circFANCA accelerates the malignant process of OSCC by modulating miR-34a/PA28γ signaling.
To investigate the upstream regulatory molecules of proteasomal activator 28γ (PA28γ), and explore its specific regulatory mechanism and potential clinical significance in OSCC. qPCR was used to examine miR-34a, circFANCA and PSME3 expression. Western blotting was adopted to detect PA28γ expression. Transwell experiments were conducted to evaluate OSCC cell migration and invasion ability. FISH was used to evaluate the subcellular localization of circFANCA and miR-34a, and RNA pull-down verified the interaction between them. The expression of circFANCA and miR-34a in clinical cohorts was assessed by ISH, and the results were subjected to survival analysis using Kaplan-Meier analysis. Here, we proved that miR-34a expression is lower in highly aggressive OSCC tissues and cell lines. Notably, miR-34a can downregulate PA28γ expression and inhibit OSCC invasion and migration. Next, we confirmed that circFANCA promoted OSCC cell metastatic ability by sponging miR-34a. Importantly, interfering with miR-34a rescued the malignant progression of OSCC induced by silencing circFANCA. Finally, clinical data showed lower miR-34a expression and higher circFANCA expression were associated with poor prognosis in OSCC patients. The circFANCA/miR-34a/PA28γ axis facilitates the metastasis of OSCC, and circFANCA and miR-34a have potential to serve as prognostic markers for OSCC patients.


Curcumin-inspired cytotoxic 3,5-bis(arylmethylene)-1-(N-(ortho-substituted aryl)maleamoyl)-4-piperidones: A novel group of topoisomerase II alpha inhibitors.
Three series of novel 3,5-bis(arylmethylene)-1-(N-(ortho-substituted aryl)maleamoyl)-4-piperidones, designed as simplified analogs of curcumin with maleic diamide tether, were synthesized and bioevaluated. These compounds displayed potent cytotoxicity towards human Molt 4/C8 and CEM T-lymphocytes as well as murine L1210 leukemic cells. In contrast, the related N-arylmaleamic acids possessed little or no cytotoxicity in these three screens. Design of these compounds was based on molecular modeling studies performed on a related series of molecule in a previous study. Representative title compounds were found to be significantly potent in inhibiting the activity of topoisomerase II alpha indicating the possible mode of action of these compounds. These compounds were also potent antioxidants in vitro and attenuated the AAPH triggered peroxyl radical production in human fibroblasts. Various members of these series were also well tolerated in both in vitro and in vivo toxicity analysis.


Detergents inhibit exocytosis in PC 12 cells: evidence for an effect on ion fluxes.
Membrane events in exocytosis were studied by examining the effect of different detergents on the K+-stimulated release of noradrenaline in the secretory cell line PC 12. The nonionic detergent Triton X-100 and the cationic detergent cetyltrimethylammonium bromide (CTAB) inhibit the noradrenaline release evoked by 55 mM K+ by 50% at very low concentrations (30 microM and 10 microM, respectively). These values are tenfold lower than the critical micellar concentrations (CMC). No such effect was seen with the anionic detergent sodium dodecyl sulphate (NaDodSO4). The inhibitory effect of 30 microM Triton X-100 is reversible, and the recovery from inhibition correlates with the loss of detergent from the cells as demonstrated by binding studies using [3H]Triton X-100. The possible relationship between this inhibition of secretion and the structural properties of the detergent was investigated. The inhibition in the presence of purified Triton X-100 subfractions turned out to be a function of the length of the oligometric ethyleneglycol chain (C6 to C26). The maximal effect was observed for Triton X-100 molecules having a chain length of 16 carbon atoms, which can penetrate just half of the lipid bilayer of the membrane. Additionally, the phase transition at 13-14 degrees C observed in an Arrhenius plot of noradrenaline release in stimulated cells was abolished. In the presence of 30 microM Triton X-100, 22Na+ uptake, 86Rb+ release, and 45Ca2+ uptake were reduced by 50-60%. These data suggest that the site of action of Triton X-100 is at the level of altering the movement of ions in PC 12 cells during the stimulatory phase of secretion.


