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Multiple myeloma (MM) is known for its immune disturbance and patients suffering from MM are thus vulnerable to opportunistic infections, including herpes zoster (HZ). As HZ infection remarkably affects patients' quality of life and poses huge economic burdens on the health system, we aim to identify the risk factors of HZ infection and evaluate the effects of different dosages, types, and durations of anti-HZ prophylaxis drugs to prevent HZ infection.551 MM patients at Taipei Veterans General Hospital in Taiwan between January 1, 2009 and August 31, 2021 were restrospectively analyzed. The patients' baseline characteristics were recorded. The primary endpoint of the study was the incidence of HZ infection among the studied patient population. Due to the lack of cost coverage from Taiwanese public health insurance on HZ prophylaxis drugs, the use of anti-HZ drugs mainly depends on physicians' preferences and patients' choices.In our study, prophylaxis was given to 283 of the patients. In the multivariate analysis, we included non-prophylaxis, age ≥ 60, corrected serum calcium ≥12 mg/dl, serum creatinine ≥2 mg/dl, serum β2-microglobulin ≥5500 mg/L, autologous stem cell transplant (SCT), and allogeneic SCT for analysis. Our results demonstrated that the non-prophylaxis group (HR: 2.37, 95% CI 1.57-3.57) and patients receiving autologous SCT (HR: 2.22, 95% CI 1.28-3.86) and allogeneic SCT (HR: 5.12, 95% CI 1.13-23.22) had higher risk of HZ infection. The difference in dosage and types of anti-HZ drugs showed similar protective effects. In patients who stopped anti-HZ prophylaxis before active cancer-related treatment, a higher risk of getting HZ infection compared to the corresponding group was also observed (adjusted HR 3.09, 95% CI 1.35-7.07, p = 0.008).We concluded that MM patients should receive HZ prophylaxis drugs while receiving active cancer-related treatment. Patients receiving SCT are also at high risk of getting HZ infection, even under prophylaxis.

Skin biopsy was the only method to provide free-intraepidermal-nerve-endings (FINEs) structural information for the differential diagnosis of small fiber neuropathy (SFN). Its invasive nature was particularly unfavorable for patients with diabetic coagulation abnormalities thus there is an unmet clinical need for a non-invasive FINEs imaging tool. Here we show a tightly-focused epi-Third-harmonic-generation microscope (TFETM) for unmyelinated FINEs imaging. Its label-free capability was confirmed by PGP9.5 immunohistochemistry staining and a longitudinal spared nerve injury model study. Moreover, through proposing a dot-connecting algorithm, we established the operational protocol to count three-dimensionally the intraepidermal nerve fibers (IENF) and define the quantitative IENF index. Our clinical trial showed that the label-free IENF index can differentially identify SFN (P-value=0.0102) and was well correlated with IENF density of skin biopsy (Pearson’s correlation, R-value= 0.98) in the DPN group. Our study suggested that the unstained dot-connecting third-harmonic microscopy imaging can noninvasively provide FINEs structure information assisting diagnosing SFN.

Glucocorticoid-induced osteoporosis (GIOP) is the most common form of secondary osteoporosis due to excessive or long-term glucocorticoid administration, disturbing the homeostasis between bone formation and bone resorption. The bone biology of zebrafish shares a high degree of similarities with mammals. In terms of molecular level, genes and signaling pathways related to skeletogenesis are also highly correlated between zebrafish and humans. Therefore, zebrafish have been utilized to develop multiple GIOP models. Taking advantage of the transparency of zebrafish larvae, their skeletal development and bone mineralization can be readily visualized through

In 2017 and 2018, Food and Drug Administration has approved YESCARTA (axicabtagene ciloleucel) and KYMRIAH (tisagenlecleucel), two chimeric antigen receptor (CAR)-engineered T-cell products, for B-cell malignancies. It also marked a watershed moment in the development of immunotherapies for cancer. Despite the successes in adults, it remains clinically applicable only in B-cell acute lymphoblastic leukemia in pediatrics. Notably, multiple clinical trials and recent case reports about childhood central nervous system (CNS) tumors, the leading cause of deaths in children, have emerged and granted promising results. With the growing consideration of the biological responses in the interaction of human immunity, the major technical obstacles such as on-target off-tumor toxicity in widespread solid tumors, antigenic heterogeneity, adaptive resistance, difficult T-cell (CD4/CD8) trafficking, and immunosuppressive environments in CNS are gradually approached and ameliorated. The new spotlights of this review are focusing on current development, and emerging treatments for pediatric CNS tumors integrating molecular research with the mainstream of CAR-T therapeutic strategies to sketch a main axis and pathway forward in the improvement of novel gene-modified-based cellular platform.

