Perspectives in immunotherapy: meeting report from the "Immunotherapy Bridge", Napoli, November 30th 2016.
The complex interactions between the immune system and tumors lead the identification of key molecules that govern these interactions: immunotherapeutics were designed to overcome the mechanisms broken by tumors to evade immune destruction. After the substantial advances in melanoma, immunotherapy currently includes many other type of cancers, but the melanoma lesson is essential to progress in other type of cancers, since immunotherapy is potentially improving clinical outcome in various solid and haematologic malignancies. Monotherapy in pre-treated NSCLC is studied and the use of nivolumab, pembrolizumab and atezolizumab as second-line of advanced NSCLC is demonstrated as well as first line monotherapy and combination therapy in metastatic NSCLC studied. Patients with HNSCC have immunotherapeutic promises as well: the FDA recently approved moAbs targeting immune checkpoint receptors. Nivolumab in combination with ipilumumab showed acceptable safety and encouraging antitumor activity in metastatic renal carcinoma. HCCs have significant amounts of genomic heterogeneity and multiple oncogenic pathways can be activated: the best therapeutic targets identification is ongoing. The treatment of advanced/relapsed EOC remain clearly an unmet need: a better understanding of the relevant immuno-oncologic pathways and their corresponding biomarkers are required. UC is an immunotherapy-responsive disease: after atezolizumab, three other PD-L1/PD-L1 inhibitors (nivolumab, durvalumab, and avelumab) were approved for treatment of platinum-refractory metastatic urothelial carcinoma. Anti-PD-1/PD-L1 monotherapy is associated with a modest response rate in metastatic breast cancer; the addition of chemotherapy is associated with higher response rates. Immunotherapy safety profile is advantageous, although, in contrast to conventional chemotherapy: boosting the immune system leads to a unique constellation of inflammatory toxicities known as immune-related Adverse Events (irAEs) that may warrant the discontinuation of therapy and/or the administration of immunosuppressive agents. Research should explore better combination with less side effects, the right duration of treatments, combination or sequencing treatments with target therapies. At present, treatment decision is based on patient's characteristics.


Ginkgo biloba extract EGb 761® in children with ADHD.
The side effects, nonresponse, and prejudices against conventional pharmacological treatments call for complementary or alternative medical treatments (CAM) for ADHD. One possible treatment, at least for cognitive problems, might be the administration of Ginkgo biloba, though evidence is currently rare. This study tests the clinical efficacy of a Ginkgo biloba special extract (EGb 761®) and its correlation with brain electrical activity in children with ADHD combined type according to DSM-IV. In this open clinical pilot study, EGb 761® was administered to 20 children with ADHD over 3 to 5 weeks. Dosage was increased to a maximum of 240 mg daily if attention problems persisted. Possible drug side effects were assessed using the Side Effect Rating Scale. Efficacy was assessed in a multilevel approach including clinical assessment, quality of life (QoL), as well as performance and preparatory brain-electrical activity evoked during a Continuous Performance Test (Cue-CNV in the CPT). A very low rate of mild adverse effects occurred during the observation period. Following EGb 761® administration, possible improvements in QoL, ADHD core symptoms as well as CPT performance were detected. Improved core symptoms were positively related to elevated CNV amplitude. This preliminary evidence suggests that EGb 761® at a maximal dosage of 240 mg daily might be a clinically useful alternative treatment for children with ADHD, but further evidence is required before firm conclusions can be made.


Bovine babesiosis: protection of cattle with culture-derived soluble Babesia bovis antigen.
Adult Hereford (Bos taurus) cattle were protected from severe reactions and death caused by the tick-borne protozoan hemoparasite Babesia bovis, 3 months after vaccination with a cell culture--derived immunogen. The immunogen consisted of filtered, freeze-dried supernatant fluid collected from long-term cultures of Babesia bovis in vitro. It was reconstituted with saponin adjuvant and injected twice subcutaneously at 2-week intervals. Serum collected from vaccinated cattle caused thickening of the merozoite surface coat, aggregation, and lysis of merozoites in vitro. This reaction was identical to that caused by serum from immune carrier cattle suggesting that the protective antigen present in culture fluids is merozoite surface coat antigen. No mortality occurred among vaccinated cattle, whereas mortality among unvaccinated cattle and Babesia bigemina--immune cattle was 62.5 percent indicating that immunity to bovine babesiosis is species-specific.


The Phenotypic Profile Associated With the FMR1 Premutation in Women: An Investigation of Clinical-Behavioral, Social-Cognitive, and Executive Abilities.
The FMR1 gene in its premutation (PM) state has been linked to a range of clinical and subclinical phenotypes among FMR1 PM carriers, including some subclinical traits associated with autism spectrum disorder (ASD). This study attempted to further characterize the phenotypic profile associated with the FMR1 PM by studying a battery of assessments examining clinical-behavioral traits, social-cognitive, and executive abilities in women carrying the FMR1 PM, and associations with FMR1-related variability. Participants included 152 female FMR1 PM carriers and 75 female controls who were similar in age and IQ, and screened for neuromotor impairments or signs of fragile X-associated tremor/ataxia syndrome. The phenotypic battery included assessments of ASD-related personality and language (i.e., pragmatic) traits, symptoms of anxiety and depression, four different social-cognitive tasks that tapped the ability to read internal states and emotions based on different cues (e.g., facial expressions, biological motion, and complex social scenes), and a measure of executive function. Results revealed a complex phenotypic profile among the PM carrier group, where subtle differences were observed in pragmatic language, executive function, and social-cognitive tasks that involved evaluating basic emotions and trustworthiness. The PM carrier group also showed elevated rates of ASD-related personality traits. In contrast, PM carriers performed similarly to controls on social-cognitive tasks that involved reliance on faces and biological motion. The PM group did not differ from controls on self-reported depression or anxiety symptoms. Using latent profile analysis, we observed three distinct subgroups of PM carriers who varied considerably in their performance across tasks. Among PM carriers, CGG repeat length was a significant predictor of pragmatic language violations. Results suggest a nuanced phenotypic profile characterized by subtle differences in select clinical-behavioral, social-cognitive, and executive abilities associated with the FMR1 PM in women.


Internal Mammary Vessels: Alternate Recipient Vessels in Microvascular Head and Neck Reconstruction.
The application of microvascular free tissue transfer for reconstruction of the head and neck is well established. Improved outcomes, as well as surgical and technologic advances, have broadened the applications of microvascular free flaps in these defects. Postoperative complications such as pharyngocutaneous fistulas, tracheal or esophageal stenoses, or recurrent pathology may occasionally require secondary or even tertiary reconstruction with free tissue transfers. The disrupted anatomy and fibrotic changes resulting from primary reconstruction, neck dissection, and irradiation present the surgeon with a high risk of provoking vascular or nervous injury when dissecting in previously operated or irradiated sites. This prompts a search for alternative recipient vessels for microvascular anastomosis. The transverse cervical, inferior thyroid, and thyrocervical trunk arteries have all been proposed as alternative recipient vessels. The internal mammary vessels (IMVs) have a proven record in breast reconstruction, but recently have been found to have an application in special circumstances in head and neck reconstruction. This investigation describes the advantages of the IMVs as suitable recipient vessels for head and neck reconstruction when access to traditional vasculature is unavailable.


Structure-Property Relations in Polymer:Fullerene Blends for Organic Solar Cells.
Organic solar cells consist of thin films combining an electron donor (often a conjugated polymer) with an electron acceptor (often a fullerene derivative), in a blend commonly referred to as bulk heterojunction material. Charge separation between the donor and the acceptor leads to the generation of carriers, which can be extracted from photovoltaic devices in the form of photocurrent. The generation mechanism of free, extractable charges has caused a lot of controversial discussion in literature. Our research has shown that all the steps involved in charge generation are strongly dependent on the arrangement of the donor and the acceptor (i.e. the structure) of the bulk heterojunction.


Impact of serum hepatocyte growth factor on treatment response to epidermal growth factor receptor tyrosine kinase inhibitors in patients with non-small cell lung adenocarcinoma.
The epidermal growth factor receptor (EGFR) mutation status has emerged as a validated biomarker for predicting the response to treatment with EGFR-tyrosine kinase inhibitors (EGFR-TKI) in patients with non-small cell lung cancer. However, the responses to EGFR-TKIs vary even among patients with EGFR mutations. We studied several other independently active biomarkers for EGFR-TKI treatment. We retrospectively analyzed the serum concentrations of 13 molecules in a cohort of 95 patients with non-small cell lung adenocarcinoma who received EGFR-TKI treatment at three centers. The pretreatment serum concentrations of amphiregulin, β-cellulin, EGF, EGFR, epiregulin, fibroblast growth factor-basic, heparin-binding EGF-like growth factor, hepatocyte growth factor (HGF), platelet-derived growth factor β polypeptide, placental growth factor, tenascin C, transforming growth factor-α, and vascular endothelial growth factor (VEGF) were measured using enzyme-linked immunosorbent assay and a multiplex immunoassay system. The associations between clinical outcomes and these molecules were evaluated. The concentrations of HGF and VEGF were significantly higher among patients with progressive disease than among those without progressive disease (P < 0.0001). HGF and VEGF were strongly associated with progression-free survival (PFS) and overall survival (OS) in a univariate Cox analysis (all tests for hazard ratio showed P < 0.0001). A stratified multivariate Cox model according to EGFR mutation status (mutant, n = 20; wild-type, n = 23; unknown, n = 52) showed that higher HGF levels were significantly associated with a shorter PFS and OS (P < 0.0001 for both PFS and OS). These observations were also consistent in the subset analyses. Serum HGF was strongly related to the outcome of EGFR-TKI treatment. Our results suggest that the serum HGF level could be used to refine the selection of patients expected to respond to EGFR-TKI treatment, warranting further prospective study.


Self-averaging in the random two-dimensional Ising ferromagnet.
We study sample-to-sample fluctuations in a critical two-dimensional Ising model with quenched random ferromagnetic couplings. Using replica calculations in the renormalization group framework we derive explicit expressions for the probability distribution function of the critical internal energy and for the specific heat fluctuations. It is shown that the disorder distribution of internal energies is Gaussian, and the typical sample-to-sample fluctuations as well as the average value scale with the system size L like ∼Llnln(L). In contrast, the specific heat is shown to be self-averaging with a distribution function that tends to a δ peak in the thermodynamic limit L→∞. While previously a lack of self-averaging was found for the free energy, we here obtain results for quantities that are directly measurable in simulations, and implications for measurements in the actual lattice system are discussed.


