RESUMEN
OBJECTIVE: This study aimed to investigate the connection between psychological factors and postoperative tinnitus in vestibular schwannoma (VS) patients following retrosigmoid microsurgery. DESIGN: Cross-sectional study. STUDY SAMPLE: Ninety-three VS patients participated, completing questionnaires on demographics, tinnitus severity (THI-12), personality traits (TIPI-G), dizziness impact (DHI), perceived health benefits (GBI), somatisation tendencies (SOMS-2), and psychological distress (HADS-D). Our analysis involved Mann-Whitney U-tests, Spearman's rank-order correlations, and false discovery rate correction. RESULTS: Most participants reported postoperative tinnitus (77/93), with 41 experiencing it preoperatively. Emotional stability correlated negatively with tinnitus presence, while tinnitus severity was associated with emotional distress. Preoperative somatisation tendencies were also positively linked to tinnitus severity. Postoperative Tinnitus was further linked to reduced perceived health benefits and increased anxiety and depression levels. Notably, age and gender showed no significant associations. CONCLUSION: This study uncovers the interplay between postoperative tinnitus and psychological factors in VS patients, highlighting emotional and cognitive dimensions. Tailored psychological interventions addressing tinnitus's psychosomatic impact may enhance patients quality of life.
RESUMEN
OBJECTIVE: Spatial memory deficits are an early symptom in Alzheimer's disease (AD), reflecting the neurodegenerative processes in the neuronal navigation network such as in hippocampal and parietal cortical areas. As no effective treatment options are available, neuromodulatory interventions are increasingly evaluated. Against this backdrop, we investigated the neuromodulatory effect of anodal transcranial direct current stimulation (tDCS) on hippocampal place learning in patients with AD or mild cognitive impairment (MCI). METHODS: In this randomized, double-blind, sham-controlled study with a cross-over design anodal tDCS of the right temporoparietal junction (2 mA for 20 min) was applied to 20 patients diagnosed with AD or MCI and in 22 healthy controls while they performed a virtual navigation paradigm testing hippocampal place learning. RESULTS: We show an improved recall performance of hippocampal place learning after anodal tDCS in the patient group compared to sham stimulation but not in the control group. CONCLUSIONS: These results suggest that tDCS can facilitate spatial memory consolidation via stimulating the parietal-hippocampal navigation network in AD and MCI patients. SIGNIFICANCE: Our findings suggest that tDCS of the temporoparietal junction may restore spatial navigation and memory deficits in patients with AD and MCI.
Asunto(s)
Enfermedad de Alzheimer , Disfunción Cognitiva , Estimulación Transcraneal de Corriente Directa , Humanos , Enfermedad de Alzheimer/terapia , Disfunción Cognitiva/terapia , Hipocampo , Trastornos de la Memoria , Aprendizaje Espacial , Estimulación Transcraneal de Corriente Directa/métodos , Método Doble CiegoRESUMEN
BACKGROUND: Since 2009, all newborns in Germany have been entitled to universal neonatal hearing screening (UNHS). UNHS with tracking of test results leads to earlier detection of hearing disorders. The Association of German Hearing Screening Centers (Verband Deutscher Hörscreening-Zentralen, VDHZ) was founded to promote nationwide tracking, validity and quality control of UNHS results. OBJECTIVES: A comparable data structure in the different screening centers, with uniform definitions of primary parameters is essential for the nationwide evaluation of UNHS results. To address the question of whether a data structure with comparable definitions already exists or still has to be created, the existing structures and primary parameter definitions in the hearing screening centers should be investigated and compared. METHODS: A survey was conducted in all hearing screening centers to assess how data on the primary UNHS parameters defined in pediatric guidelines was gathered. In the case of discrepancies, uniform definitions were created. Finally, the practicability of these definitions was evaluated. RESULTS: Due to differing definitions of primary parameters, some of the data were not comparable between the individual centers. Therefore, uniform definitions were created in a consensus process. In the centers, the screening method, the two-step first screening and the result of the first screening now correspond to these uniform definitions. Other parameters, e.g. the total number of newborns, still vary widely, rendering the comparison of screening rates almost impossible. CONCLUSION: Valid evaluation of UNHS not only requires nationwide establishment of hearing screening centers, but also unified data structures and parameter definitions.