Many market technicians claim that technical rules are effective more in bear markets than in bull markets. Using the 2008 financial crisis as the backdrop for testing, this study investigates how ...

The aim of this study is to describe the technique of pulmonary expansion by suction control from a surgical wound during nonintubated uniportal video-assisted thoracic surgery. Five patients developed oxygen desaturation intraoperatively even with facial mask ventilation. Oxygenation was completed after 3 minutes with the suction technique through the uniportal wound. All the patients underwent the operation under spontaneous ventilation, without conversion to endotracheal intubation. The suction ventilation technique can provide an alternative solution during deoxygenation conditions of nonintubated video-assisted thoracic surgery.

With advances in the understanding of characteristics of molecules, specific antigens on the surface of hematological malignant cells were identified and multiple therapies targeting these antigens as neoplasm treatments were developed. Among them, chimeric antigen receptor (CAR) T-cell therapy, which got United States Food and Drug Administration (FDA) approval for relapsed/refractory (r/r) diffuse large B-cell lymphoma (DLBCL) as well as for recurrent acute lymphoblastic leukemia (ALL) within the past five years, and for r/r mantle cell lymphoma (MCL) this year, represents one of the most rapidly evolving immunotherapies. Nevertheless, its applicability to other hematological malignancies, as well as its efficacy and persistence are fraught with clinical challenges. Currently, more than one thousand clinical trials in CAR T-cell therapy are ongoing and its development is changing rapidly. This review introduces the current status of CAR T-cell therapy in terms of the basic molecular aspects of CAR T-cell therapy, its application in hematological malignancies, adverse reactions during clinical use, remaining challenges, and future utilization.

Suboptimal cancer pain management is a worldwide problem. We examined whether an educational program on cancer pain management implemented during training could benefit primary care physicians. We enrolled all the primary care physicians who visited the oncology ward at a medical center for the first time. Educational classes on cancer pain management were conducted. The participants’ abilities in cancer pain management were measured in a pretest before the classes and approximately 2 weeks later in the first posttest. The second posttest was conducted on participants who visited the oncology ward again. All 3 tests had the same set of questions and were scored on a scale of 0 to 100. In total, 247 participants were enrolled. Less than 10% of them considered their previous education on cancer pain management adequate. The test scores increased significantly from the pretest to the first posttest (mean 65.6 vs. 89.7, p

The large amounts of engineered titanium dioxide nanoparticles (TiO2NPs) that have been manufactured have inevitably been released into the ecosystem. Reports have suggested that TiO2 is a relatively inert material that has low toxicity to animals. However, as various types of NPs increasingly accumulate in the ocean, their effects on aquatic life-forms remain unclear. In this study, a zebrafish model was used to investigate TiO2NP-induced injury and mortality. We found that the treatment dosages of TiO2NP are positively associated with increased motility of zebrafish and the bacterial counts in the water. Notably, gill but not dorsal fin and caudal fin of the zebrafish displayed considerably increased bacterial load. Metagenomic analysis further revealed that gut microflora, such as phyla Proteobacteria, Bacteroidetes, and Actinobacteria, involving more than 95% of total bacteria counts in the NP-injured zebrafish gill samples. These results collectively suggest that opportunistic bacterial infections are associated with TiO2NP-induced mortality in zebrafish. Infections secondary to TiO2NP-induced injury could be a neglected factor determining the detrimental effects of TiO2NPs on wild fish.

