Functional outcome after selective dorsal rhizotomy: a retrospective case control study.

PURPOSE: This study examines long-term benefit on functional outcomes and quality of life after selective dorsal rhizotomy (SDR) in children with spastic diplegia in Hong Kong. METHOD: This is a case control study. Individuals with spastic diplegia who were at 6 to 12 years post-SDR were recruited. Age, gender, cognition, and Gross Motor Function Classification System level-matched individuals with spastic diplegia who had not undergone SDR were recruited as controls. Outcome measures included physical level, functional level, physiological level, and quality of life. All data were compared by independent t-test. RESULTS: Individuals post-SDR (n = 15) demonstrated a significantly better range of ankle dorsiflexion in knee extension by - 5.7 ± 10.9° than the control group (n = 12). No other significant differences were observed. CONCLUSION: SDR is a safe, one-off procedure and provides long-term reduction in spasticity with no major complications. With the heterogeneity, we did not demonstrate between-group differences in long-term functional outcomes.

Isodon eriocalyx and its bioactive component Eriocalyxin B enhance cytotoxic and apoptotic effects of gemcitabine in pancreatic cancer.

BACKGROUND: Pancreatic cancer, associated with poor prognosis and low survival rate, has been the fourth leading cause of cancer-related death in the US. Although gemcitabine (Gem) is the first-line chemotherapeutic drug in the management of pancreatic cancer, the median survival extension is only 1.5 months, indicating unsatisfactory clinical results. Therefore, exploring agents that can enhance the anti-cancer activity of Gem would be an attractive strategy. PURPOSE: Our previous studies have demonstrated that eriocalyxin b (EriB), an ent­kaurane diterpenoid isolated from Isodon eriocalyx (Dunn.) Hara, possesses anti-pancreatic cancer effects, thus acting as a potential therapeutic agent. In this study, we further investigated whether EriB or the ethanol extract of I. eriocalyx (Isodon) could potentiate the cytotoxic activity of Gem in human pancreatic adenocarcinoma cells. In addition, the mechanism associated with their effects was also studied. METHODS: The anti-proliferation effect was assessed by MTT assay and Ki-67 immunostaining. The combination effect (addition, synergism and antagonism) of various agents was calculated by the Calcusyn software (Biosoft), utilizing the T.C. Chou Method. Apoptosis was detected using Annexin V and PI double staining followed by quantitative flow cytometry. Protein expression regulated by various treatments was analyzed by western blotting. RESULTS: The combination index revealed that Gem and EriB (or Isodon extract) had synergistic anti-proliferative effect. Both cellular apoptotic and anti-proliferative effects of Gem were significantly increased after combination with EriB (or Isodon extract). The underlying mechanisms involved in the combination effects were elucidated, which include: (1) increased activation of the caspase cascade; (2) reduction of PDK1 and AKT phosphorylation; (3) induction of JNK phosphorylation by Isodon and Gem combination. CONCLUSION: Gem and EriB (or Isodon extract) taken together in combination regulated PDK1/AKT1/caspase and JNK signaling and promoted apoptosis synergistically, which may contribute to the much increased anti-proliferative activity compared to either agent alone.

dcc orchestrates the development of the prefrontal cortex during adolescence and is altered in psychiatric patients.

Adolescence is a period of heightened susceptibility to psychiatric disorders of medial prefrontal cortex (mPFC) dysfunction and cognitive impairment. mPFC dopamine (DA) projections reach maturity only in early adulthood, when their control over cognition becomes fully functional. The mechanisms governing this protracted and unique development are unknown. Here we identify dcc as the first DA neuron gene to regulate mPFC connectivity during adolescence and dissect the mechanisms involved. Reduction or loss of dcc from DA neurons by Cre-lox recombination increased mPFC DA innervation. Underlying this was the presence of ectopic DA fibers that normally innervate non-cortical targets. Altered DA input changed the anatomy and electrophysiology of mPFC circuits, leading to enhanced cognitive flexibility. All phenotypes only emerged in adulthood. Using viral Cre, we demonstrated that dcc organizes mPFC wiring specifically during adolescence. Variations in DCC may determine differential predisposition to mPFC disorders in humans. Indeed, DCC expression is elevated in brains of antidepressant-free subjects who committed suicide.

