Effective Expansion: Balance between Shrinkage and Hygroscopic Expansion.

The purpose of this study was to investigate the relationship between hygroscopic expansion and polymerization shrinkage for compensation of polymerization shrinkage stresses in a restored tooth. One resin-modified glass-ionomer (RMGI) (Ketac Nano, 3M ESPE), 2 compomers (Dyract, Dentsply; Compoglass, Ivoclar), and a universal resin-based composite (Esthet•X HD, Dentsply) were tested. Volumetric change after polymerization ("total shrinkage") and during 4 wk of water storage at 37°C was measured using an optical method (n= 10). Post-gel shrinkage was measured during polymerization using a strain gauge method (n= 10). Extracted human molars with large mesio-occluso-distal slot preparations were restored with the tested restorative materials. Tooth surfaces at baseline (preparation), after restoration, and during 4 wk of 37°C water storage were scanned with an optical scanner to determine cuspal flexure (n= 8). Occlusal interface integrity was measured using dye penetration. Data were analyzed using analysis of variance and post hoc tests (significance level 0.05). All tested materials shrunk after polymerization. RMGI had the highest total shrinkage (4.65%) but lowest post-gel shrinkage (0.35%). Shrinkage values dropped significantly during storage in water but had not completely compensated polymerization shrinkage after 4 wk. All restored teeth initially exhibited inward (negative) cuspal flexure due to polymerization shrinkage. Cuspal flexure with the RMGI restoration was significantly less (-6.4 µm) than with the other materials (-12.1 to -14.1 µm). After 1 d, cuspal flexure reversed to +5.0 µm cuspal expansion with the RMGI and increased to +9.3 µm at 4 wk. After 4 wk, hygroscopic expansion compensated cuspal flexure in a compomer (Compoglass) and reduced flexure with Dyract and resin-based composite. Marginal integrity (93.7% intact restoration wall) was best for the Compoglass restorations and lowest (73.1%) for the RMGI restorations. Hygroscopic expansion was more effective in compensating shrinkage stress than would be assumed based on total shrinkage, because only post-gel shrinkage needed compensation. Effective expansion is therefore hygroscopic expansion minus post-gel shrinkage.

Taurine-magnesium coordination compound attenuates hypoxia/reoxygenation induced ion channel dysfunction in rat ventricular myocytes.

Because of the known anti-arrhythmic effects of taurine-magnesium coordination compound (TMCC), the aim of the present study was to explore the electrophysiological effects of TMCC on hypoxia/reoxygenation (H/R)-induced arrhythmias in rat ventricular myocytes. Sodium current (I Na), the L-type calcium current (I Ca,L), and the transient outward potassium current (I to) were evaluated using whole-cell patch-clamp recordings in rat ventricular myocytes following H/R injury. The H/R group significantly decreased sodium currents, while L-type calcium currents and transient outward potassium currents was significantly increased (all p<0.01). TMCC (200 and 400 µM) prevented abnormal sodium currents induced by H/R by inhibiting steady-state inactivation. It also counteracted abnormal L-type calcium currents induced by H/R by inhibiting steady-state activation and facilitating steady-state inactivation. In addition, it mitigated abnormal transient outward potassium currents induced by H/R by inhibiting steady-state activation. TMCC prevents H/R-induced arrhythmias in rat ventricular myocytes by modifying ion channel function.

Gene expression of GABA and glutamate pathway markers in the prefrontal cortex of non-suicidal elderly depressed patients.

BACKGROUND: The prefrontal cortex (PFC) is presumed to be involved in the pathogenesis of depression. METHODS: We determined the gene expression of 32 markers of the pathways of the two main neurotransmitters of the PFC, gamma-aminobutyric acid (GABA) and l-glutamic acid (glutamate), by real-time quantitative PCR in human postmortem anterior cingulate cortex (ACC) and dorsolateral PFC (DLPFC) in elderly non-suicidal patients with major depressive disorder (MDD) or bipolar disorder (BD). RESULTS: We found the transcript levels of GABA(A) receptor beta 2 (GABRB2) and post-synaptic density-95 (PSD-95) to be significantly decreased in the ACC in mood disorder. DLPFC mRNA expression of all the detected genes in the mood disorder group did not differ significantly from that of the non-psychiatric controls. LIMITATIONS: Several inherent and potentially confounding factors of a postmortem study, such as medication and cause of death, did not seem to affect the conclusions. The group size was relatively small but well documented, both clinically and neuropathologically. CONCLUSIONS: The observed alterations in the GABAergic and glutamatergic pathways indicate a diminished activity. These alterations were only present in the ACC and not in the DLPFC.

