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.     

Crystal Containing Membrane Bound Intracellular Inclusion Bodies in the Epithelium of Experimentally Infected Sinus Mucosa

The sinus mucosa of 16 rabbits was experimentally infected with Bacteroides fragilis. This paper describes and discusses large inclusion bodies, which were found in abundance by light and electron microscopy inside ciliated cells of the sinus epithelium in 3 of the studied animals. The spindle-shaped inclusions were located in the apical portion of the cytoplasm. They were bound by a trilaminar membrane with several coils to the interior as well as to the exterior. The interior of an inclusion body consisted to a large extent of electron-lucent, floccular substance, but fibrogranular aggregates and rod-shaped crystals with a line periodicity center-to-center of about 15 nm were also conspicuous. These peculiar formations may be constituted by abnormally stored material from defective synthesis of cilia.     

Nucleolin Promotes Homologous DNA Pairing in vitro

We purified to near homogeneity a previously identified 100 kDa mammalian homologous DNA pairing protein. The purified 100 kDa protein also catalyzed high levels of cell-free homologous DNA recombination activity. This ATP-dependent activity was capable of forming conservative recombinant products between two circular, double-stranded DNA molecules. We were unable to detect any DNA polymerase, DNA ligase, or 5' or 3' exonuclease activity associated with this purified material. The purified 100 kDa protein bound silver nitrate as well as a monoclonal antibody specific for nucleolin. A recombinant protein comprised of the Escherichia coli maltos-ebinding protein fused to the carboxyl-terminal two-thirds of human nucleolin possessed homologous DNA pairing activity. These data indicate that the 100 kDa homologous DNA pairing protein is nucleolin. The observation that nucleolin can carry out homologous DNA strand pairing in vitro raises the prospect that it may function similarly in vivo.     

Effects of acute and long-term atropine treatment on levels, release and response to VIP and PHI in the submandibular gland of cat and rat.

We have studied the effects of acute and long-term treatment of cats and rats with atropine on the levels, release and effects of two peptides, vasoactive intestinal polypeptide (VIP) and peptide histidine isoleucine (PHI), that probably co-exist with acetylcholine in the parasympathetic nerves supplying the submandibular gland. Atropine treatment (progressively increasing doses from 2 to 15 mg kg-1 injected s.c.) for 14 days did not alter the contents of VIP- or PHI-like immunoreactivity (-IR) in the cat submandibular gland or in three other tissues (nasal mucosa, trachea and tongue). Acute as well as long-term atropine treatment decreased the vasodilation following low-, but not high-, frequency parasympathetic nerve stimulation. During prolonged stimulation (60 min) there was a decreased vasodilatation response following both acute and long-term atropine treatment. The overflow of VIP-IR and PHI-IR following parasympathetic nerve stimulation was markedly increased by acute, but not by long-term atropine treatment. The VIP- or PHI-induced stimulation of cyclic AMP (cAMP) accumulation in the cat submandibular gland was not altered after long-term atropine treatment. Similarly, treatment of male Sprague-Dawley rats with atropine (20 mg kg-1) or imipramine (20 mg kg-1) for 14 days did not alter the sensitivity to VIP or to PHI of cAMP accumulation in the submandibular gland, nor was there any change in VIP-IR or PHI-IR content. In conclusion, although atropine treatment causes an acute increase in the overflow of VIP and PHI evoked by parasympathetic nerve stimulation, there is no depletion of peptide stores upon long-term treatment, nor is there any change in the effect of exogenous VIP and PHI on cAMP-accumulation.     

Effects of TRH and TRH analogues on the central regulation of breathing in the rat

Respiratory activity was studied in rats during light halothane anesthesia. Thyrotropin releasing hormone (TRH) and two TRH analogues: the desamidated form (TRH-OH) and gamma-butyrolactone-gamma-carbonyl-L-histidyl-L-prolinamide citrate (DN 1417) were administered intracerebroventricularly. TRH 0.5-5 micrograms induced a marked tachypnoea with a rapid onset and a duration of at least 20 min. DN 1417, a potent analogue of TRH with a very low TSH (thyroid stimulating hormone) releasing activity was more effective in stimulating respiratory frequency, while TRH-OH, regarded to have neither TSH releasing nor extra hypothalamic effects, at equimolar doses was unable to induce any changes in the respiratory pattern. When TRH was given into the fourth ventricle the dose response curve was slightly shifted to the left. In experiments employing the occluded breath technique, P0.1 was increased in the same magnitude as the mean inspiratory flow (VT/T1). The results also indicated an increase in the gain of the inflation reflex loop whereas the central bulbopontine setting for T1 and TTOT were not significantly changed. Local injection of TRH into the nucleus tractus solitarii induced a stimulation of respiratory frequency which was slower in onset compared to the response seen after injection into the lateral or fourth ventricles. Concomitantly to the respiratory changes, i.c.v. TRH injection induced a hypocarbia and an alkalosis. No changes in blood pressure or heart rate were seen. The respiratory stimulant effect of TRH could be potentiated by pretreatment with naloxone, methylatropine or a low dose of GABA. Haloperidol or propranolol did not significantly change the respiratory effects of TRH, while reserpine pretreatment seemed to blunt some of the ventilatory effects of TRH. It seems likely that TRH has few direct effects on brain stem neurones involved in the central regulation of respiration, but the main effects seem to be elicited in areas rostral to the brain stem. The respiratory stimulating effect of TRH is unrelated to TSH. Furthermore, other neurotransmitter systems might also be involved in modulation of the respiratory stimulation evoked by TRH.     

