Flavopiridol causes cell cycle inhibition and demonstrates anti-cancer activity in anaplastic thyroid cancer models.

Anaplastic thyroid cancer (ATC) is a rare, but nearly uniformly fatal disease that is typically resistant to chemotherapy and radiation. Alternative strategies to target this cancer at a molecular level are necessary in order to improve dismal outcomes for ATC patients. We examined the effects of flavopiridol, a CDK inhibitor, in a panel of ATC cell lines. When cell lines were treated over a ten-point concentration range, CAL62, KMH2 and BHT-101 cell lines had a sub micromolar half-maximal inhibitory concentration, while no effect was seen in the non-cancerous cell line IMR-90. Flavopiridol treatment resulted in decreased levels of the cell cycle proteins CDK9 and MCL1, and induced cell cycle arrest. Flavopiridol also decreased the in vitro ability of ATC cells to form colonies and impeded migration using a transwell migration assay. In vivo, flavopiridol decreased tumor weight and tumor volume over time in a patient-derived xenograft model of ATC. Given the observed in vitro and in vivo activity, flavopiridol warrants further investigation for treatment of ATC.

Reduced frontal-subcortical white matter connectivity in association with suicidal ideation in major depressive disorder.

Major depressive disorder (MDD) and suicidal behavior have been associated with structural and functional changes in the brain. However, little is known regarding alterations of brain networks in MDD patients with suicidal ideation. We investigated whether or not MDD patients with suicidal ideation have different topological organizations of white matter networks compared with MDD patients without suicidal ideation. Participants consisted of 24 patients with MDD and suicidal ideation, 25 age- and gender-matched MDD patients without suicidal ideation and 31 healthy subjects. A network-based statistics (NBS) and a graph theoretical analysis were performed to assess differences in the inter-regional connectivity. Diffusion tensor imaging (DTI) was performed to assess topological changes according to suicidal ideation in MDD patients. The Scale for Suicide Ideation (SSI) and the Korean version of the Barrett Impulsiveness Scale (BIS) were used to assess the severity of suicidal ideation and impulsivity, respectively. Reduced structural connectivity in a characterized subnetwork was found in patients with MDD and suicidal ideation by utilizing NBS analysis. The subnetwork included the regions of the frontosubcortical circuits and the regions involved in executive function in the left hemisphere (rostral middle frontal, pallidum, superior parietal, frontal pole, caudate, putamen and thalamus). The graph theoretical analysis demonstrated that network measures of the left rostral middle frontal had a significant positive correlation with severity of SSI (r=0.59, P=0.02) and BIS (r=0.59, P=0.01). The total edge strength that was significantly associated with suicidal ideation did not differ between MDD patients without suicidal ideation and healthy subjects. Our findings suggest that the reduced frontosubcortical circuit of structural connectivity, which includes regions associated with executive function and impulsivity, appears to have a role in the emergence of suicidal ideation in MDD patients.

A genome-wide association study of antidepressant response in Koreans.

We conducted a three-stage genome-wide association study (GWAS) of response to antidepressant drugs in an ethnically homogeneous sample of Korean patients in untreated episodes of nonpsychotic unipolar depression, mostly of mature onset. Strict quality control was maintained in case selection, diagnosis, verification of adherence and outcome assessments. Analyzed cases completed 6 weeks of treatment with adequate plasma drug concentrations. The overall successful completion rate was 85.5%. Four candidate single-nucleotide polymorphisms (SNPs) on three chromosomes were identified by genome-wide search in the discovery sample of 481 patients who received one of four allowed selective serotonin reuptake inhibitor (SSRI) antidepressant drugs (Stage 1). In a focused replication study of 230 SSRI-treated patients, two of these four SNP candidates were confirmed (Stage 2). Analysis of the Stage 1 and Stage 2 samples combined (n = 711) revealed GWAS significance (P = 1.60 × 10(-8)) for these two SNP candidates, which were in perfect linkage disequilibrium. These two significant SNPs were confirmed also in a focused cross-replication study of 159 patients treated with the non-SSRI antidepressant drug mirtazapine (Stage 3). Analysis of the Stage 1, Stage 2 and Stage 3 samples combined (n = 870) also revealed GWAS significance for these two SNPs, which was sustained after controlling for gender, age, number of previous episodes, age at onset and baseline severity (P = 3.57 × 10(-8)). For each SNP, the response rate decreased (odds ratio=0.31, 95% confidence interval: 0.20-0.47) as a function of the number of minor alleles (non-response alleles). The two SNPs significantly associated with antidepressant response are rs7785360 and rs12698828 of the AUTS2 gene, located on chromosome 7 in 7q11.22. This gene has multiple known linkages to human psychological functions and neurobehavioral disorders. Rigorous replication efforts in other ethnic populations are recommended.