Influence of catechins on bystander responses in CHO cells induced by alpha-particle irradiation.

In this work, we studied alpha-particle induced and medium-mediated bystander effects in Chinese hamster ovary (CHO) cells through micronucleus (MN) assay. We showed that signal transduction from irradiated cells to bystander cells occur within a short time after irradiation. We then studied the effects of ROS (reactive oxygen species)-scavenging catechins in the medium before irradiation. We observed decreases in the percentage of bystander cells with MN formation and thus proved the protection effect of catechins on bystander cells from radiation.

Influence of Magnolol on the bystander effect induced by alpha-particle irradiation.

In this work, the influence of Magnolol on the bystander effect in alpha-particle irradiated Chinese hamster ovary (CHO) cells was examined. The bystander effect was studied through medium transfer experiments. Cytokinesis-block micronucleus (CBMN) assay was performed to quantify the chromosome damage induced by alpha-particle irradiation. Our results showed that the alpha-particle induced micronuclei (MN) frequencies were suppressed with the presence of Magnolol.

Transcatheter embolisation of visceral pseudoaneurysms--technical difficulties and modification of embolisation technique.

We report 13 successful emergency embolisations for 12 pseudoaneurysms performed in 10 patients. For five pseudoaneurysms the embolisation technique was modified according to number of supplying vessels, flow rate of pseudoaneurysms, vascular anatomy and whether there was clinical evidence of re-bleeding or not. Apart from traditional embolisation technique, modified embolisation techniques are also useful for endovascular therapy of pseudoaneurysms.

Arterial embolisation in intractable primary post-partum haemorrhage: case series.

OBJECTIVE: To evaluate the efficacy and safety of arterial embolisation in the management of intractable primary post-partum haemorrhage. DESIGN. Retrospective case series. SETTING: Regional hospital, Hong Kong. PATIENTS: Nine patients aged 28 to 39 years who were treated for severe primary post-partum haemorrhage between October 2000 and January 2003. INTERVENTION: Emergency transcatheter arterial embolisation. MAIN OUTCOME MEASURES: Clinical outcome and complications. RESULTS: All nine arterial embolisations successfully arrested the haemorrhage. The main cause of primary post-partum haemorrhage was uterine atony. No serious complication arose, although one patient experienced slight numbness of the right leg. Normal menstruation resumed in all patients, except for the one who had had a hysterectomy as initial treatment. One patient became pregnant 1 year after embolisation. Patients were followed up for 10 months. CONCLUSION: In our experience, arterial embolisation is safe and efficacious, and is the treatment of choice for patients with intractable primary post-partum haemorrhage.

Investigation of photon beam models in heterogeneous media of modern radiotherapy.

This study investigates the performance of photon beam models in dose calculations involving heterogeneous media in modern radiotherapy. Three dose calculation algorithms implemented in the CMS FOCUS treatment planning system have been assessed and validated using ionization chambers, thermoluminescent dosimeters (TLDs) and film. The algorithms include the multigrid superposition (MGS) algorithm, fast Fourier Transform Convolution (FFTC) algorithm and Clarkson algorithm. Heterogeneous phantoms used in the study consist of air cavities, lung analogue and an anthropomorphic phantom. Depth dose distributions along the central beam axis for 6 MV and 10 MV photon beams with field sizes of 5 cm x 5 cm and 10 cm x 10 cm were measured in the air cavity phantoms and lung analogue phantom. Point dose measurements were performed in the anthropomorphic phantom. Calculated results with three dose calculation algorithms were compared with measured results. In the air cavity phantoms, the maximum dose differences between the algorithms and the measurements were found at the distal surface of the air cavity with a 10 MV photon beam and a 5 cm x 5 cm field size. The differences were 3.8%. 24.9% and 27.7% for the MGS. FFTC and Clarkson algorithms. respectively. Experimental measurements of secondary electron build-up range beyond the air cavity showed an increase with decreasing field size, increasing energy and increasing air cavity thickness. The maximum dose differences in the lung analogue with 5 cm x 5 cm field size were found to be 0.3%. 4.9% and 6.9% for the MGS. FFTC and Clarkson algorithms with a 6 MV photon beam and 0.4%. 6.3% and 9.1% with a 10 MV photon beam, respectively. In the anthropomorphic phantom, the dose differences between calculations using the MGS algorithm and measurements with TLD rods were less than +/-4.5% for 6 MV and 10 MV photon beams with 10 cm x 10 cm field size and 6 MV photon beam with 5 cm x 5 cm field size, and within +/-7.5% for 10 MV with 5 cm x 5 cm field size, respectively. The FFTC and Clarkson algorithms overestimate doses at all dose points in the lung of the anthropomorphic phantom. In conclusion, the MGS is the most accurate dose calculation algorithm of investigated photon beam models. It is strongly recommended for implementation in modern radiotherapy with multiple small fields when heterogeneous media are in the treatment fields.

