Observation of inverse Compton emission from a long γ-ray burst.

Long-duration γ-ray bursts (GRBs) originate from ultra-relativistic jets launched from the collapsing cores of dying massive stars. They are characterized by an initial phase of bright and highly variable radiation in the kiloelectronvolt-to-megaelectronvolt band, which is probably produced within the jet and lasts from milliseconds to minutes, known as the prompt emission1,2. Subsequently, the interaction of the jet with the surrounding medium generates shock waves that are responsible for the afterglow emission, which lasts from days to months and occurs over a broad energy range from the radio to the gigaelectronvolt bands1-6. The afterglow emission is generally well explained as synchrotron radiation emitted by electrons accelerated by the external shock7-9. Recently, intense long-lasting emission between 0.2 and 1 teraelectronvolts was observed from GRB 190114C10,11. Here we report multi-frequency observations of GRB 190114C, and study the evolution in time of the GRB emission across 17 orders of magnitude in energy, from 5 × 10-6 to 1012 electronvolts. We find that the broadband spectral energy distribution is double-peaked, with the teraelectronvolt emission constituting a distinct spectral component with power comparable to the synchrotron component. This component is associated with the afterglow and is satisfactorily explained by inverse Compton up-scattering of synchrotron photons by high-energy electrons. We find that the conditions required to account for the observed teraelectronvolt component are typical for GRBs, supporting the possibility that inverse Compton emission is commonly produced in GRBs.

Paraneoplastic syndrome of arthropathies as presenting sign for non-small cell lung cancer.

The aim of this study is to showcase an example of paraneoplastic syndrome, so other healthcare providers can be aware of early NSCLC manifestations. This is also important so providers do not dismiss review of symptoms that may not seem pertinent.

Adjunctive glycine in the treatment of obsessive-compulsive disorder in adults.

BACKGROUND: Recent preclinical findings, case reports and non-blinded studies have suggested that glutamatergic interventions may be efficacious for Obsessive-Compulsive Disorder (OCD). METHODS: We enrolled 24 adult outpatients with OCD on stabilized treatment regimens in a double-blind trial of adjunctive glycine, an NMDA glutamate receptor agonist. Participants were randomly assigned 1:1 to either placebo or glycine titrated to 60g/day, with follow-up visits scheduled at 4, 8 and 12 weeks. Yale-Brown Obsessive Compulsive Scale (Y-BOCS) was the principal outcome measure. RESULTS: Regimen non-adherence, principally related to complaints about the taste and/or nausea, resulted in only 14 individuals who were evaluable by predetermined criteria. Those receiving glycine (n=5) experienced a mean decrease of 6.04 points in Y-BOCS score, compared with a 1.00 point decrease for those receiving placebo (n=9). Using a hierarchical linear model, compared with placebo, individuals who received glycine had an average 0.82 decrease in Y-BOCS score for each week they remained in the study, not quite reaching statistical significance (p=0.053). Two of those receiving glycine were responders, versus none receiving placebo (p=0.11, ns, Fisher exact). Despite the dropouts, two participants were known to have subsequently continued taking glycine through their regular treating psychiatrist for over a year. CONCLUSIONS: The glycine condition approached efficacy for treatment of OCD in this study, with the high dropout rate related to problems with palatability and small sample size the principal caveats. This may indicate a new strategy for treatment of OCD, although confirmatory studies are clearly needed. (ClinicalTrials.gov NCT00405535.).

Graphical perception and graphical methods for analyzing scientific data.

Graphical perception is the visual decoding of the quantitative and qualitative information encoded on graphs. Recent investigations have uncovered basic principles of human graphical perception that have important implications for the display of data. The computer graphics revolution has stimulated the invention of many graphical methods for analyzing and presenting scientific data, such as box plots, two-tiered error bars, scatterplot smoothing, dot charts, and graphing on a log base 2 scale.

Variables on scatterplots look more highly correlated when the scales are increased.

Judged association between two variables represented on scatterplots increased when the scales on the horizontal and vertical axes were simultaneously increased so that the size of the point cloud within the frame of the plot decreased. Judged association was very different from the correlation coefficient, r, which is the most widely used measure of association.

Photochemical air pollution in the northeast United States.

Statistical analyses of meteorological and contaminant data and chemical kinetic modeling demonstrate that (i) the concentrations of ozone in the New Jersey-New York City metropolitan area are regional in character; (ii) ozone concentrations in Connecticut are increased by approximately 20 percent as a consequence of primary emissions in the New Jersey-New York City metropolitan region and subsequent transport; and (iii) the concentrations of a variety of products of smog chemistry in the New Jersey area are markedly increased by an increase in NO emissions, but are minimally affected by a change in hydrocarbon emissions.

Ozone concentrations in new jersey and new york: statistical association with related variables.