Insight into the mechanisms of plant growth promoting strain SNB6 on enhancing the phytoextraction in cadmium contaminated soil.
Plant growth-promoting rhizobacteria (PGPR) assisted accumulator has been proposed as a phytoextraction method to clean cadmium (Cd) in contaminated soil, while the mechanisms were few studied regrading PGPR-soil-accumulator as an assemble. In this study, we revealed the possible mechanisms of the plant growth-promotion strain SNB6 on enhancing the Cd phytoextration of vetiver grass by the analysis of the whole genome of SNB6, soil biochemical properties and plant growth response. Results showed that SNB6 encoded numerous genes needed for Cd tolerance, Cd mobilization and plant growth promotion. SNB6 increased HOAc-extractable Cd that showed a positive correlation with Cd uptake in accumulator. In addition, SNB6 improved the biochemical activities (bioavailability of nutritional substances, bacterial count, soil respiration and enzyme activity) in rhizosphere soil. Moreover, the antioxidative enzymes activities of accumulator were significantly enhanced by SNB6. Consequently, SNB6 promoted Cd uptake and biomass of accumulator, thus enhancing the Cd phytoextraction. The maximum Cd extractions in root, stem and leaf reached to 289.47 mg/kg, 88.33 mg/kg and 59.38 mg/kg, respectively. Meanwhile, the total biomass of accumulator was increased by 9.68-45.99% in SNB6 treatment. These findings could be conducive to the understanding the mechanisms of PGPR on enhancing the Cd phytoextraction of accumulator.


Hypothalamic projection to the lateral septum in the guinea pig an HRP study.
In the guinea-pig, a bilateral projection from the magnocellular dorsal nucleus (MDN) of the hypothalamus and the lateral hypothalamus (LH) to the lateral septum nucleus (LSN) was demonstrated by using horseradish peroxidase (HRP) histochemistry. The deposition of crystalline HRP into the LSN consistently resulted in labeling of cell bodies within the limits of the MDN. Labeled perikarya exhibited a typical granular appearance. The better labeling was obtained with HRP implants located in the posterior LSN. As it was previously described that most of the MDN cells were enkephalin-containing and that the posterior LSN contained enkephalinergic nerve terminals, it is suggested that the MDN may contribute to the enkephalinergic innervation of the LSN. In addition a group of labeled neurons was found in the LH. They were located ventrally and laterally in relation to the fornix column. HRP reaction product filled these neurons in a Golgi-like manner, providing information about their morphology.


SIMUS: An open-source simulator for medical ultrasound imaging. Part II: Comparison with four simulators.
Computational ultrasound imaging has become a well-established methodology in the ultrasound community. In the accompanying paper (part I), we described a new ultrasound simulator (SIMUS) for MATLAB, which belongs to the Matlab UltraSound Toolbox (MUST). SIMUS can generate pressure fields and radiofrequency RF signals for simulations in medical ultrasound imaging. It works in a harmonic domain and uses far-field and paraxial linear equations. In this article (part II), we illustrate how SIMUS compares with other ultrasound simulators (Field II, k-Wave, FOCUS, and Verasonics) for a homogeneous medium. We designed different transmit sequences (focused, planar, and diverging wavefronts) and calculated the corresponding 2-D and 3-D (with elevation focusing) RMS pressure fields. SIMUS produced pressure fields similar to those of Field II, FOCUS, and k-Wave. The acoustic fields provided by the Verasonics simulator were significantly different from those of SIMUS and k-Wave, although the overall appearance remained consistent. Our simulations tend to demonstrate that SIMUS is reliable and can be used for realistic medical ultrasound simulations.


Lipoprotein-subclass particle numbers in children with abdominal obesity.
The lipoprotein particle number (PN) profile may be a better marker of cardiovascular risks than standard serum lipid measurements. The aim of this study was to analyze the lipoprotein PNs in Japanese children with abdominal obesity and to determine the subclass profile. The participants included 164 Japanese children (79 boys and 85 girls) aged 9-13 years. We obtained waist-to-height ratios (WHtR) and serum lipids for all participants. The lipoprotein PNs in 12 subclasses were analyzed using high performance liquid chromatography (HPLC). Both boys and girls with abdominal obesity (WHtR ≧ 0.5) had significantly higher triglyceride (TG), very-low-density lipoprotein (VLDL)-PN, and all VLDL-subclass PNs compared to those without abdominal obesity. In boys with abdominal obesity, low-density lipoprotein (LDL)-PN was higher, but lipoprotein cholesterol (LDL-C) was not, and high-density lipoprotein cholesterol (HDL-C) was lower, but HDL-PN was not compared to those without abdominal obesity. In girls with abdominal obesity, LDL-C and LDL-PN were not significantly different and both HDL-C and HDL-PN were lower compared to those without abdominal obesity. Subclass analyses demonstrated that boys and girls with abdominal obesity had significantly lower very large and large HDL-PNs than those without abdominal obesity. In addition, medium, small, and very small LDL-PNs were higher in boys with abdominal obesity than those without abdominal obesity. This study found that Japanese children with abdominal obesity are affected by the lipoprotein-subclass PN profile, with sex differences in the LDL- and HDL-subclasses, which is different from results obtained by standard serum lipid measurements.