Asunto(s)
Trastornos de la Audición/clasificación , Trastornos de la Audición/diagnóstico , Pruebas Auditivas/normas , Tamizaje Masivo/normas , Tamizaje Neonatal/normas , Guías de Práctica Clínica como Asunto , Terminología como Asunto , Audiología/normas , Femenino , Alemania , Humanos , Recién Nacido , Masculino , Otolaringología/normasRESUMEN
BACKGROUND: Spasmodic torticollis patients were investigated with respect to the number of adjunct treatments used before and after the introduction of botulinum toxin therapy (Btx). The study was designed in a similar way to an earlier investigation by Birner et al. (Nervenarzt 70:903-908, 1999). MATERIAL AND METHODS: A total of 247 patients with idiopathic spasmodic torticollis were assessed at three time points for the diagnosis: before 1988 (n = 63), between 1989 and 1998 (n = 107) and after 1999 (n = 77). RESULTS: Independent of the year of diagnosis patients underwent a mean of 14.3 different treatments. In addition to Btx most of the patients were subjected to massage, physiotherapy, medication and a large number of non-medical treatments including praying. No associations to clinical or personal variables were found. Those patients with emotional disorders prior to onset of dystonia displayed a higher rate of medical and non-medical treatments in addition to Btx. CONCLUSIONS: The results confirmed those found by Birner et al.. In order to enhance compliance patients should undergo psychoeducation with respect to illness behaviour and specific history taking with respect to emotional disorders prior to dystonia.
Asunto(s)
Síntomas Afectivos/epidemiología , Síntomas Afectivos/prevención & control , Toxinas Botulínicas/administración & dosificación , Tortícolis/tratamiento farmacológico , Tortícolis/epidemiología , Adulto , Síntomas Afectivos/diagnóstico , Antidiscinéticos/administración & dosificación , Quimioterapia Adyuvante/estadística & datos numéricos , Terapia Combinada/estadística & datos numéricos , Comorbilidad , Femenino , Alemania/epidemiología , Humanos , Masculino , Persona de Mediana Edad , Prevalencia , Factores de Riesgo , Tortícolis/diagnóstico , Resultado del TratamientoRESUMEN
A critical role in place learning has been attributed to place cells within the cornu ammonis 1 (CA1) sector of the hippocampus in rodents. The role of CA1 cells in the human hippocampus with regard to place learning remains elusive. Using a virtual Morris water maze, we investigated patients with acute transient global amnesia (TGA), a rare self-limiting dysfunction of the hippocampal system. Fourteen individuals with selective and focal lesions in the CA1 sector of the hippocampus showed a profound impairment in place learning. The size of the lesions and the duration of the TGA correlated with the deficit in the performance.
Asunto(s)
Amnesia Global Transitoria/patología , Región CA1 Hipocampal/patología , Memoria , Neuronas/patología , Anciano , Anciano de 80 o más Años , Amnesia Global Transitoria/fisiopatología , Amnesia Global Transitoria/psicología , Mapeo Encefálico , Región CA1 Hipocampal/fisiopatología , Señales (Psicología) , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Aprendizaje por Laberinto , Persona de Mediana Edad , Análisis de RegresiónRESUMEN
Several recent studies have reported contradicting results concerning the relevance of the plasminogen activator inhibitor-1 (PAI-1) 4G/5G-polymorphism for myocardial infarction. In addition, the common factor V Q506 (FV:Q506) mutation is frequently discussed as a risk factor for arterial thrombosis, but evidence is rare. In order to further highlight the role of both polymorphisms in myocardial infarction, we investigated 241 young male myocardial infarction patients (< or = 45 years-of-age) aged 38.6+/-4.4 years (mean+/-SD) for the presence of both genotypes. The control group consisted of 179 healthy men aged 47.1+/-6.4 years (mean+/-SD) of the same ethnic background as the patients. Neither the distribution of the PAI-1 4G/5G-polymorphism nor the prevalence of the FV: Q506 mutation was significantly different between young patients and controls (4G/4G-genotype: chi2=2.08, NS; odds ratio 1.36, 95% confidence interval 0.89-2.06; FV:Q506 mutation: chi2=0.33, NS; odds ratio 1.33, 95% confidence interval 0.64-2.78). Moreover, the PAI-1 4G/5G-distribution did not differ significantly between patients and controls in subgroups by tertiles of triglyceride levels. In conclusion, in the present study neither homozygosity for the 4G allele of the PAI-1 4G/5G-polymorphism nor the FV:Q506 mutation led to an increased risk of myocardial infarction in young men.
