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BACKGROUND AND RESEARCH OBJECTIVE: Fatigue is one of the most prevalent symptoms in persons with systolic heart failure (HF). There remains insufficient information about the physiological and psychosocial underpinnings of fatigue in HF. The specific aims of this study were to (1) determine the psychometric properties of 2 fatigue questionnaires in patients with HF, (2) compare fatigue in patients with HF to published scores of healthy adults and patients with cancer undergoing treatment, and (3) identify the physiological (eg, hemoglobin, B-type natriuretic peptide, body mass index, and ejection fraction) and psychosocial (eg, depressed mood) correlates of fatigue in HF. SUBJECTS AND METHODS: A convenience sample of 87 HF outpatients was recruited from 2 urban medical centers. Patients completed the Fatigue Symptom Inventory, Profile of Mood States, and Short Form-36 Health Survey. RESULTS AND CONCLUSIONS: Patients with HF and patients with cancer reported similar levels of fatigue, and both patient groups reported significantly more fatigue than did healthy adults. Physical functioning and hemoglobin categories explained 30% of the variance in Fatigue Symptom Inventory-Interference Scale scores, whereas depressed mood and physical functioning explained 47% of the variance in Profile of Mood States Fatigue subscale scores. Patients with HF experienced substantial fatigue that is comparable with cancer-related fatigue. Low physical functioning, depressed mood, and low hemoglobin level were associated with HF-related fatigue. [ABSTRACT FROM AUTHOR]

Treatment of multiple myeloma (MM) is complex; however, with equal access to care, clinical outcomes for Black patients match those in other patient groups. To reveal and begin to address clinical practice barriers to equitable, patient-centered MM care, this quality improvement (QI) initiative assessed patient electronic medical records (EMRs) and surveyed patients and providers at two large hospital systems and four community-based practices. For the educational intervention, providers participated in feedback-focused grand rounds sessions to reflect on system barriers and develop action plans to improve MM care. EMR reviews revealed infrequent documentation of cytogenetics and disease staging at community-based practices compared to large hospital systems. In surveys, providers from each care setting reported different challenges in MM care. Notably, the goals of treatment for patients and providers aligned at community clinics while providers and patients from large hospital systems had discordant perspectives. However, providers in community settings underreported race-associated barriers to care and identified different factors impacting treatment decision-making than Black patients. Relative to pre-session responses, providers were more likely to report high confidence after the educational sessions in aligning treatment decisions with guidelines and clinical evidence and shared decision-making (SDM). This QI study identified discordant perceptions among providers at large hospital systems and community-based practices in providing quality MM care. Provider education yielded increased confidence in and commitment to patient-centered care.

Introduction: Universally established comprehensive clinical bulbar scales objectively assessing disease progression in amyotrophic lateral sclerosis (ALS) are currently lacking. The goal of this working group project is to design a best practice set of provisional bulbar ALS guidelines, available for immediate implementation within all ALS clinics., Methods: ALS specialists across multiple related disciplines participated in a series of clinical bulbar symposia, intending to identify and summarize the currently accepted best practices for the assessment and management of bulbar dysfunction in ALS Results: Summary group recommendations for individual speech, Augmentative and Alternative Communication (AAC), and swallowing sections were achieved, focusing on the optimal proposed level of care within each domain., Discussion: We have identified specific clinical recommendations for each of the 3 domains of bulbar functioning, available for incorporation within all ALS clinics. Future directions will be to establish a formal set of bulbar guidelines through a methodological and evidence-based approach. Muscle Nerve 59:531-531, 2019., (© 2019 Wiley Periodicals, Inc.)

Purpose of Review: In this review, we present the multidisciplinary approach to the management of the many neurological, medical, social, and emotional issues facing patients with cerebellar ataxia., Recent Findings: Our holistic approach to treatment, developed over the past 25 years in the Massachusetts General Hospital Ataxia Unit, is centered on the compassionate care of the patient and their family, empowering them through engagement, and including the families as partners in the healing process. We present the management of ataxia in adults, beginning with establishing an accurate diagnosis, followed by treatment of the multiple symptoms seen in cerebellar disorders, with a view to maximizing quality of life and effectively living with the consequences of ataxia. We discuss the importance of a multidisciplinary approach to the management of ataxia, including medical and non-medical management and the evidence base that supports these interventions. We address the pharmacological treatment of ataxia, tremor, and other associated movement disorders; ophthalmological symptoms; bowel, bladder, and sexual symptoms; orthostatic hypotension; psychiatric and cognitive symptoms; neuromodulation, including deep brain stimulation; rehabilitation including physical therapy, occupational therapy and speech and language pathology and, as necessary, involving urology, psychiatry, and pain medicine. We discuss the role of palliative care in late-stage disease. The management of adults with ataxia is complex and a team-based approach is essential.

