Radiobiological Optimization in Lung Stereotactic Body Radiation Therapy: Are We Ready to Apply Radiobiological Models?
Lung tumors are often associated with a poor prognosis although different schedules and treatment modalities have been extensively tested in the clinical practice. The complexity of this disease and the use of combined therapeutic approaches have been investigated and the use of high dose-rates is emerging as effective strategy. Technological improvements of clinical linear accelerators allow combining high dose-rate and a more conformal dose delivery with accurate imaging modalities pre- and during therapy. This paper aims at reporting the state of the art and future direction in the use of radiobiological models and radiobiological-based optimizations in the clinical practice for the treatment of lung cancer. To address this issue, a search was carried out on PubMed database to identify potential papers reporting tumor control probability and normal tissue complication probability for lung tumors. Full articles were retrieved when the abstract was considered relevant, and only papers published in English language were considered. The bibliographies of retrieved papers were also searched and relevant articles included. At the state of the art, dose-response relationships have been reported in literature for local tumor control and survival in stage III non-small cell lung cancer. Due to the lack of published radiobiological models for SBRT, several authors used dose constraints and models derived for conventional fractionation schemes. Recently, several radiobiological models and parameters for SBRT have been published and could be used in prospective trials although external validations are recommended to improve the robustness of model predictive capability. Moreover, radiobiological-based functions have been used within treatment planning systems for plan optimization but the advantages of using this strategy in the clinical practice are still under discussion. Future research should be directed toward combined regimens, in order to potentially improve both local tumor control and survival. Indeed, accurate knowledge of the relevant parameters describing tumor biology and normal tissue response is mandatory to correctly address this issue. In this context, the role of medical physicists and the AAPM in the development of radiobiological models is crucial for the progress of developing specific tool for radiobiological-based optimization treatment planning.


Clonal diversity of recurrently mutated genes in myelodysplastic syndromes.
Recent studies suggest that most cases of myelodysplastic syndrome (MDS) are clonally heterogeneous, with a founding clone and multiple subclones. It is not known whether specific gene mutations typically occur in founding clones or subclones. We screened a panel of 94 candidate genes in a cohort of 157 patients with MDS or secondary acute myeloid leukemia (sAML). This included 150 cases with samples obtained at MDS diagnosis and 15 cases with samples obtained at sAML transformation (8 were also analyzed at the MDS stage). We performed whole-genome sequencing (WGS) to define the clonal architecture in eight sAML genomes and identified the range of variant allele frequencies (VAFs) for founding clone mutations. At least one mutation or cytogenetic abnormality was detected in 83% of the 150 MDS patients and 17 genes were significantly mutated (false discovery rate ≤0.05). Individual genes and patient samples displayed a wide range of VAFs for recurrently mutated genes, indicating that no single gene is exclusively mutated in the founding clone. The VAFs of recurrently mutated genes did not fully recapitulate the clonal architecture defined by WGS, suggesting that comprehensive sequencing may be required to accurately assess the clonal status of recurrently mutated genes in MDS.


[Sclerosing stromal tumor of the ovary in a 30-year-old woman. A case report and review of the literature].
Sclerosing stromal tumor of the ovary (SST) is an extremely rare neoplasm occurring predominantly in the second and third decades of life. It is a distinct benign neoplasm that differs from fibromas, thecomas, luteinized tumors and lipoid cell tumors. It presents most often with non-specific symptoms. We describe the case of a 30-year-old woman who developed menstrual irregularities and pelvic pain. She was diagnosed and treated operatively at our Department. During surgery, a benign tumor was found in the right ovary. Light microscopic and ultrastructural study confirmed the diagnosis of sclerosing stromal tumor of the ovary.


Carbon monoxide: innovative anti-inflammatory properties of an age-old gas molecule.
Observations of the effects of carbon monoxide (CO) on mammalian systems have been known for thousands of years. To be sure, CO is deadly under certain conditions and concentrations, but perhaps as the data presented here will make clear, it also possesses other diverse functional and immunomodulatory properties. This review, together with the other reviews in this issue, will detail that over the past three decades, fundamental functional role(s) for this gas molecule are beginning to emerge. This review outlines that at low concentrations, exogenously administered CO is a molecule involved in the regulation of the inflammatory response in a variety of disease models. CO has been shown to modulate such cellular functions as cytokine production, cell proliferation and apoptosis, protecting the lungs and hearts of rodents from such stressors as endotoxin, ischemia/reperfusion injury, cardiac xenograft rejection, and asthma. Although the mechanism by which this simple diatomic gas provides this protection remains obscure, the conclusions are the same: CO at low concentrations, concentrations that are well below those that would otherwise create toxic effects, is proving beneficial in models of acute injury. CO, akin to nitric oxide, is proving to be an extraordinary signaling molecule generated by the cell that is vital in the regulation of cellular homeostasis.


Influence of the depletion region in GaAs/AlGaAs quantum well nanowire photodetector.
In semiconductor nanowire (NW) photodetectors, the Schottky barrier formed by the contact between metal and semiconductor can act as a depletion layer. For NW structures with a smaller diameter, the depletion region is especially important to the carrier transport. We prepared a GaAs/AlGaAs quantum well NW photodetector with a two-dimensional electron-hole tube, in which the two-dimensional hole tube (2DHT) formed by the inner layer of GaAs and AlGaAs has the most important role in the regulation of carriers. By adjusting the bias voltage to vary the depth of the depletion region, we have confirmed the influence of the depletion region in a 2DHT. A significant inflection point was found in the responsivity-voltage curve at 1.5 V. By combining the depletion region and 2DHT, the responsivity of the fabricated device was increased by 18 times to 0.199 A W-1 and the detectivity is increased by 5 times to 5.8 × 1010 Jones, compared to the pure GaAs NW photodetector. Reasonable combination of depletion layer and 2DHT was proved to promote high-performance NW photodetector.


Discovery and SAR of Natural-Product-Inspired RXR Agonists with Heterodimer Selectivity to PPARδ-RXR.
A known natural product, magnaldehyde B, was identified as an agonist of retinoid X receptor (RXR) α. Magnaldehyde B was isolated from Magnolia obovata (Magnoliaceae) and synthesized along with more potent analogs for screening of their RXRα agonistic activities. Structural optimization of magnaldehyde B resulted in the development of a candidate molecule that displayed a 440-fold increase in potency. Receptor-ligand docking simulations indicated that this molecule has the highest affinity with the ligand binding domain of RXRα among the analogs synthesized in this study. Furthermore, the selective activation of the peroxisome proliferator-activated receptor (PPAR) δ-RXR heterodimer with a stronger efficacy compared to those of PPARα-RXR and PPARγ-RXR was achieved in luciferase reporter assays using the PPAR response element driven reporter (PPRE-Luc). The PPARδ activity of the molecule was significantly inhibited by the antagonists of both RXR and PPARδ, whereas the activity of GW501516 was not affected by the RXR antagonist. Furthermore, the molecule exhibited a particularly weak PPARδ agonistic activity in reporter gene assays using the Gal4 hybrid system. The obtained data therefore suggest that the weak PPARδ agonistic activity of the optimized molecule is synergistically enhanced by its own RXR agonistic activity, indicating the potent agonistic activity of the PPARδ-RXR heterodimer.


Respiratory syncytial virus causes increased bronchial epithelial permeability.
Respiratory syncytial virus (RSV)-induced diseases are mediated through active cytokines released during infection. We hypothesized that RSV infection causes bronchial epithelial monolayer permeability in vitro via induction of vascular endothelial growth factor (VEGF). Human bronchial epithelial cells were infected with RSV. In some cultures, VEGF antibody was included to block VEGF response; in other cultures, palivizumab was added to block RSV infection. Permeability was assessed in real-time using electric cell-substrate impedance sensing. VEGF release was assessed using enzyme-linked immunosorbent assay. Gap formation was assessed using live cell imaging. RSV-infected cells demonstrated a decrease in the resistance of the monolayer indicating an increase in permeability; this increase was blocked with VEGF-specific antibody, and palivizumab. Intercellular gap formation developed in RSV-infected epithelial monolayers. RSV increases permeability of the bronchial airway epithelial monolayer via VEGF induction.


Evaluating the use of a novel low-cost measurement insole to characterise plantar foot strain during gait loading regimes.
Introduction: Under plantar loading regimes, it is accepted that both pressure and shear strain biomechanically contribute to formation and deterioration of diabetic foot ulceration (DFU). Plantar foot strain characteristics in the at-risk diabetic foot are little researched due to lack of measurement devices. Plantar pressure comparatively, is widely quantified and used in the characterisation of diabetic foot ulceration risk, with a range of clinically implemented pressure measurement devices on the market. With the development of novel strain quantification methods in its infancy, feasibility testing and validation of these measurement devices for use is required. Initial studies centre on normal walking speed, reflecting common activities of daily living, but evaluating response to differing gait loading regimes is needed to support the use of such technologies for potential clinical translation. This study evaluates the effects of speed and inclination on stance time, strain location and strain response using a low-cost novel strain measurement insole. Methods: The STrain Analysis and Mapping of the Plantar Aspect (STAMPS) insole has been developed, and feasibility tested under self-selected normal walking speeds to characterise plantar foot strain, with testing beyond this limited regime required. A treadmill was implemented to standardise speed and inclination for a range of daily plantar loading conditions. A small cohort, comprising of five non-diabetic participants, were examined at slow (0.75 m/s), normal (1.25 m/s) and brisk (2 m/s) walking speeds and normal speed at inclination (10% gradient). Results: Plantar strain active regions were seen to increase with increasing speed across all participants. With inclination, it was seen that strain active regions reduce in the hindfoot and show a tendency to forefoot with discretionary changes to strain seen. Stance time decreases with increasing speed, as expected, with reduced stance time with inclination. Discussion: Comparison of the strain response and stance time should be considered when evaluating foot biomechanics in diabetic populations to assess strain time interval effects. This study supports the evaluation of the STAMPS insole to successfully track strain changes under differing plantar loading conditions and warrants further investigation of healthy and diabetic cohorts to assess the implications for use as a risk assessment tool for DFU.


