Search

Background/Aims: Previously we have shown that functional declines in Parkinson’s disease (PD) and Alzheimer’s disease (AD) correlate to global measures of cognitive decline. We now determine if the correlation between cognitive impairment and functional ability in PD is similar to that in AD using individual cognitive measures. Methods: 93 PD subjects and 124 AD/MCI subjects underwent the Functional Assessment Staging (FAST), the Global Deterioration Scale (GDS), and a neuropsychological battery. Results: In PD subjects, the FAST and GDS correlated significantly with Rey Auditory Verbal Learning Test (AVLT), Controlled Oral Word Association (COWA), Animal Fluency, and Stroop but not with Clock Draw or Judgment Line Orientation (JLO). In AD/MCI subjects, FAST and GDS correlated with all neuropsychological components except Stroop. In the AD/MCI group, the UPDRS significantly correlated with the FAST, GDS, MMSE, and all neuropsychological parameters except the Stroop. In the PD group, the motor UPDRS significantly correlated significantly with FAST, GDS, MMSE and all neuropsychological parameters except Digit Span, Stroop, Clock Draw and JLO. Conclusions: Similar to AD, functional decline in PD correlates with multiple measures of cognitive impairment. Some differences between PD and AD may be explained by the influence of motor disability and declines in visuospatial function in PD.

For people with Parkinson's disease (PD), gait and postural impairments can significantly affect their ability to perform activities of daily living. Presentation of appropriate cues has been shown to improve gait in PD. Based on this, a treadmill-based system and experimental paradigm were developed to determine if people with PD can utilize real-time feedback (RTFB) of step length or back angle (uprightness) to improve gait and posture. Eleven subjects (mean age 67 ± 8 years) with mild-to-moderate PD (Hoehn and Yahr stage I–III) were evaluated regarding their ability to successfully utilize RTFB of back angle or step length during quiet standing and treadmill walking tasks during a single session in their medication-on state. Changes in back angle and step length due to feedback were compared using Friedman nonparametric tests with Wilcoxon Signed-Rank tests for post-hoc comparisons. Improvements in uprightness were observed as an increase in back angle during quiet standing ( $p = 0.005$ ) and during treadmill walking ( $p = 0.005$ ) with back angle feedback when compared to corresponding tasks without feedback. Improvements in gait were also observed as an increase in step length ( $p = 0.005$ ) during step length feedback compared to tasks without feedback. These results indicate that people with mild-to-moderate PD can utilize RTFB to improve upright posture and gait. Future work will investigate the long-term effects of this RTFB paradigm and the development of systems for clinical or home-based use.

As the population continues to age, it has become increasingly important for clinicians to recognize the clinical characteristics of normal aging. Impaired mobility is one of the most frequent effects of normal aging, and this necessitates a specific understanding of the effects of normal aging on the motor system. This article reviews the physiological basis and clinical manifestations of normal aging as related to movement disorders. The impact of normal aging on major hypokinetic and hyperkinetic movement disorders is also discussed.

Mechanisms regulating coronary vascularization are not well understood. To test hypotheses regarding the influence of key growth factors and their interactions, we studied vascular tube formation (vasculogenesis) in collagen gels onto which quail embryonic ventricles were placed and incubated in the presence of growth factors or inhibitors. Vasculogenesis in this model is dependent on tyrosine kinase receptors, since tube formation was totally blocked by genestein. Tube formation was attenuated when anti-bFGF or anti-VEGF neutralizing antibodies were added to the medium and nearly completely inhibited when the both were added. The attenuation associated with anti-VEGF was due primarily to a decrease in assembly of endothelial cells, while that associated with bFGF was primarily due to a reduction in endothelial cells. Soluble tie-2, the receptor for angiopoietins, also had an inhibitory effect and, when added with either anti-bFGF or anti-VEGF, markedly attenuated tube formation. At optimal doses, tube formation was enhanced 6.5-fold by bFGF and 2.5-fold by VEGF over the controls. Each of these growth factors was dependent upon the other for optimal induction of tube formation, since neutralizing antibodies to one markedly reduced the potency of the other. VEGF potency was also markedly reduced when soluble tie-2 was added to the medium. Tube formation was virtually totally blocked by exogenous TGF-β at doses > 1 ng/ml, while neutralizing TGF-β antibodies enhanced tube formation 2-fold in the 30 ng–30 μg range. These data provide the first documentation of multiple growth factor regulation of coronary tube formation. © 2001 Wiley-Liss, Inc.

