Vagal vasodilatory mechanisms in the pig bronchial circulation preferentially involves sensory nerves

The present study shows that in contrast to the upper trachea, where the parasympathetic vasodilatory components of both cholinergic and non-cholinergic nature are dominating, the vagal blood flow regulation in the peripheral airways of the pig supplied by the bronchial artery is entirely carried out by local release of vasodilatory mediators from capsaicin-sensitive sensory nerves. Also inhalation of the vapour phase from the major airway irritant cigarette smoke was associated with a marked increase in bronchial blood flow possibly via local axon reflexes. Capsaicin, substance P (SP) and calcitonin gene-related peptide (CGRP) caused vasodilatation in both the trachea and bronchi while vasoactive intestinal polypeptide (VIP) was most active in the trachea. These functional data were supported by immunohistochemical studies showing the presence of SP- and CGRP-containing nerves of presumably sensory origin around bronchial blood vessels while VIP-positive perivascular fibres of local parasympathetic origin were found mainly in the trachea.     

Genetics of the low density lipoprotein receptor:

Fibroblast association (plasma membrane binding plus intracellular accumulation) and degradation of radioiodinated low density lipoprotein (125I-LDL) index plasma membrane LDL receptor activity. Cultured fibroblasts from 23 subjects affected with familial hypercholesterolemia (HC) and from 95 subjects without HC (non-HCs) were tested for 125I-LDL association and degradation. Both LDL receptor activity indices were twice as high in non-HC and HC heterozygous cell strains. This is compatible with a major gene effect on LDL receptor activity. However, a considerable overlap between non-HC and HC heterozygous values was found in the 125I-LDL association assay [median (range) 970 (330-2500), and 450 (250-490), respectively] and in the degradation assay [median (range) 810 (280-2020), and 470 (160-790), respectively]. The values are expressed as ng 125I-LDL X mg cell protein-1 X 4.5 h-1. These great overlaps in the LDL receptor activity indices support the view that the influence of LDL receptor activity on the HC phenotype may be smaller than believed previously. Furthermore, for the diagnosis of HC, these LDL receptor activity assays are far more expensive and have less sensitivity and specificity than simple serum cholesterol determination. The LDL receptor-dependent 125I-LDL association values for the HC heterozygous individuals clustered into four groups. Family data supported the hypothesis that this variation could be due to four different LDL receptor variants, each coded for by different alleles at the LDL receptor locus. If confirmed, this finding may have implications for the understanding of the variable expression of HC and also of the genetic impact on lipoprotein metabolism and susceptibility to atherosclerosis in non-HCs.     

Cutaneous facilitation of transmission in reflex pathways from Ib afferents to motoneurones.

1. The effect of volleys in low threshold cutaneous afferents upon transmission of synaptic action from Ib afferents to motoneurones has been investigated with intracellular recording from alpha motoneurones to hind limb muscles. 2. There was facilitation from cutaneous afferents of transmission in excitatory and inhibitory reflex pathways from Ib afferents without any evidence for difference in effect on di- and trisynaptic pathways. It is postulated that volleys in cutaneous afferents evoke excitatory action in interneurones of these reflex pathways. 3. The time course of the facilitation suggest that cutaneous afferents have disynaptic excitatory connexions with the interneurones intercalated in the disynaptic Ib inhibitory pathways to motoneurones. 4. Some observations are reported suggesting that interneuronal transmission in Ib inhibitory pathways to motoneurones might be facilitated from Ia afferents. 5. The findings are discussed in relation to the presumed role of Ib reflex action in regulating muscle tension.     

Evaluation of the imaging properties of two generations of a CCD-based system for digital chest radiography

Two generations of a CCD-based detector system with lens-based optical coupling for digital chest radiography were evaluated in terms of presampling MTF, NPS, NEQ, DQE, linearity in response, and SNR over the detector area. Measurements were performed over a wide exposure range and at several different beam qualities. Neither the presampling MTF nor the DQE showed any general strong beam quality dependence, whereas the NPS and NEQ did when compared at specific entrance air kerma values. The exposure dependency for the DQE was found to be considerable, with the detectors showing low DQE at low exposures, and higher DQE at higher exposures. It was found that the second generation has been substantially improved compared to its predecessor regarding all the relevant parameters. The DQE(0) at an entrance air kerma of 5 microGy increased from 9% to 15%, mainly due to a better system gain (including optical coupling efficiency and matching of the energy of the emitted light photons to the sensitivity of the CCD camera). The first generation of detectors was found to have problems with bad peripheral resolution [MTF(muN/2) <0.1]. This problem was nonexistent for the second generation for which uniform resolution has been obtained [MTF(muN/2)=0.3]. A theoretical calculation of the DQE of two model systems similar to the ones evaluated was also performed, and the results were comparable to the experimentally determined data at high exposures. The model shows that both systems suffer from low optical coupling efficiency due to the large demagnification used. The main conclusion is that although the second generation has been improved, there is still a problem with low system gain leading to relatively modest DQE values, especially at low exposures.     

