Slow inward current in single cells isolated from adult human ventricles

Characteristics of the slow inward current (I _si) in human ventricular myocytes isolated from septal specimens obtained in patients undergoing corrective cardiac surgery were studied using the whole-cell clamp method. A first series of experiments was performed under normal standard superfusion. Clamping from –60 mV evoked an inward current with a threshold at about –35 mV, a maximum around +10 mV and an apparent reversal potential at about +55 mV. No overlapping transient or background outward currents were detected in the –60 to +30 mV potential range, but time-dependent and steady-state outward currents were elicited at potentials above +30 mV. An overlap of steady-state activation and inactivation curves was present between –30 and +10 mV and a slight relief from inactivation was observed for voltages positive to +10mV. The time course of inactivation consisted of fast and slow phases with time constants differing by a factor of eight. Slow time constants of inactivation were shorter at potentials that elicited larger I _si, and longer at potentials inducing smaller I _si. Recovery from inactivation evolved slowly with 100% reactivation occurring in about 4000 ms. Switching the holding potential from –60 to –40 mV led to a reversible decline of I _si without any change of the decay time constants. I _si was significantly increased by 0.1 M isoproterenol. Total or partial inhibition by inorganic (2 mM Mn²⁺, 3 mM Co²⁺, 1 mM Cd²⁺) and organic (1 M methoxyverapamil, 5 M diltiazem) calcium antagonists did not unmask any transient outward current. However, a consistent increase of I _si was reversibly observed with 3 mM 4-aminopyridine while using standard solutions. A second series of experiments carried out with K⁺- and Na⁺-free solutions did not demonstrate any significant change from data observed with standard solutions except a reduction of outward currents at steps above +30 mV and alteration of inactivation kinetics. In this experimental setting, 4-aminopyridine also increased I _si but to a lesser degree. We conclude that I _si, as compared to the outward currents, is dominant in the diseased human ventricular cells we have studied.     

IL-4–BATF signaling directly modulates IL-9 producing mucosal mast cell (MMC9) function in experimental food allergy

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Micropuncture studies on the filtration rate of single superficial and juxtamedullary glomeruli in the rat kidney

Summary Single nephron filtration rates of superficial and juxtamedullary nephrons were determined in high and low sodium rats. Single nephron GFR was calculated from TF/P inulin and tubular flow rate in superficial nephrons and single juxtamedullary GFR from corresponding data in long loops of Henle. In low sodium rats superficial nephron GFR was 23.5±6.4 (SD)×10^–6 ml/min×g KW, juxtamedullary nephron GFR was 58.2±13.6 and total kidney GFR (C _In) was 0.94±0.16 ml/min×g KW. Using these single nephron values, total kidney GFR and a total number of 30,000 glomeruli per kidney, the number of superficial and juxtamedullary glomeruli was calculated to be 23,267 and 6,733, respectively. During high sodium diet superficial nephron GFR increased to 38.1±11.3 and single juxtamedullary GFR decreased to 16.5±6.6, total kidney GFR increasing to 1.01±0.24. Calculation again revealed the same distribution of the two nephron types. End-proximal TF/P inulin in superficial nephrons was 2.36±0.36 in low sodium and 2.31±0.28 in high sodium rats. Loops of Henle TF/P inulin and intratubular flow rate were inversely related: the highest TF/P inulin values and lowest intratubular flow rates were found in the descending limb. These data quantify the distribution of superficial and juxtamedullary nephrons on a functional basis and suggest a mechanism by which the kidney adjusts sodium excretion by altering the contribution of each nephron type to total kidney GFR.Supported by the Deutsche Forschungsgemeinschaft and the U.S. Department of the Army, through its European Research Office.     

Stimulation of cranial vessels excites nociceptive neurones in several thalamic nuclei of the cat

Summary Extracellular recordings were made in the thalamus of cats anaesthetized with chloralose and urethane following electrical, mechanical and chemical stimulation of the superior sagittal sinus or middle meningeal artery. Facial receptive fields were looked for using electrical and mechanical stimuli. The locations of fifty-six cells were verified histologically. Twenty six cells were located in the ventroposteromedial nucleus (VPM) and six in its ventral periphery (VPMvp). All units in VPM had facial receptive fields, usually involving the first trigeminal division. Cells with nociceptive receptive fields or responding to the craniovascular application of bradykinin were often found in the periphery or “shell” region of VPM. Other craniovascular nociceptive cells were found in VPMvp, in the posterior group and in the intralaminar complex. This study shows that craniovascular afferents in the cat project to several thalamic nuclei and implicate VPM especially in craniovascular nociception.     