Introduction: Orgasmic latency (OL) during partnered sex (POL) and OL during masturbatory sex (MOL) in women with and without orgasmic difficulty have received minimal attention., Aim: To ascertain POL and MOL both overall and more specifically in women with and without difficulty reaching orgasm and to explore interrelationships between masturbatory and partnered latencies and sexual satisfaction., Methods: Participants for this study were 2,304 women drawn from community-based samples in the United States and Hungary who completed an investigator-derived questionnaire regarding their sexual history and response, including items related to frequency of masturbation and partnered sex, sexual desire, sexual arousal, orgasmic response, OL, distress, partner distress, and sexual satisfaction., Main Outcome Measure: Self-reported OL and related orgasmic parameters during masturbation and partnered sex in women with and without difficulty reaching orgasm were assessed., Results: POL were longer than those during MOL. Women experiencing difficulty reaching orgasm showed even longer latencies during partnered sex but comparable latencies during masturbation. Covariates related to POL included age, overall relationship quality, masturbation frequency, MOL, and level of distress about not reaching orgasm., Clinical Implications: POL in women are substantially longer than men's, suggesting the potential need for an increased repertoire of stimulatory behaviors to increase the woman's arousal., Strength and Limitations: The study was well powered and drew from a multi-national population. However, specific types of sexual stimulation during partnered and masturbatory sex were not included in this analysis., Conclusion: MOL for women and POL differ significantly, with latencies during partnered sex being substantially longer than masturbation, although women reporting the greatest difficulty reaching orgasm have the longest latencies and are likely to find masturbation more satisfying than women who do not. Rowland DL, Sullivan SL, Hevesi K, et al. Orgasmic Latency and Related Parameters in Women During Partnered and Masturbatory Sex. J Sex Med 2018;15:1463-1471., (Copyright © 2018 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: The aim of this Symposium was to develop a consensus based, bulbar assessment protocol for implementation within NEALS clinics., Methods: A one-day symposium, held in April 2017, was organized into Speech and Swallowing sections to establish summary recommendations for the assessment of bulbar dysfunction within each group., Results: Summary recommendations included speech referrals and AAC evaluations at initial visit, CNS-BFS, maximum sustained phonation, and speaking rate. Dysarthria evaluation included the speech subsystem involvement of respiration, phonation, resonance, and articulation. Specific recommendations for swallowing were established for each of the following domains: dietary/oral intake, airway defense physiologic capacity, swallow safety screen, patient-reported swallow-related outcomes, oral sensorimotor exam, and pulmonary function. Practice parameters focused upon patient education and unresolved questions included the use of videofluoscopy, monitoring diet progression, and swallow safety screening., Conclusions: The working goal is to establish a clinical bulbar protocol, designed to be incorporated within ALS clinics and ultimately to formulate a best practice set of bulbar ALS guidelines, available for implementation throughout the international ALS community.

Purpose: To determine if (1) absorbed radiation dose and (2) fluoroscopy time decreased with experience over the first 100 cases of a single surgeon's hip arthroscopy practice., Methods: Subjects who underwent hip arthroscopy for symptomatic femoroacetabular impingement and labral injury were eligible for analysis. Inclusion criteria included the first 100 subjects who underwent hip arthroscopy by a single surgeon (December 2013 to December 2014). Subject demographics, procedure details, fluoroscopy absorbed dose (milligray [mGy]), and time were recorded. Subjects were categorized by date of surgery to one of 4 possible groups (25 per group). One-way analysis of variance was used to determine if a significant difference in dose (mGy) or time was present between groups. Simple linear regression analysis was performed to determine the relation between case number and both radiation dose and fluoroscopy time., Results: Subjects underwent labral repair (n = 93), cam osteoplasty (n = 90), and pincer acetabuloplasty (n = 65). There was a significant (P < .001 for both) linear regression between case number and both radiation dose and fluoroscopy time. A significant difference in mGy was observed between groups, group 1 the highest and group 4 the lowest amounts of radiation (P = .003). Comparing individual groups, group 4 was found to have a significantly lower amount of radiation than group 1 (P = .002), though it was not significantly lower than that of group 2 (P = .09) or group 3 (P = .08). A significant difference in fluoroscopy time was observed between groups, group 1 the highest and group 4 the lowest times (P = .05). Comparing individual groups, group 4 was found to have a significantly lower fluoroscopy time than group 1 (P = .039). Correction for weight, height, and body mass index all revealed the same findings: significant (P < .05) differences in both dose and time across groups., Conclusions: The absorbed dose of radiation and fluoroscopy time decreased significantly over the first 100 cases of a single surgeon's hip arthroscopy practice learning curve., Level of Evidence: Level IV, therapeutic, retrospective, noncomparative case series., (Copyright © 2017 Arthroscopy Association of North America. Published by Elsevier Inc. All rights reserved.)