Polychlorinated biphenyls: metabolic behavior of pure isomers in pigeons, rats, and brook trout.
The metabolic behavior of pure mono-, di-, tetra-, and hexachlorobiphenyl isomers in pigeons, rats, and brook trout was investigated. Excreta from these animals were extracted and examined by chromatographic and mass spectrometric techniques. The results showed conversion of the 4-chloro-, 4,4'-dichloro-, and 2,2',5,5'-tetrachlorobiphenyl isomers into monohydroxylated derivatives by the rat and pigeon whereas no hydroxymetabolites were detected in the excreta of the brook trout. No hydroxylated products of 2,2',4,4',5,5'-hexachlorobiphenyl were detected in the excreta of pigeons, rats, or brook trout.


Cortical mechanisms for afterimage formation: evidence from interocular grouping.
Whether the retinal process alone or retinal and cortical processes jointly determine afterimage (AI) formation has long been debated. Based on the retinal rebound responses, recent work proposes that afterimage signals are exclusively generated in the retina, although later modified by cortical mechanisms. We tested this notion with the method of "indirect proof". Each eye was presented with a 2-by-2 checkerboard of horizontal and vertical grating patches. Each corresponding patch of the two checkerboards was perpendicular to each other, which produces binocular rivalry, and can generate percepts ranging from complete interocular grouping to either monocular pattern. The monocular percepts became more frequent with higher contrast. Due to adaptation, the visual system is less sensitive during the AIs than during the inductions with AI-similar contrast. If the retina is the only origin of AIs, comparable contrast appearance would require stronger retinal signals in the AIs than in the inductions, thus leading to more frequent monocular percepts in the AIs than in the inductions. Surprisingly, subjects saw the fully coherent stripes significantly more often in AIs. Our results thus contradict the retinal generation notion, and suggest that in addition to the retina, cortex is directly involved in the generation of AI signals.


Is a Combination of the Serratus Intercostal Plane Block and Rectus Sheath Block Superior to the Bilateral Oblique Subcostal Transversus Abdominis Plane Block in Laparoscopic Cholecystectomy?
The serratus intercostal plane block (SIPB) is a recently defined interfascial plane block. The oblique subcostal transversus abdominis plane block (OSTAP) is another type of interfascial plane block, and it is also used as a part of multimodal analgesia in patients undergoing laparoscopic cholecystectomy (LC). In this retrospective study, we evaluated the effects of the bilateral OSTAP and a combination of the right SIPB and bilateral rectus sheath block (RSB) on the postoperative pain and analgesia requirement in patients undergoing LC. Data of the patients who underwent LC between May 2018 and November 2018 were evaluated retrospectively. Postoperative pain was evaluated using the numeric rating scale (NRS), and 24-hour tramadol consumption and rescue analgesia requirements were compared. Bilateral OSTAP was applied to 47 patients, and SIPB+RSB was applied to 25 patients. Postoperative pain scores were similar between the two groups. In the first 24 hours, tramadol requirement in the SIPB+RSB group was significantly lower than in the OSTAP block group (p<0.001). There was no statistically significant difference between the NRS averages at different time frames between the two block groups. We found that when SIPB is used as a part of multimodal analgesia in a combination with RSB in LS, it improves the quality of analgesia and decreases the analgesic requirement compared to patients undergoing a bilateral OSTAP block. Randomized controlled trials are necessary to compare the effects of SIPB alone and in a combination with other blocks in LC.


The critical features and the mechanism of inhibition of a kinase interaction motif-based peptide inhibitor of JNK.
We previously reported that a small peptide based on amino acids 143-153 of the c-Jun N-terminal kinase (JNK)-binding domain of JIP-1 functioned as an in vitro inhibitor of JNK activity. This peptide (TI-JIP: RP-KRPTTLNLF) resembles the kinase-interaction motif (KIM = (K/R)(2-3)X(1-6)(L/I)X(L/I)), which is common to upstream activators, downstream substrates, phosphatases, and scaffold proteins present in MAPK cascades. In this study, we characterized the mechanism of JNK inhibition by this peptide and further investigated the biochemical features of this peptide resulting in potent JNK inhibition. We also tested various KIM-based peptides for their ability to inhibit JNK activity. TI-JIP was found to be competitive with respect to the phosphoacceptor substrate c-Jun (K(I) = 0.39 +/- 0.08 microm), and exhibit mixed (non-competitive) inhibition with respect to ATP. All seven substitutions of Pro-5 we tested significantly reduced the JNK inhibition, as did altering the Pro-5 to Leu-8 spacing. When we independently tested eight substitutions of either Thr-6 or Thr-7, only one substitution in each position was well tolerated. Furthermore, peptides based on the KIMs from other proteins were significantly less potent JNK inhibitors than TI-JIP, including a peptide from the JNK interactor Sab that contained all critical inhibitory residues present in TI-JIP. Therefore, despite having previously identified Arg-4, Pro-5, Leu-8, and Leu-10 in TI-JIP as independently critical for mediating JNK inhibition, we find their presence in other 11-mer peptides is not sufficient for JNK inhibition. TI-JIP is therefore a unique KIM-based inhibitor of JNK activity.


Transient laser frequency modulation spectroscopy.
Explicitly time-dependent implementations of optical frequency modulation spectroscopy have been recently applied to a wide range of problems in chemical physics. We provide a brief description of the methodology, with an emphasis on its intrinsic advantages for interrogating transient species. Several examples highlight the application of the technique to high-resolution absorption spectra of free radicals, rate measurements for gas-phase reactions, and Doppler spectroscopy of the gas-phase products of photoinitiated reactions.


[Effects of partial colonic resection in rats].
In order to study the effects of partial colectomy, 30 rats Wistar were divided into three groups: GI and GII had the cecun and the ileo cecal valve resected and proximal colectomy was performed in GI and distal in GII. GIII had distal colectomy without cecum resection. The length of the remain colon was of 5 cm in all groups. Colostomy was performed in GI, GII and GIII. Parameters evaluated: body weight, fecal composition concerning to water, lipids and proteins on preoperative time and on the 10th, 20th, 30th, 40th, 50th and 60th days of postoperative time. All statistical tests were conducted at a 5% two-sided risk level. The evaluation was made by analysis of variance techniques. Concerning to body weight, there is no significant difference on the late postoperative time in any group or when comparing the three groups on this same period. On late postoperative time, GI and GII had a large amount of fecal water, lipids and proteins when compared to the preoperative time and to GIII. On the 60th day there's no significant difference on the quantity of fecal water when comparing the three groups and the same occurs on the 50th day when considering the quantity of fecal proteins.


Integration of canal and otolith inputs by central vestibular neurons is subadditive for both active and passive self-motion: implication for perception.
Traditionally, the neural encoding of vestibular information is studied by applying either passive rotations or translations in isolation. However, natural vestibular stimuli are typically more complex. During everyday life, our self-motion is generally not restricted to one dimension, but rather comprises both rotational and translational motion that will simultaneously stimulate receptors in the semicircular canals and otoliths. In addition, natural self-motion is the result of self-generated and externally generated movements. However, to date, it remains unknown how information about rotational and translational components of self-motion is integrated by vestibular pathways during active and/or passive motion. Accordingly, here, we compared the responses of neurons at the first central stage of vestibular processing to rotation, translation, and combined motion. Recordings were made in alert macaques from neurons in the vestibular nuclei involved in postural control and self-motion perception. In response to passive stimulation, neurons did not combine canal and otolith afferent information linearly. Instead, inputs were subadditively integrated with a weighting that was frequency dependent. Although canal inputs were more heavily weighted at low frequencies, the weighting of otolith input increased with frequency. In response to active stimulation, neuronal modulation was significantly attenuated (∼ 70%) relative to passive stimulation for rotations and translations and even more profoundly attenuated for combined motion due to subadditive input integration. Together, these findings provide insights into neural computations underlying the integration of semicircular canal and otolith inputs required for accurate posture and motor control, as well as perceptual stability, during everyday life.


Acute resistance exercise augments integrative myofibrillar protein synthesis.
The purpose of this study was to determine whether an acute bout of high-intensity resistance exercise (RE) would augment integrative mixed muscle and myofibrillar protein fractional synthesis rates (FSRs) when total energy and macronutrient intake was controlled. Twelve healthy young men were studied over 24 hours and performed an acute bout of exhaustive (5 sets until volitional failure of their 85% 1-repetition maximum) unilateral leg press and knee extension exercise, such that one leg was exercised (EX) and the other served as a control (CON). (2)H(2)O (70%) was provided to measure mixed muscle and myofibrillar FSR, and muscle biopsies (vastus lateralis) were collected from the EX and CON legs 16 hours following the RE session. (2)H-labeling of body water over the course of the experiment was 0.32 ± 0.01 mole percent excess. Interestingly, integrative mixed muscle FSR (percent per hour) was similar between the CON (0.76% ± 0.08%) and EX (0.69% ± 0.06%) legs. In contrast, upon determination of myofibrillar FSR, there was an RE effect (EX, 0.94% ± 0.16% vs CON, 0.75% ± 0.08%; P < .05). High-intensity RE without prior training impacts integrative myofibrillar 24-hour FSR, perhaps without altering total responses.


Structure of the polypeptide crotamine from the Brazilian rattlesnake Crotalus durissus terrificus.
The crystal structure of the myotoxic, cell-penetrating, basic polypeptide crotamine isolated from the venom of Crotalus durissus terrificus has been determined by single-wavelength anomalous dispersion techniques and refined at 1.7 Å resolution. The structure reveals distinct cationic and hydrophobic surface regions that are located on opposite sides of the molecule. This surface-charge distribution indicates its possible mode of interaction with negatively charged phospholipids and other molecular targets to account for its diverse pharmacological activities. Although the sequence identity between crotamine and human β-defensins is low, the three-dimensional structures of these functionally related peptides are similar. Since crotamine is a leading member of a large family of myotoxic peptides, its structure will provide a basis for the design of novel cell-penetrating molecules.