This study aimed to evaluate the effects of motor imagery (MI) on walking function and balance in patients after stroke.Related randomized controlled trials (RCTs) were searched in 12 electronic databases (Cochrane Central Register of Controlled Trials, PubMed, Science Direct, Web of Science, Allied and Complementary Medicine, Embase, Cumulative Index to Nursing and Allied Health Literature, PsycINFO, China National Knowledge Infrastructure, Chinese Biomedical Literature Database, WanFang, and VIP) from inception to November 30, 2016, and Review Manager 5.3 was used for meta-analysis. References listed in included papers and other related systematic reviews on MI were also screened for further consideration.A total of 17 studies were included. When compared with "routine methods of treatment or training", meta-analyses showed that MI was more effective in improving walking abilities (standardized mean difference [SMD] = 0.69, random effect model, 95% confidence interval [CI] = 0.38 to 1.00, P 0.0001) and motor function in stroke patients (SMD = 0.84, random effect model, 95% CI = 0.45 to 1.22, P 0.0001), but no statistical difference was noted in balance (SMD = 0.81, random effect model, 95% CI = -0.03 to 1.65, P = 0.06). Statistically significant improvement in walking abilities was noted at short-term (0 to six weeks) (SMD = 0.83, fixed effect model, 95% CI = 0.24 to 1.42, P = 0.006) and long-term (≥six weeks) assessments (SMD = 0.45, fixed effect model, 95% CI = 0.25 to 0.64, P 0.00001). Subgroup analyses suggested that MI had a positive effect on balance with short-term duration (0 to six weeks) (SMD = 4.67, fixed effect model, 95% CI = 2.89 to 6.46, P 0.00001), but failed to improve balance (SMD = 0.82, random effect model, 95% CI = -0.27 to 1.90, P = 0.14) with long-term (≥six weeks) duration.MI appears to be a beneficial intervention for stroke rehabilitation. Nonetheless, existing evidence regarding the effects of MI in patients after stroke remains inconclusive because of significantly statistical heterogeneity and methodological flaws identified in the included studies. More large-scale and rigorously designed RCTs in future research with sufficient follow-up periods are needed to provide more reliable evidence on the effects of MI in post-stroke patients.

This study employs the bootstrap method to explore the evolution of the Chinese yuan. We use the following three random walks to characterize the evolution of the yuan: an IID-parameterized random walk, an ARCH(3)-parameterized random walk, and a GARCH(1,1)-parameterized random walk. To proceed, we use the bootstrap method to generate 10,000 artificial yuan series from each random walk and compute the return from the trading rule (i.e., moving average or trading range break) for each of the 10,000 artificial yuan series. Then, we construct a 95% percentile interval with these 10,000 returns to determine if the interval contains the return computed from the actual yuan series. Using daily exchange rate data from 22 July 2005 to 19 July 2019, our results show that, of the three random walks, the GARCH(1,1) random walk best portrays the yuan since the 2005 exchange rate system reform.

Background Although current neuropathic pain treatment guidelines do not recommend the use of nonsteroidal anti-inflammatory drugs (NSAIDs), whether NSAIDs can serve as a useful adjuvant to conventional multimodal therapy remains unclear. Methods The spared nerve injury (SNI) rats rapidly developed profound and long-lasting spontaneous and evoked pain behaviors, including mechanical and cold allodynia of the ipsilateral hind paw. At day 5, we first characterized the nociceptive responses to ketorolac, tramadol, pregabalin, and their combinations. Results We found that tramadol and pregabalin exerted dose-dependent analgesic effects on both spontaneous and evoked behaviors. However, ketorolac alone did not suppress any behaviors regardless of the dose. Ketorolac-tramadol and ketorolac-pregabalin produced variable degrees of additive suppression of spontaneous and evoked behavioral responses. Cold allodynia was profoundly diminished after ketorolac was added to ineffective pregabalin or tramadol. Mechanical allodynia was markedly attenuated by ketorolac-pregabalin but less so by ketorolac-tramadol mixtures. Conclusion Our data demonstrated that an NSAID alone failed to relieve spontaneous or evoked pain behaviors in the rat SNI model, but when combined with a weak opioid and α-2-δ-ligand produced a profound synergistic analgesic effect on cold allodynia and discrepant efficacy for mechanical allodynia and spontaneous pain.

