CT Angiography ASPECTS Predicts Outcome Much Better Than Noncontrast CT in Patients with Stroke Treated Endovascularly.

BACKGROUND AND PURPOSE: Noncontrast CT ASPECTS has been investigated as a predictor of outcome in patients with acute ischemic stroke. Our purpose was to investigate whether CTA source images are a better predictor of clinical and radiologic outcomes than NCCT ASPECTS in candidates for endovascular stroke therapy. MATERIALS AND METHODS: CT scans of patients (n = 124) were independently evaluated by 2 readers for baseline NCCT and CTA source image ASPECTS and for follow-up ASPECTS. An mRS of ≤2 at 3 months was considered a favorable outcome. Receiver operating characteristic curve analysis was used to assess the ability of NCCT and CTA source image ASPECTS to identify patients with favorable outcomes. A stepwise multiple regression analysis was performed to find independent predictors of outcome. RESULTS: Baseline CTA source image ASPECTS correlated better than NCCT ASPECTS with follow-up ASPECTS (r = 0.76 versus r = 0.51; P for comparison of the 2 coefficients < .001). Receiver operating characteristic curve analysis showed that baseline CTA source image ASPECTS compared with NCCT ASPECTS can better identify patients with favorable outcome (CTA source image area under the curve = 0.83; 95% CI, 0.76-0.91; NCCT area under the curve = 0.67; 95% CI, 0.58-0.77; P < .001). Finally, the stepwise regression analysis showed that lower age, good recanalization, lower time to recanalization, and good baseline CTA source image ASPECTS, not NCCT ASPECTS, were independent predictors of favorable outcome. CONCLUSIONS: CTA source image ASPECTS predicts outcome better than NCCT ASPECTS; this finding suggests CTA rather than NCCT as a main step in the decision-making process for patients with acute ischemic stroke.

Pathological Gambling in Parkinson's disease patients: Dopaminergic medication or personality traits fault?

Impulse control disorders (ICDs) are clinically relevant in Parkinson disease (PD) patients, with an established association with PD medication. Aim of our study was to study whether the increased frequency of pathological gambling (PG), reported in subgroups of PD patients, is related to specific personality tracts additional to dopaminergic medications. Thirty-seven PD patients with a personal history of PG where enrolled. Twenty one PD patients, matched for disease and dopaminergic therapy, never experiencing PG, were enrolled as controls. All subjects were tested with the Minnesota Multiphasic Inventory Personality scales (MMPI-2). Our data showed that PD group with PG exhibited significantly higher mean values of the three validity scales in comparison to the non-PG-PD group, demonstrating an higher tendency to lie. Content scales showed a significant increase of cynicism and bizarre ideation scales score in the PG-PD group, not exhibiting pathological values at the validity scales, (p: 0.02) in comparison to non-PG PD patients. According to our results, PG seems to be associated with precise personality tracts. Personality profiles of cluster A personality disturbances - Axys 2 according with DSM-5 TR (paranoid type) at MMPI-2 might be a warning index helpful in selecting dopaminergic treatment, to avoid subsequent ICDs appearance.

A randomized clinical trial to evaluate the effects of rasagiline on depressive symptoms in non-demented Parkinson's disease patients.

BACKGROUND AND PURPOSE: Depressed mood is a common psychiatric problem associated with Parkinson's disease (PD), and studies have suggested a benefit of rasagiline treatment. METHODS: ACCORDO (see the ) was a 12-week, double-blind, placebo-controlled trial to evaluate the effects of rasagiline 1 mg/day on depressive symptoms and cognition in non-demented PD patients with depressive symptoms. The primary efficacy variable was the change from baseline to week 12 in depressive symptoms measured by the Beck Depression Inventory (BDI-IA) total score. Secondary outcomes included change from baseline to week 12 in cognitive function as assessed by a comprehensive neuropsychological battery; Parkinson's disease quality of life questionnaire (PDQ-39) scores; Apathy Scale scores; and Unified Parkinson's Disease Rating Scale (UPDRS) subscores. RESULTS: One hundred and twenty-three patients were randomized. At week 12 there was no significant difference between groups for the reduction in total BDI-IA score (primary efficacy variable). However, analysis at week 4 did show a significant difference in favour of rasagiline (marginal means difference ± SE: rasagiline -5.46 ± 0.73 vs. placebo -3.22 ± 0.67; P = 0.026). There were no significant differences between groups on any cognitive test. Rasagiline significantly improved UPDRS Parts I (P = 0.03) and II (P = 0.003) scores versus placebo at week 12. Post hoc analyses showed the statistical superiority of rasagiline versus placebo in the UPDRS Part I depression item (P = 0.04) and PDQ-39 mobility (P = 0.007) and cognition domains (P = 0.026). CONCLUSIONS: Treatment with rasagiline did not have significant effects versus placebo on depressive symptoms or cognition in PD patients with moderate depressive symptoms. Although limited by lack of correction for multiple comparisons, post hoc analyses signalled some improvement in patient-rated cognitive and depression outcomes.

