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Wilson’s disease (WD) is an inherited disease caused by mutations in ATP7B and is characterized by the pathological accumulation of copper in the liver and brain. Common clinical manifestations of WD include a wide range of liver disease and neurological symptoms. In some patients, psychiatric symptoms may be the only manifestation at the time of diagnosis. The clinical features of WD are highly variable and can mimic any disease of internal medicine. Therefore, for unexplained medical diseases, the possibility of WD should not be ignored. Early diagnosis and treatment can improve the prognosis of WD patients and reduce disability and early death. Gene sequencing is becoming a valuable method to diagnose WD, and if possible, all WD patients and their siblings should be genetically sequenced. Copper chelators including D-penicillamine, trientine, and dimercaptosuccinic acid can significantly improve the liver injury and symptoms of WD patients but may have a limited effect on neurological symptoms. Zinc salts may be more appropriate for the treatment of asymptomatic patients or for the maintenance treatment of symptomatic patients. High-quality clinical trials for the drug treatment of WD are still lacking, therefore, individualized treatment options for patients are recommended. Individualized treatment can be determined based on the clinical features of the WD patients, efficacy and adverse effects of the drugs, and the experience of the physician. Liver transplantation is the only effective method to save patients with acute liver failure or with severe liver disease who fail drug treatment.

Restless legs syndrome (RLS)/Willis-Ekbom disease is a neurologic disorder characterized by a strong desire to move when at rest (usually in the evening) and paraesthesia in their lower legs. The most widely used therapies for first-line treatment of RLS are dopaminergic drugs; however, their long-term use can lead to augmentation. α2δ Ligands, opioids, iron, glutamatergic drugs, adenosine, and sleep aids have been investigated as alternatives. The pathogenesis of RLS is not well understood. Despite the efficacy of dopaminergic drugs in the treatment of this disorder, unlike in Parkinson’s disease dopaminergic cell loss in the substantia nigra has not been observed in RLS. The etiology of RLS is likely complex, involving multiple neural pathways. RLS-related genes identified in genome-wide association studies can provide insight into the mechanistic basis and pathophysiology of RLS. Here we review the current treatments and knowledge of the mechanisms underlying RLS.

During a long-duration manned spaceflight mission, such as flying to Mars and beyond, all crew members will spend a long period in an independent spacecraft with closed-loop bioregenerative life-support systems. Saving resources and reducing medical risks, particularly in mental heath, are key technology gaps hampering human expedition into deep space. In the 1960s, several scientists proposed that an induced state of suppressed metabolism in humans, which mimics 'hibernation', could be an ideal solution to cope with many issues during spaceflight. In recent years, with the introduction of specific methods, it is becoming more feasible to induce an artificial hibernation-like state (synthetic torpor) in non-hibernating species. Natural torpor is a fascinating, yet enigmatic, physiological process in which metabolic rate (MR), body core temperature (Tb ) and behavioural activity are reduced to save energy during harsh seasonal conditions. It employs a complex central neural network to orchestrate a homeostatic state of hypometabolism, hypothermia and hypoactivity in response to environmental challenges. The anatomical and functional connections within the central nervous system (CNS) lie at the heart of controlling synthetic torpor. Although progress has been made, the precise mechanisms underlying the active regulation of the torpor-arousal transition, and their profound influence on neural function and behaviour, which are critical concerns for safe and reversible human torpor, remain poorly understood. In this review, we place particular emphasis on elaborating the central nervous mechanism orchestrating the torpor-arousal transition in both non-flying hibernating mammals and non-hibernating species, and aim to provide translational insights into long-duration manned spaceflight. In addition, identifying difficulties and challenges ahead will underscore important concerns in engineering synthetic torpor in humans. We believe that synthetic torpor may not be the only option for manned long-duration spaceflight, but it is the most achievable solution in the foreseeable future. Translating the available knowledge from natural torpor research will not only benefit manned spaceflight, but also many clinical settings attempting to manipulate energy metabolism and neurobehavioural functions.

Objective To evaluate the cognitive function of Chinese patients with Parkinson's disease PD postsubthalamic nucleus deep brain stimulation (STN‐DBS). Methods Cognitive function was assessed by neuropsychological methods in PD patients. Twenty matched healthy persons served as normal controls. t test, analysis of variance, and chi‐square analysis were used to compare the difference among the groups. Reliable change index was utilized to analyze the changes in cognition from the individual level. Results (a) Improvement in motor function was significantly better after STN‐DBS (P

Differences in short-term cognitive function between mechanically ventilated patients treated with multicomponent interventions and those receiving routine nursing care have not been established because of the lack of follow-up in previous studies.This study was designed to evaluate the effects of the pain, agitation, and delirium (PAD) care bundle on delirium occurrence and clinical outcomes, specifically in terms of short-term cognitive function, in mechanically ventilated patients.Data on 243 patients with mechanical ventilation were analyzed from January 2017 to February 2019. The eligible patients were divided randomly into two groups. The control group ( n = 120) received usual care, whereas the intervention group ( n = 123) received the PAD bundle, including pain monitoring and management, light sedation and daily awakening, early mobility, sleep promotion, and delirium monitoring. The incidence and duration of delirium, ventilator time, and intensive care unit (ICU) length of stay were compared between the two groups. Upon discharge from the ICU and at 3 and 6 months after discharge, cognitive function was assessed using the Montreal Cognitive Assessment scale and compared between the two groups.The incidence of delirium was reduced significantly in the intervention group, and significant decreases in the duration of delirium, ventilator time, and ICU length of stay were found. Cognitive impairment in the intervention group was significantly lower at the 3-month follow-up assessment.The PAD bundle was shown to be associated with a lower incidence of delirium and improved clinical outcomes. Short-term cognitive impairment occurred in fewer patients who were managed with the PAD bundle after ICU discharge. Our findings indicate that the PAD bundle has the potential to improve clinical outcomes. The administrative staff of ICUs should use strategies, such as interdisciplinary teamwork, to facilitate the buy-in and implementation of interventions.

Abstract: Cancer being one of the leading causes of death among non-communicable diseases, has already posed a heavy burden on the world health system. Chemotherapy is one of the most effec-tive approaches for cancer treatment, but multidrug resistance, lack of efficacy, and toxic side ef-fects hamper efficacious cancer chemotherapy, creating an urgent need to develop novel, more ef-fective and less toxic anticancer therapeutics. Quinoxalines, as fascinating structures, constitute an important class of heterocycles in drug discovery. Quinoxaline hybrids could exert anticancer ac-tivity through diverse mechanisms and possess profound in vitro and in vivo efficacy against vari-ous cancers, including multidrug-resistant forms. Thus, quinoxaline hybrids represent useful tem-plates for the control and eradication of cancer. The purpose of the present review article is to pro-vide an emphasis on the recent developments (Jan. 2017-Jan. 2022) in quinoxaline hybrids with in-sights into their in vitro and in vivo anticancer potential as well as structure-activity relationships (SARs) to facilitate further rational design of more effective candidates.

Ceruloplasmin (CP) is the major copper transport protein in plasma, mainly produced by the liver. Glycosylphosphatidylinositol-linked CP (GPI-CP) is the predominant form expressed in astrocytes of the brain. A growing body of evidence has demonstrated that CP is an essential protein in the body with multiple functions such as regulating the homeostasis of copper and iron ions, ferroxidase activity, oxidizing organic amines, and preventing the formation of free radicals. In addition, as an acute-phase protein, CP is induced during inflammation and infection. The fact that patients with genetic disorder aceruloplasminemia do not suffer from tissue copper deficiency, but rather from disruptions in iron metabolism shows essential roles of CP in iron metabolism rather than copper. Furthermore, abnormal metabolism of metal ions and oxidative stress are found in other neurodegenerative diseases, such as Wilson’s disease, Alzheimer’s disease and Parkinson’s disease. Brain iron accumulation and decreased activity of CP have been shown to be associated with neurodegeneration. We hypothesize that CP may play a protective role in neurodegenerative diseases. However, whether iron accumulation is a cause or a result of neurodegeneration remains unclear. Further research on molecular mechanisms is required before a consensus can be reached regarding a neuroprotective role for CP in neurodegeneration. This review article summarizes the main physiological functions of CP and the current knowledge of its role in neurodegenerative diseases.

