Function In Normal Subjects Research Articles

Assessment of androgen receptor function in genital skin fibroblasts using a recombinant adenovirus to deliver an androgen-responsive reporter gene.

Mutations of the androgen receptor (AR) cause defects in virilization and can result in a spectrum of phenotypic abnormalities of male sexual development that includes patients with a completely female phenotype (complete testicular feminization) and individuals with less severe defects of virilization, such as Reifenstein syndrome. These phenotypes are not specific for mutations of the AR gene, however, and defects in other genes can also result in similar abnormalities of male development. For this reason, the diagnosis of an AR defect is laborious and requires data from endocrine studies, the family history, and in vitro binding experiments. To assist in the evaluation of patients with possible AR defects, we previously employed the use of a recombinant adenovirus to deliver an androgen-responsive gene into fibroblast cultures to assay AR function in normal subjects and patients with complete forms of androgen resistance. Although these studies demonstrated measurable differences between these two groups of subjects, we did not assay samples from patients with partial defects of androgen action. In the current study, we have modified this method to examine AR function in three groups of patients with known or suspected defects of AR function: patients with Reifenstein syndrome, patients with spinobulbar muscular atrophy, and patients with severe forms of isolated hypospadias. When assayed using this method, the AR function of patients with Reifenstein syndrome was intermediate between that of normal control subjects and that of patients with complete testicular feminization. Using the parameters established by the aforementioned experiments, we found that defective AR function can be detected in fibroblasts established from patients with spinobulbar muscular atrophy and in some patients with severe forms of isolated hypospadias, including two with a normal AR gene sequence. These results suggest that this method may have some utility in screening samples to detect defects of AR function, particularly when viewed in the context of other AR assays results.

Consolidating Dispersed Neocortical Memories: The Missing Link in Amnesia

Consolidation is often conceptualised as a general process by which memory traces can be strengthened in the brain. An alternative idea, developed here, is that a particular sort of consolidation is required for establishing memories belonging to a neurobiologically defined category-memories dispersed across multiple distinct neocortical zones. These memories are consolidated via the formation of a neocortical cell assembly that confers coherence to the set of scattered neocortical memory traces. A set of memory traces linked in this manner can subsequently serve as the basis for conscious recollection. A disruption of this neocortical consolidation process is held to be responsible for the patterns of preserved and impaired memory observed in amnesic patients. A suitable strategy for empirically testing this sort of theory requires an examination of evidence from neuropsychological studies of amnesia and from studies of the neural substrates of memory functions in normal subjects.

Dissociation between insulin sensitivity of glucose uptake and endothelial function in normal subjects.

Insulin increases limb blood flow in a time- and dose-dependent manner. This effect can be blocked by inhibiting nitric oxide synthesis. These data raise the possibility that insulin resistance is associated with endothelial dysfunction. To examine whether endothelial function and insulin sensitivity are interrelated we quantitated in vivo insulin-stimulated rates of whole body and forearm glucose uptake at a physiological insulin concentration (euglycaemic hyperinsulinaemic clamp, 1 mU.kg-1.min-1 insulin infusion for 2 h) and on another occasion, in vivo endothelial function (blood flow response to intrabrachial infusions of sodium nitroprusside, acetylcholine, and N-monomethyl-L-arginine) in 30 normal male subjects. Subjects were divided into an insulin-resistant (IR) and an insulin-sensitive (IS) group based on the median rate of whole body glucose uptake (31 +/- 2 vs 48 +/- 1 mumol.kg-1.min-1, p < 0.001). The IR and IS groups were matched for age, but the IR group had a slightly higher body mass index, percentage of body fat and blood pressure compared to the IS group. The IR group also had diminished insulin-stimulated glucose extraction (p < 0.05) compared to the IS group, while basal and insulin-stimulated forearm blood flow rates were identical. There was no difference between the IR and IS groups in the forearm blood flow response to endothelium-dependent (acetylcholine and N-monomethyl-L-arginine) or -independent (sodium nitroprusside) vasoactive drugs. In conclusion, the ability of insulin to stimulate glucose uptake at physiological insulin concentrations and endothelium-dependent vasodilatation are distinct phenomena and do not necessarily coexist.