Effects of feeding regimes and early maturation on migratory behaviour of landlocked hatchery-reared Atlantic salmon Salmo salar smolts.
The migratory behaviour of hatchery-reared landlocked Atlantic salmon Salmo salar raised under three different feeding regimes was monitored through the lower part of the River Klarälven, Sweden. The smolts were implanted with acoustic transmitters and released into the River Klarälven, 25 km upstream of the outlet in Lake Vänern. Early mature males, which had matured the previous autumn, were also tagged and released. To monitor migration of the fish, acoustic receivers were deployed along the migratory route. The proportion of S. salar that reached Lake Vänern was significantly greater for fish fed fat-reduced feed than for fish given rations with higher fat content, regardless of ration size. Fish from the early mature male group remained in the river to a greater extent than fish from the three feeding regimes. Smolt status (degree of silvering), as visually assessed, did not differ among the feeding regime groups, and moreover, fully-silvered fish, regardless of feeding regime, migrated faster and had a greater migration success than fish with less developed smolt characteristics. Also, successful migrants had a lower condition factor than unsuccessful ones. These results indicate that the migration success of hatchery-reared S. smolts released to the wild can be enhanced by relatively simple changes in feeding regimes and by matching stocking time with smolt development.


Experimental adaptive radiation in Pseudomonas.
We studied the importance of selection and constraint in determining the limits of adaptive radiation and the consequences of adaptive radiation in an experimental system. We propagated four replicate lines of the bacterium Pseudomonas fluorescens derived from a single ancestral clone in 95 environments, where growth was limited by the availability of a single carbon source for 1,000 generations. We then assayed the growth of the ancestral clone and the evolved lines in all 95 environments. Evolved lines increased their performance in almost every selection environment and invaded 70% of the novel environments as a direct response to selection. Direct responses tended to be larger in environments where growth was initially poor. Although evolved lines lost the ability to grow on about three substrates that their ancestor could readily grow on, the correlated response to selection was, on average, positive. The correlated response allowed all of our evolved populations to expand their niches and to occupy collectively the remaining novel habitats. This is inconsistent with classical theories of niche evolution. In the most extreme cases, adaptation occurred through "roundabout selection": lineages became adapted to an environment through selection in another environment but not through selection in the environment itself. Our results indicate that mutation accumulation by neutral drift was responsible for generating the majority of costs of adaptation.


Operational greenhouse-gas emissions of deep learning in digital pathology: a modelling study.
Deep learning is a promising way to improve health care. Image-processing medical disciplines, such as pathology, are expected to be transformed by deep learning. The first clinically applicable deep-learning diagnostic support tools are already available in cancer pathology, and their number is increasing. However, data on the environmental sustainability of these tools are scarce. We aimed to conduct an environmental-sustainability analysis of a theoretical implementation of deep learning in patient-care pathology. For this modelling study, we first assembled and calculated relevant data and parameters of a digital-pathology workflow. Data were breast and prostate specimens from the university clinic at the Institute of Pathology of the Rheinisch-Westfälische Technische Hochschule Aachen (Aachen, Germany), for which commercially available deep learning was already available. Only specimens collected between Jan 1 and Dec 31, 2019 were used, to omit potential biases due to the COVID-19 pandemic. Our final selection was based on 2 representative weeks outside holidays, covering different types of specimens. To calculate carbon dioxide (CO2) or CO2 equivalent (CO2 eq) emissions of deep learning in pathology, we gathered relevant data for exact numbers and sizes of whole-slide images (WSIs), which were generated by scanning histopathology samples of prostate and breast specimens. We also evaluated different data input scenarios (including all slide tiles, only tiles containing tissue, or only tiles containing regions of interest). To convert estimated energy consumption from kWh to CO2 eq, we used the internet protocol address of the computational server and the Electricity Maps database to obtain information on the sources of the local electricity grid (ie, renewable vs non-renewable), and estimated the number of trees and proportion of the local and world's forests needed to sequester the CO2 eq emissions. We calculated the computational requirements and CO2 eq emissions of 30 deep-learning models that varied in task and size. The first scenario represented the use of one commercially available deep-learning model for one task in one case (1-task), the second scenario considered two deep-learning models for two tasks per case (2-task), the third scenario represented a future, potentially automated workflow that could handle 7 tasks per case (7-task), and the fourth scenario represented the use of a single potential, large, computer-vision model that could conduct multiple tasks (multitask). We also compared the performance (ie, accuracy) and CO2 eq emissions of different deep-learning models for the classification of renal cell carcinoma on WSIs, also from Rheinisch-Westfälische Technische Hochschule Aachen. We also tested other approaches to reducing CO2 eq emissions, including model pruning and an alternative method for histopathology analysis (pathomics). The pathology database contained 35 552 specimens (237 179 slides), 6420 of which were prostate specimens (10 115 slides) and 11 801 of which were breast specimens (19 763 slides). We selected and subsequently digitised 140 slides from eight breast-cancer cases and 223 slides from five prostate-cancer cases. Applying large deep-learning models on all WSI tiles of prostate and breast pathology cases would result in yearly CO2 eq emissions of 7·65 metric tons (t; 95% CI 7·62-7·68) with the use of a single deep-learning model per case; yearly CO2 eq emissions were up to 100·56 t (100·21-100·99) with the use of seven deep-learning models per case. CO2 eq emissions for different deep-learning model scenarios, data inputs, and deep-learning model sizes for all slides varied from 3·61 t (3·59-3·63) to 2795·30 t (1177·51-6482·13. For the estimated number of overall pathology cases worldwide, the yearly CO2 eq emissions varied, reaching up to 16 megatons (Mt) of CO2 eq, requiring up to 86 590 km2 (0·22%) of world forest to sequester the CO2 eq emissions. Use of the 7-task scenario and small deep-learning models on slides containing tissue only could substantially reduce CO2 eq emissions worldwide by up to 141 times (0·1 Mt, 95% CI 0·1-0·1). Considering the local environment in Aachen, Germany, the maximum CO2 eq emission from the use of deep learning in digital pathology only would require 32·8% (95% CI 13·8-76·6) of the local forest to sequester the CO2 eq emissions. A single pathomics run on a tissue could provide information that was comparable to or even better than the output of multitask deep-learning models, but with 147 times reduced CO2 eq emissions. Our findings suggest that widespread use of deep learning in pathology might have considerable global-warming potential. The medical community, policy decision makers, and the public should be aware of this potential and encourage the use of CO2 eq emissions reduction strategies where possible. German Research Foundation, European Research Council, German Federal Ministry of Education and Research, Health, Economic Affairs and Climate Action, and the Innovation Fund of the Federal Joint Committee.


Clinical correlation of cholelithiasis in patients undergoing percutaneous endoscopic gastrostomy.
The risk factor for cholelithiasis include low physical activity. With an aging society, the number of bedridden patients who undergo percutaneous endoscopic gastrostomy (PEG) has increased, and cholelithiasis has often been found in these patients. This study aimed to evaluate the risk factors correlated with cholelithiasis in adults who underwent PEG. This retrospective single-center design study reviewed patients who underwent PEG and were confirmed to have cholelithiasis through imaging from March 1996 to December 2021. The investigated variables were age, sex, body mass index (BMI, kg/m2), cause of PEG insertion, initial physical activity status, laboratory findings on PEG insertion day, and incidence of acute cholecystitis. The differences between categorical and continuous variables were analyzed using Student's t test and chi-square test. We enrolled 576 eligible patients who underwent PEG insertion. A total of 161 patients were detected with cholelithiasis (28.0%). The overall independent risk factors for cholelithiasis in patients who underwent PEG insertion were increased C-reactive protein (CRP) levels and decreased physical activity status (bedridden state). The incidence of cholelithiasis was increased by up to 30.7%, especially in patients with bedridden status. However, the incidence of acute cholecystitis among cholelithiasis group was only 5.6%. BMI and total cholesterol were positively correlated with the size of gallbladder (GB) stones. One of the major risk factors for cholelithiasis is decreased physical activity, especially in patients who underwent PEG insertion. Abdominal imaging is recommended to confirm the presence of cholelithiasis and to consider prophylaxis for cholelithiasis, especially in bedridden patients with elevated initial CRP levels at the time of PEG insertion.


Natural history of nonfunctioning pituitary adenomas and incidentalomas: a systematic review and metaanalysis.
The natural history of pituitary incidentalomas (PIs) and nonfunctioning pituitary adenomas (NFPAs) remains poorly understood. The objective of the study was to synthesize the literature on the prognostic factors involved in the progression of PIs and NFPAs in patients followed up conservatively. We searched MEDLINE, EMBASE, and Cochrane CENTRAL. We sought to identify further studies by reviewing the reference lists from selected studies and reviews and by querying experts. Eligible studies were longitudinal observational cohort studies that enrolled patients with PIs/NFPAs and followed them up without any treatment from the time of detection and reported on mortality, lesion progression, and development of pituitary hormonal deficiency, apoplexy, or visual field defects. Reviewers working independently and in duplicate determined studies' eligibility and collected descriptive, methodological quality, and outcome data. Event rates per 100 person-years (PYs) and associated 95% confidence intervals (CIs) were estimated from each study and pooled using the random-effects model. The 11 included studies had noncomparative single-cohort design. Follow-up duration ranged from 3 to 15 yr. There was a greater tendency for tumor growth in macroadenomas (12.5 per 100 PYs; 95% CI 7.9, 17.2) and in solid lesions (5.7 per 100 PYs; 95% CI 2.3, 9.2) in comparison with microadenomas (3.3 per 100 PYs; 95% CI 2.1, 4.5) and cystic lesions (0.05 per 100 PYs; 95% CI 0.0, 0.2). The development of pituitary apoplexy and worsening of visual field defects were rare. The overall incidence of new endocrine dysfunction was 2.4 per 100 PYs; 95% CI 0.0, 6.4. The majority of these analyses were associated with significant heterogeneity. There was a trend that did not reach statistical significance for greater incidence of pituitary apoplexy and new endocrine dysfunction worsening in macroadenomas compared with microadenomas. The quality of the evidence (risk of bias) was very low due to heterogeneity, methodological limitations, and imprecision caused by the small number of events. Despite the relatively high prevalence of PIs/NFPAs, the evidence on the natural history of these entities is scarce and of low quality. PIs/NFPAs seem to have fairly rare complications that may be more common when lesions are large (>10 mm) and solid.