Morphine is the most commonly used drug for treating physical and psychological suffering caused by advanced cancer. Although morphine is known to elicit multiple supraspinal analgesic effects, its behavioral correlates with respect to the whole-brain metabolic activity during cancer-induced bone pain have not been elucidated. We injected 4T1 mouse breast cancer cells into the left femur bone marrow cavity of BALB/c mice. All mice developed limb use deficits, mechanical allodynia, and hypersensitivity to cold, which were effectively suppressed with morphine. Serial 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) was performed for each mouse before cancer induction (0 day), after cancer-induced bone pain was established (14 days), and during effective morphine treatment (16 days). The longitudinal FDG-PET imaging analysis demonstrated that cancer-induced bone pain increased glucose uptake in the insular cortex and hypothalamus and decreased the activity of the retrosplenial cortex. Morphine reversed the activation of the insular cortex and hypothalamus. Furthermore, morphine activated the amygdala and rostral ventromedial medulla and suppressed the activity of anterior cingulate cortex. Our findings of hypothalamic and insular cortical activation support the hypothesis that cancer-induced bone pain has strong inflammatory and affective components in freely moving animals. Morphine may provide descending inhibitory and facilitatory actions in the treatment of cancer-induced bone pain in a clinical setting.

Immunotherapy, including chimeric antigen receptor (CAR) T-cell therapy, immune checkpoint inhibitors, cancer vaccines, and dendritic cell therapy, has been incorporated as a fifth modality of modern cancer care, along with surgery, radiation, chemotherapy, and target therapy. Among them, CAR T-cell therapy emerges as one of the most promising treatments. In 2017, the first two CAR T-cell drugs, tisagenlecleucel and axicabtagene ciloleucel for B-cell acute lymphoblastic leukemia (ALL) and diffuse large B-cell lymphoma (DLBCL), respectively, were approved by the Food and Drug Administration (FDA). In addition to the successful applications to hematological malignancies, CAR T-cell therapy has been investigated to potentially treat solid tumors, including pediatric brain tumor, which serves as the leading cause of cancer-associated death for children and adolescents. However, the employment of CAR T-cell therapy in pediatric brain tumors still faces multiple challenges, such as CAR T-cell transportation and expansion through the blood–brain barrier, and identification of the specific target antigen on the tumor surface and immunosuppressive tumor microenvironment. Nevertheless, encouraging outcomes in both clinical and preclinical trials are coming to light. In this article, we outline the current propitious progress and discuss the obstacles needed to be overcome in order to unveil a new era of treatment in pediatric brain tumors.

Glucocorticoid-induced osteoporosis (GIOP) is the most common form of secondary osteoporosis, accounting for 20% of osteoporosis diagnoses. Using glucocorticoids for >6 months leads to osteoporosis in 50% of patients, resulting in an increased risk of fracture and death. Osteoblasts, osteocytes, and osteoclasts work together to maintain bone homeostasis. When bone formation and resorption are out of balance, abnormalities in bone structure or function may occur. Excess glucocorticoids disrupt the bone homeostasis by promoting osteoclast formation and prolonging osteoclasts' lifespan, leading to an increase in bone resorption. On the other hand, glucocorticoids inhibit osteoblasts' formation and facilitate apoptosis of osteoblasts and osteocytes, resulting in a reduction of bone formation. Several signaling pathways, signaling modulators, endocrines, and cytokines are involved in the molecular etiology of GIOP. Clinically, adults ≥40 years of age using glucocorticoids chronically with a high fracture risk are considered to have medical intervention. In addition to vitamin D and calcium tablet supplementations, the major therapeutic options approved for GIOP treatment include antiresorption drug bisphosphonates, parathyroid hormone N-terminal fragment teriparatide, and the monoclonal antibody denosumab. The selective estrogen receptor modulator can only be used under specific condition for postmenopausal women who have GIOP but fail to the regular GIOP treatment or have specific therapeutic contraindications. In this review, we focus on the molecular etiology of GIOP and the molecular pharmacology of the therapeutic drugs used for GIOP treatment.

This study compared the cardiac output (CO) obtained from PiCCO with that obtained from the noninvasive NICOM method.Twenty-one cirrhotic patients receiving liver transplantation were enrolled. During the operation, their CO was measured by the PiCCO system via the thermodilution method as the standard and by the NICOM method. Two parameters including cardiac index (CI) and stroke volume index (SVI) were collected simultaneously at three phases during the surgery including the dissection phase (T1), the anhepatic phase (T2), and the reperfusion phase (T3). Correlation, Bland and Altman methods, and linear mixed model were used to evaluate the monitoring ability of both systems.Poor correlation was noted between the data measured by NICOM and PiCCO; the correlation coefficients for CI and SVI measured between the two systems were 0.32 and 0.39, respectively. Bland and Altman analysis showed the percentage error of CI as 63.7%, and that of SVI as 66.6% for NICOM compared to PiCCO. Using the linear mixed model, the CI and SVI measured using NICOM were significantly higher than those using PiCCO (estimated regression coefficient 0.92 and 10.77, both p 0.001). Mixed model analysis showed no differences between the trends of CI and SVI measured by the two methods.NICOM provided a comparable CI and SVI trend when compared to the gold standard PiCCO, but it raises concerns as an effective CO monitor because of its tendency to overestimate CI and SVI especially during the state of high cardiac output.