Acral purpura as leading clinical manifestation of dermatitis herpetiformis: report of two adult cases with a review of the literature.
Dermatitis herpetiformis (DH) is an autoimmune disease that clinically manifests as pruritic vesicles and papules. The diagnosis of DH is often challenging because of its wide spectrum of clinical presentations. We here report 2 patients with DH in whom finger petechiae represented the initial and leading manifestation of the disease, and the confirmed diagnosis critically relied on immunopathological studies. Therefore, besides the classic causes, clinicians should also consider DH in the differential diagnosis of acral purpura, even in patients only presenting with discrete acral petechial lesions. We also review the recent literature regarding the rare cases of petechiae in adult DH patients.


Haematopoietic stem cells improve cardiac function after infarction without permanent cardiac engraftment.
Transplantation of bone marrow derived adult stem cells (BMC) improves cardiac function after acute myocardial infarction (MI). However, the cell population mediating myocardial recovery and the fate of the transplanted cells are still controversial. We determined the effects of Sca-1+ c-kit+ lin- haematopoietic BMC on cardiac function after MI and the cell fate after transplantation. Sca-1+ c-kit+ lin- BMC of male donor C57BL/6 mice were transplanted by intravenous injection into syngenic females after permanent MI. LV dimensions and function were determined by echocardiography and cardiac magnetic resonance imaging, transplanted BMC were identified by Y chromosome DNA in situ hybridization. BMC treatment completely prevented LV dilation (LV end-diastolic volume BMC 70 +/- 16 microl vs. control 122 +/- 41 microl; p < 0.05) and improved fractional shortening (BMC 22.9 +/- 8% vs. control 15.4 +/- 8.4%; p < 0.05) and ejection fraction BMC 68.2 +/- 6.6% vs. control 52 +/- 14.3%; p < 0.05) as early as 3 days after transplantation, but did not decrease infarct size (BMC 27 +/- 6% vs. control 28 +/- 7%, p = n.s.). After 4 weeks, only sporadic cells of male origin were identified in infarcted hearts (< 0.01% of periinfarct cells). Intravenous injection of Sca-1+ c-kit+ lin- in BMC after MI improves LV dimensions and function without evidence for long term engraftment.


IgE response to two new allergen proteins of Solanum melongena L. (eggplant).
A number of allergens from eggplant (Solanum melongena L.) have been previously identified. In this study, we could detect IgE reactivity of two allergic subjects' sera towards two protein bands of molecular mass of about 35 and 15 kDa. As IgE were reactive to both raw and cooked eggplant extracts, a heat-stable nature of these novel allergens is apparent.


Repression of gonadotropin-releasing hormone (GnRH) gene expression by melatonin may involve transcription factors COUP-TFI and C/EBP beta binding at the GnRH enhancer.
Melatonin activates membrane-bound G-protein-coupled receptors mt1 and MT2, but may also bind a family of orphan nuclear receptors, including RORalpha and RZRbeta, representing another potential molecular mechanism of melatonin action. Recently, we demonstrated that melatonin downregulates gonadotropin-releasing hormone (GnRH) gene expression in the GT1-7 cell line, specifically at the level of the neuron-specific GnRH gene enhancer. In this study, we have examined the region located at -1736/-1728 of the GnRH enhancer shown to be involved in the repression of GnRH by melatonin. This region includes hexameric consensus binding sites for orphan nuclear receptors, including ROR/RZR and COUP-TFI, as well as other defined consensus binding sites for AP-1 and C/EBP. Using electrophoretic mobility shift analysis (EMSA), we have demonstrated that GT1-7 nuclear proteins bind specifically to this region of the GnRH enhancer to form 4 complexes. EMSA antibody supershift analysis indicates that the transcription factors COUP-TFI and C/EBP beta bind two specific complexes, but RORalpha, Oct-1, Pbx-1, c-fos, or c-jun antibodies failed to produce any detectable supershifts. These results provide the first evidence that melatonin may mediate its direct neuroendocrine control of GnRH gene expression through transcription factor binding at specific regions of the GnRH enhancer.


