A genome-wide sib-pair scan for quantitative language traits reveals linkage to chromosomes 10 and 13.

Although there is considerable evidence that individual differences in language development are highly heritable, there have been few genome-wide scans to locate genes associated with the trait. Previous analyses of language impairment have yielded replicable evidence for linkage to regions on chromosomes 16q, 19q, 13q (within lab) and at 13q (between labs). Here we report the first linkage study to screen the continuum of language ability, from normal to disordered, as found in the general population. 383 children from 147 sib-ships (214 sib-pairs) were genotyped on the Illumina(®) Linkage IVb Marker Panel using three composite language-related phenotypes and a measure of phonological memory (PM). Two regions (10q23.33; 13q33.3) yielded genome-wide significant peaks for linkage with PM. A peak suggestive of linkage was also found at 17q12 for the overall language composite. This study presents two novel genetic loci for the study of language development and disorders, but fails to replicate findings by previous groups. Possible reasons for this are discussed.

Horner's syndrome after posterior spinal fusion in a child: a case report.

STUDY DESIGN: A case report of a complication after posterior spinal fusion. OBJECTIVES: To present the clinical findings of a Horner's syndrome after posterior spinal fusion. SUMMARY OF BACKGROUND DATA: A 14-year-old girl underwent posterior spinal fusion for idiopathic scoliosis. METHODS: Clinical examination and pharmacologic pupillary testing were used to diagnose Horner's syndrome. RESULTS: After surgery, the patient developed a left-sided Horner's syndrome. The Horner's syndrome had resolved 6 months after surgery except for slight ptosis. CONCLUSIONS: This is the first reported case of Horner's syndrome occurring after posterior spinal fusion without the use of epidural analgesia.

Acceptance and self-reported use of national occupational medicine practice guidelines.

The authors conducted a survey to ascertain post-training attitudes and self-reported use of the American College of Occupational and Environmental Medicine occupational medicine practice guidelines. Trainees were surveyed 3 to 4 months after completing a case-based practice ACOEM occupational practice guidelines seminar. Of 96 physician respondents, 95% reported that the guidelines improved their practice in some manner. Fifty-two percent of physicians thought that guideline use decreased medical costs. Seventy-one percent reported that their care complied with the guidelines in 70% or more of their cases; however, "actually considering the guidelines in particular cases" was reported by only 47%. Discussion of cases was frequent (92%) and involved physicians, patients, and other health care providers. We concluded that physicians' attitudes toward the guidelines are positive and that reported compliance is high. Guidelines are discussed frequently.

Beliefs about and use of occupational medicine practice guidelines by case managers and insurance adjusters.

Workers' compensation case managers and adjusters have increased their use of practice guidelines recently, partly in response to state regulations. However, informally reported rates of use are not as high as desired for the best managed care practices and the greatest reductions in lost work time. Although there are several studies of physicians' use of guidelines, there are few if any studies about case managers' and adjusters' beliefs about, and utilization of, either general medical or occupational medical practice guidelines. Information about attitudes, beliefs about practice guidelines, and actual use should help developers make the guidelines more usable and bring about more effective interaction among case managers, adjusters, treating physicians, and other health professionals. This article reports on pre- and post-training surveys of a cohort of case managers and adjusters who participated in a case-based guideline training course. It then compares their responses to those of the physicians whose cases they might manage.

A novel family of mammalian taste receptors.

In mammals, taste perception is a major mode of sensory input. We have identified a novel family of 40-80 human and rodent G protein-coupled receptors expressed in subsets of taste receptor cells of the tongue and palate epithelia. These candidate taste receptors (T2Rs) are organized in the genome in clusters and are genetically linked to loci that influence bitter perception in mice and humans. Notably, a single taste receptor cell expresses a large repertoire of T2Rs, suggesting that each cell may be capable of recognizing multiple tastants. T2Rs are exclusively expressed in taste receptor cells that contain the G protein alpha subunit gustducin, implying that they function as gustducin-linked receptors. In the accompanying paper, we demonstrate that T2Rs couple to gustducin in vitro, and respond to bitter tastants in a functional expression assay.

