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The p.Val142Ile variant in transthyretin (encoded by the TTR gene) is the most common genetic cause of transthyretin-related amyloidosis. This allele is particularly prevalent in communities ofAfrican descent compared with populations of different ancestries, where its frequency is two orders of magnitude lower. For this reason, p.Val142Ile has always been considered an “African” variant, with limited studies performed on individuals of European descent. However, recent reports of higher-than-expected prevalence in European-ancestry populations question the African specificity of this allele. Here we show that the high recurrence of p.Val142Ile in central Italy is due to a founder effect and not to recent admixture from African populations, highlighting how this may be the case in other communities. This suggests a probable underestimate of the global prevalence of p.Val142Ile, and further emphasizes the importance of routine inclusion of TTR in gene panels used for clinical genetic testing in hypertrophic cardiomyopathy (independently of the patient’s geographical origin), that transthyretin-related amyloidosis can mimic.

Despite no apparent defects in T cell priming and recruitment to tumors, a large subset of T cell rich tumors fail to respond to immune checkpoint blockade (ICB). We leveraged a neoadjuvant anti-PD-1 trial in patients with hepatocellular carcinoma (HCC), as well as additional samples collected from patients treated off-label, to explore correlates of response to ICB within T cell-rich tumors. We show that ICB response correlated with the clonal expansion of intratumoral CXCL13+CH25H+IL-21+PD-1+CD4+T helper cells (“CXCL13+TH”) and Granzyme K+PD-1+effector-like CD8+T cells, whereas terminally exhausted CD39hiTOXhiPD-1hiCD8+T cells dominated in nonresponders. CD4+and CD8+T cell clones that expanded post-treatment were found in pretreatment biopsies. Notably, PD-1+TCF-1+(Progenitor-exhausted) CD8+T cells shared clones mainly with effector-like cells in responders or terminally exhausted cells in nonresponders, suggesting that local CD8+T cell differentiation occurs upon ICB. We found that these Progenitor CD8+T cells interact with CXCL13+THwithin cellular triads around dendritic cells enriched in maturation and regulatory molecules, or “mregDC”. These results suggest that discrete intratumoral niches that include mregDC and CXCL13+THcontrol the differentiation of tumor-specific Progenitor exhasuted CD8+T cells following ICB.

Population-based studies assessing the prevalence and associated factors of halitosis among older adults are scarce.

Angiotensin-converting enzyme 2 (ACE2) and accessory proteases (TMPRSS2 and CTSL) are needed for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cellular entry, and their expression may shed light on viral tropism and impact across the body. We assessed the cell-type-specific expression of ACE2, TMPRSS2and CTSLacross 107 single-cell RNA-sequencing studies from different tissues. ACE2, TMPRSS2and CTSLare coexpressed in specific subsets of respiratory epithelial cells in the nasal passages, airways and alveoli, and in cells from other organs associated with coronavirus disease 2019 (COVID-19) transmission or pathology. We performed a meta-analysis of 31 lung single-cell RNA-sequencing studies with 1,320,896 cells from 377 nasal, airway and lung parenchyma samples from 228 individuals. This revealed cell-type-specific associations of age, sex and smoking with expression levels of ACE2, TMPRSS2and CTSL. Expression of entry factors increased with age and in males, including in airway secretory cells and alveolar type 2 cells. Expression programs shared by ACE2+TMPRSS2+cells in nasal, lung and gut tissues included genes that may mediate viral entry, key immune functions and epithelial–macrophage cross-talk, such as genes involved in the interleukin-6, interleukin-1, tumor necrosis factor and complement pathways. Cell-type-specific expression patterns may contribute to the pathogenesis of COVID-19, and our work highlights putative molecular pathways for therapeutic intervention.

