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1.  Total nasal resistance among Sasang constitutional types: a population-based study in Korea 
There have been many attempts to find an objective phenotype by Sasang constitutional types (SCTs) on an anatomical, physiological, and psychological basis, but there has been no research on total nasal resistance (TNR) among SCTs.
We assessed the value of the TNR in the SCTs classified by an integrated diagnostic model. Included in the study were 1,346 individuals (701 males, 645 females) who participated in the Korean Genome and Epidemiology Study (KoGES). The TNR was measured by active anterior rhinomanometry (AAR) at transnasal pressures of 100 and 150 Pascal (Pa).
The average TNR was 0.186 ± 0.004 Pa/cm3/second at 100 Pa in the Tae-eum (TE), 0.193 ± 0.007 in the So-eum (SE), and 0.208 ± 0.005 in the So-yang (SY) types. Under condition of 150 Pa the TE type had a TNR value of 0.217 ± 0.004, the SE type was 0.230 ± 0.008, and the SY type was 0.243 ± 0.005. Higher values of TNR were more likely to be reported in the SY type at 100 Pa and 150 Pa. In the stratified analysis by sex, the SY type in males and females tended to have higher TNR value than the TE and SE types at transnasal pressure of both 100 Pa and 150 Pa.
These results provide new approaches to understand the functional characteristics among the SCTs in terms of nasal physiology. Further studies are required to clarify contributing factors for such a difference.
PMCID: PMC4228428  PMID: 24180585
Sasang constitutional types; Total nasal resistance; Active anterior rhinomanometry; Transnasal pressure; Tae-eum type; So-eum type; So-yang type
2.  TNR and conservation on a university campus: a political ecological perspective 
PeerJ  2014;2:e312.
How to manage the impact of free-ranging cats on native wildlife is a polarizing issue. Conservation biologists largely support domestic cat euthanasia to mitigate impacts of free-ranging cat predation on small animal populations. Above all else, animal welfare activists support the humane treatment of free-ranging cats, objecting to euthanasia. Clearly, this issue of how to control free-ranging cat predation on small animals is value laden, and both positions must be considered and comprehended to promote effective conservation. Here, two gaps in the free-ranging cat—small-animal conservation literature are addressed. First, the importance of understanding the processes of domestication and evolution and how each relates to felid behavioral ecology is discussed. The leading hypothesis to explain domestication of wildcats (Felis silvestris) relates to their behavioral ecology as a solitary predator, which made them suited for pest control in early agricultural villages of the Old World. The relationship humans once had with cats, however, has changed because today domesticated cats are usually household pets. As a result, concerns of conservation biologists may relate to cats as predators, but cat welfare proponents come from the position of assuming responsibility for free-ranging household pets (and their feral offspring). Thus, the perceptions of pet owners and other members of the general public provide an important context that frames the relationship between free-ranging cats and small animal conservation. The second part of this paper assesses the effects of an information-based conservation approach on shifting student’s perception of a local Trap–Neuter–Return (TNR) program in introductory core science classes at the University of North Texas (UNT). UNT students are (knowingly or unknowingly) regularly in close proximity to a TNR program on campus that supports cat houses and feeding stations. A survey design implementing a tailored-information approach was used to communicate what TNR programs are, their goals, and the “conservationist” view of TNR programs. We gauged favorability of student responses to the goals of TNR programs prior to and after exposure to tailored information on conservation concerns related to free-ranging cats. Although these results are from a preliminary study, we suggest that an information-based approach may only be marginally effective at shifting perceptions about the conservation implications of free-ranging cats. Our position is that small animal conservation in Western societies occurs in the context of pet ownership, thus broader approaches that promote ecological understanding via environmental education are more likely to be successful than information-based approaches.
PMCID: PMC3970807  PMID: 24711965
TNR; Political ecology; Small animal conservation; Free-ranging cats; Domestication; Ethnobiology
3.  Nasal histamine responses in nonallergic rhinitis with eosinophilic syndrome 
Allergy & Rhinology  2015;6(2):e94-e100.
Nonallergic rhinitis with eosinophilic syndrome (NARES) is persistent, without atopy, but with ≥25% nasal eosinophilia. Hypereosinophilia seems to contribute to nasal mucosa dysfunction.
This analytical case-control study aimed at assessing the presence and severity of nonspecific nasal hyperactivity and at finding out whether eosinophilia may be correlated with the respiratory and mucociliary clearance functions.
The symptom score was assessed in 38 patients and 15 controls whose nasal smear was also tested for eosinophils and mucociliary transport (MCT). Nonspecific nasal provocation tests (NSNPT) with histamine were also carried out, and total nasal resistance (TNR) was determined.
The symptom score of NARES after NSNPT were not significantly different from the control group, and there was poor or no correlation among the single symptoms and the differences studied for every nasal reactivity class. This correlation improved when using the composite symptom score. The most severe eosinophilia was observed in high reactivity groups, and it was correlated with an increase in TNR. MCT worsened as eosinophilia and nasal reactivity increased. Unlike controls, a significant correlation was observed between the increase in MCT and TNR.
In NARES, nonspecific nasal hyperreactivity is the result of epithelial damage produced by eosinophilic inflammation, which causes MCT slow down, an increase in TNR, and nasal reactivity classes, with possible impact on classification, prognosis, and treatment control.