The recovery of some components of the renin angiotensin system in the rat pancreas after chronic exposure to hypoxic condition.

Previous studies have shown that the expression of the major components from a local pancreatic renin-angiotensin system (RAS) was upregulated after chronic exposure to oxygen deprivation (10% oxygen). In the present study, the reversibility of expression for the pancreatic RAS affected by chronic hypoxia was investigated in the pancreas. Rats were first subject to hypoxia for one Month and they were then returned to normoxic conditions for a varying period of time (1, 2, 3 and 4 weeks). The degree of recovery in the expression of RAS components was analyzed with standard curve-quantitative competitive-reverse transcription-polymerase chain reaction (SC-QC-RT-PCR), Western blot analysis and a specific assay for angiotensin-converting enzyme (ACE) activity. Results from SC-QC-RT-PCR showed that the upregulated expression of angiotensin II type 1 (AT(1)) receptor mRNA following chronic hypoxia could be completely restored to the control level after the rats were returned to the normoxic condition for 3 weeks. The reversibility of mRNA expression for angiotensin II type 2 (AT(2)) receptor and angiotensinogen was observed after the return to normoxic conditions for 2 and 3 weeks respectively when compared with that of their respective controls. Results from Western blot analysis further confirmed that the expression of AT(1) receptor protein was also reversible after return to normoxic conditions for 4 weeks. In addition, the activation of ACE activity returned to its normal level in a time-dependent manner. These data indicate that the upregulation of a local pancreatic RAS affected by chronic hypoxia could be recoverable. The significance of its reversibility and adaptability following chronic hypoxia may be of physiological relevance to the pancreas.

The impact of Abeta-plaques on cortical cholinergic and non-cholinergic presynaptic boutons in alzheimer's disease-like transgenic mice.

A previous study in our laboratory, involving early stage, amyloid pathology in 8-month-old transgenic mice, demonstrated a selective loss of cholinergic terminals in the cerebral and hippocampal cortices of doubly transgenic (APP(K670N,M671L)+PSl(M146L)) mice, an up-regulation in the single mutant APP(K670N,M671L) mice and no detectable change in the PSl(M146L) transgenics [J Neurosci 19 (1999) 2706]. The present study investigates the impact of amyloid plaques on synaptophysin and vesicular acetylcholine transporter (VAChT) immunoreactive bouton numbers in the frontal cortex of the three transgenic mouse models previously described. When compared as a whole, the frontal cortices of transgenic and control mice show no observable differences in the densities of synaptophysin-immunoreactive boutons. An individual comparison of layer V of the frontal cortex, however, shows a significant increase in density in transgenic models. Analysis of the cholinergic system alone shows significant alterations in the VAChT-immunoreactive bouton densities as evidenced by an increased density in the single (APP(K670N,M671L)) transgenics and a decreased density in the doubly transgenics (APP(K670N,M671L)+PSl(M146L)). In investigating the impact of plaque proximity on bouton density at early stages of the amyloid pathology in our doubly (APP(K670N,M671L)+PSl(M146L)) transgenic mouse line, we observed that plaque proximity reduced cholinergic pre-synaptic bouton density by 40%, and yet increased synaptophysin-immunoreactive pre-synaptic bouton density by 9.5%. Distance from plaques (up to 60 microm) seemed to have no effect on bouton density; however a significant inverse relationship was visible between plaque size and cholinergic pre-synaptic bouton density. Finally, the number of cholinergic dystrophic neurites surrounding the truly amyloid, Thioflavin-S(+) plaque core, was disproportionately large with respect to the incidence of cholinergic boutons within the total pre-synaptic bouton population. Confocal and electron microscopic observations confirmed the preferential infiltration of dystrophic cholinergic boutons into fibrillar amyloid aggregates. We therefore hypothesize that extracellular Abeta aggregation preferentially affects cholinergic terminations prior to progression onto other neurotransmitter systems. This is supported by the observable presence of non-cholinergic sprouting, which may be representative of impending neuritic degeneration.