In aggressive non-Hodgkin’s lymphoma (NHL), constitutive apoptosis of a proportion of the tumor cell population can promote net tumor growth. This is associated with the accumulation of tumor-associated macrophages (TAMs) that clear apoptotic cells and exhibit pro-oncogenic transcriptional activation profiles characteristic of reparatory, anti-inflammatory and angiogenic programs. Here we consider further the activation status of these TAMs. We compare their transcriptomic profile with that of a range of other macrophage types from various tissues noting especially their expression of classically activated (IFN-γ and LPS) gene clusters – typically antitumor – in addition to their previously described protumor phenotype. To understand the impact of apoptotic cells on the macrophage activation state, we cocultured apoptotic lymphoma cells with classically activated macrophages (M(IFN-γ/LPS), also known as M1, macrophages). Although untreated and M(IFN-γ/LPS)macrophages were able to bind apoptotic lymphoma cells equally well, M(IFN-γ/LPS)macrophages displayed enhanced ability to phagocytose them. We found that direct exposure of M(IFN-γ/LPS)macrophages to apoptotic lymphoma cells caused switching towards a protumor activation state (often referred to as M2-like) with concomitant inhibition of antitumor activity that was a characteristic feature of M(IFN-γ/LPS)macrophages. Indeed, M(IFN-γ/LPS)macrophages exposed to apoptotic lymphoma cells displayed increased lymphoma growth-promoting activities. Antilymphoma activity by M(IFN-γ/LPS)macrophages was mediated, in part, by galectin-3, a pleiotropic glycoprotein involved in apoptotic cell clearance that is strongly expressed by lymphoma TAMs but not lymphoma cells. Intriguingly, aggressive lymphoma growth was markedly impaired in mice deficient in galectin-3, suggesting either that host galectin-3-mediated antilymphoma activity is required to sustain net tumor growth or that additional functions of galectin-3 drive key oncogenic mechanisms in NHL. These findings have important implications for anticancer therapeutic approaches aimed at polarizing macrophages towards an antitumor state and identify galectin-3 as a potentially important novel target in aggressive NHL.

While the expression and/or activity of endothelial nitric oxide synthase (eNOS) has been characterized in spontaneously hypertensive (SHR) and normotensive Wistar Kyoto rat (WKY) hearts, in coronary endothelial cells (ECs) from both strains, the effect of NO on intracellular calcium concentration ([Ca2+]i) is still unknown.Coronary microvascular ECs were isolated from SHR and WKY and characterized. Immunocytochemistry and Western blot analysis showed that eNOS was similarly expressed in ECs from both strains.Measuring [Ca2+]iby imaging analysis of fura‐2‐loaded cells, we demonstrated that α‐thrombin (3−180 U l−1) induced a superimposable dose‐dependent calcium transient in ECs from both strains.In WKY ECs, S‐nitroso‐N‐acetyl‐DL‐penicillamine (SNAP) dose‐dependently (10–100 μM) and 0.1 μMatrial natriuretic factor (ANF) reduced the maximum and the decay time of α‐thrombin‐induced calcium transient. The inhibitory effects of SNAP and ANF were prevented by blocking cyclic GMP‐dependent protein kinase. Non selective eNOS inhibitors prolonged the decay time of α‐thrombin‐induced calcium transient, while the selective inducible NOS inhibitor 1400 W was ineffective. SNAP (100 μM) and 0.1 μMANF increased cyclic GMP content up to 22.9 and 42.3 fold respectively.In SHR ECs, α‐thrombin‐induced calcium transient was not modified by SNAP, ANF or eNOS inhibition. SNAP (100 μM) and 0.1 μMANF increased cyclic GMP content up to 9.3 and 51 fold respectively.In WKY ECs, SNAP dose‐dependently (10–100 μM) reduced also bradykinin‐induced calcium transient, while in SHR ECs was ineffective.We concluded that in SHR ECs, the cyclic GMP‐dependent regulation of calcium transient is lost.