PMCID: PMC4541641  PMID: 26302729
Nonspecific nasal provocation test with histamine; symptom score; mucociliary clearance; eosinophils; total nasal resistance; nonspecific nasal hyperactivity; NARES.
4.  A Swiss 3T3 variant cell line resistant to the effects of tumor promoters cannot be transformed by src. 
Molecular and Cellular Biology  1990;10(8):4155-4162.
To study the relationship between oncogenesis by v-src and normal cellular signalling pathways, we determined the effects of v-src on 3T3-TNR9 cells, a Swiss 3T3 variant which does not respond mitogenically to tumor promoters such as 12-O-tetradecanoyl-phorbol-13-acetate (TPA). We found that src was unable to transform these variant cells, whether the oncogene was introduced by infection with a murine retrovirus vector or by transfection with plasmid DNA. 3T3-TNR9 cells were not inherently resistant to transformation, since infection with similar recombinant retroviruses containing either v-ras or v-abl did induce transformation. Further analysis of Swiss 3T3 and 3T3-TNR9 cell populations infected with the v-src-containing retrovirus revealed that although the amount of v-src DNA in each was approximately the same, the level of the v-src message and protein and the overall level of phosphotyrosine expressed in the infected variants was much less than in infected parental cells. Cotransfection experiments using separate v-src and neo plasmids revealed a decrease in the number of G418-resistant colonies when transfections of TNR9 cells occurred in the presence of the src-containing plasmid, suggesting a growth inhibitory effect of v-src on 3T3-TNR9 cells, as has also been found for TPA itself. Since v-src cannot transform this variant cell line, which does not respond mitogenically to the protein kinase C agonist TPA, we suggest that src makes use of the protein kinase C pathway as part of its signalling activities.
PMCID: PMC360942  PMID: 2115120
5.  Incidence and persistence of 8-oxo-7,8-dihydroguanine within a hairpin intermediate exacerbates a toxic oxidation cycle associated with trinucleotide repeat expansion 
DNA repair  2011;10(8):887-896.
The repair protein 8-oxo-7,8-dihydroguanine glycosylase (OGG1) initiates base excision repair (BER) in mammalian cells by removing the oxidized base 8-oxo-7,8-dihydroguanine (8-oxoG) from DNA. Interestingly, OGG1 has been implicated in somatic expansion of the trinucleotide repeat (TNR) sequence CAG/CTG. Furthermore, a ‘toxic oxidation cycle’ has been proposed for age-dependent expansion in somatic cells. In this cycle, duplex TNR DNA is (1) oxidized by endogenous species; (2) BER is initiated by OGG1 and the DNA is further processed by AP endonuclease 1 (APE1); (3) a stem-loop hairpin forms during strand-displacement synthesis by polymerase β (pol β); (4) the hairpin is ligated and (5) incorporated into duplex DNA to generate an expanded CAG/CTG region. This expanded region is again subject to oxidation and the cycle continues. We reported previously that the hairpin adopted by TNR repeats contains a hot spot for oxidation. This finding prompted us to examine the possibility that the generation of a hairpin during a BER event exacerbates the toxic oxidation cycle due to accumulation of damage. Therefore, in this work we used mixed-sequence and TNR substrates containing a site-specific 8-oxoG lesion to define the kinetic parameters of human OGG1 (hOGG1) activity on duplex and hairpin substrates. We report that hOGG1 activity on TNR duplexes is indistinguishable from a mixed-sequence control. Thus, BER is initiated on TNR sequences as readily as non-repetitive DNA in order to start the toxic oxidation cycle. However, we find that for hairpin substrates hOGG1 has reduced affinity and excises 8-oxoG at a significantly slower rate as compared to duplexes. Therefore, 8-oxoG is expected to accumulate in the hairpin intermediate. This damage-containing hairpin can then be incorporated into duplex, resulting in an expanded TNR tract that now contains an oxidative lesion. Thus, the cycle restarts and the DNA can incrementally expand.
PMCID: PMC3146575  PMID: 21727036
OGG1; trinucleotide repeat expansion; toxic oxidation cycle
6.  Usefulness of F-18 FDG PET/CT in the Evaluation of Early Treatment Response After Interventional Therapy for Hepatocellular Carcinoma 
This retrospective study investigated the usefulness of F-18 fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) after interventional therapy for hepatocellular carcinoma (HCC).
Between March 2007 and November 2010, 31 patients (24 men, 7 women; mean age, 61.8 ± 11.0 years) with 45 lesions underwent PET/CT within 1 month after interventional therapy for HCC. Twenty-six patients with 40 lesions underwent transcatheter arterial chemoembolization (TACE), two patients with 2 lesions underwent radiofrequency ablation (RFA), and three patients with 3 lesions underwent percutaneous ethanol injection therapy (PEIT). Patients with a history of previous interventional therapy were excluded. Visual analysis was graded as positive when FDG was observed as an eccentric, nodular, or infiltrative pattern, and negative in case of isometabolic, hypometabolic, or rim-shaped uptake. For quantitative analysis, the standardized uptake value (SUV) was measured by region of interest technique. Maximum SUV (SUVmax) was assessed, and the ratio of SUVmax of tumor to mean SUV of normal liver (TNR) was calculated. The patients were divided into two groups, with and without residual tumor, based on 6-month clinical follow-up with serum alpha-fetoprotein and contrast-enhanced abdominal CT.
