Reflex effects following selective stimulation of J receptors in the cat

1. Experiments carried out on anaesthetized cats showed that increasing blood flow, through the lobes of a lung, by 133% (S.E. 33%) generated an average of 0.75 impulses/sec (S.E. 0.3) in ten almost silent J receptors. Equivalent activity was produced by injecting 12-18 μg phenyl diguanide/kg into the right atrium. Such activity caused marked reflex effects, i.e. apnoea, rapid shallow breathing and reduction in the knee jerk. 2. The reflex effects of J receptors were studied after blocking the activity from cardiac receptors by intrapericardial injections of xylocaine. This was necessary because left atrial injections of phenyl diguanide produced reflex respiratory effects and inhibition of the knee jerk. 3. Hypoxia, but not hypercapnia, attenuated the reflex effects of J receptors, apnoea being abolished if the Pa,O2 fell below 35 mmHg. This was a central effect as it occurred in spite of increased activity of J receptors following phenyl diguanide, and effects of hypoxia persisted after cutting both carotid nerves. 4. The only invariable reflex effect of J receptors was a reduction in the total number and the average frequency of phrenic impulses in each breath. The changes in inspiratory time (ti) and expiratory time (te) following apnoea were variable although most frequently both were reduced. In about half the observations the first effect before the apnoea was a reduction in ti, in the other half it was a reduction in te. It was concluded that an input from J receptors inhibits inspiratory and expiratory mechanisms directly. 5. In some cats apnoea and rapid shallow breathing produced by J receptors continued after interrupting their activity by vagotomy and this did not diminish the reduction in ti or te; in other cats it did. The reduction in te was at times quite independent of changes in ti, i.e. pulmonary stretch receptor activity. 6. It was concluded that J receptors must be stimulated during moderate exercise to levels that produce marked respiratory reflex effects and inhibition of muscles

The influence of the sympathetic outflow on aortic chemoreceptors of the cat during hypoxia and hypercapnia

1. An attempt has been made to reconcile differing observations, made by different groups of investigators, on the responses of aortic chemoreceptors of cats during normoxia, hypoxia and hypercapnia. 2. In cats anaesthetized with sodium pentobarbitone it was observed that during hypoxic stimulation of twelve chemoreceptors, an intravenous injection of about 20 mg sodium pentobarbitone produced hypotension which was accompanied by an initial fall in chemoreceptor activity instead of the expected increase that invariably occurred in all the receptors when hypotension was produced mechanically by distending a balloon in the right atrium (twenty-six during normoxia, eleven during hypoxia and eight during hypercapnia). 3. In twelve receptors a reflex fall in blood pressure produced by injecting 8-25 μg veratridine (Bezold-Jarisch reflex) yielded results qualitatively similar to those following injection of sodium pentobarbitone. 4. In sixteen out of twenty-five chemoreceptors it was observed that ventilating the cat with 5.6-6.7 % CO2 produced either no or little increase in activity; in nine receptors there was a clear increase in activity, which fell initially or was abolished after injecting a single dose of 20 mg sodium pentobarbitone. 5. In all seven chemoreceptors tested in seven deeply anaesthetized cats it was found that a larger dose (about 50-60 mg) of sodium pentobarbitone had no direct depressant effect on aortic chemoreceptor activity. It followed that the initial depressant effect of the much smaller doses of sodium pentobarbitone observed during hypoxic and hypercapnic stimulation (see above) must be due to reduction in the sympathetic outflow to the aortic bodies. This conclusion was supported by the results following injections of veratridine. 6. By comparing the present results with those reported previously it was concluded that the variations in the responses of aortic chemoreceptors during hypoxia and hypercapnia reported by different investigators could be partly due to variations in the level of sympathetic activity prevailing under different experimental conditions

Factors affecting movement of excitatory substances from pulmonary capillaries to type J receptors of anaesthetized cats

1. Using phenyl diguanide (PDG) as an excitatory substance, the role of certain factors that could influence the movement of such substances across the pulmonary capillaries to the J receptors was studied in cats anaesthetized with sodium pentobarbitone. This was aided by using a new method for estimating continuously in vivo the concentration (C) of PDG in the blood of the pulmonary artery. 2. Reduction of pulmonary blood flow by partial occlusion of the inferior vena cava enhanced the responses of the J receptors to PDG significantly in twelve out of thirteen trials. These effects, which occurred at a time when pulmonary capillary pressure (PCP) had fallen, could be related to the increase in the estimated mean C of PDG over the first 3 s or to the C t (concentration × time) area to 50% of peak C. The responses bore no relation to peak C or rate of rise of C. 3. The responses of the receptors to PDG increased significantly after three out of eight injections of PDG while the PCP was raised by partial occlusion of the mitral orifice; reduced responses were recorded after two injections. These results, showing relatively much weaker stimulation by PDG in spite of the enhanced level of J receptor excitability produced by the raised PCP itself, suggest that movement of PDG out of the capillaries to the J receptors must be influenced primarily by forces governing diffusion, not filtration. 4. In addition to C of PDG there appear to be other factors that influence the responses of the receptors to PDG