Caring for a child with a chronic condition has received considerable attention in the pediatric health literature. Today, approximately 1 out of 5 North American children are diagnosed with a chronic condition that requires parents to become caregivers and advocates. Although advocacy is regarded as a significant aspect to parental caregiving, more research is needed to better define this oversimplified and misrepresented concept in clinical practice and research. Subsequently, we interviewed 35 parents of children diagnosed with complex chronic conditions. Within our analysis, we identified three themes that elaborate upon how parental advocacy is socially constructed through communication behaviors and partnerships with other people (e.g., medical professionals, family, school educators). We also discuss the emotional side of advocacy, and proffer suggestions to practitioners who work with parents to form collaborative care teams.

Purpose: Communication is crucial for patient experience and biomedical outcomes. Training programs improve communication but are too resource-intensive for sustained use across an entire health care organization. This study demonstrates in a heterogeneous set of encounters the efficacy of quantitative feedback on two groups of physician communication behaviors: 1) jargon explanation, and 2) assessment of patient understanding., Methods: We used a secure Internet application to audio-record conversations between primary care physicians and 54 patients. Transcripts were quantitatively abstracted using explicit-criteria definitions for assessments of understanding and jargon explanations. These data were conveyed to physicians using a previously tested report card. Finally, physicians were audio-recorded with 48 other patients and compared against their baseline., Results: Baseline transcripts included an average of 15.5 unique jargon words. Many words were spoken more than once so the total jargon count averaged 25.1. Jargon explanations were infrequent (median of 2.6/transcript). The jargon explanation ratio (fraction of jargon words spoken after or alongside a jargon explanation for that word) averaged 0.26 out of 1.0. Assessments of understanding were found in 61.1% of transcripts, but most were "OK?" questions (median of 2.22/transcript) or close-ended assessments of understanding (median of 0.59/transcript). After the report card, use of jargon explanations improved to a median of 4.8/transcript (P<0.001), and the jargon explanation ratio improved to 0.37 (P<0.02). Assessments of understanding improved to 81.3% of transcripts (P<0.03), largely due to increased use of close-ended assessments of understanding to 1.08/transcript (P<0.006)., Conclusions: It is feasible to audio-record at the point of care, abstract transcripts at a central office and improve physician-to-patient communication quality via a report card. A larger, multifaceted program may improve patient experience and biomedical outcomes., Competing Interests: Conflicts of Interest None.

Reasons for Performing Study: Exercise-induced pulmonary haemorrhage (EIPH) is associated with impaired short-term race performance but consequences to long-term race performance of Thoroughbred racehorses are unknown. Knowledge of effects of EIPH on performance over a prolonged time would inform the need for management and treatment of this disorder., Objectives: To determine the relationship between EIPH detected on a single occasion and long-term athletic performance in Thoroughbred racehorses., Study Design: Prospective, longitudinal, observational epidemiological study conducted from 2003 to 2012., Methods: Seven hundred and forty-four Thoroughbred racehorses underwent a single tracheobronchoscopic examination to determine presence and severity of EIPH in 2003. Following retirement of all the horses from racing, career after examination and lifetime performance data (including career duration, earnings, starts, wins and placings) were abstracted from a commercial database. The association between presence and severity of EIPH and individual performance variables were analysed using survival analysis, linear regression and negative binomial regression., Results: No association was detected between the presence of any EIPH (grade ≥1) and all measures of long-term performance examined except that horses with EIPH (grade ≥2) had fewer earnings after endoscopic examination than did horses with mild EIPH or no EIPH (grades ≤1). Multiple associations were detected between the most severe form of EIPH (grade 4) and measures of long-term performance suggesting that the severity of EIPH commonly associated with epistaxis adversely affects either the horse's opportunity to race or physiologic capacity to race., Conclusions: We conclude that there is no association between EIPH grades 0, 1, 2 and 3 and long-term racing performance of Thoroughbred racehorses. These results are based on a single endoscopic evaluation of EIPH grade made during a horse's career. Further studies are required to determine the reasons for an association of severe (grade 4) EIPH with impaired long-term race performance., (© 2014 EVJ Ltd.)