Culicoides midges in Catalonia (Spain), with special reference to likely bluetongue virus vectors.
Midges of the genus Culicoides (Diptera: Ceratopogonidae) were trapped weekly from May 2001 through December 2002 on two farms in the province of Barcelona (Spain). Dosrius farm was stocked with sheep and goats whereas Bellaterra farm had only sheep. This trapping programme was carried out within the framework of an investigation into the occurrence/absence of possible vectors of bluetongue virus (BTV) in mainland Spain. A total of 30,079 Culicoides specimens were collected from 165 light trap collections, comprising nine species: C. obsoletus (Meigen), C. pulicaris (Linnaeus), C. circumscriptus Kieffer, C. newsteadi Austen, C. imicola Kieffer, C. scoticus Downes & Kettle, C. punctatus (Meigen), C. pallidicornis Kieffer and C. flavipulicaris Dzhafarov. The last five are new to Catalonia, C. pallidicornis is also new to Spain and C. flavipulicaris is new to Iberia. The seasonal occurrence of these species is described here. Of those species, C. imicola is the main BTV and African horse sickness virus (AHSV) vector in Europe, whereas species belonging to the so-called Obsoletus group (C. obsoletus and C. scoticus in our study) are considered to be potential vectors for BTV.


A clickable neurosteroid photolabel reveals selective Golgi compartmentalization with preferential impact on proximal inhibition.
Anesthetic, GABA-active neurosteroids potently augment GABAA receptor function, leading to important behavioral consequences. Neurosteroids and their synthetic analogues are also models for a wide variety of cell-permeant neuroactive compounds. Cell permeation and compartmentalization raise the possibility that these compounds' actions are influenced by their cellular partitioning, but these contributions are not typically considered experimentally or therapeutically. To examine the interplay between cellular accumulation and pharmacodynamics of neurosteroids, we synthesized a novel chemical biology analogue (bio-active, clickable photolabel) of GABA-active neurosteroids. We discovered that the analogue selectively photo-labels neuronal Golgi in rat hippocampal neurons. The active analogue's selective distribution was distinct from endogenous cholesterol and not completely shared by some non-GABA active, neurosteroid-like analogues. On the other hand, the distribution was not enantioselective and did not require energy, in contrast to other recent precedents from the literature. We demonstrate that the soma-selective accumulation can act as a sink or source for steroid actions at plasma-membrane GABA receptors, altering steady-state and time course of effects at somatic GABAA receptors relative to dendritic receptors. Our results suggest a novel mechanism for compartment-selective drug actions at plasma-membrane receptors.


Emerging antithrombotic agents: what does the intensivist need to know?
As thrombus consists of both fibrin and platelets, antithrombotic strategies involve anticoagulants and antiplatelets, alone or in combination. Traditionally, unfractionated heparin has been the most commonly used parenteral anticoagulant, but owing to its variable dose response and narrow therapeutic indices, it is being replaced by low molecular weight heparin, fondaparinux, and bivalrudin. New oral factor Xa inhibitors like apixaban and rivaroxaban are still on the horizon, awaiting definite evaluation in ACS, DVT and atrial fibrillation. On the contrary, a dramatic advance in the arena of oral anticoagulants has occurred with the introduction of dabigatran, an oral direct thrombin inhibitor. This agent showed better outcomes than oral vitamin K antagonists in patients with atrial fibrillation. The antiplatelet field has also expanded by the addition of two new agents, prasugrel and ticagrelor. These agents have been tested against clopidogrel, in patients with ACS, with superior efficacy outcomes for both agents and higher bleeding events with prasugrel. Bleeding risk associated with antithrombotics is not only a function of their inherent biochemical properties but also a reflection of how healthcare professionals choose and dose these agents in individual patients.


A Chemically Soldered Polyoxometalate Single-Molecule Transistor.
Polyoxometalates have been proposed in the literature as nanoelectronic components, where they could offer key advantages with their structural versatility and rich electrochemistry. Apart from a few studies on their ensemble behaviour (as monolayers or thin films), this potential remains largely unexplored. We synthesised a pyridyl-capped Anderson-Evans polyoxometalate and used it to fabricate single-molecule junctions, using the organic termini to chemically "solder" a single cluster to two nanoelectrodes. Operating the device in an electrochemical environment allowed us to probe charge transport through different oxidation states of the polyoxometalate, and we report here an efficient three-state transistor behaviour. Conductance data fits a quantum tunnelling mechanism with different charge-transport probabilities through different charge states. Our results show the promise of polyoxometalates in nanoelectronics and give an insight on their single-entity electrochemical behaviour.


Subcellular reprogramming of metabolism during cold acclimation in Arabidopsis thaliana.
Metabolite changes in plant leaves during exposure to low temperatures involve re-allocation of a large number of metabolites between sub-cellular compartments. Therefore, metabolite determination at the whole cell level may be insufficient for interpretation of the functional significance of cellular compounds. To investigate the cold-induced metabolite dynamics at the level of individual sub-cellular compartments, an integrative platform was developed that combines quantitative metabolite profiling by gas chromatography coupled to mass spectrometry (GC-MS) with the non-aqueous fractionation technique allowing separation of cytosol, vacuole and the plastidial compartment. Two mutants of Arabidopsis thaliana representing antipodes in the diversion of carbohydrate metabolism between sucrose and starch were compared to Col-0 wildtype before and after cold acclimation to investigate interactions of cold acclimation with subcellular re-programming of metabolism. A multivariate analysis of the data set revealed dominant effects of compartmentation on metabolite concentrations that were modulated by environmental condition and genetic determinants. While for both, the starchless mutant of plastidial phospho-gluco mutase (pgm) and a mutant defective in sucrose-phosphate synthase A1, metabolic constraints, especially at low temperature, could be uncovered based on subcellularly resolved metabolite profiles, only pgm had lowered freezing tolerance. Metabolic profiles of pgm point to redox imbalance as a possible reason for reduced cold acclimation capacity.


ASHP national survey of pharmacy practice in hospital settings: Prescribing and transcribing-2016.
The results of the 2016 ASHP national survey of pharmacy practice in hospital settings are presented. A stratified random sample of pharmacy directors at 1,315 general and children's medical-surgical hospitals in the United States were surveyed using a mixed-mode method offering a choice of completing a paper survey or an online survey. IMS Health supplied data on hospital characteristics; the survey sample was drawn from IMS's hospital database. The survey response rate was 29.8%. Drug policy development by pharmacy and therapeutics committees continues to be an important strategy for improving prescribing. Strict formulary systems are maintained in 63.0% of hospitals, and 89.7% of hospitals use clinical practice guidelines that include medications. Pharmacists have the authority to order laboratory tests in 89.9% of hospitals and order medications in 86.8% of hospitals. Therapeutic interchange policies are used in 89.2% of hospitals. Electronic health records (EHRs) have been implemented partially or completely in most hospitals (99.1%). Computerized prescriber-order-entry systems with clinical decision support are used in 95.6% of hospitals, and 92.6% of hospitals have barcode-assisted medication administration systems. Transitions-of-care programs are increasing in number, with 34.6% of hospitals now offering discharge prescription services. Pharmacists practice in 39.5% of hospital ambulatory or primary care clinics. The most common service offered by pharmacists to outpatients is anticoagulation management (26.0%). When pharmacists practice in ambulatory care clinics, 64.5% have prescribing authority through collaborative practice agreements. Pharmacists continue to expand their role in improving the prescribing of medications in both hospital and outpatient settings. The adoption of EHRs and medication-use technologies has contributed to this growth.


Alternative pre-mRNA processing regulates cell-type specific expression of the IL4l1 and NUP62 genes.
Given the complexity of higher organisms, the number of genes encoded by their genomes is surprisingly small. Tissue specific regulation of expression and splicing are major factors enhancing the number of the encoded products. Commonly these mechanisms are intragenic and affect only one gene. Here we provide evidence that the IL4I1 gene is specifically transcribed from the apparent promoter of the upstream NUP62 gene, and that the first two exons of NUP62 are also contained in the novel IL4I1_2 variant. While expression of IL4I1 driven from its previously described promoter is found mostly in B cells, the expression driven by the NUP62 promoter is restricted to cells in testis (Sertoli cells) and in the brain (e.g., Purkinje cells). Since NUP62 is itself ubiquitously expressed, the IL4I1_2 variant likely derives from cell type specific alternative pre-mRNA processing. Comparative genomics suggest that the promoter upstream of the NUP62 gene originally belonged to the IL4I1 gene and was later acquired by NUP62 via insertion of a retroposon. Since both genes are apparently essential, the promoter had to serve two genes afterwards. Expression of the IL4I1 gene from the "NUP62" promoter and the tissue specific involvement of the pre-mRNA processing machinery to regulate expression of two unrelated proteins indicate a novel mechanism of gene regulation.


[Structural components and peculiarities of Pseudomonas aeruginosa biofilm organization].
Peculiarities of the structural organization of bacterial biofilm during its formation and disintegration have been investigated on the model of Pseudomonas aeruginosa UCM B-900 (ATCC 9027). It was shown, that development of the biofilm in a stationary system on glass was a two-vector process with changes in time and space. P. aeruginosa UCM B-900 biofilm is formed from single cells, passes through the stages of base components, net structure, islands and comes to the end with integration into a complete monolayer. The biofilm degradation repeats the stages of its formation in the reverse sequence.


Children, biobanks and the scope of parental consent.
The use of stored tissue samples from children for genetic research raises specific ethical questions that are not all analogous to those raised when adult participants are concerned. These include issues with regard to consent, as it is typically a parent who consents to the use of samples from children. In this paper, we discuss the scope of parental consent. This scope has a temporal dimension and one related to the content of consent. It is not questioned that the temporal scope of parental consent is limited and that young adults have the right to decide on the fate of their samples when they reach the age of maturity. With regard to the content of consent, the question remains whether parents are allowed to give full broad consent to any possible future research on the samples of their children. We argue that they should not be allowed to do so, based on two premises. First, it is generally acknowledged that children have a right to express their own values and that they should be given the opportunity to develop their own autonomy as they grow older. Second, research and science are not completely value-free and some types of research may be more sensitive than other types. Children should be given the opportunity to express their values also in this respect.