EMG-based facial gesture recognition through versatile elliptic basis function neural network.
Recently, the recognition of different facial gestures using facial neuromuscular activities has been proposed for human machine interfacing applications. Facial electromyograms (EMGs) analysis is a complicated field in biomedical signal processing where accuracy and low computational cost are significant concerns. In this paper, a very fast versatile elliptic basis function neural network (VEBFNN) was proposed to classify different facial gestures. The effectiveness of different facial EMG time-domain features was also explored to introduce the most discriminating. In this study, EMGs of ten facial gestures were recorded from ten subjects using three pairs of surface electrodes in a bi-polar configuration. The signals were filtered and segmented into distinct portions prior to feature extraction. Ten different time-domain features, namely, Integrated EMG, Mean Absolute Value, Mean Absolute Value Slope, Maximum Peak Value, Root Mean Square, Simple Square Integral, Variance, Mean Value, Wave Length, and Sign Slope Changes were extracted from the EMGs. The statistical relationships between these features were investigated by Mutual Information measure. Then, the feature combinations including two to ten single features were formed based on the feature rankings appointed by Minimum-Redundancy-Maximum-Relevance (MRMR) and Recognition Accuracy (RA) criteria. In the last step, VEBFNN was employed to classify the facial gestures. The effectiveness of single features as well as the feature sets on the system performance was examined by considering the two major metrics, recognition accuracy and training time. Finally, the proposed classifier was assessed and compared with conventional methods support vector machines and multilayer perceptron neural network. The average classification results showed that the best performance for recognizing facial gestures among all single/multi-features was achieved by Maximum Peak Value with 87.1% accuracy. Moreover, the results proved a very fast procedure since the training time during classification via VEBFNN was 0.105 seconds. It was also indicated that MRMR was not a proper criterion to be used for making more effective feature sets in comparison with RA. This work was accomplished by introducing the most discriminating facial EMG time-domain feature for the recognition of different facial gestures; and suggesting VEBFNN as a promising method in EMG-based facial gesture classification to be used for designing interfaces in human machine interaction systems.


An Automated Sitting Posture Recognition System Utilizing Pressure Sensors.
Prolonged sitting with poor posture can lead to various health problems, including upper back pain, lower back pain, and cervical pain. Maintaining proper sitting posture is crucial for individuals while working or studying. Existing pressure sensor-based systems have been proposed to recognize sitting postures, but their accuracy ranges from 80% to 90%, leaving room for improvement. In this study, we developed a sitting posture recognition system called SPRS. We identified key areas on the chair surface that capture essential characteristics of sitting postures and employed diverse machine learning technologies to recognize ten common sitting postures. To evaluate the accuracy and usability of SPRS, we conducted a ten-minute sitting session with arbitrary postures involving 20 volunteers. The experimental results demonstrated that SPRS achieved an impressive accuracy rate of up to 99.1% in recognizing sitting postures. Additionally, we performed a usability survey using two standard questionnaires, the System Usability Scale (SUS) and the Questionnaire for User Interface Satisfaction (QUIS). The analysis of survey results indicated that SPRS is user-friendly, easy to use, and responsive.


sMap3D Corneo-Scleral Topographer Repeatability in Scleral Lens Patients.
To determine repeatability of measurements using the sMap3D Corneo-Scleral Topographer in patients presenting for scleral lens fitting. As part of our standard clinical evaluation, 25 eyes of 23 patients who presented for scleral lens fitting were examined twice in the same day with the sMap3D in this retrospective study. Sagittal height (SAG), sMap3D principal toricity magnitude (as calculated by the instrument software), and steep axis location were measured at a 16-mm chord diameter. Up gaze, primary, and down gaze positions of each eye were imaged and "stitched" by the instrument software into a single corneoscleral topography map from which the measurements were derived. The mean difference in SAG between the 2 examinations was 14 μm with an SD of 55 μm. Sixty-eight percent of cases had a difference of ≤50 μm, and 95% of cases had a difference of ≤100 μm. The mean difference in sMap3D principal toricity magnitude between examinations was 0.15 diopter (D) with an SD of 0.38 D. Eighty-four percent of cases had a difference of ≤0.5 D, and all cases had a difference of <1 D. Mean toric axis difference between examinations was 2.5° with an SD of 18.4°. Sixty-four percent of cases had an axis difference of ≤10°, and 84% had an axis difference of ≤15°. The sMap3D measurements are repeatable with regard to scleral toricity and SAG values at a 16-mm diameter and thus would be suitable to use for scleral lens fitting.


Hypogammaglobulinemia with hyper-IgM, severe T-cell defect, and abnormal recirculation of OKT4 lymphocytes in a girl with chronic lymphadenopathy.
We describe here one 8-year-old girl with an unusual form of immunodeficiency, characterized by hypogammaglobulinemia with hyper-IgM, severe T-cell defect, and chronic lymphadenopathy. Patient's B cells failed to produce IgG or IgA in vitro following stimulation with either pokeweed mitogen or Epstein-Barr virus, suggesting an intrinsic B-cell defect. Abnormal T-cell function was demonstrated by impaired in vivo delayed type hypersensitivity, reduction of mitogen-induced proliferation and interleukin 2 production, reduction of interferon-gamma production, and marked decrease of circulating OKT4+ cells. The latter cells were found in normal proportion in the patient's lymph node tissue. This finding suggests that the decrease of OKT4+ cells in peripheral blood was due to the abnormal recirculation of these cells. The identity of this syndrome with the infantile form of the acquired immunodeficiency syndrome was apparently ruled out by the failure to demonstrate HTLV-III-related sequences in patient's lymphocytes or virus-specific serum antibodies.


Bilateral retinal hemorrhages after sequential endovascular treatment of bilateral unruptured cerebral aneurysms.
To report a case of bilateral retinal hemorrhages in a patient undergoing two separate endovascular interventions for bilateral cerebral aneurysms. A comprehensive ophthalmic examination was performed after the patient underwent each of two separate endovascular interventions for bilateral cerebral aneurysms. Multimodal imaging including widefield pseudocolor fundus photography, optical coherence tomography, and widefield fluorescein angiography (FA) was obtained. A systemic workup including genetic testing and hypercoagulability studies was performed. Dilated fundus examination revealed new visually significant ipsilateral retinal hemorrhages after each endovascular procedure. FA showed evidence of a peripheral retinal microangiopathy present in both eyes before the patient underwent her second endovascular procedure. Systemic workup revealed persistently elevated serum anticardiolipin IgM antibody levels at >99th percentile. Retinal complications after endovascular intracranial interventions are uncommon. This patient who developed bilateral retinal complications was found to have persistently elevated anticardiolipin antibody levels, a risk factor for thrombosis. Patients who develop retinal complications after endovascular intracranial intervention may benefit from systemic workup for hypercoagulable conditions.


Perfusion MRI abnormalities in speech or motor transient ischemic attack patients.
Transient ischemic attack (TIA) patients may deteriorate rapidly. MRI is being increasingly used to assess such patients. One possible mechanism of neurological worsening is the presence of perfusion abnormalities. We sought to identify what proportion of TIA patients had evidence of perfusion abnormalities on MRI. TIA patients were prospectively enrolled and had a MRI completed as soon as possible. The images were assessed for the presence of perfusion abnormalities. Sixty-nine TIA patients were enrolled, and 62 had perfusion imaging. In 56 patients (81%), the symptoms had resolved before imaging. In 21 patients (33.9%), there was evidence of a perfusion abnormality defined by relative mean transit time delay. In 12 patients (19.4%), the perfusion abnormality was present despite having complete resolution of neurological symptoms. We found no relationship between the presence of a perfusion abnormality and the clinical outcome. A proportion of TIA patients have perfusion abnormalities evident on MRI.


Using the Jigsaw Technique to Teach Clinical Controversy in a Clinical Skills Course.
To evaluate the effectiveness and student perception of the jigsaw technique to engage students in a clinical controversy exercise and to assess student engagement level during each step of the process. Students were assigned individual readings pertaining to the controversy surrounding the drug oxybutynin switching from prescription to nonprescription. They met with an expert group and teaching groups during mandatory laboratory time and worked together to formulate a recommendation on the appropriateness of nonprescription conversion for a drug. A quiz taken individually was used to measure effectiveness. Student perception and level of engagement was assessed using surveys. The jigsaw technique was successful in teaching the concepts involved in the clinical controversy. Group members rated themselves and fellow participants' level of engagement as high during both the expert group and teaching group sessions. Most students reported they learned about the same or more with the jigsaw technique compared to another cooperative learning technique used in the curriculum.


The Treatment of COVID-19 With Monoclonal Antibody Therapy: Patient-Reported Outcomes.
Objective There have been many efforts to research and produce treatment modalities for COVID-19. Monoclonal antibodies have been one of the effective treatments since their approval by the US Food and Drug Administration (FDA) under emergency use authorization (EUA) in 2020. This study surveyed COVID-19 patients about their disease course and experience with monoclonal antibody treatment. Methods Patients who received monoclonal antibody treatment between February 12, 2021, and June 2, 2021, at a South Florida community hospital were enrolled in the study. This included patients over 18 years of age with a confirmed positive COVID-19 test result, with mild to moderate symptoms within 10 days of onset and identified as high risk for progression to severe disease. There were no exclusion criteria. After 30 days, patients were followed up via a structured telephone survey regarding subsequent emergency department (ED) visits for worsening COVID-19 symptoms, need for oxygenation, intubation, and death. Secondary outcomes were adverse effects and patient perceptions. Results Among the 119 patients who received monoclonal antibodies during the established time frame, 93 (78.1%) consented to participate in the telephone survey. Of these, 11.8% had a subsequent visit to the ED for worsening COVID-19 symptoms, 6.5% required oxygen, and 2.2% were admitted to the intensive care unit (ICU). There were no reported intubations or deaths. The vast majority (91.4%) would recommend monoclonal antibody treatment to others. Conclusion Patients who received monoclonal antibody therapy had low rates of subsequent ED visits and rarely required oxygen or ICU admission. The majority of patients would recommend treatment with monoclonal antibodies to others.


Mechanics, growth, and class II corrections.
Growth of the orofacial region is quantitatively described by locating the center of mandibular rotation relative to the cranial base. The center of mandibular rotation is positioned by the ratio of vertical facial growth (AFH/PFH) and the direction of condylar growth. Appliance therapy is associated with changes in the means of both of these parameters. These changes reduce or stop favorable anterior mandibular rotation and redirect the mean condylar growth vector more posteriorly. When appliance therapy is stopped, these parameters return toward their resting values. The mean direction of the condylar growth vector became even more anteriorly directed after treatment than the pretreatment mean value. These data support the hypothesis that orthodontic appliances significantly alter the facial growth pattern and when they are stopped, the growth pattern tends to rebound to or beyond the pretreatment values.