Bioequivalence assessment of metformin hydrochloride using a limited sampling strategy.

OBJECTIVE: The aim of this study was to develop a limited sampling strategy (LSS) that can be used to assess the bioequivalence of two metformin hydrochloride preparations. METHODS: Healthy subjects (n = 20) enrolled in the bioequivalence study received a single oral tablet of 1,000 mg metformin reference formulation or test formulation. The plasma concentration of metformin was determined using a validated HPLC method. A multiple linear regression analysis of the observed metformin Cmax and AUC0-24 versus the concentration of reference formulation was performed to develop LSS models for estimating these parameters. The models were internally validated by the Jackknife method. The best models were employed to assess the bioequivalence of the two metformin formulations. RESULTS: The linear relationship between pharmacokinetic parameters and a single concentration point was poor. Several models for the estimation of these parameters met the predefined criteria (r2 > 0.9). The Jackknife validation procedure revealed that LSS models based on two sampling times - C1.5 and C2 for Cmax; C4.0 and C10.0 for AUC0-24 - were accurate predictor of Cmax and AUC0-24. Prediction errors (PE) were less than 2%, and absolute prediction errors (AE) were less than 10%. PEs beyond 15% occurred in less than 5% of total samples. The bioequivalence assessment of the two metformin formulations, based on the best LSS models, provided results similar to those obtained using all the observed concentration-time data points, and indicated that the two metformin formulations were bioequivalent. CONCLUSION: A LSS method for assessing the bioequivalence of metformin formulations was established and proved to be applicable and accurate. This LSS method could be considered appropriate for a metformin bioequivalence study, providing an inexpensive cost of sampling acquisition and analysis.

Noninvasive delayed limb ischemic preconditioning attenuates myocardial ischemia-reperfusion injury in rats by a mitochondrial K(ATP) channel-dependent mechanism.

We previously demonstrated in rats that noninvasive delayed limb ischemic preconditioning (LIPC) induced by three cycles of 5-min occlusion and 5-min reperfusion of the left hind limb per day for three days confers the same cardioprotective effect as local ischemic preconditioning of the heart, but the mechanism has not been studied in depth. The aim of this project was to test the hypothesis that delayed LIPC enhances myocardial antioxidative ability during ischemia-reperfusion by a mitochondrial K(ATP) channel (mito K(ATP))-dependent mechanism. Rats were randomized to five groups: ischemia-reperfusion (IR)-control group, myocardial ischemic preconditioning (MIPC) group, LIPC group, IR-5HD group and LIPC-5HD group. The MIPC group underwent local ischemic preconditioning induced by three cycles of 5-min occlusion and 5-min reperfusion of the left anterior descending coronary arteries. The LIPC and LIPC-5HD groups underwent LIPC induced by three cycles of 5-min occlusion and 5-min reperfusion of the left hind limb using a modified blood pressure aerocyst per day for three days. All rats were subjected to myocardial ischemia-reperfusion injury. The IR-5HD and LIPC-5HD groups received the mito K(ATP) channel blocker 5-hydroxydecanoate Na (5-HD) before and during the myocardial ischemia-reperfusion injury. Compared with the IR-control group, both the LIPC and MIPC groups showed an amelioration of ventricular arrhythmia, reduced myocardial infarct size, increased activities of total superoxide dismutase, manganese-superoxide dismutase (Mn-SOD) and glutathione peroxidase, increased expression of Mn-SOD mRNA and decreased xanthine oxidase activity and malondialdehyde concentration. These beneficial effects of LIPC were prevented by 5-HD. In conclusion, delayed LIPC offers similar cardioprotection as local IPC. These results support the hypothesis that the activation of mito K(ATP) channels enhances myocardial antioxidative ability during ischemia-reperfusion, thereby contributing, at least in part, to the anti-arrhythmic and anti-infarct effects of delayed LIPC.

The supplementary motor area contributes to the timing of the anticipatory postural adjustment during step initiation in participants with and without Parkinson's disease.