Interocular differences in visual function in normal subjects

SummaryA commonly used clinical technique for determining whether visual function is abnormal, particularly when a patient is suspected of having unilateral or asymmetric disease, is to compare the visual function of the ‘suspect’ eye to that of the normal eye. This assumes that in normal patients visual function in each eye is equal and that this symmetry is maintained with age. To determine the extent of normal symmetry for clinical measures of visual function, we assessed high and low contrast visual acuity, letter contrast sensitivity and motion sensitivity (Dmin) in both eyes of a group of 91 subjects spanning an age range of 21 to 82 years. For the whole group the interocular differences in sensitivity for each of the tests approximated a Gaussian distribution. The results demonstrate that interocular differences should exceed more than 0.16 and 0.17 logMAR ( 2 lines) for high and low contrast visual acuity respectively, before patients can be considered to be outside the range of normality. For the Pelli‐Robson Chart, interocular differences must exceed 0.23 log CS (1.5 triplets, 4.5 letters) and for Dmin, more than 0.35 log minarc for the differences to be considered abnormal. For low contrast letter visual acuity, there was a trend for the absolute interocular differences to increase significantly with age, but asymmetry remained relatively constant for the other visual measures.

Interocular differences in visual function in normal subjects

A commonly used clinical technique for determining whether visual function is abnormal, particularly when a patient is suspected of having unilateral or asymmetric disease, is to compare the visual function of the ‘suspect’ eye to that of the normal eye. This assumes that in normal patients visual function in each eye is equal and that this symmetry is maintained with age. To determine the extent of normal symmetry for clinical measures of visual function, we assessed high and low contrast visual acuity, letter contrast sensitivity and motion sensitivity (Dmin) in both eyes of a group of 91 subjects spanning an age range of 21 to 82 years. For the whole group the interocular differences in sensitivity for each of the tests approximated a Gaussian distribution. The results demonstrate that interocular differences should exceed more than 0.1 6 and 0.1 7 logMAR (~ 2 lines) for high and low contrast visual acuity respectively, before patients can be considered to be outside the range of normality. For the Pelli-Robson Chart, interocular differences must exceed 0.23 log CS (1.5 triplets, 4.5 letters) and for Dmin, more than 0.35 log minarc for the differences to be considered abnormal. For low contrast letter visual acuity, there was a trend for the absolute interocular differences to increase significantly with age, but asymmetry remained relatively constant for the other visual measures.

Dopaminergic modulation of impaired cognitive activation in the anterior cingulate cortex in schizophrenia

Dopaminergic dysregulation remains an empirical cornerstone for theories concerning the causation of schizophrenia. Evidence for a dopamine system dysfunction in schizophrenia includes the psychosis-inducing effects of dopaminergic agonists and the antipsychotic potency of dopaminergic antagonists. Here we use positron emission tomography (PET) to examine the regulatory role of dopamine on cortical function in normal subjects and unmedicated schizophrenic patients. Using a factorial experimental design, we compared the effect of dopaminergic manipulation with apomorphine on a neural response to a cognitive task. In the schizophrenic patients, relative to controls, an impaired cognitive activation of the anterior cingulate cortex was significantly modulated by a manipulation of dopaminergic neurotransmission. Thus, after apomorphine, the schizophrenic subjects displayed a significantly enhanced cognitive activation of the anterior cingulate cortex relative to the controls. These data provide in vivo evidence that an impaired cognitive-task-induced activation of the anterior cingulate cortex in schizophrenic patients can be significantly modulated by a dopaminergic manipulation.

