Decreased anti-donor major histocompatibility complex class I and increased class II alloantibody response in allograft tolerance in adult rats

Permanent tolerance to allografts can be induced in adult rats by donor-specific transfusions (DST) prior to transplantation. We have previously reported, in a model of heart allograft, the presence of a heavy leukocyte infiltrate, in the allograft which displayed a strong allospecific cytotoxicity when tested in vitro against donor cells, and a strong accumulation of mRNA for granzyme A and perforin in vivo. In contrast, there was a major decrease in the accumulation of mRNA for interleukin-2 and interferon-γ. These results suggested that the DST-induced tolerance was associated with a decrease in type-1 T helper (Th1) cell function. The major role of preformed antibodies in xeno and allorejection is clearly established. Nevertheless, the consequences of alloantibody production in acute rejection and tolerance induction remains to be elucidated. We here analyze the alloantibody response in rejecting and DST-treated recipients. We show that, after transplantation, tolerant recipients, in contrast to rejecting ones, mount a low IgM alloresponse that switches to low IgG production. Detailed analysis of IgG alloantibodies in DST-treated recipients revealed that their production decrease was not equally distributed. Whereas rejecting animals mounted a strong anti-class I and II IgG alloantibody response, DST-treated recipients produced anti-class II and low titers of anti-class I IgG alloantibodies. Furthermore, among IgG subclasses, tolerant recipients predominantly produced IgG2a, a profile which, in the rat, is compatible with a Th2-controlled response. Finally, the passive transfer of immune serum from rejecting animals to DST-treated recipients could abrogate the tolerance. We suggest that the absence of anti-class I alloantibodies combined with preserved and/or increased anti-class II production plays a major role in graft tolerance in this model. These results reinforced the role of alloantibodies in rejection and in induction of tolerance.     

Mechanisms by which acute phase proteins enhance development of liver fibrosis: effects on collagenase and prolyl-4-hydroxylase activity in the rat liver

Previous experiments showed that the presence of high levels of acute phase reactants (APR) enhance CCl4-induced liver fibrosis in the rat. A high correlation was found between the degree of fibrosis and alpha 2-macroglobulin of the rat (alpha 2-macrofetoprotein, alpha M-FP) used for monitoring the acute phase response. This acute phase reaction was provoked by epinephrine just before CCl4 treatment was started. In the present study we analyzed the effect of APR by repeating these experiments and estimating liver neutral collagenase with a synthetic substrate and endogenous collagen as a substrate, and liver prolyl-4-hydroxylase. A strong depression of liver collagenase activity was found in rats with a preceding acute phase reaction contrary to the rats that underwent CCl4 treatment only. A high level of alpha M-FP correlated negatively with collagenase activity. Also in vitro alpha M-FP proved to inhibit collagenase activity. Prolyl-4-hydroxylase was increased in the rats during acute phase reaction and correlated highly and positively with alpha M-FP, haptoglobin, and ceruloplasmin. Thus high levels of APR promote development of CCl4-induced fibrosis, partly by anticollagenase activity and partly because of enhancement of prolyl-4-hydroxylase activity. The latter phenomenon can also be explained by the presence of APR, but this has to be proved.     

Prevalence of tooth agenesis correlated with jaw relationship and dental crowding

Two groups of patients were selected from the State University Dental School in Ghent--an experimental group with tooth agenesis and a control group with complete dentitions. Skeletal anomalies were diagnosed by means of lateral cephalograms according to the Sassouni analysis. The amount of crowding was measured on standardized photographs by Little's Irregularity Index. The prevalence of Class I skeletal relationship appeared to be significantly higher in the agenesis group than in the control group. Skeletal deep- and normal-bite cases occurred more often in patients with hypodontia than in the control group. As far as crowding was concerned, it was less pronounced in the hypodontia group (lateral segments) than in the control group. This conclusion held true only when the "amount" of crowding was not taken into account.     

Inhibitory dopamine receptors on sympathetic neurons innervating the cardiovascular system of the pithed rat