1The Ca2+‐antagonistic properties of lacidipine were investigated in patch‐clamp guinea‐pig ventricular myocytes.2In basal conditions, 0.1 μm lacidipine reduced the action potential duration, associated with a decrease in the L‐type calcium current (Ica,L) to 66 ± 4% of the control value, without a change in the current‐voltage relationship. Sodium current and background potassium currents were not affected. All the effects reached a steady state within 2 min.3The Ca2+‐antagonistic effect of lacidipine was voltage‐dependent: a marked negative shift (about 20 mV) of the steady‐state inactivation curve was observed with long (10 s) conditioning prepulses, but not with short (350 ms) prepulses.4The onset of and recovery from the voltage‐dependent effect caused by 0.1 μm lacidipine were significantly slower when compared to those of equiactive concentrations of nimodipine (0.5 μm) and nisoldipine (0.1 μm). ICa,Lmeasured after prepulses at —40 mV lasting 500 ms or less was unchanged (95 ± 5% of maximum current value) while it was reduced to 49±10% by nimodipine and 43 ± 9% by nisoldipine (P<0.05 vs lacidipine for both).5Similarly, the recovery from block in the presence of lacidipine was slower than with nimodipine and nisoldipine. After a prepulse of 1 s at —80 mV, ICa,Lrecovered up to 54 ± 2% of the maximum current value in the presence of lacidipine, and up to 91 ±3% and 93 ± 5% in the presence of nimodipine and nisoldipine, respectively (P<0.05 vs lacidipine).6Blockade of ICa,Lby lacidipine was use‐dependent. After ten 200 ms long pulses (1 Hz) from −80 mV, ICa,Lwas reduced to 55 ± 7% of the current measured at the first pulse. In the presence of nimodipine and nisoldipine, ICa,Lelicited by the tenth pulse amounted to 93 ± 3% and 80 ± 6% of the first pulse value, respectively (P<0.05 vs lacidipine). Lacidipine did not cause use‐dependent blockade of Ica,Lin cells stimulated with 10 ms long pulses.7These results demonstrate that lacidipine selectively inhibits ICa,Lin isolated cardiomyocytes and suggest that this effect occurs mainly through binding to the inactivated Ca2+channels.

We compared the occurrence of calcium-dependent electrophysiological alterations in left ventricular myocytes isolated from the heart of old spontaneously hypertensive (SHR) and age-matched normotensive Wistar Kyoto rats (WKY). Electrical and mechanical activity were measured in patch-clamped myocytes in which intracellular Ca2+was allowed to change freely. In parallel experiments, intracellular Ca2+concentration was monitored in fura-2-AM preloaded cells using an image analysis system. Left ventricular myocytes from SHR showed a significantly greater membrane capacitance (an index of cell size), a prolonged duration of the action potential and a higher incidence of delayed afterdepolarizations (DADs) and associated aftercontractions, and of spontaneous activity. DADs were likely generated by intracellular Ca2+waves due to spontaneous and local Ca2+release from intracellular stores. These results demonstate that DADs, possibly related to spontaneous intracellular Ca2+waves, occur frequently in hypertrophied rat cardiomyocytes and may be a relevant arrhythmogenic mechanism.

Endothelin-1 (ET-1) is synthesized and released by parathyroid epithelium. The effects of endothelin isopeptides were studied in clonal bovine parathyroid endothelial (BPE) cells. BPE cells did not produce ET-1, but showed ET_A receptors (Kd = 0.1 ± 0.02 nM, mean ± SE). ET-1 (10−8-10−11 M) increased the intracellular calcium ion concentration ([Ca2+]i) in BPE cells, while endothelin-3 (ET-3) was ineffective. The increase in [Ca2+]i was less sustained in the absence of extracellular Ca2+ ions. Moreover ET-1 induced phospholipase C (PLC) activation, as demonstrated by the increase in inositol trisphosphate. Cell growth was not affected by ET-1 in a wide range of concentrations. The present findings demonstrate: 1) BPE cells possess ET_A receptors; 2) the peptide activates PLC and increases cytosolic [Ca2+]i via both a release of Ca2+ ions from intracellular calcium pool(s) and an influx of the cation from the extracellular milieu. A possible role of ET-1 as a paracrine factor in parathyroid tissue can be hypothesized.Copyright 1993, 1999 Academic Press

The effect of the intracerebroventricular (ICV) administration of taurine on amnesia, convulsions and death caused by hypoxia was investigated in mice. Taurine in doses of 80–100 µg/mouse impaired acquisition of a single trial in passive avoidance performance, but protected mice from the learning impairment induced by hypoxia. Neither ß-alanine nor saccarose were able to mimic the effects of taurine. Taurine had no effect on amnesia induced by scopolamine injected intraperitoneally. Taurine protected against the onset of convulsions induced by hypoxia, while convulsions induced by pentylenetetrazole (PTZ) and hyperbaric oxygen were unaffected. The survival time of mice exposed to hypoxia was significantly increased by taurine treatment. These data suggest that taurine may play a role as an antihypoxic agent.

An indirect three step ELISA has been assessed in order to detect the possible release of cytochrome c, a mitochondrial protein, from isolated and perfused guinea-pig heart. The ELISA described in this study is sufficiently sensitive and accurate to measure extracellular cytochrome c. the respiratory chain (1). Cytochrome c is a very well known protein and its structure has been determined in a great number of species including man (2,3). Being the only water-soluble component of the respiratory chain and for this reason and in view of its small molecular mass, it may be lost from the organelle under pathological conditions such as a mitochondria1 damage induced by ischemiareperfusion (4,5). We have set up an immunological method to quantitatively determine cytochrome c in heart effluent.