Reasons for Performing Study: Furosemide is the most commonly used medication for exercise-induced pulmonary haemorrhage (EIPH); however, critical evaluation of the strength of evidence for efficacy of furosemide is lacking and is warranted so that evidence-based treatment decisions can be made., Objectives: To evaluate the efficacy of furosemide to reduce the severity or frequency of detection of EIPH in Thoroughbred and Standardbred racehorses., Study Design: Systematic review with meta-analyses., Methods: Primary studies were identified via searches of electronic databases, relevant texts and reference lists of published articles. Studies were not restricted by date or publication status. Only studies published in English were eligible for inclusion. Searches were performed using a predetermined search string. Randomised controlled trials, nonrandomised trials and observational studies were included. Three authors independently assessed each study using the Cochrane collaboration guidelines and Grading of Recommendations Assessment, Development and Evaluation recommendations for rating quality of evidence. Meta-analysis of studies was performed with pooled data to determine whether furosemide reduced the frequency of detection of EIPH (yes or no) as evaluated by tracheobronchoscopy or bronchoalveolar lavage fluid red blood cell number, or if furosemide reduced the severity of EIPH by at least one tracheobronchoscopic grade., Results: Seventeen studies fulfilled the inclusion criteria. The relative risk of detecting any EIPH by tracheobronchoscopy after administration of furosemide was 0.88 (pooled data from 11 studies, n = 5780; 95% confidence interval 0.79-0.97, P = 0.01). When data from only high-quality randomised controlled trials (2 studies, n = 405) were used, the relative risk of detecting endoscopically evident EIPH was 0.68 (95% confidence interval 0.58-0.79, P<0.001). The proportion of horses previously diagnosed with EIPH having a reduction of at least one EIPH grade after furosemide was 68% (2 studies, n = 405; 95% confidence interval 61-78%)., Conclusions: There is high-quality evidence, albeit limited, that administration of furosemide reduces the incidence and severity of EIPH in Thoroughbred or Standardbred racehorses., (© 2014 EVJ Ltd.)

Recent studies, both in vitro and in vivo, have suggested the involvement of the polycystic kidney disease-1 and -2 like genes, Pkd1l3 and Pkd2l1, in acid taste transduction. In mice, disruption of taste cells expressing PKD2L1 eliminates gustatory neural responses to acids. However, no previous data exist on taste responses in the absence of PKD1L3 or on behavioral responses in mice lacking either of these proteins. In order to assess the function of PKD1L3, we genetically engineered mice with a targeted mutation of the Pkd1l3 gene. We then examined taste responsiveness of mutant and wild-type mice using several different approaches. In separate groups of mice, we measured preference scores in 48-h 2-bottle tests, determined NaCl or citric acid taste thresholds using a conditioned taste aversion technique, and conducted electrophysiological recordings of activity in the chorda tympani and glossopharyngeal nerves. Multiple taste compounds representing all major taste qualities were used in the preference tests and nerve-recording experiments. We found no significant reduction in taste responsiveness in Pkd1l3 mutant mice in behavioral or electrophysiological tests when compared with wild-type controls. Therefore, further studies are needed to elucidate the function of PKD1L3 in taste bud cells.

The human T1R taste receptors are family C G-protein-coupled receptors (GPCRs) that act as heterodimers to mediate sweet (hT1R2 + hT1R3) and umami (hT1R1 + hT1R3) taste modalities. Each T1R has a large extracellular ligand-binding domain linked to a seven transmembrane-spanning core domain (7TMD). We demonstrate that the 7TMDs of hT1R1 and hT1R2 display robust ligand-independent constitutive activity, efficiently catalyzing the exchange of GDP for GTP on Galpha subunits. In contrast, relative to the 7TMDs of hT1R1 and hT1R2, the 7TMD of hT1R3 couples poorly to G-proteins, suggesting that in vivo signaling may proceed primarily through hT1R1 and hT1R2. In addition, we provide direct evidence that the hT1Rs selectively signal through Galpha(i/o) pathways, coupling to multiple Galpha(i/o) subunits as well as the taste cell specific Gbeta(1)gamma(13) dimer.