Of the 45 lesions, 24 were classified in the residual tumor group and the other 21 lesions in the no residual tumor group. No residual tumor was detected after RFA or PEIT. By visual analysis, the respective values for sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 87.5, 71.4, 77.8, 83.3, and 80.0 %. However, there were no significant differences in the SUVmax and TNR between the two groups.
It is suggested that FDG PET/CT may play a role in the evaluation of early treatment response after interventional therapy for HCC. The results indicate that FDG PET/CT visual analysis may be more useful than quantitative analysis. Further prospective studies with a large number of patients and established protocol are needed to substantiate our results.
PMCID: PMC4042986  PMID: 24900042
F-18 FDG; PET/CT; Hepatocellular carcinoma; Interventional therapy; Locoregional therapy; Response
7.  Genome-Wide Association Study of Alcohol Dependence Implicates KIAA0040 on Chromosome 1q 
Neuropsychopharmacology  2011;37(2):557-566.
Previous studies using SAGE (the Study of Addiction: Genetics and Environment) and COGA (the Collaborative Study on the Genetics of Alcoholism) genome-wide association study (GWAS) data sets reported several risk loci for alcohol dependence (AD), which have not yet been well replicated independently or confirmed by functional studies. We combined these two data sets, now publicly available, to increase the study power, in order to identify replicable, functional, and significant risk regions for AD. A total of 4116 subjects (1409 European-American (EA) cases with AD, 1518 EA controls, 681 African-American (AA) cases, and 508 AA controls) underwent association analysis. An additional 443 subjects underwent expression quantitative trait locus (eQTL) analysis. Genome-wide association analysis was performed in EAs to identify significant risk genes. All available markers in the genome-wide significant risk genes were tested in AAs for associations with AD, and in six HapMap populations and two European samples for associations with gene expression levels. We identified a unique genome-wide significant gene—KIAA0040—that was enriched with many replicable risk SNPs for AD, all of which had significant cis-acting regulatory effects. The distributions of −log(p) values for SNP-disease and SNP-expression associations for all markers in the TNN–KIAA0040 region were consistent across EAs, AAs, and five HapMap populations (0.369⩽r⩽0.824; 2.8 × 10−9⩽p⩽0.032). The most significant SNPs in these populations were in high LD, concentrating in KIAA0040. Finally, expression of KIAA0040 was significantly (1.2 × 10−11⩽p⩽1.5 × 10−6) associated with the expression of numerous genes in the neurotransmitter systems or metabolic pathways previously associated with AD. We concluded that KIAA0040 might harbor a causal variant for AD and thus might directly contribute to risk for this disorder. KIAA0040 might also contribute to the risk of AD via neurotransmitter systems or metabolic pathways that have previously been implicated in the pathophysiology of AD. Alternatively, KIAA0040 might regulate the risk via some interactions with flanking genes TNN and TNR. TNN is involved in neurite outgrowth and cell migration in hippocampal explants, and TNR is an extracellular matrix protein expressed primarily in the central nervous system.
PMCID: PMC3242317  PMID: 21956439
risk region; alcohol dependence; cis-eQTL; GWAS; alcohol & alcoholism; neurogenetics; addiction & substance abuse; biological psychiatry; GWAScis-eQTL; risk region
8.  Retinal thickness after vitrectomy and internal limiting membrane peeling for macular hole and epiretinal membrane 
To determine the retinal thickness (RT), after vitrectomy with internal limiting membrane (ILM) peeling, for an idiopathic macular hole (MH) or an epiretinal membrane (ERM). Also, to investigate the effect of a dissociated optic nerve fiber layer (DONFL) appearance on RT.
A non-randomized, retrospective chart review was performed for 159 patients who had successful closure of a MH, with (n = 148), or without (n = 11), ILM peeling. Also studied were 117 patients who had successful removal of an ERM, with (n = 104), or without (n = 13), ILM peeling. The RT of the nine Early Treatment Diabetic Retinopathy Study areas was measured by spectral domain optical coherence tomography (SD-OCT). In the MH-with-ILM peeling and ERM-with-ILM peeling groups, the RT of the operated eyes was compared to the corresponding areas of normal fellow eyes. The inner temporal/inner nasal ratio (TNR) was used to assess the effect of ILM peeling on RT. The effects of DONFL appearance on RT were evaluated in only the MH-with-ILM peeling group.
In the MH-with-ILM peeling group, the central, inner nasal, and outer nasal areas of the retina of operated eyes were significantly thicker than the corresponding areas of normal fellow eyes. In addition, the inner temporal, outer temporal, and inner superior retina was significantly thinner than in the corresponding areas of normal fellow eyes. Similar findings were observed regardless of the presence of a DONFL appearance. In the ERM-with-ILM peeling group, the retina of operated eyes was significantly thicker in all areas, except the inner and outer temporal areas. In the MH-with-ILM peeling group, the TNR was 0.86 in operated eyes, and 0.96 in fellow eyes (P < 0.001). In the ERM-with-ILM peeling group, the TNR was 0.84 in operated eyes, and 0.95 in fellow eyes (P < 0.001). TNR in operated eyes of the MH-without-ILM peeling group was 0.98, which was significantly greater than that of the MH-with-ILM peeling group (P < 0.001). TNR in the operated eyes of the ERM-without-ILM peeling group was 0.98, which was significantly greater than that of ERM-with-ILM peeling group (P < 0.001).
