Healthy Volunteer Control Subjects Research Articles

Noninvasive Visualization of the Tear Film Microaerosol During Noncontact Tonometry Measurements

To investigate the aerosol generation by a noninvasive real-time observation device and assess the conditions relating to aerosolization during intraocular pressure (IOP) measurements using a commercial noncontact tonometer (NCT). Prospective experimental and healthy eye studies. In an initial experimental study, we devised a model mannequin eye to investigate how air puff pressure and IOP of the eye affected aerosol generation. In the human study including 20 healthy volunteer control subjects, the number of tear aerosol particles generated at 20 and 40 mm Hg air puff pressures with and without eye drop was investigated. The recorded aerosol visualization video was analyzed and the number of aerosol particles generated in 5 seconds after IOP measurement was measured. The experimental and human studies confirmed the aerosol generation during NCT measurements. In the experimental study, when the air puff pressures were set at 20 and 40 mm Hg, a lower IOP (5 mm Hg) generated significantly more aerosols than a higher IOP (25 mm Hg) (20 mm Hg, P=.0159; 40 mm Hg, P=.0079). There was also a significant positive correlation between the air puff pressure and the number of aerosol particles in both high- and low-IOP eyes (P < .001). At an air puff pressure of 40 mm Hg, the amount of aerosol generated was significantly higher with eye drop than without eye drop (P=.047). NCT generates significant aerosolization from the tear film, the amount of which is determined by the IOP and the air puff pressure and the presence of eye drop use before the measurements.

Tumour-infiltrating Langerhans cells in non-melanoma skin cancer, a clinical and immunohistochemical study.

Non-melanoma skin cancer, including basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) represents 78.5% of all skin malignant tumours in Egypt. Dendritic cells can be found in almost all human tumours, they play an important role in antitumour immunity. The aim of the present study was to evaluate the percentage of Langerhans cells using CD1a in non-melanoma skin cancer, including BCC and SCC and to correlate this percentage with their clinicopathological features. The current study was performed on surgically excised specimens of 41 patients presented with non-melanoma skin cancer (26 BCC and 15 SCC) and 16 healthy volunteer control subjects. The mean and median percentage of Langerhans cells were higher in normal epidermis of control compared to malignant tumour tissue (p < 0.0001) and adjacent epidermis overlying malignant tumour tissue (p = 0.007). Langerhans cells were significantly seen in BCC cases more than SCC (p = 0.035) and they were seen in facial lesions more than those arising from other sites (p = 0.007). The reduction of Langerhans cells is a way for non-melanoma skin cancer to develop and progress. Marked reduction of Langerhans cells in SCC compared to BCC could refer to their role as a barrier against metastasis.

A Voxel-Based Magnetic Resonance Imaging Morphometric Study of Cerebral and Cerebellar Gray Matter in Patients Under 65 Years with Essential Tremor.

BackgroundThe aim of this study was to compare the morphological changes in cerebral and cerebellar gray matter in patients with essential tremor under 60-years-of-age, with age-matched and gender-matched normal healthy volunteer control subjects, using functional magnetic resonance imaging (fMRI) and voxel-based morphometry (VBM) analysis.Material/MethodsA retrospective, controlled, comparative clinical study included 17 patients with essential tremor, <60 years-of-age, and 17 age-matched and gender-matched healthy volunteer control subjects, recruited between June 2010–July 2012. MRI and VBM analysis were used to compare cerebral and cerebellar gray matter density between groups. The Washington Heights–Inwood Genetic Study of Essential Tremor (WHIGET) rating scale was used to assess tremor severity in the patient group. Clinical and demographic characteristics were recorded for all study participants.ResultsMRI and VBM analysis showed significant bilateral expansion of the cerebellum, occipital fusiform cortices, right inferior temporal gyrus, and precentral lobes in patients with essential tremor (P<0.005); reduction in gray matter was found in the left parietal lobe. The region of interest (ROI) analysis showed volume enlargement in the thalamus, midbrain, and the precuneus (P<0.005). No significant correlation between changes in gray matter and changes in clinical variables, including age, gender, tremor duration, the activity of daily living (ADL) scale, the mini-mental state examination (MMSE) scale, family history, and tremor severity were found.ConclusionsPredominantly cerebellar gray matter expansion in patients less than 60 years-of-age with essential tremor might be the result of compensation for the decline in cerebellar function.

