Natural clinical course of progressive supranuclear palsy in Chinese patients in Hong Kong.

INTRODUCTION: Progressive supranuclear palsy (PSP) is a common type of atypical parkinsonism. To the best of our knowledge, there has been no study of its natural clinical course among Chinese patients. METHODS: This retrospective study included 21 patients with PSP who had radiological evidence of midbrain atrophy (confirmed by magnetic resonance imaging) from the geriatrics clinics of Queen Mary Hospital and Tuen Mun Hospital. Clinical information was retrieved from clinical records, including age at onset, age at presentation, age at death, duration of symptoms, level of education, sex, presenting scores on Cantonese version of Mini-Mental State Examination, clinical symptoms, and history of levodopa or dopamine agonist intake and response. Clinical symptoms were clustered into the following categories and the dates of development of these symptoms were determined: motor symptoms, bulbar symptoms, cognitive symptoms, and others. RESULTS: Motor symptoms developed early in the clinical course of disease. Cox proportional hazards modelling showed that the number of episodes of pneumonia, time to vertical gaze palsy, and presence of pneumonia were predictive of mortality. Apathy, dysphagia, pneumonia, caregiver stress, and pressure injuries were predictive of mortality when analysed as time-dependent covariates. There was a significant negative correlation between the age at presentation and time to mortality from presentation (Pearson correlation=-0.54, P=0.04). Approximately 40% of caregivers complained of stress during the clinical course of disease. CONCLUSION: Important clinical milestones, including the development of dysphagia, vertical gaze palsy, significant caregiver stress, pressure injuries, and pneumonia, may guide advanced care planning for patients with PSP.

Inertially assisted nanoscale self-assembly.

We present a simple and versatile method for integrating submicron objects onto pre-determined locations on a substrate. The method relies on augmenting inertial forces using centrifugal motion and geometric constraints to guide the placement of submicron objects on a substrate with minimal requirements for surface engineering and binding chemistries. Here, we demonstrate the utility of the method for placing gold particles, metal nanorods and inorganic nanocrystals. The method has demonstrated high yield of self-assembly for submicron particles with a variety of shapes and sizes. We have been able to get a near-perfect yield for filling hundreds of traps with nanoparticles in only 20 min. Two hundred nanometer diameter nanorods were self-assembled into an array of 256 traps on the template with 92% yield. 1.4 microm and 300 nm sodium chloride crystals were self-assembled in arrays of 7000 and 576 traps, respectively, with near-perfect yield in filling each site. Due to its convenient set-up and high performance, inertially assisted self-assembly can be easily adopted and used for a variety of integration needs on the submicron scale.

Left ventricular receptors inhibit brain serotonin neurons during coronary artery occlusion.

Acute coronary artery ligation in pargyline-treated rats decreased serotonin and increased 5-hydroxyindoleacetic acid in the medulla and posterior hypothalamus. Lidocaine applied topically to the left ventricle completely prevented these alterations. No changes in serotonin were observed in the other brain regions examined. These data suggest a reflex inhibition of bulbar and hypothalamic serotonergic nerves by left ventricular receptors following acute coronary artery occlusion in the rat.

Retinoic acid induces down-regulation of Wnt-3a, apoptosis and diversion of tail bud cells to a neural fate in the mouse embryo.

The tail bud comprises the caudal extremity of the vertebrate embryo, containing a pool of pluripotent mesenchymal stem cells that gives rise to almost all the tissues of the sacro-caudal region. Treatment of pregnant mice with 100 mg/kg all-trans retinoic acid at 9.5 days post coitum induces severe truncation of the body axis, providing a model system for studying the mechanisms underlying development of caudal agenesis. In the present study, we find that retinoic acid treatment causes extensive apoptosis of tail bud cells 24 h after treatment. Once the apoptotic cells have been removed, the remaining mesenchymal cells differentiate into an extensive network of ectopic tubules, radially arranged around the notochord. These tubules express Pax-3 and Pax-6 in a regionally-restricted pattern that closely resembles expression in the definitive neural tube. Neurofilament-positive neurons subsequently grow out from the ectopic tubules. Thus, the tail bud cells remaining after retinoic acid-induced apoptosis appear to adopt a neural fate. Wnt-3a, a gene that has been shown to be essential for tail bud formation, is specifically down-regulated in the tail bud of retinoic acid-treated embryos, as early as 2 h after retinoic acid treatment and Wnt-3a transcripts become undetectable by 10 h. In contrast, Wnt-5a and RAR-gamma are still detectable in the tail bud at that time. Extensive cell death also occurs in the tail bud of embryos homozygous for the vestigial tail mutation, in which there is a marked reduction in Wnt-3a expression. These embryos go on to develop multiple neural tubes in their truncated caudal region. These results suggest that retinoic acid induces down-regulation of Wnt-3a which may play an important role in the pathogenesis of axial truncation, involving induction of widespread apoptosis, followed by an alteration of tail bud cell fate to form multiple ectopic neural tubes.