The thinning of the temporal retina and thickening of the nasal retina after ILM peeling does not appear to be disease-specific. In addition, changes in RT after ILM peeling are not related to the presence of a DONFL appearance.
PMCID: PMC3363315  PMID: 22654493
epiretinal membrane; macular hole; optical coherence tomography; retinal thickness; internal limiting membrane
9.  Genome-wide mapping of TnrA-binding sites provides new insights into the TnrA regulon in Bacillus subtilis 
MicrobiologyOpen  2015;4(3):423-435.
Under nitrogen limitation conditions, Bacillus subtilis induces a sophisticated network of adaptation responses. More precisely, the B. subtilis TnrA regulator represses or activates directly or indirectly the expression of a hundred genes in response to nitrogen availability. The global TnrA regulon have already been identified among which some directly TnrA-regulated genes have been characterized. However, a genome-wide mapping of in vivo TnrA-binding sites was still needed to clearly define the set of genes directly regulated by TnrA. Using chromatin immunoprecipitation coupled with hybridization to DNA tiling arrays (ChIP-on-chip), we now provide in vivo evidence that TnrA reproducibly binds to 42 regions on the chromosome. Further analysis with real-time in vivo transcriptional profiling, combined with results from previous reports, allowed us to define the TnrA primary regulon. We identified 35 promoter regions fulfilling three criteria necessary to be part of this primary regulon: (i) TnrA binding in ChIP-on-chip experiments and/or in previous in vitro studies; (ii) the presence of a TnrA box; (iii) TnrA-dependent expression regulation. In addition, the TnrA primary regulon delimitation allowed us to improve the TnrA box consensus. Finally, our results reveal new interconnections between the nitrogen regulatory network and other cellular processes.
PMCID: PMC4475385  PMID: 25755103
Bacillus subtilis; ChIP-on-chip; nitrogen metabolism; oxidative stress; TnrA regulator
10.  Feedback-Resistant Mutations in Bacillus subtilis Glutamine Synthetase Are Clustered in the Active Site†  
Journal of Bacteriology  2006;188(16):5966-5974.
The feedback-inhibited form of Bacillus subtilis glutamine synthetase regulates the activity of the TnrA transcription factor through a protein-protein interaction that prevents TnrA from binding to DNA. Five mutants containing feedback-resistant glutamine synthetases (E65G, S66P, M68I, H195Y, and P318S) were isolated by screening for colonies capable of cross-feeding Gln− cells. In vitro enzymatic assays revealed that the mutant enzymes had increased resistance to inhibition by glutamine, AMP, and methionine sulfoximine. The mutant proteins had a variety of enzymatic alterations that included changes in the levels of enzymatic activity and in substrate Km values. Constitutive expression of TnrA- and GlnR-regulated genes was seen in all five mutants. In gel mobility shift assays, the E65G and S66P enzymes were unable to inhibit TnrA DNA binding, while the other three mutant proteins (M68I, H195Y, and P318S) showed partial inhibition of TnrA DNA binding. A homology model of B. subtilis glutamine synthetase revealed that the five mutated amino acid residues are located in the enzyme active site. These observations are consistent with the hypothesis that glutamine and AMP bind at the active site to bring about feedback inhibition of glutamine synthetase.
PMCID: PMC1540052  PMID: 16885465
11.  Assessment of Nasal Airflow Resistance in the Healthy Population of Chattisgarh by Active Anterior Rhinomanometry 
The aim of present study was to define a normal range of total nasal airflow resistance in the healthy population of Chattisgarh. This study was conducted at the Department of Otorhinolaryngology, Medical College Raipur, Chattisgarh over 93 healthy adults. A proper otolaryngology examination was done prior to the study and all the subjects were free from any type upper respiratory tract infection. This was the main inclusion criteria for the present study. All the subjects were distributed according to age and sex. Active Anterior Rhinomanometry is the best recommended method for evaluating the objective assessment of nasal airflow resistance; it was preferred for the assessment of total nasal airway resistance in present study also. The present study concluded that the mean value of total nasal airway resistance was 0.21 at 150 Pa pressure. However the range of total nasal airway resistance was from 0.142 to 0.34 Pa/cm3/s at the same pressure. The present study presents the normal range and mean value of total nasal airway resistance for the healthy adult population of Chattisgarh. Total nasal airway resistance is independent of age and sex.
PMCID: PMC3477443  PMID: 24294574
Total nasal airflow resistance; Active anterior rhinomanometry; Chattisgarh
12.  A cross-species genetic analysis identifies candidate genes for mouse anxiety and human bipolar disorder 
Bipolar disorder (BD) is a significant neuropsychiatric disorder with a lifetime prevalence of ~1%. To identify genetic variants underlying BD genome-wide association studies (GWAS) have been carried out. While many variants of small effect associated with BD have been identified few have yet been confirmed, partly because of the low power of GWAS due to multiple comparisons being made. Complementary mapping studies using murine models have identified genetic variants for behavioral traits linked to BD, often with high power, but these identified regions often contain too many genes for clear identification of candidate genes. In the current study we have aligned human BD GWAS results and mouse linkage studies to help define and evaluate candidate genes linked to BD, seeking to use the power of the mouse mapping with the precision of GWAS. We use quantitative trait mapping for open field test and elevated zero maze data in the largest mammalian model system, the BXD recombinant inbred mouse population, to identify genomic regions associated with these BD-like phenotypes. We then investigate these regions in whole genome data from the Psychiatric Genomics Consortium's bipolar disorder GWAS to identify candidate genes associated with BD. Finally we establish the biological relevance and pathways of these genes in a comprehensive systems genetics analysis. We identify four genes associated with both mouse anxiety and human BD. While TNR is a novel candidate for BD, we can confirm previously suggested associations with CMYA5, MCTP1, and RXRG. A cross-species, systems genetics analysis shows that MCTP1, RXRG, and TNR coexpress with genes linked to psychiatric disorders and identify the striatum as a potential site of action. CMYA5, MCTP1, RXRG, and TNR are associated with mouse anxiety and human BD. We hypothesize that MCTP1, RXRG, and TNR influence intercellular signaling in the striatum.