Background Perioperative psychological distress is associated with preoperative anxiety, depression, and postoperative pain. Mirtazapine is effective as an antidepressant, anxiolytic agent, and sleep enhancer. Moreover, mirtazapine can be made as orodispersible tablets with a fast onset for patients in nil per os status. This study is to determine whether mirtazapine can help psychologically distressed patients reduce perioperative anxiety, depression, and postoperative pain. Materials and methods Patients with preoperative psychological distress, undergoing major abdominal surgery, were inquired and assigned to two groups according to their own choice. In the treatment group, patients could choose to take orodispersible mirtazapine 30 mg at each night from Preoperative Day 0 to Postoperative Day 3. There was no other intervention in the nontreatment group. Hospital Anxiety and Depression Scale (HADS), Athens Insomnia Scale (AIS), and pain scores were accessed on the day before operation (Day 0), and on the 1 st day (Day 2) and 3 rd day (Day 4) after operation. We compared the HADS, AIS, and pain scores, and morphine consumptions between the two groups on a daily basis. Marginal regression models were fitted to our correlated longitudinal data alone with the generalized estimating equations method to estimate the population average effects of time-varying mirtazapine usage on the mean values of HADS, AIS, and pain scores, and daily morphine consumptions. Results From September 2007 to December 2008, 86 patients agreed to be enrolled and 79 of them completed the study. Propensity scores and multivariate analysis showed that mirtazapine reduced HADS scores of patients in 2 days. Trial results indicated that mirtazapine lowered the AIS day index and tended to decrease night index as well. Mirtazapine may reduce patients' morphine consumption, but this effect was not statistically significant ( p = 0.2). Conclusion Mirtazapine helps reduce anxiety, depression, and insomnia scores for patients with perioperative psychological distress.

The present study aimed to investigate the overall and relative contribution of four subcomponents of vocabulary knowledge to reading comprehension. The four vocabulary subcomponents were vocabulary size, word association knowledge, collocation knowledge, and morphological knowledge. The participants were 124 college students from a university in Taipei, Taiwan. Six instruments were employed: (1) a reading comprehension test, (2) a vocabulary size test, (3) a test on word association knowledge and collocation knowledge, (4) a test of morphological knowledge, (5) motivation attitude scale, and (6) a self-efficacy scale. The results can be summarized as follows. First, after the effects of motivation and self-efficacy have been controlled, the four vocabulary subcomponents altogether contributed significantly (20%) to reading comprehension performance. Moreover, depth of vocabulary knowledge (including word association knowledge, collocation knowledge, and morphological knowledge) provided an additional explained variance (6%) in reading comprehension performance over and above vocabulary size. Finally, among the three subcomponents of depth of vocabulary knowledge, collocation knowledge explained the most proportion of variance (5.6%) in contributing to performance on reading comprehension. Based on these findings, some implications and suggestions for future research were provided.

Totally implantable vascular access device (TIVAD)-related complications interfere in the anticancer treatment and increase medical expenses. We examined whether the implantation side of central line TIVADs is associated with the occurrence of thrombotic or occlusion events. We enrolled patients with cancer who required central line TIVADs and randomised them to receive the TIVAD implantation on either the left or right side. The primary endpoint was the occurrence of catheter-related thrombotic or occlusion events. We randomised 240 patients, of which 235 received TIVAD implantation according to the protocol. In the per-protocol cohort, 117 and 118 patients received implantation on the left and right sides, respectively. Catheter-related thrombotic or occlusion events occurred in 9 (4%) patients, accounting for 0.065 events per 1000 catheter-days. Between the patients with left- and right-sided implantations, the occurrence rates (P=0.333) and the time from catheter implantation to the occurrence of thrombotic or occlusion events (P=0.328) were both similar. In the multivariate analysis, the side of implantation remained unassociated with the occurrence of thrombotic or occlusion events. The side of central line TIVAD implantation was not associated with the occurrence of catheter-related thrombotic or occlusion events in patients with cancer.