The supplementary motor area (SMA) is thought to contribute to the generation of anticipatory postural adjustments (APAs, which act to stabilize supporting body segments prior to movement), but its precise role remains unclear. In addition, participants with Parkinson's disease (PD) exhibit impaired function of the SMA as well as decreased amplitudes and altered timing of the APA during step initiation, but the contribution of the SMA to these impairments also remains unclear. To determine how the SMA contributes to generating the APA and to the impaired APAs of participants with PD, we examined the voluntary steps of eight participants with PD and eight participants without PD, before and after disrupting the SMA and dorsolateral premotor cortex (dlPMC), in separate sessions, with 1-Hz repetitive transcranial magnetic stimulation (rTMS). Both groups exhibited decreased durations of their APAs after rTMS over the SMA but not over the dlPMC. Peak amplitudes of the APAs were unaffected by rTMS to either site. The symptom severity of the participants with PD positively correlated with the extent that rTMS over the SMA affected the durations of their APAs. The results suggest that the SMA contributes to the timing of the APA and that participants with PD exhibit impaired timing of their APAs, in part, due to progressive dysfunction of circuits associated with the SMA.

Cortical excitability and age-related volumetric MRI changes.

OBJECTIVE: Normative data on transcranial magnetic stimulation (TMS)-derived measures of cortical excitability in the elderly is sparse. Nevertheless, elderly subjects are included as controls in studies utilizing TMS to investigate disease states. Age-associated increased ventricular cerebrospinal fluid CSF (vCSF) and white matter hyperintensity (WMH) MRI volumes have uncertain significance in non-demented elderly. Information regarding cortical excitability in neurologically intact elderly would augment our understanding of the pathophysiology of aging and assist in the interpretation of TMS studies involving elderly subjects. METHODS: Twenty-four healthy elderly subjects underwent TMS testing to determine outcomes of resting motor threshold (RMT) cortical silent period (cSP) and central motor conduction time for examination in relation to WMH, vCSF, and CNS volumes. RESULTS: Increased vCSF and WMH volumes were associated with decreased right and left hemisphere RMT. Smaller CNS volumes were associated with decreased right hemisphere RMT and shorted cSP. CONCLUSIONS: Commonly observed age-associated MRI changes are associated with findings consistent with increased cortical excitability. SIGNIFICANCE: Age-related MRI findings likely reflect changes at a cellular level, and may influence cognitive and motor integrity in the elderly. Future TMS studies investigating cortical excitability may wish to consider neuroimaging markers of neurodegeneration prior to enrolling elderly subjects as controls.

Movement precues in planning and execution of aiming movements in Parkinson's disease.

Two experiments tested how changing a planned movement affects movement initiation and execution in idiopathic Parkinson's disease (PD) patients. In Experiment 1, PD patients, elderly controls, and young adults performed discrete aiming movements to one of two targets on a digitizer. A precue (80% valid cue and 20% invalid cue of all trials) reflecting the subsequent movement direction was presented prior to the imperative stimulus. All groups produced slower reaction times (RTs) to the invalid precue condition. Only the subgroup of patients with slowest movement time showed a significant prolongation of movement for the invalid condition. This suggests that, in the most impaired patients, modifying a planned action also affects movement execution. In Experiment 2, two-segment aiming movements were used to increase the demand on movement planning. PD patients and elderly controls underwent the two precue conditions (80% valid, 20% invalid). Patients exhibited longer RTs than the controls. RT was similarly increased for the invalid condition in both groups. The patients, however, exhibited longer movement times, lower peak velocities, and higher normalized jerk scores of the first segment in the invalid condition compared to the valid condition. Conversely, the controls showed no difference between the valid and invalid cue conditions. Thus, PD patients demonstrated substantially pronounced movement slowness and variability when required to change a planned action. The results from both experiments suggest that modifying a planned action may continue beyond the initiation phase into the execution phase in PD patients.

Exacerbated physical fatigue and mental fatigue in Parkinson's disease.