PMCID: PMC4486840  PMID: 26190982
bipolar disorder; TNR; CMYA5; RXRG; MCTP1; anxiety; cross-species
13.  Trinucleotide repeats in human genome and exome 
Nucleic Acids Research  2010;38(12):4027-4039.
Trinucleotide repeats (TNRs) are of interest in genetics because they are used as markers for tracing genotype–phenotype relations and because they are directly involved in numerous human genetic diseases. In this study, we searched the human genome reference sequence and annotated exons (exome) for the presence of uninterrupted triplet repeat tracts composed of six or more repeated units. A list of 32 448 TNRs and 878 TNR-containing genes was generated and is provided herein. We found that some triplet repeats, specifically CNG, are overrepresented, while CTT, ATC, AAC and AAT are underrepresented in exons. This observation suggests that the occurrence of TNRs in exons is not random, but undergoes positive or negative selective pressure. Additionally, TNR types strongly determine their localization in mRNA sections (ORF, UTRs). Most genes containing exon-overrepresented TNRs are associated with gene ontology-defined functions. Surprisingly, many groups of genes that contain TNR types coding for different homo-amino acid tracts associate with the same transcription-related GO categories. We propose that TNRs have potential to be functional genetic elements and that their variation may be involved in the regulation of many common phenotypes; as such, TNR polymorphisms should be considered a priority in association studies.
PMCID: PMC2896521  PMID: 20215431
14.  Small Nuclear RNAs U11 and U12 Modulate Expression of TNR-CFTR mRNA in Mammalian Kidneys 
TNR-CFTR, discovered as a splice variant of CFTR (Cystic Fibrosis Transmembrane conductance Regulator), is distributed in different tissues such as human and rat kidney, trachea, lungs etc and is a functional chloride channel. In Kidneys, our findings show TNR-CFTR to have an unique distribution pattern with low levels of expression in renal cortex and high levels of expression in renal medulla. As shown by us previously, TNR-CFTR mRNA lacks 145 bp corresponding to segments of exons 13 and 14. This deletion causes a frame shift mutation leading to reading of a premature termination codon in exon 14. Premature termination of translation produces a functional half molecule of CFTR; TNR-CFTR. Our analysis of TNR mRNA has shown that the putative alternatively spliced intron has in its 5′ and 3′ conserved element CT and AC, respectively, that can be recognized by snRNAs U11 and U12. With these findings, we hypothesize that TNR-CFTR mRNA alternative splicing is probably mediate by splicing pathways utilizing U11 and U12 snRNAs. In this study, we have determined sequences of snRNAs U11 and U12 derived from rat kidney, which show significant homology to human U11 and U12 snRNAs. We show that there is significantly lower expression of U11 and U12 snRNAs in renal cortex compared to renal medulla in both humans and rats. This renal pattern of distribution of U11 and U12 snRNAs in both humans and rats closely follows distribution pattern of renal TNR-CFTR. Further, we have shown that blocking U11 and/or U12 mRNAs, by using antisense probes transfected in Immortalized Rat Proximal Tubule Cell line (IRPTC), decreases TNR-CFTR mRNA expression but not wild-type CFTR mRNA expression. Our results suggest that expression of U11 and/or U12 snRNAs is important for non-conventional alternative splicing process that gives rise to mRNA transcript coding for TNR-CFTR.
PMCID: PMC2992639  PMID: 18769035
CFTR; TNR-CFTR; Kidney; Small Nuclear RNA; Splicing and mRNA
15.  Acoustic rhinometry compared with posterior rhinomanometry in the measurement of histamine- and bradykinin-induced changes in nasal airway patency. 
1. Acoustic rhinometry is a relatively new method for objectively assessing nasal airway patency. In this paper we compare acoustic rhinometry with active posterior rhinomanometry. 2. Twenty normal healthy volunteers underwent nasal challenge with either histamine or bradykinin, 100 micrograms to 1000 micrograms, and responses were assessed by acoustic rhinometry. A further 20 subjects received identical nasal challenges and responses were assessed by active posterior rhinomanometry. 3. On a subsequent occasion, the subjects challenged previously with histamine, were given the selective H1-receptor antagonist, cetirizine, 10 mg orally, 3 h before repeat nasal challenge with histamine, 100-1000 micrograms. Again, responses were assessed by active posterior rhinomanometry and acoustic rhinometry. 4. The acoustic reflection measurements and the nasal airway resistance measurements showed comparable, significant dose-related changes in nasal patency to both histamine and bradykinin. Pretreatment with cetirizine blocked the histamine-induced change in nasal patency as measured by both methods. 5. We conclude that acoustic rhinometry has a number of advantages over posterior rhinomanometry. It is quick to perform, requires minimal subject co-operation and gives a reliable objective, measurement of dose-related changes in nasal airway patency before and after pharmacological treatment.