Summary Additional experimental evidence was obtained for an inhibitory function of prejunctional ₂-adrenoceptors and/or dopamine receptors located on noradrenergic neurons innervating the heart and resistance vessels of the pithed normotensive rat. Mixed ₂-adrenoceptor receptor agonists, differing in selectivity towards either receptor type, i.e. N,N-di-n-propyldopamine (DPDA), 2-N, N-di-n-propylamino-6, 7-dihydroxy-1,2,3,4-tetrahydronaphthalene (DP-6,7-ADTN), B-HT 920 and B-HT 933 (azepexole) were used.In pithed normotensive rats, DPDA (30 and 100 g/kg/min) dose-dependently inhibited the electrical stimulation-induced increase in diastolic pressure, but did not significantly affect the stimulation-evoked increase in heart rate. The inhibition exerted by DPDA was blocked by haloperidol and sulpiride (0.3 mg/kg of each), but not by yohimbine (1 mg/kg), indicating the involvement of dopamine receptors. In this respect, sulpiride and haloperidol were found approximately equipotent.DP-6,7-ADTN (10 and 30 g/kg/min) impaired both tachycardic and vasoconstrictor responses in a dose-dependent manner. Sulpiride (0.3 mg/kg) only partially restored the DP-6,7-ADTN-depressed stimulation-evoked increase in diastolic pressure, whereas yohimbine (1 mg/kg) alone was without effect. The combination of both antagonists completely prevented the inhibition caused by DP-6,7-ADTN. On the other hand, yohimbine (1 mg/kg), but not sulpiride (0.3 mg/kg), selectively antagonized the DP-6,7-ADTN-induced inhibition of stimulation-evoked tachycardia.B-HT 920 (1, 3 and 10 g/kg/min) very effectively reduced the increase in diastolic pressure and heart rate caused by electrical stimulation. Inhibitory dopamine as well as ₂-adrenoceptors participated in the vascular effects of B-HT 920, whereas ₂-adrenoceptors were only involved in the cardioinhibitory response to this agonist.B-HT 933 (0.6 and 1 mg/kg/min) dose-dependently reduced the stimulation-evoked increase in arterial pressure through selective stimulation of inhibitory ₂-adrenoceptors, dopamine receptors not taking a part.The results confirm and extend the observations that in addition to ₂-adrenoceptors inhibitory dopamine receptors are located on the sympathetic neurons connected with the arterial vasculature of the pithed normotensive rat. The sympathetic nerves innervating the rat heart do not contain inhibitory dopamine receptors; their activity only can be modulated by ₂-adrenoceptor stimulation. In the pithed normotensive rat, activation of prejunctionally located ₂-adrenoceptors more effectively inhibits the sympathetic activity directed to the heart than that to the resistance vessels.     

Patient Satisfaction with AbobotulinumtoxinA for Aesthetic Use in the Upper Face: A Systematic Literature Review and Post-hoc Analysis of the APPEAL Study

BACKGROUND: AbobotulinumtoxinA (AboBoNT-A; Dysport^®; Ipsen, Boulogne-Billancourt, France/Azzalure^®; Galderma, Lausanne, Switzerland) is a botulinum neurotoxin type A approved for aesthetic use in the treatment of glabellar lines in adult patients under 65 years in Europe, the United States, and other countries. OBJECTIVE: We sought to analyze current literature on patient satisfaction with aboBoNT-A for upper facial aesthetic indications. METHODS: A systematic review of literature databases (PubMed/MEDLINE, Embase, the Cochrane Library, and Google Scholar) was performed to identify English-language publications reporting on patients with aesthetic indications (including glabellar lines and wrinkles) receiving aboBoNT-A, that assessed patient and/or physician satisfaction with treatment, with no restrictions on comparator studies. Structured data extraction was used to enable inter-study analysis. A post-hoc analysis was also performed to assess patient satisfaction by sex and age, using results from the noninterventional APPEAL study of patients’ satisfaction with aboBoNT-A for treating glabellar lines. RESULTS: Overall, 22 original research papers were identified. Patient satisfaction rates for aboBoNT-A treatment were significantly higher versus placebo from two weeks to between three and five months postinjection. At two to three weeks postinjection, patient satisfaction rates were 52% and 99% across studies. In studies with later time points, patient satisfaction rates were 85 to 87 percent at 5 months and between 25 and 100 percent at 6 months post-injection. Physician satisfaction was also high (97%–100%, across three treatments). No notable differences in patient satisfaction by sex or age were observed in the APPEAL study. CONCLUSION: High rates of patient satisfaction have been achieved with aboBoNT-A treatment for upper facial aesthetic indications. Despite the current recommended interval of ≥12 weeks, satisfaction with the aesthetic results of aboBoNT-A therapy is still evident up to 6 months post-injection in some patients.     

