Clinical experiences in conducting empirically supported treatments for generalized anxiety disorder.
Knowledge of the efficacy of cognitive-behavioral therapy (CBT) for generalized anxiety disorder (GAD) predominantly derives from randomized controlled trials (RCTs). However, there may be unique or complex issues encountered in practice, but not necessarily in the context of a controlled clinical trial. Therefore, launching a systematic dialogue between researcher and practicing clinician can be instrumental in augmenting evidence-based therapies through identification of variables that promote and interfere with clinical effectiveness. Through an initiative sponsored by the American Psychological Association's Divisions 12 (Society for Clinical Psychology) and 29 (Psychotherapy), this study aimed to examine clinical experiences conducting CBT for GAD. The participants were 260 psychotherapists who completed an online survey on assessment and therapeutic intervention utilization and their experience of factors that limit successful GAD treatment and symptom reduction. The majority of respondents reported 20 years or less experience using ESTs for GAD, typically treating clients in outpatient clinics, treatment centers, and private practice. Some of the most commonly used interventions address clients' maladaptive cognitions and elevated anxiety and muscle tension typical of GAD. Approximately one half of respondents reported incorporating integrative techniques into treatment. Factors perceived as limiting effective GAD treatment included severity and chronicity of GAD, presence of comorbid conditions, stressful home and work environments, client motivation and resistance to treatment, and issues encountered when executing therapy techniques. This study provides researchers with clinically derived directions for future empirical investigation into enhancing efficacy of GAD treatment.


Stretching the skin immediately enhances perceived stiffness and gradually enhances the predictive control of grip force.
When manipulating objects, we use kinesthetic and tactile information to form an internal representation of their mechanical properties for cognitive perception and for preventing their slippage using predictive control of grip force. A major challenge in understanding the dissociable contributions of tactile and kinesthetic information to perception and action is the natural coupling between them. Unlike previous studies that addressed this question either by focusing on impaired sensory processing in patients or using local anesthesia, we used a behavioral study with a programmable mechatronic device that stretches the skin of the fingertips to address this issue in the intact sensorimotor system. We found that artificial skin-stretch increases the predictive grip force modulation in anticipation of the load force. Moreover, the stretch causes an immediate illusion of touching a harder object that does not depend on the gradual development of the predictive modulation of grip force.


Transcriptional expression of survivin and its splice variants in brain tumors in humans.
Survivin, one of the apoptosis inhibitor proteins, has been detected in most cancers in humans. In addition, two splice variants (survivin-2B and survivin-deltaEx3) have been identified. The authors investigated the transcription levels of survivin messenger (m)RNA and its splice variants in nine tumor cell lines, including gliomas, and in 25 brain tumor samples, by performing quantitative reverse transcription-polymerase chain reaction. The correlation between transcript expression levels and pathological findings were also analyzed. Transcription levels were measured using primer pairs specific for survivin and either of its splice variants and were normalized to the glyceraldehyde 6-phosphate dehydrogenase. Among the tumor cell lines tested, glioblastoma cell lines showed the highest levels of survivin expression. Among brain tumor samples studied, survivin was preferentially expressed in malignant brain tumors and gliomas. The relative expression level of survivin-deltaEx3/survivin was significantly higher in malignant than in benign brain tumor samples. Expression patterns were dominant for survivin-deltaEx3 in malignant brain tumors and dominant for survivin-2B in benign ones. A significant linear correlation between survivin mRNA expression and MIB-1 labeling index was demonstrated in all brain tumor samples. The authors' results indicate that quantifying the levels of survivin and its splice variants is useful for the prediction of the cell biological malignancy of gliomas, independent of their pathological features.


Total Synthesis and Stereochemical Assignment of Streptide.
Streptide (1) is a peptide-derived macrocyclic natural product that has attracted considerable attention since its discovery in 2015. It contains an unprecedented post-translational modification that intramolecularly links the β-carbon (C3) of a residue 2 lysine with the C7 of a residue 6 tryptophan, thereby forming a 20-membered cyclic peptide. Herein, we report the first total synthesis of streptide that confirms the regiochemistry of the lysine-tryptophan cross-link and provides an unambiguous assignment of the stereochemistry (3R vs 3S) of the lysine-2 C3 center. Both the 3R and the originally assigned 3S lysine diastereomers were independently prepared by total synthesis, and it is the former, not the latter, that was found to correlate with the natural product. The approach enlists a powerful Pd(0)-mediated indole annulation for the key macrocyclization of the complex core peptide, utilizes an underdeveloped class of hypervalent iodine(III) aryl substrates in a palladium-catalyzed C-H activation/β-arylation reaction conducted on a lysine derivative, and provides access to material with which the role of streptide and related natural products may be examined.


[Judicial aspects of treatment of incompetent psychiatric patients who categorically refuse treatment].
Psychiatrists in particular face a clinical, legal and social dilemma in treating their patients who are likely to categorically oppose treatment. This article illustrates this dilemma in the context of Quebec's Bill 145, resulting in the care of psychiatric patients being increasingly referred to the courts. After presenting this legislation and a case, the authors illustrate the impact of this legislation in light of their own experience and similar legislation in the United States. The mechanisms proposed by Bill 145 have proved costly in several respects as well as cumbersome and ineffective. The authors propose the establishment of an administrative tribunal as an alternative to the current recourse to the courts.


Effects of let-7c on the proliferation of ovarian carcinoma cells by targeted regulation of CDC25a gene expression.
MicroRNAs serve a role in the development of ovarian cancer (OC). The present study investigated whether let-7c is able to regulate the proliferation of OC cells by targeting cell division cycle 25A (CDC25a). The reverse transcription-quantitative polymerase chain reaction was performed to detect the expression of let-7c in OC specimens. Let-7c agomir was transfected into OC cells, and the proliferation and apoptosis of OC cells were detected. A dual-luciferase assay and western blotting were performed to analyze whether CDC25a was the target gene of let-7c as well as its interaction site. The results revealed that, in OC tissue, let-7c was downregulated when compared with normal ovarian tissue. A Cell Counting Kit-8 (CCK8) assay, colony formation assay and flow cytometry demonstrated that increased expression of let-7c was able to inhibit the proliferation and increase the apoptosis of OC cells. Western blotting revealed that upregulated let-7c is able to decrease the expression of CDC25a, and a dual-luciferase assay and a recovery assay demonstrated that let-7c was able to regulate the expression of the 3' untranslated region of CDC25a. Therefore, the roles of let-7c in inhibiting the proliferation and promoting the apoptosis of OC cells may be realized through the regulation of the expression of CDC25a. The results of the present study revealed that let-7c may be a novel target in the diagnosis and treatment of OC.


[Local blood flow into tumors during artificial hyperglycemia].
The blood flow in the rat Guerin carcinoma was measured by the hydrogen clearance method. It was shown that the blood flow in the tumour tissue decreased almost 3.5 times to the 3 hours of the intravenous glucose infusion at a dose of 80 mg X kg-1 X min-1. In some tumours the microcirculation ceased completely. The results obtained help developing the new schemes of local hyperthermia and induced hyperglycemia in the complex antitumour therapy.


Helicobacter pylori eradication rates of concomitant and sequential therapies in Korea.
The efficacy of the standard triple therapy for Helicobacter pylori eradication has decreased to an unacceptable level. We aimed to compare the efficacy of sequential and concomitant therapies as for the first-line treatments for H. pylori eradication and analyzed the effect of clarithromycin resistance on the eradication rates. Four hundred and seventy-eight patients with H. pylori infection were randomly assigned to either concomitant therapy (amoxicillin 1000 mg with clarithromycin 500 mg, metronidazole 500 mg, and pantoprazole 40 mg twice daily for 10 days) or sequential therapy (amoxicillin 1000 mg with pantoprazole 40 mg twice daily for 5 days, followed by clarithromycin 500 mg with metronidazole 500 mg and pantoprazole 40 mg twice daily for 5 days). The success of the eradication was evaluated 4-5 weeks after treatment completion. To evaluate the efficacy of the two regimens according to clarithromycin sensitivity, dual-priming oligonucleotide-based multiplex-polymerase chain reaction was also performed in the final third of the enrolled study populations. The eradication rates with concomitant or sequential therapy were 81.9% and 76.6% (P = .153) in intention-to-treat analysis, and 93.4% and 84.8% (P = .004) in per-protocol analysis, respectively. Among the 156 patients for whom dual-priming oligonucleotide-based multiplex-polymerase chain reaction was performed, 17.9% were clarithromycin resistant, and the efficacy of concomitant therapy was better than sequential therapy in the clarithromycin-resistant strains (100% vs 58.3%, P = .010). Concomitant therapy was superior to sequential therapy as the first-line treatment for H. pylori eradication, especially in clarithromycin-resistant strains in Korea.


[Prevention and control of substance abuse in the workplace: a new and significant opportunity for the occupational physician].
Substance abuse is nowadays a recurrent theme in the daily practice of occupational physicians (OP), mainly owing to recent legislation prescribing mandatory assessments for workers performing job tasks involving danger to third parties. While some degree of bureaucracy is inevitable and legislation seems to be inclined towards deterrence, it is recommended to take advantage of the opportunities offered for practical interventions which, in accordance with science and ethics, the OP can carry out in the workplace. Risk assessment, health surveillance, fitness for work, health promotion and cooperation in management issues are the areas of intervention required for the OP to fully accomplish his role in the practice of modern occupational health. We propose specific activities for the OP so as to highlight roles and obligations, based on available scientific evidence and established codes of ethics. Lastly, we wish to emphasize the overall role of the OP in taking on responsibilities shared jointly with all the parties and in the approach to the substance abuse problem in all workplaces with the ultimate goal of acting for the benefit of workers, enterprises and society in general.


Bioassisted capture and release of nanoparticles on nanolithographed ZnO films.
Using an artificial peptide library, we have identified a peptide that has strict selective affinity for ZnO surfaces. The binding affinity of the peptide on the ZnO surface can be controlled simply through changes in phosphate concentration at constant pH and temperature. In this study, we functionalized inorganic nanoparticles by orderly conjugating ZnO-binding peptides (ZnOBPs) on the surface of cadmium selenide (CdSe) nanoparticles and performed spontaneous and reversible nanopatterning of ZnOBP-displayed nanoparticles on lithographed ZnO films. Conjugation of ZnOBPs on CdSe nanoparticles caused spontaneous adsorption of the nanoparticles on a ZnO film, and fluorescence and cathodoluminescence images clearly showed specific adsorption of nanoparticles on the ZnO films lithographed on nano- and micrometer scales. The selectively bound nanoparticles on ZnO films were completely released by changing the phosphate concentration in solution; such release did not require heat or mechanical applications. Repeated capture and release of nanoparticles were achieved on the micrometer scale. Our results show the potential of material-binding peptides for nanopatterning and dynamic microarrays.