Clinical Evaluation of Tc-99m Cystine A New Renal Radiopharmaceutical

Tc-99m cystine has been proven to be a good renal agent in animals, but its clinical evaluation has not been reported. In this study, Tc-99m cystine was used for evaluation of renal function in normal subjects and patients with chronic renal failure as well as in renal transplant patients. The results are compared with similar studies that used Tc-99m DTPA and Tc-99m GHA. The clearance values also have been compared with I-131 OIH clearance. The results show that Tc-99m cystine has good radiopharmaceutical characteristics suitable for evaluation of both renal function as well as morphology.

Clinical Evaluation of Tc-99m Cystine A New Renal Radiopharmaceutical

Tc-99m cystine has been proved to be a good renal agent in animals. Its clinical evaluation has not been reported. In this study, Tc-99m cystine is used for evaluation of renal function in normal subjects and patients with chronic renal failure as well as in renal transplant patients. The results are compared with similar studies using Tc-99m DTPA and Tc-99m GHA. The clearance values also are compared with I-131 OIH. The results show that Tc-99m cystine has good radiopharmaceutical characteristics suitable for evaluation of both renal function as well as morphology.

Effects of intracoronary acetylcholine and atropine on basal and dobutamine-stimulated left ventricular contractility.

The role of cholinergic pathways in modulating left ventricular contractile function in humans is not known. This study evaluated the effect of a cholinergic agonist (acetylcholine) and antagonist (atropine) on basal and beta-adrenergically stimulated left ventricular contractile function in normal subjects and subjects with denervated hearts after cardiac transplantation. Six subjects with normal left ventricular function and seven subjects who were 1 to 3 years after cardiac transplantation were studied. Acetylcholine, atropine, and the beta-adrenergic agonist dobutamine were infused via the left main coronary artery, and changes in left ventricular contractile function were assessed by measurement of peak +dP/dt. Intracoronary dobutamine increased +dP/dt by 70 +/- 15% and 66 +/- 20% in the normal subjects and transplant recipients, respectively. Intracoronary acetylcholine and atropine alone each had no effect on left ventricular +dP/dt in either normal subjects or transplant recipients. The concurrent infusion of acetylcholine with dobutamine reduced the response to dobutamine by 66 +/- 10% and 79 +/- 9% in normal subjects and transplant recipients, respectively. The concurrent infusion of atropine with dobutamine potentiated the response to dobutamine by 25 +/- 7% in normal subjects but had no effect in transplant recipients. Stimulation and inhibition of cholinergic receptors in the human heart can modulate the positive inotropic response to beta-adrenergic stimulation.

Atrial natriuretic peptide and left atrial systolic function in normal subjects.

The purpose of this study is to elucidate factors determining the release of atrial natriuretic peptide (ANP) in normal volunteers at rest. Ten normal volunteers were included in this study. Ages ranged between twenty-seven and thirty-three years (mean twenty-seven). The authors measured plasma levels of ANP, and four cardiac chamber volumes, and their functions by cine magnetic resonance imaging using the rephased gradient-echo method. Plasma levels of ANP in 10 normal subjects were 15.0-37.1 pg/mL (mean 23.6 pg/mL). No significant relationship was seen between ANP level and heart rate or blood pressure. The level of ANP was positively correlated with left atrial (LA) emptying fraction and negatively correlated with LA minimal volume (r = 0.85, P < 0.01; r = 0.64, P < 0.05, respectively). No significant relationship was observed between plasma ANP level and left ventricular, right ventricular, or right atrial parameters. These results suggest that LA systolic function is one of the major determinants for ANP release in normal subjects at rest.

Age and Gender Effects on Nasal Respiratory Function in Normal Subjects

Age and Gender Effects on Nasal Respiratory Function in Normal Subjects

Age and gender effects on nasal respiratory function in normal subjects.