Metabolic correlates of reserve and resilience in MCI due to Alzheimer's Disease (AD)

BackgroundWe explored the presence of both reserve and resilience in late-converter mild cognitive impairment due to Alzheimer’s disease (MCI-AD) and in patients with slowly progressing amyloid-positive MCI by assessing the topography and extent of neurodegeneration with respect to both “aggressive” and typically progressing phenotypes and in the whole group of patients with MCI, grounding the stratification on education level.MethodsWe analyzed 94 patients with MCI-AD followed until conversion to dementia and 39 patients with MCI who had brain amyloidosis (AMY+ MCI), all with available baseline 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) results. Using a data-driven approach based on conversion time, patients with MCI-AD were divided into typical AD and late-converter subgroups. Similarly, on the basis of annual rate of Mini Mental State Examination score reduction, AMY+ MCI group was divided, obtaining smoldering (first tertile) and aggressive (third tertile) subgroups. Finally, we divided the whole group (MCI-AD and AMY+ MCI) according to years of schooling, obtaining four subgroups: poorly educated (Low-EDUC; first quartile), patients with average education (Average-EDUC; second quartile), highly educated (High-EDUC; third quartile), and exceptionally educated (Except-EDUC; fourth quartile). FDG-PET of typical AD, late converters, and aggressive and smoldering AMY+ MCI subgroups, as well as education level-based subgroups, were compared with healthy volunteer control subjects (CTR) and within each group using a two-samples t test design (SPM8; p < 0.05 family-wise error-corrected).ResultsLate converters were characterized by relatively preserved metabolism in the right middle temporal gyrus (Brodmann area [BA] 21) and in the left orbitofrontal cortex (BA 47) with respect to typical AD. When compared with CTR, the High-EDUC subgroup demonstrated a more extended bilateral hypometabolism in the posterior parietal cortex, posterior cingulate cortex, and precuneus than the Low- and Average-EDUC subgroups expressing the same level of cognitive impairment. The Except-EDUC subgroup showed a cluster of significant hypometabolism including only the left posterior parietal cortex (larger than the Low- and Average-EDUC subgroups but not further extended with respect to the High-EDUC subgroup).ConclusionsMiddle and inferior temporal gyri may represent sites of resilience rather than a hallmark of a more aggressive pattern (when hypometabolic). These findings thus support the existence of a relatively homogeneous AD progression pattern of hypometabolism despite AD heterogeneity and interference of cognitive reserve. In fact, cortical regions whose “metabolic resistance” was associated with slower clinical progression had different localization with respect to the regions affected by education-related reserve.

Brain Activity Stimulated by Prism Adaptation Tasks Utilized for the Treatment of Unilateral Spatial Neglect: A Study with fNIRS.

We investigated the neurological basis for efficacy of prism adaptation therapy, which is used for the treatment of poststroke unilateral spatial neglect (USN). Study subjects were 6 USN-positive (+), 6 USN-negative patients, and 6 healthy volunteer control subjects. USN was identified by the Behavioural Inattention Test (BIT). During the tasks, brain activity was assessed with fNIRS via changes in oxyHb concentration per unit length. There was no significant difference in the number of errors in the task between the 3 groups. However, in the USN(+) group there was a significantly greater reduction in oxyHb levels in the right parietal association cortex during the prism adaptation task than in the other 2 groups (P < 0.05). There was an immediate improvement in USN symptoms as well as a significant increase in oxyHb levels during the prism adaptation in the channels covering the right frontal and parietal lobes in 2 patients in the USN(+) group (P < 0.05). This result suggested that decreased activity in the right parietal association cortex, which is related to spatial perception, during the prism adaptation task and task-induced reorganization of the right frontal and parietal areas were involved in improvement in USN symptoms.