Detection and delineation of an unusual 17p11.2 deletion by array-CGH and refinement of the Smith–Magenis syndrome minimum deletion to 650 kb

Smith–Magenis syndrome (SMS) is a multiple congenital anomaly/mental retardation syndrome and it is characterized by an interstitial deletion of chromosome 17p11.2. SMS patients have a distinct phenotype which is believed to be caused by haploinsufficiency of one or more genes in the associated deleted region. Five non-deletion patients with classical phenotypic features of SMS have been reported with mutations in the retinoic acid induced 1 (RAI1) gene, located within the SMS critical interval. Happloinsufficiency of the RAI1 gene is likely to be the responsible gene for the majority of the SMS features, but other deleted genes in the SMS region may modify the overall phenotype in the patients with 17p11.2 deletions. SMS is usually diagnosed in the clinical genetic setting by FISH analysis using commercially available probes. We detected a submicroscopic deletion in 17p11.2 using array-CGH with a resolution of approximately 1 Mb in a patient with the SMS phenotype, who was not deleted for the commercially available SMS microdeletion FISH probe. Delineation of the deletion was performed using a 32K tiling BAC-array, containing 32,500 BAC clones. The deletion in this patient was size mapped to 2.7 Mb and covered the RAI1 gene. This case enabled the refinement of the SMS minimum deletion to 650 kb containing eight putative genes and one predicted gene. In addition, it demonstrates the importance to investigate deletion of RAI1 in SMS patients.     

Renal sympathetic nerve activation in relation to reserpine-induced depletion of neuropeptide Y in the kidney of the rat

The effect of reserpine treatment on renal sympathetic nerve activity and tissue levels of neuropeptide Y (NPY)-like immunoreactivity (LI) and noradrenaline (NA) were studied in rats. Injection of reserpine (1 mg kg-1 i.v.) caused a clear-cut (about 50%) increase in rectified activity of the post-ganglionic sympathetic nerves to the kidney within 15 min in chloralose-anaesthetized rats compared to a saline-treated control group. This increase in nerve activity was still maintained 120 min after the reserpine injection. The renal nerve activation was accompanied by a progressive fall in mean arterial blood pressure and an initial tachycardia. In a separate group of conscious rats, the levels of NPY-LI (1.3 +/- 0.06 pmol g-1) and NA (1.6 +/- 0.07 nmol g-1) in the kidney were significantly reduced (by 74 and 83%, respectively) 24 h after reserpine treatment (1 mg kg-1 i.v.). The reserpine-induced depletion of NPY-LI, but not that of NA, was inhibited by pretreatment with the ganglionic blocking agent chlorisondamine or the alpha 2-adrenoceptor agonist clonidine, both of which are known to decrease renal sympathetic nerve activity. The tissue content of NPY-LI in the right atrium (16.3 +/- 0.7 pmol g-1) was not reduced by reserpine. Arterial plasma NPY-LI in the rat was high (222 +/- 5 pmol l-1), and this value did not change after pretreatment with reserpine, chlorisondamine or clonidine, indicating that, in the rat, circulating NPY-LI is not a good indicator of sympatho-adrenal activity.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of different spinal cord lesions on visually guided switching of target-reaching in cats

It has previously been shown that when a target is moved, cats can change the direction of ongoing target-reaching with brief latency suggesting a tectal relay. Switching of target-reaching has now been investigated after spinal lesions: (1) dorsally in C5 interrupting cortico- (CS) and rubrospinal (RS) fibres to forelimb segments; (2) more ventrally in C5 interrupting axons of the C3-C4 propriospinal neurones (PNs) to forelimb motoneurones; and (3) ventrally in C2 interrupting tectospinal and tecto-reticulospinal fibres. Short-latency switching of target-reaching remained after lesions 1 and 2. A subsequent lesion 3 after lesion 1 or 2 prolonged the switching latency. The results show that fast switching, presumably relayed in tectum, can be made when the cat utilizes C3-C4 PNs or interneurones in the forelimb segments for target-reaching. For both neuronal systems, the longer-latency switching after ventral C2 lesion is assumed to be cortically relayed and mediated by the CS and RS tracts.     