Identification of a common 6-pyruvoyl-tetrahydropterin synthase mutation at codon 87 in Chinese phenylketonuria caused by tetrahydrobiopterin synthesis deficiency.
Deficiency in 6-pyruvoyl-tetrahydropterin synthase (PTPS) activity is the major cause of tetrahydrobiopterin (BH4)-deficient phenylketonuria. Two single base alterations of PTPS cDNA, a C-to-T transition at nucleotide 259 and a novel A-to-G transition at nucleotide 155 (according to cDNA sequence), were identified in two Chinese PTPS-deficient siblings by the reverse transcription-polymerase chain reaction (RT-PCR). The C-to-T transition at nucleotide 259 results in an amino acid change from proline to serine at codon 87 (Pro87Ser), and the A-to-G transition at nucleotide 155 causes an amino acid change from asparagine to serine at codon 52 (Asn52Ser) of PTPS. The C259T missense mutation can be identified by analysis of the BbvI restriction fragments of the PCR-amplified PTPS cDNA product, and was found to account for 42% (11/26) of 26 Chinese PTPS mutant alleles studied. However, none of 100 normal alleles screened were found to have this change. This result indicates that the C259T transition may be a common mutation in Chinese PTPS-deficient patients.


The effects of long haul transport on pregnant, non-lactating dairy cows.
The transport of dairy cows from the North to the South Island of New Zealand has been common in recent years. The aims of this study were to determine the serum biochemical and bodyweight responses of cows to such a journey, and to investigate the effects of pre-transport hay feeding. Pregnant, non-lactating Jersey cows from two herds were transported by road (1196 km) and ferry (5 hours) over a 3-4 day period. Cows in each herd were allocated to three 4-day pre-transport feeding treatments (grass only, grass + hay, 3 days of grass then 1 day of hay). Twelve experimental cows selected from each treatment group were weighed and blood sampled before transport, on arrival, and 24 and 48 hours after arrival. Additional blood samples were collected from experimental animals in one herd before and after one of the overnight rest stops during the journey. Sera were analysed for serum betahydroxybutyrate, total protein, calcium and magnesium concentrations and creatine kinase (CK) activity. Cow bodyweights declined by 6 9% during the journey and although they increased after arrival, they were still lower (p<0.001) than pre-transport values 48 hours after arrival. Serum magnesium fell (p<0.001) from pretransport concentrations of 0.95 mmol/l (Herd 1) and 0.83 mmol/l (Herd 2) to mean values of 0.50 mmol/l for both herds after transport. Total protein and CK concentrations increased during the first day of transport in Herd 2 cows, but then declined during the subsequent overnight rest stop. Pre-transport feeding treatments did not consistently affect cow bodyweight or blood biochemical responses to transport. Transported cows benefited from overnight rest, feeding and watering in terms of hydration and muscle status, but bodyweight and serum magnesium concentrations were significantly reduced by the overall journey, emphasising the requirement for suitable mineral supplementation and careful feeding and selection of pregnant cows before long-haul transport.


Passive immunization with an extended half-life monoclonal antibody protects Rhesus macaques against aerosolized ricin toxin.
Inhalation of ricin toxin (RT), a Category B biothreat agent, provokes an acute respiratory distress syndrome marked by pro-inflammatory cytokine and chemokine production, neutrophilic exudate, and pulmonary edema. The severity of RT exposure is attributed to the tropism of the toxin's B subunit (RTB) for alveolar macrophages and airway epithelial cells, coupled with the extraordinarily potent ribosome-inactivating properties of the toxin's enzymatic subunit (RTA). While there are currently no vaccines or treatments approved to prevent RT intoxication, we recently described a humanized anti-RTA IgG1 MAb, huPB10, that was able to rescue non-human primates (NHPs) from lethal dose RT aerosol challenge if administered by intravenous (IV) infusion within hours of toxin exposure. We have now engineered an extended serum half-life variant of that MAb, huPB10-LS, and evaluated it as a pre-exposure prophylactic. Five Rhesus macaques that received a single intravenous infusion (25 mg/kg) of huPB10-LS survived a lethal dose aerosol RT challenge 28 days later, whereas three control animals succumbed to RT intoxication within 48 h. The huPB10-LS treated animals remained clinically normal in the hours and days following toxin insult, suggesting that pre-existing antibody levels were sufficient to neutralize RT locally. Moreover, pro-inflammatory markers in sera and BAL fluids collected 24 h following RT challenge were significantly dampened in huPB10-LS treated animals, as compared to controls. Finally, we found that all five surviving animals, within days after RT exposure, had anti-RT serum IgG titers against epitopes other than huPB10-LS, indicative of active immunization by residual RT and/or RT-immune complexes.


Multiplanar functional imaging of the larynx and hypopharynx with multislice spiral CT.
The purpose of this study is to evaluate multislice spiral CT (MSCT) in multiplanar functional imaging of the larynx and hypopharynx and to define the optimal image planes for the delineation of the tumor and specific anatomical structures. Forty patients with suspected tumors of the larynx or hypopharynx were examined with MSCT during quiet breathing (QB), E-phonation (EP) and modified Valsalva maneuver (VM). Images were read in the axial, coronal and sagittal planes. Overall image quality, delineation of the tumor and anatomic structures for different conditions and orientations were graded using a three-point scale; the conditional permutation test was applied to detect quality differences. Differences between image types were statistically significant. The axial plane was superior in overall image quality and the delineation of the tumor, pyriform sinus, vocal cords and fat within the parapharyngeal/visceral space. The coronal plane was best for delineating the ventricle and the paraglottic space, the sagittal plane for the retropharyngeal and the preepiglottic space. For tumor detection, sensitivity, specificity and accuracy were 0.92, 1.0 and 0.93 for QB.ax, 0.94, 0.8 and 0.92 for EP.ax and 0.85, 1.0 and 0.87 for VM.ax, respectively. Examination during QB should be the standard procedure; additional scanning with EP improved tumor assessment.


Treating metastatic solid tumors with bortezomib and a tumor necrosis factor-related apoptosis-inducing ligand receptor agonist antibody.
Resistance of tumors to cell death signals poses a complex clinical problem. We explored the therapeutic potential and in vivo toxicity of a combination of bortezomib, a proteasome inhibitor, and MD5-1, a tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor (DR5) agonist monoclonal antibody, in mouse carcinomas. METHODS; Mice bearing Renca-FLAG (renal) or 4T1 (mammary) tumors were treated with bortezomib and/or MD5-1 and examined for lung metastases (Renca-FLAG: n = 93; 4T1: n = 40) or monitored for survival (Renca-FLAG: n = 143). Toxicity was assessed by histopathology and hematology. Viability and apoptotic signaling in Renca-FLAG and 4T1 cells treated with bortezomib alone or in combination with TRAIL were analyzed using 3-[4,5-dimethyiazol-2-yl-5]-[3-carboxymethyloxyphenyl]-2-[4-sulfophenyl]-2H tetrazolium assay and by measuring mitochondrial membrane depolarization and caspase-8 and caspase-3 activation. All statistical tests were two-sided. Bortezomib (20 nM) sensitized Renca-FLAG and 4T1 cells to TRAIL-mediated apoptosis (mean percent decrease in numbers of viable cells, bortezomib + TRAIL vs TRAIL: Renca-FLAG, 95% vs 34%, difference = 61%, 95% confidence interval [CI] = 52% to 69%, P < .001; 4T1, 85% vs 20%, difference = 65%, 95% CI = 62% to 69%, P < .001). Sensitization involved activation of caspase-8 and caspase-3 but not mitochondrial membrane depolarization, suggesting an amplified signaling of the extrinsic cell death pathway. Treatment with bortezomib and MD5-1 reduced lung metastases in mice carrying Renca and 4T1 tumors (mean number of metastases, bortezomib + MD5-1 vs MD5-1: Renca-FLAG, 1 vs 8, difference = 7, 95% CI = 5 to 9, P < .001; 4T1, 1 vs 12, difference = 11, 95% CI = 9 to 12, P < .001) and increased median survival of mice bearing Renca-FLAG tumors (bortezomib + MD5-1 vs bortezomib + control isotype antibody: 22 of 30 [73%] were still alive at day 180 vs median survival of 42 days [95% CI = 41 to 44 days, P < .001]) in the absence of obvious toxicity. Bortezomib combined with DR5 agonist monoclonal antibody may be a useful treatment for metastatic solid tumors.


Deep Supervised Learning Using Local Errors.
Error backpropagation is a highly effective mechanism for learning high-quality hierarchical features in deep networks. Updating the features or weights in one layer, however, requires waiting for the propagation of error signals from higher layers. Learning using delayed and non-local errors makes it hard to reconcile backpropagation with the learning mechanisms observed in biological neural networks as it requires the neurons to maintain a memory of the input long enough until the higher-layer errors arrive. In this paper, we propose an alternative learning mechanism where errors are generated locally in each layer using fixed, random auxiliary classifiers. Lower layers could thus be trained independently of higher layers and training could either proceed layer by layer, or simultaneously in all layers using local error information. We address biological plausibility concerns such as weight symmetry requirements and show that the proposed learning mechanism based on fixed, broad, and random tuning of each neuron to the classification categories outperforms the biologically-motivated feedback alignment learning technique on the CIFAR10 dataset, approaching the performance of standard backpropagation. Our approach highlights a potential biological mechanism for the supervised, or task-dependent, learning of feature hierarchies. In addition, we show that it is well suited for learning deep networks in custom hardware where it can drastically reduce memory traffic and data communication overheads. Code used to run all learning experiments is available under https://gitlab.com/hesham-mostafa/learning-using-local-erros.git.


Course of objective memory impairment in non-demented subjects attending a memory clinic and predictors of outcome.
The aim of the study was to investigate the course of objective memory impairment in non-demented subjects who attended a memory clinic and to test predictors of outcome. Non-demented subjects (N=74) were included when they were older than 40 years and had a baseline score on the delayed recall of a word learning test below the tenth percentile. Subjects with memory impairment due to known somatic or neurological causes were excluded. The subjects were reassessed after 2 and 5 years. At the 5-year follow-up, 42% of the subjects had no memory impairment, 19% of the subjects had memory impairment without dementia, and 39% of the subjects had Alzheimer type dementia (AD). Predictors at baseline of reversible memory impairment in a multivariate analysis were age, scores on the MMSE and delayed recall, and the degree of functional impairment. Predictors at baseline of AD in a multivariate analysis were age and the score on the MMSE. The apolipoprotein E genotype and the presence of depression at baseline were not predictors of outcome. The positive predictive value was 72% for reversible memory impairment and 81% for AD. Memory impairment is often reversible and therefore its presence alone is not sufficient to consider subjects as preclinically demented. Predictive accuracy can be increased by including simple measures such as age, the scores on the MMSE and delayed recall, and the degree of functional impairment.