The T2Rs belong to a multi-gene family of G-protein-coupled receptors responsible for the detection of ingested bitter-tasting compounds. The T2Rs are conserved among mammals with the human and mouse gene families consisting of about 25 members. In the present study we address the signalling properties of human and mouse T2Rs using an in vitro reconstitution system in which both the ligands and G-proteins being assayed can be manipulated independently and quantitatively assessed. We confirm that the mT2R5, hT2R43 and hT2R47 receptors respond selectively to micromolar concentrations of cycloheximide, aristolochic acid and denatonium respectively. We also demonstrate that hT2R14 is a receptor for aristolochic acid and report the first characterization of the ligand specificities of hT2R7, which is a broadly tuned receptor responding to strychnine, quinacrine, chloroquine and papaverine. Using these defined ligand-receptor interactions, we assayed the ability of the ligand-activated T2Rs to catalyse GTP binding on divergent members of the G(alpha) family including three members of the G(alphai) subfamily (transducin, G(alphai1) and G(alphao)) as well as G(alphas) and G(alphaq). The T2Rs coupled with each of the three G(alphai) members tested. However, none of the T2Rs coupled to either G(alphas) or G(alphaq), suggesting the T2Rs signal primarily through G(alphai)-mediated signal transduction pathways. Furthermore, we observed different G-protein selectivities among the T2Rs with respect to both G(alphai) subunits and G(betagamma) dimers, suggesting that bitter taste is transduced by multiple G-proteins that may differ among the T2Rs.

The presence of one or more calcium-dependent ecto-ATPases (enzymes that hydrolyze extracellular 5'-triphosphates) in mammalian taste buds was first shown histochemically. Recent studies have established that dominant ecto-ATPases consist of enzymes now called nucleoside triphosphate diphosphohydrolases (NTPDases). Massively parallel signature sequencing (MPSS) from murine taste epithelium provided molecular evidence suggesting that NTPDase2 is the most likely member present in mouse taste papillae. Immunocytochemical and enzyme histochemical staining verified the presence of NTPDase2 associated with plasma membranes in a large number of cells within all mouse taste buds. To determine which of the three taste cell types expresses this enzyme, double-label assays were performed with antisera directed against the glial glutamate/aspartate transporter (GLAST), the transduction pathway proteins phospholipase Cbeta2 (PLCbeta2) or the G-protein subunit alpha-gustducin, and serotonin (5HT) as markers of type I, II, and III taste cells, respectively. Analysis of the double-labeled sections indicates that NTPDase2 immunoreactivity is found on cell processes that often envelop other taste cells, reminiscent of type I cells. In agreement with this observation, NTPDase2 was located to the same membrane as GLAST, indicating that this enzyme is present in type I cells. The presence of ecto-ATPase in taste buds likely reflects the importance of ATP as an intercellular signaling molecule in this system., (Copyright 2006 Wiley-Liss, Inc.)

Taste receptors cells are responsible for detecting a wide variety of chemical stimuli. Several molecules including both G protein coupled receptors and ion channels have been shown to be involved in the detection and transduction of tastants. We report on the expression of two members of the transient receptor potential (TRP) family of ion channels, PKD1L3 and PKD2L1, in taste receptor cells. Both of these channels belong to the larger polycystic kidney disease (PKD or TRPP) subfamily of TRP channels, members of which have been demonstrated to be non-selective cation channels and permeable to both Na(+) and Ca(2+). Pkd1l3 and Pkd2l1 are co-expressed in a select subset of taste receptor cells and therefore may, like other PKD channels, function as a heteromer. We found the taste receptor cells expressing Pkd1l3 and Pkd2l1 to be distinct from those that express components of sweet, bitter and umami signal transduction pathways. These results provide the first evidence for a role of TRPP channels in taste receptor cell function.

To identify genes important for taste receptor cell function, we analyzed the sequences and expression patterns of clones isolated from a mouse taste receptor cell-enriched cDNA library. Here, we report the analyses of two novel genes, Gpr113 and Trcg1. Gpr113 encodes a G-protein-coupled receptor belonging to family 2B, members of which are characterized by having long N-terminal, extracellular domains. The predicted N-terminal extracellular domain of GPR113 contains 696 amino acids with two functional domains, a peptide hormone-binding domain and a G-protein-coupled receptor proteolytic site. Expression analyses indicate that Gpr113 expression is highly restricted to a subset of taste receptor cells. TRCG1 is also selectively expressed in a subset of taste receptor cells. Trcg1 is alternatively spliced and encodes Trcg1 isoforms of 209 and 825 amino acids. BLAST searches of genomic sequences indicate that a putative homolog of Trcg1 resides on human chromosome 15q22.