PMCID: PMC1364706  PMID: 8148216
16.  Abnormal protein kinase C down regulation and reduced substrate levels in non-phorbol ester-responsive 3T3-TNR9 cells. 
Molecular and Cellular Biology  1990;10(5):2122-2132.
The cell line TNR9 (E. Butler-Gralla and H. R. Herschman, J. Cell. Physiol. 107:59-67, 1981) in a Swiss 3T3 cell variant that expresses protein kinase C (PKC) but is mitogenically nonresponsive to the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA). We have found that PKCs purified from variant and parental cells are identical as judged by kinase activity, protease mapping, and column chromatography. We analyzed cellular levels and subcellular location of PKC in TPA-treated 3T3 and TNR9 cells via immunoprecipitation of [35S]methionine-labeled protein and assay of immune-complex PKC kinase activity. TNR9 cells grew to higher densities than parental 3T3 cells. TNR9 cells at maximal density did not down regulate PKC in response to long-term TPA treatment. We compared the 80-kilodalton (kDa) PKC substrate phosphorylation in 3T3 and TNR9 cells by using two-dimensional gels and found that TNR9 cells treated with TPA for 30 min contained only 10 to 15% as much 32Pi associated with the 80-kDa as did parental cells. The TNR9 80-kDa substrate was present at reduced levels compared with the parental-cell 80-kDa substrate as judged by immunoblot and silver staining. Thus, the loss of mitogenic responsiveness to TPA in TNR9 cells is accompanied by resistance to TPA-mediated down regulation of PKC and reduced phosphosubstrate levels.
PMCID: PMC360560  PMID: 2325648
17.  Smoking Cessation Pharmacotherapy Preferences in Rural Primary Care 
Pharmacotherapy is a critical adjunct to smoking cessation therapy. Little is known about relative preferences for these agents among smokers in primary care settings.
In the context of a population-based clinical trial, we identified 750 smokers in primary care practices and independent of their stage of change offered them a free treatment course of either bupropion or transdermal nicotine replacement (TNR). Smokers opting for pharmacotherapy completed standardized contraindication screens that were reviewed by the patient's primary care physician.
Most participants (67%) requested pharmacotherapy. Use of pharmacotherapy was positively associated with higher nicotine dependence and readiness to quit. Of the smokers requesting pharmacotherapy, 51% requested bupropion and 49% requested TNR. Choice of bupropion was related to no history of heart disease and no previous use of bupropion. Although potential contraindications to treatments were identified for 21.7% of bupropion and 6.6% or TNR recipients, physicians rarely felt that these potential contraindications precluded the use of these agents.
When cost is removed as a barrier, a large proportion of rural smokers are eager to use smoking cessation pharmacotherapy, especially agents that they have not tried before. Although some comorbid conditions and concurrent drug therapies were considered contraindications, particularly to bupropion, physicians rarely considered these clinically significant risks enough to deny pharmacotherapy.
PMCID: PMC2821185  PMID: 18236294
tobacco; smoking cessation; pharmacotherapy preference; nicotine replacement; bupropion
18.  Regional Peak Mucosal Cooling Predicts the Perception of Nasal Patency 
The Laryngoscope  2013;124(3):589-595.
Nasal obstruction is the principal symptom that drives patients with rhinosinus disease to seek medical treatment. However, patient perception of obstruction often bears little relationship to actual measured physical obstruction of airflow. This lack of an objective clinical tool hinders effective diagnosis and treatment. Previous work has suggested that the perception of nasal patency may involve nasal trigeminal activation by cool inspiratory airflow; we attempt to derive clinically relevant variables following this phenomenon.
Study design
Prospective healthy cohort.
Twenty-two healthy subjects rated unilateral nasal patency in controlled room air using a visual analog scale, followed by rhinomanometry, acoustic rhinometry and butanol lateralization thresholds (BLT). Each subject then immediately underwent a CT scan, enabling the construction of a “real-time” computational fluid dynamics (CFD) nasal airway model, which was used to simulate nasal mucosa heat loss during steady resting breathing.
Among all measured and computed variables, only CFD-simulated peak heat loss posterior to the nasal vestibule significantly correlated with patency ratings (r=−0.46, p<0.01). Linear discriminant analysis predicted patency categories with 89% success rate, with BLT and rhinomanometric nasal resistance being two additional significant variables. As validation, CFD simulated nasal resistance significantly correlated with rhinomanometrically measured resistance (r=0.41, p<0.01).
These results reveal that our noses are sensing patency via a mechanism involving localized peak nasal mucosal cooling. The analysis provides a strong rationale for combining the individualized CFD with other objective and neurological measures to create a novel clinical tool to diagnose nasal obstruction and to predict and evaluate treatment outcomes.
PMCID: PMC3841240  PMID: 23775640
Nasal congestion; nasal obstruction; TRPM8; nasal cooling; cool perception; nasal trigeminal sensitivity
19.  Perceiving Nasal Patency through Mucosal Cooling Rather than Air Temperature or Nasal Resistance 
PLoS ONE  2011;6(10):e24618.