MicroRNA-362-3p Inhibits Migration and Invasion via Targeting BCAP31 in Cervical Cancer.
Cervical cancer (CC) is the most common malignant tumor in gynecology, and metastasis is an important cause of patient death. MiRNAs (microRNAs) have been found to play key roles in cervical cancer metastasis, but the effect of miR-362-3p in CC is unclear. This study aimed to investigate the role of miR-362-3p in cervical cancer migration and invasion. We compared the expression levels of miR-362-3p in cervical cancer tissues and adjacent normal cervical tissues. In CC tissues, miR-362-3p expression was significantly down-regulated, which is related to the cancer stage and patient survival. MiR-362-3p can effectively inhibit the migration and invasion of cervical cancer cells. The dual-luciferase reporter assay results showed that BCAP31 (B cell receptor associated protein 31) is a direct target protein of miR-362-3p. The results of the immunohistochemical examination of clinical tissue samples showed that BCAP31 was abnormally highly expressed in cervical cancer, which was positively correlated with the clinical stage. BCAP31 knockdown exerted similar effects as miR-362-3p overexpression. Further GSEA analysis showed that BCAP31 may participate in multiple biological processes, such as protein transport, metabolism, and organelle organization. Our results suggest that miR-362-3p inhibits migration and invasion via directly targeting BCAP31 in cervical cancer, and restoring miR-362-3p levels may be a new treatment strategy for cervical cancer in the future.


Prevalence, seasonality, and growth of enterococci in raw and pasteurized milk in Victoria, Australia.
This study investigated the prevalence, seasonality, and species variety of enterococci present in raw milk factory silos and pasteurized milk in 3 dairying regions in Victoria, Australia, over a 1-yr period. Additionally, the growth ability of thermoduric enterococci isolated in this study (Enterococcus faecalis, E. faecium, E. hirae, and E. durans) was determined in milk at temperatures likely to occur during storage, transport, and distribution, and before domestic consumption (4 and 7°C). Enterococci were detected in 96% of 211 raw milk samples, with an average count of 2.48 log10 cfu/mL. Counts were significantly lower in winter than summer (average 1.84 log10 cfu/mL) and were different between factories but not regions. Enterococcus faecalis was the most prevalent species isolated from raw milk in every factory, comprising between 61.5 and 83.5% of enterococcal species across each season. Enterococci were detected in lower numbers in pasteurized milk than in raw milk and were below the limit of detection on spread plates (<10 cfu/mL) after factory pasteurization. Residual viable cells were only detected following enrichment using 100-mL samples of milk, with 20.8% of the samples testing positive; this equated to a decrease in the average raw milk enterococci count of >4 log10 cfu/mL following pasteurization. Although E. faecalis predominated in raw milk and E. durans was found in only 2.9% of raw milk samples, E. durans was the most prevalent species detected in pasteurized milk. The detection of enterococci in the pasteurized milk did not correlate with higher enterococci counts in the raw milk. This suggested that the main enterococci populations in raw milk were heat-sensitive and that thermoduric enterococci survived pasteurization in a small numbers of instances. All of the thermoduric enterococci that were assessed for growth at likely refrigeration temperatures were able to grow at both 4 and 7°C in sterile milk, with generation times of 35 to 41h and 16 to 22h, respectively. Thermoduric enterococci were detected in pasteurized milk stored at 4°C for 2 wk (typically 1 to 9 cells/100mL, up to 2.82 log10 cfu/mL), demonstrating the potential of enterococci to survive pasteurization and contribute to milk spoilage at refrigeration temperatures. This is particularly relevant for milk that is aseptically packaged to exclude gram-negative psychrotrophic bacteria and kept above the recommended storage temperature of ≤5°C.


Pregnancy following the "insensitive ovary syndrome".
A patient in whom the "insensitive ovary syndrome" was followed by a successful pregnancy is reported and discussed. Conception occurred while this patient was receiving estrogen therapy. The marked differences in her ovarian responsivity to endogenous and exogenous gonadotropin stimulation remain enigmatic.


Mutations in TBC1D24, a gene associated with epilepsy, also cause nonsyndromic deafness DFNB86.
Inherited deafness is clinically and genetically heterogeneous. We recently mapped DFNB86, a locus associated with nonsyndromic deafness, to chromosome 16p. In this study, whole-exome sequencing was performed with genomic DNA from affected individuals from three large consanguineous families in which markers linked to DFNB86 segregate with profound deafness. Analyses of these data revealed homozygous mutation c.208G>T (p.Asp70Tyr) or c.878G>C (p.Arg293Pro) in TBC1D24 as the underlying cause of deafness in the three families. Sanger sequence analysis of TBC1D24 in an additional large family in which deafness segregates with DFNB86 identified the c.208G>T (p.Asp70Tyr) substitution. These mutations affect TBC1D24 amino acid residues that are conserved in orthologs ranging from fruit fly to human. Neither variant was observed in databases of single-nucleotide variants or in 634 chromosomes from ethnically matched control subjects. TBC1D24 in the mouse inner ear was immunolocalized predominantly to spiral ganglion neurons, indicating that DFNB86 deafness might be an auditory neuropathy spectrum disorder. Previously, six recessive mutations in TBC1D24 were reported to cause seizures (hearing loss was not reported) ranging in severity from epilepsy with otherwise normal development to epileptic encephalopathy resulting in childhood death. Two of our four families in which deafness segregates with mutant alleles of TBC1D24 were available for neurological examination. Cosegregation of epilepsy and deafness was not observed in these two families. Although the causal relationship between genotype and phenotype is not presently understood, our findings, combined with published data, indicate that recessive alleles of TBC1D24 can cause either epilepsy or nonsyndromic deafness.


The New Red Algal Subphylum Proteorhodophytina Comprises the Largest and Most Divergent Plastid Genomes Known.
Red algal plastid genomes are often considered ancestral and evolutionarily stable, and thus more closely resembling the last common ancestral plastid genome of all photosynthetic eukaryotes [1, 2]. However, sampling of red algal diversity is still quite limited (e.g., [2-5]). We aimed to remedy this problem. To this end, we sequenced six new plastid genomes from four undersampled and phylogenetically disparate red algal classes (Porphyridiophyceae, Stylonematophyceae, Compsopogonophyceae, and Rhodellophyceae) and discovered an unprecedented degree of genomic diversity among them. These genomes are rich in introns, enlarged intergenic regions, and transposable elements (in the rhodellophycean Bulboplastis apyrenoidosa), and include the largest and most intron-rich plastid genomes ever sequenced (that of the rhodellophycean Corynoplastis japonica; 1.13 Mbp). Sophisticated phylogenetic analyses accounting for compositional heterogeneity show that these four "basal" red algal classes form a larger monophyletic group, Proteorhodophytina subphylum nov., and confidently resolve the large-scale relationships in the Rhodophyta. Our analyses also suggest that secondary red plastids originated before the diversification of all mesophilic red algae. Our genomic survey has challenged the current paradigmatic view of red algal plastid genomes as "living fossils" [1, 2, 6] by revealing an astonishing degree of divergence in size, organization, and non-coding DNA content. A closer look at red algae shows that they comprise the most ancestral (e.g., [2, 7, 8]) as well as some of the most divergent plastid genomes known.


Use of X-Ray and Neutron Scattering Methods with Volume Measurements to Determine Lipid Bilayer Structure and Number of Water Molecules/Lipid.
In this chapter I begin with a historical perspective of membrane models, starting in the early twentieth century. As these membrane models evolved, so did experiments to characterize the structure and water content of purified lipid bilayers. The wide-spread use of the X-ray gravimetric, or Luzzati method, is critically discussed. The main motivation of the gravimetric technique is to determine the number of water molecules/lipid, n(W), and then derive other important structural quantities, such as area/lipid, A(L). Subsequent experiments from the Nagle/Tristram-Nagle laboratory using X-ray and neutron scattering, first determine A(L) and then calculate n(W), using molecular lipid V(L) and water V(W) volumes. This chapter describes the details of our volume experiments to carefully measure V(L). Our results also determine n(W)', the steric water associated with the lipid headgroup, and how our calculated value compares to many literature values of tightly-associated headgroup water.


Effect of bottle colour and storage conditions on browning of orange wine.
We investigated the effect of bottle colour, storage temperature and storage time on the browning of orange wine. Kozan orange variety was used for the production of wine. The fermentation was performed spontaneously at 20 degrees C. The wine was bottled in three differently coloured bottles: clear white, green and brown. Then each was divided into two parts: one part was stored at 13-14 degrees C in the cellar and the other at 23-26 degrees C in the laboratory for 150 days. During the storage, browning index and ascorbic acid content of the wines were measured at day 0, 75 and 150. The results showed that the use of brown bottles and the short-time storage reduced the browning in orange wines, however, storage at two different temperatures did not significantly affect the browning index.


What messages can foster safer sex among young women? Experimental evidence concerning the role of emotions and moral norms.
Through a 2 × 2 × 2 quasi experimental design (N = 254), this research investigated if a social campaign eliciting positive emotions and activating moral norms might enhance condom negotiation skills, intended and estimated condom among young women with or without past sexual experience with casual partners. Emotions had a main effect on one of the six condom negotiation strategies we considered; for most of the other variables an interaction effect with moral norms and/or past behaviour emerged. Concerning estimated condom use, positive emotions worked better than negative ones when moral norms were salient. With respect to negotiations skills, positive rather than negative emotions seemed more effective for women with past causal sexual experience. In women without this kind of experience, positive emotions seemed to work better when moral norms were salient. Moral norms had a main effect on negotiation self-efficacy, but not in the predicted direction: when moral norms were more salient women were found to be less confident about their negotiation ability. These results suggest that a message which makes moral norms salient should at the same time elicit positive emotions in order to be effective; moreover, messages should be carefully tailored according to women's past behaviour.


[Home monitoring of patients after prosthetic valve replacement. Early detection of valve dysfunction].
Despite enormous progress concerning material and design, patients with artificial heart valves still face a considerable risk of serious complications (e.g., hemorrhage, thromboemboli, redos) which sum up to 4.9-22.4% for the first 10 postoperative years depending on type and position of the implanted prosthetic valve. Nowadays, technical defects of mechanical valves are negligible and relevant complications are rather a consequence of long-term anticoagulation therapy. To avoid these complications, the authors consider a strict control of both the anticoagulation therapy and the functional integrity of the prosthetic valve to be inevitable. Therefore, with the aim of risk minimization the patient should be enabled to cooperate by means of methods which are easy to handle in his everyday environment. First multicentric results of a new method of early detection of valve dysfunction are presented.


Microbiologic assessments to enhance periodontal diagnosis.
Associations between microbes and progressive periodontal lesions provide the biologic rationale for using specific organisms as bacteriologic markers for disease activity. Rapid, specific and relatively inexpensive laboratory tests to identify bacteria have facilitated increased testing by clinicians. However, assays must be interpreted with regard to current concepts of etiology and pathogenesis of periodontal diseases. This paper addresses commonly used microbiologic assays and their shortcomings.