Intima-media thickness and arterial distensibility in Behçet's disease.

The etiology of Behçet's disease, a systemic vasculitis, is unknown. Vascular involvement may be seen in 25% of patients with Behçet's disease. Vasculitis make the prognosis of Behçet's disease severe. The aim of this study is to examine the structural and functional changes and relations of these changes with progression and prognosis of Behçet's disease. For this purpose, 40 patients with Behçet's disease and 40 healthy volunteer control subjects were analyzed, additionally patients with Behçet's disease were divided into 2 subgroups as those with vascular complications and those without vascular complications. Intima-media thickness and arterial distensibility were measured in all subjects with carotid artery ultrasonography. Carotid artery distensibility was significantly lower in the patient group compared to the control group (0.67 +/- 0.2, 0.93 +/- 0.4, p < 0.05), and carotid artery IMT was significantly higher (0.59 +/- 12, 0.80 +/- 0.11, p < 0.05). A statistically significant increase in IMT has been detected (0.77 +/- 11, 0.86 +/- 11, p < 0.05) in patients with Behçet's disease with vascular involvement compared to patients with Behçet's disease without vascular involvement, arterial distensibility in patients with vascular disease was similar with those who has no vascular disease (0.69 +/- 0.25, 0.63 +/- 0.25, p > 0.05). There was a significant negative linear regression between arterial distensibility and systolic blood pressure (SBP) (B = -1 x 10(-2), p < 0.05), and a significant positive linear regression has also been found between IMT and SBP and diastolic blood pressure (DBP) and pulse pressure (PP) (B = 6.8 x 10(-3) for SBP, p < 0.05, B = 6.9 x 10(-3) for DBP, p < 0.05, B = 6 x 10(-3) for PP, p < 0.05). As a result, IMT increases and AD decreases in patients with Behçet's disease compared to results in the control group. Although more studies are required for this subject, use of noninvasive parameters such as IMT and AD, which reflect the structural and functional characteristics of vasculature, may be useful to define disease progression and subjects at high risk.

Fas and Fas ligand: expression and soluble circulating levels in cutaneous malignant melanoma.

The Fas/Fas ligand (FasL) system plays a key part in maintaining tissue homeostasis via the induction of apoptosis. Functional impairment of the Fas/FasL system is associated with the development and progression of malignancies. Malignant melanoma cells and tissues have been shown to express Fas and FasL to variable extents. To demonstrate the expression and the presence of soluble circulating levels of Fas and FasL in cutaneous malignant melanoma. Biopsy specimens of 42 patients with primary melanoma and nine patients with cutaneous metastatic melanoma were obtained for immunohistochemistry studies. All patients were followed for at least 5 years. In another 46 patients with melanoma (15 stage I and II; 11 stage III; and 20 stage IV) and in 10 healthy volunteer control subjects circulating levels of Fas and FasL were analysed with commercial ELISA tests. FasL was strongly positive in 38 (90%) of 42 primary melanomas; two of nine metastases did not express FasL. In the primary melanomas Fas was strongly or intensely positive in 17 (40%), moderately or weakly positive in 10 (24%) and negative in 15 (36%) of 42 melanomas. Soluble Fas plasma levels in patients with metastatic malignant melanoma were significantly elevated over those in the control group (P = 0.01). The absence of Fas in most of the thick melanomas that did not metastasize, and in insitu melanomas, might be taken as a theoretical factor for a good prognosis. Soluble Fas is increased in patients with metastatic melanoma and might be associated with poor prognosis.

Regional size reduction in the human corpus callosum following pre- and perinatal brain injury.