Sensory origin of lobeline-induced sensations: a correlative study in man and cat

1. Intravenous injections of lobeline HCl into twenty-six normal young male human volunteers produced sensations of choking, pressure or fumes in the throat and upper chest at a mean threshold dose of 12 μg kg-1. 2. Reflex changes in breathing pattern usually appeared just before the sensations. Increasing the dose of lobeline increased the intensity of the sensations gradually until a dry cough appeared at a mean threshold dose of 24.3 μg kg-1. At these doses there was a mean difference of 0.3 s in the latencies for sensation and respiratory reflex; in four subjects there was no difference at all. 3. In cats anaesthetized with 35 μg kg-1 sodium pentobarbitone, injecting 25-67 μg kg-1 lobeline into the right atrium sensitized thirteen out of seventeen rapidly adapting receptors (RARs). In three out of four cats lobeline had no excitatory effect on the RARs in the absence of normal activity (i.e. when it was injected while artificial respiration was suspended), but on restarting the respiration the activity increased greatly. After injecting lobeline, the activity increased during inflation or deflation or in both phases of the respiratory cycle. It also increased greatly during deflation produced by suction of air from the lungs after lobeline. Such presumed increased activity in the RARs of man produced by forced expiration to residual volume at the time lobeline-induced sensations were expected did not enhance the sensations in any subject. 4. In all the subjects tested, forced expiration alone, which should stimulate RARs, never produced a dry cough or sensations similar to those produced by lobeline.5. The results suggest that since the reflex respiratory effects of lobeline are due to J receptors, the sensations and cough can also be attributed to them, since both events occur at about the same time, and also because the RARs, and the slowly adapting receptors (SARs), do not seem to play a primary role in producing or potentiating the sensations

CisMols Analyzer: identification of compositionally similar cis-element clusters in ortholog conserved regions of coordinately expressed genes

Combinatorial interactions of sequence-specific trans-acting factors with localized genomic cis-element clusters are the principal mechanism for regulating tissue-specific and developmental gene expression. With the emergence of expanding numbers of genome-wide expression analyses, the identification of the cis-elements responsible for specific patterns of transcriptional regulation represents a critical area of investigation. Computational methods for the identification of functional cis-regulatory modules are difficult to devise, principally because of the short length and degenerate nature of individual cis-element binding sites and the inherent complexity that is generated by combinatorial interactions within cis-clusters. Filtering candidate cis-element clusters based on phylogenetic conservation is helpful for an individual ortholog gene pair, but combining data from cis-conservation and coordinate expression across multiple genes is a more difficult problem. To approach this, we have extended an ortholog gene-pair database with additional analytical architecture to allow for the analysis and identification of maximal numbers of compositionally similar and phylogenetically conserved cis-regulatory element clusters from a list of user-selected genes. The system has been successfully tested with a series of functionally related and microarray profile-based co-expressed ortholog pairs of promoters and genes using known regulatory regions as training sets and co-expressed genes in the olfactory and immunohematologic systems as test sets. CisMols Analyzer is accessible via a Web interface at

Assessment of molecular markers for anti-malarial drug resistance after the introduction and scale-up of malaria control interventions in western Kenya