Alterations in brain serotonin during congestive heart failure in the cardiomyopathic Syrian hamster.

Serotonin and its major metabolite 5-hydroxyindoleacetic acid were measured in the pons-medulla, midbrain, posterior hypothalamus, anterior hypothalamus, thalamus, and cerebellum of cardiomyopathic hamsters and their age-matched controls during the early and terminal stages of the cardiomyopathy. During the stage of cardiac decompensation, significant increases were observed in the concentration of serotonin in pons-medulla (2.30 +/- 0.07 vs 1.74 +/- 0.04; P less than 0.001) and posterior hypothalamus (3.49 +/- 0.04 vs. 3.04 +/- 0.11; P less than 0.005) and in 5-hydroxyindoleacetic acid in pons-medulla (1.42 +/- 0.05 vs 0.97 +/- 0.05; P less than 0.001) and posterior hypothalamus (1.65 +/- 0.02 vs 1.32 +/- 0.07; P less than 0.001). No changes were noted in any of the brain regions of control animals. We conclude that congestive heart failure may be associated with alterations in activity of bulbohypothalamic serotonergic nerves.

Decreased brain serotonin turnover after short term (two-hour) adrenalectomy in rats: a comparison of four turnover methods.

Within the first 2 h after adrenalectomy in rats there is a marked decrease in hypothalamic, brain stem, and hippocampal serotonin (5HT) turnover. This adrenalectomy-induced decrease in brain 5HT turnover was demonstrated in this study using four different methods. These include 1) accumulation of 5HT after monoamine oxidase inhibition with pargyline, 2) decline of 5-hydroxyindoleacetic acid after pargyline, 3) accumulation of 5-hydroxytryptophan after aromatic L-amino acid decarboxylase inhibition with m-hydroxybenzylhydrazine, and 4) accumulation of 5-hydroxyindoleacetic acid after probenecid. The adrenalectomy-induced decreases in 5HT turnover in these areas were prevented by glucocorticoid treatment with either corticosterone or dexamethasone. The similarity of the results obtained with four different methods of assessment of brain 5HT turnover provides strong evidence to suggest that the activity of 5HT neurons, in at least three brain areas, is decreased within the first 2 h after adrenalectomy. Also, it seems likely that glucocorticoid withdrawal is the important factor in this adrenalectomy-induced decrease in brain 5HT turnover. In addition, an increase in hypothalamic 5HT turnover in response to the surgical stress of sham adrenalectomy could be demonstrated. The adrenalectomy-induced decreases in brain 5HT turnover were also prevented by the administration of the serotonin receptor antagonist, pizotifen. In addition, serotonin receptor blockade with pizotifen inhibited the effect of corticosterone to normalize the adrenalectomy-induced changes in both the plasma ACTH concentration and brain 5HT turnover. These data provide further support for an interaction between glucocorticoids and brain 5HT neurons.

Brain serotonin turnover correlates inversely with plasma adrenocorticotropin during the triphasic response to adrenalectomy in rats.

After bilateral adrenalectomy in adult male rats a triphasic change occurs in the plasma concentration of radioimmunoassayable ACTH. Plasma ACTH is markedly elevated at 2 h, returns almost to normal at 20 h, and is again markedly elevated 92 h after adrenalectomy. We have examined brain serotonin (5HT) turnover during this period using two nonsteady state methods: accumulation of 5HT after monoamine oxidase inhibition with pargyline and decline of 5-hydroxyindoleacetic acid (5HIAA) after pargyline. Both endpoints demonstrated decreases in hypothalamic and brain stem 5HT turnover 2 and 92 h after adrenalectomy, but normal 5HT turnover 20 h after adrenalectomy. Thus, we demonstrated inverse relationships between 5HT turnover in both the hypothalamus and brain stem and the plasma ACTH concentration throughout the period of triphasic change after adrenalectomy. The adrenalectomy-induced increases in plasma ACTH and decreases in brain 5HT turnover both 2 and 92 h after adrenalectomy are inhibited by treatment with small doses of corticosterone. The data strongly suggest that the activity of some brain 5HT neurons changes after adrenalectomy in a triphasic pattern and, further, that these changes are related in part to glucocorticoid withdrawal. 5HT receptor antagonists blunted corticosterone inhibition of the adrenalectomy-induced decreases in brain 5HT turnover, providing further evidence for an interaction between glucocorticoids and brain 5HT neurons. The data are consistent with a role of brain 5HT neurons in the adrenalectomy-induced triphasic changes in ACTH secretion.