Lacidipine is a new 1,4-dihydropyridine derivative with potent and long-lasting antihypertensive activity. We used intracellular microelectrodes to characterize the electrophysiologic properties of lacidipine on different cardiac preparations. Lacidipine (10−8-10−6M) dose-dependently decreased contractility of driven sheep Purkinje fibers. For concentrations ≤ l0−7M, this effect was associated with a selective decrease of the plateau height. Higher concentrations (3 × 10−7and 10 −6M), however, affected action potential amplitude, overshoot, and maximum rate of depolarization. In the same range of concentrations, lacidipine did not affect normal automaticity of guinea-pig sinus node and sheep Purkinje fibers. Lacidipine (10−6M) consistently blocked barium-induced abnormal automaticity in Purkinje fibers and reduced the amplitude and Vmaxof the slow action potentials induced by histamine (10−5M) in guinea pig papillary muscle depolarized by potassium (22 mM). The effect of lacidipine on the slow inward current (Isi) was studied in shortened Purkinje fibers under voltage-clamp conditions. Lacidipine (10−7-10−6M) reduced the Isiwithout affecting the I-V relationship. None of the effects of lacidipine was reversed by 2-h washout. The results indicate that lacidipine has calcium-antagonistic properties in cardiac tissues. Its cardiac effects occur at concentrations 100 times higher than those active in the vascular smooth muscle. The lack of recovery of the lacidipine effects suggests that its interaction with the calcium channel may occur at an inner site of the cell membrane.

Background:Patients with advanced cirrhosis show defective platelet aggregation, which is dependent, at least in part, on intrinsic platelet abnormalities. The aim of this study was to evaluate the activating and inhibitory pathways of platelet signal transduction in cirrhotfc patients. Methods:Twelve cirrhotic patients and 12 control subjects participated in this study. Measurements were performed on washed platelets. Results:Thrombin-stimulated inositol 1,4,5-trisphosphate production was reduced fivefold, and the increase in cytosolic calcium concentration was significantly lower in platelets from cirrhotic patients following stimulation with thrombin, platelet activating factor, or U-46619. In addition, the activity of the platelet Na+/H+antiporter, evaluated after an acid load, was significantly lower in platelets from cirrhotic patients (0.90 ± 0.19 vs. 1.37 ± 0.16 Δ pH1/min, P= 0.07). Cirrhotic patients also showed a significantly increased basal intraplatelet content of both 5′-cyclic adenosine monophosphate (cAMP) (2724 ± 330 vs. 1561 ± 258 fmol/108platelets, P< 0.05) and 5′-cyclic guanosine monophosphate (cGMP) (217 ± 18 vs. 159 ± 29 fmol/108platelets, P< 0.05). Conclusions:Our results indicate that in platelets from cirrhotic patients, defective early signal transduction is associated with an increase in platelet cAMP and cGMP, thus revealing new mechanisms contributing to the defective platelet function in this disease.

The effect of the NSAIDs indomethacin, indoprofen, diclofenac and acetylsalicylic acid on the increase in guanosine 3′:5′‐cyclic monophosphate (cyclic GMP) induced by nitric oxide‐donor agents was tested in human whole platelets and in platelet crude homogenate.In whole platelets, indomethacin reduced the increase in cyclic GMP induced by the nitric oxide‐donors (NO‐donors) sodium nitroprusside (NaNP) and S‐nitroso‐N‐acetylpenicillamine (SNAP) in a dose‐dependent way, its IC50being 13.7 μmand 15.8 μm, respectively.Of the other cyclooxygenase inhibitors tested, only indoprofen reduced the increase in cyclic GMP induced by both NO‐donors in a dose‐dependent way (IC50=32.7 μm, NaNP and 25.0 μm, SNAP), while acetylsalicylic acid (up to 1000 μm) and diclofenac (up to 100 μm) were ineffective.However, in platelet crude homogenate neither indomethacin nor indoprofen reduced the cyclic GMP production.Indomethacin (10 μm), indoprofen (30 μm), diclofenac (100 μm) and acetylsalicylic acid (1000 μm) showed a comparable efficacy in inhibiting platelet thromboxane B2(TXB2) production, suggesting that the inhibitory effect of indomethacin and indoprofen on the increase in cyclic GMP induced by both NO‐donors was not mediated by inhibition of cyclooxygenase.In vitro, the NSAIDs analysed did not interfere with nitrite production of SNAP.The unhomogeneous behaviour of NSAIDs on the increase in cyclic GMP induced by NO‐donors in whole platelets may contribute to the different pharmacological and toxicological characteristics of the drugs, providing new knowledge on the effect of indomethacin and indoprofen.