The use of proteomics in biomarker discovery in neurodegenerative diseases

Biomarkers for neurodegenerative diseases should reflect the central pathogenic processes of the diseases. The field of clinical proteomics is especially well suited for discovery of biomarkers in cerebrospinal fluid (CSF), which reflects the proteins in the brain under healthy conditions as well as in several neurodegenerative diseases. Known proteins involved in the pathology of neurodegenerative diseases are, respectively, normal tau protein, beta-amyloid (1-42), synaptic proteins, amyloid precursor protein (APP), apolipoprotein E (apoE), which previously have been studied by protein immunoassays. The objective of this paper was to summarize results from proteomic studies of differential protein patterns in neurodegenerative diseases with focus on Alzheimer's disease (AD). Today, discrimination of AD from controls and from other neurological diseases has been improved by simultaneous analysis of both beta-amyloid (1-42), total-tau, and phosphorylated tau, where a combination of low levels of CSF-beta-amyloid 1-42 and high levels of CSF-tau and CSF-phospho-tau is associated with an AD diagnosis. Detection of new biomarkers will further strengthen diagnosis and provide useful information in drug trials. The combination of immunoassays and proteomic methods show that the CSF proteins express differential protein patterns in AD, FTD, and PD patients, which reflect divergent underlying pathophysiological mechanisms and neuropathological changes in these diseases.     

Sarcopenia Definitions as Predictors of Fracture Risk Independent of FRAX®, Falls,and BMD in the Osteoporotic Fractures in Men (MrOS) Study: A Meta-Analysis

Dual-energy X-ray absorptiometry (DXA)-derived appendicular lean mass/height² (ALM/ht²) is the most commonly used estimate of muscle mass in the assessment of sarcopenia, but its predictive value for fracture is substantially attenuated by femoral neck (fn) bone mineral density (BMD). We investigated predictive value of 11 sarcopenia definitions for incident fracture, independent of fnBMD, fracture risk assessment tool (FRAX^®) probability, and prior falls, using an extension of Poisson regression in US, Sweden, and Hong Kong Osteoporois Fractures in Men Study (MrOS) cohorts. Definitions tested were those of Baumgartner and Delmonico (ALM/ht² only), Morley, the International Working Group on Sarcopenia, European Working Group on Sarcopenia in Older People (EWGSOP1 and 2), Asian Working Group on Sarcopenia, Foundation for the National Institutes of Health (FNIH) 1 and 2 (using ALM/body mass index [BMI], incorporating muscle strength and/or physical performance measures plus ALM/ht²), and Sarcopenia Definitions and Outcomes Consortium (gait speed and grip strength). Associations were adjusted for age and time since baseline and reported as hazard ratio (HR) for first incident fracture, here major osteoporotic fracture (MOF; clinical vertebral, hip, distal forearm, proximal humerus). Further analyses adjusted additionally for FRAX-MOF probability (n = 7531; calculated ± fnBMD), prior falls (y/n), or fnBMD T-score. Results were synthesized by meta-analysis. In 5660 men in USA, 2764 Sweden and 1987 Hong Kong (mean ages 73.5, 75.4, and 72.4 years, respectively), sarcopenia prevalence ranged from 0.5% to 35%. Sarcopenia status, by all definitions except those of FNIH, was associated with incident MOF (HR = 1.39 to 2.07). Associations were robust to adjustment for prior falls or FRAX probability (without fnBMD); adjustment for fnBMD T-score attenuated associations. EWGSOP2 severe sarcopenia (incorporating chair stand time, gait speed, and grip strength plus ALM) was most predictive, albeit at low prevalence, and appeared only modestly influenced by inclusion of fnBMD. In conclusion, the predictive value for fracture of sarcopenia definitions based on ALM is reduced by adjustment for fnBMD but strengthened by additional inclusion of physical performance measures. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).