Acute lymphoid changes and ongoing immune activation in SIV infection.

Two features of simian immunodeficiency virus (SIV) infection are emphasized: a transitory decrease in CD4 T cells in the first 2 weeks of infection followed by CD8 T-cell rise, and immune cell activation occurring by 4 weeks and persisting throughout the illness. The short-term changes included a fall in CD4 T cells by 2 weeks with partial recovery by 4 weeks and a CD8 rise that starts at 2 weeks. Subsequent characterization of CD4 T cells showed reduced expression of HLA-DR and CD25 (IL-2 receptor alpha chain) antigens later in SIV infection. Immune cell activation is evident in increased serum levels of neopterin and soluble CD8 antigen. Serum beta 2-microglobulin changes are less marked. Activation of CD8 T cells is reflected by increased percentages of cells expressing HLA-DR antigen. The B-cell numbers increased late in the course of SIV infection. Increased expression of the CD78 (Leu 21) activation phenotype was also seen in some monkeys. The immune activation changes (serum neopterin levels) induced by SIV infection in rhesus macaques appear to be associated with duration of illness, although the number of monkeys observed until death were too few for conclusive data. Thus, immune activation as well as T-cell deficiency may reflect significant immunopathogenic processes in SIV-induced disease.

The effects of the cyclosporin A, a P-glycoprotein inhibitor, on the pharmacokinetics of baicalein in the rat: a microdialysis study.

1. Baicalein is a bioactive flavonoid isolated from the root of Scutellaria baicalensis Georgi, a medicinal herb that has been used since ancient times to treat bacterial infections. As little is known concerning its pharmacokinetics, this study focussed on its pharmacokinetics as well as the possible roles of the multidrug transporter P-glycoprotein on its distribution and disposition. 2. Three microdialysis probes were simultaneously inserted into the jugular vein, the hippocampus and the bile duct of male Sprague-Dawley rats for sampling in biological fluids following the administration of baicalein (10, 30 and 60 mg kg(-1)) through the femoral vein. The P-glycoprotein inhibitor cyclosporin A was used to help delineate its roles. 3. The study design consisted of two groups of six rats in parallel: control rats which received baicalein alone and the cyclosporin A treated-group in which the rats were injected cyclosporin A, a P-glycoprotein inhibitor, 10 min prior to baicalein administration. 4. Cyclosporin A treatment resulted in a significant increase in elimination half-life, mean residence time and area under the concentration versus time curve (AUC) of unbound baicalein in the brain. However, AUC in the bile was decreased. 5. The decline of baicalein in the hippocampus, blood and bile suggested that there was rapid exchange and equilibration between the peripheral compartment and the central nervous system. In addition, the results indicated that baicalein was able to penetrate the blood-brain barrier as well as undergoing hepatobiliary excretion. 6. Although no direct transport studies were undertaken and multiple factors may affect BBB penetration and hepatobiliary excretion, strong association of the involvement of P-glycoprotein in these processes is indicated.

Inhibition of aldosterone production by testosterone in male rats.

In vivo and in vitro experiments were designed to assess the effect of testosterone on aldosterone secretion in male rats. Orchidectomized rats were injected subcutaneously with oil or testosterone propionate ([TP] 2 mg/kg) for 7 days. Intact rats were injected with oil only. The results indicate that the plasma aldosterone level was higher in orchidectomized versus intact and TP-replaced rats. In the in vitro study, testosterone caused a marked decrease of aldosterone secretion by zona glomerulosa (ZG) cells, but failed to alter the accumulation of intracellular adenosine 3',5'-cyclic monophosphate (cAMP). Testosterone significantly decreased the corticotropin (ACTH)-stimulated production of aldosterone and accumulation of cAMP in rat ZG cells. The conversion of corticosterone to aldosterone and of 25-OH-cholesterol to pregnenolone, as well as angiotensin II (ANG II)-stimulated production of aldosterone, were decreased by testosterone. These results suggest that testosterone inhibits the basal and ANG II- and ACTH-stimulated release of aldosterone, via inhibition of aldosterone synthase activity and cytochrome P-450 side-chain cleavage (P450scc) activity, and ACTH-stimulated cAMP accumulation in rat ZG cells.