Effects of intravenously administered hypertonic urea solution

Summary and Conclusions In 12 patients with increased intracranial pressure, caused by an expanding process, a hypertonic urea solution was intravenously administered during a craniotomy. At different times before, during and after the operation, the electrolytes, urea, glucose and total protein values were determined in various body fluids and tissues.This study disclosed that the urea administered was distributed through both the intracellular and the extracellular space after 20 minutes. The values of the electrolytes, except the calcium, in the extracellular fluid remained constant after administration of the urea solution; the total protein value, however, showed a considerable decrease.It was established that the blood-brain barrier plays no appreciable role in the mechanism of action of hypertonic urea solutions in dehydrating the brain tissue; the blood-C. S. P. and brain-C. S. F. barriers may do.

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Zusammenfassung Bei 12 Patienten mit intrakranieller Drucksteigerung infolge eines raumbeengenden Prozesses wurde Harnstofflösung intravenös während der Schädeleröffnung gegeben. Zu verschiedenen Zeitpunkten vor, während und nach der Operation wurden Elektrolyt, Harnstoff, Glukose und Gesamteiweiß quantitativ bestimmt und zwar sowohl in verschiedenen Körperflüssigkeiten wie auch in Geweben.Die Untersuchungen ergaben, daß der verabfolgte Harnstoff in 20 Minuten sich sowohl auf den intrazellulären, wie den extrazellulären Raum verteilt hat. Die Elektrolytwerte, mit Ausnahme von Kalzium, blieben nach der Harnstoffinfusion in den extrazellulären Flüssigkeiten unverändert, der Gesamteiweißwert nahm dagegen beträchtlich ab.Es wurde festgestellt, daß die Bluthirnschranke keine wesentliche Rolle für die entwässernde Wirkung des Harnstoffes auf das Hirngewebe spielt, während die Blut-Liquor-Schranke und die Hirn-Liquor-Schranke vielleicht von Bedeutung sind.

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Resumen Después de una craniectomía se administró una solución de urea hipertónica por via intravenosa a 12 pacientes que presentaban una presión intracraneal creciente a causa de una exposición de la hipófisis. Periódicamente, antes, durante y después de la operación se determinaron los valores de los electrolitos, de la urea, de la glucosa y de las proteinas totales en los diferentes líquidos y tejidos del organismo.Este estudio demostróque la urea administrada se distribuia a través del espacio intra y extracelular al cabo de 20 minutos. Los valores de los electrolitos, excepto el calcio, permanecieron constantes en el líquido extracelular después de la administración de la solución de urea; el valor de las proteinas totales, sin embargo, mostró un descenso considerable.Se concluyó que la barrera hemato-encefálica no juega ningún papel apreciable en los mecanismos de acción de las soluciones de urea hipertónica en la deshidratación del tejido cerebral; tal vez lo juegue en las barreras sangre-liquido cofalo-raquídeo y cerebro-líquido cefalo-raquídeo.

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Résumé Lors d'une craniotomie, une solution d'urée hypertonique fut administrée par voie intraveineuse chez 12 patients présentant une pression intracrânienne grandissante causée par une expansion de l'apophyse. De temps en temps, avant, pendant et après l'opération, les valeurs des électrolytes, de l'urée, du glucose et de la protéine totale étaient déterminées dans les différents liquides et tissus du corps.Cette étude démontra que l'urée administrée était distribuée à travers l'espace intra et extraecllulaire au bout de 20 minutes. Les valeurs des électrolytes, excepté le calcium, demeurèrent constantes dans le liquide extracellulaire après l'administration de la solution d'urée; la valeur de la protéïne totale, pourtant, montrait une baisse considérable.Il fut établi que la barrière hémato-encéphalique ne joue aucun rôle appréciable dans le mécanisme d'action des solutions d'urée hypertonique dans la déshydratation du tissu cérébral; les barrières sang-liquide céphalorachidien et cerveau-liquide céphalo-rachidien, peut-être.

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Riassunto In 12 pazienti con ipertensione endocranica, causata da un processo espansivo, è stata somministrata durante la craniotomia dell'urea in soluzione ipertonica per via venosa. A diversi tempi prima, durante e dopo l'intervento, sono stati dosati gli elettroliti, l'urea, il glueosio e le proteine totali in vari fluidi e tessuti corporei. Queste ricerche hanno evidenziato che l'urea viene distribuita tra spazio intracellulare ed extracellulare in 20 minuti. I livelli degli elettroliti, eccetto il calcio, rimangono costanti nel liquido extracellulare dopo la somministrazione di urea, i valori della proteinemia totali invece mostrano una notevole diminuizione.E' stato stabilito che la barriera emato-cerebrale non gioca alcun ruolo apprezzabile nel meccanismo d'azione dell'urea ipertonica nel disidratare il tessuto cerebrale; un ruolo importante potrebbe essere inveoe giocato dalla barriera emato-liquorale e tra liquor e sistema nervoso.