Functional study of the different haplotypes cDNA in the coding region of CⅡTA gene

Objective To study the function of 4 different haplotypes cDNA which are constructed by two non-homonymy single nueleotide polymorphism (SNP) sites C19170G (Leu45Val) and C30799G (Ala500Gly) in the coding region of human CⅡTA gene. Methods HeLa cells were transfeeted with eu-karyotic expression vectors containing four different haplotypes cDNA. C Ⅱ TA mRNA and HLA classⅡanti-gen (HLA-DR, DP, DQ) were respectively detected by RT-PCR and indirect cell immunofluoreseence tech-nique in the untransfected and transfeeted with four eukaryotic expression vectors and empty vectors HeLa cells. The quantity of HLA classⅡ antigen were analyzed by flow eytometry. Results No expression of CⅡTA mRNA and HLA class Ⅱ antigen were observed on original HeLa cells and empty vector transfected cells. CⅡTA mRNA expression was emerged, and the expression of HLA class Ⅱ antigen were observed in the HeLa cells transfected with eukaryotic expression vectors containing four different haplotypes cDNA. And there were not significantly different with the levels of HLA class Ⅱ antigen expression among HeLa cells transfected with eukaryotic expression vectors containing four different haplotypes cDNA ( P > 0.05 ). Con-dusion The SNP of Chinese at the sites C19170G(Leu45Val) and C30799G(Ala500Gly) in the coding site of C Ⅱ TA gene did not influence capability of CⅡTA trans-aetivating HLA class Ⅱgene expression.     

Processing of binaural stimuli by cat superior olivary complex neurons

Summary A method was developed to record stereotactically from the cat Superior Olivary Complex (SOC) using glass micropipettes. Sound stimulation was given through a closed system that permitted independent variation of interaural time (time) and intensity (int) differences. The most common binaural units found (n = 34) were ipsilateral excitatory, contralateral inhibitory (EI¹), cells of the Lateral Superior Olive (LSO). Some Medial Superior Olive (MSO) cells and presumed MSO ascending afferents were found but, as noted by other authors, we found it difficult to obtain single unit recordings from this nucleus. The LSO EI cells were mostly sensitive to higher frequencies and showed Peristimulus Time Histograms (PSTHs) consisting of a sharp On response followed by a plateau when stimulated with Best Frequency (BF) tone bursts or noise bursts. This On response was sensitive to time and int such that ipsilateral time lead or intensity increase resulted in a stronger response. The response reached a minimum around zero time or int. No sharp peaks or dips were seen in the physiological range needed for localization, instead the response increased with increasing ipsilateral lead or intensity to the maximum values tested (2048 s time, 30 dB int). In the physiological range the time and int response were complementary (both increasing response as ipsilaterality was increased). Provided enough sound energy in the unit's sensitive region was present, the same time curves were produced when BF tone bursts, masked tone bursts, sharp onset tone bursts or noise bursts were used. Changing the time of the carrier of the tone burst alone had no effect (except for one cell with a BF of 560 Hz), only the relative time of arrival of the stimulus envelope seemed to be important. In contrast to these LSO EI cells MSO-type units showed EI or EE predominantly low frequency phase-locked responses. When stimulated with interaurally phase shifted (pha) BF tones the unit response was a cyclic function of pha. Some cells (all that were tested, n = 6 including the 560 Hz LSO EI cell) showed these cyclic responses when stimulated with noise bursts or non-BF tones. However, these characteristic delays were not necessarily in the physiological range, i.e. we could find no evidence that these units were responding to time/pha values corresponding to a particular sound source direction. In both LSO and MSO it seems that integration of information higher in the CNS from a population of these cells is necessary for unambiguous coding of sound source direction. The time intensity trading ratios measured in two MSO type cells (11 and 26 /dB) were clearly different to those measured in LSO EI cells (n = 6, 99–550 s/dB). These ratios correspond approximately to those of the psychophysical time and int images measured by Hafter and Jeffress (1968).Supported by the Deutsche Forschungsgemeinschaft (SFB 45)     