The correlation between the binding of a ß-adrenoceptor antagonist, (-)[3H]-dihydroalprenolol (DHAP), and the adrenergic inhibition of histamine release by acetylcholine and by compound 48/80 was studied with isolated purified rat mast cells and in rat mast cell crude membrane fractions.

Taurine, homotaurine, GABA and muscimol, given intraventricularly to the conscious, unrestrained rabbit cause hypothermia and a reduction in skeletal muscle tone. Taurine and homotaurine desynchronize areas of the motor and limbic cortices, while GABA and muscimol synchronize both tracings and markedly depress the arousal reaction following external stimuli.

A study was conducted on a new acid peroxygen system based disinfectant (Virkon), in order to assess its in vitro efficacy. The chemical was tested on different bacteria (Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli), spores (Bacillus subtilis) and on the Hepatitis B surface antigen (HBsAg), and compared in its activity with phenol and glutaraldehyde (calculation of the ‘phenol coefficient’ and the ‘glutaraldehyde coefficient’). The constancy of speed of disinfection, the coefficient of concentration, the minimal inhibitory concentration (MIC) were also determined, and the destruction of the HBsAg antigenic activity was studied using an ELISA kit. The sporicidal efficacy of Virkon was assessed by cultivating spores in agar nutrient after contact with different dilutions of the disinfectant. The results of the tests showed that Virkon has a high concentration coefficient (mean value of k: 0.374/min) and a wide range of action. The low MIC demonstrates how little concentrations of Virkon can inactivate all studied bacteria. The disinfectant was also able to destroy the hepatitis B surface antigen, and it demonstrated good activity against spores, especially if used in physiologic solution. These characteristics, coupled with the absence of irritation or toxic effects on animals showed by other studies, make wide fields of application for the new disinfectant foreseeable.

The antinociceptive effect of (+/-)-3-alpha-tropanyl 2-(4-Cl-phenoxy)butyrate [corrected] (SM-21) (10-40 mg kg(-1) s.c., 10-30 mg kg(-1) i.p., 20-60 mg kg(-1) p.o., 3-20 mg kg(-1) i.v. and 5-20 microg per mouse i.c.v.) was examined in rodents and guinea pigs by using the hot-plate, abdominal constriction, tail-flick and paw-pressure tests. The antinociception produced by (+/-)-SM-21 was prevented by atropine, pirenzepine and hemicholinium-3 but not by quinpirole, R-(alpha)-methylhistamine, [1-[2(methylsufonyl)amino]ethyl]-4-piperidinyl]methyl-5-floro++ +-2-methoxy-1H-indole-3-carboxylate hydrochloride, N6-cyclopentyladenosine, 1-(2-methoxyphenyl)-4-[4-(2-phthalimido)butyl]piperazine hydrobromide, naloxone, 3-aminopropyl-diethoxy-methyl-phosphinic acid or reserpine. On the basis of the above data, it can be postulated that (+/-)-SM-21 exerted an antinociceptive effect mediated by a central potentiation of cholinergic transmission. Affinity profiles of (+/-)-SM-21 for muscarinic receptor subtypes, determined by functional studies (rabbit vas deferens for M1, guinea pig atrium for M2, guinea pig ileum for M3 and immature guinea pig uterus for putative M4) have shown a selectivity ratio M2/M1 of 4.6 that, although very low, might be responsible for the antinociception induced by (+/-)-SM-21 through an increase in ACh extracellular levels. In the antinociceptive dose range, (+/-)-SM-21 did not impair mouse performance evaluated by the rota-rod and hole-board tests.