Adequate perception of nasal airflow (i.e., nasal patency) is an important consideration for patients with nasal sinus diseases. The perception of a lack of nasal patency becomes the primary symptom that drives these patients to seek medical treatment. However, clinical assessment of nasal patency remains a challenge because we lack objective measurements that correlate well with what patients perceive.The current study examined factors that may influence perceived patency, including air temperature, humidity, mucosal cooling, nasal resistance, and trigeminal sensitivity. Forty-four healthy subjects rated nasal patency while sampling air from three facial exposure boxes that were ventilated with untreated room air, cold air, and dry air, respectively. In all conditions, air temperature and relative humidity inside each box were recorded with sensors connected to a computer. Nasal resistance and minimum airway cross-sectional area (MCA) were measured using rhinomanometry and acoustic rhinometry, respectively. General trigeminal sensitivity was assessed through lateralization thresholds to butanol. No significant correlation was found between perceived patency and nasal resistance or MCA. In contrast, air temperature, humidity, and butanol threshold combined significantly contributed to the ratings of patency, with mucosal cooling (heat loss) being the most heavily weighted predictor. Air humidity significantly influences perceived patency, suggesting that mucosal cooling rather than air temperature alone provides the trigeminal sensation that results in perception of patency. The dynamic cooling between the airstream and the mucosal wall may be quantified experimentally or computationally and could potentially lead to a new clinical evaluation tool.
PMCID: PMC3192719  PMID: 22022361
20.  Diagnostic Ability of FDG-PET/CT in the Detection of Malignant Pleural Effusion 
Medicine  2015;94(29):e1010.
We investigated the role of F-18 fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) for the differential diagnosis of malignant and benign pleural effusion.
We studied 36 consecutive patients with histologically proven cancer (excluding malignant mesothelioma) who underwent FDG-PET/CT for suspected malignant pleural effusion. Fourteen patients had cytologically proven malignant pleural effusion and the other 22 patients had either negative cytology or clinical follow-up, which confirmed the benign etiology. We examined the maximum standardized uptake values (SUVmax) of pleural effusion and the target-to-normal tissue ratio (TNR), calculated as the ratio of the pleural effusion SUVmax to the SUVmean of the normal tissues (liver, spleen, 12th thoracic vertebrae [Th12], thoracic aorta, and spinalis muscle). We also examined the size and density (in Hounsfield units) of the pleural effusion and pleural abnormalities on CT images.
TNR (Th12) and increased pleural FDG uptake compared to background blood pool were significantly more frequent in cases with malignant pleural effusion (P < 0.05 for both). The cutoff TNR (Th12) value of >0.95 was the most accurate; the sensitivity, specificity, and accuracy for this value were 93%, 68%, and 75%, respectively.
FDG-PET/CT can be a useful method for the differential diagnosis of malignant and benign pleural effusion.
PMCID: PMC4603013  PMID: 26200610
21.  Both CAG repeats and inverted DNA repeats stimulate spontaneous unequal sister-chromatid exchange in Saccharomyces cerevisiae 
Nucleic Acids Research  2004;32(18):5677-5684.
Genomic regions containing trinucleotide repeats (TNRs) are highly unstable, as the repeated sequences exhibit a high rate of mutational change, in which they undergo either a contraction or an expansion of repeat numbers. Although expansion of TNRs is associated with several human genetic diseases, the expansion mechanism is poorly understood. Extensive studies in model organisms have indicated that instability of TNRs occurs by several mechanisms, including replication slippage, DNA repair and recombination. In all models, the formation of secondary structures by disease-associated TNRs is a critical step in the mutation process. In this report, we demonstrate that TNRs and inverted repeats (IRs) both of which have the potential to form secondary structures in vivo, increase spontaneous unequal sister-chromatid exchange (SCE) in vegetatively growing yeast cells. Our results also show that TNR-mediated SCE events are independent of RAD50, MRE11 and RAD51, whereas IR-stimulated SCEs are dependent on the RAD52 epistasis-group genes. We propose that many TNR expansion mutations occur by SCE.
PMCID: PMC524308  PMID: 15494455
22.  Trinucleotide Repeat DNA Alters Structure to Minimize the Thermodynamic Impact of 8-Oxo-7,8-dihydroguanine† 
Biochemistry  2011;51(1):52-62.
In the phenomenon of trinucleotide repeat (TNR) expansion, an important interplay exists between DNA damage repair of 8-oxo-7,8-dihydroguanine (8-oxoG) and non-canonical structure formation. We show that TNR DNA adapts its structure to accommodate 8-oxoG. Using chemical probe analysis, we find that CAG repeats composing the stem-loop arm of a three-way junction alter the population of structures in response to 8-oxoG by positioning the lesion at or near the loop. Furthermore, we find that oligonucleotides composed of odd-numbered repeat sequences, which form populations of two structures, will also alter their structure to place 8-oxoG in the loop. However, sequences with an even number of repeats do not display this behavior. Analysis by differential scanning calorimetry indicates that when the lesion is located within the loop, there are no significant changes to the thermodynamic parameters as compared to the DNA lacking 8-oxoG. This contrasts with the enthalpic destabilization observed when 8-oxoG is base paired to C and indicates that positioning 8-oxoG in the loop avoids the thermodynamic penalty associated with 8-oxoG base pairing. Since formation of stem-loop hairpins is proposed to facilitate TNR expansion, these results highlight the importance of defining the structural consequences of DNA damage.