This morphometric study examined two aspects of corpus callosum development: pediatric cortico-callosal topography and developmental neuroplasticity subsequent to perinatal brain injury. In vivo magnetic resonance imaging was used to quantify the total midsagittal cross-sectional area and five anterioposterior subregions of the callosum in 10 children with focal lesions and 86 healthy volunteer control subjects. Nine of the ten children with early injury showed a reduction in the total area of the callosum relative to matched controls. The area of the total callosum cross-section was inversely proportional to the size of lesion. All patients displayed region-specific size reduction. This regional thinning bore a topographical relationship to the lesion sites. Reduction in anterior subregions 1, 2 and 3 was respectively associated with lesions in the anterior inferior frontal area, the middle and superior frontal region, and the precentral area. Attenuation of subregion 4 corresponded to anterior parietal lesions, and thinning of subregion 5 occurred with posterior parietal injury. This cortical-callosal pattern coincides with adult and nonhuman primate mappings. Callosal thinning despite the early onset of the lesions suggests limits to developmental neuroplasticity.

Quantitative head injury assessment: magnetic resonance spectroscopy and intensive care management during MR

Objective: To quantify central neuronal damage in patients with acute traumatic brain injury (TBI), to determine if brain tissue ischaemia was present using lactate as a marker, and to describe methods of delivering intensive anaesthetic care within a magnetic resonance scanner. Design: Patients underwent T2 weighted magnetic resonance and spectroscopic imaging (SI) early after TBI. Setting: A tertiary referral centre for neurosurgery and neurointensive care in Scotland. Subjects: Eight adults with TBI imaged 4-26 days (mean 13) after injury. Findings were compared to six healthy volunteer control subjects. Measurements and results: A significant reduction of N-acetyl aspartate (NAA- a neurone specific amino acid) was found in areas of brain with obvious lesions on T2 weighted imaging (p<0.001), and in areas where there were no obvious T2 lesions (p<0.02) compared with volunteer control spectra. We found no evidence of lactate. Conclusions: SI may be useful in assessing the extent of neuronal injury...

Quantitative head injury assessment: magnetic resonance spectroscopy and intensive care management during MR

Objective: To quantify central neuronal damage in patients with acute traumatic brain injury (TBI), to determine if brain tissue ischaemia was present using lactate as a marker, and to describe methods of delivering intensive anaesthetic care within a magnetic resonance scanner. Design: Patients underwent T2 weighted magnetic resonance and spectroscopic imaging (SI) early after TBI. Setting: A tertiary referral centre for neurosurgery and neurointensive care in Scotland. Subjects: Eight adults with TBI imaged 4-26 days (mean 13) after injury. Findings were compared to six healthy volunteer control subjects. Measurements and results: A significant reduction of N-acetyl aspartate (NAA- a neurone specific amino acid) was found in areas of brain with obvious lesions on T2 weighted imaging (p&lt;0.001), and in areas where there were no obvious T2 lesions (p&lt;0.02) compared with volunteer control spectra. We found no evidence of lactate. Conclusions: SI may be useful in assessing the extent of neuronal injury which compliments CT and MRI information. Traumatic brain injury affects all age groups and the associated morbidity has devastating consequences, SI may therefore assist clinicians in the management of these patients in the future. As demand for MR imaging of intensive care patients increases, clinicians will require to continue to develop safe working practices and maintain intensive care monitoring and therapies during these investigations.

Comparison of Left Ventricular Function and Volumes During Transesophageal Atrial Pacing Combined With Two-Dimensional Echocardiography in Patients With Syndrome X, Atherosclerotic Coronary Artery Disease, and Normal Subjects

