Membrane attack complex of complement and 20 kDa homologous restriction factor (CD59) in myocardial infarction

In order to investigate the mechanism of deposition of the complement membrane attack complex (MAC) in cardiomyocytes in areas of human myocardial infarction, the 20 kDA homologous restriction factor of complement (HRF20; CD59) and complement components (C1q, C3d and MAC) were analysed immunohistochemically using specific antibodies. Myocardial tissues obtained at autopsy from nine patients who died of acute myocardial infarction were fixed in acetone and embedded in paraffin. The ages of the infarcts ranged from about 3.5 h to 12 days. In cases of myocardial infarction of 20 h or less, MAC deposition was shown in the infarcted cardiomyocytes without loss of HRF20. Where the duration was 4 days or more, the cardiomyocytes with MAC deposition in the infarcted areas also showed complete loss of HRF20. Outside the infarcts, HRF20 in the cardiomyocytes was well preserved without MAC deposition. The present study suggests that the initial MAC deposition in dead cardiomyocytes can occur as a result of degradation of plasma-membrane by a mechanism independent of complement-mediated injury to the membrane. Loss of HRF20 from dead cardiomyocytes may not be the initial cause of MAC deposition, but may accelerate the deposition process of MAC in later stages of infarction.     

Differential contribution of the FcRγ chain to the surface expression of the T cell receptor among T cells localized in epithelia: analysis of FcRγ-deficient mice

The function of the Fc receptors γ chain (FcR_γ) for the expression of the T cell receptor (TCR) complex and for T cell development, especially for T cells localized in epithelia, was investigated by analyzing FcR_γ-deficient mice. In wildtype mice, CD8αα⁺β^?TCRαβ⁺ T cells of intestinal intraepithelial lymphocytes (i-IEL) utilized CD3ζ homodimers and ζ-FcR_γ heterodimers, whereas CD8α α⁺β^?TCR_γδ⁺ i-IEL used ζ-FcR_γ and FcR_γ homodimers in the TCR complex. On the other hand, these T cells in FcR_γ-deficient mice contained only ζ homodimers. The surface expression of the TCR complex was reduced in CD8αα⁺β^?i-IEL and dendritic epidermal T cells (DETC) in these mice, whereas the development of these T cells was normal. The degree of reduction appeared to depend on the expression level of FcR_γ. In contrast to these populations, TCR_γδ⁺ intraepithelial T cells in reproductive organs (r-IEL) were dramatically decreased, suggesting that the development of r-IEL is FcR_γ-dependent, probably due to the predominant usage of FcR_γ homodimers in the TCR complex. These results indicate that the FcR_γ chain contributes differently to the TCR expression and to the development of T cells localized in epithelia.     

Mixed connective tissue disease with fatal pulmonary hypertension and a review of literature

Summary The paper presents an autopsy case of mixed connective tissue disease (MCTD) with pulmonary hypertension (PH) and a review of literature. A 33-year-old woman with Raynaud's phenomenon and dyspnea of one year duration was diagnosed as having MCTD on the basis of a higher titer (1:163,840) of serum antibodies to the ribonucleoprotein (RNP). Cardiac catheterization showed complicating PH, confirmed an autopsy by the findings of concentric intimal cellular proliferation and typical plexiform lesions in the small arteries and arterioles of the lung, suggesting primary PH. Fatal PH with MCTD has been reported only 6 cases in literature including our case. All were young females, with histopathological findings consistent with plexogenic pulmonary arteriopathy in 5 cases and with recurrent pulmonary thromboembolism in the other. The aetiology of PH is still unknown, but it may be due to vasoconstriction evoked by the hyper-reactivity of the vessels.     

Sensitization to mechanical stimulation by inflammatory mediators and by mild burn in canine visceral nociceptors in vitro