[Study on the relationship between airway bacterial infections and acute exacerbations in patients with chronic obstructive pulmonary disease].
The purpose of this study was to observe the bacterial infections of respiratory tract in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD). 130 patients with AECOPD in outpatient department, emergency room or in wards were studied prospectively. Patients were divided into different groups according to both Anthonisen's classification and their lung function status. Sputum were cultured together with bacteria positive rate and types of AECOPD as well as the damage degree of lung function were analyzed. Of 130 sputum samples, 50 showed positive through culture (38.5%) and 60 strains of pathogens were isolated. Predominant pathogens isolated would include Haemophilus parainfluenzae (20/60), Streptococcus pneumoniae (5/60) and Haemophilus influenzae (10/60). Positive rate of bacterial culture in type 1 AECOPD was 55.0%, higher than those of type 2 (38.3%) and type 3 (18.5%)(P = 0.01) and was increasing with the decrease of lung function of patients with AECOPD (P < 0.02). Positive rate of bacterial culture in patients of type 1 AECOPD was the highest one. Haemophilus parainfluenzae was one of the most important pathogens in AECOPD. There seemed a correlation between positive result of bacterial culture and the severity of COPD.


Aggressive simultaneous radiochemotherapy with cisplatin and paclitaxel in combination with accelerated hyperfractionated radiotherapy in locally advanced head and neck tumors. Results of a phase I-II trial.
Simultaneous radiochemotherapy (sRCT) is the treatment of first choice in locally advanced head and neck cancers. We have tested a very aggressive combination protocol with cisplatin and escalated paclitaxel in combination with accelerated hyperfractionated radiotherapy to assess the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), overall toxicity, and response rate. The trial recruited 24 patients (21 males, three females, mean age 57 years) treated at our department from 1998 through 2001. Irradiation was administered in daily doses of 2 Gy up to 30 Gy followed by 1.4 Gy twice daily up to 70.6 Gy to the primary tumor and involved nodes and 51 Gy to the clinically negative regional nodes. The chemotherapy schedule included cisplatin in a fixed dose of 20 mg/m(2) on days 1-5 and 29-33 and paclitaxel at increasing dose levels of 20, 25, 30 mg/m(2) twice weekly over the whole treatment time. Patients were recruited in cohorts of three to six, and the MTD was reached if two out of six patients in one cohort developed DLT. DLT was defined as any grade 4 toxicity or any grade 3 toxicity requiring treatment interruption or unplanned hospitalization or any grade 3 neurotoxicity. We recruited mainly patients with large tumors for this protocol; all patients were stage IV, and the mean tumor volume (primary + metastases) amounted to 72 +/- 61 cm(3). The mean follow-up was 30 months (range 4-39 months). One early death (peritonitis and sepsis at day 10) occurred, and 23 patients were evaluable for acute toxicity and response. The MTD of paclitaxel was reached at the third dose level (30 mg/m(2) paclitaxel twice weekly). The DLT was severe mucositis grade 3 (n = 1) and skin erythema grade 4 (n = 2). After determining the MTD, another 14 patients were treated at the recommended dose level of paclitaxel with 25 mg/m(2) twice weekly. In summary, 13/23 patients (57%) developed grade 3 and 10/23 (43%) grade 2 mucositis. Two patients (9%) had grade 4, five (22%) grade 3, and 16 (69%) grade 2 dermatitis. One patient died at day 30 of neutropenic infection. In one patient, a grade 2 nephrotoxicity appeared requiring cessation of cisplatin chemotherapy. 18/23 patients (78%) required blood transfusion (1-3 units) and 16/23 (70%) i.v. antibiotics. 14 patients (61%) achieved a complete and nine (39%) a partial remission, yielding an overall response rate of 100%. In summary, six patients died of local tumor progression (n = 2), distant metastases (n = 2), or therapy-related complications (n = 2) during follow-up. The 3-year overall survival was 71%. Tumor volume was not a risk factor for failure in this protocol (mean tumor volume in relapse-free vs. progressive patients 71 +/- 65 cm(3) vs. 64 +/- 38 cm(3)). All patients have, so far, developed only slight late effects (fibrosis, lymphedema) with no grade 3-4 late sequelae. This very aggressive sRCT protocol yielded excellent response and survival figures but was associated with a very high rate of acute toxicity (8% therapy-related deaths). A maximal supportive treatment is therefore required.


Protein enrichment of apple pomace and use in feed for Nile tilapia.
The purpose of this paper is to investigate the protein enrichment of apple pomace by Gongronella butleri through solid-state cultivation and addition of this material as feed for tilapia fry (Oreochromis niloticus). Factorial experimental design was used for the assessment of culture conditions to determine the effects of the source of nitrogen, initial moisture, and granulometry on the protein enrichment of apple pomace. During culture, the consumption of reducing sugars and the production of soluble protein were determined. The best conditions obtained were with urea (5% w/w), initial moisture of 70% and granulometry in the range from 0.85 to 1.70 mm, producing 19.63% of soluble protein. The fry submitted to the diet containing treated apple pomace presented an increase of 44% in body mass, demonstrating that apple pomace biotransformed may represent an excellent food supplement.


Large-scale proximity extension assay reveals CSF midkine and DOPA decarboxylase as supportive diagnostic biomarkers for Parkinson's disease.
There is a need for biomarkers to support an accurate diagnosis of Parkinson's disease (PD). Cerebrospinal fluid (CSF) has been a successful biofluid for finding neurodegenerative biomarkers, and modern highly sensitive multiplexing methods offer the possibility to perform discovery studies. Using a large-scale multiplex proximity extension assay (PEA) approach, we aimed to discover novel diagnostic protein biomarkers allowing accurate discrimination of PD from both controls and atypical Parkinsonian disorders (APD). CSF from patients with PD, corticobasal syndrome (CBS), progressive supranuclear palsy (PSP), multiple system atrophy and controls, were analysed with Olink PEA panels. Three cohorts were used in this study, comprising 192, 88 and 36 cases, respectively. All samples were run on the Cardiovascular II, Oncology II and Metabolism PEA panels. Our analysis revealed that 26 and 39 proteins were differentially expressed in the CSF of test and validation PD cohorts, respectively, compared to controls. Among them, 6 proteins were changed in both cohorts. Midkine (MK) was increased in PD with the strongest effect size and results were validated with ELISA. Another most increased protein in PD, DOPA decarboxylase (DDC), which catalyses the decarboxylation of DOPA (L-3,4-dihydroxyphenylalanine) to dopamine, was strongly correlated with dopaminergic treatment. Moreover, Kallikrein 10 was specifically changed in APD compared with both PD and controls, but unchanged between PD and controls. Wnt inhibitory factor 1 was consistently downregulated in CBS and PSP patients in two independent cohorts. Using the large-scale PEA approach, we have identified potential novel PD diagnostic biomarkers, most notably MK and DDC, in the CSF of PD patients.


Polyarticular disability: a functional assessment.
The purpose of this study was to design and evaluate a system for the functional evaluation of patients with polyarticular disease. A single assessment can be done in approximately 15 minutes. Extensive prior preparation is not required. The evaluation is reproducible and the numerical characterization agrees well with a physician's overall assessment of functional impairment. The subscores can be used independently of the total score to focus on specific areas of disability. Use of the evaluation in other institutions has produced a high degree of reliability. Statistical evaluation has demonstrated areas of weakness that have been eliminated or modified to increase reliability of the system.


Activation of cholecystokinin (CCK 1) and serotonin (5-HT 3) receptors increases the discharge of pancreatic vagal afferents.
Cholecystokinin and serotonin are released from the gastrointestinal tract in response to the products of digestion and play critical roles in mediating pancreatic secretion via vago-vagal reflex pathways. This study was designed to investigate the effects of activation of cholecystokinin CCK(1) and serotonin (5-hydroxytryptamine, 5-HT) 5-HT(3) receptors on pancreatic vagal afferent discharge and to determine whether there is an interaction between these receptors. Male Sprague Dawley rats anaesthetised with isoflurane (1.5%/100% O(2)) were used in all experiments. The effects of systemic administration of cholecystokinin and the serotonin 5-HT(3) receptor agonist phenylbiguanide on pancreatic vagal afferent discharge were recorded before and after administration of cholecystokinin CCK(1) and serotonin 5-HT(3) receptor antagonists. Cholecystokinin (0.1-10 microg/kg, i.v.) and phenylbiguanide (1 and 10 microg/kg, i.v.) increased pancreatic vagal afferent discharge dose-dependently. Cholecystokinin CCK(1) receptor antagonists, lorglumide (10 mg/kg, i.v.) and devazepide (0.5 mg/kg, i.v.), reduced cholecystokinin- and phenylbiguanide-induced increases in pancreatic vagal afferent discharge significantly (n=5, P<0.05). On the other hand, serotonin 5-HT(3) receptor blockade with granisetron (1 mg/kg, i.v.) or MDL72222 ([(1S,5R)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl] 3,5-dichlorobenzoate; 0.1 mg/kg, i.v.) inhibited the pancreatic vagal afferent discharge responses to phenylbiguanide but not those to cholecystokinin. This study has confirmed that cholecystokinin and phenylbiguanide activate pancreatic vagal afferent discharge via activation of cholecystokinin CCK(1) and serotonin 5-HT(3) receptors, respectively. In addition, it has demonstrated that (i) the serotonin 5-HT(3) agonist phenylbiguanide acts partly via an interaction with cholecystokinin CCK(1) receptors, and (ii) the actions of cholecystokinin are not dependent on serotonin 5-HT(3) receptor activation.


Self-Driven Desalination and Advanced Treatment of Wastewater in a Modularized Filtration Air Cathode Microbial Desalination Cell.
Microbial desalination cells (MDCs) extract organic energy from wastewater for in situ desalination of saline water. However, to desalinate salt water, traditional MDCs often require an anolyte (wastewater) and a catholyte (other synthetic water) to produce electricity. Correspondingly, the traditional MDCs also produced anode effluent and cathode effluent, and may produce a concentrate solution, resulting in a low production of diluate. In this study, nitrogen-doped carbon nanotube membranes and Pt carbon cloths were utilized as filtration material and cathode to fabricate a modularized filtration air cathode MDC (F-MDC). With real wastewater flowing from anode to cathode, and finally to the middle membrane stack, the diluate volume production reached 82.4%, with the removal efficiency of salinity and chemical oxygen demand (COD) reached 93.6% and 97.3% respectively. The final diluate conductivity was 68 ± 12 μS/cm, and the turbidity was 0.41 NTU, which were sufficient for boiler supplementary or industrial cooling. The concentrate production was only 17.6%, and almost all the phosphorus and salt, and most of the nitrogen were recovered, potentially allowing the recovery of nutrients and other chemicals. These results show the potential utility of the modularized F-MDC in the application of municipal wastewater advanced treatment and self-driven desalination.