Lack of effect of corticotropin releasing factor on hypothalamic dopamine and serotonin synthesis turnover rates in rats.

Catecholamine and serotonin neurons in the hypothalamus regulate the secretion of corticotropin releasing factor (CRF). We considered the possibility that CRF might in turn affect the activity of these aminergic neurons. We examined the effect of intracisternal administration of synthetic CRF on the synthesis turnover rates of dopamine and serotonin in the hypothalamus of adult male rats using two different methods to assess turnover. In one study, we measured the accumulation of L-dihydroxyphenylalanine (L-DOPA) or 5-hydroxytryptophan (5-HTP) in mediobasal hypothalamus after L-aromatic amino acid decarboxylase inhibition with m-hydroxybenzylhydrazine 20 min before sacrifice, and in the second study we measured the accumulation of dopamine, norepinephrine, epinephrine and serotonin after monoamine oxidase inhibition with pargyline 20 min before sacrifice. The commercial CRF which we administered intraarterially increased plasma ACTH and corticosterone concentrations. Intracerebral CRF 5 to 20 micrograms 20 min before sacrifice or 20 micrograms 110 min before sacrifice did not alter the m-hydroxybenzylhydrazine-induced accumulation of L-DOPA or 5-HTP when compared with saline vehicle-injected controls. CRF 20 micrograms did not alter basal concentration or pargyline-induced accumulation of the catecholamines or serotonin in whole hypothalamus when compared with saline vehicle-injected controls. Thus, intracisternal administration of CRF did not alter hypothalamic dopamine or serotonin synthesis rates as assessed by two nonsteady state turnover methods. The data suggest that the release of CRF from neurons in hypothalamus does not alter the activity of catecholamine or serotonin neurons in the hypothalamus of normal adult male rats.

The vasorelaxant effect of evodiamine in rat isolated mesenteric arteries: mode of action.

The roles of the endothelium, Ca2+ and K+ fluxes in the evodiamine-induced attenuation of vascular contractile responses to vasoactive agents were examined. The results showed that: (1) in rat mesenteric artery rings, evodiamine elicited a concentration-dependent attenuation in the contractile response generated by phenylephrine. The inhibitory potency was greater for intact than for endothelium-denuded preparations. Thus, the vasodilator action of evodiamine appeared to be partially endothelium-interactive (dependent). (2) Evodiamine pretreatment had a greater inhibitory effect on the phenylephrine-induced tonic contraction (via Ca2+ influx) than on the phasic contraction (via Ca2+ release). In addition, evodiamine was more potent to inhibit the restoration by CaCl2 of contractile responses to phenylephrine than a potassium depolarizing solution in media that had been kept calcium-free. These results suggest that block of the Ca2+ influx through receptor-mediated Ca2+ channels may be the major mechanism underlying the vasodilator effect of evodiamine. (3) A K+ channel blocker, tetraethylammonium, almost completely abolished the vasodilatation induced by minoxidil (a known K+ channel opener) but not evodiamine. The possible involvement of K+ channel activation of the vasodilator effect produced by evodiamine was therefore excluded.

Inhibition of serotonin synthesis within the medulla and posterior hypothalamus by cardiac vagal afferents during acute myocardial ischemia in the rat.

Serotonin synthesis, as estimated by the accumulation of 5-hydroxytryptophan 25 min following aromatic-L-amino acid decarboxylase inhibition, was measured in the medulla, pons-midbrain and posterior and anterior hypothalamus of rats subjected to left coronary artery ligation and their sham-operated controls. Left coronary artery ligation led to reduction in the rate of serotonin synthesis in the medulla and posterior hypothalamus. The topical administration of lidocaine to the left ventricle or vagotomy completely obviated these occlusion-induced changes. We conclude that there is an inhibition of serotonergic activity in the medulla and posterior hypothalamus after left coronary artery occlusion in the rat. The afferent signal arises from receptors in the ischemic left ventricle and is conducted by the vagus.

Increase of plasma neuropeptide Y-like immunoreactivity following chronic hypoxia in the rat.

In an attempt to understand the changes of circulating neuropeptide Y (NPY) during hypoxia, the plasma level of NPY was investigated by radioimmunoassay. Exposure of rats to hypobaric hypoxia at an altitude of 18,000 ft for 4 weeks causes an increase of pulmonary pressure and an elevation of plasma NPY-like immunoreactivity (NPY-LI). However, the systemic blood pressure was not elevated by this chronic hypoxia. Also, plasma noradrenaline (NA) estimated by chromatographic analysis (HPLC-ECD) was not markedly raised. Failure of bretylium and guanethidine, sympathetic neuron blockers, in reducing the plasma NPY-LI level of these rats ruled out the participation of adrenergic nervous terminals. Adrenal medulla seems responsible for this elevation of plasma NPY-LI because this magnitude disappeared in adrenalectomized rats. These data suggest that chronic hypoxia induced an elevation of circulating NPY from the adrenal gland of rats.