Nine patients with syndrome X were compared with 2 groups of patients known to have coronary artery disease (CAD) (8 patients who developed regional wall motion abnormalities [group ECHO+] and 6 patients who showed only ST depression at echo-pacing [group ECG+]) and with 6 healthy volunteer control subjects. Left ventricular function at rest was normal in all patients. End-diastolic and end-systolic volumes (ml/m2) and ejection fraction were calculated at baseline and at peak of echo-pacing using a Simpson’s biplane method. No regional wall motion abnormalities were observed during the echo-pacing in patients with syndrome X or in the volunteers. End-diastolic volume decreased in patients with syndrome X, in the volunteers (from 47 ± 11 to 30 ± 12 and from 72 ± 7 to 38 ± 6, respectively, p <0.01 for both), and in ECG+ patients (from 48 ± 10 to 33 ± 6, p <0.05), whereas it did not change in ECHO+ patients. End-systolic volume decreased in patients with syndrome X and in the volunteers (from 17 ± 5 to 11 ± 4 and from 28 ± 6 to 16 ± 4, respectively, p <0.01 for both), whereas it did not change or else slightly increased in patients with CAD (from 18 ± 10 to 16 ± 5 for ECG+ patients and from 19 ± 5 to 24 ± 9 for ECHO+ patients, p = NS for both), regardless of whether regional wall motion abnormalities appeared. Ejection fraction decreased in ECG+ and ECHO+ patients (from 64 ± 12 to 52 ± 11 and from 62 ± 9 to 44 ± 13, respectively, p <0.01 for both), whereas it did not change in patients with syndrome X and in the volunteers (from 64 ± 8 to 61 ± 8 and from 61 ± 7 to 58 ± 7, respectively, p = NS for both). During echo-pacing in syndrome X patients no regional wall motion was detected. Left ventricular volumes and ejection fraction showed the same patterns of variation in these patients as they did in the healthy control subjects, in contrast with those patients with CAD, whether or not regional wall motion abnormalities appeared in the latter.

Higher concentrations of matrix metalloproteinases in bronchoalveolar lavage fluid of patients with adult respiratory distress syndrome.

This study was designed to investigate possible involvement of type IV collagenolytic matrix metalloproteinases (MMPs; 72-kDa type IV collagenase [MMP-2], 92-kDa type IV collagenase [MMP-9]), and the respective specific tissue inhibitors of these MMPs (TIMP-2 and TIMP-1) in the development of adult respiratory distress syndrome (ARDS). We determined the concentrations of these enzymes in the bronchoalveolar lavage fluid (BALF) from patients with ARDS using newly developed sensitive one-step sandwich enzyme immunoassay methods. BALF obtained from the 17 patients and eight healthy volunteer control subjects were also used for the analysis of the number of the cellular component. Concentrations of the 7S portion of type IV collagen and laminin in the BALF were measured as markers of basement membrane disruption. In the BALF from the ARDS patients, the concentrations of MMP-2 (66.7 +/- 57.0 ng/ml versus < 7.0 ng/ml for controls, p < 0.01) and MMP-9 (118.0 +/- 309.3 ng/ml versus 9.0 +/- 9.5 ng/ml for controls, p < 0.05), and the specific inhibitor of MMP-9 (TIMP-1) (161.0 +/- 145.0 ng/ml versus < 50 ng/ml for controls, p < 0.01) were significantly higher compared with those for healthy control subjects. In the ARDS patients, the concentrations of MMP-2 correlated both with those of 7S collagen and laminin; MMP-9 with the concentration of 7S collagen and the number of neutrophils. These findings suggest that the increased concentration of collagenolytic MMPs in lung plays a role in the pathogenesis of ARDS.

Brain morphology, dopamine, and eye-tracking abnormalities in first-episode schizophrenia. Prevalence and clinical correlates.