Bedside multimarker testing for risk stratification in chest pain units: The chest pain evaluation by creatine kinase-MB, myoglobin, and troponin I (CHECKMATE) study.
Earlier, rapid evaluation in chest pain units may make patient care more efficient. A multimarker strategy (MMS) testing for several markers of myocardial necrosis with different time-to-positivity profiles also may offer clinical advantages. We prospectively compared bedside quantitative multimarker testing versus local laboratory results (LL) in 1005 patients in 6 chest pain units. Myoglobin, creatine kinase-MB, and troponin I were measured at 0, 3, 6, 9 to 12, and 16 to 24 hours after admission. Two MMS were defined: MMS-1 (all 3 markers) and MMS-2 (creatine kinase-MB and troponin I only). The primary assessment was to relate marker status with 30-day death or infarction. More patients were positive by 24 hours with MMS than with LL (MMS-1, 23.9%; MMS-2, 18.8%; LL, 8.8%; P=0.001, all comparisons), and they became positive sooner with MMS-1 (2.5 hours, P=0.023 versus LL) versus MMS-2 (2.8 hours, P=0.026 versus LL) or LL (3.4 hours). The relation between baseline MMS status and 30-day death or infarction was stronger (MMS-1: positive, 18.8% event rate versus negative, 3.0%, P=0.001; MMS-2: 21.9% versus 3.2%, P=0.001) than that for LL (13.6% versus 5.5%, P=0.038). MMS-1 discriminated 30-day death better (positive, 2.0% versus negative, 0.0%, P=0.007) than MMS-2 (positive, 1.8% versus negative, 0.2%; P=0.055) or LL (positive, 0.0% versus negative, 0.5%; P=1.000). Rapid multimarker analysis identifies positive patients earlier and provides better risk stratification for mortality than a local laboratory-based, single-marker approach.


Can causality be determined from proximal tubular reabsorption and peritubular physical factors?
Many studies in the literature have drawn conclusions regarding the mechanism of change in absolute proximal tubular reabsorption (APR) based on steady-state measurements of proximal reabsorptive rates and the peritubular capillary. The proximal reabsorptive rate, APR, is the product of the effective reabsorptive pressure (ERP) and the peritubular capillary reabsorptive coefficient (LpAR) (APR = ERP . LpAR). The ERP is defined by the net hydrostatic and oncotic pressure gradient acting across the capillary wall from interstitium to peritubular capillary flow. The relationship APR = ERP . LpAR is predefined, and steady-state measurements do not permit determination of causality because primary changes in any variable obligate a proportional change in a second variable. As an example of the difficulties in interpretation of this type of analysis, we have examined the APR and factors contributing to ERP and LpAR before and after the administration of benzolamide, a carbonic anhydrase inhibitor, to saline-expanded Munich-Wistar rats. Alterations in peritubular capillary fluid uptake cannot always be interpreted as casual mechanisms for changes in absolute fluid reabsorption but may result from primary alterations in epithelial transport.


Co-overexpression FIT with AtbHLH38 or AtbHLH39 in Arabidopsis-enhanced cadmium tolerance via increased cadmium sequestration in roots and improved iron homeostasis of shoots.
Cadmium (Cd) is toxic to plant cells. Under Cd exposure, the plant displayed leaf chlorosis, which is a typical symptom of iron (Fe) deficiency. Interactions of Cd with Fe have been reported. However, the molecular mechanisms of Cd-Fe interactions are not well understood. Here, we showed that FER-like Deficiency Induced Transcripition Factor (FIT), AtbHLH38, and AtbHLH39, three basic helix-loop-helix transcription factors involved in Fe homeostasis in plants, also play important roles in Cd tolerance. The gene expression analysis showed that the expression of FIT, AtbHLH38, and AtbHLH39 was up-regulated in the roots of plants treated with Cd. The plants overexpressing AtbHLH39 and double-overexpressing FIT/AtbHLH38 and FIT/AtbHLH39 exhibited more tolerance to Cd exposure than wild type, whereas no Cd tolerance was observed in plants overexpressing either AtbHLH38 or FIT. Further analysis revealed that co-overexpression of FIT with AtbHLH38 or AtbHLH39 constitutively activated the expression of Heavy Metal Associated3 (HMA3), Metal Tolerance Protein3 (MTP3), Iron Regulated Transporter2 (IRT2), and Iron Regulated Gene2 (IREG2), which are involved in the heavy metal detoxification in Arabidopsis (Arabidopis thaliana). Moreover, co-overexpression of FIT with AtbHLH38 or AtbHLH39 also enhanced the expression of NICOTIANAMINE SYNTHETASE1 (NAS1) and NAS2, resulting in the accumulation of nicotiananamine, a crucial chelator for Fe transportation and homeostasis. Finally, we showed that maintaining high Fe content in shoots under Cd exposure could alleviate the Cd toxicity. Our results provide new insight to understand the molecular mechanisms of Cd tolerance in plants.


Anger as Seeing Red: Perceptual Sources of Evidence.
A class of metaphors links the experience of anger to perceptions of redness. Whether such metaphors have significant implications for understanding perception is not known. In Experiment 1, anger (versus sadness) concepts were primed and it was found that priming anger concepts led individuals to be more likely to perceive the color red. In Experiment 2, anger states were directly manipulated, and it was found that evoking anger led individuals to be more likely to perceive red. Both experiments showed that the observed effects were independent of the actual color presented. These findings extend the New Look, perceptual, metaphoric, and social cognitive literatures. Most importantly, the results suggest that emotion representation processes of a metaphoric type can be extended to the perceptual realm.


Earliest floral grave lining from 13,700-11,700-y-old Natufian burials at Raqefet Cave, Mt. Carmel, Israel.
Flowering plants possess mechanisms that stimulate positive emotional and social responses in humans. It is difficult to establish when people started to use flowers in public and ceremonial events because of the scarcity of relevant evidence in the archaeological record. We report on uniquely preserved 13,700-11,700-y-old grave linings made of flowers, suggesting that such use began much earlier than previously thought. The only potentially older instance is the questionable use of flowers in the Shanidar IV Neanderthal grave. The earliest cemeteries (ca. 15,000-11,500 y ago) in the Levant are known from Natufian sites in northern Israel, where dozens of burials reflect a wide range of inhumation practices. The newly discovered flower linings were found in four Natufian graves at the burial site of Raqefet Cave, Mt. Carmel, Israel. Large identified plant impressions in the graves include stems of sage and other Lamiaceae (Labiatae; mint family) or Scrophulariaceae (figwort family) species; accompanied by a plethora of phytoliths, they provide the earliest direct evidence now known for such preparation and decoration of graves. Some of the plant species attest to spring burials with a strong emphasis on colorful and aromatic flowers. Cave floor chiseling to accommodate the desired grave location and depth is also evident at the site. Thus, grave preparation was a sophisticated planned process, embedded with social and spiritual meanings reflecting a complex preagricultural society undergoing profound changes at the end of the Pleistocene.


The Mycobacterium tuberculosis complex-restricted gene cfp32 encodes an expressed protein that is detectable in tuberculosis patients and is positively correlated with pulmonary interleukin-10.
Human tuberculosis (TB) is caused by the bacillus Mycobacterium tuberculosis, a subspecies of the M. tuberculosis complex (MTC) of mycobacteria. Postgenomic dissection of the M. tuberculosis proteome is ongoing and critical to furthering our understanding of factors mediating M. tuberculosis pathobiology. Towards this end, a 32-kDa putative glyoxalase in the culture filtrate (CF) of growing M. tuberculosis (originally annotated as Rv0577 and hereafter designated CFP32) was identified, cloned, and characterized. The cfp32 gene is MTC restricted, and the gene product is expressed ex vivo as determined by the respective Southern and Western blot testing of an assortment of mycobacteria. Moreover, the cfp32 gene sequence is conserved within the MTC, as no polymorphisms were found in the tested cfp32 PCR products upon sequence analysis. Western blotting of M. tuberculosis subcellular fractions localized CFP32 predominantly to the CF and cytosolic compartments. Data to support the in vivo expression of CFP32 were provided by the serum recognition of recombinant CFP32 in 32% of TB patients by enzyme-linked immunosorbent assay (ELISA) as well as the direct detection of CFP32 by ELISA in the induced sputum samples from 56% of pulmonary TB patients. Of greatest interest was the observation that, per sample, sputum CFP32 levels (a potential indicator of increasing bacterial burden) correlated with levels of expression in sputum of interleukin-10 (an immunosuppressive cytokine and a putative contributing factor to disease progression) but not levels of gamma interferon (a key cytokine in the protective immune response in TB), as measured by ELISA. Combined, these data suggest that CFP32 serves a necessary biological function(s) in tubercle bacilli and may contribute to the M. tuberculosis pathogenic mechanism. Overall, CFP32 is an attractive target for drug and vaccine design as well as new diagnostic strategies.


[Awareness - medico legal aspects].
In general there are 3 significant malpractice risks for anaesthesiologists: insufficient supervision especially in case of patients, who have a known awareness risk, technical mistakes in the preparation or controlling of anaesthesia and no or insufficient therapeutic reaction if awareness has occurred. As long as awareness cannot be avoided during anaesthesia this risk should be explained to the patient. But the information should be given by the physician very subtly and carefully.Until today there have been only 3 court decisions in Germany concerning awareness. In all cases the claims have been dismissed. There is no Federal Court decision dealing with informed consent in case of awareness.


Five critical quality criteria for artificial intelligence-based prediction models.
To raise the quality of clinical artificial intelligence (AI) prediction modelling studies in the cardiovascular health domain and thereby improve their impact and relevancy, the editors for digital health, innovation, and quality standards of the European Heart Journal propose five minimal quality criteria for AI-based prediction model development and validation studies: complete reporting, carefully defined intended use of the model, rigorous validation, large enough sample size, and openness of code and software.