Factors influencing dental students' specialty choice: a survey of ten graduating classes at one institution.

The aim of this study was to survey ten graduating classes at Harvard School of Dental Medicine regarding students' specialty choice and factors influencing that choice. Students were surveyed once in 2008 (for the Classes of 2007-11) and again in 2013 (for the Classes of 2012-16). A prior article reported results regarding students' interest in and experiences with prosthodontics; this article presents results regarding their interest in all dental specialties and factors influencing those interests. Of a total 176 students in the Classes of 2012-16, 143 responded to the survey, for a response rate of 81%, compared to a 95% response rate (167 of total 176 students) for the Classes of 2007-11. The results showed that orthodontics was the most popular specialty choice, followed by oral and maxillofacial surgery. From the 2008 to the 2013 survey groups, there was an increase in the percentages of students planning to pursue oral and maxillofacial surgery, pediatric dentistry, and postdoctoral general dentistry. The educational debt these students expected to accrue by graduation also increased. The largest percentage of students chose "enjoyment of providing the specialty service" as the factor most influencing their specialty choice. "Prior dental school experience" and "faculty influence" were greater influences for students pursuing specialties than those pursuing postdoctoral general dentistry. Increased interest in particular disciplines may be driven by high debt burdens students face upon graduation. Factors related to mentoring especially influenced students pursuing specialties, demonstrating the importance of student experiences outside direct patient care for exposure to the work of specialists beyond the scope of predoctoral training. This finding suggests that dental schools should increase mentoring efforts to help students make career decisions based not on financial burden but rather on personal interest in the specialty, which is likely to have a more satisfying result for them in the long run.

Association of the choline acetyltransferase gene with responsiveness to acetylcholinesterase inhibitors in Alzheimer's disease.

INTRODUCTION: The response to acetylcholinesterase inhibitors (AChEIs) of Alzheimer's disease (AD) patients varies depending on the genetic characteristics of the patient. We have examined the association of response to AChEIs and genetic polymorphisms in AD patients. METHODS: 158 patients with AD underwent treatment with AChEIs, and the therapeutic effect was assessed with the Korean version of the Mini Mental State Examination (K-MMSE). The association of 25 SNPs located in 3 genes (CHAT, CHT and ACHE) with changes in the K-MMSE score was analyzed. RESULTS: The response to AChEIs in AD patients was significantly associated with 2 SNPs on the intronic region of CHAT rs2177370 (uncorrected P=0.0025, FDR controlled P=0.026) and rs3793790 (uncorrected P=0.0024, FDR controlled P=0.026). CONCLUSION: The results of our study confirmed again that genetic polymorphism of CHAT has an influence on drug response in AD.

Dental students' perceptions of and experiences with prosthodontics: ten graduating classes at one institution.