One hundred and ninety-seven normal individuals between the ages of 5 and 73 years were evaluated to determine nasal resistance, nasal cross-sectional area, and respiratory mode during quiet breathing. Subjects were categorized into three age groups. Nasal resistance and respiratory mode were directly determined using posterior rhinomanometry and the SNORT technique, respectively. Nasal cross-sectional area was estimated using the hydrokinetic equation. Results indicated significant effects of age on all variables; significant gender differences were found for respiratory mode. Weak correlations were found between respiratory mode and nasal resistance. The results are presented as normative data on nasorespiratory characteristics to facilitate diagnostic and treatment decisions relative to individuals with normal morphology as well as to patients with craniofacial anomalies. A fundamental issue of both clinical and theoretical importance arising from the study pertains to the definitions of normality and impairment.

Effects of 830 nm continuous wave laser diode irradiation on median nerve function in normal subjects

The presence, magnitude, and nature of the effect that low intensity laser irradiation has on nerve function, growth, and repair constitute a contentious area of research. We have addressed one aspect of this controversy by systematically examining the influence of 830 nm laser radiation on median nerve function. In particular, we investigated median nerve motor and sensory distal latencies, action potential amplitudes, action potential areas, and conduction velocities as well as dorsal hand skin temperatures in 33 normal subjects in a double-blinded, randomized controlled study. All subjects received identical treatment: 30 seconds of "irradiation" at 10 points over the course of the right median nerve (five sites on the forearm and five sites distal to the wrist crease) with either an active (1.2 J/point) or inactive (0 J/point) 40 mW 830 nm continuous wave IR laser diode. Latencies, conduction velocities, amplitudes, areas, and skin temperatures were collected bilaterally at a baseline immediately prior to irradiation and at intervals of 1, 5, 10, 15, 20, and 30 minutes following treatment. Analysis of the results reveals that motor and sensory distal latencies were decreased in the treated limbs of the laser-treated group relative to the control group by 3-4% (P < .016 and .046, respectively, rank sum test). No significant differences in these quantities were found between the limbs within either group. Similarly, no alterations of action potential amplitudes, action potential areas, forearm conduction velocities, or skin temperatures were detected within or between the groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Early systemic and renal responses to nephrectomy in normotensive kidney donors

The present studies were designed to assess the effect of uninephrectomy (UNX) on arterial pressure and renal excretory function in normal subjects. Baseline values of arterial pressure, renal function, parameters of the renin-angiotensin and renal kallikrein-kinin systems and the response to acute saline loading (VE, 1800 ml in 3 h) were estimated in 18 kidney donors prior to and 1 year following UNX. Within the follow-up period of 14 +/- 1 months mean arterial pressure (MAP) increased by 7 +/- 2 mmHg, creatinine clearance decreased by 38 +/- 4%, plasma renin activity (PRA) decreased, urinary kallikrein remained unchanged, and the renal response to VE was blunted. According to individual changes in MAP associated with UNX, subjects were classified as responders (R, increase in MAP > or = 10%, n = 8) and non-responders (NR, n = 10). Age, incidence of a family history of hypertension, decrease in creatinine clearance, and predonation PRA, urinary kallikrein, and the natriuretic response to VE were similar in the two groups. However, following UNX, PRA decreased whereas 24-h urinary sodium and thus sodium intake increased only in the R group. In conclusion, in normotensive subjects a 50% reduction in renal mass may result in a consistent increase in MAP and sometimes the development of de novo hypertension (4/18 subjects). Baseline characteristics as well as the predonation renal response to VE do not provide a means of detecting kidney donors in whom arterial pressure will increase consistently after UNX.(ABSTRACT TRUNCATED AT 250 WORDS)

Visual half-field testing of memory functions in patients considered for surgical treatment of intractable complex partial epilepsy.

The present research employed the visual half-field (VHF) technique to assess memory functions in normal subjects and in patients with unilateral temporal lobe epilepsy prior to surgery. Two studies were conducted. In Study 1, concrete and abstract words were presented to the left (LVF) or the right visual half field (RVF), and measures were made of response latencies, naming, free recall, and recognition. In Study 2, pictures depicting random shapes with low verbal association values were presented, and measures were made of latencies for identification and recognition of the shapes. Overall, the results showed a RVF advantage for words, but no lateralization for shapes. A selective hemisphere memory deficit was obtained for abstract words in patients with left temporal lobe lesions. Otherwise, no obvious lesion-related differences were found in the preoperative analyses. It is concluded that VHF testing of verbal information, but not abstract visuo-spatial information, is discriminative in assessing hemispheric functions in normal subjects and patients with temporal-lobe epileptic lesions.