One major breakthrough in cystic fibrosis research in the past decade is the development of drugs that target the root cause of the disease — dysfunctional CFTR protein. One of the compounds, Ivacaftor or Kalydeco, which has been approved for clinical use since 2012, acts by promoting the gating function of CFTR. Our recent studies have led to a gating model that features energetic coupling between nucleotide-binding domain (NBD) dimerization and gate opening/closing in CFTR's transmembrane domains (TMDs). Based on this model, we showed that ATP analogs can enhance CFTR gating by facilitating NBD dimerization, whereas Ivacaftor works by stabilizing the open channel conformation of the TMDs. This latter idea also explains the near omnipotence of Ivacaftor. Furthermore, this model identifies multiple approaches to synergistically boost the open probability of CFTR by influencing distinct molecular events that control gating conformational changes.

The role of ultrasound examination in detection of postprocedure complications from totally implantable venous access devices (TIVAD) placement is still uncertain. In a cohort of 665 cancer outpatients, we assessed a quick ultrasound examination protocol in early detection of mechanical complications of catheterization. Immediately after TIVAD placement, an ultrasound examination and chest radiography were performed to detect hemothorax, pneumothorax, and catheter malposition. The two methods were compared. Of the 668 catheters inserted, 628 were placed into axillary veins and 40 into internal jugular veins. The ultrasound examination took 2.5 ± 1.1 min. No hemothorax was detected, and neither pneumothorax nor catheter malposition was evident among the 40 internal jugular vein cannulations. Ultrasound and chest radiography examinations of the 628 axillary vein cannulations detected five and four instances of pneumothorax, respectively. Ultrasound detected all six catheter malpositions into the internal jugular vein. However, ultrasound failed to detect two out of three malpositions in the contralateral brachiocephalic vein and one kinking inside the superior vena cava. Without revision surgery, the operating time was 34.1 ± 15.6 min. With revision surgery, the operating time was shorter when ultrasound detected catheter malposition than when chest radiography was used (96.8 ± 12.9 vs. 188.8 ± 10.3 min, p

The pathogenic G551D mutation of CFTR converts one of the two ATP-binding sites from excitatory to inhibitory., Cystic fibrosis (CF), one of the most common lethal genetic diseases, is caused by loss-of-function mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which encodes a chloride channel that, when phosphorylated, is gated by ATP. The third most common pathogenic mutation, a glycine-to-aspartate mutation at position 551 or G551D, shows a significantly decreased open probability (Po) caused by failure of the mutant channel to respond to ATP. Recently, a CFTR-targeted drug, VX-770 (Ivacaftor), which potentiates G551D-CFTR function in vitro by boosting its Po, has been approved by the FDA to treat CF patients carrying this mutation. Here, we show that, in the presence of VX-770, G551D-CFTR becomes responsive to ATP, albeit with an unusual time course. In marked contrast to wild-type channels, which are stimulated by ATP, sudden removal of ATP in excised inside-out patches elicits an initial increase in macroscopic G551D-CFTR current followed by a slow decrease. Furthermore, decreasing [ATP] from 2 mM to 20 µM resulted in a paradoxical increase in G551D-CFTR current. These results suggest that the two ATP-binding sites in the G551D mutant mediate opposite effects on channel gating. We introduced mutations that specifically alter ATP-binding affinity in either nucleotide-binding domain (NBD1 or NBD2) into the G551D background and determined that this disease-associated mutation converts site 2, formed by the head subdomain of NBD2 and the tail subdomain of NBD1, into an inhibitory site, whereas site 1 remains stimulatory. G551E, but not G551K or G551S, exhibits a similar phenotype, indicating that electrostatic repulsion between the negatively charged side chain of aspartate and the γ-phosphate of ATP accounts for the observed mutational effects. Understanding the molecular mechanism of this gating defect lays a foundation for rational drug design for the treatment of CF.