Asunto(s)
Factor V/genética , Mutación , Infarto del Miocardio/genética , Inhibidor 1 de Activador Plasminogénico/genética , Adulto , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo Genético , Factores de RiesgoRESUMEN
Several studies have indicated that plasma viscosity contributes to cardiovascular risk in men. So far, a significant relationship between plasma viscosity and the severity of coronary heart disease has not been found. Thus, the present study is the first to report on the relationship of plasma viscosity and the severity of coronary heart disease. In a collective of 1142 male myocardial infarction patients, plasma viscosity and additional laboratory parameters were determined. Atherosclerotic changes were quantified by coronary angiography. Patients were divided into groups without any, and with one to three stenosed vessels. We found a positive relationship between plasma viscosity and the severity of coronary heart disease, even after adjusting groups for age, fibrinogen, and use of diuretics. Mean plasma viscosity ranged from 1.141+/-0.035 mPa s in patients without stenosed vessels to 1.162+/-0.044 mPa s in patients who had three coronary vessels with stenoses >50%. Differences between the groups were significant (P<0.001 to 0.05), with two exceptions: differences between patients without any and with one stenosed vessel, as well as between patients with one and two stenosed vessels, did not reach the significance level. On the whole, we can give further support to the hypothesis that cardiovascular risk factors and coronary heart disease may be linked by plasma viscosity.
Asunto(s)
Viscosidad Sanguínea , Enfermedad Coronaria/sangre , Infarto del Miocardio/sangre , Enfermedad Coronaria/fisiopatología , Humanos , Modelos Logísticos , Masculino , Persona de Mediana EdadRESUMEN
The present investigation was performed to determine the dependence of the length of stay in community hospitals and rehabilitation clinics from patient characteristics and physical activity at the end of treatment. Comparing age, end-diastolic volume index, left ventricular ejection fraction, number of stenosed coronary arteries, number of bypass grafts, levels of physical exercise, body mass index and the ratio total cholesterol/HDL-cholesterol, no significant differences were found in patients, who reached the rehabilitation clinic in the early postoperative period (7.4 +/- 2.0 days, n = 98), after 15-28 days (n = 74) or later than 28 days (n = 156) after bypass-surgery. Similar results were observed in 103 patients after heart-valve replacement, who arrived at the rehabilitation clinic after a corresponding length of hospital care like the bypass patients. Also, no significant differences in the clinical characteristics and physical activity appeared in patients who were admitted in the early phase (9.2 +/- 4.5 days) after transmural myocardial infarction (n = 37) and those entering the rehabilitation clinic after 26.7 +/- 9.4 days of hospital stay (n = 32). The absence of any relationship between the length of stay in hospitals on the one hand and severity of the heart disease on the other hand points out that the whole duration of stay in community hospitals and rehabilitation clinics after surgical intervention and also after transmural myocardial infarction could be drastically shortened by an optimal cooperation of both, hospitals and rehabilitation clinics, without any impairment of clinical results.