It is important for members of the dental specialties to understand what motivates students to enter the specialty in order to ensure its continuing development and ability to meet patient needs. The aim of this study was to compare ten graduating classes at Harvard School of Dental Medicine (HSDM) regarding students' experiences with and perceptions of prosthodontics and factors influencing those interested in pursuing prosthodontics as a specialty. In 2013, HSDM students in the classes of 2012-16 were surveyed, achieving a response rate of 81%. Survey questions sought information regarding specialty choice, factors influencing the choice, student experiences with prosthodontics, and student perceptions of the dental disciplines. Responses were compared to those from a prior study of the HSDM classes of 2007-11. The responses showed a decrease in negative student experiences with prosthodontics. The students regarded prosthodontics highly for its impact on patient quality of life; however, students interested in pursuing prosthodontics as a specialty decreased. All students said provider enjoyment was most important in choice of specialty. Cost of program, patient type, and program location were factors that especially influenced students interested in prosthodontics. The improved student experiences with and perspectives on prosthodontics may be a result of a curriculum change that led to more prosthodontics procedures and case completions by students. The fall in students interested in prosthodontics may have resulted from prosthodontic faculty transitions that occurred when the survey was conducted, as well as large debt burdens in spite of the fact that prosthodontists' earnings are among the highest in dentistry. Faculty must educate and mentor students about the realities of the profession, provide positive learning experiences in the field, and encourage students who enjoy prosthodontics to pursue specialty training.

Pediatric tracheostomy revisited: a nine-year experience using horizontal intercartilaginous incision.

OBJECTIVES/HYPOTHESIS: To describe our tracheostomy procedure using a vertical skin incision and a horizontal intercartilaginous incision and to compare our postoperative results with those in the recent literature. STUDY DESIGN: Retrospective chart review and literature review. METHODS: One hundred eleven children underwent tracheostomy using a vertical skin incision and a horizontal intercartilaginous incision over a 9-year period. A retrospective chart review was undertaken with respect to the following variables: demographics, weight, primary diagnosis, surgical indication, follow-up duration, decannulation, interval between tracheostomy and decannulation, and complications experienced. In addition, the outcomes were compared to results from a literature review. RESULTS: Of the 111 patients, 56 had a history of prolonged intubation, 52 had upper airway obstruction, and three underwent tracheostomy for tracheobronchial toileting. Three (2.7%) patients experienced early major complications without major sequelae, and 14 (12.6%) experienced late major complications. Twenty-one (18.9%) patients were decannulated during the follow-up period, whereas 17 (17.8%) died of their primary disease or tracheostomy-related complications (15 died of their primary disease and two died of tracheostomy-related complications). The complication rates showed overall no differences, but our patient series showed significantly less stomal granulation tissue formation and non-significant trend for less suprastomal collapse as compared with previous literature. CONCLUSIONS: Pediatric tracheostomy using a vertical skin incision and horizontal intercartilaginous incision is comparable with the conventional procedure in terms of complication and mortality rates. Future randomized controlled studies are mandatory to directly compare conventional tracheotomy using a vertical skin incision and a horizontal intercartilaginous incision with our procedure. LEVEL OF EVIDENCE: 4.

Therapeutic drug monitoring of mirtazapine in a routine outpatient setting in Asian psychiatric patients.

INTRODUCTION: Mirtazapine is an antidepressant that acts by enhancing serotonergic and noradrenergic neurotransmission. This study aimed to evaluate mirtazapine pharmacokinetic data from Korean psychiatric patients and to identify the potential factors affecting its steady-state concentration. METHODS: A total of 337 samples of steady-state mirtazapine concentrations from 188 adult psychiatric outpatients were retrospectively evaluated. Serum mirtazapine concentrations were measured by high-performance liquid chromatography-tandem mass spectrometry. RESULTS: Median mirtazapine concentration was 43.6 µg/L (164.37 nmol) at a daily dosage range of 7.5-60 mg. At the steady state, mirtazapine dose had a positive correlation with the drug concentration. Mean concentration-to-dose (C/D) ratio was 1.48 µg/L/mg/day (5.58 nmol/mg/day), which was higher than that in a previous study in Caucasian subjects. Age and paroxetine co-medication were positively associated with C/D ratio. Initial mirtazapine concentration and C/D ratio did not show an association with responsiveness in depressive patients. DISCUSSION: This study presented the therapeutic drug monitoring data for mirtazapine and pharmacokinetic variations of mirtazapine in an Asian population. A further study could be helpful for clinical decision making based on the characteristics of patients.