Cystic fibrosis (CF) is caused by loss-of-function mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene encoding a phosphorylation-activated but ATP-gated chloride channel. Previous studies suggested that VX-770 [ivacaftor, N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide], a CFTR potentiator now used in clinics, increases the open probability of CFTR by shifting the gating conformational changes to favor the open channel configuration. Recently the chloride channel blocker and CFTR potentiator 5-nitro-2-(3-phenylpropylamino) benzoate (NPPB) has been reported to enhance CFTR activity by a mechanism that exploits the ATP hydrolysis-driven, nonequilibrium gating mechanism unique to CFTR. Surprisingly however, NPPB increased the activity of nonhydrolytic G551D-CFTR, the third most common disease-associated mutation. Here, we further investigated the mechanism of NPPB’s effects on CFTR gating by assessing its interaction with well-studied VX-770. Interestingly, once G551D-CFTR was maximally potentiated by VX-770, NPPB further increased its activity. However, quantitative analysis of this drug–drug interaction suggests that this pharmacologic synergism is not due to independent actions of NPPB and VX-770 on CFTR gating; instead, our data support a dependent mechanism involving two distinct binding sites. This latter idea is further supported by the observation that the locked-open time of a hydrolysis-deficient mutant K1250A was shortened by NPPB but prolonged by VX-770. In addition, the effectiveness of NPPB, but not of VX-770, was greatly diminished in a mutant whose second nucleotide-binding domain was completely removed. Interpreting these results under the framework of current understanding of CFTR gating not only reveals insights into the mechanism of action for different CFTR potentiators but also brings us one step forward to a more complete schematic for CFTR gating.

Weak opioid combined with acetaminophen (APAP) has been proven to provide better analgesic efficacy and cause fewer complications than either drug alone. However, there are questions about whether different opioids, tramadol and propoxyphene, provide similar efficacy or safety. Thus, we investigated Ultracet (37.5 mg tramadol/325 mg APAP) and Depain-X (65 mg propoxyphene/650 mg APAP). The primary aims of this study were to compare the analgesic efficacy and adverse effects of single-dose oral Ultracet versus Depain-X in acute postoperative pain.This was a randomized, open-label, active-controlled parallel study on patients with postsurgical pain. Sixty patients who sustained moderate postsurgical pain (visual analog scale(3)3 cm) after undergoing implantation of venous access were randomized to two groups to receive either Ultracetor Depain-X for postoperative analgesia. Assessment items included pain intensity and pain relief ratings at the first 4 hours, and adverse events.There were initially 107 patients who were enrolled in this trial, but up to 45 (42.1%) of them were withdrawn during the study. In these 62 patients who complied with treatment (Ultracet: Depain-X = 29: 33), pain relief scale indicated that Ultracet could provide a better analgesic effect than Depain-X provided at 1 hour (p0.05). At 4 hours, the pain score in the Ultracet group was significantly lower than that in the Depain-X group (p0.05). Adverse events, such as drowsiness, dizziness, and skin itching did not differ in both groups.Among patients with mild to moderate postoperative wound pain, single-dose Ultracet can provide slightly better analgesic efficacy than Depain-X in terms of onset and duration. Depain-X is no longer marketed in Europe, America, Taiwan and other countries, therefore, Ultracet can serve as a good substitute for treating postoperative pain.

Previous research has shown that people use warmth and competence as basic dimensions to evaluate others and to interpret their behavior, but little research has examined the conditions under which low-warmth targets are liked. A series of 3 experiments involving 4 vignettes showed, in general, that low-warmth targets were better liked when they exhibited higher competence and that high-status persons displayed greater tolerance toward the low-warmth person of low status. Exceptions to these patterns were predicted and found as a function of the type of organizational context in which evaluations were made: groups that place priority on individual goals over common goals and groups that are performance oriented rather than relationship oriented. Target gender interacted with competence and relative status.

Authors' previous research demonstrated the existence of Post hoc Explanation Bias, which is contrary to scientific thinking People did not prefer predictions to post hoc explanations. If this thinking bias reflects primitive "Search- ing for Explanation" mental set, the authors hypothesized that based on this mental set, people may emphasize on plausibility of every individual explanation than the existence of alternative explanations. This in turn generated the second hypothesis, that the attention on plausibility may lead to the neglect of the contradiction of existing explanations and induce local coherence. Two experiments were designed to test these hypotheses. In Experiment 1, 228 college students were asked to indicate to what degree they thought the explanation presented after each unusual event was acceptable. Results are consis- tent with the plausibility hypothesis: (1) participants demonstrated less acceptance of the explanation offered if he had own explanation; (2) the number of alternative explanations had no effect on participants' acceptance of the particular explana- tion offered. In Experiment 2, 284 college students were asked to evaluate the probability that an explanation was true (Argument A) in one story and the feasibility of a suggestion (Argument ~A) in the other. The result evidently supports the local coherence hypothesis.