Randomized trial of safinamide add-on to levodopa in Parkinson's disease with motor fluctuations.

Levodopa is effective for the motor symptoms of Parkinson's disease (PD), but is associated with motor fluctuations and dyskinesia. Many patients require add-on therapy to improve motor fluctuations without exacerbating dyskinesia. The objective of this Phase III, multicenter, double-blind, placebo-controlled, parallel-group study was to evaluate the efficacy and safety of safinamide, an α-aminoamide with dopaminergic and nondopaminergic mechanisms, as add-on to l-dopa in the treatment of patients with PD and motor fluctuations. Patients were randomized to oral safinamide 100 mg/day (n = 224), 50 mg/day (n = 223), or placebo (n = 222) for 24 weeks. The primary endpoint was total on time with no or nontroublesome dyskinesia (assessed using the Hauser patient diaries). Secondary endpoints included off time, Unified Parkinson's Disease Rating Scale (UPDRS) Part III (motor) scores, and Clinical Global Impression-Change (CGI-C). At week 24, mean ± SD increases in total on time with no or nontroublesome dyskinesia were 1.36 ± 2.625 hours for safinamide 100 mg/day, 1.37 ± 2.745 hours for safinamide 50 mg/day, and 0.97 ± 2.375 hours for placebo. Least squares means differences in both safinamide groups were significantly higher versus placebo. Improvements in off time, UPDRS Part III, and CGI-C were significantly greater in both safinamide groups versus placebo. There were no significant between-group differences for incidences of treatment-emergent adverse events (TEAEs) or TEAEs leading to discontinuation. The addition of safinamide 50 mg/day or 100 mg/day to l-dopa in patients with PD and motor fluctuations significantly increased total on time with no or nontroublesome dyskinesia, decreased off time, and improved parkinsonism, indicating that safinamide improves motor symptoms and parkinsonism without worsening dyskinesia.

Transcranial direct current stimulation of the affected hemisphere does not accelerate recovery of acute stroke patients.

BACKGROUND AND PURPOSE: Transcranial direct current stimulation (TDCS) is a potential tool to improve motor deficits in chronic stroke patients. Safety and efficacy of this procedure in acute stroke patients have not yet been addressed. METHODS: We performed in our stroke unit a single-centre randomized, double-blind, sham-controlled study to investigate safety and efficacy of anodal TDCS of the affected hemisphere in acute stroke patients. The second day from stroke onset, 50 acute stroke patients received either five-daily sessions of anodal (n=25) at 2mA for 20min or sham TDCS (n=25) to the ipsilesional primary motor cortex (M1). Motor deficit was assessed by the short form of the Fugl-Meyer motor scale (FM) and overall neurological deficit by the National Institute of Health Stroke Scale (NIHSS) at onset, at 5days after stroke and after 3months. RESULTS: No side effects were detected during either TDCS or sham. In both groups, there was a significant improvement in NIHSS and FM scores, which did not significantly differ when comparing TDCS and sham. CONCLUSIONS: Five-daily sessions of anodal TDCS to the ipsilesional M1 appear to be safe in acute stroke patients but do not improve clinical outcome.

Different patterns of cardiac sympathetic denervation in tremor-type compared to akinetic-rigid-type Parkinson's disease: molecular imaging with ¹²³I-MIBG.