Reversing the substrate specificities of phenylalanine and tyrosine hydroxylase: aspartate 425 of tyrosine hydroxylase is essential for L-DOPA formation.
The catalytic domains of the pterin-dependent enzymes phenylalanine hydroxylase and tyrosine hydroxylase are homologous, yet differ in their substrate specificities. To probe the structural basis for the differences in specificity, seven residues in the active site of phenylalanine hydroxylase whose side chains are dissimilar in the two enzymes were mutated to the corresponding residues in tyrosine hydroxylase. Analysis of the effects of the mutations on the isolated catalytic domain of phenylalanine hydroxylase identified three residues that contribute to the ability to hydroxylate tyrosine, His264, Tyr277, and Val379. These mutations were incorporated into full-length phenylalanine hydroxylase and the complementary mutations into tyrosine hydroxylase. The steady-state kinetic parameters of the mutated enzymes showed that the identity of the residue in tyrosine hydroxylase at the position corresponding to position 379 of phenylalanine hydroxylase is critical for dihydroxyphenylalanine formation. The relative specificity of tyrosine hydroxylase for phenylalanine versus tyrosine, as measured by the (V/K(phe))/(V/K(tyr)) value, increased by 80000-fold in the D425V enzyme. However, mutation of the corresponding valine 379 of phenylalanine hydroxylase to aspartate was not sufficient to allow phenylalanine hydroxylase to form dihydroxyphenylalanine at rates comparable to that of tyrosine hydroxylase. The double mutant V379D/H264Q PheH was the most active at tyrosine hydroxylation, showing a 3000-fold decrease in the (V/K(phe))/(V/K(tyr)) value.


Nausea and vomiting of pregnancy: prevalence, severity and relation to psychosocial health.
Symptoms of nausea and vomiting are commonly experienced during early pregnancy (nausea and vomiting of pregnancy or NVP) and have been associated with stress, anxiety, and depression in pregnancy. However, nausea and vomiting in late pregnancy is a little-studied phenomenon. The purpose of our study was to examine the prevalence, severity, and psychosocial determinants of NVP during early and late pregnancy. Data were originally from a longitudinal and epidemiological study of depression in pregnancy and postpartum in a cohort of 648 Canadian women conducted from 2005 to 2008. Measures included the Nausea and Vomiting in Pregnancy Instrument (NVPI), the Cambridge Worry Scale (CWS), and the Edinburgh Postnatal Depression Scale (EPDS). Demographic, maternal/obstetrical, psychological, and behavioral variables related to NVP were also examined. Odds ratios and 95% confidence intervals were calculated for all risk factors investigated using multiple logistic regression, controlling for potential confounders. The prevalence of NVP was 63.3% (n = 551) at Time 1 (early pregnancy) and 45.4% (n = 575) at Time 2 (late pregnancy). Severity of symptoms was associated with earlier gestation, antiemetic medication use, employment status, and symptoms of major depression. Maternal smoking and having the support of three or more persons were protective for NVP. This study suggests that screening for NVP should be ongoing throughout pregnancy and measures that address NVP, poor social support, and depression are warranted. Further research is needed in regard to effective management of this very common and distressing condition.


Identification and characterization of putative Aeromonas spp. T3SS effectors.
The genetic determinants of bacterial pathogenicity are highly variable between species and strains. However, a factor that is commonly associated with virulent Gram-negative bacteria, including many Aeromonas spp., is the type 3 secretion system (T3SS), which is used to inject effector proteins into target eukaryotic cells. In this study, we developed a bioinformatics pipeline to identify T3SS effector proteins, applied this approach to the genomes of 105 Aeromonas strains isolated from environmental, mutualistic, or pathogenic contexts and evaluated the cytotoxicity of the identified effectors through their heterologous expression in yeast. The developed pipeline uses a two-step approach, where candidate Aeromonas gene families are initially selected using Hidden Markov Model (HMM) profile searches against the Virulence Factors DataBase (VFDB), followed by strict comparisons against positive and negative control datasets, greatly reducing the number of false positives. This approach identified 21 Aeromonas T3SS likely effector families, of which 8 represent known or characterized effectors, while the remaining 13 have not previously been described in Aeromonas. We experimentally validated our in silico findings by assessing the cytotoxicity of representative effectors in Saccharomyces cerevisiae BY4741, with 15 out of 21 assayed proteins eliciting a cytotoxic effect in yeast. The results of this study demonstrate the utility of our approach, combining a novel in silico search method with in vivo experimental validation, and will be useful in future research aimed at identifying and authenticating bacterial effector proteins from other genera.


Fear of COVID-19 changes the motivation for physical activity participation: Polish-Chinese comparisons.
COVID-19 has brought people many negative emotions, such as fear and anxiety about the epidemic. However, when people in different countries face the COVID-19 epidemic, the impact is also different due to different cultural and sports habits. Therefore, this study compares China and Poland's sports motivations in the face of COVID-19 anxiety to find out the cultural differences behind them. In the study were N = 674 participants (female n = 407, male n = 260, other n = 4). Their average age was M = 29.86, SD = 11.03. There were n = 381 participants in the Chinese sample, and n = 293 in Polish. The scales used for the purpose of the study were the Inventory of Physical Activity Objectives (IPAO) and the Coronavirus Anxiety Scale (CAS). The study results showed that the increased level of COVID-19 anxiety changed selected motives for physical activity, and different changes of motives characterized women and men as well as people of different ages. As predicted in the study model, culture was the moderator of the shifts of the selected motives. The understanding of what motivates individuals to participate in sport seems to have significant value, especially for health practitioners and researchers to design appropriate interventions and programs to increase activity.


Harnessing pluralism for better health in Bangladesh.
How do we explain the paradox that Bangladesh has made remarkable progress in health and human development, yet its achievements have taken place within a health system that is frequently characterised as weak, in terms of inadequate physical and human infrastructure and logistics, and low performing? We argue that the development of a highly pluralistic health system environment, defined by the participation of a multiplicity of different stakeholders and agents and by ad hoc, diffused forms of management has contributed to these outcomes by creating conditions for rapid change. We use a combination of data from official sources, research studies, case studies of specific innovations, and in-depth knowledge from our own long-term engagement with health sector issues in Bangladesh to lay out a conceptual framework for understanding pluralism and its outcomes. Although we argue that pluralism has had positive effects in terms of stimulating change and innovation, we also note its association with poor health systems governance and regulation, resulting in endemic problems such as overuse and misuse of drugs. Pluralism therefore requires active management that acknowledges and works with its polycentric nature. We identify four key areas where this management is needed: participatory governance, accountability and regulation, information systems, and capacity development. This approach challenges some mainstream frameworks for managing health systems, such as the building blocks approach of the WHO Health Systems Framework. However, as pluralism increasingly defines the nature and the challenge of 21st century health systems, the experience of Bangladesh is relevant to many countries across the world.


A metabolomic study of biomarkers of meat and fish intake.
Background: Meat and fish intakes have been associated with various chronic diseases. The use of specific biomarkers may help to assess meat and fish intake and improve subject classification according to the amount and type of meat or fish consumed.Objective: A metabolomic approach was applied to search for biomarkers of meat and fish intake in a dietary intervention study and in free-living subjects from the European Prospective Investigation into Cancer and Nutrition (EPIC) study.Design: In the dietary intervention study, 4 groups of 10 subjects consumed increasing quantities of chicken, red meat, processed meat, and fish over 3 successive weeks. Twenty-four-hour urine samples were collected during each period and analyzed by high-resolution liquid chromatography-mass spectrometry. Signals characteristic of meat or fish intake were replicated in 50 EPIC subjects for whom a 24-h urine sample and 24-h dietary recall were available and who were selected for their exclusive intake or no intake of any of the 4 same foods.Results: A total of 249 mass spectrometric features showed a positive dose-dependent response to meat or fish intake in the intervention study. Eighteen of these features best predicted intake of the 4 food groups in the EPIC urine samples on the basis of partial receiver operator curve analyses with permutation testing (areas under the curve ranging between 0.61 and 1.0). Of these signals, 8 metabolites were identified. Anserine was found to be specific for chicken intake, whereas trimethylamine-N-oxide showed good specificity for fish. Carnosine and 3 acylcarnitines (acetylcarnitine, propionylcarnitine, and 2-methylbutyrylcarnitine) appeared to be more generic indicators of meat and meat and fish intake, respectively.Conclusion: The meat and fish biomarkers identified in this work may be used to study associations between meat and fish intake and disease risk in epidemiologic studies. This trial was registered at clinicaltrials.gov as NCT01684917.


[Surgical education: from teledidactics to virtual training].
The assessment of efficacy and quality of computer-assisted learning is today under evaluation. The Authors propose to use distant learning in the surgical knowledge teaching. In Italy, thanks to the Ministry of University and Scientific Research, a Master on distant learning in Medicine is now starting in 11 Italian Universities under the coordination of the second Faculty of Medicine of the University of Rome 'La Sapienza'. Thanks to the help of medicine and surgery teachers and informatics and telecommunication engineers, this Master is a first step to form and to license medical and surgical specialists experts in distant learning and videoconferencing telemedicine. Videoconferencing system can support Telementoring. Telementoring isn't an exclusive methodology but it is an additional methodology to tradictional didactic for clinicians and surgeons. It allows personal virtual trainings using computers and telecommunication systems.


A novel electrode for supercapacitors: efficient PVP-assisted synthesis of Ni3S2 nanostructures grown on Ni foam for energy storage.
In this academic research, we report the polyvinylpyrrolidone (PVP) assisted synthesis of a Ni3S2 electrode material containing a plentiful number of active sites on Ni foam by a novel hydrothermal approach. Interestingly, the Ni3S2 electrode is a highly efficient electroactive material, as evidenced by the physical and electrochemical characterization. Based on the physical characterization, the constructed Ni3S2 nano architecture exhibited plentiful electroactive sites, quick charge/discharge transportation and better maximum conductivity, which gave rise to enhanced electrochemical activity for large-scale supercapacitors (SCs). Besides, the electrochemical characterization of the as-developed Ni3S2 electrode obviously displayed a faradaic battery-based redox profile, which is distinct from the profiles of carbon-type materials. The battery-based PVP-assisted Ni3S2 electrode achieved impressive electrochemical activity, namely exceptional SC activity with a superior specific capacity of ∼316.8 mA h g-1 at 2 A g-1 current density, high rate capability with ∼91.4% of capacity retained at 20 A g-1, and superb cycling performance with ∼96.7% of capacity retained at 6 A g-1 after 4000 cycles. Thus, considering the best findings above, the as-developed PVP-assisted Ni3S2 is a highly efficient candidate for SCs and could effectively serve in various advanced energy storage applications.