The Asian lady beetle Harmonia axyridis is an important predator of several agricultural pests, including aphids and whiteflies, and thus can contribute to pest management. Commercial viability as a pest control method requires that the beetle can be mass-reared, and that workable conditions for extended shelf-life can be guaranteed. One of the features of Harmonia's life cycle is that it enters diapause in the adult stage when the length of the photophase starts shortening in late summer. Reduction of juvenile hormone (JH) titer has been demonstrated to be the common endocrine mechanism inducing reproductive diapause in insects. However, whether H. axyridis enters diapause dependent on JH shutdown and how the JH level is regulated before diapause remains unknown.Like in other insects, the absence of JH triggers the induction and maintenance of reproductive diapause in H. axyridis, indicated by JH measurements and the knockdown of an intracellular JH receptor methoprene-tolerant (Met). Methoprene, a JH analog, significantly reversed diapause into reproduction via Met. Combined with RNA-sequencing and RNA interference, we also demonstrated that JH biosynthesis rather than the JH degradation pathway determines the reduction of JH titer in diapausing females.Our results reveal the vital role of JH in regulating reproductive diapause in female H. axyridis. Harmonia axyridis diapause could thus be manipulated by targeting JH production and JH signaling. © 2021 Society of Chemical Industry.

To investigate the prevalence of psychotic depression and the differences in sociodemographic and clinical characteristics and prescription patterns of psychotropic medications between patients with psychotic depression (PD) and patients with nonpsychotic depression (NPD) in China.We conducted a cross-sectional study in 13 major psychiatric hospitals or the psychiatric units of general hospitals in China from September 1, 2010, to February 28, 2011. PD was defined according to the psychotic disorder section of the Mini International Neuropsychiatric Interview (MINI). The sociodemographic and clinical characteristics and the prescription patterns of psychotropic medications were compared between the PD and NPD groups. Multivariate logistic regression analysis was used to investigate factors associated with an increased likelihood of PD.Among 1172 MDD patients, the prevalence of psychotic features was 9.2% in the present study. The logistic regression analysis indicated that unmarried (OR = 2.08, p 0.001), frequent depressive episodes (OR = 2.10, p = 0.020), depressive episodes with suicidal ideation and attempts (OR = 1.91, p = 0.004), and patients who were prescribed any antipsychotics (OR = 2.94, p 0.001) were associated with psychotic features in patients with MDD.Cross-sectional design, retrospective recall of some data CONCLUSION: The prevalence of PD is high in China, and there were some differences in demographic and clinical characteristics between patients with PD and patients with NPD. Clinicians should regularly assess psychotic symptoms and consider intensive treatment and close monitoring when treating subjects with PD.

Sleep disorders are one of the most common non-motor symptoms in Parkinson's disease (PD). It can cause a notable decrease in quality of life and functioning in PD patients, as well as place a huge burden on both patients and caregivers. The most cited sleep disorders in PD included insomnia, restless legs syndrome (RLS), rapid eye movement (REM), sleep behavior disorders (RBD), excessive daytime sleepiness (EDS) and sleep disordered breathing (SDB), which can appear alone or several at the same time. In this review, we listed the recommended pharmacological treatments for common sleep disorders in PD, and discussed the recommended dosages, benefits and side effects of relative drugs. We also discussed non-pharmacological treatments to improve sleep quality, including sleep hygiene education, exercise, deep brain stimulation, cognitive behavior therapy and complementary therapies. We tried to find proper interventions for different types of sleep disorders in PD, while minimizing relative side effects.

To investigate the anesthetic effect of combined acupuncture-medicine anesthesia in microwave ablation of benign thyroid nodules and its effect on serum β-endorphin.A total of 60 patients who met the inclusion criteria and received microwave ablation of benign thyroid nodules were randomly divided into the treatment group and the control group, with 30 patients in each. The patients in the treatment group were given combined acupuncture-medicine anesthesia, and those in the control group were given intravenous anesthesia. The two groups were compared in terms of the sedative and analgesic effects of anesthesia, amount of anesthetics used, incidence rate of intraoperative snore and respiratory depression, and change in serum β-endorphin level before anesthesia, before surgery, and after the surgery.Both groups obtained satisfactory anesthetic effects. Compared with the control group, the sedation score, the amounts of fentanyl and propofol used, the incidence rates of intraoperative snore and respiratory depression in the treatment group were obviously lower (In microwave ablation of benign thyroid nodules, combined acupuncture-medicine anesthesia has good sedative and analgesic effects and can reduce the amounts of anesthetics used as well as the incidence rates of intraoperative snore and respiratory depression. The analgesic effect of acupuncture anesthesia is associated with increased β-endorphin secretion.

Induced pluripotent stem cell (iPSC) line, THSJTUi001-A, was generated from a 26-year-old Chinese male patient with Wilson's disease carrying a homozygous Arg778Leu mutation in ATP7B gene, using non-integrated episomal reprogramming vectors. This cell line had normal karyotype, expressed pluripotency markers and could differentiate into the three germ layers in vivo.

The black soldier fly (BSF) Hermetia illucens has a strong tolerance to cadmium stress. This helps to use BSF in entomoremediation of heavy metal pollution. Rich metallothionein (MT) proteins were thought to be important for some insects to endure the toxicity of heavy metal. We identified and characterized three MTs genes in BSF (BSFMTs), including BSFMT1, BSFMT2A, and BSFMT2B. Molecular modeling was used to predict metal binding sites. Phylogenetic analysis was used to identify gene families. Overexpression of the recombinant black soldier fly metallothioneins was found to confer Cd tolerance in Escherichia coli. Finally, functions of BSFMTs in BSF were explored through RNA interference (RNAi). RNAi results of BSFMT2B showed that the larval fresh weight decreased significantly, and the larvae mortality increased significantly. This study suggests that BSFMTs have important properties in Cd detoxification and tolerance in BSF. Further characterization analyses of physiological function about metallothioneins are necessary in BSF and other insects.

Postherpetic neuralgia (PHN) is one of the most intractable pain disorders and often does not respond to medication, physical, and interventional procedures. Coblation technology has been demonstrated to have potential for neuralgia, but there are rare reports of the efficacy and security of coblation for PHN. The thoracic segment is the most common predilection part of PHN, so we conducted this long-term study to investigate the results of coblation for the treatment of thoracic PHN.The aim of this study was to determine the efficacy and security of computed tomography (CT)-guided coblation of the thoracic nerve root for treatment of PHN.Self before-after controlled clinical assessment.Department of Pain Management, Xuanwu Hospital, Capital Medical University.Seventy-seven patients with thoracic PHN sustained for at least 6 months and refractory to conservative therapy were identified. Patients underwent CT-guided percutaneous coblation to ablate the thoracic nerve root for thoracic PHN. The therapeutic effects were evaluated using a Visual Analog Scale (VAS), medication doses, and pain-related quality of life (QoL) scale before coblation, and at 1 week, and at 1, 3, and 6 months after the procedure. Patients who achieved more than 50% pain relief were defined as responders. In addition, adverse effects were also recorded to investigate the security of this procedure.The VAS score significantly decreased from 7.22 ± 1.15 before the coblation to 3.51 ± 1.12 (P = 0.01), 3.02 ± 1.21 (P = 0.006), 3.11 ± 2.15 (P = 0.014), and 2.98 ± 2.35 (P = 0.008) at 1 week, and at 1, 3, and 6 months after the procedure, respectively. The number of responders were 56 (77.78%), 54 (75%), 55 (76.39%), and 54 (75%) at 1 week, and at 1, 3, and 6 months after the procedure, respectively. The doses of anticonvulsants and analgesics were decreased significantly at all time points after the procedure compared with before treatment (P0.05). Patient responses on the Brief Pain Inventory Short Form indicated mean scores that were significantly lower than baseline across all domains of pain interference with QoL at all evaluations (P = 0.001). Most of the patients had mild numbness and it did not affect the daily activities after the procedure. No other severe adverse events occurred during or after the procedure.A single-center study, relatively small number of patients, short duration of review of medical record, and the retrospective study.CT-guided percutaneous thoracic nerve root coblation is an effective and safe method for the treatment of thoracic PHN, and the procedure can also significantly improve the QoL in patients with PHN.

This study aimed to evaluate the efficacy and safety of quetiapine fumarate extended-release (XR) in the treatment of Chinese patients with acute schizophrenia. Multicenter, double-blind, double-dummy, active-controlled non-inferiority randomized study in Chinese patients (n = 388) with schizophrenia randomly assigned to quetiapine XR or chlorpromazine for 6 weeks. Primary outcome was the change from baseline in Positive and Negative Syndrome Scale (PANSS) total score at the end of treatment. Safety objectives included adverse event (AE) monitoring, laboratory test results, and electrocardiograms. Changes in PANSS total score were -33.4 for quetiapine XR and -35.9 for chlorpromazine (P > 0.05). Least squares mean changes were: positive subscale, -9.9 ± 0.53 and -11.1 ± 0.51; negative subscale, -5.9 ± 0.50 and -6.7 ± 0.48; general psychopathology subscale, -12.9 ± 0.74 and -13.9 ± 0.71; aggression and hostility cluster scores, -4.8 ± 0.33 and -5.4 ± 0.32; and depression cluster scores, -1.8 ± 0.18 and -1.7 ± 0.18, for quetiapine XR and chlorpromazine, respectively. For quetiapine XR, AEs were constipation, dizziness, insomnia, and agitation, and nine patients (4.6%) discontinued due to AEs. For chlorpromazine, AEs were extrapyramidal symptoms, constipation, insomnia, dizziness, and agitation, and 17 patients (8.9%) discontinued due to AEs; two patients reported serious AEs. Quetiapine XR monotherapy was not inferior to chlorpromazine for treating acute schizophrenia in Chinese patients and was well tolerated.