Iron loading and secondary multi-trace element deficiency in a dairy herd fed silage grass grown on land fertilized with sewage sludge.
Recycling sewage sludge by applying it to agricultural land is strategically important in the European Union and is regulated by Directive 86/278/EEC, aimed at protecting the soil and humans from the presence of unwanted substances. However, because of the ruminant feeding habits, there is a risk that animals grazed on pasture or fed crops grown on land treated in this way may ingest biosolids adhered to foliage and/or on the top soil. This paper describes an episode of toxicity in a dairy herd consuming silage from a field fertilized with sewage sludge produced in a wastewater treatment plant. The affected cows were recumbent, unable to rise and suffered diarrhoea. Analysis of tissues (fresh weight) from a cow that subsequently died revealed severe hepatic iron loading (6720 mg/kg) and secondary multi-trace element hepatic deficiency, particularly of copper (0.812 mg/kg) and manganese (0.436 mg/kg), but also selenium (0.164 mg/kg) and zinc (19.9 mg/kg). The study findings indicate that the use of sewage sludge in agriculture can cause secondary multi-trace element deficiencies in ruminants. Careful attention should be taken when crops are ensilaged avoiding top-soil sewage sludge contamination, since the acidification process may greatly increase Fe bioavailability.


The Involvement of Immune Cells Between Ischemic Stroke and Gut Microbiota.
Ischemic stroke, a disease with high mortality and disability rate worldwide, currently has no effective treatment. The systemic inflammation response to the ischemic stroke, followed by immunosuppression in focal neurologic deficits and other inflammatory damage, reduces the circulating immune cell counts and multiorgan infectious complications such as intestinal and gut dysfunction dysbiosis. Evidence showed that microbiota dysbiosis plays a role in neuroinflammation and peripheral immune response after stroke, changing the lymphocyte populations. Multiple immune cells, including lymphocytes, engage in complex and dynamic immune responses in all stages of stroke and may be a pivotal moderator in the bidirectional immunomodulation between ischemic stroke and gut microbiota. This review discusses the role of lymphocytes and other immune cells, the immunological processes in the bidirectional immunomodulation between gut microbiota and ischemic stroke, and its potential as a therapeutic strategy for ischemic stroke.


"People suffer and we see this": a qualitative study of the forms of patient psychological distress encountered by physiotherapists.
Psychological distress is a common response to many conditions physiotherapists treat. It is also common for a person's experience of distress to be associated with multiple stressors. This qualitative study explored physiotherapists' perceptions of the types of patient psychological distress they encountered in their clinical practice. A qualitative research approach was adopted. Twenty-three physiotherapists were recruited through purposive maximum variation sampling. To participate, physiotherapists had to self-report having encountered at least one patient they perceived to be experiencing psychological distress in the last 12 months. Data analysis was completed using Iterative Thematic Inquiry. Five themes were identified in the study: 1) distress extends beyond physical health issues; 2) fear of the future; 3) the emotional toll of loss; 4) trauma is often part of the story; and 5) losing hope. The results of this study highlight that patient psychological distress presents in a variety of forms and appears to be multifaceted and multifactorial in nature. As patients' experiences of psychological distress are relevant to physiotherapy practice, mental health capabilities need to be embedded within physiotherapy training.