In this work, we described the incidence and the characteristics of calcium waves in cardiomyocytes isolated from aged normotensive rats (Wistar Kyoto, WKY) and age-matched spontaneously hypertensive rats (SHR) using imaging analysis of fura-2-loaded left ventricular cardiomyocytes. Left ventricular cardiomyocytes were isolated by enzymatic digestion from hearts of 18-20 month old WKY and aged-matched SHR. Intracellular calcium concentration did not differ in either strain, whereas the incidence of cells presenting calcium waves was greater in cardiomyocytes isolated from SHR. Moreover, cardiomyocytes isolated from SHR were significantly longer than those isolated from WKY. The calcium wave frequency was lower in SHR cardiomyocytes, while the velocity of the calcium waves was similar in both strains. Our results suggest that alterations in the calcium handling of SHR may contribute to the increased incidence of arrhythmias described in SHR hearts.

The amino-oxidase and collagen content of dermal tissue was evaluated in 10 patients with severe idiopathic scoliosis and in a control group of 7 patients with poliomyelitic scoliosis, that were to undergo surgical correction of their skeletal deformity. A greater dermal content of neutral salt soluble collagen was found in the patients with idiopathic scoliosis, compared with the control group. Statistically the difference was highly significant. Mono-amino-oxidase activity, however, was found to be significantly decreased in dermal extracts obtained from patients affected by idiopathic scoliosis in comparison with controls. The involvement of mono-amino-oxidase in the crosslinking of collagen and the possible classification of idiopathic scoliosis as a systemic disease of connective tissue are discussed.

We studied the interaction between the synthetic prostacyclin analog iloprost and the aggregating agent a-thrombin by measuring the internal calcium ion concentration ([Ca2+]i) of human fura-2-loaded platelets. Iloprost (0.003–100 µg/l) did not modify the resting calcium level; when added 2 minutes before exposure of the platelets to a submaximally active concentration of a-thrombin (10 U/l), iloprost dose-dependently antagonized the increase in [Ca2+]i. To evaluate if iloprost retained this antagonistic effect even after a prolonged contact, which is well known to cause a “desensitization” phenomenon, platelets were prein-cubated with iloprost (35 µg/l) for 3 hours. After washout, the effect of newly added iloprost (0.01–100 µg/l) on the a-thrombin-induced increase in [Ca2+]i was tested. Iloprost was still able to antagonize the increase in [Ca2+]i induced by a-thrombin in “desensitized” platelets; however, the dose-inhibitory response curve was significantly shifted to the right when compared with that obtained in control platelets (i.e., platelets preincubated for 3 hours with iloprost's solvent), and the resulting IC50 was significantly higher: 1.78 versus 0.2 µg/l (p<0.001). Since the maximal inhibitory effect of iloprost could also be reached under these experimental conditions, we conclude that iloprost retains its ability to antagonize the increase in [Ca2+]i induced by a-thrombin in desensitized platelets.

Platelet-derived growth factor (PDGF) is a key mitogen for hepatic stellate cells (HSC) and has been shown to be implicated in liver tissue repair and fibrogenesis. In this study the relationship between PDGF-induced intracellular Ca2+ concentration ([Ca2+]i) increase and mitogenesis in cultured human HSC was evaluated. In high-density cell cultures (80-90% subconfluence), PDGF induced a significant increase in [Ca2+]i, characterized by a short-lasting peak phase, which was followed by a long-lasting plateau phase. The plateau phase was abolished in the absence of extracellular Ca2+. However, in low-density cell cultures (30-40% subconfluence), the plateau phase was absent or markedly less pronounced. In parallel sets of experiments, PDGF was significantly less effective in inducing mitogenesis in low-density cell cultures than in high-density cell cultures and was totally ineffective in the absence of extracellular Ca2+. These results suggest that 1) spatial and time dynamics of PDGF-induced [Ca2+]i increase are dependent on cell density and 2) PDGF-induced mitogenesis requires extracellular Ca2+ influx.

1. The effects of noradrenaline and isoprenaline on the repolarization phase of the action potential have been studied in the Purkinje fibres of sheep heart, electrically driven at constant rates.

1. The regional distribution (auricles, ventricles and septum) of histamine and its release during anaphylaxis were studied in isolated perfused guinea‐pig hearts.

Taurine, given intracerebroventricularly to the conscious unrestrained rabbit, causes hypothermia and a reduction in skeletal muscle tone. Evidence has been produced that the latter effect is of a central, supraspinal origin.

The article discusses the history of the relationship between business consolidation and economic competition in the U.S. from the 1860s through the early 21st century. An overview of various industries that became dominated by a few big companies, including the steel and technology industries, is provided.