Background Although it is well known that drug pressure selects for drug-resistant parasites, the role of transmission reduction by insecticide-treated bed nets (ITNs) on drug resistance remains unclear. In this study, the drug resistance profile of current and previous first-line anti-malarials in Kenya was assessed within the context of drug policy change and scale-up of ITNs. National first-line treatment changed from chloroquine (CQ) to sulphadoxine-pyrimethamine (SP) in 1998 and to artemether-lumefantrine (AL) in 2004. ITN use was scaled-up in the Asembo, Gem and Karemo areas of western Kenya in 1997, 1999 and 2006, respectively. Methods Smear-positive samples (N = 253) collected from a 2007 cross-sectional survey among children in Asembo, Gem and Karemo were genotyped for mutations in pfcrt and pfmdr1 (CQ), dhfr and dhps (SP), and at pfmdr-N86 and the gene copy number in pfmdr1 (lumefantrine). Results were compared among the three geographic areas in 2007 and to retrospective molecular data from children in Asembo in 2001. Results In 2007, 69 and 85% of samples harboured the pfmdr1-86Y mutation and dhfr/dhps quintuple mutant, respectively, with no significant differences by study area. However, the prevalence of the pfcrt-76T mutation differed significantly among areas (p <0.02), between 76 and 94%, with the highest prevalence in Asembo. Several 2007 samples carried mutations at dhfr-164L, dhps-436A, or dhps-613T. From 2001 to 2007, there were significant increases in the pfcrt-76T mutation from 82 to 94% (p <0.03), dhfr/dhps quintuple mutant from 62 to 82% (p <0.03), and an increase in the septuple CQ and SP combined mutant haplotype, K 76 Y 86 I 51 R 59 N 108 G 437 E 540 , from 28 to 39%. The prevalence of the pfmdr1-86Y mutation remained unchanged. All samples were single copy for pfmdr1. Conclusions Molecular markers associated with lumefantrine resistance were not detected in 2007. More recent samples will be needed to detect any selective effects by AL. The prevalence of CQ and SP resistance markers increased from 2001 to 2007 in the absence of changes in transmission intensity. In 2007, only the prevalence of pfcrt-76T mutation differed among study areas of varying transmission intensity. Resistant parasites were most likely selected by sustained drug pressure from the continued use of CQ, SP, and mechanistically similar drugs, such as amodiaquine and cotrimoxazole. There was no clear evidence that differences in transmission intensity, as a result of ITN scale-up, influenced the prevalence of drug resistance molecular markers

Long-Term Care Facilities: Important Participants of the Acute Care Facility Social Network?

Background: Acute care facilities are connected via patient sharing, forming a network. However, patient sharing extends beyond this immediate network to include sharing with long-term care facilities. The extent of long-term care facility patient sharing on the acute care facility network is unknown. The objective of this study was to characterize and determine the extent and pattern of patient transfers to, from, and between long-term care facilities on the network of acute care facilities in a large metropolitan county. Methods/Principal Findings: We applied social network constructs principles, measures, and frameworks to all 2007 annual adult and pediatric patient transfers among the healthcare facilities in Orange County, California, using data from surveys and several datasets. We evaluated general network and centrality measures as well as individual ego measures and further constructed sociograms. Our results show that over the course of a year, 66 of 72 long-term care facilities directly sent and 67 directly received patients from other long-term care facilities. Long-term care facilities added 1,524 ties between the acute care facilities when ties represented at least one patient transfer. Geodesic distance did not closely correlate with the geographic distance among facilities. Conclusions/Significance: This study demonstrates the extent to which long-term care facilities are connected to the acute care facility patient sharing network. Many long-term care facilities were connected by patient transfers and further added many connections to the acute care facility network. This suggests that policy-makers and health officials should account for patient sharing with and among long-term care facilities as well as those among acute care facilities when evaluating policies and interventions. © 2011 Lee et al

Global analyses of TetR family transcriptional regulators in mycobacteria indicates conservation across species and diversity in regulated functions

BACKGROUND: Mycobacteria inhabit diverse niches and display high metabolic versatility. They can colonise both humans and animals and are also able to survive in the environment. In order to succeed, response to environmental cues via transcriptional regulation is required. In this study we focused on the TetR family of transcriptional regulators (TFTRs) in mycobacteria. RESULTS: We used InterPro to classify the entire complement of transcriptional regulators in 10 mycobacterial species and these analyses showed that TFTRs are the most abundant family of regulators in all species. We identified those TFTRs that are conserved across all species analysed and those that are unique to the pathogens included in the analysis. We examined genomic contexts of 663 of the conserved TFTRs and observed that the majority of TFTRs are separated by 200 bp or less from divergently oriented genes. Analyses of divergent genes indicated that the TFTRs control diverse biochemical functions not limited to efflux pumps. TFTRs typically bind to palindromic motifs and we identified 11 highly significant novel motifs in the upstream regions of divergently oriented TFTRs. The C-terminal ligand binding domain from the TFTR complement in M. tuberculosis showed great diversity in amino acid sequence but with an overall architecture common to other TFTRs. CONCLUSION: This study suggests that mycobacteria depend on TFTRs for the transcriptional control of a number of metabolic functions yet the physiological role of the majority of these regulators remain unknown. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12864-015-1696-9) contains supplementary material, which is available to authorized users