Objective: To examine the associations of methionine synthase (MTR), methionine synthase reductase (MTRR), and methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms with the susceptibility to nonsyndromic cleft lip with or without cleft palate (NSCL/P). Methods: Between May 2012 and August 2014, 147 NSCL/P patients (case group) and 129 healthy volunteers (control group) were recruited for the study. The MTR A2756G, MTRR A66G, MTHFR C677T and MTHFR A1298C polymorphisms were assessed by polymerase chain reaction–restriction fragment length polymorphism. Haplotype analyses were performed with SHEsis software. Logistic regression analysis was used to evaluate the possible risk factors for NSCL/P. Generalized multifactor dimensionality reduction (GMDR) was applied to detect gene–gene interactions. Results: MTR A2756G, MTRR A66G, and MTHFR C677T gene polymorphisms were associated with the risk of NSCL/P (all p

Amyotrophic lateral sclerosis (ALS), commonly termed as motor neuron disease (MND) in UK, is a chronically lethal disorder among the neurodegenerative diseases, meanwhile. ALS is basically irreversible and progressive deterioration of upper and lower motor neurons in the motor cortex, brain stem and medulla spinalis. Riluzole, used for the treatment of ALS, was demonstrated to slightly delay the initiation of respiratory dysfunction and extend the median survival of patients by a few months. In this study, the key biochemical defects were discussed, such as: mutant Cu/Zn superoxide dismutase, mitochondrial protectants, and anti-excitotoxic/ anti-oxidative / anti-inflammatory/ anti-apoptotic agents, so the related drug candidates that have been studied in ALS models would possibly be further used in ALS patients.

Wilson's disease (WD), also called hepatolenticular degeneration, is an autosomal recessive inheritance disorder of copper metabolism characterized by the multiple mutations in the ATP-ase 7B gene of chromosome 13q. About half of the WD patients have neurological or psychiatric symptoms. As WD is a kind of medicable or nearly curable neurodegenerative disease in the field of medicine, early consideration/examination and without delay/ life-long treatment usually lead to better prognoses. The drugs, also named as anticopper agents, are commonly used in clinics including D-penicillamine, trientine, sodium dimercaptosuccinate, dimercaptosuccinic acid, zinc and tetrathiomolybdate. This provides detailed reviews about these medicines.

Dementia, which can be induced by diverse factors, is a clinical syndrome characterized by the decline of cognitive function. Behavioral and psychological symptoms of dementia (BPSD) include depression, agitation, and aggression. Dementia causes a heavy burden on patients and their caregivers. Patients with BPSD should be assessed comprehensively by practitioners and offered appropriate non-pharmacologic and pharmacologic therapy. Non-pharmacologic therapy has been recommended as the basal treatment for BPSD; however, pharmacologic therapy is required under many situations. Medications, including antipsychotic agents, antidepressants, sedative and hypnotic agents, mood stabilizers, cholinesterase inhibitors, and amantadine, are extensively used in clinical practice. We have reviewed the progression of pharmacologic therapy for BPSD.

Postoperative shed autologous blood reinfusion techniques have been used for decades in total knee arthroplasty (TKA), but the effectiveness of this procedure is still a matter of debate. This multicenter retrospective study investigated the medical records of patients who underwent unilateral and bilateral TKA from January 1, 2015 to December 31, 2017 in three hospitals. According to whether postoperative shed autologous blood reinfusion was used, the patients were divided into the control group and the shed autologous blood reinfusion group. The volume of perioperative infusion of red blood cells and plasma, the blood transfusion-related costs, and the postoperative hospital stay were compared between the two groups of patients. A total of 200 unilateral and 74 bilateral TKA were included after successful matching. Among the patients who underwent unilateral TKA, the control group and the shed autologous blood reinfusion group had 95 and 91 patients, respectively, who received allogeneic blood infusion (P = 0.268). There was no significant difference in the number of units of allogeneic red blood cells infused (P = 0.154), while the transfusion-related cost was increased (P

To study Jianpi Qingre Huoxue decoction( JPQRHX) in preventing colon cancer by observing SW480 cells proliferation,apoptosis,cycle and the expression of P-β-catenin, and to research its mechanism.SW480 cells were incubated with serum containing blank serum, different concentrations of JPQRHX decocition and PI3 K blocking agent LY294002 for 24 h,respectively. Cell proliferation was detected by MTT assay, cell cycle and apoptosis were detected by flow cytometry. The protein translocation of P-β-catenin was assayed by immunofluorescent staining.The inhibitory rate and apoptosis rate in JPQRHX decoction group were higher than control group( P0. 05),respectively. S phase cells were increased significantly, and G1 phase cells and LY294002 group cells were decreased significantly( P0. 05). The P-β-catenin in JPQRHX decoction groups were mainly expressed in membrane, while the P-β-catenin in the control group was characterized by deletion in membrane and increased in nucleus.JPQRHX decoction has the ability in curing colon cancer, and the mechanism is associated with altering the expression of P-β-catenin in the cells nucleus, blocking SW480 cells cycle at G1 phase, inhibiting SW480 cells proliferation, and inducing SW480 cell apoptosis.

Combined intravenous and local intrathecal administration of meropenem in patients after craniotomy is widely used to treat intracranial infections. However, the optimal dosing regimen of meropenem has not been investigated, posing a risk to treatment efficacy. We aimed to identify significant factors associated with inter-individual variability in cerebrospinal fluid (CSF) pharmacokinetics of meropenem and to evaluate potential intravenous and intrathecal meropenem dosing regimens for the treatment of patients with intracranial infections. After the diagnosis of intracranial infection, 15 patients with an indwelling drain tube received intravenous and intrathecal administration of meropenem. Blood and cerebrospinal fluid (CSF) samples were obtained at the scheduled time to measure meropenem concentration. Plasma and CSF concentration-time data were fit simultaneously using a nonlinear mixed-effects modeling approach. A 3-compartmental model was selected to characterize the in vivo behavior of meropenem. Through population modeling, multiple covariates were tested about their impact on the meropenem pharmacokinetics. Considering CSF outflow via drain tube leading to a drug loss, the drug clearance in CSF (CLCSF) was added to describe this drug loss. The covariate selection indicated that the drainage volume (mL/d) had a significant positive correlation with CLCSF. Bootstrap and visual predictive check suggested a robust and reliable pharmacokinetic model was structured. The established final population model was useful to apply with simulation to identify meropenem dosing regimens for the treatment of patients with intracranial infections. With the goal of CSF concentrations exceeding the minimum inhibitory concentration during the therapy, we created a simple to use dosage regimen table to guide clinicians with drug dosing.

Background Collagen triple helix repeat containing-1 (CTHRC1), which was firstly identified overexpressed in the adventitia and neointima of injured rat arteries, could inhibit collagen expression and increase cell migration. It was then found to be ubiquitously expressed in numerous cell types such as fibroblasts and smooth muscle cells, and aberrantly up-regulated in several malignant tumors. However, the functional role of CTHRC1 and its related mechanism in breast cancer still remains unclear. Methods CTHRC1 expressions in breast cancer tissues and cells were assessed by qRT-PCR, western blot and immunohistochemistry. The relative expression level of miR-134, miR-155, miR-30c and miR-630 in breast cancer cells respectively was detected by qRT-PCR. Wild type (Wt) and Mutant type (Mut) CTHRC1 3’UTR sequences were cloned into a psi-CHECK2 reporter vector, and the relative luciferase activity was detected by dual-luciferase reporter assay in indicated cells. The effect of ectopic expression of miR-30c or gain and loss of CTHRC1 on cell viability, cell proliferation, cell cycle progression and apoptosis, cell invasion and migration was respectively detected by CCK-8 assay, colony formation assay, flow cytometry analysis, transwell invasion/migration assay. Protein levels of β-catenin, active β-catenin, normal and phosphorylated form of GSK-3β were detected by western blot in indicated cells. Immunofluorescence staining of β-catenin was performed to observe nuclear localization. Results We found CTHRC1 was frequently up-regulated in human breast cancer cells and tissues. Then our cohort study and further meta-analysis validated high expression of CTHRC1 was associated with aggressive clinicopathological features and poor clinical outcome of breast cancer patients. In addition, CTHRC1 promoted cell proliferation, invasion and migration and suppressed cell apoptosis in breast cancer, which might be by activating GSK-3β/β-catenin signaling and inhibiting Bax/Caspase-9/Caspase-3 signaling respectively; and these biological functions of CTHRC1 could be directly negatively regulated by miR-30c. Conclusion Taken together, we identified the role of miR-30c/CTHRC1 axis in breast cancer progression and demonstrated CTHRC1 may serve as a prognostic biomarker and therapeutic target for breast cancer. Electronic supplementary material The online version of this article (doi:10.1186/s13046-017-0564-7) contains supplementary material, which is available to authorized users.