Objectives/Hypothesis: To assess if relocation pharyngoplasty (RP) causes velopharyngeal dysfunction in patients with obstructive sleep apnea (OSA) by evaluating perioperative nasalance, nasality, voice, and articulation. Study Design: Prospective, comparative study. Methods: Twenty-four OSA patients selected for RP (two women and 22 men; mean age, 35 years) were enrolled for the study of velopharyngeal function in speech. The RP procedure involved removal of supratonsillar adipose tissue, preservation of all palatal muscular structure, splinting the lateral pharyngeal wall, and anterior advancing of the soft palate. Measurements of nasalance (vowel /a/, /i/, consonant /m/, oronasal, oral, and nasal texts), nasality (mirror-fogging test, degree of nasality, Gutzmann test and Bzoch hypernasality test), voice (acoustic analysis), and articulation (velar sound) were taken before RP and 3 months after the procedure and compared. Results: Comparative analysis of clinical measures showed that no significant differences were found following RP in nasalance (except for the vowel /a/), nasality, articulation, and voice. The only difference with regard to vowel /a/ showed, instead of an increase, a significant decrease of nasalance from 17.3 ± 10.8 to 11.3 ± 6.7 (P = .004), which may be attributed to the advancing and lifting of the soft palate in RP, leading to relaxation of the levator veli palatine and uvular muscles, which facilitates their contraction in velopharyngeal closure during particular vowel phonation. Conclusions: RP for OSA does not cause velopharyngeal insufficiency in terms of voice, nasality, and articulation in spite of anterior advancement of the soft palate, but does induce a nondetrimental change in nasalance. Laryngoscope, 2010

Evidence shows that the gamma coefficient (Goodman & Kruskal, 1954) as a measure of association between two classifications either overestimated or underestimated the degree of association in the 2 × 2 case in most situations, underestimated the degree in the m × 2 (m > 2) case, and was subject to restricted-range and fineness/coarseness effects. This study is to treat the degree of association as the extent to which the percentage of observations falling into a class on one classification can be increased by an increase from one class to another on the other classification. A statistic computing the relative magnitude of the percentage increase to its maximal increase, designated as Cp , is ideal for measuring the degree without being contaminated by other factors. Moreover, the value of Cp is accurate and stable across different portions of classification data and free from restricted-range and fineness/coarseness effects.

This study investigated how shallow processing (complexity rating), deep processing (pleasantness rating), and semantic generation (translating from English) of Chinese words affects conscious memory (CM) and unconscious memory (UM) of the words with three implicit tests: word association, word identification, and word-stem completion. A metacognition-based dissociation procedure was used to estimate the two forms of memory for each test. Except for the shallow condition preceding the word-association test, all three study conditions produced a positive effect on the estimate of CM. The estimate of UM did not benefit from any of the study conditions in the word-association test, it benefited from the shallow and deep conditions but did not benefit from the generation condition in the stem-completion test, and it benefited from the shallow condition but did not benefit from the deep and generation conditions in the word-identification test. Implications of these results for CM and UM operations are discussed.

Background: Gabapentin (GBP) is known to suppress neuropathic hypersensitivity of primary afferents and the spinal cord dorsal horn. However, its supra-spinal action sites are unclear. We identify the brain regions where GBP changes the brain glucose metabolic rate at the effective dose that alleviates mechanical allodynia using 18 F-fluorodeoxyglucose-positron emission tomography (FDG-PET) scanning. Results: Comparing the PET imaging data before and after the GBP treatment, the spared nerve injury-induced increases of glucose metabolism in the thalamus and cerebellar vermis were reversed, and a significant decrease occurred in glucose metabolism in the medial prefrontal cortex (mPFC), including the anterior cingulate cortex. GBP treatment also reversed post-SNI connectivity increases between limbic cortices and thalamus. Conclusions: Our results indicate that GBP analgesic effect may be mediated by reversing central hypersensitivity, and suppressing mPFC, a crucial part of the cortical representation of pain, in the brain.