OBJECTIVE: To characterize fatigue in Parkinson's disease (PD). BACKGROUND: Fatigue is a recognized problem in PD. Fatigue can be in the physical realm or in the mental realm. Fatigue has not been characterized in PD. METHODS: We characterized fatigue in 39 PD patients and 32 age-matched normal controls using five questionnaires: A. The Multidimensional Fatigue Inventory (MFI), which measures five dimensions of fatigue independently including general fatigue, physical fatigue, reduced motivation, reduced activity, and mental fatigue. B. The Fatigue Severity Inventory (FSI), which quantifies fatigue in general. C. The Profile of Mood States (POMS), which assesses six subjective subscales: tension-anxiety, depression-dejection, anger-hostility, fatigue-inertia, vigor-activity, and confusion-bewilderment. D. Center for Epidemiological Studies-Depression Scale (CES-D). E. Visual Analog linear scale of energy (VA-E). RESULTS: PD patients scored higher in all of the five dimensions of fatigue in the MFI including general fatigue, physical fatigue, reduced motivation, reduced activity, and mental fatigue (P < 0.001 except for mental fatigue P = 0.005). The severity of physical fatigue did not correlate with that of mental fatigue. PD patients scored higher on the FSI, POMS, CES-D, and scored lower on the VA-E. The scores in the FSI correlated with general fatigue, physical fatigue, reduced activity, and reduced motivation but not with mental fatigue in the MFI. Depression correlated with all dimensions of fatigue except physical fatigue in the MFI. Disease severity, as measured by Modified Hoehn and Yahr staging, did not correlate with any of the measures. CONCLUSIONS: PD patients have increased physical fatigue and mental fatigue compared to normals. Physical fatigue and mental fatigue are independent symptoms in PD that need to be assessed and treated separately.

[Inhibitive effect of puerarin on increased NO production by neonatal cardiomyocytes during hypoxia/reoxygenation injury].

OBJECTIVE: To investigate the effect of puerarin (Pue) on nitric oxide (NO) produced by neonatal rat cardiomyocytes during hypoxia/reoxygenation injury. METHOD: NO contents in the culture supernatants sampled from different groups (control, model, and therapeutic groups with 1, 0.1, 0.01 g.L-1 Pue) at different time were assayed with nitrate reductase method. RESULT: NO content of model increased after reperfusion (P < 0.01), while it increased sharply at 6 h after reperfusion and kept thereafter. Only at 6 h after reperfusion did Pue in these three doses inhibit NO production (P < 0.01) and kept to the 24 h after reperfusion. CONCLUSION: Pue exerts inhibitive effect only after NO production is enhanced sharply during hypoxia/reperfusion injury in a dose-dependent trend.

Effects of diminished and conflicting sensory information on balance in patients with cerebellar deficits.

We studied the effects of altered sensory information on standing balance in 25 patients with cortical cerebellar atrophy (CCA), nine patients with olivoponto-cerebellar atrophy (OPCA), and 10 normal subjects. The total sway path and its components, the anteroposterior (AP) sway path and the lateral sway path, were measured under six conditions: (1) standing on a fixed platform with the eyes open and visual surroundings fixed, (2) standing on a fixed platform with the eyes closed, (3) standing on a fixed platform with the eyes open and visual surroundings AP sway referenced, (4) standing on an AP sway-referenced platform with the eyes open and visual surroundings fixed, (5) standing on an AP sway-referenced platform with the eyes closed, and (6) standing on an AP sway-referenced platform with the eyes open and visual surroundings AP sway referenced. Patients swayed more than normal subjects during normal stance (condition 1), when the visual information was absent (condition 2) or distorted (condition 3), and when the proprioceptive information from the ankles was distorted (condition 4). Patients swayed much more than normal, and most fell, when two sensory modalities were affected under condition 5 (proprioceptive information distorted and visual information absent) and condition 6 (both proprioceptive information and visual information distorted). When the patients' sway was normalized to that of the first condition, however, only their lateral sway was greater than the sway in normal subjects. Unlike in normal subjects, the patients' lateral sway varied with the AP sway to approximately the same degree in each condition for conditions 1-5. Clinical ratings of gait and balance were highly correlated with the sway measures. Quantitative testing of standing balance with altered sensory information has better sensitivity than normal stance testing.

Preserved cognitive processes in cerebellar degeneration.

Aspects of cognitive processing in patients with cerebellar degeneration (CD) were studied in order to examine the validity of recent findings that CD patients demonstrate deficits in visuospatial cognition and verbal-associative learning. Two groups of patients with CD were compared to stratified matched control groups on tests examining selective visual attention, visual spatial attention, mental rotation of geometric designs, and memory for the temporal order of words they were previously exposed to. CD patients performed similarly to their matched controls across all tasks. These results indicate that the reported cognitive deficits of CD patients are quite selective and need further specification in order to more fully describe their relationship to cerebellar dysfunction.

Use of buspirone for treatment of cerebellar ataxia. An open-label study.