Ethnopharmacological relevance Herb pair, the most fundamental and simplest form of herb compatibility, serves as the basic building block of traditional Chinese medicine formulae. The Danshen–Honghua herb pair (DH), composed of Salviae Miltiorrhizae Radix et Rhizoma (Danshen in Chinese) and Carthami Flos (Honghua in Chinese), has remarkable clinical efficacy to cure cardio-cerebrovascular diseases. This study was designed to investigate the pharmacodynamics of DH in comparison with single herbs and pharmacokinetics of DH relative to Danshen in acute myocardial ischemic injury. Materials and methods Sixty male Wistar rats were divided into control, model and drug treated groups. The acute myocardial ischemia rat model was induced by administering 85 mg/kg/d isoproterenol (ISO) subcutaneously for two consecutive days. For pharmacodynamic study, histopathological and biochemical analysis were performed to assess the anti-myocardial ischemic effects. While for pharmacokinetic study, a UPLC–MS/MS method was developed for determination of nine main active ingredients, namely danshensu, protocatechuic acid, protocatechualdehyde, caffeic acid, lithospermic acid, rosmarinic acid, salvianolic acid B, salvianolic acid A and salvianolic acid C in rat plasma. Results The histopathological and biochemical analysis revealed that DH exerted enhanced anti-myocardial ischemic effects against the ISO-induced myocardial ischemia compared with single herbs. The pharmacokinetic study indicated that DH could significantly increase the t1/2z of danshensu, Tmax, AUC0-∞ and MRT0-t of protocatechuic acid in comparison with Danshen alone in normal rats, but more importantly elevate systemic exposure level and prolong t1/2z of protocatechualdehyde, caffeic acid, Tmax of danshensu in acute myocardial ischemia rats. Conclusions Our findings demonstrated the greater effects of DH after the compatibility in ISO-induced acute myocardial ischemia rats at pharmacodynamic and pharmacokinetic levels and provided valuable information for clinical application of herb pairs.

Deep brain stimulation (DBS) is an effective technique for treating Parkinson's disease (PD) in the middle and advanced stages. The subthalamic nucleus (STN) is the most common target for clinical treatment using DBS. While STN-DBS can significantly improve motor symptoms in PD patients, adverse cognitive effects have also been reported. The specific effects of STN-DBS on cognitive function and the related mechanisms remain unclear. Thus, it is imperative to identify the influence of STN-DBS on cognition and investigate the potential mechanisms to provide a clearer view of the various cognitive sequelae in PD patients. For this review, a literature search was performed using the following inclusion criteria: (1) at least 10 patients followed for a mean of at least 6 months after surgery since the year 2006; (2) pre- and postoperative cognitive data using at least one standardized neuropsychological scale; and (3) adequate reporting of study results using means and standard deviations. Of ∼170 clinical studies identified, 25 cohort studies (including 15 self-controlled studies, nine intergroup controlled studies, and one multi-center, randomized control experiment) and one meta-analysis were eligible for inclusion. The results suggest that the precise mechanism of the changes in cognitive function after STN-DBS remains obscure, but STN-DBS certainly has effects on cognition. In particular, a progressive decrease in verbal fluency after STN-DBS is consistently reported and although executive function is unchanged in the intermediate stage postoperatively, it tends to decline in the early and later stages. However, these changes do not affect the improvements in quality of life. STN-DBS seems to be safe with respect to cognitive effects in carefully-selected patients during a follow-up period from 6 months to 9 years.

The aim of this study was to investigate the long-term results of computed tomography (CT)-guided percutaneous radiofrequency thermocoagulation (PRT) for glossopharyngeal neuralgia (GPN). A retrospective review of medical records for patients with GPN who were treated with CT-guided PRT between 2003 and 2014 was performed to investigate baseline characteristics and immediate outcomes during the hospitalization. Long-term pain relief outcomes and complications were obtained via telephone survey. Duration of pain-free was assessed by Kaplan–Meier analysis. Eighty patients with GPN were treated with CT-guided PRT, and 71 patients could be contacted for the follow-up. The mean length of follow-up after PRT was 56.2 ± 43.3 months. Pain relief occurred in 63 patients (78.8%) immediate after the PRT procedure. The percentage of patients who remained in an “excellent” or “good” pain relief condition was 73.2%, 63.0%, 53.2%, and 43.0% at 1, 3, 5, and 10 years. Postprocedure complication included dysesthesias, dysphagia, and diminished gag reflex. No mortality was observed during or after PRT procedures. This study indicates that CT-guided PRT is a safe and effective method for patients with GPN and should be considered as an alternative treatment for these patients.

To explore the effect of a self-made guiding needle of steel wire in guiding the wire through the tibial tunnel for the treatment of avulsion fractures of tibial posterior cruciate ligament with open reduction and wire fixation.From February 2011 to June 2014, a total of 22 patients with avulsion fractures of tibial posterior cruciate ligament underwent surgical treatments were analyzed, including 14 males and 8 females with an average age of 35.6 years old (ranged, 17 to 63 years old). According to Meyers classification, 9 patients were classified as type II, 13 patients were classified as type III. All the patients underwent open reduction and wire fixation with medial knee "L" shape approach. A wire guiding needle was used to guide the wire through the tibial tunnel during operation.With the assistance of wire guidance needles, wires passed through the tibial tunnel rapidly during the operation in all the 22 patients. All the patients were followed up, X-ray imagings 6 months after operation showed the fractures healed well. The average follow-up time in all patients was 6 months (ranged, 6 to 12 months). The averaged Lysholm knee score in 22 knee was 92.7 +/- 3.4. All patients' posterior drawer test were negative.Self-made wire guiding needle can simplify the operation procedures in which the wires pass through the tibial tunnel, shorten the operation time, reduce the surgical trauma and complications, and be worthy of clinical application.

BACKGROUND Patients with thoracic neuropathic pain often do not respond to medication and physical therapy. Coblation technology has been demonstrated to have potential for pain management. METHODS Fifteen patients underwent computed tomography-guided percutaneous coblation to ablate the thoracic paravertebral nerve for their medication-resistant thoracic neuropathic pain. The pain intensity was assessed by visual analog scale (VAS) 1 day before surgery and 1 week and 1, 3, and 6 months after surgery, and the difference between preoperative and postoperative VAS values was determined to evaluate the pain relief effectiveness. Patients who achieved > 50% pain relief were defined as responders, and the ratio in all patients was calculated. The number of patients who reported mild pain (VAS ≤ 3) was recorded, and the ratio in all responders was calculated. In addition, adverse effects were also recorded to investigate the security of procedure. RESULTS Twelve (80%) responders achieved > 50% pain relief. The VAS score of responders significantly decreased from 7.42 ± 1.38 before surgery to 2.17 ± 1.11 (P = 0.000), 1.92 ± 1.16 (P = 0.000), 1.75 ± 0.97 (P = 0.000), and 1.58 ± 1.08 (P = 0.000) at 1 week, 1, 3, and 6 months after surgery, respectively. The number of responders with mild pain was 10 (83.3%), 11 (91.7%), 12 (100%), and 12 (100%) at 1 week, 1, 3, and 6 months after surgery, respectively. All responders and 1 nonresponder reported slight numbness after the surgery. CONCLUSION Percutaneous thoracic paravertebral nerve coblation guided by computed tomography is a potential method for the treatment of thoracic neuropathic pain.