Selective inhibition by dactinomycin of NANC sensory bronchoconstriction and [125I]NKA binding due to NK-2 receptor antagonism.

In the present study, dactinomycin (10(-5) M) inhibited the non-adrenergic, non-cholinergic bronchoconstriction upon antidromic vagal nerve stimulation (1 Hz for 1 min) in the isolated perfused guinea-pig lung by 84%. The release of calcitonin gene-related peptide was unchanged, however, suggesting a postjunctional action. Dactinomycin (10(-5), 5 x 10(-5) M) also reduced non-adrenergic non-cholinergic bronchial contractions (maximally by 75%) induced by electrical field stimulation or capsaicin, while the cholinergic component and non-adrenergic non-cholinergic relaxation remained intact. The neurokinin-2 receptor antagonist L-659,877 (10(-6) M) had a similar effect as dactinomycin, inhibiting the non-adrenergic non-cholinergic bronchial contractions by 69%, while the neurokinin-1 receptor antagonist CP-96,345 (10(-6) M) had no effect. The bronchoconstriction evoked by neurokinin A, the selective neurokinin-2 receptor agonist Nle10neurokinin A (4-10) and capsaicin was markedly inhibited by dactinomycin while the contraction induced by substance P (SP), the selective neurokinin-1 receptor agonist Sar9Met(O2)11SP, endothelin-1 and acetylcholine was not affected. In autoradiographic experiments on guinea-pig lung, [125I]neurokinin A-labelled sections showed dense binding in the bronchial smooth muscle layer. Dactinomycin inhibited the specific binding of [125I]neurokinin A in a concentration-dependent manner (IC50 = 6.3 x 10(-6) M) and 66% of [125I]neurokinin A total binding was inhibited by 10(-4) M dactinomycin. In the rat colon, [125I]neurokinin A binding to neurokinin-2 sites on circular smooth muscle was inhibited by dactinomycin with an IC50 value of 7.9 x 10(-6) M. Dactinomycin failed to reduce increased nerve-evoked contractions or those caused by Nle10neurokinin A (4-10) per se in the rat vas deferens, which are considered to be mediated by neurokinin-2 receptor activation. In the rat portal vein, dactinomycin did not influence the contractions caused by the neurokinin-3 selective agonist Pro7neurokinin B. In conclusion, dactinomycin selectively inhibited neurokinin-2 receptor activation in guinea-pig lung and rat colon, but not in rat vas deferens, which may depend on the existence of different neurokinin-2 receptor subtypes. Neurokinin A is most likely the main endogenous excitatory non-adrenergic non-cholinergic transmitter in guinea-pig bronchi.     

Baroreflex modulation of sympathetic activity and sympathetic neurotransmitters in humans

We raised and lowered arterial pressures with stepwise intravenous infusions of phenylephrine and nitroprusside in ten healthy young men and measured changes of R-R intervals, post-ganglionic peroneal nerve muscle sympathetic activity, and antecubital vein plasma noradrenaline and neuropeptide Y concentrations. Respiratory peak-valley R-R interval changes declined with arterial pressure reductions, but did not rise with pressure elevations. Sympathetic activity was modulated by respiration over the entire range of pressures and, at each pressure, was more prominent in expiration than inspiration. Levels of muscle sympathetic nerve activity were low during supine rest, were suppressed almost completely during small increases of pressure, and were increased proportionally during pressure reductions. Over a range of average diastolic pressures from 69 to 89 mmHg, antecubital vein plasma noradrenaline levels were related linearly (r = 0.86, P = 0.0001) to muscle sympathetic nerve activity. Neuropeptide Y levels increased proportionally with muscle sympathetic nerve activity during pressure reductions, but did not decline during pressure elevations. Our results suggest that in man, muscle sympathetic outflow is modulated finely by small changes of baroreceptor input, and that during pharmacologically induced changes of arterial pressure, changes of antecubital vein plasma noradrenaline concentrations provide excellent estimates of changes of sympathetic nerve traffic to skeletal muscle.