In view of the evidence that thyroid hormone administration has angiogenic effects on the hypertrophic myocardium, we tested the hypothesis that the capillary supply in the hypertrophic myocardium surviving infarction would be improved by administration of the thyroid hormone analog, diiodothyroproprionic acid (DITPA). We administered DITPA (MI-DITPA) or saline (MI-saline), s.c., to rats for 10 days following experimental infarction of the left ventricle (LV). Morphometric methods were used to assess capillarity and myocyte cross-sectional area in three regions of the left ventricle: (1) border (next to the scar of infarction); (2) adjacent (next to the border); and (3) remote (interventricular septum). Infarct size ranged from 20–85% of the LV free-wall, and both groups had similar mean infarct size. Capillary length density (L v ) was significantly higher in the remote region of the treated group than in the MI-saline rats. L v in the border region, which experienced the most marked increase in cardiocyte cross-sectional area, was not significantly lower than in the other regions, indicating a more marked angiogenic response. In hearts with large infarcts (≥40%) L v in the border region was higher in the DITPA group than in the non-treated rats. In the MI-DITPA group, cardiocyte size in the border region was positively correlated with that of the other regions, which contrasts with the negative correlations noted for the MI-saline rats. These data suggest that DITPA therapy (1) may improve maximal perfusion potential of the hypertrophied myocardium surviving a myocardial infarction, and (2) is selectively effective in the border region of hearts with large infarcts.

Objective Our overall aims were to elucidate the temporal and spatial sequence of coronary vascularization during development in the rat, and to determine whether basic fibroblast growth factor expression corresponds to any phase of the vascularization process. Methods Immunohistochemical, histochemical, morphometric and in situ hybridization analyses were performed on prenatal and postnatal hearts of various ages. Results Coronary vascularization, which begins at embryonic day 13 (E13) with blood island-like structures in the epicardium, progresses from this layer toward the endocardium as indicated by a transmural gradient of vascular volume throughout the ventricles. Vascular smooth muscle first appears in E17 hearts at the time a capillary-like plexus coalesces and penetrates the aorta to form the main coronary arteries. These vessels maintain an anastomatic morphology and must undergo subsequent remodeling in order to assume adult branching characteristics. The early postnatal period is characterized by development of the arterial tree and the enzymatic differentiation of the arteriolar and venular ends of the capillary bed. Although bFGF is expressed both prenatally and postnatally, the highest mRNA expression was noted during the early period of vascularization (E14 and E15), and the early neonatal period (1–6 days) which corresponds to a period of substantial microvascular growth. Conclusions Coronary vascularization follows a temporal sequence which includes transmural expansion of the capillary bed, arteriolar formation subsequent to vascular penetration of the aorta, and postnatal growth, differentiation, and remodeling. Since high levels of bFGF expression are correlated with key time points in coronary vascular growth, bFGF may play an important role in this process.

From two human populations (one pediatric and one adult), clinically diagnosed with Staphylococcus epidermidis (S. epidermidis) sepsis of similar severity, bacteria were isolated from pre-antibiotic blood samples and evaluated for virulence. The LD50 of the bacteria in a mouse model was performed, with evaluation of animals dying acutely following intravenous S. epidermidis administration. More simple assays of virulence were also performed, including bacterial adherence to a fibrin clot and carbohydrate specific lectin binding. The eight pediatric-host S. epidermidis isolates required a significantly larger dose to produce lethality in dosed animals (LD50) when compared to the 20 adult-host S. epidermidis isolates. The fibrin clot assay, a test that has corroborated bacterial virulence in endocarditis models, did not differentiate the groups: all but one of the 28 isolates were well above the adherence seen with the ATCC control, suggesting endocarditis-producing potential. Glycocalyx (slime) from eight of the more virulent isolates showed reactivity with a glucose-specific biotinylated lectin which was lacking in other isolates. Necropsy of mice dying at 12 hr showed S. epidermidis strain differences in specific organ effects. Overall, this study demonstrates the utility of the LD50 to provide a highly sensitive quantification of bacterial virulence. Necropsy of test animals dying acutely has showed an apparent organ tropism of some of these isolates which are usually considered harmless commensals.

