Surgical treatment of nasopharyngeal cancer - a consensus recommendation from two Chinese associations.

BACKGROUND: Surgical treatment is playing an increasingly important role in the management of nasopharyngeal carcinoma (NPC). This consensus focuses on the indications for optimal surgery, and surgical methods in the whole process of treatment for NPC to provide a useful reference to assist these difficult clinical decisions. METHODOLOGY: A thorough review of available literature on NPC and surgery was conducted by the Association for the prevention and treatment of nasopharyngeal carcinoma in China, international exchange and promotion Association for medicine and healthcare, and the Committee on nasopharyngeal cancer of Guangdong provincial anticancer association. A set of questions and a preliminary draft guideline was circulated to a panel of 1096 experienced specialists on this disease for voting on controversial areas and comments. A refined second proposal, based on a summary of the initial voting and different opinions expressed, was recirculated to the experts in two authoritative medical science and technology academic groups in the prevention and treatment of NPC in China for review and reconsideration. RESULTS: The initial round of questions showed variations in clinical practice even among similar specialists, reflecting the lack of high-quality supporting data and resulting difficulties in formulating clinical decisions. Through exchange of comments and iterative revisions, recommendations with high-to-moderate agreement were formulated on general treatment strategies and details of surgery, including indications and surgical approaches. CONCLUSION: By standardizing the surgical indications and practice, we hope not only to improve the surgical outcomes, but also to highlight the key directions of future clinical research in the surgical management of NPC.

[Performance of human papillomavirus typing test in cervical precancer lesions and cervical cancer screening].

Objective: To evaluate the performance of Hybribio human papillomavirus (HPV) typing test kit for high risk HPV-DNA typing detection in screening of cervical precancer lesions. Methods: A total of 9 914 women were recruited in Henan, Shanxi, and Guangdong provinces from June to July 2017. All women underwent HPV DNA test. The women who diagnosed as HPV positive and cytological examination ≥ atypical squamous cells of undetermined significance (ASCUS) or HPV negative and cytological examination≥low-grade squamous intraepithelial lesions (LSIL) underwent colposcopy biopsy and pathological examination. Using the pathological diagnosis as the gold standard, the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and 95% confidence interval (CI) of high-risk HPV and HPV16/18 tests were calculated. Results: The mean age of 9 914 subjects was (45.0±9.3) years old. Among them, 1 302 subjects were detected as high risk HPV positive, including 211 of HPV16 positive and 64 of HPV18 positive. According to the pathological gold standard of cervical intraepithelial neoplasia grade 2 (CIN2) or worse, the sensitivity and specificity of high risk-HPV and HPV 16/18 for triaging ASCUS women were 90.6% (95%CI: 75.8%-96.8%) and 78.0% (95%CI: 74.5%-81.2%) as well as 56.3% (95%CI: 39.3%-71.8%) and 95.7% (95%CI: 93.8%-97.1%), respectively. The sensitivity and specificity of high risk-HPV and HPV 16/18 for cervical precancer lesions screening were 95.1% (95%CI: 88.1%-98.1%) and 87.6% (95%CI: 86.9%-88.2%) as well as 65.9% (95%CI: 55.1%-75.2%) and 97.8% (95%CI: 97.5%-98.1%), respectively. Conclusions: The Hybribio HPV test kit has a relative high sensitivity and specificity for cervical precancer lesions screening and ASCUS triaging. It is reliable for HPV DNA detection and cervical cancer screening.

Structural exercise-based intervention for health problems in individuals with autism spectrum disorders: a pilot study.

