A HYPOTHALAMIC DIGOXIN-MEDIATED MODEL FOR AUTISM

The isoprenoid pathway and its metabolites--digoxin, dolichol, and ubiquinon--were assessed in autism. The isoprenoid pathway and digoxin status was also studied for comparison in individuals of differing hemispheric dominance to determine the role of cerebral dominance in the genesis of autism. There was an upregulation of the isoprenoid pathway as evidenced by elevated HMG CoA reductase activity in autism. Digoxin, an endogenous Na+-K+ ATPase inhibitor secreted by the hypothalamus, was found to be elevated and RBC membrane Na+-K+ ATPase activity was found to be reduced in autism. Membrane Na+-K+ ATPase inhibition can result in increased intracellular Ca2+ and reduced magnesium levels. Hypothalamic digoxin can modulate conscious and subliminal perception and its dysfunction may lead to autism. Digoxin can also preferentially upregulate tryptophan transport over tyrosine resulting in increased levels of depolarizing tryptophan catabolites--serotonin, quinolinic acid (NMDA agonist), strychnine (blocks glycinergic inhibitory transmission), and nicotine (promotes dopamine release) and decreased levels of hyperpolarizing tyrosine catabolites--dopamine, noradrenaline, and morphine--contributing to membrane Na+-K+ ATPase inhibition. Increased nicotine levels can produce increased dopaminergic transmission in the presence of low dopamine levels. NMDA excitotoxicity could result from hypomagnesemia induced by membrane Na+K+ ATPase inhibition and quinolinic acid, an NMDA agonist acting on the NMDA receptor. Hypomagnesemia and increased dolichol level can affect glycoconjugate metabolism and membranogenesis leading on to disordered synaptic connectivity in the limbic allocortex and defective presentation of viral antigens and neuronal antigens contributing to autoimmunity and viral persistance important in the pathogenesis. Membrane Na+-K+ ATPase inhibition can produce immune activation, a component of autoimmunity. Mitochondrial dysfunction consequent to altered calcium/magnesium ratios and reduced ubiquinone levels can result in increased free radical generation and reduced free radical scavenging and defective apoptosis leading to abnormal synaptogenesis. Autism can thus be considered a syndrome of hypothalamic digoxin hypersecretion consequent to an upregulated isoprenoid pathway. The biochemical patterns including hyperdigoxinemia observed in autism correlated with those obtained in right hemispheric chemical dominance. Right hemispheric chemical dominance is a predisposing factor for autism     

Relationship between Head Size and Latency of the Auditory Brainstem Response: Le Rapport qui existe entre le volume de la těle et la latence des réponses auditives du tronc cérébral

This investigation examines the relationship between the head size of 22 normally hearing individuals and the latency of their respective auditory brainstem responses (ABR). The absolute latency of wave V and the I-V interpeak interval were examined in 12 female and 10 male subjects with varying head sizes. Strong positive correlations were obtained between head size and the latency of both wave V and the I-V interpeak interval. The evidence suggests that this relationship is based upon subject differences in brain size which is reflected in head size. Head size appears to be an important source of intersubject variability which should be considered in order to increase the clinical usefulness of the ABR.

Cette recherche étudie le rapport qui existe entre le volume de la těte et la latence des réponses auditives du tronc cérébral (ABR) chez 22 individus possédant une ouie normale. Nous avons étudié la latence absolue de l'onde V et Pintervalle entre pics des ondes I-V chez 12 femmes et 10 hommes dont le volume de la těte variait. Nous avons observé des corrélations positives fort con-vaincantes entre le volume de la těte et la latence de l'onde V et de l'intervalle entre pics 1-V. Cette preuve bien établie suggère que ce rapport est lié à la différence entre le volume du cerveau qui correspond au volume de la těte. Le volume de la těte semble ětre une source importante de variabilité interindividuelle et devrait ětre pris en considération afin d'augmenter l'application clinique de l'ABR.     

Effects of Reflex Middle-Ear Muscle Contractions on Cochlear Responses to Bone-Conducted Sound

The effects of contralaterally elicited middle-ear muscle (MEM) reflexes on cochlear microphonic responses to air- and bone-conducted tones were examined in decerebrate cats. Stapedius effects on bone conduction were almost identical in configuration and amplitude to those on air conduction at all frequencies. However, tensor tympani effects were more complex, the configuration of the bone-conduction effects varying with the location of the transducer on the skull and with frequency. The relative contributions of the two muscles to the effects of joint contractions varied markedly between animals. It is suggested that non-reflex MEM contractions associated with activity of the facial musculature might provide protection against masking of environmental sounds by the low-frequency bone-conducted sound generated by such activity     

VEMP responses are not affected in non-insulin-dependent diabetes mellitus patients with or without polyneuropathy

Conclusion. Vestibular evoked myogenic responses (VEMPs) are not affected in non-insulin-dependent diabetes mellitus (NIDDM) patients with or without polyneuropathy. Objective. To compare VEMP responses of NIDDM patients and healthy subjects. Subjects and methods. VEMP responses were collected from 25 NIDDM patients with polyneuropathy (PNP), 13 NIDDM patients without PNP and 21 healthy subjects using click stimulation. After excluding ears with hearing loss (HL) (worse than 25 dB) the VEMP responses (p13 and n21 latencies and amplitude) recorded in 105 dB stimulus intensity were compared. Results. There was no statistically significant difference between groups. VEMP responses were found to be normal in NIDDM patients with or without PNP.     