Cup positioning and its effect on polyethylene wear of vitamin E- and non-vitamin E-supplemented liners in total hip arthroplasty: radiographic outcome at 5-year follow-up.
Aseptic loosening remains a challenging problem after total hip arthroplasty. Accurate cup placement and supplementation of antioxidants in acetabular liners might reduce material failure rates. The aim of this study is to assess the effect of the cup position on the wear behaviour of UHMWPE-XE and UHMWPE-X liners in vivo using virtual radiographs. We conducted a prospective, randomized, controlled, multicenter trial. Clinical data of 372 probands were analyzed. Anteroposterior pelvic X-rays of 324 patients immediately postoperatively and after 1 and 5 years were evaluated by the RayMatch® analysis software regarding cup position and wear behaviour. Mean cup anteversion was 20.3° (± 7.4) and inclination was 41.9° (± 7.0) postoperatively. 62.3% of all patients had an anteversion and inclination within the Lewinnek safe zone. Anterior and anterolateral approaches led to significantly higher cup anteversion compared to lateral approaches (27.3° ± 5.5; 20.9° ± 7.2; 17.5° ± 6.6; p < 0.001 and p = 0.001, respectively). Mean anteversion increased to 24.6° (± 8.0) after 1 year (p < 0.001). Only one revision occurred because of implant dislocation. Wear rates from UHMWPE-X and UHMWPE-XE did not differ significantly. Anteversion angles ≥ 25° correlated to increased polyethylene wear (23.7 µm/year ± 12.8 vs. 31.1 µm/year ± 22.8, p = 0.012) and this was amplified when inclination angles were ≥ 50° (23.6 µm/year ± 12.8 vs. 38.0 µm/year ± 22.7, p = 0.062). Anterior approaches lead to the highest inaccuracy of cup placement, but cup positioning outside the Lewinnek safe zone does not necessarily cause higher dislocation rates. Moreover, mean anteversion increased by approximately four degrees within the first year after operation, which is expected to be functional due to a regularization of pelvic tilt after intervention. Mid-term wear rates of UHMWPE-X and UHMWPE-XE liners are comparable, but steep cup positions lead to significantly increased polyethylene wear. In summary, a re-evaluation of target zones for intraoperative cup positioning might be considered. In the long-term reduced oxidative embrittlement could lead to superior wear behaviour of vitamin E-blended liners.


14-Bromo-12-chloro-2,16-dioxa-penta-cyclo-[18.104.22.168(1,21).0(3,8).0(10,15)]henicosa-3(8),10,12,14-tetra-ene-7,20-dione.
In the title compound, C19H16BrClO4, both the fused xanthene rings and one of the cyclo-hexane rings adopt envelope conformations, while the other cyclo-hexane ring is in a chair conformation. In the crystal, mol-ecules are linked by C-H⋯O hydrogen bonds, forming infinite chains running along [10-1] incorporating R 2 (2)(16) ring motifs. In addition, C-H⋯π inter-actions and weak π-π stacking inter-actions [centroid-centroid distance = 3.768 (3) Å] help to consolidate the packing.


An extensive projection of fish dorsolateral tegmental cells to the optic tectum revealed by intra-axonal dye marking.
The cells of the dorsolateral tegmental (DLT) nucleus in the crucian carp (Carassius carassius) were physiologically identified and marked with Lucifer dye. All the identified DLT cells receive both visual and rhombencephalic inputs. These cells project their axons into the contralateral tectum via the tectal commissure as well as into the ipsilateral tectum. The most striking characteristic of the DLT cells was the wide distribution of their axonal branching in the ipsilateral tectum.


Unilateral Biportal Endoscopic Posterior Cervical Foraminotomy: An Outcome Comparison With the Full-endoscopic Posterior Cervical Foraminotomy.
Retrospective control study. To compare the curative effects of unilateral biportal endoscopic posterior cervical foraminotomy (UBE-PCF) with full-endoscopic posterior cervical foraminotomy (FPCF). There are few studies directly comparing outcomes between UBE-PCF and FPCF. The objective of this study was to compare outcomes between UBE-PCF and FPCF. A retrospective control study was conducted for 69 patients of cervical radiculopathy from July 2019 to December 2021. Clinical outcomes scores, including neck disability index, visual analog scale (VAS)-arm, and VAS-neck were evaluated. Serum creatine kinase levels and the size of the operating hole were measured. Postoperative neck disability index, VAS-neck, and VAS-arm scores showed statistically significant improvement over preoperative scores (P<0.01). The operating time was significantly shorter in the UBE-PCF group (P<0.001). No significant differences were found in serum creatine kinase levels between the 2 groups (P>0.05). The mean area of the operating hole was 1.47+0.05 cm2 in the FPCF group and 1.79+0.11 cm2 in the UBE-PCF group. The difference was statistically significant (P<0.001). Both UBE-PCF and FPCF are safe and effective procedures for cervical radiculopathy. Predictable and sufficient decompression could be achieved by UBE-PCF in a shorter operation time. Treatment Benefits Level III.