Evolution of Tumor Metabolism might Reflect Carcinogenesis as a Reverse Evolution process (Dismantling of Multicellularity).
Carcinogenesis occurs through a series of steps from normal into benign and finally malignant phenotype. This cancer evolutionary trajectory has been accompanied by similar metabolic transformation from normal metabolism into Pasteur and/or Crabtree-Effects into Warburg-Effect and finally Cannibalism and/or Lactate-Symbiosis. Due to lactate production as an end-product of glycolysis, tumor colonies acquire new phenotypes that rely on lactate as energetic fuel. Presence of Warburg-Effect indicates that some tumor cells undergo partial (if not complete) de-endosymbiosis and so cancer cells have been become unicellular microorganism (anti-Dollo's Law) specially when they evolve to develop cannibalism as way of metabolism while oxidative types of cells that rely on lactate, as their energetic fuel, might represent extra-endosymbiosis. Thus, at the end, the cancer colony could be considered as integrated metabolic ecosystem. Proper understanding of tumor metabolism will contribute to discover potential anticancer agents besides conventional chemotherapy.


Evaluating the utilization of educational materials in communicating about Lynch syndrome to at-risk relatives.
Facilitating family communication about Lynch syndrome is a public health priority since following appropriate screening guidelines can decrease morbidity and mortality. The aims of this study were to (1) ascertain what educational materials individuals with Lynch syndrome provide to at-risk relatives, and (2) identify relationships between receiving educational materials and pursuing clinical follow-up. Seventy-four participants, recruited from the Stanford Cancer Institute and a support group, completed an online questionnaire; 50 were first to be diagnosed with a Lynch syndrome mutation in their family (probands) and 24 were first or second-degree relatives. Probands reported informing 88 % (184/209) of first-degree relatives and 64 % (161/252) of second-degree relatives of the mutation. Probands shared their genetic counseling note with 53 % of relatives; other resources, including family letters, personal notes, testing laboratory information, online resources, support group information, and genetics referrals, were given to 33 % or fewer relatives. Probands reported that female relatives (p = 0.028) and first-degree relatives (p ≤ 0.001) were more likely to be given materials. Relatives who received an educational material were more likely to follow up with a clinician (74 vs 22 %, p ≤0.001) and attend a genetic counseling appointment (43 vs 16 %, p ≤ 0.001). First-degree relatives who received an educational material were more likely to have undergone genetic testing (51 vs 19 %, p = 0.012) and cancer screening (69 vs 29 %, p = 0.001). Facilitating information transmission in families with Lynch syndrome using educational materials may play a role in informed clinical decision-making and cascade screening of at-risk relatives.


Prenatal diagnosis of acute massive fetomaternal hemorrhage.
We present here 2 cases of acute and 2 cases of chronic massive fetomaternal hemorrhage. A sinusoidal fetal heart rate pattern may indicate chronic fetomaternal hemorrhage, but, when increased variability is observed in fetal monitoring, maternal hemoglobin F should be measured to exclude acute fetomaternal hemorrhage.


Immunosuppression of humoral and cell-mediated responses in calves associated wtih inoculation of Mycoplasma bovis.
Calves were given (subcutaneous inoculations) viable Mycoplasma bovis with and without Freund's complete adjuvant (FCA). In the calves given M bovis with FCA, immediate and delayed cutaneous reactivity to formolized M bovis and increases in serum indirect hemagglutination (IHA) titers were pronounced. None of the calves showed evidence of an anamnestic response to a 2nd inoculation of M bovis. Treatment of the test serums from all calves with 2-mercaptoethanol (2-ME) revealed the presence of increased immunoglobulin M-IHA activities throughout the 70-day postinoculation (PI) period. Strong cell-mediated responses, as shown by the lymphocyte-activation test, were not observed until PI day 44. Lymphocytes from calves given M bovis with FCA gave the greatest response to M bovis antigens. However, the lymphocyte activation response to M bovis rapidly decreased after day 44 PI. The in vitro lymphocyte responses to phytohemagglutinin (PHA), as well as the control rates of lymphocyte incorporation of tritiated thymidine, appeared to be depressed as a result of the M bovis inoculations. The aqueous "supernatant" of M bovis was generally suppressive to in vitro lymphocyte blastogenesis. Mycoplasma bovis appeared to affect the immune responsiveness of the host directly by either stimulation of suppressor cell function or transiently depressing T-lymphocyte activities. The addition of FCA with M bovis had an enhancing effect on humoral and cell-mediated responses probably by increasing macrophage presentation of antigen to T-lymphocytes. The delayed development of cell-mediated immune responses may assist in the explanation of why some hosts are unsuccessful in mounting an effective immune response against M bovis.


Genomic regulatory blocks underlie extensive microsynteny conservation in insects.
Insect genomes contain larger blocks of conserved gene order (microsynteny) than would be expected under a random breakage model of chromosome evolution. We present evidence that microsynteny has been retained to keep large arrays of highly conserved noncoding elements (HCNEs) intact. These arrays span key developmental regulatory genes, forming genomic regulatory blocks (GRBs). We recently described GRBs in vertebrates, where most HCNEs function as enhancers and HCNE arrays specify complex expression programs of their target genes. Here we present a comparison of five Drosophila genomes showing that HCNE density peaks centrally in large synteny blocks containing multiple genes. Besides developmental regulators that are likely targets of HCNE enhancers, HCNE arrays often span unrelated neighboring genes. We describe differences in core promoters between the target genes and the unrelated genes that offer an explanation for the differences in their responsiveness to enhancers. We show examples of a striking correspondence between boundaries of synteny blocks, HCNE arrays, and Polycomb binding regions, confirming that the synteny blocks correspond to regulatory domains. Although few noncoding elements are highly conserved between Drosophila and the malaria mosquito Anopheles gambiae, we find that A. gambiae regions orthologous to Drosophila GRBs contain an equivalent distribution of noncoding elements highly conserved in the yellow fever mosquito Aëdes aegypti and coincide with regions of ancient microsynteny between Drosophila and mosquitoes. The structural and functional equivalence between insect and vertebrate GRBs marks them as an ancient feature of metazoan genomes and as a key to future studies of development and gene regulation.


MELK mediates the stability of EZH2 through site-specific phosphorylation in extranodal natural killer/T-cell lymphoma.
Oncogenic EZH2 is overexpressed and extensively involved in the pathophysiology of different cancers including extranodal natural killer/T-cell lymphoma (NKTL). However, the mechanisms regarding EZH2 upregulation is poorly understood, and it still remains untargetable in NKTL. In this study, we examine EZH2 protein turnover in NKTL and identify MELK kinase as a regulator of EZH2 ubiquitination and turnover. Using quantitative mass spectrometry analysis, we observed a MELK-mediated increase of EZH2 S220 phosphorylation along with a concomitant loss of EZH2 K222 ubiquitination, suggesting a phosphorylation-dependent regulation of EZH2 ubiquitination. MELK inhibition through both chemical and genetic means led to ubiquitination and destabilization of EZH2 protein. Importantly, we determine that MELK is upregulated in NKTL, and its expression correlates with EZH2 protein expression as determined by tissue microarray derived from NKTL patients. FOXM1, which connected MELK to EZH2 signaling in glioma, was not involved in mediating EZH2 ubiquitination. Furthermore, we identify USP36 as the deubiquitinating enzyme that deubiquitinates EZH2 at K222. These findings uncover an important role of MELK and USP36 in mediating EZH2 stability in NKTL. Moreover, MELK overexpression led to decreased sensitivity to bortezomib treatment in NKTL based on deprivation of EZH2 ubiquitination. Therefore, modulation of EZH2 ubiquitination status by targeting MELK may be a new therapeutic strategy for NKTL patients with poor bortezomib response.


High-efficacy subcellular micropatterning of proteins using fibrinogen anchors.
Protein micropatterning allows proteins to be precisely deposited onto a substrate of choice and is now routinely used in cell biology and in vitro reconstitution. However, drawbacks of current technology are that micropatterning efficiency can be variable between proteins and that proteins may lose activity on the micropatterns. Here, we describe a general method to enable micropatterning of virtually any protein at high specificity and homogeneity while maintaining its activity. Our method is based on an anchor that micropatterns well, fibrinogen, which we functionalized to bind to common purification tags. This enhances micropatterning on various substrates, facilitates multiplexed micropatterning, and dramatically improves the on-pattern activity of fragile proteins like molecular motors. Furthermore, it enhances the micropatterning of hard-to-micropattern cells. Last, this method enables subcellular micropatterning, whereby complex micropatterns simultaneously control cell shape and the distribution of transmembrane receptors within that cell. Altogether, these results open new avenues for cell biology.


Cognitive inhibition and thought disorder in schizophrenia.
In schizophrenia, inhibitory control is reported to be disturbed and has been associated with formal thought disorder (TD). The negative priming task (NP) is used as a measure for inhibition; however, controversial results are found in the literature. The aim of this study was to evaluate cognitive inhibition in schizophrenia and TD. Additionally, the influence of the course of disease and of medication were evaluated. The NP was used to compare TD patients (n = 17) with non-TD (n = 19) and healthy controls (n = 21). Results showed similar performance among TD and non-TD patients, and controls. No influence of the course of disease or medication was found. Our results are in line with recent studies, where patients, irrespective of TD, show normal performance in the NP.


First Insight into Exploration and Cognition in Wild Caught and Domesticated Sea Bass (Dicentrarchus labrax) in a Maze.
European sea bass aquaculture is so recent that very little is known on the effects of the early steps of its domestication. Behavioural parameters are sensitive indicators of the domestication process since they are generally impacted as soon as the first generation. The present work compared wild-caught and domesticated sea bass juvenile swimming activity, exploration and ability to learn to discriminate between two 2-D objects associated to a simple spatial task that enabled the tested individual to visually interact with an unfamiliar congener (the reward) located behind a transparent wall at the end of one of the two arms of a maze. Ten fish from each origin were individually tested 3 times in a row during 3 days (9 trials in total). Fish were placed in a start box closed by a transparent wall located in front of two 2-D objects. Fish were filmed during 10 min after the removal of the start box wall. Different swimming variables including angular velocity, total distance travelled and velocity mean, were analyzed from videos as well as the time spent in each of 6 virtual zones including the reward zone near the congener (Cong) and the zone opposite to the reward zone (OpCong). Two learning criteria were chosen: the number of successful turns and time to reach Cong. Behavioural differences were found between domesticated and wild fish. Angular velocity was higher in wild fish while the distance travelled and the velocity mean were higher in domesticated ones. Wild and domesticated fish spent most of the time in Cong and in OpCong. No differences were seen in learning ability between wild and domesticated fish. However, our findings for learning require confirmation by further studies with larger numbers of learning sessions and experiments designed to minimise stress. This study therefore demonstrated an impact of domestication on swimming behaviour but not on spatial learning.