Asunto(s)
Actividades Cotidianas/clasificación , Puente de Arteria Coronaria , Enfermedades de las Válvulas Cardíacas/cirugía , Prótesis Valvulares Cardíacas , Tiempo de Internación , Infarto del Miocardio/cirugía , Adulto , Anciano , Puente de Arteria Coronaria/rehabilitación , Prueba de Esfuerzo , Femenino , Estudios de Seguimiento , Prótesis Valvulares Cardíacas/rehabilitación , Humanos , Masculino , Persona de Mediana Edad , Centros de Rehabilitación , Resultado del TratamientoRESUMEN
We investigated the vessel status of coronary and peripheral arteries and those arteries supplying the brain in 929 consecutive male patients admitted to a coronary rehabilitation unit. The severity of coronary atherosclerosis was scored using coronary angiography. Changes in extracranial brain vessels and manifest cerebrovascular disease (CVD) were determined by B-mode ultrasound and Doppler examination. Peripheral arterial disease (PAD) was diagnosed using base-line and stress oscillography. We assessed variables of coagulation, fibrinolysis, and the acute phase response. There was a significant increase in plasma fibrinogen, plasminogen, d-dimer and C-reactive protein (CRP) with increasing severity of coronary heart disease. Compared to men with unaffected arteries, men with 3 diseased coronary arteries had 58% greater d-dimer concentrations. Patients with CVD and PAD, respectively, also had significantly higher fibrinogen, d-dimer and CRP concentrations. We did not find an association between plasminogen activator inhibitor activity and the severity of coronary atherosclerosis. In conclusion, plasma fibrinogen, d-dimer and CRP concentrations were significantly related to atherosclerosis in the coronary, peripheral and extracranial brain arteries.
Asunto(s)
Reacción de Fase Aguda , Arteriosclerosis/sangre , Coagulación Sanguínea , Proteínas Sanguíneas/análisis , Enfermedad Coronaria/sangre , Fibrinólisis , Arteriosclerosis Intracraneal/sangre , Enfermedades Vasculares Periféricas/sangre , Arteriosclerosis/epidemiología , Biomarcadores/sangre , Glucemia/análisis , Presión Sanguínea , Índice de Masa Corporal , Proteína C-Reactiva/análisis , Enfermedad Coronaria/diagnóstico por imagen , Productos de Degradación de Fibrina-Fibrinógeno/análisis , Fibrinógeno/análisis , Humanos , Lípidos/sangre , Lipoproteínas/sangre , Masculino , Persona de Mediana Edad , Inhibidor 1 de Activador Plasminogénico/sangre , Estudios Prospectivos , Radiografía , Factores de Riesgo , Índice de Severidad de la Enfermedad , Fumar/sangreRESUMEN
Despite many investigations in a variety of experimental settings, uncertainty remains concerning the size of the genetic contribution to plasma fibrinogen levels. We used the polymerase chain reaction to amplify the polymorphic sites for the restriction enzymes TaqI in the alpha-fibrinogen gene and HaeIII, HindIII and BclI in the beta-fibrinogen gene. Three hundred and eighty-four male coronary heart disease patients were investigated. Two alleles for each enzyme (+ or - designating, respectively, the presence or absence of the cutting site) were detected. The HaeIII and HindIII cutting sites were in complete linkage disequilibrium. A small but significant increase in fibrinogen level was associated with the rare cutting sites of HaeIII/HindIII, BclI and TaqI. At all polymorphic sites homozygosity for the frequent alleles was associated with about 0.20 g/l lower plasma fibrinogen concentrations than heterozygosity at the respective sites (p < 0.05). The frequencies and natures of the rare alleles were as follows: TaqI (+) 0.28, HaeIII/HindIII (-) 0.22 and BclI (+) 0.17. Mean fibrinogen levels in patients heterozygous for each of the four polymorphisms were 0.47 g/l greater than in subjects homozygous for the frequent allele at each cutting site (HaeIII/HindIII + -, TaqI + -, BclI + -: fibrinogen level 3.58 g/l (n = 32); HaeIII/HindIII + +, TaqI - -, BclI - -: fibrinogen level 3.11 g/l (n = 99), p = 0.003). Each polymorphism accounted for between 0.5 and 1.4% of the overall variance in fibrinogen concentration. Together, the polymorphisms in HaeIII, HindIII and TaqI explained 5.8% of overall variance, a proportion equivalent to that explained by age, smoking and body mass index (5.5%).(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Enfermedad Coronaria/sangre , Fibrinógeno/genética , Genes , Polimorfismo de Longitud del Fragmento de Restricción , Alelos , Secuencia de Bases , Fibrinógeno/análisis , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Datos de Secuencia MolecularRESUMEN