Cyanobacteria and similar organisms produced most of the oxygen found in Earth's atmosphere, which implies that early photosynthetic organisms would have lived in an atmosphere that was rich in CO2 and poor in O2. We investigated the tolerance of several cyanobacteria to very high (>20 kPa) concentrations of atmospheric CO2. Cultures of Synechococcus PCC7942, Synechocystis PCC7942, Plectonema boryanum, and Anabaena sp. were grown in liquid culture sparged with CO2-enriched air. All four strains grew when transferred from ambient CO2 to 20 kPa partial pressure of CO2 (pCO2), but none of them tolerated direct transfer to 40 kPa pCO2. Synechococcus and Anabaena survived 101 kPa (100%) pCO2 when pressure was gradually increased by 15 kPa per day, and Plectonema actively grew under these conditions. All four strains grew in an anoxic atmosphere of 5 kPa pCO2 in N2. Strains that were sensitive to high CO2 were also sensitive to low initial pH (pH 5-6). However, low pH in itself was not sufficient to prevent growth. Although mechanisms of damage and survival are still under investigation, we have shown that modern cyanobacteria can survive under Earth's primordial conditions and that cyanobacteria-like organisms could have flourished under conditions on early Mars, which probably had an atmosphere similar to early Earth's.

Positional cloning of hereditary deafness genes is a direct approach to identify molecules and mechanisms underlying auditory function. Here we report a locus for dominant deafness, DFNA36, which maps to human chromosome 9q13-21 in a region overlapping the DFNB7/B11 locus for recessive deafness. We identified eight mutations in a new gene, transmembrane cochlear-expressed gene 1 (TMC1), in a DFNA36 family and eleven DFNB7/B11 families. We detected a 1.6-kb genomic deletion encompassing exon 14 of Tmc1 in the recessive deafness (dn) mouse mutant, which lacks auditory responses and has hair-cell degeneration. TMC1 and TMC2 on chromosome 20p13 are members of a gene family predicted to encode transmembrane proteins. Tmc1 mRNA is expressed in hair cells of the postnatal mouse cochlea and vestibular end organs and is required for normal function of cochlear hair cells.

Chemosensory receptors are critical for the survival of many mammalian species, and their genes can comprise up to 1% of mammalian genomes. Odorant, taste, and vomeronasal receptors are being discovered and functionally characterized at a rapid pace which has been further accelerated by the availability of the human genome sequence. Five multigene families, consisting of >1,000 genes in the mouse, have been proposed to encode functional chemoreceptors. Although all of the chemoreceptor gene families encode G-protein coupled receptors, they are largely unrelated and uniquely specialized for the processing of different chemosensory modalities. Using members of the families as molecular probes, great insights are being gained into the different organizational strategies used by these sensory systems to encode information in both the periphery and the brain.

In the gustatory system, the recognition of sugars, amino acids and bitter-tasting compounds is the function of specialized G protein-coupled receptors. Recently, two members of novel subfamily of G protein-coupled receptors were proposed to function as taste receptors based on their specific expression in taste receptor cells. Here, we report the identification of a third member, T1R3, of this family of receptors. T1R3 maps near the telomere of mouse chromosome 4 rendering it a candidate for the Sac locus, a primary determinant of sweet preference in mice. Consistent with its candidacy for the Sac locus, T1R3 displays taste receptor cell-specific expression. In addition, taster and non-taster strains of mouse harbor different alleles of T1R3.

Mutations in myosin XV are responsible for congenital profound deafness DFNB3 in humans and deafness and vestibular defects in shaker 2 mice. By combining direct cDNA analyses with a comparison of 95.2 kb of genomic DNA sequence from human chromosome 17p11.2 and 88.4 kb from the homologous region on mouse chromosome 11, we have determined the genomic and mRNA structures of the human (MYO15) and mouse (Myo15) myosin XV genes. Our results indicate that full-length myosin XV transcripts contain 66 exons, are >12 kb in length, and encode 365-kDa proteins that are unique among myosins in possessing very long approximately 1200-aa N-terminal extensions preceding their conserved motor domains. The tail regions of the myosin XV proteins contain two MyTH4 domains, two regions with similarity to the membrane attachment FERM domain, and a putative SH3 domain. Northern and dot blot analyses revealed that myosin XV is expressed in the pituitary gland in both humans and mice. Myosin XV transcripts were also observed by in situ hybridization within areas corresponding to the sensory epithelia of the cochlea and vestibular systems in the developing mouse inner ear. Immunostaining of adult mouse organ of Corti revealed that myosin XV protein is concentrated within the cuticular plate and stereocilia of cochlear sensory hair cells. These results indicate a likely role for myosin XV in the formation or maintenance of the unique actin-rich structures of inner ear sensory hair cells., (Copyright 1999 Academic Press.)