The concentrations of ozone at nine measurements sites in New Jersey and New York during the period 1 May through 30 September 1973 have been examined. Daily fluctuations in the ozone concentrations at any two sites are highly correlated. The concentrations are lower with low levels of solar radiation and also with high wind speed. The average ozone concentration shows only minor differences between weekdays and weekends, despite markedly different traffic patterns.

Sunday and workday variations in photochemical air pollutants in new jersey and new york.

Concentration distributions of air contaminants and meteorological variables in New Jersey and New York for workdays (Mondays through Fridays, omitting holidays) and Sundays are compared by means of quantile-quantile plots. The ozone distributions are slightly higher on Sundays, and the primary pollutant distributions are lower. These results raise serious questions about the validity of current concepts underlying ozone reduction in urban atmospheres.

Photochemical air pollution: transport from the New York City area into Connecticut and Massachusetts.

Photochemical air pollution resulting from primary emissions in the New York City metropolitan area is transported by prevailing winds on a 300-kilometer northeast trajectory through Connecticut and as far as northeastern Massachusetts. As a result, southwestern Connecticut has the highest ozone concentrations in the region and there is a substantial increase in ozone concentrations in Massachusetts. The ozone concentrations of air entering the New York City metropolitan area are often already above the federal standard of 0.08 part per million, but the concentration distribution is well below concentration distributions at downwind sites in Connecticut.

High-dose glycine treatment of refractory obsessive-compulsive disorder and body dysmorphic disorder in a 5-year period.

This paper describes an individual who was diagnosed with obsessive-compulsive disorder (OCD) and body dysmorphic disorder (BDD) at age 17 when education was discontinued. By age 19, he was housebound without social contacts except for parents. Adequate trials of three selective serotonin reuptake inhibitors, two with atypical neuroleptics, were ineffective. Major exacerbations following ear infections involving Group A beta-hemolytic streptococcus at ages 19 and 20 led to intravenous immune globulin therapy, which was also ineffective. At age 22, another severe exacerbation followed antibiotic treatment for H. pylori. This led to a hypothesis that postulates deficient signal transduction by the N-methyl-D-aspartate receptor (NMDAR). Treatment with glycine, an NMDAR coagonist, over 5 years led to robust reduction of OCD/BDD signs and symptoms except for partial relapses during treatment cessation. Education and social life were resumed and evidence suggests improved cognition. Our findings motivate further study of glycine treatment of OCD and BDD.

Automatic detection of unstained viable cells in bright field images using a support vector machine with an improved training procedure.

Detection of unstained viable cells in bright field images is an inherently difficult task due to the immense variability of cell appearance. Traditionally, it has required human observers. However, in high-throughput robotic systems, an automatic procedure is essential. In this paper, we formulate viable cell detection as a supervised, binary pattern recognition problem and show that a support vector machine (SVM) with an improved training algorithm provides highly effective cell identification. In the case of cell detection, the binary classification problem generates two classes, one of which is much larger than the other. In addition, the total number of samples is extremely large. This combination represents a difficult problem for SVMs. We solved this problem with an iterative training procedure ("Compensatory Iterative Sample Selection", CISS). This procedure, which was systematically studied under various class size ratios and overlap conditions, was found to outperform several commonly used methods, primarily owing to its ability to choose the most representative samples for the decision boundary. Its speed and accuracy are sufficient for use in a practical system.

A new preprocessing approach for cell recognition.

In this paper, we describe a novel strategy for combining fisher's linear discriminant (FLD) preprocessing with a feedforward neural network to classify cultured cells in bright field images. This technique was applied to various experimental scenarios utilizing different imaging environments, and the results were compared with those for the traditional principal component analysis (PCA) preprocessing. Our FLD preprocessing was shown to be more effective than PCA due in large part to the fact that FLD maximizes the ratio of between-class to within-class scatter. The new cell recognition algorithm with FLD preprocessing improves accuracy while the speed is suitable for practical applications.

Hypothesis: the MHC-restricted T-cell receptor as a structure with two multistate allosteric combining sites.

This paper presents a dual-recognition model of the T-cell receptor that has been constructed to account for the phenomenon of MHC restriction as well as the paradoxical ability of T-cells to be both multispecific and precisely specific at the same time. In our model the combining sites for antigen and MHC are not independent as in classical dual-recognition models, but interact with each other by an allosteric mechanism. We envision a flexible receptor with combining sites for antigen and MHC that are capable of existing in a multitude of distinct complementarity states. MHC and antigen molecules act as allosteric effectors such that one ligand perturbs the conformation and therefore the specificity of the site for the other ligand. An essential feature of the model is that different MHC determinants induce different conformations at the anti-antigen site. In this way the receptor acquires multiple specificities. Within a particular complementarity state, precise recognition results from the requirement that antigen and MHC exhibit positive cooperativity in their binding to the T-cell receptor. Positive cooperativity is also the basis for MHC restriction. Reaction mechanisms are presented which describe the requirement that antigen and MHC both induce conformational changes in order to generate high-affinity binding to either ligand. As a precedent for the multistate allosteric receptor model, we discuss the properties of allosteric enzymes, especially ribonucleotide reductase, whose properties are analogous to those we have postulated for the T-cell receptor. Also discussed is the possibility that molecules such as Ly2, L3T4 and the Mls antigen, which have been found to play a role in antigen recognition, function as affinity-enhancing allosteric effectors that interact with the constant portion of the T-cell receptor.