Emergency embolization of spontaneous ruptured hepatocellular carcinoma: correlation between survival and Child-Pugh classification.

From February 1994 to April 2000, 29 emergency gelfoam embolizations for spontaneous ruptured hepatocellular carcinoma (HCC) performed in 28 patients were retrospectively reviewed. There were 11 patients in Child's A, 11 in Child's B and six in Child's C classification of cirrhosis. The duration of the procedure, artery embolized and complications were reviewed, and the Child-Pugh classification of each patient was correlated with their mean survival period. Embolization was done in 12 right hepatic arteries, two left hepatic arteries and 15 proper hepatic arteries. In one patient, the left hepatic artery was embolized initially but the proper hepatic artery was also embolized because another subcapsular liver tumour was found after reviewing the preangiogram CT scan. The entire procedure took 40-170 min (mean = 86 min) with no periprocedural complication. Following embolization, the mean survival period for Child's A class was 218.3 days, Child's B class was 83.4 days and Child's C class was 11.0 days. Transcatheter embolization is an effective treatment to arrest bleeding in spontaneous ruptured HCC. Patients with Child's A class cirrhosis have the longest survival. Selective embolization of either the right or the left hepatic artery alone carries the potential risk of missing multifocal HCC that might not be easily appreciated during angiography.

Activation of PI3-kinase is required for AMPA receptor insertion during LTP of mEPSCs in cultured hippocampal neurons.

Hippocampal CA1 homosynaptic long-term potentiation (LTP) is expressed specifically at activated synapses. Increased insertion of postsynaptic alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid receptors (AMPARs) appears to be crucial for CA1 LTP. However, the mechanism underlying AMPAR insertion during LTP remains largely unknown. We now report that phosphatidylinositol 3-kinase (PI3K) is complexed with AMPARs at synapses and activated by selective stimulation of synaptic N-methyl-D-aspartate (NMDA) receptors. Activation of the AMPAR-associated PI3K is required for the increased cell surface expression of AMPARs and LTP. Thus, our results strongly suggest that the AMPAR-PI3K complex may constitute a critical molecular signal responsible for AMPAR insertion at activated CA1 synapses during LTP, and consequently, this lipid kinase may serve to determine the polarity of NMDA receptor-dependent synaptic plasticity.

Aging causes a preferential loss of cholinergic innervation of characterized neocortical pyramidal neurons.

Aging is known to markedly affect the number and structural characteristics of both pre- and post-synaptic sites in the cerebral cortex. There is evidence that lamina V pyramidal neurons, and their basilar dendrites in particular, are affected by age-related decline. Furthermore, layer V is the area where the greatest overall age- related losses in the total population of synaptic boutons and of cholinergic boutons are observed. Since both pyramidal neurons and cortical cholinergic input are characteristically compromised in aging, we investigated whether aging altered the pattern of cholinergic boutons in apposition to the soma, proximal and distal basal dendrites of intracellularly labeled lamina V large pyramidal neurons in the parietal cortex of young and aged rats. We observed a significant age-related decrease in the population of both total and cholinergic boutons apposed to proximal and distal dendrites of layer V large pyramidal neurons. However, the age-related decreases of cholinergic presynaptic boutons were higher than those in the total bouton population apposed to the pyramidal neurons. The average decrease in cholinergic boutons in aged rats was 3.7-fold more pronounced than the diminution in the overall number of presynaptic boutons. Our results add important new evidence in support of the concept that the age-related learning and memory deficits are attributable, at least partially, to a decline in the functional integrity of the forebrain cholinergic systems.