Sterilization effect of atmospheric pressure non-thermal air plasma on dental instruments.

PURPOSE: Autoclaves and UV sterilizers have been commonly used to prevent cross-infections between dental patients and dental instruments or materials contaminated by saliva and blood. To develop a dental sterilizer which can sterilize most materials, such as metals, rubbers, and plastics, the sterilization effect of an atmospheric pressure non-thermal air plasma device was evaluated. MATERIALS AND METHODS: After inoculating E. coli and B. subtilis the diamond burs and polyvinyl siloxane materials were sterilized by exposing them to the plasma for different lengths of time (30, 60, 90, 120, 180 and, 240 seconds). The diamond burs and polyvinyl siloxane materials were immersed in PBS solutions, cultured on agar plates and quantified by counting the colony forming units. The data were analyzed using one-way ANOVA and significance was assessed by the LSD post hoc test (α=0.05). RESULTS: The device was effective in killing E. coli contained in the plasma device compared with the UV sterilizer. The atmospheric pressure non-thermal air plasma device contributed greatly to the sterilization of diamond burs and polyvinyl siloxane materials inoculated with E. coli and B. subtilis. Diamond burs and polyvinyl siloxane materials inoculated with E. coli was effective after 60 and 90 seconds. The diamond burs and polyvinyl siloxane materials inoculated with B. subtilis was effective after 120 and 180 seconds. CONCLUSION: The atmospheric pressure non-thermal air plasma device was effective in killing both E. coli and B. subtilis, and was more effective in killing E. coli than the UV sterilizer.

Sterilization effect of atmospheric pressure non-thermal air plasma on dental instruments

PURPOSE: Autoclaves and UV sterilizers have been commonly used to prevent cross-infections between dental patients and dental instruments or materials contaminated by saliva and blood. To develop a dental sterilizer which can sterilize most materials, such as metals, rubbers, and plastics, the sterilization effect of an atmospheric pressure non-thermal air plasma device was evaluated. MATERIALS AND METHODS: After inoculating E. coli and B. subtilis the diamond burs and polyvinyl siloxane materials were sterilized by exposing them to the plasma for different lengths of time (30, 60, 90, 120, 180 and, 240 seconds). The diamond burs and polyvinyl siloxane materials were immersed in PBS solutions, cultured on agar plates and quantified by counting the colony forming units. The data were analyzed using one-way ANOVA and significance was assessed by the LSD post hoc test (alpha=0.05). RESULTS: The device was effective in killing E. coli contained in the plasma device compared with the UV sterilizer. The atmospheric pressure non-thermal air plasma device contributed greatly to the sterilization of diamond burs and polyvinyl siloxane materials inoculated with E. coli and B. subtilis. Diamond burs and polyvinyl siloxane materials inoculated with E. coli was effective after 60 and 90 seconds. The diamond burs and polyvinyl siloxane materials inoculated with B. subtilis was effective after 120 and 180 seconds. CONCLUSION: The atmospheric pressure non-thermal air plasma device was effective in killing both E. coli and B. subtilis, and was more effective in killing E. coli than the UV sterilizer.

Anomalous waveforms observed in laboratory-formed gas hydrate-bearing and ice-bearing sediments.