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This study was supported by a grant from the Netherlands Organization for the Advancement of Pure Research (Nederlandse Organisatie voor Zuiver-Wetenschappelijk Onderzoek, Z. W. O.).     

侧脑室注射血管紧张素Ⅱ促进内源性洋地黄样因子释放

目的 探讨侧脑室注射血管紧张素Ⅱ对内源性洋地黄样因子（EDLF）释放的影响。方法 大鼠侧脑室注射血管紧张素Ⅱ及侧脑室注射Saralasin或损毁第三脑室前腹区（AV3V）预处理,放射免疫方法测定血清EDLF浓度的变化。结果 侧脑室注射AngⅡ可引起血清EDLF浓度升高;Saralasin预处理或海人酸损毁AV3V区可阻断侧脑室注射AngⅡ引起的血清EDLF升高效应。结论 侧脑室注射血管紧张素Ⅱ促进EDLF释放。     

Evolution of renal replacement therapy in East Germany from 1989 to 1992

Diminished availability of facilities for renal replacementtherapy is known to cause spuriously low acceptance and treatmentrates. In this context the evolution of renal replacement therapyin the former German Democratic Republic is a useful model tostudy and to quantify some of the relevant factors. We performed a survey in all dialysis units for adults in EastGermany (excluding East Berlin) by questionnaire, achievinga response rate of 97%. From December 1989 to December 1992the number of dialysis centres increased from 53 to 96 (+81%),reaching 6.7 centres p.m.p. Of these facilities, 45% were hospitalunits, 29% private units, and 26% dialysis units run by non-profithealth care organizations. The number of dialysis stations forregular dialysis treatment increased from 602 to 1276 (+112%),i.e. 89 stations p.m.p. In parallel, the number of chronic dialysispatients increased from 2127 to 3848 (+81%), i.e. 267 patientsp.m.p. A more detailed survey was carried out in Thüringen andpart of Sachsen, in a region covering 5 million inhabitants.The acceptance rate for chronic dialysis treatment has increasedfrom 49 to 107 patients p.m.p. (+115%). The average age of newpatients increased from 49 to 59 years, the proportion of patientsaged 65 years increased from 16 to 42% and the proportion ofdiabetics from 13 to 35%. Introduction of alternative treatmentmodalities became possible, with 2.3% of the patients receivinghaemofiltrations and 3% CAPD. The proportion of HBs-antigen-positivepatients decreased from 14.2% to 5%. At the end of 1989 in the former GDR (excluding East Berlin),773 patients and, at the end of 1992, 1153 patients were alivewith functioning renal transplants (+49%). The annual rate oftransplantations was 254 in 1989, and 283 in 1992 (+11%), i.e.18 transplantations p.m.p. (including East Berlin). At the end of 1989 2900 patients (193 p.m.p.), and at the endof 1992 5001 patients (347 p.m.p.), werealive on renal replacementtherapy (dialysis or functioning renal transplant) in East Germany,excluding East Berlin; this represents a 72% increase. The figures in East Germany are now almost equivalent to thosein West Germany regarding the number of admissions (incidence),whereas the number of patients on renal replacement therapyis still lower (prevalence).     

Blood cholesterol and apolipoprotein B levels in relation to intakes of animal and plant proteins in US adults

Few studies have examined the association between specific sources of protein and blood lipids in a national sample of adults. We examined this relationship in a sample of adults 20 years and older who participated in phase 1 (1988-91) of the Third National Health and Nutrition Examination Survey, a representative sample of the United States non-institutionalized population. After excluding those participants who reported having been told they had high blood cholesterol concentrations, the final sample size was 6228. Mean intakes of different sources of proteins, as a percentage of total protein, were compared in quartiles of blood lipids. Intakes were adjusted for age, sex and race. Additional adjustments were made for other dietary variables, recall day, BMI, smoking, and income. We observed a lower percentage meat, fish and poultry (MFP) protein intake, including a lower percentage of beef and pork protein, among persons in the lowest quartile of serum total cholesterol and apolipoprotein B (ApoB) concentrations than among persons in the higher quartiles. The percentage of plant protein intake was higher in the lowest quartile than in the highest quartile of serum cholesterol. We also observed a higher percentage of fruit protein intake with lower serum cholesterol and ApoB concentrations. We conclude that in this cross-sectional sample, consumption of MFP proteins was consistently higher among persons with higher cholesterol concentrations while consumption of plant proteins was consistently higher among persons with lower cholesterol concentrations. Our findings support the importance of assessing intake of specific protein sources, especially in studies that address dietary intake in relation to blood lipids.