Antithrombotic therapy of patients with atrial fibrillation discharged after major non-cardiac surgery. 1-year follow-up. Sub-analysis of PRAGUE 14 study.
The study investigated the discharge antithrombotic medication in patients with atrial fibrillation (AF) after major non-cardiac surgery and the impact on one-year outcomes. A subgroup of 366 patients (mean age 75.9±10.5 years, women 42.3%, acute surgery 42.9%) undergoing major non-cardiac surgery and having any form of AF (30.6% of the total population enrolled in the PRAGUE-14 study) was followed for 1 year. Antithrombotics (interrupted due to surgery) were resumed until discharge in 51.8% of patients; less frequently in men (OR 0.6 (95% CI 0.95 to 0.35); p = 0.029), and in patients undergoing elective surgery (OR 0.6 (95% CI 0.91 to 0.33); p = 0.021). Dual antiplatelet therapy was resumed more often (91.7%) in comparison to aspirin monotherapy (57.3%; p = 0.047), and vitamin K antagonist (56.3%; p = 0.042). Patients with AF had significantly higher one-year mortality (22.1%) than patients without AF (14.1%, p = 0.001). The causes of death were: ischaemic events (32.6% of deaths), bleeding events (8.1%), others (N = 51; 59.3%, 20 of them died due to cancer). Non-reinstitution of aspirin until discharge was associated with higher one-year mortality (17.6% vs. 34.8%; p = 0.018). Preoperatively interrupted antithrombotics were re-administrated at discharge only in half of patients with AF, less likely in male patients and those undergoing elective surgery. The presence of AF was recognized as a predictor of one-year mortality, especially if aspirin therapy was not resumed until discharge. ClinicalTrials.gov NCT01897220.


Gene of the month: the 2019-nCoV/SARS-CoV-2 novel coronavirus spike protein.
The year 2020 has seen a major and sustained outbreak of a novel betacoronavirus (severe acute respiratory syndrome (SARS)-coronavirus (CoV)-2) infection that causes fever, severe respiratory illness and pneumonia, a disease called COVID-19. At the time of writing, the death toll was greater than 120 000 worldwide with more than 2 million documented infections. The genome of the CoV encodes a number of structural proteins that facilitate cellular entry and assembly of virions, of which the spike protein S appears to be critical for cellular entry. The spike protein guides the virus to attach to the host cell. The spike protein contains a receptor-binding domain (RBD), a fusion domain and a transmembrane domain. The RBD of spike protein S binds to Angiotensin Converting Enzyme 2 (ACE2) to initiate cellular entry. The spike protein of SARS-CoV-2 shows more than 90% amino acid similarity to the pangolin and bat CoVs and these also use ACE2 as a receptor. Binding of the spike protein to ACE2 exposes the cleavage sites to cellular proteases. Cleavage of the spike protein by transmembrane protease serine 2 and other cellular proteases initiates fusion and endocytosis. The spike protein contains an addition furin cleavage site that may allow it to be 'preactivated' and highly infectious after replication. The fundamental role of the spike protein in infectivity suggests that it is an important target for vaccine development, blocking therapy with antibodies and diagnostic antigen-based tests. This review briefly outlines the structure and function of the 2019 novel CoV/SARS-CoV-2 spike protein S.


Tests of fetal wellbeing in the third trimester of pregnancy.
Five different products secreted by the fetoplacental unit into the maternal circulation were measured in 272 patients when they were 34 weeks pregnant. The most useful indicator of present pathology or future complications of pregnancy was a placental protein, pregnancy associated plasma protein. A which was raised in pre-eclamptic toxaemia, antepartum haemorrhage and premature labour. The highest values were recorded in pre-eclampsia before any signs of the disease were evident. Schwangerschafts protein 1 was also raised in pre-eclampsia and antepartum haemorrhage but only after the disease had presented. Placental lactogen was also raised in pre-eclampsia and its measurement may have some predictive value. Total oestriol was lowered in fetal growth retardation and the unconjugated steroid raised in pre-eclampsia and lowered in retarded fetal growth.


Antitumor activity of (R,R')-4-methoxy-1-naphthylfenoterol in a rat C6 glioma xenograft model in the mouse.
(R,R')-4-methoxy-1-naphthylfenoterol (MNF) inhibits cancer cell proliferation in vitro through cell-type specific modulation of β2-adrenergic receptor and/or cannabinoid receptor function. Here, we report an investigation into antitumor activity of MNF in rat C6 glioma cells. The potent antiproliferative action of MNF in these cells (IC50 of ∼1 nmol/L) was refractory to pharmacological inhibition of β2-adrenergic receptor while a synthetic inverse agonist of cannabinoid receptor 1 significantly blocked MNF activity. The antitumor activity of MNF was then assessed in a C6 glioblastoma xenograft model in mice. Three days after subcutaneous implantation of C6 cells into the lower flank of nude mice, these animals were subjected to i.p. injections of saline or MNF (2 mg/kg) for 19 days and tumor volumes were measured over the course of the experiment. Gene expression analysis, quantitative RT-PCR and immunoblot assays were performed on the tumors after treatment. Significant reduction in mean tumor volumes was observed in mice receiving MNF when compared with the saline-treated group. We identified clusters in expression of genes involved in cellular proliferation, as well as molecular markers for glioblastoma that were significantly downregulated in tumors of MNF-treated mice as compared to saline-injected controls. The efficacy of MNF against C6 glioma cell proliferation in vivo and in vitro was accompanied by marked reduction in the expression of cell cycle regulator proteins. This study is the first demonstration of MNF-dependent chemoprevention of a glioblastoma xenograft model and may offer a potential mechanism for its anticancer action in vivo.


Injuries of the ankle and foot.
The important points in evaluation of the traumatized foot and ankle are discussed in detail. Also considered are specific injuries, including contusion; injuries of the musculotendinous unit, ligaments, and capsule; stress fractures; and puncture wounds.


Effect of ribosome shielding on mRNA stability.
Based on the experimental evidence that translating ribosomes stabilize the mRNAs, we introduce and study a theoretical model for the dynamic shielding of mRNA by ribosomes. We present an improved fitting of published decay assay data in E. coli and show that only one third of the decay patterns are exponential. Our new transcriptome-wide estimate of the average lifetimes and mRNA half-lives shows that these timescales are considerably shorter than previous estimates. We also explain why there is a negative correlation between mRNA length and average lifetime when the mRNAs are subdivided in classes sharing the same degradation parameters. As a by-product, our model indicates that co-transcriptional translation in E. coli may be less common than previously believed.


Adoption of a Nationwide Shared Medical Record in France: Lessons Learnt after 5 Years of Deployment.
Information sharing among health practitioners, either for coordinated or unscheduled care, is necessary to guarantee care quality and patient safety. In most countries, nationwide programs have provided tools to support information sharing, from centralized care records to health information exchange between electronic health records (EHRs). The French personal medical record (DMP) is a centralized patient-controlled record, created according to the opt-in consent model. It contains the documents health practitioners voluntarily push into the DMP from their EHRs. Five years after the launching of the program in December 2010, there were nearly 570,000 DMPs covering only 1.5% of the target population in December 2015. Reasons for this poor level of adoption are discussed in the perspective of other countries' initiatives. The new French governmental strategy for the DMP deployment in 2016 is outlined, with the implementation of measures similar to the US Meaningful Use.


Effects of stimulus repetition on the naming behavior of an aphasic adult: a clinical report.
This report describes the content of a management program aimed at enhancing naming skills in an adult aphasic. A single therapeutic variable, stimulus repetition, was examined as to its effect upon the aims of the management program. The data indicate that large amounts of stimulus repetition did not enhance naming skills in this S more than did small amounts of stimulus repetition. More importantly, the data suggest that the application of a systematic management program did enhance the naming skills of this subject. The need to investigate the clinical effectiveness of routinely employed therapeutic variables is discussed.


[Incidence of vertigo and dizziness disorders at a university hospital].
Subjects were 626 patients reporting vertigo or dizziness seen at the University Hospital Department of Otolaryngology from April 2001 to September 2003. Patients were diagnosed based on diagnostic criteria prescribed by the Japan Society for Equilibrium Research. The most common peripheral vestibular disorder was benign paroxysmal positional vertigo (32%), followed by Meniere's disease (12%). All peripheral vestibular disorders accounted for 65%. Central vestibular disorder accounted for 7%, of which space-occupying lesions in the posterior fossa accounted for 1.0% and cerebral infarction 1.9%. Dizziness due to orthostatic hypotension accounted for 4.0%. Among past reports on clinical statistics of vertigo, the incidence of vertigo and dizziness disorders differed greatly, but our research and the past 2 reports based on diagnostic criteria prescribed by the Japan Society for Equilibrium Research showed almost the same incidence, i.e., BPPV of 30-40%, Meniere's disease of 7-10%, other peripheral vestibular disorders of 15-20%, and central vestibular disorder of 6-8%. Unified diagnostic criteria are thus important in the statistical analysis of vertigo disorders.


Radiomics in breast cancer classification and prediction.
Breast Cancer (BC) is the common form of cancer in women. Its diagnosis and screening are usually performed through different imaging modalities such as mammography, magnetic resonance imaging and ultrasound. However, mammography and ultrasound-imaging techniques have limited sensitivity and specificity both in identifying lesions and in differentiating malign from benign lesions, especially in presence of dense breast parenchyma. Due to the higher resolution of magnetic resonance images, MRI represents the method with the higher specificity and sensitivity among all the available tools, in both lesions' identification and diagnosis. However, especially for diagnosis, even MRI has limitations that are only partially solved if combined with mammography. Unfortunately, due to the limits of all these imaging tools, in order to have a certain diagnosis, patients often receive painful and costly bioptics procedures. In this context, several computational approaches have been developed to increase sensitivity, while maintaining the same specificity, in BC diagnosis and screening. Amongst these, radiomics has been increasingly gaining ground in oncology to improve cancer diagnosis, prognosis and treatment. Radiomics derives multiple quantitative features from single or multiple medical imaging modalities, highlighting image traits which are not visible to the naked eye and hence significantly augmenting the discriminatory and predictive potential of medical imaging. This review article aims to summarize the state of the art in radiomics-based BC research. The dominating evidence extracted from the literature points towards a high potential of radiomics in disentangling malignant from benign breast lesions, classifying BC types and grades and also in predicting treatment response and recurrence risk. In the era of personalized medicine, radiomics has the potential to improve diagnosis, prognosis, prediction, monitoring, image-based intervention, and assessment of therapeutic response in BC.