Design and Performance Evaluation of a Fully Integrated Knitted Knee Brace for Knee Motion Sensing.
The use of e-textiles in wearable sensor design has recently received much interest in many applications, such as robotics, rehabilitation, personal wellness, and sports. Particularly in the rehabilitation domain, it has provided a potential alternative tool for telerehabilitation. In this paper, we designed and evaluated a knitted knee brace with interconnects, resistors, and sensors for real-time kinematic data acquisition. The real-time data acquisition is transmitted using a printed circuit board (PCB) connected to the knee brace through snap pins. The knitted knee brace was tested on three male and one female participant , aged between 30 and 50 years old. All participants were instructed to perform a walking activity at 1.5 km/h for a duration of 10 seconds on the Advanced Mechanical Technology, Inc (AMTI) treadmill over two sessions. The results demonstrated that the fully integrated knitted wearable knee brace could monitor and track human joint locomotion in real time with a standard deviation of 0.39V and 0.41V , respectively, for these two sessions. However, double peak signals were noticeable from the knitted knee brace at a mean of 80.54% during the gait cycles across the four subjects; this observation could be due to the coupled motion along the transverse and coronal planes during the activity.


Prevalence of congenital toxoplasmosis among a series of Turkish women.
Toxoplasma gondii infection during pregnancy causes congenital malformations. Pregnant women should be screened for this infection since it is preventable and treatable. To study the sero prevalence of Toxoplasma gondii infection among pregnant women living in lzmir, Turkey. A blood sample was obtained from 4651 women aged between 15 and 45 years, during their first trimester of pregnancy. IgM and IgG antibodies against Toxoplasma gondii were measured using an ELISA assay. Among women with both IgG and IgM antibodies positive, an IgG avidity test was performed, using a VIDAS kit. IgG antibodies were positive in 1871 (39.9%) participants. Of these, 48 (2.5%) also had positive IgM antibodies. In 41 of these 48 women, the IgG avidity test was performed and only one woman had a low avidity. This woman was treated with Spiramycin. Her offspring had an intrauterine growth retardation and oligohydramnios. A chorioretinitis was diagnosed in the offspring of other woman with both antibodies positive. In this series, the prevalence of congenital toxoplasmosis was low. However, women with positive antibodies against Toxoplasma Gondii should be further studied and followed during their pregnancy.


Weight and metabolic outcomes after 2 years on a low-carbohydrate versus low-fat diet: a randomized trial.
Previous studies comparing low-carbohydrate and low-fat diets have not included a comprehensive behavioral treatment, resulting in suboptimal weight loss. To evaluate the effects of 2-year treatment with a low-carbohydrate or low-fat diet, each of which was combined with a comprehensive lifestyle modification program. Randomized parallel-group trial. (ClinicalTrials.gov registration number: NCT00143936) 3 academic medical centers. 307 participants with a mean age of 45.5 years (SD, 9.7 years) and mean body mass index of 36.1 kg/m(2) (SD, 3.5 kg/m(2)). A low-carbohydrate diet, which consisted of limited carbohydrate intake (20 g/d for 3 months) in the form of low-glycemic index vegetables with unrestricted consumption of fat and protein. After 3 months, participants in the low-carbohydrate diet group increased their carbohydrate intake (5 g/d per wk) until a stable and desired weight was achieved. A low-fat diet consisted of limited energy intake (1200 to 1800 kcal/d; <or=30% calories from fat). Both diets were combined with comprehensive behavioral treatment. Weight at 2 years was the primary outcome. Secondary measures included weight at 3, 6, and 12 months and serum lipid concentrations, blood pressure, urinary ketones, symptoms, bone mineral density, and body composition throughout the study. Weight loss was approximately 11 kg (11%) at 1 year and 7 kg (7%) at 2 years. There were no differences in weight, body composition, or bone mineral density between the groups at any time point. During the first 6 months, the low-carbohydrate diet group had greater reductions in diastolic blood pressure, triglyceride levels, and very-low-density lipoprotein cholesterol levels, lesser reductions in low-density lipoprotein cholesterol levels, and more adverse symptoms than did the low-fat diet group. The low-carbohydrate diet group had greater increases in high-density lipoprotein cholesterol levels at all time points, approximating a 23% increase at 2 years. Intensive behavioral treatment was provided, patients with dyslipidemia and diabetes were excluded, and attrition at 2 years was high. Successful weight loss can be achieved with either a low-fat or low-carbohydrate diet when coupled with behavioral treatment. A low-carbohydrate diet is associated with favorable changes in cardiovascular disease risk factors at 2 years. National Institutes of Health.


Immunoglobulin in clinically uninvolved skin in systemic lupus erythematosus: association with renal disease.
23 of 42, or 55%, of patients with systemic lupus erythematous had immunoglobulin deposits along the epidermal basement membrane of uninvolved skin (positive lupus band test [LBT]). In patients with low serum complement levels, 91% had a positive LBT), as compared with 15% in those with normal complement levels. The LBT was positive in 70% of patients with clinical and laboratory evidence of renal disease, but in only 31% of patients without renal disease. 81% of patients with the more severe histologic forms of lupus nephritis, i.e., proliferative glomerulonephritis and membranous glomerulonephritis, and positive tests, whereas only 23% with mesangial glomerulitis or normal histologic findings were positive. Immunoglobulins of the same class found in the skin were detected in the glomeruli of patients examined by renal biopsy. These results suggest that there is a relationship between the occurrence of immunoglobulin in the epidermal basement membrane and the presence of the more severe forms of lupus nephritis.


Chip-scale high Q-factor glassblown microspherical shells for magnetic sensing.
A whispering gallery mode resonator based magnetometer using chip-scale glass microspherical shells is described. A neodynium micro-magnet is elastically coupled and integrated on top of the microspherical shell structure that enables transduction of the magnetic force experienced by the magnet in external magnetic fields into an optical resonance frequency shift. High quality factor optical microspherical shell resonators with ultra-smooth surfaces have been successfully fabricated and integrated with magnets to achieve Q-factors of greater than 1.1 × 107 and have shown a resonance shift of 1.43 GHz/mT (or 4.0 pm/mT) at 760 nm wavelength. The main mode of action is mechanical deformation of the microbubble with a minor contribution from the photoelastic effect. An experimental limit of detection of 60 nT Hz-1/2 at 100 Hz is demonstrated. A theoretical thermorefractive limited detection limit of 52 pT Hz-1/2 at 100 Hz is calculated from the experimentally derived sensitivity. The paper describes the mode of action, sensitivity and limit of detection is evaluated for the chip-scale whispering gallery mode magnetometer.


Bonnie Berger named ISCB 2019 ISCB Accomplishments by a Senior Scientist Award recipient.
The International Society for Computational Biology (ISCB) honors a leader in the fields of computational biology and bioinformatics each year with the Accomplishments by a Senior Scientist Award. This award is the highest honor conferred by ISCB to a scientist who is recognized for significant research, education, and service contributions. Bonnie Berger, Simons Professor of Mathematics and Professor of Electrical Engineering and Computer Science at the Massachusetts Institute of Technology (MIT) is the 2019 recipient of the Accomplishments by a Senior Scientist Award. She is receiving her award and presenting a keynote address at the 2019 Joint International Conference on Intelligent Systems for Molecular Biology/European Conference on Computational Biology in Basel, Switzerland on July 21-25, 2019.


Febrile young infants with abnormal urine dipstick at low risk of invasive bacterial infection.
To develop and validate a prediction rule to identify well-appearing febrile infants aged ≤90 days with an abnormal urine dipstick at low risk of invasive bacterial infections (IBIs, bacteraemia or bacterial meningitis). Ambispective, multicentre study. The derivation set in a single paediatric emergency department (ED) between 2003 and 2017. The validation set in 21 European EDs between December 2017 and November 2019. Two sets of well-appearing febrile infants aged ≤90 days with an abnormal urine dipstick (either leucocyte esterase and/or nitrite positive test). Prevalence of IBI in low-risk infants according to the RISeuP score. We included 662 infants in the derivation set (IBI rate:5.2%). After logistic regression, we developed a score (RISeuP score) including age (≤15 days old), serum procalcitonin (≥0.6 ng/mL) and C reactive protein (≥20 mg/L) as risk factors. The absence of any risk factor had a sensitivity of 96.0% (95% CI 80.5% to 99.3%), a negative predictive value of 99.4% (95% CI 96.4% to 99.9%) and a specificity of 32.9% (95% CI 28.8% to 37.3%) for ruling out an IBI. Applying it in the 449 infants of the validation set (IBI rate 4.9%), sensitivity, negative predictive value and specificity were 100% (95% CI 87.1% to 100%), 100% (95% CI 97.3% to 100%) and 29.7% (95% CI 25.8% to 33.8%), respectively. This prediction rule accurately identified well-appearing febrile infants aged ≤90 days with an abnormal urine dipstick at low risk of IBI. This score can be used to guide initial clinical decision-making in these patients, selecting infants suitable for an outpatient management.


Dietary Nitrate from Plant Foods: A Conditionally Essential Nutrient for Cardiovascular Health.
Under specific conditions, such as catabolic stress or systemic inflammation, endogenous nutrient production becomes insufficient and exogenous supplementation (for example, through dietary intake) is required. Herein, we propose consideration of a dietary nitrate from plant foods as a conditionally essential nutrient for cardiovascular health based on its role in nitric oxide homeostasis. Nitrate derived from plant foods may function as a conditionally essential nutrient, whereas nitrate obtained from other dietary sources, such as drinking water and cured/processed meats, warrants separate consideration because of the associated health risks. We have surveyed the literature and summarized epidemiological evidence regarding the effect of dietary nitrate on cardiovascular disease and risk factors. Meta-analyses and population-based observational studies have consistently demonstrated an inverse association of dietary nitrate with blood pressure and cardiovascular disease outcomes. Considering the available evidence, we suggest 2 different approaches to providing dietary guidance on nitrate from plant-based dietary sources as a nutrient: the Dietary Reference Intakes developed by the National Academies of Sciences, Engineering, and Medicine, and the dietary guidelines evaluated by the Academy of Nutrition and Dietetics. Ultimately, this proposal underscores the need for food-based dietary guidelines to capture the complex and context-dependent relationships between nutrients, particularly dietary nitrate, and health.