This study aimed to identify the role and regulation of thymic stromal lymphopoietin (TSLP) in asthmatic airway remodelling. To identify the expression of TSLP, α smooth muscle actin (α-SMA) and collagen I in bronchial tissues, bronchial biopsy specimens were collected from patients with asthma and healthy controls and stained with specific antibodies, respectively. To characterize the signalling pathways regulated by TSLP, we silenced or overexpressed TSLP in human lung fibroblast (HLF-1) cells by shRNA approaches or transfection and detected the expression of TSLP receptor (TSLPR) by enzyme-linked immunosorbent assay and Western blot analysis. In TSLP signalling pathway, the protein expression of total signal transducer and activator of transcription 3 (STAT3), STAT5, the phosphorylation of STAT3 (pSTAT3) and STAT5 (pSTAT5), TSLP, α-SMA and collagen I were also detected by Western blotting. In addition, the α-SMA, collagen I and mRNA expression were determined by real-time reverse-transcription. To further confirm the TSLP-STAT3 signalling pathway in HLF-1 cells, we inhibited STAT3 activity by targeted small molecules and then detected TSLP-induced expression of α-SMA and collagen I in both mRNA and protein levels by quantitative real-time reverse-transcription and Western blotting, respectively. First, overexpression of TSLP, α-SMA and collagen I was detected in epithelium collected from patients with asthma. Second, STAT3 activity and the expression of α-SMA and collagen I were controlled, regulated by TSLP. Specifically, the pSTAT3, α-SMA and collagen I were induced by the introduction of TSLP in HLF-1 cells, and the repression of α-SMA and collagen I was detected after TSLP silencing. Third, no changes of pSTAT5 were found in the presence of the STAT3 inhibitor, and TSLP-induced α-SMA and collagen I upregulation is in a STAT3 dependent manner. If we inhibit STAT3 activity by STAT3 targeted small molecules, TSLP-induced α-SMA and collagen I upregulation cannot be detected. The functions of TSLP in asthmatic airway remodelling were performed through STAT3 signalling pathway.

Based on our recent findings that resveratrol, a natural plant polyphenol found in red grape skins as well as other food products, induces apoptosis via a caspase-independent intrinsic pathway in human lung adenocarcinoma cells, this study is designed to explore whether SB203580, a p38 inhibitor, potentiates the resveratrol-induced apoptosis of human lung adenocarcinoma (A549) cells. We found that pretreatment with SB203580 enhanced the resveratrol-induced apoptosis by accelerating the intrinsic apoptotic pathway including Bax activation, loss of mitochondrial membrane potential, and activation of both caspase-9 and -3. Although treatment with resveratrol alone did not induce caspase-8 activation, cotreatment with both SB203580 and resveratrol not only enhanced FasL cleavage but also activated caspase-8, indicating that the extrinsic apoptotic pathway may be involved in the synergistic effect. Collectively, we for the first time demonstrate that SB203580 synergistically enhances the resveratrol-induced apoptosis by accelerating Bax-mediated intrinsic pathway and initiating extrinsic pathway, suggesting a possible alternative therapeutic strategy for human lung cancer.

We investigated the development of the magnitude and phase alignment of steady-state visual evoked potentials induced by 5 Hz intermittent photic stimulation in 46 children (3 to 16 years) and 8 adults, as a function of age. We found that, over the occipital region, magnitude values were the highest in 8-11-year old children, but decreased with age over all other cerebral regions. Phase alignment values increased with age over the occipital, parietal and frontal cerebral regions. We interpret these findings in terms of the development of functional interactions between different cortical areas involved in the processing of visual stimuli.

The C-Jun N-terminal Kinase (JNK) inhibitor SP600125 is widely used to inhibit the JNK-mediated Bax activation and cell apoptosis. However, this report demonstrates that SP600125 synergistically enhances the dihydroartemisinin (DHA)-induced human lung adenocarcinoma cell apoptosis by accelerating Bax translocation and subsequent intrinsic apoptotic pathway involving mitochondrial membrane depolarization, cytochrome c release, caspase-9 and caspase-3 activation. The dynamical analysis of GFP-Bax mobility inside single living cells using fluorescence recovery after photobleaching revealed that SP600125 aggravated the DHA-induced decrease of Bax mobility and Bax translocation. These results for the first time present a novel pro-apoptotic action of SP600125 in DHA-induced apoptosis.

Our recent studies have shown that high concentration of taxol induced a caspase-independent paraptosis-like cell death and cytoplasmic vacuolization derived predominantly from endoplasmic reticulum (ER) swelling in human lung carcinoma cell lines (ASTC-a-1). In this report, we further explored the relationship between taxol-induced cell death and vacuolization, and the roles of protein synthesis, mitogen-activated protein kinase kinases (MEK), c-jun N-terminal kinase (JNK) and P38 in taxol-induced paraptosis. Enhanced green fluorescent protein (EGFP) was used to probe the cell morphological change, while ER-targeted red fluorescent protein (er-RFP) was used to probe ER spatial distribution. Real-time monitoring of the ER swelling dynamics during the formation of vacuolization inside single living cells co-expressing EGFP and er-RFP further demonstrated that taxol-induced cytoplasmic vacuolization was from the ER restructuring due to fusion and swelling. PI staining showed that taxol-induced vacuolization was not necrosis. These results further demonstrated that the taxol-induced cell death was neither apoptosis nor necrosis, and fitted the criteria of paraptosis characterized by cytoplasmic vacuolization, caspase-independence, lack of apoptotic morphology and insensitivity to broad caspase inhibitor. Our data further indicated that taxol-induced paraptosis required neither protein synthesis nor the participation of MEK, JNK, and P38, which was different from the insulin-like growth factor I receptor (IGFIR)-induced paraptosis. These results suggest that high concentration of taxol activates an alternative paraptotic cell death pathway.

Taxol (Paclitaxel) is an important natural product for the treatment of solid tumors such as ovarian, breast, non-small-cell lung tumors, and some head and neck carcinomas. Different concentrations of taxol trigger distinct effects on cell death forms. In present study, cell counting kit (CCK-8) assay, confocal fluorescence microscopy imaging, flow cytometry (FCM) and western blotting (WB) analysis were used to analyze the characteristics of cell death induced by low (35 nM) and high (70 microM) concentration of taxol respectively in human lung adenocarcinoma (ASTC-a-1) cells. Our results showed that low concentration of taxol induced cell death dominantly in apoptotic fashion associated with nuclear fragmentation, protein synthesis, phosphatidylserine (PS) externalization, G2/M cell cycle arrest, Bax translocation into mitochondria and caspase-3 activation, whereas high concentration of this drug induced significant cytoplasm vacuolization, mitochondria swelling and paraptosis-like cell death form without protein synthesis that is necessary for paraptosis. Although the mechanism of high concentration of taxol-induced paraptosis-like cell death has not been clear, this finding might have a potential implication for cancer therapy, especially for apoptosis-resistant cancer.

In this study, microfiber films were used as scaffolds for the purpose of vascular tissue engineering. The microfiber films were prepared by electrospinning of poly (l-lactide) (PLLA) and polyvinyl pyrrolidone (PVP). PLLA and PVP with different ratios were blended with dichloromethane as a spinning solvent at room temperature. The properties of the composite microfiber films were investigated by differential scanning calorimetry (DSC), scanning electron microscopy (SEM) and contact angle measurement. The SEM images showed that the morphology of the microfiber films was mainly affected by the weight ratios of PLLA/PVP. The DSC results demonstrated that PLLA and PVP mixed uniformly. And the hydrophilicity of the films measured increased along with the decrease of the PLLA/PVP ratio. Vascular smooth muscle cells (VSMCs) were used to test the cytocompatibility. Cell morphology and cell proliferation were measured by SEM, laser scanning confocal microscopy (LSCM) and MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay after 2, 4, 6 days of culture. The results indicated that the cell morphology and proliferation on the composite films were better than that on the pure PLLA film. Furthermore, morphology and proliferation of VSMCs became better with decreasing of the weight ratio of PLLA/PVP. In addition, adhesion of platelet on the films was observed by SEM. The SEM images showed that the number of adhered platelets decreased with increment of PVP content in the films. The electrospinning microfiber composite films of PLLA and PVP would have potential use as the scaffolds for vascular tissue engineering.

Increasing evidence indicates that beta-amyloid (Abeta) oligomers rather than monomers or fibrils are the major toxic agents that specifically inhibit synaptic plasticity and long-term potentiation (LTP) in Alzheimer's disease (AD). Neutralization of Abeta oligomeric toxicity was found to reverse memory deficits. Here, we report four single-chain variable fragment (scFv) antibodies isolated from the naive human scFv library by phage display that specifically recognized Abeta oligomers but not monomers and fibrils. These conformation-dependent scFv antibodies inhibit both Abeta fibrillation and cytotoxicity and bind to the same type of eptitope displayed on the Abeta oligomers. Such scFv antibodies specifically targeting toxic Abeta oligomers may have potential therapeutic and diagnostic applications for AD.