Androgen dependent expression of AT1 receptor and its regulation of anion secretion in rat epididymis.

Our previous studies have provided solid evidence for the presence of an intrinsic angiotensin-generating system in the rat epididymis, which plays an important role in the regulation of the anion and thus fluid secretion by the epididymal epithelium. In the present study, the effect of androgen on the expression of AT(1)receptor and its subsequent regulation of anion secretion by the epididymis were investigated using Western blotting, semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) and in vitro electrophysiological approaches. Results from Western blotting analysis showed that the expression of AT(1)receptor protein was almost abolished by castration whereas its expression was completely restored to the control level when the castrated rats were hormonally replaced with testosterone. Efferent duct ligation, however, appeared not to affect the expression of AT(1)receptor protein by the epididymis. Results from RT-PCR showed that mRNA expression of AT(1)receptor was consistent with that observed in protein expression. Results from short-circuit current (I(SC)) showed that castration almost abolished the angiotensin II-induced I(SC). However, efferent duct ligation did not affect the angiotensin II-induced I(SC), which was completely blocked in the presence of losartan, a specific antagonist of the AT(1)receptor. These data indicate that the expression of epididymal AT(1)receptor is predominantly influenced by testicular androgens but not by testicular factors. This androgen-dependent expression of AT(1)receptor could have a role in the control of AT(1)receptor-mediated anion secretion and thus fluid secretion by the rat epididymis.

Cholinergic nerve terminals establish classical synapses in the rat cerebral cortex: synaptic pattern and age-related atrophy.

This study addresses the issue of whether cholinergic varicosities in the cerebral cortex establish 'classical synapses' or whether they communicate with their targets non-synaptically by 'volume transmission'. Most recent studies in the neocortex have suggested that acetylcholine acts non-synaptically, however in the present study we provide ultrastructural evidence that suggests synaptic mechanisms prevail. This conclusion is based upon our ultrastructural observations that cholinergic boutons--as revealed by immunoreactivity for the specific cholinergic market, vesicular acetylcholine transporter--establish a high percentage of classical synapses in layer V of the rat parietal cortex. Furthermore, the combination of this approach with the intracellular labeling of large pyramidal neurons on slice preparations revealed significant incidences of cholinergic contacts abutting preferentially on dendritic shafts. Finally, we have gathered information suggesting that cholinergic boutons undergo atrophy with aging which could be related to the well-known cholinergic and cognitive decline. These results illustrate that the cholinergic terminations in the neocortex establish proper synaptic connections and that they experience important age-dependent atrophy.

Transit dose of an Ir-192 high dose rate brachytherapy stepping source.

Clinical dosimetry for high dose rate (HDR) brachytherapy with a single stepping source generally neglects the transit dose. This study investigates the effects of the transit dose in the target volume of an HDR brachytherapy stepping source. A video method was used to analyse the entrance, exit and the interdwell transit speed of the source for different path lengths and step sizes ranging from 2.5 mm to 995 mm. The transit speed was found to vary with the step size and path length. For the travelled distances of 2.5, 5.0, 10.0, 230 and 995 mm, the average transit speeds were 54, 72, 233, 385 and 467 mm s(-1) respectively. The results also show that the manufacturer has attempted to compensate for the effects of interdwell transit dose by reducing the actual dwell time of the source. A well-type chamber was used to determine the dose differences between two sets of measurements, one being the stationary dose only and the other being the sum of stationary and transit doses. Single catheters of active lengths of 20 and 40 mm, different dwell times of 0.5, 1, 2 and 5 s and different step sizes of 2.5, 5 and 10 mm were used in the measurements with the well-type chamber. Most of the measured dose differences between stationary and stationary plus interdwell source movement were within 2%. The additional dose due to the source transit can be as high as 24.9% for the case of 0.5 s dwell time, 10 mm step size and 20 mm active length. The dose difference is mainly due to the entrance and exit source movement but not the interdwell movement.

Loss of presynaptic and postsynaptic structures is accompanied by compensatory increase in action potential-dependent synaptic input to layer V neocortical pyramidal neurons in aged rats.