In Caucasians, a histidine for glutamine substitution (Gln-->His) at residue 360 in apolipoprotein (apo) A-IV leads to an electrophoretically detectable polymorphism whose contribution to lipid metabolism regulation is controversial. In this study of 426 male and 188 female coronary heart disease patients, we analyzed the impact of this polymorphism on lipid metabolism, particularly high-density lipoprotein (HDL). The frequency of the rarer apo A-IV (360:His) allele was .069. This polymorphism exerted opposite effects in men and women in terms of serum concentrations of total cholesterol; triglycerides; HDL cholesterol; LDL cholesterol; lipoprotein (Lp) A-I; and apo A-I, A-II, and B. Only the difference in Lp A-I levels between male apo A-IV (360:Gln/Gln) homozygotes and apo A-IV (360:Gln/His) heterozygotes was significant (P < .05). In randomly selected subgroups of 38 male and 15 female apo A-IV (360:Gln/His) heterozygotes and 104 male and 15 female apo A-IV (360:Gln) homozygotes, heterozygosity for apo A-IV (360:Gln/His) in both sexes was associated with lower plasma cholesteryl ester transfer protein (CETP) activity (P < .05) and higher serum apo A-IV concentrations (P < .01 in men). Moreover, only men had significantly higher mean plasma activity levels of lecithin:cholesterol acyltransferase (LCAT) (P < .01).(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Apolipoproteínas A/genética , HDL-Colesterol/metabolismo , Enfermedad Coronaria/metabolismo , Glutamina/genética , Glicoproteínas , Histidina/genética , Polimorfismo Genético , Anciano , Alelos , Proteínas Portadoras/sangre , Proteínas de Transferencia de Ésteres de Colesterol , Femenino , Frecuencia de los Genes , Humanos , Masculino , Persona de Mediana Edad , Fenotipo , Fosfatidilcolina-Esterol O-Aciltransferasa/sangre , Factores SexualesRESUMEN
Previous studies have identified moderately elevated plasma concentrations of homocyst(e)ine as an independent risk factor for coronary heart disease (CHD). The atherogenicity of homocyst(e)ine has mostly been attributed to its effects on endothelial cells, platelets, and the hemostatic system. In this case-control study of 199 male CHD patients and 156 age-matched control subjects, we analyzed the role of homocyst(e)ine as a cardiovascular risk marker in the context of traditional risk factors as well as of plasma fibrinogen, plasminogen, and viscosity. Both univariate and multivariate regression analyses revealed that homocyst(e)ine levels were significantly correlated with age, fibrinogen, and plasma viscosity in both study groups. Geometric mean homocyst(e)ine levels by univariate analysis were significantly higher in patients than in control subjects (8.9 versus 7.8 mumol/L, P < .001). This difference remained significant on multiple logistic function analysis after being adjusted for body mass index, systolic blood pressure, serum cholesterol, and high-density lipoprotein cholesterol but not after additional adjustment for fibrinogen. By contrast, geometric mean fibrinogen levels after adjustment for homocyst(e)ine levels were significantly different between patients and control subjects (296.4 versus 230.8 mg/dL, P < .001). Within the group of CHD patients, both fibrinogen and homocyst(e)ine significantly increased in parallel with the number of stenosed coronary vessels. We conclude that hyperhomocyst(e)inemia is an independent coronary risk factor and that its interrelation with fibrinogen levels merits further study.