Hyperalgesia to mechanical stimulation and heat is commonly observed in inflamed conditions. Although sensitization to heat is well documented and its mechanism has also been well studied, it remains unclear whether and how nociceptors are sensitized to mechanical stimulation. Therefore we conducted in vitro investigation of which inflammatory mediators (bradykinin, histamine, prostaglandin E2, and protons) sensitize nociceptors to suprathreshold mechanical stimulation and at what concentrations. In addition, we studied the effects of possible second messengers for these mediators downstream of the receptors and also the effects of mild burn. Single polymodal receptor activities were recorded in canine testis-spermatic nerve preparations excised from deeply anesthetized dogs. Mechanical stimulation was applied to the identified receptive field for 10 s with a servo-controlled mechanical stimulator. Bradykinin at 0.001 microM induced neither excitation nor facilitation of the mechanical response; however, it facilitated the mechanical response at 0.01 microM and higher, levels at which significant excitation was also induced by bradykinin alone. Histamine excited the nociceptor and sensitized it to mechanical stimulation at 10 microM and higher. PG E(2) also sensitized the mechanical response, but starting at 1 microM, without inducing excitation by itself. The effects of two possible intracellular messengers for these mediators were studied using forskolin (10 microM), which increases intracellular cAMP, and a protein-kinase-C-stimulating phorbol ester, phorbol 12,13-dibutyrate (0.1 microM). Both substances reversibly facilitated the mechanical response of testicular polymodal receptors. In contrast, low-pH solution (pH: 6.6-4.5) seldom induced excitation and failed to facilitate the mechanical response. After 55 degrees C, 30-s heat stimulation, testicular polymodal receptors were sensitized to mechanical stimulation. These results demonstrated that inflammatory mediators and burn sensitized nociceptor responses to mechanical stimulation and provide support for the idea that peripheral nociceptor sensitization is a mechanism involved in hyperalgesia to mechanical stimulation in inflamed tissues.     

Successful Single-Lung Transplant for the Dominant Side: A Case Report

Although single-lung transplant on the side with better lung function is challenging in patients with significantly asymmetrical lung function between the right and left sides, it sometimes can be a realistic option because of the recipient's condition and from the viewpoint of organ sharing. We report our experience with a successful case of single-lung transplant on the side with a pulmonary perfusion ratio of 89%. The transplant was performed with the patient under central venoarterial extracorporeal membrane oxygenation through a clamshell incision, and the patient had an acceptable short- and long-term outcome with a remarkable improvement of lung function.     

The geographic distribution of un-immunized children in Ontario,Canada: Hotspot detection using Bayesian spatial analysis

BackgroundIn Ontario, Canada, little is currently known about the extent to which un-immunized children may cluster geographically. Our objectives were to: describe the geographic distribution of fully un-immunized children; identify geographic clusters (hotspots) of un-immunized children; and to characterize the contribution of spatial effects and covariates on hotspots, where found.MethodsOur analytic cohort consisted of Ontario students aged 7–17 years in the 2016–2017 school year. We defined students as un-immunized if they had zero doses of any vaccine and a non-medical exemption recorded in Ontario’s registry. We calculated unadjusted proportions of un-immunized students by Census Subdivision (CSD) and then used a sequential approach to identify hotspots starting first with hotspot identification at the CSD level and then probed identified hotspots further by Dissemination Area (DA) and including covariates. Hotspots were identified using the Besag-York-Mollie Bayesian spatial model and were defined as areas with >95% probability of having two times the proportion of un-immunized students, relative to the province overall.ResultsWe identified 15,208 (0.94%) un-immunized children within our cohort consisting of more than 1.61 million students. Unadjusted proportions of un-immunized students varied greatly by geography, ranging from 0% to 21.5% by CSD. We identified 16 hotspot CSDs which clustered in five distinct areas, all of which were located in southern Ontario. The contribution of covariates and spatial effects on the risk of having un-immunized students varied greatly across hotspot areas.ConclusionsAlthough the provincial proportion (0.94%) of un-immunized students is small, geographical clustering of such students is evident in Ontario and in some areas presents an important risk for future outbreaks. Further qualitative work within these hotspot areas would be a helpful next step to better characterize the factors associated with vaccine refusal in these communities.     

Contractile force and resting tension in the presence of halothane and increased extracellular potassium or decreased extracellular pH in isolated guinea pig atria