We studied the efficacy and pharmacokinetics of azithromycin in a rabbit tissue-cage Staphylococcus aureus abscess model. A dosage of 15 mg/kg/day azithromycin was administered to rabbits with 24 h or 2 week old infected tissue cages and to uninfected controls. Concentrations of azithromycin were higher in the infected compared with the uninfected tissue cages. Azithromycin was effective in reducing the bacterial concentrations in both groups of infected tissue cages by approximately 3 log10 cfu/mL compared with untreated controls after 8 days of therapy. Fifty percent of the 24 h and 29% of the 2 week infected tissue cages became culture-negative.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is now widely used to alleviate symptoms of Parkinson’s disease (PD). The specific aim of this study was to identify posture control measures that may be used to improve selection of DBS parameters in the clinic and this was carried out by changing the DBS stimulation amplitude. A dynamic posture shift paradigm was used to assess posture control in 4 PD STN-DBS subjects. Each subject was tested at 4 stimulation amplitude settings. Movements of the center of pressure and the position of the pelvis were monitored and several quantitative indices were calculated. The presence of any statistically significant changes in several normalized indices due to reduced/no stimulation was tested using the one-sample t test. The peak velocity and the average movement velocity during the initial and mid phases of movement towards the target posture were substantially reduced. These results may be explained in terms of increased akinesia and bradykinesia due to altered stimulation conditions. Thus, the dynamic posture shift paradigm may be an effective tool to quantitatively characterize the effects of DBS on posture control and should be further investigated as a tool for selection of DBS parameters in the clinic.

Deep Brain Stimulation (DBS) of the subthalamic nucleus (STN) is now widely used to alleviate symptoms of Parkinson's disease (PD). The long-term goal is to develop a quantitative tool to facilitate selection of DBS settings in the clinic since the typical parameter selection process may not adequately consider the effects of DBS on posture control. The aim of this study was to characterize the effects of changing the stimulation amplitude of DBS on posture control in PD. A dynamic posture shift paradigm involving target acquisition was used to assess posture control in 4 PD STN-DBS subjects. Each subject was tested at 4 stimulation amplitude settings: Clinically-determined (CD) settings, moderate (approx. 70% CD), low (approx. 30% CD), and off (no stimulation). Movements of the center of pressure and the position of the pelvis were monitored and several quantitative indices were calculated. The most substantial change was reductions in the peak velocity and the average movement velocity during the initial and mid phases of movement towards the target posture. These results may be explained in terms of increased akinesia and bradykinesia in the altered stimulation conditions. Thus, the dynamic posture shift paradigm can reveal changes in posture control capabilities, as evidenced by changes in movement velocity, due to alterations in DBS stimulation settings.

In the sixth chapter of his notebooks Ramanujan introduced a method of summing divergent series which assigns to the series the value of the associated Euler-MacLaurin constant that arises by applying the Euler-MacLaurin summation formula to the partial sums of the series. This method is now called the Ramanujan summation process. In this paper we calculate the Ramanujan sum of the exponential generating functions $\sum_{n\geq 1}\log n e^{nz}$ and $\sum_{n\geq 1}H_n^{(j)} e^{-nz}$ where $H_n^{(j)}=\sum_{m=1}^n \frac{1}{m^j}$. We find a surprising relation between the two sums when $j=1$ from which follows a formula that connects the derivatives of the Riemann zeta - function at the negative integers to the Ramanujan summation of the divergent Euler sums $\sum_{n\ge 1} n^kH_n, k \ge 0$, where $H_n= H_n^{(1)}$. Further, we express our results on the Ramanujan summation in terms of the classical summation process called the Borel sum., 25 pages

We sought to define quantitative electroencephalographic (EEG) measures as biomarkers of both early and late cognitive decline in Parkinson's disease (PD). PD subjects classified as cognitively normal (PD-CogNL), mild cognitive impairment (PD-MCI), and dementia (PD-D) were studied. Cognitive status and neuropsychological testing was correlated with background rhythm and frequency band EEG power across five frequency bands. We conclude that global EEG measures have potential use as biomarkers in the study of both early and late cognitive deterioration in PD, including for evaluating its treatment. PD-MCI has mean quantitative EEG characteristics that represent an intermediate electrophysiological state between PD-CogNL and PD-D.