OBJECTIVE: Exercise-based intervention promises to be more effective in a structured framework for individuals with autism spectrum disorders (ASD). The aim of this study was to observe changes in behavior of individuals with ASD by investigating their physical status after the structured exercise-based intervention. PATIENTS AND METHODS: The exercise intervention integrated an 8-week exercise program that included aerobic, resistive, and neuromuscular exercises. Body composition and the Autism Treatment Evaluation Checklist (ATEC) were evaluated to assess changes after the exercise-based intervention. RESULTS: After the exercise intervention, the fat mass of individuals with ASD were significantly reduced, and their behavior improved markedly. CONCLUSIONS: This pilot study demonstrated that individuals with ASD require long-term, structured exercise-based intervention, and that such exercise-based intervention is effective for improving their health.

Discovery of talatisamine as a novel specific blocker for the delayed rectifier K+ channels in rat hippocampal neurons.

Blocking specific K+ channels has been proposed as a promising strategy for the treatment of neurodegenerative diseases. Using a computational virtual screening approach and electrophysiological testing, we found four Aconitum alkaloids are potent blockers of the delayed rectifier K+ channel in rat hippocampal neurons. In the present study, we first tested the action of the four alkaloids on the voltage-gated K+, Na+ and Ca2+ currents in rat hippocampal neurons, and then identified that talatisamine is a specific blocker for the delayed rectifier K+ channel. External application of talatisamine reversibly inhibited the delayed rectifier K+ current (IK) with an IC50 value of 146.0+/-5.8 microM in a voltage-dependent manner, but exhibited very slight blocking effect on the voltage-gated Na+ and Ca2+ currents even at the high concentration of 1-3 mM. Moreover, talatisamine exerted a significant hyperpolarizing shift of the steady-state activation, but did not influence the steady state inactivation of IK and its recovery from inactivation, suggesting that talatisamine had no allosteric action on IK channel and was a pure blocker binding to the external pore entry of the channel. Our present study made the first discovery of potent and specific IK channel blocker from Aconitum alkaloids. It has been argued that suppressing K+ efflux by blocking IK channel may be favorable for Alzheimer's disease therapy. Talatisamine can therefore be considered as a leading compound worthy of further investigations.

Huperzine A, a nootropic alkaloid, inhibits N-methyl-D-aspartate-induced current in rat dissociated hippocampal neurons.

Huperzine A, a nootropic alkaloid isolated from a Chinese herb, has been proposed as one of the most promising agents to treat Alzheimer's disease. Recently, the agent was found to inhibit the N-methyl-D-aspartate (NMDA) receptors in rat cerebral cortex in addition to causing an inhibitory effect on acetylcholinesterase. In the present study, the mechanisms underlying NMDA receptor inhibition were investigated using whole-cell voltage-clamp recording in CA1 pyramidal neurons acutely dissociated from rat hippocampus. Huperzine A reversibly inhibited the NMDA-induced current (IC(50)=126 microM, Hill coefficient=0.92), whereas it had no effect on the current induced by alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate or kainate. The effect was non-competitive, and showed neither 'voltage-dependency', nor 'use-dependency'. The IC(50) values of huperzine A were neither altered by changing the concentrations of glycine (2-0.2 microM) and pH (7.4-6.7) in the external solution, nor by addition of Zn(2+) (5 microM) and dithiothreitol (5 mM) to the external solution. However, addition of spermine (200 microM) to the external solution caused a parallel shift to the right of the huperzine A concentration-response curve. From these we suggest that huperzine A acts as a non-competitive antagonist of the NMDA receptors, via a competitive interaction with one of the polyamine binding sites. The potential relevance of NMDA receptor antagonist activity of huperzine A to the treatment of Alzheimer's disease is discussed.

Electrophysiological and morphological properties of pyramidal and nonpyramidal neurons in the cat motor cortex in vitro.