To gain a better understanding of the direct actions of halothane on myocardial function in ischaemia, we studied the effects of increasing extracellular potassium concentration and decreasing extracellular pH (acidosis), alone or in combination with halothane, on the contractile force and resting tension in isolated atria. Guinea pig left atria were superfused with Tyrode’s solution and stimulated at 1 Hz. Isometric contractile force and resting tension were measured using a force displacement transducer. Perfusate potassium concentrations were increased from 5.4 mmol · L⁻¹ to either 8.1 mmol · L⁻¹ or 10.8 mmol · L⁻¹ by adding KCl to the standard Tyrode’s solution, and its pH was decreased from 7.4 to either 7.0 or 6.5 by decreasing bicarbonate. In standard Tyrode’s solution (potassium 5.4 mmol · L⁻¹, pH 7.4), halothane 0.5–2% reduced contractile force in a dose-dependent manner (P < 0.05); the effective concentration of halothane for 50% inhibition of contractile force (IC₅₀) was 1.3%. Both increasing extracellular potassium and decreasing extracellular pH decreased the contractile force in a potassium-or pH-dependent fashion. The negative inotropism of halothane (1%) was not altered by increasing potassium concentrations, whereas 1% halothane caused a greater decrease in contractile force at pH 6.5 than at pH 7.4. Halothane (1%) enhanced the acidosis (pH 6.5)-induced increases in resting tension. Arrhythmias were produced in one of eight preparations during acidosis, while four of eight preparations demonstrated arrhythmias during acidosis in the presence of halothane. These data suggest that acidosis and halothane may have a synergistic interaction on the contractile force and resting tension of the atria. The increase in resting tension observed during acidosis/ halothane conditions suggests than an increase in cytosolic calcium is associated with these synergistic interactions between acidosis and halothane. Pour mieux comprendre l’action direct de l’halothane sur la fonction myocardique pendant l’ischémie, nous avons étudié les effets de l’augmentation du potassium extracellulaire et de la diminution du pH extracellulaire (acidose), seuls ou en association avec l’halothane, sur la force contractile et la tension de repos d’oreillettes isolées. Des oreillettes gauches de cobaye furent perfusées avec une solution de Tyrode et stimulées à 1 Hz. La force contractile isométrique et la tension de repos ont été mesurées avec un transducteur de force de déplacement. Les concentrations de potassium perfusées ont été augmentées de 5,4 mmol · L⁻¹ à 8,1 mmol · L⁻¹ ou à 10,8 mmol · L⁻¹ par l’ajout de KCl à la solution standard de Tyrode, et son pH abaissé de 7,4 à 7,0 ou 6,5 par baisse des bicarbonates. Avec la solution standard de Tyrode (potassium 5,4 mmol · L⁻¹, pH 7,4), l’halothane (0.5–2%) diminue la force contractile proportionnellement à la dose (P < 0,05); la concentration efficace d’halothane requise pour produire une inhibition de 50% de la force contractile (IC_5O) a été de 1,3%. L’augmentation du potassium extracellulaire et la diminution du pH extracellulaire réduisent toutes les deux la force contractile proportionnellement au potassium ou au pH. L’inotropisme négatif de l’halothane (1%) n’est pas modifié par l’augmentation de la concentration de potassium alors que l’halothane produit une diminution plus importante de la force contractile à un pH de 6,5 que de 7,4. L’halothane (1%) exagère l’augmentation de la tension de repos induite par l’acidose (pH 6,5). Des arrythmies sont apparues sur une des huit préparations pendant l’acidose en présence d’halothane. Ces données suggèrent que l’acidose et l’halothane pourraient avoir une activité synergique sur le force contractile et la tension de repos des oreillettes. L’augmentation de la tension de repos observée pendant l’acidose combinée à l’halothane suggère l’association d’une augmentation du calcium cytosolique avec des interactions synergiques entre l’acidose et l’halothane.     

Caffeine enhances the stimulant effect of methamphetamine,but may not affect induction of methamphetamine sensitization of ambulation in mice

Methamphetamine (MAP: 1 and 2 mg/kg SC) and caffeine (CAF: 1, 3, 10 and 30 mg/kg SC) dose-dependently increased ambulation in mice. Repeated administration (5 times at 3 to 4-day intervals) of MAP, but not CAF, induced sensitization to its effect. Furthermore, the mice repeatedly receiving CAF showed no significant change in the sensitivity to MAP. Combined administration of MAP with CAF increased the effect. In the combinations of MAP (1 mg/kg) with CAF (3, 10 and 30 mg/kg), and MAP (2 mg/kg) with CAF (1 and 3 mg/kg), the effect was enhanced by the repeated administration. However, MAP sensitization was not modified by the combination with CAF in the repeated administration schedule, except in the combination of MAP (1 mg/kg) with CAF (30 mg/kg). The ambulation-increasing effects of MAP (1 mg/kg), CAF (10 mg/kg) and combination of MAP with CAF were almost equivalently inhibited by SCH 23390 (0.01 and 0.1 mg/kg SC) and YM-09151-2 (0.01 and 0.1 mg/kg SC). However, the inhibitory effects of apomorphine (0.05 mg/kg SC) andN ⁶-(L-phenylisopropyl)-adenosine (0.1 and 0.2 mg/kg SC) were stronger for CAF than for MAP and the combination, and those of -methyl-p-tyrosine (200 mg/kg IP, 4 h before) and reserpine (1 mg/kg SC, 4 h before) were stronger for MAP and CAF alone than for the combination. The present results suggest that, although the combination of MAP and CAF enhances the ambulation-increasing effect through an interaction at dopaminergic system, CAF may not significantly modify the induction of MAP sensitization in mice.