Asunto(s)
Enfermedad Coronaria/etiología , Fibrinógeno/análisis , Homocisteína/sangre , Lipoproteínas/sangre , Adulto , Factores de Edad , Viscosidad Sanguínea , Humanos , Masculino , Persona de Mediana Edad , Factores de RiesgoRESUMEN
A glutamine/histidine polymorphism at residue 360 in apolipoprotein (apo) A-IV that generates two electrophoretically detectable isoforms, apo A-IV-1 and apo A-IV-2, affects the plasma concentration of lipoprotein(a) (Lp[a]) in a healthy population. To verify this unexpected association we analyzed the effect of the apo A-IV polymorphism on Lp(a) serum concentrations in 275 male coronary heart disease patients. Allele frequencies of apo A-IV-1 and apo A-IV-2 were 0.917 and 0.083, respectively. In addition, apo A-IV-1/2 heterozygotes showed a 30% lower geometric mean concentration of Lp(a) than apo A-IV-1/1 homozygotes in this study. The relative frequency of Lp(a) concentrations > 20 mg/dl was significantly increased by a factor of 2.25 in apo A-IV-1/1 homozygotes. Other lipid parameters were not significantly affected by this apo A-IV polymorphism. Because of the relations between Lp(a) and the fibrinolytic system, we also analyzed the effect of the apo A-IV polymorphism on hemostatic variables. Apo A-IV-1/2 heterozygosity was associated with a 70% higher geometric mean plasma concentration of D-dimer, i.e., proteolytic fragments of cross-linked fibrin. Plasma concentrations of prothrombin fragments F1 + F2, fibrinogen, plasminogen, and plasminogen activator inhibitor-1 were unaffected. In conclusion, our results indicate a hitherto unappreciated role of the apo A-IV gene or a closely linked locus for the regulation of Lp(a) metabolism and hemostasis and also possibly for atherosclerosis and thrombosis.
Asunto(s)
Apolipoproteínas A/genética , Enfermedad Coronaria/sangre , Productos de Degradación de Fibrina-Fibrinógeno/análisis , Glutamina/análisis , Histidina/análisis , Lipoproteína(a)/sangre , Enfermedad Coronaria/etiología , Hemostasis , Humanos , Lipoproteína(a)/genética , Masculino , Polimorfismo Genético , Receptores de LDL/genéticaRESUMEN
Therapeutic experiences with cochlear implants in late adult deafness have become so large that implants now belong to the accepted methods of therapy for profoundly deaf patients. Affected patients often recognize speech through simple auditory means. In the last 5 years increased numbers of children with congenital or infantile deafness have also been successfully treated with cochlear implants. Some reports have already been published about clinical experiences and rates of success. In this paper some positive results are shown, but the limitations of treatment and the necessity for accurate preoperative diagnosis must be understood. The further development of treatment for deaf implants requires refinements in phoniatric and pedaudiological techniques.
Asunto(s)
Implantes Cocleares , Sordera/congénito , Adolescente , Umbral Auditivo , Niño , Terapia Combinada , Sordera/rehabilitación , Humanos , Trastornos del Desarrollo del Lenguaje/rehabilitación , Masculino , Inteligibilidad del Habla , Percepción del HablaRESUMEN
In 3715 survivors (pts) of an acute myocardial infarction (3343 males and 372 females), of ages between 20 and 80 years (mean 52.9 +/- 7.7 years), lipid-metabolism, amount of cigarette-smoking, severity of coronary artery disease (CHD) by selective coronary arteriography, and age at first manifestation of CHD documented by myocardial infarction were investigated. In contrast to normals, there is a significant reduction of disorders of lipid-metabolism with increasing age. The rate of cigarette-smoking is lower in the elderly. Females are affected by MI 3.6 to 5.3 years later than are males. There was a strong correlation between the degree of lipid-disorders and the severity of CHD, whereas the lipid-disturbances were mostly marked in the younger pts. Dependent on the degree of the underlying lipid-disorder, CHD strikes pts at a younger age, whereby the Chol/HDL-Chol-ratio is most sensitive. In a similar manner, cigarette-smoking transfers the manifestation-date of CHD "dose-dependent" to a younger age. Smokers with a daily consumption of more than 40 cigarettes are 9.2 years younger at the time of first myocardial infarction than are non-smokers. In older pts the influence of lipid-disorders and smoking becomes smaller, compared with the risk-factor "age", but it is also significant. The proven correlation between the risk-profile and the age at first myocardial event stresses the need for preventive and educative strategies.