Novel monoclonal antibodies to cyclosporine A: characterization and epitope mapping with cyclosporine analogs and cyclophilin.

Monoclonal antibodies to cyclosporine A (Cs), a potent immunosuppressant, were generated in BALB/c mice using a novel antigen prepared by linking Cs to a protein carrier via a photoactive cross-linking reagent, 4-benzoylbenzoic acid (BBa). Twenty-two monoclonal anti-Cs antibodies were generated, using Cs-BBa-bovine serum albumin (Cs-BBa-BSA) as the immunogen. They were characterized with respect to affinity by Scatchard analysis of a radioimmunoassay (RIA), and with respect to specificity by an ELISA in which a series of singly substituted Cs derivatives were examined as inhibitors. McAb affinities ranged from 5 x 10(-8) M to 2 x 10(-10) M. Based on ELISA inhibition data with Cs analogs, and on the binding to two Cs-BSA conjugates in which opposite sides of the Cs molecule are exposed, the antibodies fell into five epitope recognition groups. Binding to Cs was also studied by ELISA in competition with cyclophilin (CyP), a Cs-binding protein whose epitope specificity has been well characterized. Competition by CyP was found to correlate with antibody specificity, not with affinity, i.e. CyP competed best with antibodies having specificities most similar to that of CyP. Epitope mapping can, therefore, be accomplished in a system in which two different species of binding proteins compete for the same antigen. This type of characterization may be useful in identifying antibodies whose combining sites mimic those of a receptor.

Growth hormone receptor mutations in children with idiopathic short stature.

Homozygous or compound heterozygous mutations in the GH receptor (GHR) gene result in GH insensitivity syndrome. Previous reports have shown that some heterozygous mutations may induce a partial insensitivity to GH, but others appear to have limited effect on growth. To investigate further these observations, we analyzed the GHR gene in 17 subjects with idiopathic short stature (ISS). All subjects had a height 2 SD or more below the mean and/or abnormal growth velocity. In addition, serum GH levels were 10 ng/mL or more and insulin-like growth factor I levels were normal or low. A novel heterozygous mutation resulting in a valine to isoleucine change (V144I) in exon 6 in the extracellular domain was found in one subject. His mother and one brother had significant short stature and also had the identical mutation. Affected family members also had a polymorphism in exon 6 of the GHR gene, which has been present in other subjects who had short stature and heterozygous mutations of the GHR gene. The other subjects with ISS had normal GHR genes. However, eight subjects had neutral polymorphisms distributed throughout the GHR locus. Accumulating evidence suggests that GHR gene mutations account for up to 5% of all ISS patients. These mutations should be considered when other causes of short stature have been eliminated.

Clinical, biochemical, and molecular investigations of a genetic isolate of growth hormone insensitivity (Laron's syndrome).

We have characterized the GH receptor mutation that is responsible for extreme short stature and GH insensitivity in a Bahamian genetic isolate. Heights of affected individuals ranged from -4.0 to -6.3 SD. Like others with Laron's syndrome, they had normal to high serum GH concentrations and low serum insulin-like growth factor I concentrations. Circulating levels of GH-binding protein activity were below limits of detection. Amplification of exons 2-7 and screening with single strand conformational polymorphism analysis located an abnormality in exon 7. Sequencing identified homozygosity for a C to T transition in the third position of codon 236. Reverse transcription and PCR amplification of complementary DNA from lymphocytes showed that this same sense mutation generated a new splice donor site 63 bp 5' to the normal exon 7 splice site. This novel site was used to the exclusion of the normal site in homozygotes. Both normal and variant messenger ribonucleic acid species were detected in heterozygotes. The predicted protein lacks 21 amino acids, including those defining the WS-like motif of the GH receptor extracellular domain. The high frequency of Laron's syndrome in this isolated island population probably reflects the introduction of the G236 splice mutation by a settler early in the 300-yr history of English settlement.

Antibodies to cyclosporine A (CsA) by a novel route and their use to monitor cyclosporine levels by radioimmunoassay (RIA).