Electrophysiological and morphological properties of the neurons in cat motor cortex were investigated using intracellular recording and staining techniques in a brain slice preparation. In response to intracellular injection of depolarizing current pulses, four distinct types of firing patterns were observed among cat neocortical neurons. Regular-spiking neurons were characterized by their repetitive firing from which conspicuous frequency adaptation was observed. Doublet-or-burst firing cells were marked with their tendency to fire 2-5 clustered spikes at the onset of depolarizing pulse. In doublet-or-burst firing neurons, but not in regular-spiking neurons, a low-threshold calcium current was revealed by single-electrode voltage clamp. Both regular-spiking and doublet-or-burst firing neurons had relatively wide action potentials. Fast-spiking neurons could fire extremely narrow action potentials at a very high frequency. Their frequency-to-intensity slope of steady-state firing was significantly higher than that of the other neurons. In contrast, narrow-spiking neurons had the smallest frequency-to-intensity slope for steady-state firing, although their action potentials were as narrow as those of the fast-spiking neurons. Both regular-spiking and doublet-or-burst firing neurons were identified as pyramidal neurons, and were found in all layers below layer I. Their apical dendrites were densely coated with dendritic spines. Narrow-spiking neurons were only recorded in layer V. They were large pyramidal cells with scare spines on their apical dendrites. Fast-spiking neurons were all nonpyramidal interneurons. Seven out of eight labelled fast-spiking cells had beaded dendrites without spines. Their axons had a large number of varicosities, and arborized extensively to form a dense plexus of terminals in the vicinity of their soma. The remaining neuron was found to be a spiny nonpyramidal neuron in layer V. These results demonstrate that, in addition to the three types of firing patterns previously identified in rodent neocortex, a group of neurons in the cat motor cortex express another type of firing behaviour which is characterized by extremely narrow action potential and very small frequency-to-intensity slope. Correlation with the morphological data shows that these neurons are large layer V pyramidal cells rather than nonpyramidal interneurons.

Different mechanisms underlying the repolarization of narrow and wide action potentials in pyramidal cells and interneurons of cat motor cortex.

Two different types of action potentials were observed among the pyramidal cells and interneurons in cat motor cortex: the narrow action potentials and the wide action potentials. These two types of action potentials had similar rising phases (528.8 +/- 77.0 vs 553.1 +/- 71.8 mV/ms for the maximal rising rate), but differed in spike duration (0.44 +/- 0.09 vs 1.40 +/- 0.39 ms) and amplitude (57.31 +/- 8.22 vs 72.52 +/- 8.31 mV), implying that the ionic currents contributing to repolarization of these action potentials are different. Here we address this issue by pharmacological manipulation and using voltage-clamp technique in slices of cat motor cortex. Raising extracellular K+ concentration (from 3 mM to 10 mM), applying a low dose of 4-aminopyridine (2-200 microM) or administering a low concentration of tetraethylammonium (0.2-1.0 mM) each not only broadened the narrow action potentials, but also increased their amplitudes. In contrast, high K+ medium or low dose of tetraethylammonium only broadened the wide action potentials, leaving their amplitudes unaffected, and 4-aminopyridine had only a slight broadening effect on the wide spikes. These results implied that K+ currents were involved in the repolarization of both types of action potentials, and that the K+ currents in the narrow action potentials seemed to activate much earlier than those in the wide spikes. This early activated K+ current may counteract the rapid sodium current, yielding the extremely brief duration and small amplitude of the narrow spikes. The sensitivity of the narrow spikes to 4-aminopyridine may not be mainly attributed to blockade of the classical A current (IA), because depolarizing the membrane potential to inactivate IA did not reproduce the effects of 4-aminopyridine. Blockade of Ca2+ influx slowed the last two-thirds repolarization of the wide action potentials. On the contrary, the narrow action potentials were not affected by Ca(2+)-current blockers, but if they were first broadened by 4-aminopyridine or tetraethylammonium, subsequent application of Ca(2+)-free medium caused further broadening, suggesting that the narrow action potentials were too brief to activate the Ca(2+)-activated potassium currents for their repolarization. Therefore, the effects of low concentrations of tetraethylammonium on the narrow spikes appeared to be mainly due to blockade of an outward current that was different from the tetraethylammonium-sensitive Ca(2+)-activated potassium current (IC). In the neurons with the narrow spikes, voltage-clamp experiments revealed two voltage-gated outward currents that were sensitive to tetraethylammonium and 4-aminopyridine, respectively. Both currents were activated rapidly following the onset of depolarizing steps. Interestingly, the tetraethylammonium-sensitive current was a transient outward current that inactivated rapidly (tau < or = 5 ms), while the 4-aminopyridine-sensitive current was relatively persistent during maintained depolarization. The 4-aminopyridine-sensitive current did not show obvious inactivation even at membrane potential of -40 mV, which completely inactivated the transient tetraethylammonium-sensitive, current. The results indicate that different potassium currents are involved in the repolarization of the narrow and wide action potentials in cat motor cortex. A novel tetraethylammonium-sensitive transient outward current and a 4-aminopyridine-sensitive outward current are responsible for the short duration and small amplitude of the narrow action potentials in the interneurons and some of the layer V pyramidal cells. These two currents are voltage-gated and Ca(2+)-independent. For the wide action potentials that characterize most pyramidal neurons, a Ca(2+)-independent tetraethylammonium-sensitive outward current and a Ca(2+)-activated potassium current are the main contributors to their repolarization.