OBSTRUCTIVE SLEEP APNEA SYNDROME (OSAS) HAS BEEN SHOWN TO AGGREGATE SIGNIFICANTLY WITHIN FAMILIES.1–3 FAMILY STUDIES HAVE SUGGESTED that the risk of OSAS may be from 2- to 4-fold as great in relatives of patients with OSAS than in controls,4 and that nearly 40% of the variance in the apnea hypopnea index (AHI) of patients with OSAS may be explained by genetic factors.1 It is likely that genetic factors accompanied with craniofacial structure, body fat distribution and neural control of the upper airway muscles interact to produce the OSAS phenotype.5–7 However, the role of specific genes that influence the development of OSAS has not been identified. Although several previous studies had presumed that several susceptible genes, such as angiotensin converting enzyme (ACE), ApoE4, and insulin receptor substrate (IRS) −1 might be involved in the pathogenesis of OSAS,8–10 the genetic markers for this disorder remain elusive. Several lines of pharmacological, neurobehavioral, and therapeutic evidence have implicated that serotonin (5-HT) is involved in the pathogenesis of OSAS.11–13 By regulating the magnitude and duration of serotonergic responses, the serotonin transporter (5-HTT) is central to the fine tuning of brain serotonergic neurotransmission and of the peripheral actions of 5-HT.14 The 5-HTT protein is encoded by a single gene, the solute carrier family 6, member 4, SLC6A4 (i.e., 5-HTT), which locates on chromosome 17q11.1–17q12.15,16 Two common polymorphisms have been described in the gene: a deletion /insertion of 44 bp in the promoter region approximately 1 kb upstream of the transcription site (5-HTTLPR) and a variable number of tandem repeats in intron 2 (STin2.VNTR) containing 9,10, or 12 copies of a 16–17 bp repeat element located in intron 2.16–18 These polymorphisms make the 5-HTT a strong candidate gene for study in sleep disorders. In previous studies, the rat with 5-HTT gene knockout showed disturbed sleep.19 Yilmaz et al. reported that the 12/10 and LL genotypes were overrepresented in 20 male patients with OSAS.20 To further assess whether the 5-HTT gene could be implicated in the vulnerability to OSAS, we performed an independent case-control association study in a Chinese Han population.

Dear Editor, It was with great interest that we read the timely reply from Dr. Gebauer and Dr. Amling concerning our letter entitled “Letter to the Editor concerning Gebauer et al.: Subdental synchondrosis and anatomy of the axis in aging: a histomorphometric study on 30 autopsy cases. Eur Spine J 15(3):292–298, 2006”, which was sent to the Journal’s editor. First, we would like to thank the authors’ expound reply. Nevertheless, there exists a lot of unsatisfying arguments in the authors’ reply. And we also prepared some evidences to contradict them. The authors criticized that although our observations of the remnants of the subdental synchondosis on our clinical CT and MRI studies confirm their observations, we draw the wrong conclusion, that the subdental synchondosis located below the level of the C1–C2 articulation must be located at the center of the axis body. Also, the author pointed out that there is no report in the literature describing the subdental synchondosis located at the body of the axis. Unfortunately, we indeed found that there existed literature described by Blocky that the remnants of the subdental synchondrosis located at the body of the second vertebrae, “There is a rudimentary island of cartilage in the body of the adult axis. This has been known at least since Bardeen described its origin in 1910” [5]. Fielding et al. also depicted that “At birth, the odontoid process is separated from the body of the axis by a wide cartilaginous plate. This epiphyseal plate does not lie at the anatomical base of the odontoid process (the level of the superior articular facets of the axis), but is situated well below that level—that is, it lies with the body of the axis where it is continuous with the neurocentral synchondrosis.” in their article [9]. After carefully reviewing the literatures and our clinical observations on the CT and MRI studies, and even the sagittal and coronal slices of the axis, we are dare to draw this conclusion that the remnants of the subdental synchondosis located below the level of the C1–C2 articulation must be located at the center of the axis body. Here, we would like to have a review with readers about the axis anatomic features descriptions in the Osteology section of The Bartleby.com edition of Gray’s Anatomy of the Human Body, “The most distinctive characteristic of this bone is the strong odontoid process which rises perpendicularly from the upper surface of the body. The body is deeper in front than behind, and prolonged downward anteriorly so as to overlap the upper and fore part of the third vertebra. It presents in front a median longitudinal ridge, separating two lateral depressions for the attachment of the Longus colli muscles. Its under surface is concave from before backward and covex from side to side. The dens or odontoid process exhibits a slight constriction or neck, where it joins the body” [13]. Although there is no distinctive descriptions the exactly border of the axis body, we can at least know that the bony structure below the upper surface articulations of C2 belongs to the axis body. And this is generally accepted by clinical, radiological and morphological experts. Until now most of the literatures concerning the morphological measurements of the dens and the axis body defined as that the dens height was the apex to the level of a plane through the superior-most aspect of the superior articular facets and the height of the C2 vertebral body was determined as from the level of a plane through the superior-most aspect of the superior articular facets to the anterior or the posterior edge of the body along the vertical midline of the second vertebrae [8, 14, 15, 17]. Also, our observations of the frontal sections of the axis (see Fig. 1a–c) and CT and MRI studies strongly confirm us that the remnants of the subdental synchondosis located at the center of the adult axis body. Fig. 1 On the frontal-plane of C2, two principle trabeculae group are seen to form two arches: one arising from the lateral cortex of the dens to the inferior cortex of the lateral masses of the axis, which is indicating that the load paths from articular facets ... We completely agree with the authors’ depict on the typical locations for Type II fracture (see authors’ Fig. 1a), which is defined as the junction of the odontoid process with the body of the axis according to Anderson and D’Alozo classification [4]—this area is also described as the waist or the neck or the base of the dens by other authors [6, 7, 12, 14, 16]. Nevertheless, the authors argue that they classified the fracture as Type II (see authors’ Fig. 1c, d), because the facture line does not involve the cranial facets of the axis, even though a clear distinction to a Type III fracture is difficult, as the fracture line runs through the transition area between the fracture localizations for Type II and Type III fractures. In the original article of the fracture classification scheme of odontoid fracture introduced by Anderson and D’Alozo, Type II fracture was defined as a fracture occurring at the junction of the odontoid process with the body of the second cervical vertebrae, and in Type III, the fracture line extends downward into the body of the second vertebrae. Obviously, when the fracture line runs through the transition area between the fracture localizations for Type II and Type III fractures, it should be classified as Type III fracture, not Type II fracture, according to Anderson and D’Alozo [4]. In the serial studies of Amling et al. [1–3, 10, 11] on the internal anatomy of the axis, the authors only studied sagittal slices of the axis. We are sorry to point out that it was of great limitations to reveal the real architecture of the cancellous bone of the axis with only sagittal plane of the axis samples, frontal sections give some additional indications. The trabecular patterns of the axis give significant clues about the normal stresses it bears and transmits. These patterns provide insight into the biomechanical behaviors of C2. In a frontal section of the axis, two principle trabeculae group are seen to form two arches: one arising from the superior articulation facets cortex to the C2 end plate (Fig. 1a) and the other taking origin from the lateral cortex of the dens to the inferior cortex of the lateral masses of the axis (Fig. 1b). In particular, we would like to draw the readers’ attention that lower intensity trabecular network around the remnants of the subdental synchondosis in the center of the axis body. According to the famous Wolff Law—that the form of bone is produced in response to the stresses that it has to bear. The decreased intensity trabeculae around the remnants of the subdental synchondosis suggests that this area of bone normally transmits very little load. This finding is in accordance with Heggeness and Doherty’s finding [14]. It strongly suggests that even obviously decreased mean trabucalar bone volume was observed in this region in sagittal plane of the axis, conclusion that this morphologic characteristic contributes to the occurrence of fractures within this region should not be drawn by the authors. Because the observations were done only in sagittal plane of the axis, and the frontal sections of the axis shows that the decreased intensity trabeculae of this region is most likely a reflection of relatively diminished forces transmitted, and this observation is consistent with the idea that the trabeculae around the remnants of the subdental synchondosis in the axis body is shielded from a number of forces by the principle trabeculae group arches of the axis (see Fig. 1c). Finally, we would like to describe a new anatomic feature of possible clinical significant observed on the anterior surface body of the C2, that the axis presents in front a median longitudinal ridge (see Fig. 1d), and also a not obvious transverse ridge (see Fig. 1d) connecting to the lateral masses of the axis. The median longitudinal ridge intersects the transverse ridge forming a “promontory” on the anterior surface of the axis (see Fig. 1d). And the “promontory” is what we use as an important landmark of the axis, that we repeatedly observed the remnants of the subdental synchondosis in adult axis is below this level on CT studies (n = 43, age ranging from 10 to 78 years), so we consider it as the inferior boundary of the base of the dens. This anatomic feature may not be clearly observed only on the median sections of the axis, which has been pointed out by the authors. However, as aforementioned, only the sagittal planes studies of the axis could not reveal the real trabecular behaviors of the axis. This “promontory” may not be repeatedly observed on the sagittal planes of the axis samples, but on the complete axis and/or the 3D reconstruction of the axis CT slices. Again, we are unfortunate to point out that there some errors have been made by the authors in the author’s reply, that two black arrows have been marked at the wrong places on sagittal planes of the axis samples (see authors’ Fig. 1e, f, the last two axis sagittal sample). Actually, they are the bony promontories at the inferior border of the atlanto-odontoid joint surface of the odontoid process (see Fig. 1e), which can especially be observed in old people, these should not be regarded as “promontory” on the anterior surface of the axis body. Again, it reveals the limitations of only study on the sagittal plane of the axis samples by the authors. Again we thank the authors for this fruitful discussion, and we are extremely happy to participate in this elaborate discussion on this issue, and also we are expecting more experts participate in this discussion.