The aim of this study was to evaluate the correlation between the clinical motor phenotypes of Parkinson's disease (PD) and ¹²³I-MIBG myocardial uptake. In total, 53 patients with PD [31 males and 22 females, mean age 62±10 years; 19 Hoehn & Yahr (H&Y) stage 1, 9 stage 1.5, 15 stage 2 and 10 at stage 3] were examined and subdivided into different clinical forms on the basis of dominance of resting tremor (n=19, TDT) and bradykinesia plus rigidity (n=34, ART). This status was correlated with the semi-quantitative analysis of ¹²³I-MIBG myocardial uptake. An age-matched control group of 18 patients was recruited (8 males and 10 females, mean age 62.4±16.3 years). ¹²³I-MIBG myocardial uptake significantly correlated with disease duration in early (r²=0.1894; P=0.0028) and delayed images (r²=0.1795; P=0.0037) in PD patients, while no correlation was found when considering age at examination, UPDRS III motor examination section score and H&Y score. PD patients showed a reduced ¹²³I-MIBG myocardial uptake compared to the control group in early (P=0.0026) and delayed images (P=0.0040), and ¹²³I-MIBG myocardial uptake was significantly lower in delayed images in TDT patients compared with ART patients (P=0.0167). A decrease was detected in the heart-to-mediastinum (H/M) ratio in delayed images compared to that of the early images in TDT patients (P=0.0040) and in the whole PD population (P=0.0012), while no differences were found in ART patients (P=0.1043). The results of the present study revealed that the cardiac sympathetic system is more severely impaired in TDT than in ART patients and ¹²³I-MIBG molecular imaging has the potential help in improving therapeutic planning in these patients.

Acute stroke treatment using the Penumbra endovascular mechanical thrombolysis device: a single-centre experience.

PURPOSE: Ischaemic stroke due to occlusion of large cerebral vessels has a poor prognosis. The clinical outcome is related to efficacy and timing of recanalisation of the occluded arteries. We report our experience with a thrombus aspiration device (Penumbra), and focus on pre- and postprocedural management. MATERIALS AND METHODS: We retrospectively reviewed 18 consecutive patients with acute ischaemic stroke due to the occlusion of large cerebral vessels who were treated with mechanical thrombolysis at our centre between September 2009 and July 2010. Preprocedural symptoms were quantified using the National Institutes of Health Stroke Scale (NIHSS). Mechanical thrombolysis was performed with the Penumbra system. Intravenous thrombolysis was done only if <3 h had elapsed since symptom onset. Associated vessel stenoses were treated with stenting. All patients underwent neurological examination and postprocedural magnetic resonance angiography (MRA) at 3 and 6 months. RESULTS: Mechanical thrombolysis using the Penumbra system was performed in all cases. A total of 83% of treated vessels had a value of 2/3 according to the Thrombolysis in Cerebral Infarction (TICI) scale. In seven patients (39%) intravenous thrombolysis was unsuccessful, and salvage mechanical thrombolysis followed. Three patients died after the procedure (16.7%). Five patients (27.8%) required a stenting procedure. All patients reported a significant improvement in symptoms (mean baseline NIHSS 19.6±5.6; mean postprocedural NIHSS, 7.8±5.5 p<0.0001) CONCLUSIONS: Our preliminary experience with the Penumbra mechanical thrombolysis system confirms previously reported results showing the efficacy and safety of the device in treating acute stroke caused by the occlusion of large intracranial vessels.

Different patterns of nigrostriatal degeneration in tremor type versus the akinetic-rigid and mixed types of Parkinson's disease at the early stages: molecular imaging with 123I-FP-CIT SPECT.

The various associations of motor and non-motor symptoms, the onset of motor complications, the cognitive disorder's appearance and other factors make Parkinson's disease (PD) a heterogeneous syndrome with multiple phenotypes. The necessity of discriminating between different forms of PD could have a role in understanding the pathophysiology of extrapyramidal signs with clinical implications. The aim of this study was to evaluate if there is a relationship between the clinical motor phenotypes of PD and the scintigraphic pattern of 123I-FP-CIT single photon emission computed tomography (SPECT). We examined 47 patients with early idiopathic PD (25 males; 22 females; mean age 58±2 years) and subdivided them in different clinical forms on the basis of dominance of resting tremor (n=20), bradykinesia plus rigidity (n=20) and the presence of both clinical signs [mixed type (MT, n=7)]. We correlated this status with the semi-quantitative analysis of SPECT with 123I-FP-CIT. Tremor type patients showed a lower reduction of 123I-FP-CIT uptake compared to akinetic-rigid type patients in contralateral caudate (P=0.0139) and putamen (P=0.0028) nuclei. 123I-FP-CIT uptake was higher in the ipsilateral caudate (P=0.0050) and putamen (P=0.0012) of tremor type patients compared to akinetic-rigid type patients. Comparisons of the striatal uptake in the tremor type and akinetic-rigid type patients with the MT patients revealed significant differences only in the ipsilateral and contralateral caudate. Our data indicate that in akinetic-rigid patients the dopaminergic system is more involved compared to that in the tremor type patients and that this difference is present from the initial stage of the disease. Moreover, our results suggest that PD phenotypes could be related not only to the dopaminergic involvement but also to other systems.