T2Rs function as bitter taste receptors.

Bitter taste perception provides animals with critical protection against ingestion of poisonous compounds. In the accompanying paper, we report the characterization of a large family of putative mammalian taste receptors (T2Rs). Here we use a heterologous expression system to show that specific T2Rs function as bitter taste receptors. A mouse T2R (mT2R-5) responds to the bitter tastant cycloheximide, and a human and a mouse receptor (hT2R-4 and mT2R-8) responded to denatonium and 6-n-propyl-2-thiouracil. Mice strains deficient in their ability to detect cycloheximide have amino acid substitutions in the mT2R-5 gene; these changes render the receptor significantly less responsive to cycloheximide. We also expressed mT2R-5 in insect cells and demonstrate specific tastant-dependent activation of gustducin, a G protein implicated in bitter signaling. Since a single taste receptor cell expresses a large repertoire of T2Rs, these findings provide a plausible explanation for the uniform bitter taste that is evoked by many structurally unrelated toxic compounds.

Spontaneous respiration anesthesia for respiratory papillomatosis.

Several anesthetic techniques for microlaryngeal laser surgery in children have been advocated. The objective of this study was to evaluate the operative conditions and safety of the spontaneous respiration anesthesia technique for carbon dioxide laser surgery in children with recurrent respiratory papillomatosis (RRP). The anesthetic and operative records of 60 pediatric patients with RRP who underwent microlaryngeal laser surgeries between 1991 and 1997 were reviewed. Papilloma location, severity of involvement, oxygen saturation, airway stability, need for intubation, duration of procedure, and complications were recorded. The patients underwent 744 surgical procedures. Two hundred two procedures were randomly studied (statistical power > or = 80%). The supraglottis and glottis were most commonly involved. Most of the papillomas were graded as moderate or severe disease. Complications occurred in 11 procedures. The surgical procedure was completed in all cases. No variable had predictive value regarding the outcome. Spontaneous respiration anesthesia is an efficient and relatively safe technique for microlaryngeal laser surgery in children with RRP.

Synthesis of dihydroxanthone derivatives and evaluation of their inhibitory activity against acetylcholinesterase: unique structural analogs of tacrine based on the BCD-ring of arisugacin.

A general approach to synthesis of dihydroxanthone derivatives is described here. In vitro evaluation of these dihydroxanthones demonstrated that some derivatives possess moderate anti-cholinesterase activities and better selectivities than tacrine for acetylcholinesterase over butyrylcholinesterase. Structural effects on anti-cholinesterase activities were also examined, and docking experiments were carried out to provide preliminary understandings of these experimental observations.

Construction injury rates may exceed national estimates: evidence from the construction of Denver International Airport.

BACKGROUND: Construction of Denver International Airport (DIA) provided a unique opportunity to describe the magnitude of injury on a major construction project for which complete data on injury and hours at risk were available for over 32,000 employees working 31 million hours. METHODS: Comprehensive payroll data for all workers, who were paid standard Davis-Bacon wages, allowed calculation of person-hours at risk by job classification. Complete reporting, facilitated by a single workers' compensation plan covering all contracts and by an on-site medical clinic and designated provider system, allowed us to determine both total and lost-work-time (LWT) injury rate per 200,000 hours at risk by industrial sector, company size, and year of construction. Workers' compensation payment rates were calculated and compared with expected loss rates, derived by the National Council on Compensation Insurance, by sector, company size, and year. RESULTS: DIA's overall total injury rates were over twice those published by the Bureau of Labor Statistics (BLS) for the construction industry for each year of DIA construction. Differences in LWT injury rates were more modest. Total injury rates were also at least twice BLS's rates for all contractor sizes. The injury rate pattern by company size at DIA differed from BLS's in that small firms had injury rates that were lower than or comparable to most other size categories; BLS's rates for small firms were lower than those for all but the very largest (250 or more employees) contractors. DIA's total workers' compensation (WC) payment rate of $7.06 per $100 payroll was only 11% higher than Colorado-specific expected loss rates reported by the National Council on Compensation Insurance. DISCUSSION: Complete reporting, facilitated by the existence of a single WC plan, an on-sites medical clinic, and designated medical providers, yielded injury rates significantly higher than previously reported. The relatively small difference between DIA payment rates significantly higher than previously that the discrepancy between DIA's injury rates and national estimates is due to underreporting of non-LWT injuries of the BLS. The burden of on-site work-related construction injury may be higher and more costly than has been evident from national data.