Excitatory amino acids acting on metabotropic glutamate receptors broaden the action potential in hippocampal neurons.

Activation of metabotropic glutamate receptors (mGluRs, QP or ACPD receptors) has recently been shown to cause depolarization, blockade of the slow after-hyperpolarization and depression of calcium currents in hippocampal pyramidal cells. Here, we report evidence for a new mGluR-mediated effect: slowing of the spike repolarization in CA1 cells in rat hippocampal slices. During blockade of the ionotropic glutamate receptors, the mGluR agonists trans-1-amino-cyclopentyl-1,3-dicarboxylate (t-ACPD), quisqualate or L-glutamate caused spike broadening. In contrast, the ionotropic receptor agonist alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA) was ineffective. The spike broadening may act in concert with the other mGluR effects, e.g. by further increasing the influx of Ca2+ ions which, in turn, may contribute to synaptic modulation.

Dissociation of supraspinal and spinal morphine analgesia by reserpine.

Reserpine antagonized systemic morphine analgesia as measured by tail-flick latency but the antagonism was surmountable by increasing the morphine dose. Reserpine had no effect on the intrathecal morphine analgesia while the analgesic action of intraventricular morphine was practically eliminated by reserpine.

GABAA receptor-mediated feedback inhibition in pyramidal neurons of cat motor cortex.

Feedback or recurrent inhibition is generally proposed as a basic component of circuit organization in the brain. However, there is little direct evidence for its existence in the cortex, nor for the nature of the neurotransmitters and receptors involved. Here we address this issue by analyzing the potentials following a single action potential in cat neocortical pyramidal neurons. Using 3 M KCl-filled electrodes, we observed a distinct depolarizing potential that was superimposed on the spike after-potentials in seven out of 81 recorded and the resemblance between its falling phase and the passive decay of membrane potential suggested that the depolarizing potential originated from the cell body or proximal dendrites. This potential was blocked by bicuculline methiodide (10 microM), but not by phaclofen (0.2 mM), suggesting that it was a reversed recurrent IPSP mediated by GABAA receptors.

Comparison of the effects of cholinesterase inhibitors on [3H]MK-801 binding in rat cerebral cortex.