Semaphorins constitute a large and growing gene family, several members of which are axon guidance molecules. We report the characterization of sema4g, a novel class IV member of the semaphorin gene family, located on mouse chromosome 19. sema4g is expressed early in development in the brain, spinal cord, and several sensory organs as well as specific populations of projection neurons, compatible with the well-established function of semaphorins as axon guidance molecules.

In recent years, considerable progress has been made in understanding how the olfactory system uses neural space to encode sensory information. In this review, we focus on recent studies aimed at understanding the organizational strategies used by the mammalian olfactory system to encode information. The odorant receptor gene family is discussed in the context of its genomic organization as well as the specificity of olfactory sensory neurons. These data have important consequences for the mechanisms of odorant receptor gene choice by a given sensory neuron. Division of the olfactory epithelium into zones that express different sets of odorant receptors is the first level of input organization. The topographical relationship between periphery and olfactory bulb represents a further level of processing of information and results in the formation of a highly organized spatial map of information in the olfactory bulb. There, local circuitry refines the sensory input through various lateral interactions. Finally, the factors that may drive the development of such a spatial map are discussed. The onset of expression and the establishment of the zonal organization of odorant receptor genes in the epithelium are not dependent upon the presence of the olfactory bulb, suggesting that the functional identity of olfactory sensory neurons is determined independently of target selection.

Odorant receptors (ORs) on nasal olfactory sensory neurons are encoded by a large multigene family. Each member of the family is expressed in a small percentage of neurons that are confined to one of several spatial zones in the nose but are randomly distributed throughout that zone. This pattern of expression suggests that when the sensory neuron selects which OR gene to express it may be confined to a particular zonal gene set of several hundred OR genes but select from among the members of that set via a stochastic mechanism. Both locus-dependent and locus-independent models of OR gene choice have been proposed. To investigate the feasibility of these models, we determined the chromosomal locations of 21 OR genes expressed in four different spatial zones. We found that OR genes are clustered within multiple loci that are broadly distributed in the genome. These loci lie within paralogous chromosomal regions that appear to have arisen by duplications of large chromosomal domains followed by extensive gene duplication and divergence. Our studies show that OR genes expressed in the same zone map to numerous loci; moreover, a single locus can contain genes expressed in different zones. These findings raise the possibility that OR gene choice may be locus-independent or involve consecutive stochastic choices.

In mammals, odors are detected by approximately 1000 different types of odorant receptors (ORs), each expressed by a fraction of neurons in the olfactory epithelium. Neurons expressing a given OR are confined to one of four spatial zones but are distributed randomly throughout that zone. In the olfactory bulb, the axons of neurons expressing different ORs synapse at different sites, giving rise to a highly organized and stereotyped information map. An important issue is whether the epithelial and bulbar maps evolve independently or are linked, for example, by retrograde influences of the bulb on the epithelium. Here we examined the onset of expression and patterning of genes encoding ORs and sensory transduction molecules during mouse embryogenesis and in mice lacking olfactory bulbs. Our results argue for an independent development of epithelial and bulbar maps and an early functional development that may be pertinent to pattern development in the olfactory bulb.

The ability of mammals to discriminate thousands of structurally diverse odorants appears to derive from the existence of a multigene family that encodes approximately 1000 different odorant receptors. Recent studies have used this family to explore how the olfactory system organizes sensory information. These studies reveal striking patterns of organization suggesting that incoming sensory information is first broadly organized in the nose and is then transformed in the olfactory bulb into a stereotyped and highly organized spatial map.

In the mammalian olfactory system, information from approximately 1000 different odorant receptor types is organized in the nose into four spatial zones. Each zone is a mosaic of randomly distributed neurons expressing different receptor types. In these studies, we have obtained evidence that information highly distributed in the nose is transformed in the olfactory bulb of the brain into a highly organized spatial map. We find that specific odorant receptor gene probes hybridize in situ to small, and distinct, subsets of olfactory bulb glomeruli. The spatial and numerical characteristics of the patterns of hybridization that we observe with different receptor probes indicate that, in the olfactory bulb, olfactory information undergoes a remarkable organization into a fine, and perhaps stereotyped, spatial map. In our view, this map is in essence an epitope map, whose approximately 1000 distinct components are used in a multitude of different combinations to discriminate a vast array of different odors.