Convolution backprojection image reconstruction for spotlight mode synthetic aperture radar.
Convolution backprojection (CBP) image reconstruction has been proposed as a means of producing high-resolution synthetic-aperture radar (SAR) images by processing data directly in the polar recording format which is the conventional recording format for spotlight mode SAR. The CBP algorithm filters each projection as it is recorded and then backprojects the ensemble of filtered projections to create the final image in a pixel-by-pixel format. CBP reconstruction produces high-quality images by handling the recorded data directly in polar format. The CBP algorithm requires only 1-D interpolation along the filtered projections to determine the precise values that must be contributed to the backprojection summation from each projection. The algorithm is thus able to produce higher quality images by eliminating the inaccuracies of 2-D interpolation, as well as using all the data recorded in the spectral domain annular sector more effectively. The computational complexity of the CBP algorithm is O(N (3)).


Comparison of EQ-5D-3L and metabolic components between patients with hyperhidrosis and the general population: a propensity score matching analysis.
It is important to understand the characteristics of patients with hyperhidrosis, which are different from the general population, for treating hyperhidrosis. Sympathetic overactivity, which might play an important role in hyperhidrosis, can contribute to metabolic diseases and the decreased quality of life (QoL). We compared the metabolic components and health-related QoL between patients with hyperhidrosis and the general population. We conducted a case-control study and compared the characteristics of the patients (N = 196) with hyperhidrosis and propensity score-matched controls (N = 196) selected from the Korean National Health and Nutrition Examination Survey. Metabolic components and EQ-5D-3L (EQ-5D) index were compared using a two-way mixed analysis of covariance after adjusting for confounders. Patients with hyperhidrosis had significantly higher waist circumference (estimated mean values ± SD for patients and the control group, 85.5 ± 10.8 cm vs 81.3 ± 10.3 cm, p < 0.001), blood pressure (SBP, 121.1 ± 16.9 vs 111.7 ± 10.3, p < 0.001 AND DBP, 77.5 ± 12.8 vs 73.6 ± 8.6, p < 0.001, respectively), fasting glucose (97.1 ± 11.3 vs 91.5 ± 9.2, p < 0.001), and the number of components of metabolic syndrome (1.4 ± 1.3 vs 1.0 ± 1.2, p = 0.002), and significantly lower estimated glomerular filtration rate (144.3 ± 53.2 vs 158.3 ± 55.7, p = 0.002) and EQ-5D values (estimated mean values (standard error) for patients and the control group, 0.92 (0.01) vs 0.97 (0.01), p < 0.001) compared to the control group after adjustment. The patients with hyperhidrosis had more central obesity and unfavorable metabolic parameters and a lower EQ-5D index compared with the general population, emphasizing clinical importance of hyperhidrosis to be cured in aspect of metabolic components as well as patients' QOL.


Objective and Subjective Clinical Swallowing Outcomes via Telehealth: Reliability in Outpatient Clinical Practice.
Purpose The COVID-19 pandemic has drastically increased the use of telehealth. Prior studies of telehealth clinical swallowing evaluations provide positive evidence for telemanagement of swallowing. However, the reliability of these measures in clinical practice, as opposed to well-controlled research conditions, remains unknown. This study aimed to investigate the reliability of outcome measures derived from clinical swallowing tele-evaluations in real-world clinical practice (e.g., variability in devices and Internet connectivity, lack of in-person clinician assistance, or remote patient/caregiver training). Method Seven raters asynchronously judged clinical swallowing tele-evaluations of 12 movement disorders patients. Outcomes included the Timed Water Swallow Test (TWST), Test of Masticating and Swallowing Solids (TOMASS), and common observations of oral intake. Statistical analyses were performed to examine inter- and intrarater reliability, as well as qualitative analyses exploring patient and clinician-specific factors impacting reliability. Results Forty-four trials were included for reliability analyses. All rater dyads demonstrated "good" to "excellent" interrater reliability for measures of the TWST (intraclass correlation coefficients [ICCs] ≥ .93) and observations of oral intake (≥ 77% agreement). The majority of TOMASS outcomes demonstrated "good" to "excellent" interrater reliability (ICCs ≥ .84), with the exception of the number of bites (ICCs = .43-.99) and swallows (ICCs = .21-.85). Immediate and delayed intrarater reliability were "excellent" for most raters across all tasks, ranging between ICCs of .63 and 1.00. Exploratory factors potentially impacting reliability included infrequent instances of suboptimal video quality, reduced camera stability, camera distance, and obstruction of the patient's mouth during tasks. Conclusions Subjective observations of oral intake and objective measures taken from the TWST and the TOMASS can be reliably measured via telehealth in clinical practice. Our results provide support for the feasibility and reliability of telehealth for outpatient clinical swallowing evaluations during COVID-19 and beyond. Supplemental Material https://doi.org/10.23641/asha.13661378.


Pneumonia with serological evidence of acute infection with the Chlamydia-like microorganism "Z".
"Z" is a recently discovered microorganism that may belong to a new genus in the family Chlamydiaceae. Using an ELISA test we developed, we measured levels of serum antibody against "Z" for 308 paired sera obtained from adult patients hospitalized with community-acquired pneumonia (CAP). In 114 patients (37%), serological evidence of past infection with "Z" was found. In eight patients (2.6%) there was serological evidence of acute infection with this pathogen. In four of these eight patients, no other pathogen for CAP was identified despite an intensive serological investigation encompassing 13 etiological agents. The four patients were about 30 yr old, and three of them had no history of chronic illness. Their illness was characterized by high fever, a nonproductive cough, gastrointestinal symptoms, a shift to the left in the white blood cell count, and a prompt, dramatic response to erythromycin therapy. We conclude that the microorganism "Z", or a close variant, is infectious for humans, in some cases causing CAP. In these cases the disease is mild and responds quickly to treatment with erythromycin.


A mixed radiopaque - radiolucent lesion in the anterior mandible associated with multiple impacted teeth: A radiodiagnostic challenge?
Desmoplastic ameloblastoma (DA) exhibits important differences in gender, anatomic distribution, radiographic findings, and histologic appearance compared to other types of ameloblastoma. Radiologically, DA is seen either as ill-defined mass containing osteolytic and sclerotic areas or as multifocal radiodense flecks within radiolucent background resembling a honeycomb. The radiographic differential diagnosis includes fibro-osseous lesions such as cemento-ossifying fibroma, fibrous dysplasia, calcifying odontogenic cyst, and chronic sclerosing osteomyelitis. Thus, DA should primarily be included in the differential diagnosis of a mixed radiopaque-radiolucent lesion with diffuse borders in the anterior premolar region of the jaws. This report adds to the literature of mixed radiolucent-radiopaque lesions which may not always be histopathologically diagnosed as a fibro-osseous lesion but could turn out to be a DA. This report also benefits the dental community by cautioning them to be aware of DA that can be associated with multiple unerupted teeth which is quite a rare finding.


Comparison of Cardiovascular Disease Risk Factors Among African Immigrants and African Americans: An Analysis of the 2010 to 2016 National Health Interview Surveys.
Background Racial/ethnic minorities, especially non-Hispanic blacks, in the United States are at higher risk of developing cardiovascular disease. However, less is known about the prevalence of cardiovascular disease risk factors among ethnic sub-populations of blacks such as African immigrants residing in the United States. This study's objective was to compare the prevalence of cardiovascular disease risk factors among African immigrants and African Americans in the United States. Methods and Results We performed a cross-sectional analysis of the 2010 to 2016 National Health Interview Surveys and included adults who were black and African-born (African immigrants) and black and US-born (African Americans). We compared the age-standardized prevalence of hypertension, diabetes mellitus, overweight/obesity, hypercholesterolemia, physical inactivity, and current smoking by sex between African immigrants and African Americans using the 2010 census data as the standard. We included 29 094 participants (1345 African immigrants and 27 749 African Americans). In comparison with African Americans, African immigrants were more likely to be younger, educated, and employed but were less likely to be insured (P<0.05). African immigrants, regardless of sex, had lower age-standardized hypertension (22% versus 32%), diabetes mellitus (7% versus 10%), overweight/obesity (61% versus 70%), high cholesterol (4% versus 5%), and current smoking (4% versus 19%) prevalence than African Americans. Conclusions The age-standardized prevalence of cardiovascular disease risk factors was generally lower in African immigrants than African Americans, although both populations are highly heterogeneous. Data on blacks in the United States. should be disaggregated by ethnicity and country of origin to inform public health strategies to reduce health disparities.


Network measures for dyadic interactions: stability and reliability.
Social network analysis (SNA) is a general heading for a collection of statistical tools that aim to describe social interactions and social structure by representing individuals and their interactions as graph objects. It was originally developed for the social sciences, but more recently it was also adopted by behavioral ecologists. However, although SNA offers a full range of exciting possibilities for the study of animal societies, some authors have raised concerns about the correct application and interpretation of network measures. In this article, we investigate how reliable and how stable network measures are (i.e. how much variation they show under re-sampling and how much they are influenced by erroneous observations). For this purpose, we took a data set of 44 nonhuman primate grooming networks and studied the effects of re-sampling at lower re-sampling rates than the originally observed ones and the inclusion of two types of errors, "mis-identification" and "mis-classification," on six different network metrics, i.e. density, degree variance, vertex strength variance, edge weight disparity, clustering coefficient, and closeness centrality. Although some measures were tolerant toward reduced sample sizes, others were sensitive and even slightly reduced samples could yield drastically different results. How strongly a metric is affected seems to depend on both the sample size and the structure of the specific network. The same general effects were found for the inclusion of sampling errors. We, therefore, emphasize the importance of calculating valid confidence intervals for network measures and, finally, we suggest a rough research plan for network studies.


Leukotriene B4-mediated sterile inflammation promotes susceptibility to sepsis in a mouse model of type 1 diabetes.
Type 1 diabetes mellitus (T1DM) is associated with chronic systemic inflammation and enhanced susceptibility to systemic bacterial infection (sepsis). We hypothesized that low insulin concentrations in T1DM trigger the enzyme 5-lipoxygenase (5-LO) to produce the lipid mediator leukotriene B4 (LTB4), which triggers systemic inflammation that may increase susceptibility to polymicrobial sepsis. Consistent with chronic inflammation, peritoneal macrophages from two mouse models of T1DM had greater abundance of the adaptor MyD88 (myeloid differentiation factor 88) and its direct transcriptional effector STAT-1 (signal transducer and activator of transcription 1) than macrophages from nondiabetic mice. Expression of Alox5, which encodes 5-LO, and the concentration of the proinflammatory cytokine interleukin-1β (IL-1β) were also increased in peritoneal macrophages and serum from T1DM mice. Insulin treatment reduced LTB4 concentrations in the circulation and Myd88 and Stat1 expression in the macrophages from T1DM mice. T1DM mice treated with a 5-LO inhibitor had reduced Myd88 mRNA in macrophages and increased abundance of IL-1 receptor antagonist and reduced production of IL-β in the circulation. T1DM mice lacking 5-LO or the receptor for LTB4 also produced less proinflammatory cytokines. Compared to wild-type or untreated diabetic mice, T1DM mice lacking the receptor for LTB4 or treated with a 5-LO inhibitor survived polymicrobial sepsis, had reduced production of proinflammatory cytokines, and had decreased bacterial counts. These results uncover a role for LTB4 in promoting sterile inflammation in diabetes and the enhanced susceptibility to sepsis in T1DM.