To characterize the pathophysiology of schizophrenia and to identify biologic markers in first-episode patients with no or little prior treatment exposure. Prospective study of an inception cohort. Psychiatric division of an academic medical center with a suburban metropolitan catchment area. 70 patients in their first episode of schizophrenia (77%) or schizoaffective disorder (23%) with no (70%) or limited prior neuroleptic exposure (30%), and 50 healthy volunteer control subjects. ASSESSMENT MEASURES: Demographic and clinical evaluations of natural history and psychopathology; methylphenidate hydrochloride and apomorphine hydrochloride stimulation tests as measures of central nervous system dopamine activity; brain magnetic resonance imaging; eye-tracking examinations. Preliminary analyses demonstrate that pathobiologic features previously identified in heterogeneous and primarily chronically ill patients are also present in subgroups during their first episode. These include psychotogenic response to methylphenidate (59%), abnormal growth hormone (GH) secretion (50%), abnormal brain morphology (31%), and eye-tracking dysfunction (51%). An association of pathobiologic variables with increased symptom severity and earlier age of onset was observed but not statistically significant. The strongest associations among biologic variables were for the following: GH secretion and psychotogenic response to methylphenidate, which may reflect increased dopamine agonist neural activity; decreased GH response to apomorphine and third-ventricle enlargement, which may represent a neuropathologic correlate of anterior pituitary abnormalities; and morphologic abnormalities of the medial temporal lobe and third ventricle were associated with normal eye tracking, suggesting that these pathobiologic features are mediated by distinct processes. These phenomena appear to be a consequence of the disease rather than the effects of chronicity, drug treatment, or institutionalization. It remains to be determined if these biologic phenomena will remain stable over time or change with disease progression. A companion article examines the clinical significance of these findings.

Abnormal pedal thermoregulation in interstitial cystitis.

Isolated cold stress tests were used to evaluate the thermoregulatory capacity in the feet of 19 patients with interstitial cystitis (IC) and of 11 healthy volunteer control subjects. Mean pedal skin temperature fell more rapidly in the IC group as compared with controls; significant differences were found at 10-min (P = 0.002) and 20-min (P = 0.0008) cooling. Mean skin temperature remained lower in the IC group throughout the study. Sixteen feet (42%) in the IC group and five (22%) of the control feet failed to return to within 2 degrees C of baseline temperature during the 20-min recovery period. These findings may reflect abnormal vasomotor control in the IC group and, if so, may be indicative of increased spinal sympathetic activity in interstitial cystitis.

Taurine deficiency after intensive chemotherapy and/or radiation

Taurine, a nonessential amino acid (AA), is the most abundant free AA in the intracellular space. We measured plasma AA concentrations in 36 patients 7-28 d after intensive chemotherapy and/or radiation. Plasma taurine concentrations were uniformly low in all patients (20.0 +/- 6.4 mumol/L, mean +/- SD). Plasma taurine in 11 healthy volunteer control subjects was 45.0 +/- 20.3 mumol/L (P less than 0.001). Other AA concentrations, specifically those of precursor AAs methionine and cystine, were normal. We prospectively measured plasma AA concentrations in 12 patients before starting and 6-10 d after completing intensive cytotoxic treatment. Values before treatment were 37.2 +/- 11.6, 109.6 +/- 30.7, and 18.5 +/- 4.8 for taurine, cystine, and methionine, respectively, and were 24.3 +/- 6.0, 111.2 +/- 23.8, and 24.0 +/- 14.5 after treatment. Pretreatment plasma taurine correlated directly with the magnitude of decrease in plasma taurine during cytotoxic treatment (n = 12, r = 0.85, P less than 0.01). Intensive cytotoxic chemotherapy and/or radiation leads to a reduction in plasma taurine concentrations without any change in its precursor AAs, methionine and cystine. The clinical relevance of plasma taurine depletion will need further study.

Clinical and Pharmacologic Study of Orally Administrated Uridine

Effects of oral administrations of uridine were investigated in a study of six healthy volunteer control subjects and nine patients with metastatic colorectal cancer. Oral uridine was studied as single-dose administrations at doses escalating from 0.3 to 12 g/m2 and as multiple-dose administrations every 6 hours for 3 days at doses from 5 to 10 g/m2. The maximum tolerated dose (MTD) was 10 to 12 g/m2 for a single dose of uridine and 5 g/m2 for the multiple-dose regimen. Diarrhea was the dose-limiting toxic effect. Single-dose oral uridine resulted in an increase in plasma uridine concentrations in the range of 60 to 80 microM after doses of 8 to 12 g/m2. At these doses, bioavailability of oral uridine ranged from 5.8% to 9.9%. At the MTD of 5 g/m2 in the multiple-dose uridine schedule, steady-state plasma uridine levels of approximately 50 microM were achieved. Further studies should explore the role of oral uridine in the modulation of the toxicity of fluorouracil.