Managed care workers' compensation outcome measurements: how can a clinic compete?

Clear guidelines and standards established for physicians by managed care organizations are not similarly applied to clinics. Generally, measures of quality of care and service for clinics are ill-defined. Dr. Mueller details six steps to creating a meaningful, achievable set of outcome measures so that clinic organizations can improve and promote their care.

The vibrator mutation causes neurodegeneration via reduced expression of PITP alpha: positional complementation cloning and extragenic suppression.

The mouse vibrator mutation causes an early-onset progressive action tremor, degeneration of brain stem and spinal cord neurons, and juvenile death. We cloned the vibrator mutation using an in vivo positional complementation approach and complete resequencing of the resulting 76 kb critical region from vibrator and its parental chromosome. The mutation is an intracisternal A particle retroposon insertion in intron 4 of the phosphatidylinositol transfer protein alpha gene, causing a 5-fold reduction in RNA and protein levels. Expression of neurofilament light chain is also reduced in vibrator, suggesting one signaling pathway that may underlie vibrator pathology. The vibrator phenotype is suppressed in one intercross. We performed a complete genome scan and mapped a major suppressor locus (Mvb-1) to proximal chromosome 19.

Disruption of the nuclear hormone receptor RORalpha in staggerer mice.

Homozygous staggerer (sg) mice show a characteristic severe cerebellar ataxia due to a cell-autonomous defect in the development of Purkinje cells. These cells show immature morphology, synaptic arrangement, biochemical properties and gene expression, and are reduced in numbers. In addition, sg heterozygotes show accelerated dendritic atrophy and cell loss, suggesting that sg has a role in mature Purkinje cells. Effects of this mutation on cerebellar development have been studied for 25 years, but its molecular basis has remained unknown. We have genetically mapped staggerer to an interval of 160 kilobases on mouse chromosome 9 which was found to contain the gene encoding RORalpha, a member of the nuclear hormone-receptor superfamily. Staggerer mice were found to carry a deletion within the RORalpha gene that prevents translation of the ligand-binding homology domain. We propose a model based on these results, in which RORalpha interacts with the thyroid hormone signalling pathway to induce Purkinje-cell maturation.

A mutational study of the C-terminal zinc-finger motif of the Escherichia coli UvrA protein.

The cysteine 763 residue in the C-terminal zinc-finger region of Escherichia coli UvrA protein was subjected to random mutagenesis, and the results suggested that the UvrA mutants with a small amino acid (Ser, Ala, or Gly) substituting for the cysteine 763 were almost as active as the wild-type in supporting nucleotide excision repair, but its replacement with a large, bulky amino acid (Tyr, Trp, or Phe) rendered the mutants inactive. The C763F mutant UvrA protein was purified for further characterization, and it was found this mutant UvrA protein lost its DNA binding (single-stranded or double-stranded DNA) activity and those other activities dependent on DNA binding, such as formation of damage-specific UvrA2B complexes and the supercoiling reaction. However, this mutant protein retained vigorous ATPase activity and was capable of negatively complementing the wild-type UvrA in JM109 strain. The purified C763F mutant UvrA protein contains a single zinc ion/molecule, half that of the wild-type. It appears that the C763F mutation destabilizes the zinc-anchored structure in the C-terminal zinc finger region, and as a result, the C763F mutant UvrA protein lost its ability to bind DNA.