Experimental and numerical study on Cu and Cd migration in different functional-area soils under simulated rainfall conditions.
Natural rainfall exerts a significant influence on the migration of heavy metals in soil. However, the knowledge of migration characteristics and release kinetics of heavy metals in contaminated soils under different rainfall intensities still remains unclear. In this study, the simulated rainfall of different intensities was designed to experimentally and numerically investigate Cu and Cd movements in different functional-area (agriculture, industrial, urban) soils. A HYDRUS-2D model was optimized to simulate the migration process of Cu and Cd in soil under different rainfall conditions. The hydraulic properties and solute transport parameters used in the model were estimated based on isothermal adsorption and chloride ion penetration experimental measurements and related model fitting. Furthermore, Cu and Cd BTCs (Breakthrough Curves) were fitted using the HYDRUS-2D inverse solution function with two-site model. The results showed that the order of the migration capacity of Cu and Cd in different functional-area soils was agriculture soil > industrial soil > urban soil, and Cd had a greater risk of groundwater pollution than Cu. With the increase of rainfall intensity, the high proportion of the exchangeable state of Cu and Cd in contaminated soil is easy to be released. Furthermore, the model was proved to describe the distribution of Cu and Cd in the soil profile very well. The present results can improve understanding of the environmental behavior of Cu and Cd in different functional-areas soils and can be used as a basis for risk assessment of Cu and Cd polluting groundwater.


Accumulation and Translocation of Essential and Nonessential Elements by Tomato Plants (Solanum lycopersicum) Cultivated in Open-Air Plots under Organic or Conventional Farming Techniques.
A 5-month experiment was performed to study the accumulation of several inorganic elements in tomato plants cultivated using organic or synthetic fertilizer. Plants were harvested in triplicate at six sampling dates during their life cycle. Statistical and chemometric analysis of data indicated the sequestration of toxic elements and of Na, Zn, Fe, and Co in roots, while the rest of the elements, including Cd, were mainly translocated to aboveground organs. A general decreasing trend in element concentrations with time was observed for most of them. A negative correlation between some element concentrations and ripening stage of fruits was identified. Conventionally grown plants seemed to accumulate more Cd and Tl in their tissues, while organic ones were richer in some nutrients. However, there was no clear effect of the fertilizer used (organic vs synthetic) on the elemental composition of fruits.


Successful endoscopic removal of foreign body lacerating into the duodenum.
Video 1The endoscope was advanced under direct visualization to the third part of the duodenum. A foreign body consistent with a ballpoint pen was identified in the duodenum. The sharp end of the pen formed a deep laceration through the second portion of the duodenum. The blunt end of the pen was ulcerated into the third portion of the duodenum with 2 additional pressure ulcers located in close proximity. Removal of the pen was first attempted using a snare without success. The foreign body was then successfully removed with a rat tooth. The second portion of the duodenum showed minimal oozing with contained deep laceration. The third portion of the duodenum showed 2 pressure ulcers.


The role of metabolism in the testing of developmental toxicants.
The delivery of potential developmental toxicants to the conceptus is dependent on several metabolic and pharmacokinetic factors. Within the maternal-embryo/fetal unit, maternal, placental, and embryo/fetal factors must be considered. These factors include blood flow, permeability, biotransformation, and elimination. Pharmacokinetic models based on data gathered from appropriate in vivo and in vitro studies may be used to describe the effect of these factors on toxicant delivery to the conceptus. Several known human developmental toxicants are discussed in terms of the metabolic and pharmacokinetic factors controlling their delivery to the conceptus. Metabolic events, including activation and/or detoxification, have been reported for the majority of the toxicants examined. Thus it would appear that the role of metabolism should be considered during the testing of potential developmental toxicants.


Deletion of the NF2 region in both meningioma and juxtaposed meningioangiomatosis: case report supporting a neoplastic relationship.
We report a case of juxtaposed atypical meningioma and meningioangiomatosis (MA) in an 8-year-old boy with no clinical stigmata or family history of neurofibromatosis. We studied the proliferative activity and genetic changes in the two lesions in an attempt to define their biologic and pathogenetic relationships. The MIB-1 index was 11% in the meningioma and <1% in the MA, indicating increased proliferative activity in the meningioma. Fluorescence in situ hybridization was done for two chromosomal regions commonly deleted in meningiomas. There was loss of the neurofibromatosis 2 locus (22q12) in both the meningioma and MA. Conversely, the region of 1p32 was not deleted. Our results indicate that both the meningioma and MA arose from the same clonal process, with the meningioma probably undergoing additional, but undefined, genetic alterations that confer upon it a more proliferative potential. This loss of 22q12 in the MA raises doubt about the presumed hamartomatous nature of MA.