The clinical efficacy of L-DOPA and STN-DBS share a common marker: reduced GABA content in the motor thalamus.

At odd with traditional views, effective sub-thalamic nucleus (STN) deep brain stimulation (DBS), in Parkinson's disease (PD) patients, may increase the discharge rate of the substantia nigra pars reticulata and the internal globus pallidus (GPi), in combination with increased cyclic guanosine monophosphate (cGMP) levels. How these changes affect the basal ganglia (BG) output to the motor thalamus, the crucial structure conveying motor information to cortex, is critical. Here, we determined the extracellular GABA concentration in the ventral anterior nucleus (VA) during the first delivery of STN-DBS (n=10) or following levodopa (LD) (n=8). Both DBS and subdyskinetic LD reversibly reduced (-30%) VA GABA levels. A significant correlation occurred between clinical score and GABA concentration. By contrast, only STN-DBS increased GPi cGMP levels. Hence, STN-ON and MED-ON involve partially different action mechanisms but share a common target in the VA. These findings suggest that the standard BG circuitry, in PD, needs revision as relief from akinesia may take place, during DBS, even in absence of reduced GPi excitability. However, clinical amelioration requires fast change of thalamic GABA, confirming, in line with the old model, that VA is the core player in determining thalamo-cortical transmission.

Low frequency stimulation of the nucleus tegmenti pedunculopontini increases cortical metabolism in parkinsonian patients.

BACKGROUND AND PURPOSE: To evaluate the effects of 25-Hz deep brain stimulation of the nucleus tegmenti pedunculopontini (PPTg) on brain metabolic activity. METHODS: Six patients with Parkinson's disease (PD) who had bilateral stereotactic implantation of PPTg at least 12 months prior to evaluation were included in our study. All underwent, in separate sessions, 18-FDG-PET in core assessment programme for intra-cerebral transplantation as well as motor evaluation [Unified Parkinson's disease rating scale (UPDRS)--Section III] and a battery of cognitive testing. RESULTS: PPTg-ON (low bipolar contacts, 25 Hz) promoted a significant increase of glucose utilization in bilateral prefrontal areas including dorsolateral prefrontal cortex (DLPFC, BA9), orbito-frontal cortex (BA47), anterior cingulate (BA 25-32), superior frontal gyrus (BA 10) and supramarginal gyrus (BA40); a significant increase of uptake and consumption of FDG also occurred in the left ventral striatum, left subgyral (BA 46), right insula (BA 13) and right superior temporal gyrus (BA 22). PPTg-ON was associated with a significant decrease of glucose utilization in the left cerebellar anterior lobe (culmen) and right cerebellar posterior lobe (declive). In the same patients, PPTg-ON improved delayed recall (P < 0.05) and executive functions whilst the UPDRS revealed a modest (-21%) and variable treatment effect. CONCLUSIONS: Low frequency stimulation of PPTg, a sub-region of the pedunculopontine nucleus complex, causes a minor motor benefit but a peculiar profile of cognitive improvement associated with a significant increase in FDG consumption in both prefrontal areas and mono-lateral ventral striatum. These data are consistent with multiple limbic and/or associative domains modulated by PPTg stimulation in our patients with PD.

Deep brain stimulation of the pedunculopontine tegmentum and subthalamic nucleus: effects on gait in Parkinson's disease.

