenues, each of which deemphasizes the "special water" approach, are briefly addressed and are as follows: 1) influence of temperature and time; 2) mass transfer processes; 3) burial diagenesis of epigenetic dolomites; 4) fluid-inclusion studies. At elevated temperatures the dolomite problem essentially disappears (ordered dolomite can be made in the laboratory in days at 100 degrees C). What is more, at temperatures above 60 degrees C, Ca-rich waters become dolomitizing fluids, which makes most natural subsurface waters capable of dolomitization. At low temperatures, time may be the key element, so that seawater will become a major dolomitizing fluid only where stable circulation systems, such as Kohout convention, can drive seawater through carbonate platforms for many thousands to millions of years. This paper has tried to show that currently favored models of dolomitization carry serious uncertainties, enough to warn us to look more critically at the validity of these models, and also, it is hoped, enough to spur new efforts to find new solutions to the problems of dolomitization.

Comparative influence of load versus inotropic states on indexes of ventricular contractility: experimental and theoretical analysis based on pressure-volume relationships.

Abstract: We examined the quantitative influence of carefully controlled alterations in end-diastolic volume and afterload resistance on multiple simultaneously determined ejection and isovolumetric phase indexes of left ventricular contractile function in 23 isolated supported canine ventricles. The influence of load change on each index was compared with its sensitivity to inotropic stimulation, and this sensitivity was in turn contrasted to the response of the end-systolic pressure-volume relationship (ESPVR). Experimental data demonstrated various degrees of load sensitivity among the indexes, with a generally curvilinear relationship between load and index response for both preload and afterload alterations. The curvilinear nature of these relationships meant that over a select range of loading, many indexes demonstrated relative load independence. They also often displayed greater sensitivity to inotropic change than the ESPVR, and both factors help explain their enduring clinical utility. To further explore the influence of load and contractile state on several of the indexes, we developed a theoretical analysis, using variables common to pressure-volume relationships, in which these dependencies could be derived. The theoretical models fit very well with the experimental data, and reaffirmed the frequently curvilinear nature of the relationships. We conclude that while many clinical indexes of ventricular contractile function show significant load dependence, the information they provide can be reasonably interpreted within defined ranges of load and inotropic alteration. Any advantage of the ESPVR will derive not from the magnitude of its response to inotropic change, which is smaller than most other indexes, but from its relative insensitivity to load alteration over a wider range of load.

Cardiac myosin induces myocarditis in genetically predisposed mice.

Abstract: After infection with coxsackie virus B3 (CB3), H-2 congenic mice on an A- background develop immunologically mediated myocarditis associated with an increased titer of myosin autoantibody, part of which is specific for the cardiac myosin isoform. The present study demonstrates that cardiac myosin itself induces severe myocarditis and high titers of myosin autoantibodies in A/J, A.SW/SnJ, and A.CA/SnJ mice. As in CB3-induced myocarditis, one population of these autoantibodies was specific for cardiac myosin. A.BY/SnJ and B10.A/SgSnJ mice also developed the disease after immunization, but the prevalence and the myosin autoantibody titers were lower. In contrast, C57BL/6J and C57BL/10J mice were resistant to myocarditis induced by cardiac myosin and did not develop increased myosin autoantibodies or cardiac myosin-specific autoantibodies. Immunization with skeletal muscle myosin had no effect compared with controls injected with complete Freund's adjuvant, thereby suggesting that the immunogenic epitopes are unique to the cardiac myosin isoform. Furthermore, we found that susceptibility to myocarditis induced by cardiac myosin is influenced by the major histocompatibility complex and by genes not closely linked to the major histocompatibility complex. Because there are parallels between myocarditis induced by cardiac myosin and that induced by CB3, this new animal model can be used to analyze the pathologic mechanisms in autoimmune heart disease.

Chronic glaucoma selectively damages large optic nerve fibers.

Abstract: To determine whether glaucoma selectively injures a particular size of optic nerve fiber (and its cell body), we induced chronic experimental glaucoma in one eye each of ten monkeys. With automated image analysis, the number and diameter of optic nerve fibers were compared between each glaucomatous eye and its normal fellow eye. Fibers larger than the normal mean diameter atrophied more rapidly in glaucomatous eyes, though no fiber size was spared from damage. The mean fiber diameter for glaucomatous eyes was 0.74 micron, significantly lower than the mean for ten fellow eyes, 0.85 micron (P less than 0.005). There was preferentially greater atrophy of fibers of all sizes in the superior and inferior peripheral nerve sectors, as seen in human eyes with glaucoma. The more rapid atrophy of larger fibers appeared to result from two causes. The areas that suffer most rapid loss of fibers in experimental glaucoma normally contain a high proportion of larger diameter fibers. Furthermore, larger fibers were lost preferentially even in areas of the optic nerve with mild damage, indicating their inherent susceptibility to injury by glaucoma. The tendency for large fibers to be lost in glaucoma has implications for future improvements in testing for early glaucoma damage.