Newborn Hearing Screening: Time to Act!
The present study was carried out with the aim of assessing the outcomes of otoacoustic hearing screening in newborns coupled with the three stage protocol. It was a hospital based observational study which was conducted over a time period of twelve months at a tertiary care institute to screen 2000 live neonates for congenital hearing impairment using OAE, followed up by tympanometry and BERA, if required. 2000 neonates were screened for hearing impairment. 406 were in high risk group and the rest in non-high risk group. Seven neonates had absent V wave on BERA. Five of them were high risk babies and the rest two were non-high risk ones. In order to ensure that early detection and effective intervention are possible for all neonates with hearing impairment, UNHS should be performed. Three stage UNHS protocol using OAE and BERA showed that the implementation of UNHS for congenital childhood hearing loss for all neonates would be beneficial.


A preliminary report on anti-depressant therapy and its effects on hope and immunity.
Psychological states such as bereavement and depression have been associated with suppression of the immune response. The authors present a pilot study utilizing the anti-depressant, maprotiline hydrochloride (Ludiomil) to determine its effects on the mental depression and immune reactions of T&B lymphocytes in patients with neurotic depression (dysthymic disorder by DSM III). Hope scores, derived from the content analysis of verbal samples, and Beck depression scores were examined as they covaried with various indices of immune response before and 3 months after the patients were administered either maprotiline or no anti-depressant medication. Although the study did not provide definitive findings regarding improved response following treatment of depressed patients with maprotiline hydrochloride, it did suggest further avenues of research for investigation.


Neuropsychological Functioning in Primary Dystonia: Updated and Expanded Multidomain Meta-Analysis.
Primary dystonia is conventionally considered as a motor disorder, though an emerging literature reports associated cognitive dysfunction. Here, we conducted meta-analyses on studies comparing clinical measures of cognition in persons with primary dystonia and healthy controls (HCs). We searched PubMed, Embase, Cochrane Library, Scopus, and PsycINFO (January 2000-October 2020). Analyses were modeled under random effects. We used Hedge's g as a bias-corrected estimate of effect size, where negative values indicate lower performance in dystonia versus controls. Between-study heterogeneity and bias were primarily assessed with Cochran's Q, I2 , and Egger's regression. From 866 initial results, 20 studies met criteria for analysis (dystonia n = 739, controls n = 643; 254 effect sizes extracted). Meta-analysis showed a significant combined effect size of primary dystonia across all studies (g = -0.56, P < 0.001), with low heterogeneity (Q = 25.26, P = 0.15, I2 = 24.78). Within-domain effects of primary dystonia were motor speed = -0.84, nonmotor speed = -0.83, global cognition = -0.65, language = -0.54, executive functioning = -0.53, learning/memory = -0.46, visuospatial/construction = -0.44, and simple/complex attention = -0.37 (P-values <0.01). High heterogeneity was observed in the motor/nonmotor speed and learning/memory domains. There was no evidence of publication bias. Moderator analyses were mostly negative but possibly underpowered. Blepharospasm samples showed worse performance than other focal/cervical dystonias. Those with inherited (ie, genetic) disease etiology demonstrated worse performance than acquired. Dystonia patients consistently demonstrated lower performances on neuropsychological tests versus HCs. Effect sizes were generally moderate in strength, clustering around -0.50 SD units. Within the speed domain, results suggested cognitive slowing beyond effects from motor symptoms. Overall, findings indicate dystonia patients experience multidomain cognitive difficulties, as detected by neuropsychological tests. © 2022 International Parkinson and Movement Disorder Society.


Mechanism underlying follicular hyperproliferation and oncogenesis in hidradenitis suppurativa.
Hidradenitis suppurativa (HS) is a skin disorder that causes chronic painful inflammation and hyperproliferation, often with the comorbidity of invasive keratoacanthoma (KA). Our research, employing high-resolution immunofluorescence and data science approaches together with confirmatory molecular analysis, has identified that the 5'-cap-dependent protein translation regulatory complex eIF4F is a key factor in the development of HS and is responsible for regulating follicular hyperproliferation. Specifically, eIF4F translational targets, Cyclin D1 and c-MYC, orchestrate the development of HS-associated KA. Although eIF4F and p-eIF4E are contiguous throughout HS lesions, Cyclin D1 and c-MYC have unique spatial localization and functions. The keratin-filled crater of KA is formed by nuclear c-MYC-induced differentiation of epithelial cells, whereas the co-localization of c-MYC and Cyclin D1 provides oncogenic transformation by activating RAS, PI3K, and ERK pathways. In sum, we have revealed a novel mechanism underlying HS pathogenesis of follicular hyperproliferation and the development of HS-associated invasive KA.