Nephrocalcinosis among children at king hussein medical center: Causes and outcome.
Nephrocalcinosis (NC) is defined as deposition of calcium crystals in the renal parenchyma and tubules. This is a retrospective review of all the data of 63 children presented to Pediatric Nephrology Clinic at King Hussein Medical Center (KHMC) over a 15-year period with bilateral NC. We determine their causes, clinical presentation and evaluate their growth and renal function during their follow-up. Thirty-five (55.5%) cases were males and 28 (44.5%) were females. The median (range) age at presentation was four (2-192) months. The most common leading cause to NC was hereditary tubulopathy in 48% followed by hyperoxaluria in 35%. The cause of NC remained unknown in 3% and Vitamin D excess accounts for 5% of the cases. The most presenting symptom was a failure to thrive (68%) and the second most common symptom was abdominal pain and recurrent urinary tract infection was found in 40%, polyuria and polydipsia were found in 32% of cases, and 16% of cases were diagnosed incidentally. At a median follow-up of 38 (14-200) months, estimated glomerular filtration rate had decreased from 84.0 (42-110) mL/min per 1.73 m2 body surface area to 68.2 (10-110) mL/min/1.73 m2 body surface (P = 0.001). This study illustrated the need for a national registry of rare renal diseases to help understand the causes of these conditions in our populations and provide support to affected patients and their families.


Breeding and trade of wildlife in Santa Catarina state, Brazil.
The wildlife trade is becoming increasingly more relevant in discussions concerning conservation biology and the sustainable management of natural resources. The aim of this study was to document the trade and breeding of wildlife in Santa Catarina state, in southern Brazil. Data was collected from annual reports (1996-2008) of wildlife breeders which were sent to IBAMA. By the end of 2008, there were 79 wildlife breeders and 11 wildlife traders distributed in Santa Catarina. Commercial breeding accounted for the highest number of breeders (51%). In total, there are 213 species of wild animals bred in the state: 177 birds, 19 mammals and 17 reptiles. Of these, 48% are native to Santa Catarina, 32% occur in other Brazilian states and 20% are exotic to Brazil. Nine percent of the species bred are vulnerable or endangered. It was observed that some breeders reported breeding unauthorized species. Altogether, 93 species are bred illegally by 19 breeders. Of these species, 48 are native to Santa Catarina and three are classified as vulnerable or in danger of extinction. We hope the data presented in this paper contributes to the development of conservation strategies and conscious use of wildlife resources in Brazil.


The multifaceted role of podoplanin expression in hepatocellular carcinoma.
The role of podoplanin in hepatocellular carcinoma (HCC) is not clear yet. The aim of our study was to evaluate the expression of podoplanin in HCC and to determine its role in hepatocarcinogenesis. We performed immunohistochemistry with monoclonal D2-40 antibody, on paraffin-embedded tissue sections of 72 patients diagnosed with HCC. Lymphatic vessels density (LVD) was increased in patients who had vascular invasion at the time of diagnosis (P=0.018) and in those with associated cirrhosis (P=0.006). Tumor cells showing podoplanin expression were correlated with histological grade (P=0.040). Podoplanin-expressing cancer associated fibroblasts (CAFs) were correlated with both LVD (P=0.019) and tumor cells (P=0.015). Our results sustain the dual role of podoplanin in HCC by its involvement in both HCC tumorigenesis, lymphatic neovascularization and tumor invasion invasiveness. A possible crosstalk between epithelial and stromal tumor cells in HCC tumor microenvironment may be mediated by podoplanin, but this hypothesis needs further studies to elucidate this interrelation.


[Immuno-elimination and clearance of Rh-positive erythrocytes in Rh-negative volunteers following administration of anti-D-immunoglobulin].
The prophylactic treatment of Rhesus-negative women to prevent Rhesus-sensitization has been accepted worldwide, although the working mechanism of the anti-D-immunoglobulin is still unknown. We have used Cr-51-labelled red blood cells to investigate the immune clearance of the cells in Rhesus-negative volunteers following injection of anti-D. Intravenous application of anti-D-immunoglobulin resulted in an accelerated elimination of the Rhesus-positive erythrocytes from the peripheral blood in contrast to the intramuscular treatment with the same dosage. But we had not been able to investigate whether the intravenous route might result in a more effective prophylaxis. In result of the application of IgG-anti-D sequestration can be observed in the spleen. This organ seems to be of great importance for the working mechanism of the anti-D-immunoglobulin. On the other hand splenectomized patients showed reduced clearance rates. In these cases the liver may be involved in the elimination of the red blood cells. F(ab')2-fragments, which cannot pass the placental barrier, seemed to be ineffective with respects to immunosuppression. As patients showing the Du-variant can be sensitized against -- D -- they also should receive anti-D-immunoglobulin for prophylaxis.


Nosocomial pneumonia and the role of gastric pH. A meta-analysis.
To examine the differential effect of drugs used for stress ulcer prophylaxis on nosocomial pneumonia in critically ill patients. Computerized bibliographic search of published and unpublished research. Independent review of 48 randomized controlled trials of prophylaxis identified eight relevant studies. The population, intervention, and outcomes were evaluated by duplicate independent review. The incidence of pneumonia was lower in critically ill patients receiving antacids and/or histamine-2-receptor antagonists as compared with patients receiving no stress ulcer prophylaxis (common odds ratio 0.42, 95 percent CI 0.17 to 1.11). When stress ulcer prophylactic therapy was titrated to achieve a gastric pH of 3.5 or greater, there was a trend favoring a decreased incidence of pneumonia (0.66, 95 percent CI 0.24 to 1.78). In trials comparing sucralfate with pH-altering drugs, the common odds ratio of 0.55 (0.28 to 1.06) suggests a 45 percent risk reduction with the use of sucralfate. Stress ulcer prophylaxis with drugs which raise gastric pH does not increase the incidence of pneumonia in comparison to placebo or control therapy. The use of sucralfate is associated with a lower incidence of nosocomial pneumonia in comparison to agents which raise gastric pH. However, methodologic deficiencies, small sample sizes, and the failure to examine the effects of antacids and histamine-2-receptor antagonists separately make a large prospective randomized trial necessary to confirm or refute these findings.


Measurement of intraindividual airway tone heterogeneity and its importance in asthma.
While airways have some degree of baseline tone, the level and variability of this tone is not known. It is also unclear whether there is a difference in airway tone or in the variability of airway tone between asthmatic and healthy individuals. This study examined airway tone and intraindividual airway tone heterogeneity (variance of airway tone) in vivo in 19 individuals with asthma compared with 9 healthy adults. All participants underwent spirometry, body plethysmography, and high-resolution computed tomography at baseline and after maximum bronchodilation with albuterol. Airway tone was defined as the percent difference in airway diameter after albuterol at total lung capacity compared with baseline. The amount of airway tone in each airway varied both within and between subjects. The average airway tone did not differ significantly between the two groups (P = 0.09), but the intraindividual airway tone heterogeneity did (P = 0.016). Intraindividual airway tone heterogeneity was strongly correlated with airway tone (r = 0.78, P < 0.0001). Also, it was negatively correlated with the magnitude of the distension of the airways from functional residual capacity to total lung capacity at both baseline (r = -0.49, P = 0.03) and after maximum bronchodilation (r = -0.51, P = 0.02) in the asthma, but not the healthy group. However, we did not find any relationship between intraindividual airway tone heterogeneity and conventional lung function outcomes. Intraindividual airway tone heterogeneity appears to be an important characteristic of airway pathophysiology in asthma.


Transrectal versus transperineal 14-core prostate biopsy in detection of prostate cancer: a comparative evaluation at the same institution.
The ideal bioptic strategy for CaP detection is still to be completely defined. The aim of our study is to compare transperineal (TP) and transrectal (TR) approaches, in a 14-core initial prostate biopsy for CaP detection. A prospective controlled study was conducted enrolling 108 consecutive patients with a PSA level greater than 4 ng/mL and/or an abnormal DRE. TR versus TP 14-core initial prostatic biopsies were performed on 54 and 54 patients, respectively, with a randomisation ratio of 1:1. The cancer detection rates were 46.29 (25 out of 54 patients), and 44.44% (24 out of 54 patients), respectively, using the TR or the TP approach (p = 0.846). The overall cancer core rate was significantly higher when the TP approach was used: 21.43% (162 out of 756 cores) and 16.79% (127 out of 756 cores), with the TP and the TR approach, respectively (p = 0.022). The cores were significantly longer performing TP approach: at the site "1" (14.92 versus 12.97 mm, p = 0.02); at "5" (15.53 versus 13.69 mm, p = 0.037); at "7" (15.06 versus 12.86 mm, p = 0.001); at "9" (14.92 versus 13.38 mm, p = 0.038); at "11" (16.32 versus 12.31 mm, p = 0.0001); at "12" (15.14 versus 12.19 mm, p = 0.0001); at "13" (17.49 versus 13.98 mm, p = 0.0001); at "14" (16.77 versus 13.36 mm, p = 0.0001). As to the biopsy related pain, the mean pain level perceived by patients during the TR approach was 1.56 ± 1.73 versus 1.42 ± 1.37 registered during TP approach (p = 0.591). No significant differences were found in cancer detection rate, cancer core rate between TP and TR approaches for prostatic biopsy. Even in terms of complication rate or pain level, it cannot be concluded that one procedure is superior to the other one. Apparently, strictly following our protocol, TP approach seems to offer a better sampling at the level of the apex and the TZ, however without adding any significant advantage in terms of overall cancer detection rate.


Somatostatin and epinephrine decrease insulin messenger ribonucleic acid in HIT cells through a pertussis toxin-sensitive mechanism.
The sites of action for somatostatin and epinephrine to inhibit insulin secretion have been reported to be exclusively in the exocytotic pathway. We used HIT cells, a clonal line of beta-cells, to examine whether these hormones might have as yet undescribed, nonexocytotic effects on insulin messenger RNA levels. We observed that both somatostatin and epinephrine not only inhibit insulin secretion (53 +/- 2% and 50 +/- 2% of control, respectively) but also decrease insulin mRNA levels (54 +/- 5% and 66 +/- 5% of control, respectively) and insulin content in HIT cells (61 +/- 2% and 51 +/- 1% of control, respectively). The latter two effects are discernible by 24 h, maximal by 48 h, and are prevented by preincubation of HIT cells with pertussis toxin. These new observations suggest that somatostatin and epinephrine negatively modulate insulin availability through a guanine nucleotide binding protein-mediated step in insulin synthesis before the exocytotic pathway. This general mechanism may allow these two hormones to serve as more long-term regulators of insulin availability in distinction to their shorter term and more readily reversible inhibitory effects on the exocytotic pathway.