Cross-resistance between fluconazole and ravuconazole and the use of fluconazole as a surrogate marker to predict susceptibility and resistance to ravuconazole among 12,796 clinical isolates of Candida spp.
Cross-resistance within a class of antimicrobial agents is a problem that is often encountered with antibacterial agents, and it is also an issue with antifungal agents. A current example is ravuconazole, a new triazole antifungal with an expanded spectrum and potency against Candida spp., Aspergillus spp., and other opportunistic fungal pathogens. The present study addresses the issue of cross-resistance between fluconazole and ravuconazole and the use of fluconazole as a surrogate marker to predict the susceptibility of Candida spp. to ravuconazole. Reference broth microdilution MIC results for 12,796 strains of Candida spp. isolated from more than 200 medical centers worldwide were used. Ravuconazole MICs and tentative interpretive categories (susceptible, </=1 microg/ml; resistant, >/=2 microg/ml) were compared with those of fluconazole by using regression statistics and error rate bounding analyses. For all 12,796 isolates, the absolute categorical agreement rate was 92.5% (rate of false-susceptible results, or very major errors [VME], 0.1%). Ravuconazole was active (MIC, </=1 microg/ml) against 99.9% of the fluconazole-susceptible isolates, 96% of the fluconazole-susceptible dose-dependent isolates, and 49% of the fluconazole-resistant isolates, including 99% of the Candida krusei isolates. Since ravuconazole is 16- to 32-fold more potent than fluconazole, the performance of fluconazole as a surrogate marker for ravuconazole susceptibility was improved by designating those isolates with fluconazole MICs of </=32 microg/ml susceptible to ravuconazole, resulting in a categorical agreement rate of 98.3%, with a VME rate of 0.3% (99 and 0.4%, respectively, when C. krusei was omitted). Cross-resistance between fluconazole and ravuconazole applies most directly to fluconazole-resistant Candida glabrata and is variable among other species of Candida. Fluconazole may serve as a surrogate marker to predict the susceptibility of Candida spp. to ravuconazole.


Functional characterization of bacterial oligosaccharyltransferases involved in O-linked protein glycosylation.
Protein glycosylation is an important posttranslational modification that occurs in all domains of life. Pilins, the structural components of type IV pili, are O glycosylated in Neisseria meningitidis, Neisseria gonorrhoeae, and some strains of Pseudomonas aeruginosa. In this work, we characterized the P. aeruginosa 1244 and N. meningitidis MC58 O glycosylation systems in Escherichia coli. In both cases, sugars are transferred en bloc by an oligosaccharyltransferase (OTase) named PglL in N. meningitidis and PilO in P. aeruginosa. We show that, like PilO, PglL has relaxed glycan specificity. Both OTases are sufficient for glycosylation, but they require translocation of the undecaprenol-pyrophosphate-linked oligosaccharide substrates into the periplasm for activity. Whereas PilO activity is restricted to short oligosaccharides, PglL is able to transfer diverse oligo- and polysaccharides. This functional characterization supports the concept that despite their low sequence similarity, PilO and PglL belong to a new family of "O-OTases" that transfer oligosaccharides from lipid carriers to hydroxylated amino acids in proteins. To date, such activity has not been identified for eukaryotes. To our knowledge, this is the first report describing recombinant O glycoproteins synthesized in E. coli.


Hepatitis C virus entry into hepatocytes: molecular mechanisms and targets for antiviral therapies.
Hepatitis C virus (HCV) is a major cause of liver cirrhosis and hepatocellular carcinoma. Preventive modalities are absent and the current antiviral treatment is limited by resistance, toxicity, and high costs. Viral entry is required for initiation, spread, and maintenance of infection, and thus is a promising target for antiviral therapy. HCV entry is a highly orchestrated process involving viral and host cell factors. These include the viral envelope glycoproteins E1 and E2, CD81, scavenger receptor BI, and tight junction proteins claudin-1 and occludin. Recent studies in preclinical models and HCV-infected patients have demonstrated that the virus has developed multiple strategies to escape host immune responses during viral entry. These include evasion from neutralizing antibodies and viral spread by cell-cell transmission. These challenges have to be taken into account for the design of efficient antiviral strategies. Thus, a detailed understanding of the mechanisms of viral entry and escape is a prerequisite to define viral and cellular targets and develop novel preventive and therapeutic antivirals. This review summarizes the current knowledge about the molecular mechanisms of HCV entry into hepatocytes, highlights novel targets and reviews the current preclinical and clinical development of compounds targeting entry. Proof-of-concept studies suggest that HCV entry inhibitors are a novel and promising class of antivirals widening the preventive and therapeutic arsenal against HCV infection.


Elevator buttons as unrecognized sources of bacterial colonization in hospitals.
Elevators are ubiquitous and active inside hospitals, potentially facilitating bacterial transmission. The objective of this study was to estimate the prevalence of bacterial colonization on elevator buttons in large urban teaching hospitals. A total of 120 elevator buttons and 96 toilet surfaces were swabbed over separate intervals at 3 tertiary care hospitals on weekdays and weekends in Toronto, Ontario. For the elevators, swabs were taken from 2 interior buttons (buttons for the ground floor and one randomly selected upper-level floor) and 2 exterior buttons (the "up" button from the ground floor and the "down" button from the upper-level floor). For the toilet surfaces, swabs were taken from the exterior and interior handles of the entry door, the privacy latch, and the toilet flusher. Samples were obtained using standard bacterial collection techniques, followed by plating, culture, and species identification by a technician blind to sample source. The prevalence of colonization of elevator buttons was 61% (95% confidence interval 52%-70%). No significant differences in colonization prevalence were apparent in relation to location of the buttons, day of the week, or panel position within the elevator. Coagulase-negative staphylococci were the most common organisms cultured, whereas Enterococcus and Pseudomonas species were infrequent. Elevator buttons had a higher prevalence of colonization than toilet surfaces (61% v. 43%, p = 0.008). Hospital elevator buttons were commonly colonized by bacteria, although most pathogens were not clinically relevant. The risk of pathogen transmission might be reduced by simple countermeasures.


Dietary total antioxidant capacity and its association with sleep, stress, anxiety, and depression score: A cross-sectional study among diabetic women.
Diabetes as a common chronic disease leads to several serious disabilities and complications. Patients with type 2 diabetes are involved with psychological and sleep disorders which diet can be effective in the management of these problems. The present study aimed to investigate the association of Dietary Total Antioxidant Capacity (DTAC) and sleep, stress, anxiety, and depression among diabetic women. This cross-sectional study conducted on 265 women with type 2 diabetes. A validated food frequency questionnaire was filled to evaluate dietary intakes. We calculated DTAC based on amounts of antioxidant in each dietary item using the ferric reducing ability of plasma (FRAP) and oxygen radical absorbance capacity (ORAC) databases. Pittsburgh Sleep Quality Index was used to assess sleep quality. Moreover, 21 items Depression, Anxiety, and Stress Scale was used to assess mental disorders. Subjects in the highest tertile of FRAP and ORAC score compared to those in the lowest tertile of these scores had 94% and 87% lower risk of poor sleep, respectively. The odds of depression were negatively related to the highest tertile of FRAP and ORAC score (OR: 0.21, 95%CI: 0.09-0.50 and OR: 0.21, 95%CI: 0.10-0.48, respectively). Participants with the highest tertile of FRAP compared to those within the lowest tertile of FRAP score had a 59% lower risk of anxiety. The odds of stress were negatively related to the highest tertile of FRAP and ORAC score (OR: 0.10, 95%CI: 0.04-0.23 and OR: 0.13, 95%CI: 0.06-0.29, respectively). There is a significant association between DTAC, sleep status and psychological disorders. However, prospective studies in both genders should be conducted to confirm the actual relationship.


Risk factors associated with prolonged intubation and laryngeal injury.
A prospective study evaluated potential risk factors associated with laryngeal injury after prolonged endotracheal tube intubation for longer than 3 days. Ninety-seven patients were evaluated after oral endotracheal tube intubation (mean, 9 days). This study updates a previously reported evaluation of 44 patients. The additional sample size has provided findings of unreported patient risk factors of laryngeal injury and confirmation of previous associations. The majority of the 97 patients had some type of laryngeal injury, ranging from mild mucosal erythema to ulceration, granuloma formation, or true vocal cord immobility. Patient examinations were continued until the larynx returned to normal or stabilized or the patient was lost to follow-up. Postextubation examinations in the survival group revealed the following. (1) Laryngeal erythema occurred in 94%, and ulceration occurred in 76% of the patients with resolution within 6 weeks. (2) Laryngeal granulomas occurred in 44% of the patients; the majority of the granulomas (57%) developed an average of 4 weeks after extubation. Associated risk factors included duration of endotracheal tube intubation (p < 0.05) and presence of nasogastric tube (p < 0.05). (3) Vocal cord immobility was observed in 16 patients (20%). Eight patients had true vocal cord immobility noted initially after extubation, and the remaining eight had true vocal cord immobility an average of 4 weeks after extubation. Initial and delayed true vocal cord immobility were associated with duration of intubation and size of endotracheal tube (p < 0.01). Delayed true vocal cord immobility developed only in patients with a size 8 endotracheal tube.(ABSTRACT TRUNCATED AT 250 WORDS)


Mechanism of Hydrogen-Bonded Complex Formation between Ibuprofen and Nanocrystalline Hydroxyapatite.
Nanocrystalline hydroxyapatite (nanoHA) is the main hard component of bone and has the potential to be used to promote osseointegration of implants and to treat bone defects. Here, using active pharmaceutical ingredients (APIs) such as ibuprofen, we report on the prospects of combining nanoHA with biologically active compounds to improve the clinical performance of these treatments. In this study, we designed and investigated the possibility of API attachment to the surface of nanoHA crystals via the formation of a hydrogen-bonded complex. The mechanistic studies of an ibuprofen/nanoHA complex formation have been performed using a holistic approach encompassing spectroscopic (Fourier transform infrared (FTIR) and Raman) and X-ray diffraction techniques, as well as quantum chemistry calculations, while comparing the behavior of the ibuprofen/nanoHA complex with that of a physical mixture of the two components. Whereas ibuprofen exists in dimeric form both in solid and liquid state, our study showed that the formation of the ibuprofen/nanoHA complex most likely occurs via the dissociation of the ibuprofen dimer into monomeric species promoted by ethanol, with subsequent attachment of a monomer to the HA surface. An adsorption mode for this process is proposed; this includes hydrogen bonding of the hydroxyl group of ibuprofen to the hydroxyl group of the apatite, together with the interaction of the ibuprofen carbonyl group to an HA Ca center. Overall, this mechanistic study provides new insights into the molecular interactions between APIs and the surfaces of bioactive inorganic solids and sheds light on the relationship between the noncovalent bonding and drug release properties.