Asunto(s)
Enfermedad Coronaria/fisiopatología , Infarto del Miocardio/fisiopatología , Adulto , Factores de Edad , Anciano , Glucemia/metabolismo , Colesterol/sangre , Enfermedad Coronaria/rehabilitación , Femenino , Humanos , Lipoproteínas/sangre , Masculino , Persona de Mediana Edad , Infarto del Miocardio/rehabilitación , Factores de Riesgo , Fumar/efectos adversos , Triglicéridos/sangreRESUMEN
The methods of "objective" hearing tests are presented and possible mistakes discussed. Two cases are reported pointing to the necessity of confirming the results of "objective" hearing tests in infants via conventional methods of reflex and play audiometry. Diagnosis in infant audiometry should be effected on an inpatient basis.
Asunto(s)
Trastornos de la Audición/diagnóstico , Pruebas Auditivas/métodos , Audiometría/métodos , Niño , Preescolar , Diagnóstico Diferencial , Femenino , Humanos , MasculinoRESUMEN
5 beta,14 beta-Androstane-3 beta,-14-diol, the lead (minimum) structure in digitalis compounds, shows the same characteristics of interaction with Na/K-ATPase as ordinary digitalis compounds judged by the following six criteria: (I) shape of the concentration-inhibition curves, (II) species differences in affinity for the enzyme, (III) apparent competition with K+, (IV) competition with digitoxigenin for binding to the enzyme, (V) stabilization of phosphoenzyme formed from ATP, and (VI) enhancement of phosphorylation from orthophosphate.
Asunto(s)
Androstano-3,17-diol/metabolismo , Androstanoles/metabolismo , Glicósidos Digitálicos/metabolismo , ATPasa Intercambiadora de Sodio-Potasio/antagonistas & inhibidores , Androstano-3,17-diol/análogos & derivados , Androstano-3,17-diol/farmacología , Sitios de Unión , Unión Competitiva , Corteza Cerebral/enzimología , Glicósidos Digitálicos/farmacología , Humanos , Cinética , Músculos/enzimología , ATPasa Intercambiadora de Sodio-Potasio/metabolismo , Relación Estructura-ActividadRESUMEN
The inhibitory potency of altogether 95 steroidal compounds (including cardenolides, bufadienolides and their glycosides) on the Na/K-ATPases (Na+/K+-transporting ATPases, EC 3.6.1.37) from human cardiac muscle, human brain cortex and guinea-pig cardiac muscle was compared to probe the complementary chemotopology of the inhibitor binding site areas on the three enzyme variants. The changes of potency, resulting from systematic variations of the geometry of steroid skeleton and the character as well as the structure of side chains at C3 or/and C17 of steroid backbone, allowed the following major conclusions. With the human cardiac and cerebral enzyme forms, the paired K0.5 (K'D) values for 77 steroid derivatives, covering seven orders of ten, were highly correlated. On an average, the total of compounds showed a 1.5-fold higher affinity to the cardiac enzyme. This tiny differentiation did not appear to be connected with an important difference in the chemotopology of the complementary subsites for steroid nucleus binding on the two enzyme forms. With the human and guinea-pig cardiac enzyme variants, the K0.5 values for 69 steroid derivatives, covering six orders of ten, were determined. For 41 5 beta, 14 beta-androstane derivatives only, the paired K0.5 values showed a close correlation. Here, the human enzyme variant exhibited 27-fold higher affinity. However, the paired K0.5 values determined on both enzymes for 28 steroid derivatives of differing structural features were but poorly correlated. Essentially, the geometries of the steroid nucleus determined the differential contributions of the side chains at C3 and C17 to the integral inhibitory potency on the two enzyme variants. Thus, the species differences in the potency of cardiac glycosides were traced to species differences in the complementarity of the steroid binding subsites. Hence, estimates of the potency of new steroidal compounds obtained on the guinea-pig cardiac enzyme can be neither quantitatively nor qualitatively easily extrapolated to the human cardiac enzyme. The extrathermodynamic analysis of the data opened major new insights in the structure-activity relationships concerning the role of C14 beta-OH, the character of the lead structure in cardioactive steroid lactones, and the significance of the configuration of A/B ring junction.