Background Transcription factor pancreatic duodenal homeobox-1 (PDX-1) is critical for β-cell differentiation and insulin gene expression. In this study, we investigated the role of PDX-1 in ductal-to-islet cell transdifferentiation, islet cell apoptosis, and proliferation in addition to other regulators associated with these processes in two developing β-cell models. Materials and methods CAPAN-1 cells were cultured with the GLP-1 analogue Exendin-4 (Ex-4) to induce transdifferentiation to an insulin-producing phenotype. Expression patterns of PDX-1, somatostatin receptors (SSTR) 1, 2, and 5, p27, and p38 were analyzed. To model pancreatic regeneration in vivo , subtotal pancreatectomies were performed in rats and remnant pancreata were compared to sham laparotomy controls to determine islet size, morphology, apoptosis, and PDX-1 expression. Results In Ex-4-treated cells, PDX-1 expression increased 67% above basal levels within 24 h and was followed by a 10-fold decline in expression by the end of the study. Expression of cell-cycle inhibitor p27 was down-regulated by 81% at 24 h, while levels of the pro-apoptotic modulator p38 significantly increased 4-fold. When compared to controls, SSTR1 expression declined, while SSTR2 and SSTR5 expression were significantly up-regulated in treated cells. Immunofluorescence of pancreatic remnants following subtotal pancreatectomy revealed increased PDX-1 staining at 24 h followed by a significant decline at 72 h post-pancreatectomy. Conclusion GLP-1 analogue Ex-4 resulted in up-regulation of PDX-1 in CAPAN-1 cells and PDX-1 was up-regulated in proliferating islets following subtotal pancreatectomy in rats. The increase was seen in the first 24 h. These findings suggest a possible relationship between PDX-1 and the state of islet proliferation, islet-to-ductal transdifferentiation, apoptosis, and the expression of SSTRs.

Rationale: The prevalence of chronic obstructive pulmonary disease (COPD) in China is largely unknown. Objectives: To obtain the COPD prevalence in China through a largepopulation, spirometry-based, cross-sectional survey of COPD. Methods: Urban and rural population-based cluster samples were randomlyselectedfromsevenprovinces/cities.Allresidents40years of age or older in the selected clusters were interviewed with a standardized questionnaire revised from the international BOLD (Burden of Obstructive Lung Diseases) study. Spirometry was performed on all eligibleparticipants.Patientswithairflowlimitation(FEV1/FVC , 0.70) were further examined by post-bronchodilator spirometry, chest radiograph, and electrocardiogram. Post-bronchodilator FEV1/ FVCoflessthan70%wasdefinedasthediagnosticcriterionofCOPD. Measurements and Main Results: Among 25,627 sampling subjects, 20,245 participants completed the questionnaire and spirometry (response rate, 79.0%). The overall prevalence of COPD was 8.2% (men, 12.4%; women, 5.1%). The prevalence of COPD was significantly higher in rural residents, elderly patients, smokers, in those with lower body mass index, less education, and poor ventilation in the kitchen, in those who were exposed to occupational dusts or biomass fuels, and in those with pulmonary problems in childhood and family history of pulmonary diseases. Among the patients who hadCOPD,35.3%wereasymptomatic;only35.1%reportedlifetime diagnosis of bronchitis, emphysema, or other COPD; and only 6.5% have been tested with spirometry. Conclusions: COPD is prevalent in individuals 40 yearsof age or older in China.

There is increasing evidence for a possible association between chronic obstructive pulmonary disease (COPD) and the use of biomass fuels for cooking and heating in developing countries. Data on the prevalence of COPD and objective measurements of indoor pollution from biomass fuel have not been widely available from China. A study was undertaken to investigate the prevalence of COPD in two study communities in Guangdong province in China and to measure the association between COPD and indoor biomass fuel air pollution.A cluster disproportional random sampling survey was performed in populations aged over 40 years in urban (Liwang) and rural (Yunyan) areas in Guangdong, China. Spirometry was performed in all subjects and a post-bronchodilator ratio of the forced expiratory volume in 1 s to forced vital capacity of0.70 was defined as COPD. Measurements of indoor and outdoor air pollutants were also performed in a random sample of households.The overall prevalence of COPD in the two areas (Liwang and Yunyan) was 9.4%. The prevalence of COPD in both the whole population and a subpopulation of non-smoking women in rural Yunyan was significantly higher than in urban Liwang (12.0% vs 7.4%, and 7.2% vs 2.5%, respectively). The use of biomass fuel was higher in rural Yunyan than in urban Liwang (88.1% vs 0.7%). Univariate analysis showed a significant association between COPD and exposure to biomass fuel for cooking. Multivariate analysis showed a positive association between COPD and urban/rural area (surrogate for fuel type and local exhaust ventilation in kitchen) after adjustment for sex, age group, body mass index, education, occupational exposure, respiratory disease in family, smoking status, life quality and cough in childhood; similar results were found in non-smoking women. Pollutants measurements showed that concentrations of carbon monoxide, particulate matter with an aerodynamic diameteror=10 microm, sulphur dioxide and nitrogen dioxide in the kitchen during biomass fuel combustion were significantly higher than those during LPG combustion.Indoor pollutants from biomass fuels may be an important risk factor for COPD in rural South China.

Background Studies have demonstrated that adenovirus subtype 5 mediated rat insulin promoter directed thymidine kinase (A-5-RIP-TK)/ganciclovir (GCV) gene therapy resulted in significant enhanced cytotoxicity to both PANC-1 and MIA PaCa2 pancreatic cancer cells in vitro . However, little is known about the effect in vivo . In this study we examine the in vivo safety and efficacy of intravenous A-5-RIP-TK/GCV gene therapy. Materials and methods 1×10 6 Mia PaCa2 cells were injected intraperitoneally (i.p.) into SCID mice to create a mouse model of human pancreatic cancer. A-5-RIP-TK gene construct was administered intravenously (i.v.), followed by i.p. GCV administration. Intravenous injection of A-5-RIP-lacZ reporter gene constructs was used for evaluation of Ad-RIP-gene expression in tumors and other tissues. Optimal adenoviral and GCV doses and treatment duration were determined. Tumor volume, serum insulin, and glucose levels were measured. Immunohistochemical staining of pancreata and tumors were performed to assess morphology and hormone expression and apoptotic rates were determined. Results All A-5-RIP-TK/GCV-treated mice had reduced tumor volume compared with controls, but maximal tumor volume reduction was observed with 10 8 vp followed by GCV treatment for 4 wk. A-5-RIP-TK/GCV gene therapy contributed to significant survival advantage in MIA PaCa2 bearing mice, and the greatest survival benefit was observed with 10 8 vp and was not affected by length of treatment of GCV. A-5-RIP-TK/GCV therapy increased PDX-1 expression and tumor cells apoptosis, and altered islet morphology. However, A-5-RIP-TK/GCV gene therapy caused diabetes associated with islet cell apoptosis, increased δ-cells and reduced pancreatic polypeptide (PP)-cell numbers. Conclusions Systemically administered A-5-RIP-TK/GCV is an effective treatment of pancreatic cancer. A-5-RIP-TK/GCV cytotoxicity to malignant cells varies with adenoviral dose and length of GCV treatment. However, A-5-RIP-TK/GCV is associated with islet cell toxicity and diabetogenesis. The type of diabetes observed is distinct from Types 1 and 2 and is associated with islet cell apoptosis and reduced δ- and PP-cells.