Populus euphratica XTH overexpression enhances salinity tolerance by the development of leaf succulence in transgenic tobacco plants.
Populus euphratica is a salt-tolerant tree species that develops leaf succulence after a prolonged period of salinity stress. In the present study, a putative xyloglucan endotransglucosylase/hydrolase gene (PeXTH) from P. euphratica was isolated and transferred to tobacco plants. PeXTH localized exclusively to the endoplasmic reticulum and cell wall. Plants overexpressing PeXTH were more salt tolerant than wild-type tobacco with respect to root and leaf growth, and survival. The increased capacity for salt tolerance was due mainly to the anatomical and physiological alterations caused by PeXTH overexpression. Compared with the wild type, PeXTH-transgenic plants contained 36% higher water content per unit area and 39% higher ratio of fresh weight to dry weight, a hallmark of leaf succulence. However, the increased water storage in the leaves in PeXTH-transgenic plants was not accompanied by greater leaf thickness but was due to highly packed palisade parenchyma cells and fewer intercellular air spaces between mesophyll cells. In addition to the salt dilution effect in response to NaCl, these anatomical changes increased leaf water-retaining capacity, which lowered the increase of salt concentration in the succulent tissues and mesophyll cells. Moreover, the increased number of mesophyll cells reduced the intercellular air space, which improved carbon economy and resulted in a 47-78% greater net photosynthesis under control and salt treatments (100-150 mM NaCl). Taken together, the results indicate that PeXTH overexpression enhanced salt tolerance by the development of succulent leaves in tobacco plants without swelling.


Human embryonic stem cell lines isolation, cultivation, and characterization.
A large number of human embryonic stem cell (hESC) lines have been derived worldwide since the first hESC line establishment in 1998. Despite many common characteristics, most important of which is the pluripotency, hESC lines vary significantly in their transcriptional profiles, genetic, and epigenetic state. These differences may arise both from individual genetics of the cell lines and from variations in their handling such as isolation and cultivation. In order to minimize the latter differences, the standardized protocols of cultivation and inter-laboratory comprehensive studies should be performed. In this report, we summarized our experience of derivation and characterization of hESC lines as well as of adaptation of hESCs to novel cultivation protocols. We have successfully derived five hESC lines and characterized them by previously established criteria, including expression of specific markers and the capacity to differentiate both in vitro and in vivo. Four of these lines, namely hESM01-04, were initially derived using mouse fibroblasts as a feeder and currently are maintained under feeder-free, serum-free conditions using mTeSR1 and Matrigel. The fifth line, hESMK05 was derived in feeder-free, serum-free conditions using mTeSR1 and Matrigel. Cell lines retain their pluripotent status and normal karyotype for more than 70 passages and are available to the scientific community.


The Eyes are the Windows of the Soul.
Medical Specialties such as Ophthalmology extend historically back to the beginning of recorded history. Before there was photography to record physical abnormalities of living creatures, there was art and artists who did the recording in their works. Fortunately, many such recordings have been preserved, usually in museums. They provide the graphic evidence of the same medical problems which our ancestors suffered and survived but which we still do but now understand and can ameliorate better. The purpose of this paper is to provide and study several more examples of these art works, to illuminate these historical aspects of medicine, ophthalmology and binocular vision and life.


An epitope imprinting method on the surface of magnetic nanoparticles for specific recognition of bovine serum album.
In this study, we reported an epitope imprinting method on the surface of core-shell magnetic nanoparticles (NPs) for the recognition of target bovine serum album (BSA). The epitope was selected as the template molecule from the nonapeptide of surface-exposed C-terminus of BSA. The core-shell magnetic epitope molecularly imprinted polymers (Fe3O4@EMIPs) exhibited a specific capture activity for the corresponding target protein, BSA. The magnetic NPs made it easy to separate the imprinted material from solution by an external magnetic field, and the thin imprinted layer presented fast kinetics for the rebinding of the target protein. Moreover, the Fe3O4@EMIPs could separate BSA from the bovine blood sample. The epitope imprinting approach combined with magnetic NPs provided an easy and fast method for the specific recognition of BSA.


Microarray-Based Gene Expression Analysis Identifies Potential Diagnostic and Prognostic Biomarkers for Waldenström Macroglobulinemia.
Waldenström macroglobulinemia (WM), also known as lymphoplasmacytic lymphoma, is rare but a clinicopathologically distinct B-cell malignancy. This study assessed differentially expressed genes (DEGs) to identify potential WM biomarkers and uncover the underlying the molecular mechanisms of WM progression using gene expression profiles from the Gene Expression Omnibus database. DEGs were identified using the LIMMA package and their potential functions were then analyzed by using the gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses and the protein-protein interaction (PPI) network analysis by using the Search Tool for the Retrieval of Interacting Genes/Proteins database. Data showed that among 1,756 DEGs, 926 were upregulated and 830 were downregulated by comparing WM BM CD19+ with normal PB CD19+ B cell samples, whereas 241 DEGs (95 upregulated and 146 downregulated) were identified by comparing WM BM CD138+ with normal BM CD138+ plasma cell samples. The DEGs were enriched in different GO terms and pathways, including the apoptotic process, cell cycle arrest, immune response, cell adhesion, mitogen-activated protein kinase signaling pathway, toll-like receptor signaling pathway, and the gonadotropin-releasing hormone signaling pathway. Hub nodes in the PPI network included CDK1, JUN, CREBBP, EP300, CAD, CDK2, and MAPK14. Bioinformatics analysis of the GSE9656 dataset identified 7 hub genes that might play an important role in WM development and progression. Some of the candidate genes and pathways may serve as promising therapeutic targets for WM.


Concurrent participation in screening for cervical, breast, and bowel cancer in England.
To determine how many women participate in all three recommended cancer screening programmes (breast, cervical, and bowel). During their early 60s, English women receive an invitation from all the three programmes. For 3060 women aged 60–65 included in an England-wide breast screening case–control study, we investigated the number of screening programmes they participated in during the last invitation round. Additionally, using the Fingertips database curated by Public Health England, we explored area-level correlations between participation in the three cancer screening programmes and various population characteristics for all 7014 English general practices with complete data. Of the 3060 women, 1086 (35%) participated in all three programmes, 1142 (37%) in two, 526 (17%) in one, and 306 (10%) in none. Participation in all three did not appear to be a random event (p < 0.001). General practices from areas with less deprivation, with more patients who are carers or have chronic illnesses themselves, and with more patients satisfied with the provided service were significantly more likely to attain high coverage rates in all programmes. Only a minority of English women is concurrently protected through all recommended cancer screening programmes. Future studies should consider why most women participate in some but not all recommended screening.


Genomic regions controlling shape variation in the first upper molar of the house mouse.
Numerous loci of large effect have been shown to underlie phenotypic variation between species. However, loci with subtle effects are presumably more frequently involved in microevolutionary processes but have rarely been discovered. We explore the genetic basis of shape variation in the first upper molar of hybrid mice between Mus musculus musculus and M. m. domesticus. We performed the first genome-wide association study for molar shape and used 3D surface morphometrics to quantify subtle variation between individuals. We show that many loci of small effect underlie phenotypic variation, and identify five genomic regions associated with tooth shape; one region contained the gene microphthalmia-associated transcription factor Mitf that has previously been associated with tooth malformations. Using a panel of five mutant laboratory strains, we show the effect of the Mitf gene on tooth shape. This is the first report of a gene causing subtle but consistent variation in tooth shape resembling variation in nature.


The Full-Size ABCG Transporters Nb-ABCG1 and Nb-ABCG2 Function in Pre- and Postinvasion Defense against Phytophthora infestans in Nicotiana benthamiana.
The sesquiterpenoid capsidiol is the major phytoalexin produced by Nicotiana and Capsicum species. Capsidiol is produced in plant tissues attacked by pathogens and plays a major role in postinvasion defense by inhibiting pathogen growth. Using virus-induced gene silencing-based screening, we identified two Nicotiana benthamiana (wild tobacco) genes encoding functionally redundant full-size ABCG (PDR-type) transporters, Nb-ABCG1/PDR1 and Nb-ABCG2/PDR2, which are essential for resistance to the potato late blight pathogen Phytophthora infestans Silencing of Nb-ABCG1/2 compromised secretion of capsidiol, revealing Nb-ABCG1/2 as probable exporters of capsidiol. Accumulation of plasma membrane-localized Nb-ABCG1 and Nb-ABCG2 was observed at the site of pathogen penetration. Silencing of EAS (encoding 5-epi-aristolochene synthase), a gene for capsidiol biosynthesis, reduced resistance to P. infestans, but penetration by P. infestans was not affected. By contrast, Nb-ABCG1/2-silenced plants showed reduced penetration defense, indicating that Nb-ABCG1/2 are involved in preinvasion defense against P. infestans Plastidic GGPPS1 (geranylgeranyl diphosphate synthase) was also found to be required for preinvasion defense, thereby suggesting that plastid-produced diterpene(s) are the antimicrobial compounds active in preinvasion defense. These findings suggest that N. benthamiana ABCG1/2 are involved in the export of both antimicrobial diterpene(s) for preinvasion defense and capsidiol for postinvasion defense against P. infestans.


Optimization of a GDNF production method based on Semliki Forest virus vector.
Human glial cell line-derived neurotrophic factor (hGDNF) is the most potent dopaminergic factor described so far, and it is therefore considered a promising drug for Parkinson's disease (PD) treatment. However, the production of therapeutic proteins with a high degree of purity and a specific glycosylation pattern is a major challenge that hinders its commercialization. Although a variety of systems can be used for protein production, only a small number of them are suitable to produce clinical-grade proteins. Specifically, the baby hamster kidney cell line (BHK-21) has shown to be an effective system for the expression of high levels of hGDNF, with appropriate post-translational modifications and protein folding. This system, which is based on the electroporation of BHK-21 cells using a Semliki Forest virus (SFV) as expression vector, induces a strong shut-off of host cell protein synthesis that simplify the purification process. However, SFV vector exhibits a temperature-dependent cytopathic effect on host cells, which could limit hGDNF expression. The aim of this study was to improve the expression and purification of hGDNF using a biphasic temperature cultivation protocol that would decrease the cytopathic effect induced by SFV. Here we show that an increase in the temperature from 33°C to 37°C during the "shut-off period", produced a significant improvement in cell survival and hGDNF expression. In consonance, this protocol led to the production of almost 3-fold more hGDNF when compared to the previously described methods. Therefore, a "recovery period" at 37°C before cells are exposed at 33°C is crucial to maintain cell viability and increase hGDNF expression. The protocol described constitutes an efficient and highly scalable method to produce highly pure hGDNF.