The effect of negative stimulus presentations on observing-response rates.

Theories of observing differ in predicting whether or not a signal for absence of reinforcement (S-) is capable of reinforcing observing responses. Experiments in which S- was first removed from and then restored to the procedure have yielded mixed results. The present experiments suggest that failure to control for the direct effect of presenting S- may have been responsible. Pigeons and operant procedures were used. Experiment 1 showed that presentations of S-, even when not contingent on observing, can raise the rate of an observing response that was reinforced only by presentations of a signal (S+) that accompanied a schedule of food delivery. Experiment 2 showed that this effect resulted from bursts of responding that followed offsets of S-. Experiment 3 showed that, when the presence of S- was held constant, lower rates occurred when S- was dependent on, rather than independent of, observing. These results support theories that characterize S- as incapable of reinforcing observing responses.

Testing the reinforcing properties of S-: a replication of Lieberman's procedure.

A critical issue in testing theories of observing is whether the stimulus associated with extinction (the S-) reinforces observing responses. In previous experiments, subjects have been trained to make observing responses that produce both the S- and the stimulus correlated with reinforcement (the S+). Then, either the S+ or the S- has been withheld. Conflicting results have been attributed to differences among species. In the present experiments, pecking one key by master pigeons was reinforced with grain on a variable-ratio extinction schedule. Yoked pigeons received the grain on a variable-interval, extinction schedule controlled by the variable-ratio performances of the master birds. For both groups, concurrent pecking on a second key was reinforced on a variable-interval schedule with displays of discriminative stimuli. Subsequently, either the S+ or the S- was eliminated from the procedure. Omission of S+ produced a large decrease, as predicted by traditional conditioned reinforcement accounts of observing. By itself, S- did not maintain observing. A smaller and less reliable decrease, comparable to that obtained by Lieberman (1972) with rhesus monkeys, occurred when S- was eliminated. This replication with pigeons of Lieberman's results indicates that they are not species-specific, and the fact that observing was not maintained by S- alone suggests that the decrease obtained when S- was omitted is not attributable to the reinforcing power of S-.

Separating the effects of salience and disparity on the rate of observing.

Pigeons producing deliveries of grain on a mixed variable-interval, extinction schedule by pecking a center key could also produce discriminative stimuli on concurrent variable-interval schedules by pecking the left or right observing key. The stimuli produced by each observing key were varied independently. In the first experiment, the negative discriminative stimulus was at the far end of the spectrum from the key illumination accompanying the mixed schedule and from the positive discriminative stimulus. When the magnitude of the difference between the latter two stimuli (salience) was varied, more pecks occurred on the observing key producing the larger of the two differences than on the key producing the smaller difference. In the second experiment, the stimulus accompanying the mixed schedule was at the far end of the spectrum, and the magnitude of the difference between the two discriminative stimuli (disparity) was varied. The proportion of pecks occurring on each observing key shifted systematically in the direction of the key producing the larger difference. The salience of the discriminative stimuli and their disparity each has an independent influence on the frequency of observing when the other is controlled, but the effect of the salience appears to be the more substantial.

The acquisition of observing.

Pigeons were exposed to stimuli correlated with the presence or absence of a variable-interval 60-second schedule of reinforcement only while they depressed a crossbar or "perch." In the first experiment, the stimuli were different tilts of a line displayed on the key. When the difference in brightness between the line and the background (salience) was maximal, seven of eight birds acquired the discrimination, but when the difference was reduced by 50%, only one succeeded. In the second experiment, wavelength of chamber illumination served as the relevant dimension. Neither experiment showed a large effect attributable to the magnitude of the difference (disparity) between the positive and the negative stimulus. Individual differences in time spent observing were positively correlated with level of discrimination in the presence of the stimuli. All birds produced the positive stimulus for a greater proportion of the available time than they did the negative stimulus. This may be the mechanism that provides selective reinforcement of observing. Finally, the formation of a discrimination was analyzed in terms of changes in the proportion of time spent in contact with the discriminative stimuli.