The identification and cloning of genes encoding odorant receptors has provided molecular probes with which to examine the molecular mechanisms and organizational strategies underlying olfactory information processing. Recent studies using odorant receptor genes have revealed unexpected patterns of expression that provide new insights into how information may be organized in the nose and in the axonal projection from the nose to the brain.

The mammalian olfactory system is capable of discriminating a vast array of structurally diverse odors. We have identified a novel multigene family whose unusual size and diversity suggest that odor discrimination may rely heavily on the existence of many hundreds of different types of odorant receptors which are differentially expressed by olfactory sensory neurons in the nasal cavity. We have found that the members of this family are segregated in their expression into a series of distinct, and highly specified, zones within the olfactory epithelium. Our experiments suggest that the odorant receptor expression zones may provide for an initial organization of sensory information in the nasal cavity which is maintained in the transmission of this information to the olfactory bulb of the brain.

The mechanisms by which mammals discriminate a vast array of diverse odors are poorly understood. To gain insight into the organizational strategies underlying this discriminatory capacity, we have examined the spatial distribution of odorant receptor RNAs in the mouse olfactory epithelium. We have observed topographically distinct patterns of receptor RNAs suggesting that the nasal cavity is divided into a series of expression zones. The zones exhibit bilateral symmetry in the two nasal cavities and are organized along the dorsal-ventral and medial-lateral axes. Within each zone, a neuron may select a gene for expression from a zonal gene set via a stochastic mechanism. The observed zonal patterning may serve as an initial organizing step in olfactory sensory information coding.

With long stays for computed tomographic scans and x-ray exams and long trips to ICUs, patients with trauma may need extra fluids, drugs, or equipment outside the emergency department. Putting everything in a backpack saves time, leaves the nurse's hands free, and does not take up room on the stretcher.

The 21 kd NusG protein is essential for E. coli viability. Cells depleted for NusG were defective for factor-dependent transcription termination. Rho-induced polarity in the gal operon and the Rho-dependent lambda tR1 and lambda tL1 terminators were suppressed in NusG-deficient cells. NusG depletion inactivated the phage HK022 Nun termination factor. In contrast, the factor-independent lambda tl terminator was fully active in NusG-depleted cells and could be suppressed by phage lambda N function.

The Escherichia coli Nus factors act in conjunction with the bacteriophage lambda N protein to suppress transcription termination on the lambda chromosome. NusA binds both N and RNA polymerase and may also interact with other Nus factors. To search for additional components of the N antitermination system, we isolated host revertants that restored N activity in nusA1 mutants. One revertant, nusG4, was mapped to the rif region of the E. coli chromosome and shown to represent a point mutation near the 3' end of the nusG gene. The nusG4 mutation also suppressed nusE71 but not nusASal, nusB5, nusC60 (rpoB60), or nusD026 (rho026). However, nusG+ expressed from a multicopy plasmid suppressed nusD026 and related rho mutants for both lambda and phage T4 growth. These results suggest that NusG may act as a component of the N antitermination complex. In addition, the data imply a role for NusG in Rho-dependent termination.

Two genes, secE and nusG, situated between the tufB and ribosomal protein rplKAJL operons in the rif region at 90 min on the Escherichia coli chromosome, have been sequenced and characterized. The secE gene encodes a 127-amino-acid-long polypeptide, which is an integral membrane protein essential for protein export (P. J. Schatz, P. D. Riggs, A. Jacq, M. J. Fath, and J. Beckwith, Genes Dev. 3:1035-1044, 1989). The nusG gene encodes a 181-amino-acid-long polypeptide and is involved in transcription antitermination. The protein product of nusG is essential for bacterial viability. The secE-nusG genes are cotranscribed, with transcripts initiated at the PEG promoter and terminated at the Rho-independent terminator in the region of the rplK promoter. The majority of transcripts are processed at a number of sites in the 5' untranslated leader region by RNase III and are possibly also processed by a second unidentified nuclease. The role of transcript processing in the regulation of secE and nusG has not yet been established. The juxtaposition and coregulation of a protein export factor and a transcriptional factor raise questions concerning a functional connection between the two processes.

This report describes a patient who developed dyspnea and bilateral pulmonary infiltrates following exposure to cephradine. The role of cephradine was substantiated by rechallenge.