Insulin resistance after oral glucose tolerance testing in patients with major depression.

An association between affective disorders and alterations in glucose utilization has been recognized. The authors administered a 5-hour oral glucose tolerance test (GTT) to 28 depressed patients and 21 healthy volunteer control subjects and measured serum glucose as well as plasma insulin and glucagon responses. Depressed patients demonstrated significantly higher basal glucose levels, greater cumulative glucose responses after the GTT, and larger cumulative insulin responses after the GTT than control subjects. Values for cumulative glucagon did not significantly differ between groups. These findings indicate the presence of a functional state of insulin resistance during major depressive illness and suggest the presence of a more generalized biological disturbance in some depressed patients.

Multiple hormonal responses to insulin-induced hypoglycemia in depressed patients and normal volunteers.

Studies have shown that some depressed patients may demonstrate multiple hormonal response abnormalities after a neuroendocrine challenge test; this finding has suggested the strategy of measuring several hormones after an insulin tolerance test. The authors gave insulin tolerance tests to 72 depressed patients and 51 age- and sex-matched healthy volunteer control subjects and measured glucose, cortisol, prolactin, and human growth hormone (GH) responses. Although there were no differences between patients and control subjects in the mean decrease in glucose levels after the insulin tolerance test, depressed men demonstrated significantly lower prolactin and GH levels after the test.

Abnormal prolactin responsivity to dopaminergic suppression in hyperprolactinemic patients

Previous in vivo studies have shown that the constant infusion of dopamine suppresses prolactin (PRL) levels to within the normal range in a variety of hyperprolactinemic states, but there are no data on the relative suppressibility of the lactotroph in patients with hyperprolactinemia or on their metabolism of dopamine. Consequently, six patients with elevated PRL levels received a dopamine infusion of 4 μg/kg/min to study PRL clearance while another eight patients underwent a graded infusion at rates of 0, 1, 2 and 4 μg/kg/min to test PRL suppressibility. In four patients of the latter group an 8 μg/kg/min infusion rate was added. Healthy volunteer control subjects underwent comparable studies. PRL was measured by radioimmunoassay and dopamine by radioenzymatic techniques. The absolute PRL levels at each infusion rate were greater in the patients than in the control subjects. During the 4 μg/kg/min infusion rate, the respective PRL concentrations were 8.2 ± 1.8 and 2.0 ±0.1 ng/ml, (p < 0.001), despite higher dopamine levels in the patients (45.5 ± 6.7 versus 33.5 ± 3.8 ng/ml, p < 0.05). Neither increasing the infusion rate to 8 μg/kg/min nor prolonging the 4 μg/kg/min infusion for 6 hours decreased PRL levels further (9.6 ± 3.3 and 10.8 ± 2.5 ng/ml, respectively). Relative PRL resistance to dopamine in the hyperprolactinemic patients was demonstrated by (1) a significantly more shallow slope of the regression line of PRL versus dopamine concentrations and (2) the concentration of dopamine causing 50 percent PRL suppression (14.7 versus 6.8 ng/ml, p < 0.02). PRL metabolism was not disordered in the patients with elevated PRL levels, since the half-life ( t 1 2 ) of the early phase of PRL clearance during their prolonged 4 μg/kg/min dopamine infusion was similar to that present in the control subjects (58.5 ± 5.9 versus 53.7 ± 9.4 min). Thus, these data demonstrate both an absolute and relative lactotroph refractoriness to dopamine in hyperprolactinemic states and suggest that there remains either a dopamine-resistant cell population, and/or continued PRL release from an enlarged cell mass, despite maximal inhibitory dopamine concentrations.