Human testis-specific PGK gene lacks introns and possesses characteristics of a processed gene

Abstract: Phosphoglycerate kinase (PGK) (ATP:3-phospho-D-glycerate 1-phosphotransferase, EC 2.7.2.3) is a metabolic enzyme functioning in the Embden-Meyerhof pathway that converts glucose (or fructose) to pyruvate. Two functional loci for the production of PGK have been identified in the mammalian genome. PGK-1 is an X-linked gene expressed constitutively in all somatic cells and premeitotic germ cells. The human PGK-1 gene consists of 11 exons and 10 introns encompassing a region approximately 23 kilobases (kb) in length. PGK-2 is an autosomal gene expressed in a tissue-specific manner exclusively in the late stages of spermatogenesis. In the present study, a molecular analysis of a human genomic clone of PGK-2 originally isolated by Szabo et al. has revealed that this autosomal sequence completely lacks introns and contains characteristics of a processed gene, or 'retroposon', including the remnants of a poly(A)+ tail and bounding direct repeats. Typically such processed sequences form non-functional pseudogenes that have evolved multiple genetic lesions which preclude translation of any transcript into a functional polypeptide. For example, an X-linked processed pseudogene of PGK-1 (psi PGK-1) in humans has been identified and shown to contain premature termination codons in all reading frames. It was therefore unexpected to find that the intronless autosomal PGK sequence reported here is not a pseudogene, but is rather a functional gene that has retained a complete open reading frame, and is actively expressed in mammalian spermatogenesis. Both the unusual conservation of function in this processed PGK-2 gene and its tissue-specific expression in spermatogenesis are best explained as a compensatory response to the inactivation of the X-linked PGK-1 gene in spermatogenic cells before meiosis.

Water-Quality Trends in the Nation's Rivers

Abstract: Water-quality records from two nationwide sampling networks now permit nationally consistent analysis of long-term water-quality trends at more than 300 locations on major U.S. rivers. Observed trends in 24 measures of water quality for the period from 1974 to 1981 provide new insight into changes in stream quality that occurred during a time of major changes in both terrestrial and atmospheric influences on surface waters. Particularly noteworthy are widespread decreases in fecal bacteria and lead concentrations and widespread increases in nitrate, chloride, arsenic, and cadmium concentrations. Recorded increases in municipal waste treatment, use of salt on highways, and nitrogen fertilizer application, along with decreases in leaded gasoline consumption and regionally variable trends in coal production and combustion during the period appear to be reflected in water-quality changes.

Airways obstruction and the risk for lung cancer.

Abstract: The presence of airways obstruction identify in middle-aged male smokers at increased risk for lung cancer. This hypothesis was tested in a sample of patients with moderate to severe obstruction from the Intermittent Positive Pressure Breathing Trial and a sample of patients with no obstruction to moderate obstruction from the Johns Hopkins Lung Project, all of whom were followed for the development of lung cancer. On follow-up, the risk of developing lung cancer was found to be associated with entry values for age, smoking, and ventilatory status by linear, proportional hazard, and log-linear adjustment techniques. Among cigarette smokers, the presence of airways obstruction was more of an indicator for the subsequent development of lung cancer than was age or the level of smoking. The risk for lung cancer also increased in proportion to the degree of airways obstruction. These data suggest that smokers with ventilatory obstruction are at greater risk for lung cancer than are smokers without obstruction.

Paranasal sinuses: CT imaging requirements for endoscopic surgery.

Abstract: Recent advances in the understanding of mucociliary activity and the pathophysiology of the nasal cavity and paranasal sinuses have revolutionized the surgical management of chronic and/or recurrent sinusitis Meticulous radiographic delineation of the small structures in this region, coupled with endoscopic evaluation, provides detailed preoperative information regarding morphology and pathology This information has led to more focused endoscopic surgical procedures, which have dramatically reduced patient morbidity As a consequence, there is now worldwide interest among otolaryngologists in the radiologic definition of paranasal regional anatomy For effective interactions between radiologist and otolaryngologist, the former must be prepared to render interpretations that address these "microanatomic" locales This communication is directed at familiarizing the radiologist with these observations and concepts, considering both normal and disturbed anatomy with their attendant pathophysiologic and ther