Reduction in both presynaptic and postsynaptic structures in the aging neocortex may significantly affect functional synaptic properties in this area. To directly address this issue, we combined whole-cell patch-clamp recording of spontaneously occurring postsynaptic currents (PSCs) with morphological analysis of layer V pyramidal neurons in the parietal cortex of young adult (1- to 2-month-old) and aged (28- to 37-month-old) BN x F344 F(1) hybrid rats. Analysis of spontaneous PSCs was used to contrast functional properties of basal synaptic input with structural alterations in the dendritic tree of pyramidal neurons and density of terminals in contact with these cells. We observed significant changes in a number of morphological parameters of pyramidal neurons in aged rats. These include smaller cell body size and fewer basal dendritic branches (but not of oblique dendrites and dendritic tufts) and spines. Ultrastructural analysis also revealed a lower density of presynaptic terminals per unit length of postsynaptic membrane of labeled pyramidal neurons in the aged brain. This reduction in both presynaptic and postsynaptic elements was paralleled by a significant decrease in frequency of tetrodotoxin-insensitive miniature (action potential-independent) PSCs (mPSCs). The frequency of excitatory and inhibitory mPSCs was reduced to the same extent. In contrast, no significant change was observed in the frequency of spontaneous PSCs recorded in absence of tetrodotoxin (sPSCs), indicating an increase in action potential-dependent (frequency(sPSCs) - frequency(mPSCs)) input to pyramidal neurons in the aged group. This functional compensation may explain the lack of drastic loss of spontaneous neuronal activity in normal aging.

Testicular hormonal regulation of the renin-angiotensin system in the rat epididymis.

Evidence for the existence of an intrinsic angiotensin system based on locally formed angiotensinogen as a precursor for angiotensin production has been demonstrated in the rat epididymis. The data strongly support the presence of an epididymal renin-angiotensin system (RAS) which may be important for epididymal and sperm functions. In the present study, the effects of castration and testicular hormonal replacement on the expression of RAS components from the rat epididymis are investigated at the gene and protein levels. Results from northern blot and western blot analyses consistently showed that the expression of angiotensinogen mRNA and protein was apparently abolished by castration whereas their expression was completely restored to control levels when the castrated rats were hormonally replaced with either testosterone alone or with combined testosterone and estradiol. Northern blot did not detect any signal for angiotensinogen mRNA while western blot could detect a weak signal for angiotensinogen protein when the castrated rats were replaced with estradiol alone. Renin could be detected neither in control, castrated nor hormonally replaced rats. Moreover, the expression of angiotensin II receptor, type I (AT1) was almost abolished by castration as demonstrated by northern blot and reverse transcription-polymerase chain reaction. These data indicate that the expression of RAS by the rat epididymis at the levels of its precursor angiotensinogen and its receptor AT1, is subject to the regulation of testicular hormones and its expression appears to be predominantly testosterone-dependent.

Angiotensinogen expression by rat epididymis: evidence for an intrinsic, angiotensin-generating system.

Previous studies have suggested the presence of an intrinsic renin-angiotensin system (RAS) in the rat epididymis with functions in epididymal activity and sperm maturation. In the present study, the localization and expression of angiotensinogen, the component of the RAS which is indispensable for intracellular angiotensin generation, were investigated by immunochemistry, hybridization histochemistry and by reverse-transcriptase polymerase chain reaction (RT-PCR). Western blot analysis of protein from the epididymis confirmed the presence of angiotensinogen with the expected molecular mass of about 60 kDa, in agreement with results from other tissues. Immunocytochemistry showed the regional localization of immunoreactivity for angiotensinogen in the rat epididymis. In situ hybridization histochemistry further demonstrated the expression of angiotensinogen mRNA by the epididymal epithelium in a region-specific manner along the length of the rat epididymis. RT-PCR confirmed that the rat epididymis expresses angiotensinogen mRNA. On the other hand, mRNA of renin was not detected in the rat epididymis using Northern blot and RT-PCR analyses. The present study strongly supports the existence of an intrinsic, angiotensin-generating system based on locally formed angiotensinogen as a precursor for angiotensin production. This epididymal RAS may have paracrine or autocrine roles in mediating the epididymal and sperm functions.