Determinants of Doppler indexes of left ventricular diastolic function in normal subjects (the Framingham heart study)

Normative Doppler values and determinants of left ventricular (LV) diastolic function in healthy subjects have not been fully elucidated. Subjects from the Framingham Heart Study were examined to describe reference values and determinants of echocardiographic Doppler indexes of diastolic function. One hundred twenty-seven randomly selected, rigorously defined, normal subjects, approximately evenly distributed by sex and age from the third through the eighth decades were studied by Doppler echocardiography. Normative values for 7 frequently used Doppler indexes of LV diastolic function are presented. Doppler indexes of LV diastolic function change dramatically with age; the peak velocity of early filling divided by late filling (peak velocity E/A) ranges from a mean of 2.08 ± 0.55 for subjects in their third decade to 0.84 ± 0.29 for those in their eighth decade. A peak velocity E/A ratio <1 is abnormal in subjects aged <40 years, but occurs in most subjects aged ⪰70 years. The high correlations between age and Doppler indexes of LV diastolic function;are not greatly attenuated after adjustment for other clinical parameters associated with diastolic function; the multivariate partial correlation coefficient between age and peak velocity E/A is −0.80 (p <0.0001). Heart rate, PR interval, LV systolic function, sex and systolic blood pressure are minor determinants of Doppler indexes of diastolic function. Body mass index, left atrial diameter, and LV wall thickness, internal dimension and mass have little or no association with Doppler indexes in healthy subjects. Age is the predominant determinant of Doppler indexes of LV diastolic function in normal subjects, whereas heart rate, PR interval, sex, systolic blood pressure and LV systolic function have a lesser impact. The independence of the age-diastolic function relation from changes in physiology and LV geometry is consistent with an intrinsic reduction in LV distensibility with advancing age. These findings indicate that Doppler diastolic function should be assessed with reference to age-specific normative values.

Changes in central and peripheral nervous system function during hypoglycemia in man: an electro-physiological quantification.

We measured somatosensory evoked potentials (SEP) in normal subjects during acute (group A) and moderately prolonged (group B) hypoglycemia. We considered the following parameters: peripheral conduction velocity (wrist-Erb CV), conduction time (CT) between brachial plexus and the cervical cord (Erb-N13) and central CT from the cervical cord/lower brainstem lemniscal pathway to the cortex (N13-N20). In group A, the electrophysiological parameters did not change significantly throughout the study. In group B, mean N13-N20 CT increased from a basal values of 5.82 +/- 0.11 to 6.22 +/- 0.11 msec at 105 min (p less than 0.02) and 6.33 +/- 0.11 msec at 120 min (p less than 0.05). This study indicates that neither acute nor moderately prolonged hypoglycemia influence the peripheral nerve function in normal subjects and provides evidence that hypoglycemia as low as 2.4 mmol/L, lasting more than 60 min, can significantly increase the conduction time of central somatosensory pathways.

Effect of mental stress on platelet function in normal subjects and in patients with coronary artery disease.

We studied the effect of emotional stress (mental arithmetic for 10 min) in 10 postinfarction patients and in 10 age-matched apparently healthy subjects as controls. Blood samples for platelet function studies and for the determination of epinephrine levels in serum were taken in basal conditions, at the end of mental stress and after 30 min of recovery. Patients were studied twice, in washout of medications and after oral administration of dipyridamole, 200 mg twice a day for 6 consecutive days. Mental stress induced in patients significant increments in different hemodynamic parameters (heart rate, systolic blood pressure and diastolic blood pressure) and in serum epinephrine levels. Concomitantly, the test produced a significant increase in platelet aggregation (induced by 3 microM ADP or 1 microgram/ml collagen), the formation of circulating platelet aggregates and an increase in plasma thromboxane B2 levels. Hemodynamic parameters and platelet function tests returned to baseline values after 30 min. Similar activation of hemodynamic parameters, similar increase in epinephrine levels and lower increase in platelet function by emotional stress were observed in control subjects. Treatment of patients with dipyridamole had no effect on stress-induced increase in hemodynamic parameters and epinephrine levels, but decreased stress-related platelet activation. These data can contribute to a better understanding of the complex relationships between psychosocial factors, the hemostatic system and vascular disease.