Acoustic transmission measurements of compressional, P, and shear, S, wave velocities rely on correctly identifying the P- and S-body wave arrivals in the measured waveform. In cylindrical samples for which the sample is much longer than the acoustic wavelength, these body waves can be obscured by high-amplitude waveform features arriving just after the relatively small-amplitude P-body wave. In this study, a normal mode approach is used to analyze this type of waveform, observed in sediment containing gas hydrate or ice. This analysis extends an existing normal-mode waveform propagation theory by including the effects of the confining medium surrounding the sample, and provides guidelines for estimating S-wave velocities from waveforms containing multiple large-amplitude arrivals.

Comparison of initial stability parameters and histomorphometric analysis of implants inserted into extraction sockets: human fresh cadaver study.

PURPOSE: To evaluate the initial stability parameters (insertion torque value [ITV], implant stability quotient [ISQ], and Periotest value [PTV]) of implants inserted just after tooth extraction in human fresh cadavers and to examine the relationship between initial stability parameters and bone-to-implant contact ratio (BICR). MATERIALS AND METHODS: This study was undertaken in three fresh human cadavers, which were divided into six groups. A total of 48 sites (four maxillary sites and four mandibular sites in each of the six groups) were selected for the experiment. Extractions were performed under minimal surgical trauma and each manufacturer's recommended formal surgical procedure was followed to place implants. Initial stability parameters (ITV, ISQ via two different instruments, PTV) were measured. Specimens were prepared to analyze histologic findings and BICR. RESULTS: A total of 44 implants were included in this study. Statistically significant correlations were found between ITV and ISQ1 (r = 0.555, P < .001), ITV and ISQ2 (r = 0.398, P < .007), ITV and PTV (r = -0.452, P < .002), ISQ1 and ISQ2 (r = 0.603, P < .001), ISQ1 and PTV (r = -0.576, P < .001), and ISQ2 and PTV (r = -0.423, P < .004). No statically significant correlations were found between BICR and the initial stability parameters. CONCLUSION: The initial stability parameters have statistically significant correlations to each other. However, the initial stability parameters do not seem to present a reliable parameter to predict the area of bone-to-implant contact.

Full-length adiponectin protects hepatocytes from palmitate-induced apoptosis via inhibition of c-Jun NH2 terminal kinase.

Hepatic apoptosis is elevated in patients with non-alcoholic steatohepatitis and is correlated with the severity of the disease. Long-chain saturated fatty acids, such as palmitate, induce apoptosis in liver cells. The present study examined adiponectin-mediated protection against saturated fatty acid-induced apoptosis in the human hepatoma cell line, HepG2. Cells were cultured in a control media (i.e. without fatty acids) or the same media containing 250 micromol L(-1) of albumin-bound oleate or palmitate for 24 h. The adiponectin concentrations used were: 0, 1, 10 or 100 microg mL(-1) (n = 4-6 per treatment). Palmitate and thapsigargin, but not oleate, activated caspase-3 and decreased cell viability in the absence of adiponectin. Adiponectin reduced palmitate- and thapsigargin-induced activation of caspase-3 and cell death in a dose-dependent manner. Phosphatidylinositol 3-kinase and AMP-activated protein kinase inhibitors abolished the effects of adiponectin. Adiponectin-induced inhibition of palmitate- and thapsigargin-induced apoptosis was not the result of an augmentation in the unfolded protein response or the increased expression of genes encoding the inhibitor of apoptosis proteins, inhibitor of apoptosis protein-2 and X-linked mammalian inhibitor of apoptosis protein. Palmitate and thapsigargin, but not oleate, increased c-Jun NH(2) terminal kinase phosphorylation in the absence of adiponectin. Adiponectin blocked palmitate- and thapsigargin-induced activation of c-Jun NH(2) terminal kinase and reduced apoptosis. These data suggest that adiponectin is an important determinant of saturated fatty acid-induced apoptosis in liver cells and may have implications for fatty acid-mediated liver cell injury in adiponectin-deficient individuals.

Bispectral index values during sevoflurane-nitrous oxide general anesthesia in women undergoing cesarean delivery: a comparison between women with and without prior labor.