Turnover of central biogenic amines in two-kidney, one-clip renal hypertensive rats.

Turnover rates, as estimated from the accumulation of the intermediates dihydroxyphenylalanine (DOPA) and 5-hydroxytryptophan (5-HTP) following decarboxylase inhibition, were used to investigate the relationship between central catecholaminergic and serotonergic neurons and the development of hypertension in 2-kidney, 1-clip renal hypertensive rats. Results indicated that at one week following clipping, DOPA accumulation was increased in the midbrain-pons. At 5 weeks no changes were observed. At 20 weeks a lower accumulation of both DOPA and 5-HTP was observed in the posterior hypothalamus while in the medulla oblongata DOPA accumulation was lower and in the midbrain-pons 5-HTP accumulation was reduced.

Turnover of central biogenic amines in one-kidney, one-clip renal hypertensive rats.

Turnover rates, as estimated from the accumulation of the intermediates, 3,4-dihydroxyphenylalanine (DOPA) and 5-hydroxytryptophan (5-HTP) following decarboxylase inhibition, were used to investigate the relationship between central catecholaminergic and serotonergic neurons and the development of hypertension in the one-kidney, one-clip renal hypertensive rats. Results indicated that at one week following clipping, 5-HTP accumulation was decreased in the posterior hypothalamus. At 5 weeks no changes were observed. At 20 weeks higher accumulations of both DOPA and 5-HTP were observed in the medulla oblongata while in the anterior hypothalamus DOPA accumulation was increased.

Differential expression of glial fibrillary acidic protein (GFAP) in the retinae and visual cortices of rats with experimental renal hypertension.

To examine the expression of the GFAP protein in the retina and visual cortex under normal and pathological conditions, hypertension was induced in adult male Sprague-Dawley rats by applying silver clips onto renal arteries and the change in GFAP expression was followed by Western blotting and immunocytochemical staining. One week after operation when the induced hypertension was at the initial stage, GFAP expression in the retina was reduced to half of the sham control. By 4 weeks, when consistent hypertension was developed, a further decrease in the level of GFAP expression in the retina to one third of the sham control was observed. Immunocytochemical staining showed that the number of GFAP-positive cells in the nerve fiber layer of the retina of the hypertensive rat was reduced to less than one third of the sham control. However, similar changes in GFAP expression in the visual cortex of hypertensive rats were not observed. This study represents the first report to date on GFAP expression in the retina and visual cortex and includes discussion of the possible mechanisms through which GFAP expression is mediated.

Prolactin increases the activity of tuberoinfundibular and nigroneostriatal dopamine neurons: prolactin antiserum inhibits the haloperidol-induced increases in dopamine synthesis rates in median eminence and striatum of rats.

The role of PRL in mediating the haloperidol-induced increase in tuberoinfundibular dopamine synthesis rate was assessed by studying the effects of administration of PRL antiserum. Antiserum to PRL generated in rabbits and not cross-reacting with other anterior pituitary hormones was administered IV to adult, male rats which received haloperidol 2.5 mg/kg or tartaric acid vehicle SC 22 hr and 12 hr before measurement of dopamine turnover. Comparable groups of haloperidol or vehicle-treated animals received normal rabbit serum as control. Dopamine synthesis or turnover rate was estimated by measurement of accumulation of L-dihydroxyphenylalanine following inhibition of L-aromatic amino acid decarboxylase with m-hydroxybenzylhydrazine. Haloperidol increased median eminence dopamine synthesis rate, and PRL antiserum completely prevented this effect, supporting the thesis that the haloperidol-induced increase in tuberoinfundibular dopamine turnover is mediated by PRL. PRL antiserum did not alter basal median eminence dopamine synthesis rate in male rats. In addition to its effect in median eminence, PRL antiserum blunted the haloperidol-induced increase in striatal dopamine synthesis rate, suggesting that the haloperidol-induced increase in nigroneostriatal dopamine turnover is mediated in part by PRL. Neither haloperidol nor PRL antiserum altered serotonin synthesis rate in mediobasal hypothalamus or striatum. The data provide further support for a mechanism by which PRL can regulate its own secretion. They also suggest that prolactin alters the activity not only of tuberoinfundibular but also of nigroneostriatal neurons.