Effects of Extracorporeal Shock Wave-Mediated Transdermal Local Anesthetic Drug Delivery on Rat Caudal Nerves

Cavitation plays a substantial role in the clinical effects of extracorporeal shock wave therapy (ESWT). It is also generally accepted as a major mechanism in sonophoresis. To identify the enhancing effect of extracorporeal shock wave-mediated transdermal drug delivery, 24 Wistar rats were randomly assigned to four groups: (i) topical application of a eutectic mixture of local anesthetics (EMLA); (ii) 1-MHz ultrasound; (iii) ESWT pre-treatment combined with EMLA application; (iv) ESWT concurrent with EMLA application on rat tails. The degree of anesthesia was assessed using the amplitude and latency of sensory nerve action potentials within 5?min after a 60-min EMLA application. The results indicated that ESWT pre-treatment and concurrent ESWT accelerated the anesthetic effects of the EMLA cream on the tail nerve (p?<?0.05). This finding might indicate that shock wave-mediated transdermal drug delivery is possible during the ESWT period.     

Prognostic Implications of Mitral Annular Plane Systolic Excursion in Patients with Hypertension and a Clinical Indication for Cardiac Magnetic Resonance Imaging: A Multicenter Study

ObjectivesThis study sought to evaluate the prognostic value of cardiac magnetic resonance (CMR)-derived mitral annular plane systolic excursion (MAPSE) in a large multicenter population of patients with hypertension.BackgroundIn patients with hypertension, cardiac abnormalities are powerful predictors of adverse outcomes. Long-axis mitral annular movement plays a fundamental role in cardiac mechanics and is an early marker for a number of pathological processes. Given the adverse consequences of cardiac involvement in hypertension, the authors hypothesized that lateral MAPSE may provide incremental prognostic information in these patients.MethodsConsecutive patients with hypertension and a clinical indication for CMR at 4 U.S. medical centers were included in this study (n = 1,735). Lateral MAPSE was measured in the 4-chamber cine view. The primary endpoint was all-cause death. Cox proportional hazards regression modeling was used to examine the association between lateral MAPSE and death. The incremental prognostic value of lateral MAPSE was assessed in nested models.ResultsOver a median follow-up period of 5.1 years, 235 patients died. By Kaplan-Meier analysis, risk of death was significantly higher in patients with a lateral MAPSE < median (10 mm) (log-rank; p < 0.0001). Lateral MAPSE was associated with risk of death after adjustment for clinical and imaging risk factors (hazard ratio [HR]: 1.402-per-millimeter decrease; p < 0.001). Addition of lateral MAPSE in this model resulted in significant improvement in the C-statistic (0.735 to 0.815; p < 0.0001). Continuous net reclassification improvement was 0.739 (95% confidence interval: 0.601 to 0.902). Lateral MAPSE remained significantly associated with death even after adjustment for feature tracking global longitudinal strain (HR: 1.192-per-millimeter decrease; p < 0.001). Lateral MAPSE was independently associated with death among the subgroups of patients with preserved ejection fraction (HR = 1.339; p < 0.001) and in those without history of myocardial infarction (HR: 1.390; p < 0.001).ConclusionsCMR-derived lateral MAPSE is a powerful, independent predictor of mortality in patients with hypertension and a clinical indication for CMR, incremental to common clinical and CMR risk factors. These findings may suggest a role for CMR-derived lateral MAPSE in identifying hypertensive patients at highest risk of death.     

Churg–Strauss Syndrome Associated with Rapid Deterioration of Left Ventricular Diastolic Dysfunction and Conduction Disturbance

Cardiac involvement in Churg–Strauss syndrome (CSS) is a major cause of mortality. Here we report a case of a 75‐year‐old woman with eosinophilic endomyocarditis due to CSS. An electrocardiogram showed intraventricular conduction delay, and echocardiography showed an impaired relaxation pattern and biventricular apical thickening. Magnetic resonance imaging revealed subendocardial delayed enhancement with biventricular apical thrombi. Endomyocardial biopsy showed perivascular eosinophilic infiltration. Despite resolution of the hypereosinophilia after steroid therapy, her left ventricular (LV) diastolic function worsened into a restrictive pattern and she died with a ventricular escape rhythm on her 14th day in the hospital. This case is unusual in that there was rapid progression of the LV diastolic dysfunction and conduction disturbance due to CSS.