OBJECTIVE: This study examines the effects of subthalamic nucleus (STN) deep brain stimulation (DBS) and pedunculopontine tegmentum (PPTg) DBS in advanced Parkinson's disease using gait analysis. METHODS: Five people underwent bilateral DBS in both the STN and PPTg. Gait analysis was performed one year after neurosurgery using an optoelectronic system. The effects of DBS (STN, PPTg and STN+PPTg) were studied in two clinical conditions: without (Off) and during (On) antiparkinsonian therapy. RESULTS: PPTg and STN DBS were associated with changes in spatio-temporal and kinematics variables. CONCLUSIONS: Although experimental data cannot be generalized widely due to the small sample, PPTg DBS appears to affect the neuronal circuits subserving gait.

Deep brain stimulation of pedunculopontine tegmental nucleus (PPTg) promotes cognitive and metabolic changes: a target-specific effect or response to a low-frequency pattern of stimulation?

Deep brain stimulation (DBS) is a reliable treatment for advanced Parkinson's disease (PD) patients, but a possible risk of worsening cognitive functions, although modest, may postpone or halt DBS clinical indication. In a small cohort of PD patients we have pioneered the simultaneous implantation of both the subthalamic nucleus (STN) and the pedunculopontine tegmental nucleus (PPTg). Here we describe the cognitive test performance and the corresponding cortical metabolic activity, as assessed through 18-fluorodeoxyglucose (FDG)-positron emission tomography (PET), of these six PD patients tested in PPTg-ON vs- PPTg-OFF condition. PPTg-ON condition (at low frequency, 25 Hz) induced better performance in tests exploring both executive and attentive domains, which were coupled with an increased glucose utilization in prefrontal and frontal bilateral cortical areas, including both lateral (i.e., BA9) and more antero-medial cortices (BA 25-32). Moreover, during PPTg-ON, a surprising increase of FDG consumption was also observed in the left ventral striatum. These data are consistent with the hypothesis of a positive effect of 25 Hz PPTg-DBS on PD patients' cognitive profile, probably due to a facilitatory effect exerted by PPTg on both associative and limbic pathways.

Pathological gambling from dopamine agonist and deep brain stimulation of the nucleus tegmenti pedunculopontine.

In patients with Parkinson's disease, aberrant or excessive dopaminergic stimulation is commonly indicated as the trigger factor in unmasking impulse control disorders (ICDs) such as pathological gambling. We had the opportunity to follow a patient who experienced Parkinson's disease 7 years ago when he was using pramipexole and again, recently, when he was treated with levodopa (L-dopa) and low frequency stimulation of the nucleus of the pedunculopontine tegmentus (PPTg) but no dopamine agonists. The same patient had shown, when studied with fluorodeoxyglucose-positron emission tomography in the condition PPTg-ON, a peculiar increased activity in the left ventral striatum. This case report confirms that, in a predisposed personality, ICD may arise from the perturbation of endogenous pathways, which connect the brainstem to the basal ganglia.

Cerebellar magnetic stimulation decreases levodopa-induced dyskinesias in Parkinson disease.

BACKGROUND: The neural mechanisms and the circuitry involved in levodopa-induced dyskinesia (LID) are still partially obscure. LID can be considered the consequence of an abnormal pattern or code of activity that originates and is conveyed from the basal ganglia to the thalamus and the cortical motor areas. However, not only striatothalamocortical motor circuits but also other interconnected pathways could be implicated in its pathogenesis. METHODS: In a series of experiments, we applied repetitive transcranial magnetic stimulation (rTMS) over the lateral cerebellum in a group of patients with advanced Parkinson disease, to investigate whether modulation of cerebellothalamocortical circuits by means of rTMS may result in a modification of a dyskinetic state induced by levodopa ingestion. RESULTS: We found that a single session of cerebellar continuous theta burst stimulation (cTBS) was capable of transiently reducing LID. In the same patients, we observed that cerebellar cTBS changed the profile of activation of intracortical circuits in the contralateral primary motor cortex. Cerebellar cTBS reduced short intracortical inhibition and increased long intracortical inhibition, inducing a cortical reorganization that is associated with a reduction of LID. Furthermore, in another experiment, we observed that a 2-week course of bilateral cerebellar cTBS induced persistent clinical beneficial effects, reducing peak-dose LID for up to 4 weeks after the end of the daily stimulation period. CONCLUSIONS: Our study demonstrates that cerebellar continuous theta burst stimulation has an antidyskinetic effect in Parkinson disease patients with levodopa-induced dyskinesia, possibly due to modulation of cerebellothalamocortical pathways.