Adaptive changes of juxtamedullary glomerular filtration in the remnant kidney

The participation of surviving juxtamedullary nephrons in the adaptive changes of glomerular filtration that occur in response to loss of functioning nephron mass was examined by direct micropuncture of the rat renal papilla. The solitary remnant kidney (RK) in rats with an 85% reduction of renal mass demonstrated strikingly elevated values for single nephron glomerular filtration rate (SNGFR) in both superficial (46.1±3.2 nl/min) and juxtamedullary (73.5±6.1 nl/min) nephrons in comparison to respective values observed in normal hydrophenic rats (superficial SNGFR=15.0±1.9nl/min,P<0.001, and juxtamedullary SNGFR=30.2±3.2 nl/min,P<0.001). In RK rats, the proximal portions of both superficial and juxtamedullary nephrons exhibited a marked increase in absolute fluid reabsorption as well as a markedly enhanced delivery of fluid to more distal portions of the nephron. These observations indicate that similar, not preferential, functional adaptations in glomerular filtration occur concommitantly in both superficial and juxtamedullary nephrons consequent to reduction of renal mass.     

Chronopharmacokinetics of beta-receptor blocking drugs of different lipophilicity (propranolol,metoprolol, sotalol,atenolol) in plasma and tissues after single and multiple dosing in the rat

Summary Comparative pharmacokinetic studies with the -receptor blocking drugs propranolol, metoprolol, sotalol and atenolol, differing greatly in lipophilicity, and their main route of elimination were performed in light-dark-synchronized rats after equimolar single (6 moles/kg) or multiple (6x6 moles/kg) drug application. Drug concentrations were determined in plasma and various target organs of the drugs, e.g. heart, muscle, lung and brain, after drug application in the light period (L) and dark period (D), respectively. After single drug administration pharmacokinetic parameters of all drugs depended on the L and D conditions. Elimination half-lives in plasma and organs were shorter during D than during L. No L-D-differences were found in initial drug concentrations of the hydrophilic drugs sotalol and atenolol. In contrast, C₀-values of the lipophilic propranolol in highly perfused organs (muscle, lung, brain) and of metoprolol in muscle tissue were significantly higher in D than in L. No obvious temporal dependency was found in other pharmacokinetic parameters (AUC, plasma clearance,V _d) with the exception inV _d of propranolol. Due to the different physico-chemical properties of the compounds inter-drug-differences in pharmacokinetic parameters including drug accumulation into lung and brain tissue were observed. Multiple drug dosing abolished the circadian-phase-dependency in the elimination half-lives of the drugs due to an increase in D. Only for the highly lipophilic propranolol half-lives in highly perfused organs were still shorter in D than in L. It is concluded that L-D-differences in drug half-lives after single dose application are mainly due to circadian variations in drug elimination with a higher hepatic (propranolol, metoprolol) or renal (sotalol, atenolol) elimination in the activity period of rats during D. Additional studies with propranolol on heart rate of conscious rats revealed that a maximum in -receptor blockade was achieved at 10 moles/kg in L but not in D. Thus, it is assumed that abolition of circadian-phase-dependency in half-lives after 6x6 moles/kg of the drugs may be due to the longer lasting and more pronounced -receptor blockade after multiple drug dosing over a period of several hours in D. Thereby, liver-flow-dependent elimination of propranolol and metoprolol and renal elimination of sotalol and atenolol is reduced to base-line levels found in L.Parts of this work were presented at the 22nd Spring Meeting (Lemmer 1981) and at the Joint Meeting (Lemmer et al. 1983a) of the German Pharmacological Society     

以单病种过程质量管理促进临床诊疗同质化

单病种质量管理丰富了过程质量管理的内涵,是提升医疗质量管理水平的重要手段。利用单病种过程质量管理实现医疗质量管理同质化,需要从临床诊疗工作同质化、数据同质化、医疗质量评价同质化三方面发力,引导医疗机构运用单病种质量监测信息项开展国家、省级和院内、院际间的质量比较,从而推进临床诊疗过程质量管理同质化。