Toll-like receptor 2 and 4 have opposing roles in the pathogenesis of cigarette smoke-induced chronic obstructive pulmonary disease.
Chronic obstructive pulmonary disease (COPD) is the third leading cause of morbidity and death and imposes major socioeconomic burdens globally. It is a progressive and disabling condition that severely impairs breathing and lung function. There is a lack of effective treatments for COPD, which is a direct consequence of the poor understanding of the underlying mechanisms involved in driving the pathogenesis of the disease. Toll-like receptor (TLR)2 and TLR4 are implicated in chronic respiratory diseases, including COPD, asthma and pulmonary fibrosis. However, their roles in the pathogenesis of COPD are controversial and conflicting evidence exists. In the current study, we investigated the role of TLR2 and TLR4 using a model of cigarette smoke (CS)-induced experimental COPD that recapitulates the hallmark features of human disease. TLR2, TLR4, and associated coreceptor mRNA expression was increased in the airways in both experimental and human COPD. Compared with wild-type (WT) mice, CS-induced pulmonary inflammation was unaltered in TLR2-deficient ( Tlr2-/-) and TLR4-deficient ( Tlr4-/-) mice. CS-induced airway fibrosis, characterized by increased collagen deposition around small airways, was not altered in Tlr2-/- mice but was attenuated in Tlr4-/- mice compared with CS-exposed WT controls. However, Tlr2-/- mice had increased CS-induced emphysema-like alveolar enlargement, apoptosis, and impaired lung function, while these features were reduced in Tlr4-/- mice compared with CS-exposed WT controls. Taken together, these data highlight the complex roles of TLRs in the pathogenesis of COPD and suggest that activation of TLR2 and/or inhibition of TLR4 may be novel therapeutic strategies for the treatment of COPD.


A newly designed heterodiene and its application to construct six-membered heterocycles containing an N-O bond.
A new type of zwitterionic nitrosoalkene generated in situ from dehydrohalogenation of α-halo-N-alkylhydroxamic acids was designed. [4+2] cycloadditions of this heterodiene to olefins provide a facile route to construct six-membered heterocycles containing an N-O bond and a new protocol for 1,2-syn carbohydroxylate alkenes with a hydroxyl and acetamide group. DFT calculations support a concerted cycloaddition pathway and the solvent HFIP can stabilize the transition state through H-bonding interaction.


Orbital exenteration with spontaneous granulation.
Excision of the orbital contents by orbital exenteration is required in the treatment of some eyelid and orbital carcinomas. Allowing the orbit to heal spontaneously with granulation tissue has several advantages over the popular technique of lining the orbital walls with a split-thickness skin graft. The use of granulation tissue is simpler, since it avoids the needs for obtaining a skin graft, and the final result is cosmetically more acceptable, because a shallower cavity occurs compared with the skin graft technique. The main disadvantages are that it takes longer for the orbit to heal and dressing changes are required more frequently. The spontaneous granulation technique has provided excellent results in 12 patients with exenterated orbits.


[Peripheral vertigo classification of the Otoneurology Committee of the Spanish Otorhinolaryngology Society: diagnostic agreement and update (version 2-2011)].
In 2008, the Otoneurology committee of the SEORL-PCF published a classification of peripheral vertigo, based on clinical criteria. The objective of this study was to validate this classification through analysing the diagnostic agreement among several medical assessors. Seven medical assessors, all with clinical experience, from 6 different hospitals, participated in the study. One of them selected the clinical histories of 50 consecutive patients who had consulted as a result of balance disorders (24 men and 26 women) with an average age of 53.5 years. These clinical histories -without any information that would identify the patient, the diagnosis established and the treatment- were sent to another 6 assessors. Each of these investigators established their own diagnosis, trying to adjust it to the epigraphs of the classification. Of the 50 patients, there was substantial agreement as to the diagnosis (4 or more evaluators indicated the same one) in 31 cases (26 with a positive diagnosis and 5 with a negative one, which could not be included in any epigraph). The kappa index, which measures the level of accordance between 2 or more assessors, was 0.4198 (moderate level of agreement). Unanimity was achieved in only 7 cases (4 BPPV, 2 Ménière's disease and 1 vertigo associated with migraine). The current classification, with the criteria it includes, allows labelling with an acceptable consensus to only 62% of the patients. Therefore, a modification in the classification is proposed in relation with the probable BPPV epigraph, as well a revision of the entries for vertigo-migraine and vertigo associated with migraine.


Cognitive predictors of problem drinking and AUDIT scores among college students.
Evidence from a number of substance abuse populations suggests that substance abuse is associated with a cluster of differences in cognitive processes. However, investigations of this kind in non-clinical samples are relatively few. The present study examined the ability of alcohol-attentional bias (an alcohol Stroop task), impulsive decision-making (a delay discounting task), and impaired inhibitory control (a GO-NOGO task) to: (a) discriminate problem from non-problem drinkers among a sample of college students; (b) predict scores on the Alcohol Use Disorders Identification Test (AUDIT; a measure of alcohol consumption, drinking behaviour, and alcohol-related problems) across all of the student drinkers; (c) predict AUDIT scores within the subgroups of problem and non-problem student drinkers. In logistic regression controlling for gender and age, student drinkers with elevated alcohol-attentional bias and impulsive decision-making were over twice as likely to be a problem than a non-problem drinker. Multiple regression analysis of the entire sample revealed that all three cognitive measures were significant predictors of AUDIT scores after gender and age had been controlled; the cognitive variables together accounted for 48% of the variance. Moreover, subsequent multiple regressions revealed that impaired inhibitory control was the only significant predictor of AUDIT scores for the group of non-problem drinkers, and alcohol-attentional bias and impulsive decision-making were the only significant predictors of AUDIT scores for the group of problem drinkers. Finally, both impulsive decision-making and impaired inhibitory control were significantly correlated with alcohol-attentional bias across the whole sample. Implications are discussed relating to the development of problematic drinking.


Preparation and shipping of Onchocerca volvulus material.
Instructions are provided for selection of nodules, isolation of female Onchocerca volvulus and shipping to obtain suitable, intact and live worms for drug-screening and metabolic studies in vitro as well as material for isolation of enzymes, receptors, antigens etc.


Immunotherapeutic targeting of Wilms' tumor protein.
The expression of Wilms' tumor protein (WT1)-derived peptides on malignant cell surfaces and recognition of those peptides by cellular and humoral immune responses suggest that WT1 may be a promising potential target antigen in immunotherapeutic trials. With a high frequency of expression in hematopoietic as well as solid tumors, WT1 is a broadly applicable target. Both in vivo mouse model and in vitro human studies have demonstrated the ability of WT1-specific cytotoxic T-lymphocytes to lyse WT1-expressing malignancies without harming normal tissue. WT1-peptide vaccination, in combination with adjuvants, has demonstrated the ability to activate WT1-specific immune responses and evidence of clinical activity. Because peptide-based vaccines are human leukocyte antigen-restricted, other more broadly applicable strategies are now being developed to activate WT1-specific immune responses, including the use of WT1-specific viral vectors.


* Composite Biomaterial as a Carrier for Bone-Active Substances for Metaphyseal Tibial Bone Defect Reconstruction in Rats.
Restoring lost bone is a major challenge in orthopedic surgery. Currently available treatment strategies have shortcomings, such as risk of infection, nonunion, and excessive resorption. Our primary aim was to study if a commercially available gentamicin-containing composite calcium sulfate/hydroxyapatite biomaterial (GBM) could serve as a carrier for local delivery of bone morphogenic protein-2 (BMP-2) and zoledronic acid (ZA) in a tibia defect model in rats. Empty and allograft-filled defects were used as controls. A 3 × 4-mm metaphyseal bone defect was created in the proximal tibia, and the rats were grouped according to defect filling: (1) Empty, (2) Allograft, (3) GBM, (4) GBM + ZA, and (5) GBM + ZA + BMP-2. In vivo microcomputed tomography (micro-CT) images at 4 weeks showed significantly higher mineralized tissue volume (MV) in the intramedullary defect region and the neocortical/callus region in all GBM-treated groups. After euthanization at 8 weeks, ex vivo micro-CT showed that addition of ZA (GBM + ZA) and BMP-2 (GBM + ZA + BMP-2) mainly increased the neocortical and callus formation, with the highest MV in the combined ZA and BMP-2-treated group. Qualitative histological analysis, verifying the increased neocortical/callus thickness and finding of trabecular bone in all GBM-treated groups, supported that the differences in MV measured with micro-CT in fact represented bone tissue. In conclusion, GBM can serve as a carrier for ZA and BMP-2 leading to increased MV in the neocortex and callus of a metaphyseal bone defect in rats.


An Arabidopsis F-box protein acts as a transcriptional co-factor to regulate floral development.
Plants flower in response to both environmental and endogenous signals. The Arabidopsis LEAFY (LFY) transcription factor is crucial in integrating these signals, and acts in part by activating the expression of multiple floral homeotic genes. LFY-dependent activation of the homeotic APETALA3 (AP3) gene requires the activity of UNUSUAL FLORAL ORGANS (UFO), an F-box component of an SCF ubiquitin ligase, yet how this regulation is effected has remained unclear. Here, we show that UFO physically interacts with LFY both in vitro and in vivo, and this interaction is necessary to recruit UFO to the AP3 promoter. Furthermore, a transcriptional repressor domain fused to UFO reduces endogenous LFY activity in plants, supporting the idea that UFO acts as part of a transcriptional complex at the AP3 promoter. Moreover, chemical or genetic disruption of proteasome activity compromises LFY-dependent AP3 activation, indicating that protein degradation is required to promote LFY activity. These results define an unexpected role for an F-box protein in functioning as a DNA-associated transcriptional co-factor in regulating floral homeotic gene expression. These results suggest a novel mechanism for promoting flower development via protein degradation and concomitant activation of the LFY transcription factor. This mechanism may be widely conserved, as homologs of UFO and LFY have been identified in a wide array of plant species.