OBJECTIVE: To evaluate the efficacy of buspirone hydrochloride, a serotonin (5-hydroxytryptamine1A) agonist, in treating patients with cerebellar ataxia. DESIGN: Open-label study in which 20 patients (14 with cerebellar cortical atrophy and six with olivopontocerebellar atrophy) received buspirone hydrochloride, up to 60 mg/d, for 8 weeks. SETTING: Research hospital. MAIN OUTCOME MEASURES: Clinical, physiological, and psychological assessment. RESULTS: Nine patients with mild or moderate cerebellar dysfunction who completed the study showed significant improvement in clinical and self-assessment ratings, but not in a motor performance test, posturography (data were incomplete), State-Trait Anxiety Inventory, and Beck Depression Inventory. Seven patients with severe cerebellar dysfunction who completed the study had no improvement on any measure. CONCLUSIONS: Buspirone may be effective in treating mild to moderate cerebellar ataxia. A double-blind study of the efficacy of buspirone in cerebellar ataxia is warranted.

Regional cerebral blood flow during a self-paced sequential finger opposition task in patients with cerebellar degeneration.

The brain regions controlling self-paced sequential finger movements in patients with cerebellar degeneration were studied by measuring changes in regional cerebral blood flow (rCBF) in eight patients using bolus injections of H2(15)O and PET. The results were compared with those obtained in eight normal age-matched control subjects. Patients and control subjects performed a self-paced sequential finger opposition task with the right hand, completing a sequence of movements every 4-6 s. Both groups had strong increases in the adjusted rCBF contralaterally in the primary motor cortex (M1) and ventral premotor area (PMv), in the caudal supplementary motor area (SMA) and cingulate motor area (CMA), and bilaterally in the prefrontal cortex (PFC), the lobus parietalis inferior (LPI), putamen and cerebellum. The cerebellum, PMv, rostral CMA, PFC and LPI were more active in the control subjects than in the patients, and the M1, SMA, caudal CMA and putamen were more active in the patients than in the control subjects. The reduced activity of the cerebellar neurons in the patients produced a complex pattern of rCBF increases and decreases in other brain regions. Our results suggest that for the preparation and execution of sequential finger movements, patients with cerebellar degeneration use a medial premotor system, including the SMA and caudal CMA, as well as the M1 and putamen, rather than the PMv, PFC, LPI and rostral CMA.

Brainstem reflexes in patients with olivopontocerebellar atrophy.

In 4 patients with familial olivopontocerebellar atrophy (OPCA) we have recently described an abnormal movement of facial muscles characterized by rhythmic muscle twitching during voluntary activation (facial action myoclonus). In the present article, we present the results of a neurophysiological study of brainstem reflexes in those 4 patients, in 4 other patients with OPCA but without facial action myoclonus, in 3 patients with pure cerebellar cortical atrophy, and in 6 normal volunteers used as control subjects. All patients had similar clinical features, but only the patients with facial action myoclonus and only one of the other patients with OPCA had brainstem atrophy detected on magnetic resonance imaging. Electrophysiological abnormalities were found in all patients with facial action myoclonus and consisted of myokymia in perioral muscles at rest, spread of spontaneous and reflex blinking to the orbicularis oris, and enhanced long-latency facial reflex responses to stimuli applied to the facial or trigeminal nerve. Other relevant electrophysiological abnormalities were the absence of jaw jerk in 2 patients, the absence of an R1 response of the blink reflex in 1 patient, and a markedly reduced compound muscle action potential of the facial nerve in another patient. Comparable electrophysiological abnormalities were found in only 1 of the patients with OPCA but without facial action myoclonus, and in none of the patients with pure cerebellar cortical atrophy. Facial action myoclonus is a clinical manifestation of a global brainstem functional derangement that may characterize a subgroup of patients with OPCA or constitute a distinctive step in the natural evolution of some forms of the disease.

Facial action myoclonus in patients with olivopontocerebellar atrophy.

We studied four patients with familial olivopontocerebellar atrophy (OPCA) who had abnormal twitching of the cheeks and perioral muscles induced by facial movements. With the muscles at rest, electromyographic (EMG) recordings of the orbicularis oris and risorius muscles revealed myokymic discharges in the absence of visible movements. With voluntary contraction, the EMG showed synchronous discharges in the orbicularis oris and risorius muscles ipsilaterally associated with visible twitching. The duration of the EMG bursts was 10 to 75 ms with a frequency of 8 to 25 Hz, which suggested that the abnormal twitching was most consistent with a myoclonic disorder. Because it was induced by activation of the facial muscles, this movement disorder represents a form of action myoclonus.