Huperzine A, a selective inhibitor of acetylcholinesterase, was recently demonstrated to exert an antagonist effect on N-methyl-D-aspartate (NMDA) receptor in rat cerebral cortex. In the present study, the effects of six cholinesterase inhibitors, e.g. huperzine A, huperzine B, tacrine, donepezil (E2020), physostigmine and galanthamine on [3H]dizocilpine (MK-801) binding to synaptic membrane of rat cerebral cortex were compared. Their IC50 values (mean +/- SD) were 36.9 +/- 12.1, 316.8 +/- 93.2, 33.2 +/- 3.7, 135.0 +/- 15.1, 50.4 +/- 7.4, and 3344 +/- 295 microM, respectively. The rank order of potency is tacrine approximately huperzine A > physostigmine > donepezil > huperzine B >> galanthamine. There is no correlation between their activities to inhibit [3H]MK-801 binding and to inhibit acetylcholinesterase (r = +0.563, P = 0.245). The results suggest that most cholinesterase inhibitors available exhibit an antagonist effect on NMDA receptor in rat cerebral cortex in addition to their inhibitory effect on acetylcholinesterase.

Similar potency of the enantiomers of huperzine A in inhibition of [(3)H]dizocilpine (MK-801) binding in rat cerebral cortex.

The inhibition of huperzine A, a potential therapeutic agent to treat Alzheimer's disease, on rat cortical acetylcholinesterase was found to be highly stereospecific. In the present study the effect of the enantiomers of huperzine A on [(3)H]dizocilpine (MK-801) binding to synaptic membrane of rat cerebral cortex was compared. The natural (-)-huperzine A and the synthetic (+)-huperzine A inhibited the specific binding of [(3)H]MK-801 with a similar potency. The IC(50) values were 65+/-7 and 82+/-12 microM (n=5 for each enantiomer, P=0.248), respectively. The result indicates that huperzine A inhibits N-methyl-D-aspartate (NMDA) receptor in rat cerebral cortex without stereoselectivity.

Modulation of medical prefrontal cortical D1 receptors on the excitatory firing activity of nucleus accumbens neurons elicited by (-)-Stepholidine.

(-)-Stepholidine (SPD), with D1 agonistic action, elicited an excitatory firing activity of nucleus accumbens (NAc) neurons by intravenous administration, but this effect was hardly observed by iontophoresis of SPD into the NAc. The present study intends to determine whether D1 receptors in the medial prefrontal cortex (mPFC) are involved in the action of SPD on the firing activity of NAc neurons in the chloral hydrate-anesthetized male rats. The results showed that the intra-mPFC microinjected SCH-23390 (D1 antagonist, 30 mM), but not the D2 antagonist spiperone (30 mM), significantly attenuated the enhanced firing activity induced by intravenous injection of SPD (2 mg/kg). Similarly, the excitatory firing of NAc neurons was also exhibited by the microinjection of either SPD or D1 agonist SKF-38393 into the mPFC. The SPD-induced excitatory effect was in a dose-dependent way from 277.8 +/- 51.3% (10 mM) to 1105.4 +/- 283.5% (30 mM) of NAc basal firing, which was completely reversed by SCH-23390 (i.v.). Furthermore, the direct D1 agonistic action of SPD on the mPFC neuron was observed with microiontophoresis. These results indicate that SPD possesses a direct agonistic action on the mPFC D1 receptors, by which it modulates the firing activity of NAc neurons.

Seasonal abundance, age composition, and body size of salt-marsh Anopheles (Diptera: Culicidae) in south Florida.

Five CO2-baited light traps operated fortnightly between November 1989 and May 1991 near a salt marsh in Vero Beach, FL, caught 1,961 Anopheles crucians Wiedemann (s.l.) and 691 An. atropos Dyar & Knab. Both species were most abundant in winter and least abundant in summer; their numbers correlated inversely with lagged mean ambient temperatures. Annual parous rates were 55% for An. crucians and 58% for An. atropos and varied little seasonally. Wing lengths of female An. crucians measured for eight consecutive months were negatively correlated with ambient temperatures, and parous females of this species had significantly longer wings than nullipars. Parous rates and wing length classes were positively correlated among An. crucians, confirming that larger mosquitoes are longer-lived.

Electrophysiological study on biphasic firing activity elicited by D(1) agonistic-D(2) antagonistic action of (-)-stepholidine in nucleus accumbens.