Effect of Postural Changes and Isometric Exercise on Doppler-Derived Measurements of Diastolic Function in Normal Subjects

To determine if simple maneuvers that occur in daily life, such as changes in body position and isometric handgrip exercise, affect Doppler-derived measurements of diastolic function, we studied 22 normal male subjects in the supine position at rest and during several postural manipulations and during handgrip exercise. Comparison of values obtained in the 80 degrees upright tilt position with those obtained in the standard supine position revealed significant decreases in early diastolic flow velocity (peak E) (-25 +/- 3 percent; p less than 0.001), late diastolic flow velocity (peak A) (-9 +/- 3 percent; p less than 0.01), and the ratio of early to late flow velocities (E/A ratio) (-17 +/- 4 percent; significant increases in deceleration time (+55 +/- 10 percent; p less than 0.001) and isovolumic relaxation time (+38 +/- 4 percent; p less than 0.001). Comparison of values obtained with supine isometric exercise with those obtained during the preceding supine resting state revealed significant decreases in peak E (-12 +/- 3 percent; p less than 0.001) and the E/A ratio (-21 +/- 4 percent; p less than 0.001) and significant increases in peak A (+15 +/- 4 percent; p less than 0.001) and isovolumic relaxation time (+16 +/- 3 percent; p less than 0.001). The response of Doppler-derived measurements of diastolic function to postural changes and isometric exercise is complex and multifactorial. Interpretation of these measurements must take into account changes in loading conditions.

Reflex anal dilatation: effect of parting the buttocks on anal function in normal subjects and patients with anorectal and spinal disease.

Anal dilatation in response to gentle parting of the buttocks has been advocated as a sign of sexual abuse in children, but nothing is known of the physiology of this response or its existence in normal subjects, in patients with spinal disease, and in patients with a weak sphincter and whether it can be elicited after training. To answer these questions we investigated the effect of parting the buttocks on anal function. Combined anal manometry and electromyography was conducted in six normal subjects (five men, one woman, aged 19-53 years), in 18 patients with faecal incontinence (three men, 15 women, aged 30-80 years), and in seven paraplegic patients (six men, one woman, aged 25-36 years), in four of whom the posterior sacral roots had been cut. Parting the buttocks in normal subjects reduced the pressure in the anal canal from 102 (20) to 14 (3) cm H2O (mean (SEM), p less than 0.00001), but did not cause the anus to gape. This drop in pressure was associated with increased electrical activity in the external anal sphincter. Normal subjects could consciously relax the external anal sphincter and reduce the anal pressure but not so as to result in anal gaping during traction on the buttocks, even after anal dilatation. Stimulation of the anal lining by moving a probe in and out of the anal canal increased the activity of the external anal sphincter, raising anal pressures. Paraplegic patients who had lost conscious control of their external sphincters showed anal gaping when the buttocks were parted. A similar phenomenon was seen in patients with faecal incontinence who had weakness of the external anal sphincter, while incontinent patients with weakness of both sphincters showed anal gaping even at rest. Inasmuch as the results of our study can be applied to children, the data suggest that reflex anal dilatation should only be used to support a diagnosis of sexual abuse if sphincter function is otherwise normal and there is no evidence of cerebrospinal disease. Although our results do not support the notion that children could become so conditioned to repeated digital or penile penetration of the anus that they can cause the anus to gape when the buttocks are parted, neither do they exclude it.