Using in vivo mouse models, we have demonstrated that the insulin promoter-driven suicidal gene therapy (RIPTK) could be used in the treatment of mouse insulinoma and human pancreatic cancer cells. However, limitations of this therapy include tumor cells lack of sufficient PDX-1 protein and low levels of transgene expression mediated by liposome delivery system. The purpose of this study was to determine 1) whether transient transfection of PDX-1 into selected pancreatic cancer cells would lead to increased RIPTK cytotoxicity, and 2) whether an adenoviral delivery system would increase the overall RIPTK gene expression in vitro.RIPlacZ and RSVlacZ plasmid DNA as well as AdCMVlacZ and AdRIPlacZ were used in transfection assays in human pancreatic cancer cell lines PANC-1 and MIA PaCa2 (n = 8). An expression plasmid DNA containing the mouse PDX-1 cDNA was also used. LacZ reporter assays were performed. RIPTK genes constructed either in plasmid or in adenoviral vectors were used in cytotoxic assays. RT-PCR assays were used to determine PDX-1 expression levels.PDX-1 protein was detected in the human pancreatic ductal carcinoma cell line PANC-1, a little in MIA PaCa2 cells. Liposome mediated (L) RSVlacZ and RIPlacZ transfection in PANC-1 cells resulted in 10.1% and 9.3% transgene expression, respectively. Co-delivery of PDX-1 had no significant effect on RSVlacZ expression (9.3%, P = NS) but significantly increased RIPlacZ gene expression (14.9% P0.05). Adenoviral mediated (Ad) RIPlacZ transgene was highly expressed in PANC-1 cells (66.1%) and the reporter activity was further enhanced when PDX-1 was co-delivered (70.2%, P0.05). Liposomal transfection of MIA PaCa2 cells using RSVlacZ and RIPlacZ reporter genes resulted in 9.3% and 1.0% gene expression, respectively. Co-transfection of PDX-1 in these cells resulted in a significant activation of RIPlacZ gene expression (14.5%, P0.05) with no effects on RSVlacZ treated cells (9.8%). AdCMVlacZ and AdRIPlacZ significantly increased reporter activities in MIA PaCa2 cells (63.0% and 9.8%, respectively). Transfection of PDX-1 also significantly enhanced the AdRIPlacZ activities (46.0%, P0.05), with no significant effect in AdCMVlacZ treated cells (68.2%). The cytotoxic effect of liposome-RIPTK/ganciclovir (GCV) in PANC-1 cells was 18.6% and increased to 22.8% when PDX-1 was co-transfected into the cells (P = NS). MIA PaCa2 cells treated with RIPTK alone resulted in 4.9% cell death and increased to 18.2% when exogenous PDX-1 was co-delivered (P0.05). The AdRIPTK gene delivery with GCV treatment caused significant cytotoxic effect in PANC-1 (29.3%) and MIA PaCa2 (12.4%) compared with untreated cells. The cytotoxic effects were further increased to 43.4% and 29.4% in PANC-1 and MIA PaCa2 cells, respectively, when PDX-1 was co-transfected (P0.05 for both).These data demonstrated that adenoviral mediated gene delivery resulted in a significant increase of transgene expression compared with liposomal delivery systems. RIPTK mediated cytotoxicity was also significantly enhanced via co-delivery of exogenous PDX-1 in these cells. Thus, these results also indicated that PDX-1 plays critical roles in insulin promoter activation and demonstrated that PDX-1 production is essential for insulin promoter-directed gene therapy.

Little has been reported about the demographic and clinical features of major depressive disorder (MDD) with comorbid dysthymia in Chinese patients. This study examined the frequency of comorbid dysthymia in Chinese MDD patients together with the demographic and clinical correlates and prescribing patterns of psychotropic drugs.Consecutively collected sample of 1178 patients with MDD were examined in 13 major psychiatric hospitals in China. Patients' demographic and clinical characteristics and psychotropic drugs prescriptions were recorded using a standardized protocol and data collection procedure. The diagnosis of dysthymia was established using the Mini International Neuropsychiatric Interview. Medications ascertained included antidepressants, antipsychotics, benzodiazepines, and mood stabilizers.One hundred and three (8.7%) patients fulfilled criteria for dysthymia. In multiple logistic regression analyses, compared to non-dysthymia counterparts, MDD patients with dysthymia had more depressive episodes with atypical features including increased appetite, sleep, and weight gain, more frequent lifetime depressive episodes, and less likelihood of family history of psychiatric disorders. There was no significant difference in the pattern of psychotropic prescription between the 2 groups.There are important differences in the demographic and clinical features of comorbid dysthymia in Chinese MDD patients compared with previous reports. The clinical profile found in this study has implications for treatment decisions.

Freezing of gait (FOG) is a heterogeneous symptom. Studies of treatment for FOG are scarce. Levodopa and monoamine oxidase inhibitors (rasagiline and selegiline) have shown effective improvement for FOG. Other drugs, such as L-threo-3, 4-dihydroxyphenylserine, amantadine, and botulinum toxin have exhibited some beneficial effects. The present review summarizes the potential drug treatment for FOG in Parkinsonism.

The objective of this study was to determine whether rat insulin promoter (RIP) could, in a mouse model, direct expression of an adenovirus-mediated reporter gene specifically into pancreatic islets via systemic delivery.Five hundred and eight base pairs of the RIP DNA sequence were constructed into an adenoviral vector containing a lacZ reporter gene (Adeno-RIP-lacZ). The cytomegalovirus (CMV) promoter was constructed to drive lacZ reporter-gene expression (Adeno-CMV-lacZ) and used as controls. In vitro transient transfection assays were performed to determine levels of reporter-gene expression and compared with that of liposome-mediated plasmid transfection. SCID mice were bred and housed in the barrier BL-4 animal facility. At 2 months of age, the human pancreatic cancer cell PANC-1 was intraperitoneally injected into male mice. Two months after the tumor cell inoculation, mice were injected with 10(7) adenoviral particles via tail veins. After gene delivery, mice were sacrificed at different time points to determine transgene expression levels. Complete necropsies were performed. Morphological alterations were determined using hematoxylin and eosin (HE) staining, and distribution of the reporter lacZ gene was determined by immunohistochemistry analyses.Adenoviral-driven reporter-gene expression resulted in more than 5 times higher transgene expression compared with conventional plasmid transfections. In Adeno-RIP-lacZ-injected mice, lacZ expression was specifically detected in pancreatic islets. By contrast, in Adeno-CMV-lacZ-injected mice, lacZ gene expression was observed in multiple organs and tissues. Mononuclear cell infiltration and liver cell inflammation were found in Adeno-CMV-lacZ-treated mice. Similar phenomena were observed in islet cells of Adeno-RIP-lacZ-treated mice. A significantly higher level of reporter-gene expression was also found at the edge of in-vivo-inoculated human pancreatic tumors.These results demonstrate that RIP-directed reporter-gene expression was found specifically in mouse pancreatic islets and implanted human pancreatic cancer cells. These data thus demonstrate that the combination of an adenoviral vector and a tissue-specific promoter could lead to an enhanced and more specific transgene expression in vivo.

The development of the endocrine pancreas is regulated by numerous transcription and growth factors. Somatostatin (SST) is present in many tissues and acts as a neurotransmitter and autocrine/paracrine/endocrine regulator in response to ions, nutrients, peptides, and hormones as well as neurotransmitters. In the pancreas, there is evidence that SST acts an inhibitory paracrine regulator of hormone secretion. Somatostatin receptors (SSTRs) are a family of 5 transmembrane G protein-coupled receptors, which are widely expressed in mammals including humans. SSTRs regulate multiple downstream signal transduction pathways that mediate inhibitory effects. These receptors also exhibit age- and tissue-specific expression patterns. Interactions of SST and SSTRs are not only important during normal pancreas development, but have also been implicated in many pancreatic diseases such as diabetes mellitus and pancreatic cancer. In this review article, we use evidence from recently published animal studies to present the critical roles of SST and SSTRs proteins in the development of the endocrine pancreas.

During the last decade significant advances in gene therapy have made it possible to treat various pancreatic disorders in both animal models and in humans. For example, insulin gene delivery to non-beta-cell tissues has been shown to reverse hyperglycemia in diabetic mice, and islet transplantation, based on in vitro differentiation of beta cells and concomitant gene targeting to prevent host autoimmune responses, has become more feasible. Additionally, introduction of the glucokinase regulatory protein and protein kinase C-zeta have been shown to improve glucose tolerance in non-insulin-dependent diabetes mellitus animal models. Pancreatic cancer studies utilize several DNA-based strategies for tumor treatment including introduction of tumor suppressor genes, suppression of oncogenes, suicide gene/prodrug therapy, and restricted replication-competent virus therapy. Tumor-specific targeting is an important part of suicide gene therapy, and tumor-specific promoters are used for cell-specific targeting. Tumor-specific suicide gene therapy directed by the rat insulin promoter has been used to eliminate insulinoma tumors in a mouse model. This review compiles a compendium of information related to the treatment of pancreatic disorders using gene therapy.