Structural and Insulating Behaviour of High-Permittivity Binary Oxide Thin Films for Silicon Carbide and Gallium Nitride Electronic Devices.
High-κ dielectrics are insulating materials with higher permittivity than silicon dioxide. These materials have already found application in microelectronics, mainly as gate insulators or passivating layers for silicon (Si) technology. However, since the last decade, the post-Si era began with the pervasive introduction of wide band gap (WBG) semiconductors, such as silicon carbide (SiC) and gallium nitride (GaN), which opened new perspectives for high-κ materials in these emerging technologies. In this context, aluminium and hafnium oxides (i.e., Al2O3, HfO2) and some rare earth oxides (e.g., CeO2, Gd2O3, Sc2O3) are promising high-κ binary oxides that can find application as gate dielectric layers in the next generation of high-power and high-frequency transistors based on SiC and GaN. This review paper gives a general overview of high-permittivity binary oxides thin films for post-Si electronic devices. In particular, focus is placed on high-κ binary oxides grown by atomic layer deposition on WBG semiconductors (silicon carbide and gallium nitride), as either amorphous or crystalline films. The impacts of deposition modes and pre- or postdeposition treatments are both discussed. Moreover, the dielectric behaviour of these films is also presented, and some examples of high-κ binary oxides applied to SiC and GaN transistors are reported. The potential advantages and the current limitations of these technologies are highlighted.


The standardized-taper root canal preparation--Part 1. Concepts for variably tapered shaping instruments.
To introduce the concept of variable taper instruments for predictable and ergonomic root canal preparation, and demonstrate the design features of Greater Taper files. Optimal root canal shaping is difficult to practice and teach with traditional instruments. Instrument sequences are complex, with up to 18 instruments and 63 procedural stages, providing almost limitless scope for poor results and iatrogenic error. In the first of six articles, Dr Buchanan describes the Variable Taper concept, which grew from such frustrations, and represents a new concept in file design. Milled from NiTi alloys in tapers of 0.06, 0.08, 0.10 and 0.12 mm mm-1, with accessory files for wide canals, their design embodies the key shaping features of adequate coronal enlargement, full deep shape, and predictable apical resistance form case after case. The ease and simplicity of their use is described, and enhanced cleaning and obturation outcomes discussed in relation to their unique design features. Canal preparation is difficult to practice and teach with traditional K-files and Gates Glidden drills. Variable Taper files are designed to offer the optimal preparation features of adequate (not excessive) coronal enlargement, full deep shape, and apical resistance form in a simple instrument sequence. Variable Taper technique is simple to master, and offers predictable cleaning and obturation outcomes, even in inexperienced hands.


[Indications for a nerve suture in certain forms of injury to the median and ulnar nerves].
The investigation of 20 patients with an injury of the median and ulnar nerve on the forearm has shown that absence of anesthesia is possible in the autonomic area after a complete interruption of one of these nerves. Indications for suturing the median and ulnar nerves after partial disturbance of their conductivity on the forearm can be established but on the basis of a clinical examination, intraoperative data with the investigation of electrodiagnosis before and during the operation.


The Surgical Morbidity And Oncological Outcome Of Total Laparoscopic Radical Trachelectomy Versus Total Laparoscopic Radical Hysterectomy For Early Stage Cervical Cancer: A Retrospective Study With 11-Year Follow-Up.
The objective of this study was to evaluate the surgical morbidity and oncological outcome of total laparoscopic radical trachelectomy (TLRT) and total laparoscopic radical hysterectomy (TLRH) in patients with early-stage cervical cancer. We performed a retrospective study to compare the outcomes of patients with stage IB1 cervical cancer who underwent TLRT to patients treated with TLRH from January 2005 to December 2016. Forty-six patients underwent TLRT and 73 patients underwent TLRH between January 2005 and December 2016. The median age was 30 (19-40) years for TLRT group compared to 43 (31-65) years for TLRH group. No significant difference was found for the tumor size, histology, and pathology grade between TLRT group and TLRH group. In the TLRT group, the median operative time was 200 mins (range, 150-360 mins) and the median blood loss was 200 mL (range, 50-400mL). In the TLRH group, the median operative time was 240 mins (range, 180-380) and the median blood loss was 250mL (range, 10-1500mL). The median follow-up time was 80 months for TLRT group and 72 months for TLRH group. No patient in TLRT group developed recurrence. However, there were 2 recurrences diagnosed in the TLRH group. TLRT appears to have equal surgical morbidity and oncological outcome to TLRH in stage IB1 cervical cancer. Intraoperative complications did not differ significantly between these two groups. However, postoperative complications were fewer observed in TLRT. Because of the natural limitations of the retrospective study, the clinical value should be confirmed by multi-institutional prospective trial in the future.


Aprepitant versus metoclopramide, both combined with dexamethasone, for the prevention of cisplatin-induced delayed emesis: a randomized, double-blind study.
A combination of aprepitant, a 5-HT3 receptor antagonist (r.a.), and dexamethasone is recommended for the prophylaxis of cisplatin-induced nausea and vomiting in the acute phase, and aprepitant + dexamethasone (A + D) in the delayed phase. The aim of this study was to verify if A + D is superior to metoclopramide plus dexamethasone (M + D) in preventing delayed emesis in cancer patients receiving the same prophylaxis for acute emesis. A randomized double-blind study comparing A + D versus M + D was completed in previously untreated cancer patients. Before chemotherapy, all patients were treated with intravenous palonosetron 0.25 mg and dexamethasone 12 mg, and oral aprepitant 125 mg. On day 2-4, patients randomly received oral dexamethasone 8 mg plus aprepitant 80 mg once daily (days 2-3) or metoclopramide 20 mg four times daily plus dexamethasone 8 mg bid. Primary endpoint was rate of complete response (no vomiting, no rescue treatment) in day 2-5 after chemotherapy. Due to difficulty in the accrual of patients, 303 of the 480 planned patients were enrolled, 284 were fully evaluable, 147 receiving A + D, 137 M + D. Day 1 results were similar in both arms. On day 2-5, complete response rate was not significantly different (80.3% with A + D versus 82.5% with M + D, P < 0.38, respectively), and all secondary endpoints were also similar (complete protection, total control, no vomiting, no nausea, and score of Functional Living Index-Emesis; P < 0.24). Adverse events incidence was not significantly different between the two treatments. In cancer patients submitted to cisplatin-based chemotherapy, receiving the same antiemetic prophylaxis for acute emesis, A + D is not superior to M + D in preventing delayed emesis, and both treatments present similar toxicity. NCT00869310.


For balance in the historiography of psychology: Reply to Brock (2017).
Adrian Brock (2017) critiques my article (Lovett, 2006) on the new history of psychology. However, his critique repeatedly misrepresents my views. Moreover, he misrepresents the views of some new historians of psychology. I use a variety of examples from his paper to illustrate his misrepresentations, and I reply on each of these points. I conclude by reflecting more broadly on the issues raised by historiographic debates, especially with reference for the future of the history of psychology in psychology departments. (PsycINFO Database Record


A mutant of E. coli that restricts growth of bacteriophage T4 at elevated temperatures.
After nitrosoguanidine mutagenesis, a Phage Host Defective (phd) mutant of E. coli HfrH was isolated that supported the growth of T4D wild-type bacteriophage at 30 degrees, but not at 40 degrees or higher. Eleven independent spontaneous mutants of T4 (go mutants) were isolated that overcame the growth restriction at high temperature. All of these mutants were located within three percent recombination of a gene 39 amber mutation in the clockwise direction on the standard map. In mixed infections, the representative go mutant chosen for further study seems to be recessive to its wild-type allele. Temperature-shift experiments suggested that the mutated host function involved in phage growth is a "late" function, beginning in mid-eclipse.--Electrophoresis of phage proteins labelled early and late in infection showed that under restrictive conditions early protein synthesis was normal, but that certain late proteins were absent. However, measurements of DNA synthesis showed that under restrictive conditions the amount of phage DNA synthesized, and especially the amount of DNA sedimenting as high molecular weight replicative intermediate, was reduced. Pulse-chase experiments showed that the phage DNA made under restrictive conditions was not rapidly degraded.


Reliability of intravitreal nepafenac in rabbits.
The purpose of this experiment was to investigate the possible toxic effects of Nepafenac, a nonsteroidal anti-inflammatory molecule, after its intravitreal application in various concentrations. Forty pigmented rabbits were randomly divided into 4 groups, each including 10 rabbits. The active ingredient Nepafenac was prepared to be applied in different doses, for intravitreal use. Under topical anesthesia, following pupil dilatation, 0.3, 0.5, 0.75, and 1.5 mg doses of Nepafenac was applied intravitreally into the right eye. In each rabbit, the right eye was considered to be the study group. Saline was injected intravitreally into the left eye of each rabbit, and these eyes were considered to be the control group. Immediately after the injection and at the 1st, 4th, and 8th weeks, fundus examination by indirect ophthalmoscopy and intraocular pressure measurement were conducted. Furthermore, electroretinographic (ERG) recordings were taken at the 4th and 8th weeks. At the end of the 8th week, eyes of the surviving 26 rabbits were enucleated, and then animals were sacrificed. Following necessary fixation procedures, histopathological investigations were conducted by using a light and electron microscope. In the histological cross sections, differences between the eyes with injection and the control group were evaluated, and total retinal thickness, inner nuclear layer thickness, and outer nuclear layer thickness were measured. No pathology was found by clinical examination of either group. In the photopic and scotopic full-field ERG, conducted before the injection and in the 4th and 8th weeks after the injection, no statistically significant difference was determined between the study group and the control group. In the histological evaluation of the preparations, there were no statistically significant differences in the retina thickness of control and study groups. In the electron microscopic examinations, there were no toxicity findings in the eyes with injection. Our data show that intravitreal application of 0.3, 0.5, 0.75, and 1.5 mg doses of Nepafenac active substance is nontoxic to the rabbit retina.


Effects of repeated oral doses of dexnorfenfluramine on 5-HT levels and 5-HT uptake sites in rat brain.
The effects of oral dexnorfenfluramine (DNF; 1-4 mg/kg, twice daily for 4 days), the active metabolite of dexfenfluramine, were examined on rat regional brain indole contents and [3H]citalopram binding. Two hours after the last dose, serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) were dose-dependently lowered at doses above 1.5 mg/kg, with slight regional differences. Cortical 5-HT uptake sites were reduced only at the highest dose. Above 2 mg/kg DNF also caused a more lasting reduction (4 weeks) of regional indoles and cortical 5-HT uptake sites. At this longer time while the decrease in hippocampal 5-HT levels and cortical 5-HT uptake sites remained essentially constant, cortical and striatal 5-HT levels were lowered less than at 2 h, suggesting a return toward control values.