Anti-cyclosporine antibodies were generated in rabbits, using an antigen derived from CsA. CsA was linked to carrier proteins by means of a photoactive cross-linking reagent, 4-benzoylbenzoic acid (BBa), an alpha, beta-unsaturated ketone. In the presence of CsA, photolysis of BBa results in hydrogen abstraction and random insertion into the cyclosporine molecule, generating a population of CsA with carboxyl groups at various positions. Immunization with CsA-BBa-bovine serum albumin gave rise to high affinity antibodies to CsA, with Kd = 9.8 +/- 2.8 x 10(-11) M, as determined by Scatchard analysis. Specificity was determined by competition experiments in a radioimmunoassay (RIA), using a panel of six cyclosporine derivatives, substituted at different positions. The derivatives could be arranged into three groups according to their affinities. One derivative with the lowest affinity had a bulky O-t-butyl-D-serine in place of D-alanine in position 8. Serum CsA levels in 25 transplant patients were measured by RIA, and compared to levels determined with a commercially available polyclonal antibody, which is routinely used clinically. The rabbit antiserum gave values that correlated well with the results using the commercial antibody.

Pertechnetate scintigraphy in primary congenital hypothyroidism.

UNLABELLED: Primary congenital hypothyroidism (PCH) is currently detected effectively by heel-stick screening. When elevated thyrotropin (TSH) and/or decreased T4 are found in the blood of neonates, they are recalled, values are confirmed in venous blood and thyroxine replacement therapy (TRT) is immediately instituted, thus cretinism or severe retardation is prevented. However, in a significant percentage of neonates with abnormal blood levels of T4 or TSH, the disorder is transient. To help determine the exact cause of PCH and the possibility of transient PCH, pinhole thyroid imaging is performed 30 min after an intravenous injection of 18.5 MBq (500 microCi) 99mTc-pertechnetate (TcPT). Patients with a nonvisualized gland or patients with images suggesting dyshormonogenesis are reevaluated at age 3-4 y to exclude transient PCH. METHODS: To define the role of TcPT imaging in determining the exact etiology of PCH and the possibility of its being transient, we reviewed data from 103 neonates with PCH who had scintigraphy in our laboratory between 1970 and 1996 and we correlated the results with clinical outcome. RESULTS: Four patterns of thyroid scintigrams were recognized and these determined patient classification: (a) normal in 7 patients with false-positive heel-stick screening but normal venous blood hormone levels; (b) hypoplasia-ectopia in 32 patients requiring lifelong TRT; (c) nonvisualization in 35 patients-32 with agenesis requiring lifelong TRT and 3 with fetal thyroid suppression by maternal antibodies whose TRT was discontinued at a later age; and (d) dyshormonogenesis (markedly increased TcPT concentration) in 29 patients-25 with permanent PCH requiring lifelong TRT and 4 with transient PCH in whom TRT was discontinued. Of the 25 patients with dyshormonogenesis, 12 belonged to five families with two or three siblings having the same disorder. CONCLUSION: TcPT thyroid scintigraphy in the neonate with PCH provides a more specific diagnosis, is useful for selecting patients for re-evaluation to uncover transient PCH and discontinue TRT and defines dyshormonogenesis, which is familial and requires genetic counseling. It is also cost-effective.

CD4 but not CD8 is comodulated with the T-cell antigen receptor (TCR) after activation of a CD4+ CD8+ human leukemia line with staphylococcal enterotoxin.

Recent studies support the possibility of an interaction between CD4/8 and the TCR complex. To determine if there is specificity in this interaction, we have studied the comodulation of CD4/8 with the CD3/TCR complex on a CD4+ CD8+ human leukemic T-cell line stimulated with staphylococcal enterotoxin A (SEA) bound to Raji cells. FACS analysis revealed that CD3 and the TCR were modulated from the surface. CD4 and not CD8 was comodulated with the T-cell receptor complex, supporting the existence of a docking site on the TCR with selectivity for CD4 or CD8 but not both. Fewer than 45 SEA molecules per presenting cell led to detectable comodulation. The ratio of %CD4/%TCR modulation varied with both time and the amount of SEA used for stimulation. ConA or PHA induced modulation of CD3 but, unlike SEA, failed to induce IL-2 secretion, suggesting multiple pathways and states of T-cell activation. Our findings also suggest that some human T leukemic lines can respond to antigen.

Kenny-Caffey syndrome and microorchidism.

We report on two adolescent boys with Kenny-Caffey syndrome and microorchidism. The first patient had elevated levels of serum follicle-stimulating hormone, but normal levels of luteinizing hormone and testosterone. There was no evidence of a microdeletion of the Y chromosome. The second patient had Leydig cell hyperplasia with normal seminiferous tubules and spermatogenesis, and normal pituitary histologic findings at autopsy. The presence of microorchidism in these patients confirms the previous observations and suggests subfertility, but does not fully clarify the pathogenesis.