En bloc resection of the recurrent pleural mesothelioma and reconstruction of the chest wall after immunotherapy: A case report.
Malignant pleural mesothelioma (MPM) is associated with previous asbestos exposure, while more clinical insights into this disease have come from other case studies. Maximal cytoreduction is critical in disease control and might help to improve the prognosis. Here, a 41-year-old female presented with a 6-month history of a mass detected in the chest wall following resection of a right pleural mesothelioma 2 years previously. A fluorodeoxyglucose positron emission tomography/computed tomography scan showed a right chest wall mass with a blurred boundary 8.9 cm × 3.7 cm in size. The patient had received one cycle of bevacizumab, carboplatin, and pemetrexed, and two cycles of nivolumab, ipilimumab, and gemcitabine 5 months before admission. We subsequently resected the tumor, the involved diaphragm, and the fifth and sixth ribs, and titanium mesh and continuous suture were used to close the thoracic cage. The fixed paraffin-embedded tissues showed epithelioid pleural mesothelioma. The patient received nivolumab and ipilimumab postoperatively, and no recurrence was detected 16 months after surgery. En bloc resection with reconstructive surgery effectively removed the locally advanced malignancy and restored the biological function of the thorax with a favorable prognosis. Neoadjuvant immunotherapy might therefore be conducive to radical resection and perioperative immunotherapy might improve the prognosis.


[Between Freud and Ferenczi: their patients. One aspect of their relationship].
The importance given to the subject of patients and their treatment in the correspondence exchanged between Freud and Ferenczi for more than twenty-five years (1908-1933) is one aspect of the very dense relationship established betweem the two correspondents throughout this long period of time. The exchanges on the subject of their patients deal all at once with their psychoanalytic practice and the clinical, theoretical and technical problems it involved. Countertransference and the question of how to handle it within the psychoanalytic cure provide the main thread in their constant questioning about their treatments. Thus, a number of cures examined within this correspondence--those of friends or colleagues such as Ernest Jones, Anton von Freund, Elma Palos and Eugenia Sokolnicka--involved in each case specific counter-transferential problems that are evoked and commented upon. However it was the analysis that Ferenczi underwent with Freud (between 1914 and 1916) that definitively marked the relationship between the two protagonists, as well as playing a determining role relationship between the two protagonists, as well as playing a determining role in what they were most given to share as from then, that is, their analytic passion.


Using a Role-Play Simulation Game to Promote Systems Thinking.
Learning is a dynamic process where the learner discovers new knowledge and constructs new insights. The "Friday Night in the ER"© role-play simulation game facilitates system thinking, data-based decision making, and collaboration. Nurse educators in academe and health care settings can use this game to practice the essential skills of nurse professionals. J Contin Nurs Educ. 2018;49(1):10-11.


Aptasensor designed via the stochastic tunneling-basin hopping method for biosensing of vascular endothelial growth factor.
The Systematic Evolution Ligands by Exponential Enrichment (SELEX) is common used for selection of high affinity single-stranded DNA (ssDNA) aptamer with target protein. However, we do not know what the most stable configuration of the selected aptamer bound with target protein is. Therefore, a systematic search process using the stochastic tunneling-basin hopping (STUN-BH) method is proposed to find the most stable configuration of the ssDNA aptamer specific for vascular endothelial growth factor (VEGF) capture (AptVEGF; 5'-TGTGGGGGTGGACGGGCCGGGTAGA-3'). After the most stable configuration was obtained by the STUN-BH method, molecular dynamics (MD) simulation was carried out to investigate the thermal stability of AptVEGF/VEGF at 300 K in both vacuum and water. All molecular simulations were conducted with the large-scale atomic/molecular massively parallel simulator (LAMMPS), and the AMBER99SB force field was used to describe the atomic interactions for the current AptVEGF/VEGF system. The three most stable AptVEGF/VEGF configurations obtained by the STUN-BH method indicated that AptVEGF residues exhibit greater affinity for VEGF surface loop fragments as compared with surface alpha helix and beta sheet fragments. Results indicated that after the first AptVEGF (AptVEGF I) occupies most of the VEGF loop fragment, the second AptVEGF (AptVEGF II) is adsorbed by the rest of the VEGF loop fragment and the VEGF Chain B beta sheet fragment, resulting in a 24.8% reduction in binding strength as compared to that of AptVEGF I. Furthermore, when AptVEGF I and AptVEGF II chains were stably adsorbed by VEGF, the third AptVEGF (AptVEGF III) chain can only partially attach to VEGF, as confirmed by real AptVEGF-VEGF binding experiments. Lastly, we demonstrated that the aptasensor constructed according to MD simulation is highly sensitive for VEGF with a linear detection range of 10 pg/mL-10 ng/mL.


Noggin proteins are multifunctional extracellular regulators of cell signaling.
Noggin is an extracellular cysteine knot protein that plays a crucial role in vertebrate dorsoventral patterning. Noggin binds and inhibits the activity of bone morphogenetic proteins via a conserved N-terminal clip domain. Noncanonical orthologs of Noggin that lack a clip domain ("Noggin-like" proteins) are encoded in many arthropod genomes and are thought to have evolved into receptor tyrosine kinase ligands that promote Torso/receptor tyrosine kinase signaling rather than inhibiting bone morphogenic protein signaling. Here, we examined the molecular function of noggin/noggin-like genes (ApNL1 and ApNL2) from the arthropod pea aphid using the dorso-ventral patterning of Xenopus and the terminal patterning system of Drosophila to identify whether these proteins function as bone morphogenic protein or receptor tyrosine kinase signaling regulators. Our findings reveal that ApNL1 from the pea aphid can regulate both bone morphogenic protein and receptor tyrosine kinase signaling pathways, and unexpectedly, that the clip domain is not essential for its antagonism of bone morphogenic protein signaling. Our findings indicate that ancestral noggin/noggin-like genes were multifunctional regulators of signaling that have specialized to regulate multiple cell signaling pathways during the evolution of animals.


In vivo evaluation of liver function by multimodal imaging in an alcohol-induced liver injury model.
Visually evaluating liver function is a hot topic in hepatology research. There are few reliable and practical visualization methods for evaluating the liver function in vivo in experimental studies. In this study, we established a multimodal imaging approach for in vivo liver function evaluation and compared healthy mice with chronic alcoholic liver injury (cALI) model mice to explore its potential applicability in experimental research. In vivo fluorescence imaging (IVFI) technology was utilized to visually represent the clearance of indocyanine green from the liver of both healthy mice and mice with cALI. The reserve liver function was evaluated via IVFI using the Cy5.5-galactosylated polylysine probe, which targets the asialoglycoprotein receptor of hepatocytes. Hepatic microcirculation was assessed through laser speckle perfusion imaging of hepatic blood perfusion. The liver microstructure was then investigated by in vivo confocal laser endomicroscopy imaging. Finally, hepatic asialoglycoprotein receptor expression, histology, and the levels of serum alanine aminotransferase and aspartate aminotransferase were measured. In vivo multimodal imaging results intuitively and dynamically showed that indocyanine green clearance [mean ± standard deviation (SD): 30.83±14.71, 95% confidence interval (CI): 20.3 to 41.35], the fluorescence signal intensity (mean ± SD: 1,217.92±117.63; 95% CI: 1,148.38 to 1,290.84) and fluorescence aggregation area (mean ± SD: 5,855.80±1,271.81; 95% CI: 5,051.57 to 6,653.88) of Cy5.5-galactosylated polylysine targeting the asialoglycoprotein receptor, and hepatic blood perfusion (mean ± SD: 1,494.86±299.33; 95% CI: 1,316.98 to 1,690.16) in model mice were significantly lower than those in healthy mice (all P<0.001). Compared to healthy mice, the model mice exhibited a significant decline in liver asialoglycoprotein receptor expression (mean ± SD: 219.03±16.34; 95% CI: 208.97 to 230.69; P<0.001), increased serum alanine aminotransferase (mean ± SD: 149.70±47.89 U/L; 95% CI: 81.75 to 128.89; P=0.01) and aspartate aminotransferase levels (mean ± SD: 106.30±36.13 U/L; 95% CI: 122.01 to 180.17; P=0.021), hepatocyte swelling and deformation, disappearance of the hepatic cord structure, partial necrosis, and disintegration of hepatocytes. The imaging features of fluorescence signals in liver regions, hepatic blood perfusion and microstructure were biologically related to hepatic asialoglycoprotein receptor expression, serum indices of liver function, and histopathology in model mice. Utilizing in vivo multimodal imaging technology to assess liver function is a viable approach for experimental research, providing dynamic and intuitive visual evaluations in a rapid manner.


[Questionnaire on coping with current stress].
The stress and coping process questionnaire ("UBV") is a new situation-reaction instrument aiming at the multidimensional assessment of components and processes of stress and coping behavior. The subject evaluates on different scales his/her situation appraisals, emotional reactions, coping objectives and coping behaviors in relation to prototypical stressful situations as presented in three stages (begin, continuation, and positive or negative outcome). The article gives a summary of theoretical foundations of the questionnaire, its structure and scales, and a number of reliability and validity studies. The results of the studies suggest a great variety of possible applications of the questionnaire (which offers also preliminary stanine-norms) as in the clinical domain (e.g. anxiety disorders) as in the domain of health psychology. The instrument provides also intervention-oriented informations and applies to the evaluation of stress and coping treatment programs. It is available in a german, english and french version.


Fatigue presentation, severity, and related outcomes in a prospective cohort following post-COVID-19 hospitalization in British Columbia, Canada.
Increasing evidence on long-term health outcomes following SARS CoV-2 infection shows post-viral symptoms can persist for months. These symptoms are often consistent with those of Myalgic Encephalomyelitis or Chronic Fatigue Syndrome (ME/CFS). The aim of the present study was to examine the prevalence and outcome predictors of post-viral fatigue and related symptoms 3- and 6-months following symptom onset. A prospective cohort of patients hospitalized with Coronavirus disease (COVID-19) (n = 88) were recruited from a Post-COVID-19 Respiratory Clinic (PCRC) in Vancouver, Canada to examine predictors of long-term fatigue and substantial fatigue. Multivariable mixed effects analyses examined the relationship between patient predictors, including pre-existing comorbidities, patient reported outcome measures, and fatigue and substantial fatigue at follow-up. The number of patients experiencing fatigue or substantial fatigue at 3 months post-infection were 58 (67%) and 14 (16%) respectively. At 6 months these numbers declined to 47 (60%) patients experiencing fatigue and 6 (6%) experiencing substantial fatigue. Adjusted analysis, for sex, age, and time, revealed the number of pre-existing comorbidities to be associated with fatigue (OR 2.21; 95% CI 1.09-4.49; 0.028) and substantial fatigue (OR 1.73; 95% CI 1.06-2.95; 0.033) at 3 months follow-up. Except for shortness of breath, self-care, and follow-up time, all follow-up variables were found to be associated with fatigue and substantial fatigue at 3 months. Fatigue and substantial fatigue are common after COVID-19 infection but often diminish over time. A significant number of patients continue to exhibit long-term fatigue at 6 months follow-up. Further research is needed to clarify the causality of viral infections in the development and severity of fatigue as a symptom and in meeting post-viral fatigue syndrome or ME/CFS diagnostic criteria.