Deep brain stimulation of CM/PF of thalamus could be the new elective target for tremor in advanced Parkinson's Disease?

Aim of this study was to investigate whether Deep Brain Stimulation (DBS) of the Centre Median Nucleus/Parafascicular (CM/PF) Complex is useful in reducing extrapyramidal symptoms in advanced Parkinson's Disease (PD) patients. In particular, we compared the action of CM/PF and subthalamic nucleus (STN) DBS on resting hand tremor using EMG surface of ulnar and radial right-hand muscles. Our results show that C/M DBS is very effective in reducing tremor, indicating this complex as a new target in advanced PD patients.

Acute vs chronic effects of l-dopa on bladder function in patients with mild Parkinson disease.

OBJECTIVE: To compare acute and chronic effects of l-dopa on bladder function in levodopa-naive Parkinson disease (PD) patients who had urinary urgency. METHODS: We evaluated 26 l-dopa-naive PD patients at a university-based PD center with a first urodynamic session with a double examination: in the off treatment condition and 1 hour after acute challenge with carbidopa/l-dopa 50/200 mg; then, a chronic l-dopa monotherapy was administered (mean dose 300 +/- 150 mg). Two months later, patients underwent a second urodynamic session with a single evaluation 1 hour after the acute carbidopa/l-dopa challenge. RESULTS: The first acute l-dopa challenge significantly worsened bladder overactivity (neurogenic overactive detrusor contractions threshold [NDOC-t; 32% of worsening] and bladder capacity [BC; 22% of worsening]); on the contrary, l-dopa challenge during chronic administration ameliorated the first sensation of bladder filling (FS; 120% of improvement), NDOCT-t (93% improvement), and BC (33% of improvement) vs the values obtained with acute administration. An 86% significant improvement of FS in comparison with the basal value was observed. CONCLUSIONS: The acute and chronic l-dopa effects may be due to the different synaptic concentrations or to the activation of postsynaptic mechanisms obtained by chronic administration.

Repetitive transcranial magnetic stimulation of the motor cortex ameliorates spasticity in multiple sclerosis.

OBJECTIVE: To investigate whether repetitive transcranial magnetic stimulation (rTMS) can modify spasticity. METHODS: We used high-frequency (5 Hz) and low-frequency (1 Hz) rTMS protocols in 19 remitting patients with relapsing-remitting multiple sclerosis and lower limb spasticity. RESULTS: A single session of 1 Hz rTMS over the leg primary motor cortex increased H/M amplitude ratio of the soleus H reflex, a reliable neurophysiologic measure of stretch reflex. Five hertz rTMS decreased H/M amplitude ratio of the soleus H reflex and increased corticospinal excitability. Single sessions did not induce any effect on spasticity. A significant improvement of lower limb spasticity was observed when rTMS applications were repeated during a 2-week period. Clinical improvement was long-lasting (at least 7 days after the end of treatment) when the patients underwent 5 Hz rTMS treatment during a 2-week protocol. No effect was obtained after a 2-week sham stimulation. CONCLUSIONS: Repetitive transcranial magnetic stimulation may improve spasticity in multiple sclerosis.

Deep brain stimulation in Parkinson's disease patients: biochemical evidence.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) in Parkinson's disease (PD) patients augments STN-driven excitation of the internal globus pallidus (GPi). However, other DBS-induced changes are largely unknown. Here we report the biochemical effects of STN-DBS in two basal ganglia stations (putamen--PUT--and GPi) and in a thalamic relay nucleus, the anteroventral thalamus (VA). In six advanced PD patients undergoing surgery, microdialysis samples were collected from GPi, PUT and VA before, during and after one hour of STN-DBS. cGMP was measured in the GPi and PUT as an index of glutamatergic transmission, whereas GABA was measured in the VA. During clinically effective STN-DBS, we found a significant decrease in GABA extracellular concentrations in the VA (-25%). Simultaneously, cGMP extracellular concentrations were enhanced in the PUT (+200%) and GPi (+481%). DBS differentially affects fibers crossing the STN area: it activates the STN-GPi pathway while inhibiting the GPi-VA one. These findings support a thalamic dis-inhibition, as the main responsible for the clinical effect of STN-DBS. This, in turn, re-establishes a more physiological level of PUT activity.