Factor(s) responsible for the increase in alkaline phosphatase activity of postmitotic granulocytes from normal individuals and patients with chronic myeloid leukemia.
Using postmitotic granulocytes (PMGs) with low neutrophil alkaline phosphatase activity (NAP activity), factor(s) having the capacity to increase their NAP activity were examined in vitro. A high activity of the factor was demonstrated in the cystic fluid of a human squamous cell carcinoma, which is known to produce a large amount of granulocyte-macrophage colony-stimulating factor (GM-CSF). The NAP-stimulating factor increased NAP values both in PMGs from normal bone marrow and PMGs from patients with chronic myeloid leukemia (CML), and NAP values in cells treated with the factor approached or rose above those of normal peripheral granulocytes after 48 hr of culture. The effect of the factor was specific in that the factor caused stimulation only in granulocytic series. These findings may indicate that increases in NAP activity reflect maturation or granulocytes and that low NAP activity of neutrophils derived from patients with CML is due to the immaturity of these cells. The relationship between the factor responsible for the increase in NAP activity and GM-CSF is also discussed.


Efficacy of Beauveria bassiana against the red imported fire ant, Solenopsis invicta (Hymenoptera: Formicidae), in Taiwan.
Combining biological control and chemical control could be used for controlling red imported fire ant (RIFA), Solenopsis invicta, more effectively. Beauveria bassiana F256, a local strain from Taiwan, was evaluated for its efficacy in the control of S. invicta under both laboratory and field conditions. The efficacies of different doses of B. bassiana (Bb) using direct application and bait formulation methods were compared. The number of RIFA workers killed by the direct application of Bb or by bait were significantly higher than those of the control, with different rates of efficacy under laboratory conditions. Under field conditions, the direct application of Bb into RIFA mounds was more efficient in inactivating the mounds than the bait application. It was shown that B. bassiana is able to control S. invicta under both laboratory and field conditions and can be used as a biocontrol agent against RIFA in Taiwan.


Functional proteomic profiling reveals KLK13 and TMPRSS11D as active proteases in the lower female reproductive tract.
Background: Cervical-vaginal fluid (CVF) hydrates the mucosa of the lower female reproductive tract and is known to contain numerous proteases. The low pH of CVF (4.5 or below in healthy women of reproductive age) is a uniquely human attribute and poses a challenge for the proteolytic functioning of the proteases identified in this complex biological fluid. Despite the abundance of certain proteases in CVF, the proteolytic activity and function of proteases in CVF is not well characterized. Methods: In the present study, we employed fluorogenic substrate screening to investigate the influence of pH and inhibitory compounds on the proteolytic activity in CVF. Activity-based probe (ABP) proteomics has evolved as a powerful tool to investigate active proteases within complex proteomes and a trypsin-specific ABP was used to identify active proteases in CVF. Results: Serine proteases are among the most abundant proteins in the CVF proteome. Labeling human CVF samples with the trypsin-specific ABP revealed serine proteases transmembrane protein serine 11D and kallikrein-related peptidase 13 as active proteases in CVF. Furthermore, we demonstrated that the proteolytic activity in CVF is highly pH-dependent with an almost absolute inhibition of trypsin-like proteolytic activity at physiological pH levels. Conclusions: These findings provide a framework to understand proteolytic activity in CVF. Furthermore, the present results provide clues for a novel regulatory mechanism in which fluctuations in CVF pH have the potential to control the catalytic activity in the lower female reproductive tract.


Reliability and reproducibility of retinal oxygen saturation measurements using a predefined peri-papillary annulus.
To determine the reliability and reproducibility of the Vesselmap Oximetry Module for arteriolar and venular oxygen saturation (SO2 ) of the same retinal area, specified by a peripapillary annulus, in healthy subjects. Fundus oximetry images were obtained, using a standardized protocol by a single observer, from the right eye of 20 healthy individuals. Age range was 19-45 years old, and images were analysed using the oximetry module of the Vesselmap System (Imedos, UG, Germany). Intra-observer reliability (assessment of two measurements of SO2 values performed 5 days apart); interobserver reliability (assessment of SO2 performed by two different trained observers); and intrasubject reproducibility (comparison of SO2 measurements of two different images of the same subject and retinal area, taken 10 min apart) were assessed. The standard deviations between the repeated measurements (SDr), together with the intraclass correlation coefficient (ICC), of these three parameters were calculated. The SDr for intra-observer reliability was 0.56% and 0.55% for arteriolar and venular SO2 , respectively. The results were similar for intrasubject reproducibility (0.69% and 0.79% for arteriolar and venular SO2, respectively); interobserver reliability, however, was higher (SDr 1.22% and 1.01% for arteriolar and venular SO2 , respectively). The ICC values for intra-observer reliability were 0.99 for both arteriolar and venular SO2 . The results were similar for both interobserver reliability (0.94 for arteriolar SO2 and 0.96 for venular SO2 ) and intrasubject reproducibility (0.98 for both arteriolar and venular SO2 ). Retinal oxygen saturation values taken using the oximetry module of the Vesselmap System are highly reliable and reproducible, provided the image quality is standardized, the same measurement area is analysed in each image, and the number of observers analysing the images is kept to a minimum.


An immunohistological comparison of primary lung carcinosarcoma and sarcoma.
We wished to assess the antigenic expression of primary lung tumors diagnosed as either carcinosarcoma or sarcoma in order to determine whether this information would be useful in distinguishing the two. We therefore immunohistochemically analyzed six pulmonary carcinosarcomas and five primary lung sarcomas for the presence of carcinoembryonic antigen (CEA), S100 protein, cytokeratin and vimentin using commercially available monoclonal and polyclonal antibodies on formalin fixed tissues. Six of six carcinosarcomas stained positively for cytokeratin while none of the sarcomas stained. In three carcinosarcomas both the carcinomatous and sarcomatous areas were positive while in three only the carcinomatous areas were positive. CEA staining was present in five carcinosarcomas and absent in all the sarcomas. CEA positivity was strong and not confined to those tumors with obvious gland formation. Staining for S100 protein was positive in two carcinosarcomas but only in those areas showing chondroid differentiation. Immunohistochemical staining for vimentin using two different monoclonal antibodies gave inconsistent results. We conclude that in differentiating between a carcinosarcoma and a sarcoma of the lung, immunohistochemical staining for both cytokeratin and CEA are useful with cytokeratin marginally preferable. The data indicate that carcinosarcoma of the lung, like that of the upper aerodigestive tract, expresses antigens suggesting both epithelial and mesenchymal differentiation.


Traditional medicine and an inclusive model of health seeking behaviour in Zimbabwe.
This paper examines research conducted in Zimbabwe over the past three decades on the patterns of use of traditional medicine in Zimbabwe. While much is known about patterns of choice between traditional vs. orthodox medicine, little is known about when and under what circumstances Zimbabweans use other medical therapies. A more inclusive model of health seeking behaviour that entails a more encompassing definition of traditional medicine and a broader spectrum of health care alternatives is advocated.


Garlic-derived compound S-allylmercaptocysteine inhibits hepatocarcinogenesis through targeting LRP6/Wnt pathway.
Whether and how garlic-derived S-allylmercaptocysteine (SAMC) inhibits hepatocellular carcinoma (HCC) is largely unknown. In the current study, the role of low-density lipoprotein receptor (LDLR)-related protein 6 (LRP6) in HCC progression and the anti-HCC mechanism of SAMC was examined in clinical sample, cell model and xenograft/orthotopic mouse models. We demonstrated that SAMC inhibited cell proliferation and tumorigenesis, while induced apoptosis of human HCC cells without influencing normal hepatocytes. SAMC directly interacted with Wnt-pathway co-receptor LRP6 on the cell membrane. LRP6 was frequently over-expressed in the tumor tissue of human HCC patients (66.7% of 48 patients) and its over-expression only correlated with the over-expression of β-catenin, but not with age, gender, tumor size, stage and metastasis. Deficiency or over-expression of LRP6 in hepatoma cells could partly mimic or counteract the anti-tumor properties of SAMC, respectively. In vivo administration of SAMC significantly suppressed the growth of Huh-7 xenograft/orthotopic HCC tumor without causing undesirable side effects. In addition, stable down-regulation of LRP6 in Huh-7 facilitated the anti-HCC effects of SAMC. In conclusion, LRP6 can be a potential therapeutic target of HCC. SAMC is a promising specific anti-tumor agent for treating HCC subtypes with Wnt activation at the hepatoma cell surface.


Dissection of the posterior part of the neck.
The operation described consists of an anatomic en bloc dissection of posterior and deep cervical lymphatic channels and nodes. The procedure is cosmetically and functionally acceptable and provides adequate clearance of lymphatics from the posterior part of the neck. It is recommended for selected cutaneous lesions of the parietal, occipital and mastoid scalp as well as of the skin of the posterior part of the neck.


Identification of genes upregulated in ALK-positive and EGFR/KRAS/ALK-negative lung adenocarcinomas.
Activation of the EGFR, KRAS, and ALK oncogenes defines 3 different pathways of molecular pathogenesis in lung adenocarcinoma. However, many tumors lack activation of any pathway (triple-negative lung adenocarcinomas) posing a challenge for prognosis and treatment. Here, we report an extensive genome-wide expression profiling of 226 primary human stage I-II lung adenocarcinomas that elucidates molecular characteristics of tumors that harbor ALK mutations or that lack EGFR, KRAS, and ALK mutations, that is, triple-negative adenocarcinomas. One hundred and seventy-four genes were selected as being upregulated specifically in 79 lung adenocarcinomas without EGFR and KRAS mutations. Unsupervised clustering using a 174-gene signature, including ALK itself, classified these 2 groups of tumors into ALK-positive cases and 2 distinct groups of triple-negative cases (groups A and B). Notably, group A triple-negative cases had a worse prognosis for relapse and death, compared with cases with EGFR, KRAS, or ALK mutations or group B triple-negative cases. In ALK-positive tumors, 30 genes, including ALK and GRIN2A, were commonly overexpressed, whereas in group A triple-negative cases, 9 genes were commonly overexpressed, including a candidate diagnostic/therapeutic target DEPDC1, that were determined to be critical for predicting a worse prognosis. Our findings are important because they provide a molecular basis of ALK-positive lung adenocarcinomas and triple-negative lung adenocarcinomas and further stratify more or less aggressive subgroups of triple-negative lung ADC, possibly helping identify patients who may gain the most benefit from adjuvant chemotherapy after surgical resection.