Objectives: To systematically investigate the ability of Parkinson’s disease patients to discretely and dynamically scale the size of continuous movements and to assess the impact of movement size on outcome variability. Methods: Ten patients with Parkinson’s disease (mean age 72 years) were compared with 12 healthy elderly controls (mean age 70 years). The subjects wrote with a stylus on a graphics tablet. In experiment 1 they drew circles, matching the size of five target circles ranging in magnitude from a radius of 0.5 cm up to 2.5 cm. In experiment 2 they drew spirals with a radius of at least 2 cm. In both experiments the drawings were initially performed as accurately as possible then as fast and accurately as possible. Results: In both experiments the patients and controls drew at a similar speed. The within trial variability of the pen trajectory was greater for patients than controls, and increased disproportionately with the size of the movement. When the emphasis was on size rather than variability (circles), the patients’ drawing movements were the same size as controls. When the emphasis was on accuracy of pen trajectory (that is, minimum variability) rather than size (spirals), the patients’ drawing movements were smaller than controls. Conclusions: The movements made by Parkinson’s disease patients are hypometric partly as an adaptive strategy used to reduce movement variability. This strategy is used primarily when the requirement to make accurate movements outweighs the need to make large movements.

Recognition of peptide Ags by T cells through the TCR can be highly specific. In this report we show the degeneracy of Ag recognition at both MHC and TCR levels. We present evidence that unrelated promiscuous Th cell epitopes from various protein sources exhibit sufficient structural homology, despite minimal structural identity, to elicit cross-reactive proliferative responses at the bulk T cell level. This epitopic mimicry was also observed when peptide (CS.T3378–395 and TT830–844)-specific CD4+ T cell lines and T cell hybridoma clones were used in proliferation and Ag presentation assays. A scrambled CS.T3378–395 peptide did not show any proliferation, indicating that the specificity of the cross-reactive responses may be linked with the primary structure of the peptides. Blocking of CS.T3378–395-specific CD4+ T cell proliferation by anti-MHC class II mAb showed that recognition of promiscuous T cell epitopes is largely in association with MHC class II molecules. These findings suggest that promiscuous Th epitopes may be useful in designing peptide-based vaccine constructs. At the same time these results show that at the T cell level there may be a great deal of immunological cross-reactivity between heterologous pathogens, and because of this the host’s response to a pathogen may be modified by its previous experience with other unrelated pathogens.

We tested the hypothesis that early vascularization of the embryonic heart is enhanced after bolus injections of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) into the vitelline vein before the onset of myocardial vasculogenesis (3.5 days, stage 21). Electron and light microscopy were utilized to obtain morphometric data. At stages 29 and 31, myocardial vessel volume or numerical density were higher in embryos injected with 50 ng bFGF than in the saline-injected controls. A VEGF injection increased vascular volume density at stage 29 and both volume and numerical density at stage 31. bFGF, but not VEGF, was associated with an enhancement of the sinusoidal system (spongy layer of the ventricle) at stage 29. This effect disappeared by stage 31. In conclusion, 1) enhancement of bFGF or VEGF before myocardial vascularization increases vascular growth, but the initial effect of bFGF is greater; 2) the effects of these growth factors on vascular volume and numerical density are temporally dependent; and 3) bFGF, in addition to its effects on the coronary vasculature, influences ventricular modeling by apparently acting on myocytes as well as endothelial cells.

We studied the efficacies of ofloxacin, rifampin, and clindamycin in a Staphylococcus aureus abscess model and seven antimicrobial regimens in an intracellular killing assay. Ofloxacin plus rifampin was the most effective regimen in the abscess model, and rifampin and ofloxacin were the most active regimens in the intracellular killing assay.

Microbial growth and antimicrobial bacterial killing are both diminished in abscesses. It was postulated that zinc depletion in abscesses, perhaps secondary to a neutrophil protein resembling calprotectin, may be partly responsible for these effects. In a rabbit tissue-cage abscess model, pooled abscess supernatant concentration of zinc was < 1.53 microM. The addition of 41.7 microM zinc had no effect on Staphylococcus aureus growth or the bacterial killing effect of cefazolin in serum. In abscess fluid supernatants, bacterial growth without antibiotic and bacterial killing by cefazolin were both enhanced by the addition of zinc. Fractionation of the abscess fluid with ultrafiltration membranes showed that these effects could be reproduced with the fraction between 30 and 50 kDa. These findings suggest that a protein in abscess fluid supernatants that resembles the neutrophil protein calprotectin may, through its zinc binding effects, inhibit microbial growth within an abscess but also inhibit the activity of bactericidal antibiotics.