BACKGROUND: An end-tidal concentration of 1% sevoflurane (1% ET(SEVO)) in 50% nitrous oxide (N(2)O) during elective cesarean delivery has been associated with bispectral index (BIS) values >60, which are associated with an increased risk of awareness. We hypothesized that BIS values during sevoflurane-N(2)O general anesthesia for cesarean delivery would be lower in women with prior labor compared with women without prior labor. METHODS: Forty patients undergoing cesarean delivery were enrolled in this observational study. One group had urgent surgery after labor (labor group, n = 20) and the other had elective surgery without labor (control group, n = 20). General anesthesia was induced with thiopental 4 mg/kg, followed by succinylcholine 1.5 mg/kg, and maintained with 1% ET(SEVO) and 50% N(2)O in oxygen. BIS values, systolic arterial blood pressure, heart rate, plasma stress hormone concentrations, Apgar scores, and postoperative analgesia variables were assessed and compared between groups. RESULTS: BIS values during the period between intubation and delivery were lower in the labor group than in the control group (P < 0.001). Plasma norepinephrine concentrations increased at delivery compared with baseline in both groups. They were higher in the labor group than in the control group both at baseline and at delivery. Systolic arterial blood pressure, heart rate, Apgar scores, surgical characteristics, and plasma concentrations of vasopressin and cortisol were not different between groups. Postoperative visual analog scale pain scores were similar between groups, while the labor group consumed less analgesics (P < 0.01) during the first 24 h after the operation. CONCLUSIONS: Prior labor was associated with lower intraoperative BIS values during sevoflurane/N(2)O general anesthesia and reduced postoperative analgesic consumption in women undergoing cesarean delivery compared with women without prior labor.

Prognostic indicators of gastric carcinoma confined to the muscularis propria.

AIMS: Gastric carcinoma confined to the muscularis propria (MPGC) is considered an intermediate-stage carcinoma. A method of discriminating between more favourable and less favourable prognostic groups of this entity is critically needed in dealing with this heterogeneous disease. The aim of this study was to examine the correlation between survival of patients with MPGC and its various clinicopathological parameters. METHODS AND RESULTS: Various clinicopathological parameters were studied in 171 tissue samples including: macroscopic appearance, size, age, sex, stage, invasion depth, Lauren and Ming classifications, extent, lymphatic emboli and nodal metastasis. Tumours macroscopically resembling early gastric cancers, younger patient age, absence of lymphatic tumour emboli and lower stage were significantly associated with better prognosis of MPGC by univariate analysis. Tumours macroscopically resembling early gastric cancers, younger patient age and Lauren's diffuse type were significantly associated with a better prognosis of MPGC by multivariate analysis. CONCLUSIONS: These indicators are practical parameters for predicting patient prognosis in clinical practice. The description of these parameters should be carefully noted in the final report and pathologists should evaluate the macroscopic appearance of MPGC.

Retrofitting an existing implant overdenture to a new and redesigned intraoral framework: a clinical report.

The esthetics and function of a tissue borne, implant retained overdenture are two of the most important factors that define a patient's acceptance of the prosthesis. In this clinical report, an existing implant overdenture, which was esthetically acceptable to the patient but which had no incorporated retentive components in the substructure framework, was retrofitted to a newly designed and fabricated implant framework. The added retentive components on the new framework increased the patient's overall masticatory function, reduced the frequency of dental visits, and allowed the patient to retain the original overdenture.

A custom-fabricated device for chairside organization of multiple implant components.

Organizing multiple and varied implant components in preparation for providing treatment for a patient with a complex implant prosthesis can be a challenge to even the most experienced practitioner. The many implant abutment component options available, especially when different sizes and types of abutments will be used in 1 arch, can create confusion for both dentist and assistant, hindering chairside efficiency. This article describes the fabrication and use of a custom chairside implant components organizer.