Impact of freeze-thaw cycles on circulating inflammation marker measurements.
Circulating inflammation markers are being increasingly measured in prospective cohorts to investigate cancer etiology. However, it is unclear how the measurements are affected by the freeze-thaw cycles of the specimens prior to marker analysis. We compared concentrations of 45 inflammation markers between paired serum vials of 55 participants in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial that have undergone one (T1), two (T2), and three (T3) freeze-thaw cycles at the time of assay. We computed the difference of analyte concentrations across paired vials (T1 vs. T2, T2 vs. T3) and tested whether the difference deviated from zero using the Wilcoxon signed-rank test. We also calculated Spearman rank correlation and weighted kappa statistics for T1 vs. T2 and T2 vs. T3 comparisons to assess agreement in rank ordering of subjects. Measurements between paired T1 and T2 samples were largely similar, with the difference not statistically deviating from zero for 36 of the 45 markers. In contrast, tests of the difference between paired T2 and T3 samples were statistically significant for 36 markers. However, the rank ordering of participants by marker concentration remained largely consistent across T2 and T3 samples, with Spearman correlation coefficients >0.8 for 42 markers and weighted kappas >0.7 for 37 markers. We recommend that studies measuring inflammation markers use previously unthawed specimens to the extent possible, or match on the number of prior freeze-thaw cycles in nested case-control studies.


Leptin-induced ER-α-positive breast cancer cell viability and migration is mediated by suppressing CCN5-signaling via activating JAK/AKT/STAT-pathway.
In menopausal women, one of the critical risk factors for breast cancer is obesity/adiposity. It is evident from various studies that leptin, a 16 kDa protein hormone overproduced in obese people, plays the critical role in neovascularization and tumorigenesis in breast and other organs. However, the mechanisms by which obesity influences the breast carcinogenesis remained unclear. In this study, by analyzing different estrogen receptor-α (ER-α)-positive and ER-α-negative BC cell lines, we defined the role of CCN5 in the leptin-mediated regulation of growth and invasive capacity. We analyzed the effect of leptin on cell viability of ER-α-positive MCF-7 and ZR-75-1 cell lines and ER-α-negative MDA-MB-231 cell line. Additionally, we also determined the effect of leptin on the epithelial-mesenchymal transition (EMT) bio-markers, in vitro invasion and sphere-formation of MCF-7 and ZR-75-1 cell lines. To understand the mechanism, we determined the impact of leptin on CCN5 expression and the functional role of CCN5 in these cells by the treatment of human recombinant CCN5 protein(hrCCN5). Moreover, we also determined the role of JAK-STAT and AKT in the regulation of leptin-induced suppression of CCN5 in BC cells. Present studies demonstrate that leptin can induce cell viability, EMT, sphere-forming ability and migration of MCF-7 and ZR-75-1 cell lines. Furthermore, these studies found that leptin suppresses the expression of CCN5 at the transcriptional level. Although the CCN5 suppression has no impact on the constitutive proliferation of MCF-7 and ZR-75-1 cells, it is critical for leptin-induced viability and necessary for EMT, induction of in vitro migration and sphere formation, as the hrCCN5 treatment significantly inhibits the leptin-induced viability, EMT, migration and sphere-forming ability of these cells. Mechanistically, CCN5-suppression by leptin is mediated via activating JAK/AKT/STAT-signaling pathways. These studies suggest that CCN5 serves as a gatekeeper for leptin-dependent growth and progression of luminal-type (ER-positive) BC cells. Leptin may thus need to destroy the CCN5-barrier to promote BC growth and progression via activating JAK/AKT/STAT signaling. Therefore, these observations suggest a therapeutic potency of CCN5 by restoration or treatment in obese-related luminal-type BC growth and progression.


[Insufficiency of the cervical lymph vessel system; lymphostatic encephalopathy and retinopathy following cervical block dissection].
There are no lymphatic vessels in the CNS, in the retina and in the optic disk. In spite of this, however, cervical lymphostasis will result in lymphostatic encephalopathy and ophthalmopathy.


CALLING SONG DISPLACEMENT IN A ZONE OF OVERLAP AND HYBRIDIZATION.
The ground crickets Allonemobius fasciatus and A. socius meet in a mosaic zone of overlap and hybridization stretching from the East Coast to at least Illinois. To test whether male calling song differences were enhanced in sympatry, we analyzed the songs of crickets from inside and outside the zone of overlap along two transects. No evidence of calling song displacement was found in A. socius males from populations within the zone of overlap. On the other hand, A. fasciatus displayed calling song displacement in three populations. Our results are consistent with the hypothesis that the selective pressure exerted by the challenge from a related species is frequency dependent. While not a conclusive demonstration, the observed shifts in calling song are strongly suggestive of reproductive character displacement.


Oxidative stress and nitric oxide are increased in obese children and correlate with cardiometabolic risk and renal function.
Oxidative stress and nitric oxide (NO) appear to represent important links between obesity and cardiovascular, metabolic and/or renal disease. We investigated whether oxidative stress and NO production/metabolism are increased in overweight and obese prepubertal children and correlate with cardiometabolic risk and renal function. We performed a cross-sectional evaluation of 313 children aged 8-9 years. Anthropometrics, 24-h ambulatory blood pressure, pulse wave velocity (PWV), insulin resistance (homoeostasis model assessment index (HOMA-IR)), inflammatory/metabolic biomarkers, estimated glomerular filtration rate (eGFR), plasma total antioxidant status (TAS), plasma and urinary isoprostanes (P-Isop, U-Isop), urinary hydrogen peroxide (U-H2O2), and plasma and urinary nitrates and nitrites (P-NOx, U-NOx) were compared among normal weight, overweight and obese groups, according to WHO BMI z-score reference. U-Isop were increased in the obese group, whereas U-NOx were increased in both overweight and obese children. U-Isop were positively correlated with U-H2O2, myeloperoxidase (MPO), high-sensitivity C-reactive protein, HOMA-IR and TAG. TAS correlated negatively with U-Isop and MPO and positively with PWV. HOMA-IR and U-H2O2 were associated with higher U-Isop, independently of BMI and eGFR, and total cholesterol and U-H2O2 were associated with U-NOx, independently of BMI, eGFR values and P-NOx concentration. In overweight and obese children, eGFR decreased across P-NOx tertiles (median: 139·3 (25th, 75th percentile 128·0, 146·5), 128·0 (25th, 75th percentile 121·5, 140·4), 129·5 (25th, 75th percentile 119·4, 138·3), P for linear trend=0·003). We conclude that oxidant status and NO are increased in relation to fat accumulation and, even in young children, they translate into higher values of cardiometabolic risk markers and affect renal function.


Visual Field Progression After Glaucoma Surgery in Pseudoexfoliation versus Primary Glaucoma.
To compare visual field progression in severity-matched pseudoexfoliation glaucoma (XFG) and primary glaucoma after intraocular pressure (IOP) reduction by filtering surgery. Patients with XFG (n=32), primary open-angle glaucoma (POAG, n=33) or primary angle closure glaucoma (PACG, n=28) that underwent routine cataract and glaucoma filtering surgery by the same surgeon (APR) between May 2017 and September 2021, were included for this prospective study. Rate of progression (ROP) was determined using guided progression analysis and compared between XFG and primary glaucoma. Multivariate regression was done to analyse the factors responsible for progression in each group. Visual field progression after surgery was noted in 48 eyes (n=11 XFG, 18 POAG and 19 PACG eyes) at a mean follow-up of 10±5.6 months after surgery with RVI seen in 18 of 48 eyes. The final IOP (p=0.8) and mean ROP (p=0.09) were not significantly different between XFG and primary glaucoma. The XFG eyes had a greater number of eyes (36%) showing an ROP worse than -5dB/yr, with 45% of eyes showing an IOP spike >5mm Hg, and a higher mean IOP spike between visits. The ROP in eyes with RVO and >5mm Hg IOP spikes was greater in XFG than in POAG or PACG. In the multivariate analysis, higher IOP fluctuations >5mm Hg, and associated retinal vein occlusions (RVO) were significant factors for visual progression greater than -5dB/year (R2=53.5%) in POAG and XFG eyes. Age, gender, baseline MD, and number of medications before surgery or at final follow-up did not influence visual progression rates in either group. A higher IOP fluctuation >5mm Hg and associated RVO were the significant factors predicting visual field progression after filtering surgery in XFG and POAG eyes. Control of both IOP-dependent and -independent mechanisms of VF progression is therefore essential in these eyes.


A review of pharmacogenetics of adverse drug reactions in elderly people.
Older adults are more susceptible to the prevalence of therapeutic failure and adverse drug reactions (ADRs). Recent advances in genomic research have shed light on the crucial role of genetic variants, mainly involving genes encoding drug-metabolizing enzymes, drug transporters and genes responsible for a compound's mechanism of action, in driving different treatment responses among individuals, in terms of therapeutic efficacy and safety. The interindividual variations of these genes may account for the differences observed in drug efficacy and the appearance of ADRs in elderly people. The advent of whole genome mapping techniques has allowed researchers to begin to characterize the genetic components underlying serious ADRs. The identification and validation of these genetic markers will enable the screening of patients at risk of serious ADRs and to establish personalized treatment regimens.The aim of this review was to provide an update on the recent developments in geriatric pharmacogenetics in clinical practice by reviewing the available evidence in the PubMed database to September 2012. A Pubmed search was performed (years 1999-2012) using the following two search strategies: ('pharmacogenomic' OR 'pharmacogenetic ') AND ('geriatric' or 'elderly ') AND 'adverse drug reactions'; [gene name] AND ('geriatric' or 'elderly ') AND 'adverse drug reactions', in which the gene names were those contained in the Table of Pharmacogenomic Biomarkers in Drug Labels published online by the US Food and Drug Administration ( http://www.fda.gov/drugs/scienceresearch/researchareas/pharmacogenetics/ucm083378.htm ). Reference lists of included original articles and relevant review articles were also screened. The search was limited to studies published in the English language.