PMCID: PMC3254800  PMID: 22148399
23.  CAG/CTG Repeats Alter Affinity for the Histone Core and Positioning of DNA in the Nucleosome† 
Biochemistry  2012;51(49):9814-9825.
Trinucleotide repeats (TNRs) occur throughout the genome and their expansion has been linked to several neurodegenerative disorders, including Huntington’s Disease. TNRs have been studied using both oligonucleotides and plasmids; however, less is know about how repetitive DNA responds to genomic packaging. Here, we investigate the behavior of CAG/CTG repeats incorporated into nucleosome core particles, the most basic unit of chromatin packaging. To assess the general interaction between CAG/CTG repeats and the histone core, we determined the efficiency with which various TNR-containing DNA substrates form nucleosomes, revealing that even short CAG/CTG tracts are robust incorporators. However, presence of the Huntingtin gene flanking sequence (htt) decreases incorporation. Enzymatic and chemical probing revealed repositioning of the DNA in the nucleosome as the number of CAG/CTG repeats increased, regardless of the flanking sequence. Notably, the periodicity of the repeat tract remained unchanged as a function of length and is consistently 10.7 base pairs per helical turn. In contrast, the periodicity of the non-repetitive flanking sequence varies, and is smaller than the repeat tract at ~10.0–10.5 base pairs per turn. Furthermore, while the CAG/CTG repeats remain as canonical duplex in the nucleosome, nucleosome formation causes kinking in a secondary repeat tract in the htt gene, comprised of CCG/CGG repeats. This work highlights the innate ability of CAG/CTG repeats to incorporate and to position in nucleosomes and how that behavior is modulated by the htt flanking sequence. In addition, it illuminates the differences in packaging of healthy and diseased length repeat tracts within the genome.
PMCID: PMC3567209  PMID: 23157165
24.  Opinions from the Front Lines of Cat Colony Management Conflict 
PLoS ONE  2012;7(9):e44616.
Outdoor cats represent a global threat to terrestrial vertebrate conservation, but management has been rife with conflict due to differences in views of the problem and appropriate responses to it. To evaluate these differences we conducted a survey of opinions about outdoor cats and their management with two contrasting stakeholder groups, cat colony caretakers (CCCs) and bird conservation professionals (BCPs) across the United States. Group opinions were polarized, for both normative statements (CCCs supported treating feral cats as protected wildlife and using trap neuter and release [TNR] and BCPs supported treating feral cats as pests and using euthanasia) and empirical statements. Opinions also were related to gender, age, and education, with females and older respondents being less likely than their counterparts to support treating feral cats as pests, and females being less likely than males to support euthanasia. Most CCCs held false beliefs about the impacts of feral cats on wildlife and the impacts of TNR (e.g., 9% believed feral cats harmed bird populations, 70% believed TNR eliminates cat colonies, and 18% disagreed with the statement that feral cats filled the role of native predators). Only 6% of CCCs believed feral cats carried diseases. To the extent the beliefs held by CCCs are rooted in lack of knowledge and mistrust, rather than denial of directly observable phenomenon, the conservation community can manage these conflicts more productively by bringing CCCs into the process of defining data collection methods, defining study/management locations, and identifying common goals related to caring for animals.
PMCID: PMC3435309  PMID: 22970269
25.  Predictive role of nasal functionality tests in the evaluation of patients before nocturnal polysomnographic recording 
Obstructive sleep apnoea syndrome is a disease characterized by a collapse of the pharyngeal airway resulting in repeated episodes of airflow cessation, oxygen desaturation, and sleep disruption. It is a common disorder affecting at least 2-4% of the adult population. The role of nasal resistance in the pathogenesis of sleep disordered breathing and sleep apnoea has not been completely clarified. Aim of the present study was to establish whether nasal resistance and nasal volumes, measured by means of Active Anterior Rhinomanometry and Acoustic Rhinometry together with Muco-Ciliary Transport time play a positive predictive role in the evaluation of Obstructive sleep apnoea syndrome patients before running a nocturnal polysomnographic recording. A retrospective study was performed analysing 223 patients referred for suspected Obstructive sleep apnoea syndrome. All patients were submitted to complete otorhinolaryngological evaluation and underwent nocturnal polysomnography. On the basis of polysomnographic data analysis, the apnoea-hypopnoea index and snoring index, patients were classified into two groups: Group 1 (110/223 patients) with a diagnosis of mild-moderate Obstructive sleep apnoea syndrome (apnoea-hypopnoea index < 30) and Group 2 (113/223 patients) affected by snoring without associated hypoxaemia/hypercapnia. A control group of 76 subjects, not complaining of sleep disorders and free from nasal symptoms was also selected. The results showed, in all the snoring and Obstructive sleep apnoea syndrome patients, total nasal resistance and increased Muco-Ciliary Transport time compared to standard values. Furthermore, the apnoea-hypopnoea index was significantly higher in patients with higher nasal resistence and significantly different between the groups. These results allow us to propose the simultaneous evaluation of nasal functions by Active Anterior Rhinomanometry, Acoustic Rhinometry, and Muco-Ciliary Transport time in the selection of patients undergoing polysomnography.
PMCID: PMC3203739  PMID: 22064751
Sleep respiratory disorders; Obstructive sleep apnoea syndrome; Nasal functionality tests; Polysomnography

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