Our previous work has demonstrated that (-)-stepholidine (SPD) has dual action, ie D(1) agonistic-D(2) antagonistic action on DA receptors in the nigra-striatal dopamine (DA) system. The present study attempted to ascertain its dual action on the mesolimbic DA system. The firing activities of the nucleus accumbens (NAc) neurons were extracellularly recorded with intravenous and iontophoretic administration of the drug in 6-hydroxydopamine (6-OHDA)-lesioned and intact rats. The results showed that SPD produced a consistently biphasic firing of NAc neurons during the cumulative doses of 0.02 2 mg/kg, iv. When the rats were pretreated with D(2) antagonist spiperone, SPD only exerted an increasing effect, which was subsequently reversed by the D(1) antagonist SCH-23390. Moreover, SCH-23390 could prevent the rate of increase elicited by SPD at high doses, presumably due to the D(1) agonistic action of SPD on the activity of NAc neuron. On the other hand, the inhibition of NAc firing elicited by either D(2) agonist LY171555 or D(1)/D(2) agonists apomorphine was completely reversed by SPD, suggesting an antagonistic action of SPD to D(2) receptors. In 6-OHDA-lesioned rats, iontophoresis of SPD also had an inhibitory effect in the majority of NAc neurons (91%) as SKF-38393 did. This inhibition could be completely blocked by the ejection of SCH-23390, but not by spiperone. These results indicate that SPD also has a D(1) agonistic-D(2) antagonistic dual action on NAc neuron activity, which may be beneficial to the treatment of schizophrenia.

Efficacy of Tiopronin in treatment of severe non-alcoholic fatty liver disease.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is a clinicopathologic syndrome of which the main feature is diffuse macrovesicular hepatic steatosis caused by deposition of excessive free fatty acid and triglyceride in liver parenchyma. AIM: To observe the efficacy of Tiopronin in treatment of severe nonalcoholic fatty liver disease (NAFLD). PATIENTS AND METHODS: 30 patients with severe NAFLD were treated with Tiopronin for 3 months. 30 healthy people were selected as control. The body mass index (BMI) and plasma levels of endotoxin (ET), leptin, IL-6 and IL-8 were measured before and after treatment. RESULTS: The serum levels of ET, leptin, IL-6 and IL-8 in severe NAFLD group were significantly higher than those in control group (p < 0.05). After treatment with Tiopronin, these indexes were significantly lower than before (p < 0.05). CONCLUSIONS: The intestinal endotoxemia (IETM) occurs in patients with severe NAFLD. Leptin, IL-6 and IL-8 play important roles in pathogenesis of NAFLD. Tiopronin can reduce the levels of ET, leptin, IL-6 and IL-8 for treatment of NAFLD.

Increased numbers of T helper 17 cells and the correlation with clinicopathological characteristics in multiple myeloma.

OBJECTIVE: T helper 17 (Th17) cells play important roles in adaptive immunity and are involved in several inflammatory and autoimmune diseases, but little is known about their role in tumour immunity. The current study investigated the involvement of Th17 cells in multiple myeloma. METHODS: Flow cytometry was used to investigate the frequencies of Th17 cells in peripheral blood mononuclear cells from 30 patients with multiple myeloma and from 14 healthy control subjects. The concentrations of Th17-associated cytokines (interleukin [IL]-6, IL-17, IL-1ß and IL-23) were measured by enzyme-linked immunosorbent assay. RESULTS: There was a significantly increased proportion of Th17 cells, and increased plasma concentrations of Th17-associated cytokines, in patients with multiple myeloma compared with healthy controls. There was a significant relationship between the proportion of Th17 cells and clinical tumour stage, serum lactate dehydrogenase concentration and serum creatinine concentration. CONCLUSIONS: Th17 cells might be important therapeutic targets in multiple myeloma and could facilitate a better outcome for tumour immunotherapy.