Modeling the competitive sorption and transport of Ni(II) and Zn(II) in soils: Comparing two multicomponent approaches.
The mobility of contaminants in soil is controlled by sorption reactions which can be affected by the presence of other solutes that compete for sorption sites. The ability to model such effects is necessary for evaluating the environmental risk of a given contaminant. In this study, the competitive sorption and transport of nickel (Ni) and zinc (Zn) in Olivier and Windsor soils was investigated using batch equilibration and miscible displacement experiments. During batch experiments, the sorption of Ni and Zn was mutually reduced in multicomponent systems, indicating that the metal cations compete for sorption sites. When applied concurrently, the retardation of both ions decreased and peak effluent concentrations increased relative to single ion experiments, demonstrating that competition increased the mobility of both ions during miscible displacement experiments. A novel Freundlich-type multicomponent isotherm (CDI) and its kinetic analog (CDIT) were developed and compared to the commonly used SRS isotherm and SRS-based kinetic approach (SRST) in describing the experimental data. The CDI provided a superior description of the competitive batch data, especially at low surface coverage, and may therefore be more applicable to multicomponent sorption than the SRS. The Olivier and Windsor transport data were best described by the CDIT and SRST, respectively, however, both models generally described the data well. Since both approaches gave comparable descriptions of the transport data while the CDI outperformed the SRS in describing the batch data, the CDI/CDIT may be more generally applicable to multicomponent systems and warrants further study.


Radiosensitivity of human tumour cells is correlated with the induction but not with the repair of DNA double-strand breaks.
Nine human tumour cell lines (four mammary, one bladder, two prostate, one cervical, and one squamous cell carcinoma) were studied as to whether cellular radiosensitivity is related to the number of initial or residual double-strand breaks (dsb). Cellular sensitivity was measured by colony assay and dsb by means of constant- and graded-field gel electrophoresis (CFGE and GFGE, respectively). The nine tumour cell lines showed a broad variation in cellular sensitivity (SF2 0.17-0.63). The number of initial dsb as measured by GFGE ranged between 14 and 27 dsb/Gy/diploid DNA content. In contrast, normal fibroblasts raised from skin biopsies of seven individuals showed only a marginal variation with 18-20 dsb/Gy/diploid DNA content. For eight of the nine tumour cell lines, there was a significant correlation between the number of initial dsb and the cellular radiosensitivity. The tumour cells showed a broad variation in the amount of dsb measured 24 h after irradiation by CFGE, which, however, was not correlated with the cellular sensitivity. This residual damage was found to be influenced not only by the actual number of residual dsb, but also by apoptosis and cell cycle progression which had impact on CFGE measurements. Some cell line strains were able to proliferate even after exposure to 150 Gy while others were found to degrade their DNA. Our results suggest that for tumour cells, in contrast to normal cells, the variation in sensitivity is mainly determined by differences in the initial number of dsb induced.


The diversity of the structure and genomic integration sites of HTLV-1 provirus in MT-2 cell lines.
A human T-lymphotropic virus Type 1 (HTLV-1) positive cell line, MT-2, derived from human cord leukocytes co-culturing with adult T cell leukemia/lymphoma (ATL) cells is commonly used in HTLV-1 research; however, the details of provirus integrated in MT-2 genome have not yet been characterized. In this study, five types of HTLV-1 proviral sequences were detected in 11 different sites of the genome in a reference MT-2 cell line. The five types of HTLV-1 proviral sequences were one complete proviral genome, two types of proviruses with deletion of large internal viral sequences (5.3 and 3.9 kB), one provirus with a large deletion (6.2 kB) from 5'LTR to position 6257, and one provirus of LTR only. The provirus with identical deletion of large internal viral sequence (5.3 kB) was found to be integrated into six different sites (chromosomes). A complete provirus and three of four types of defective provirus were consistently detected in two other MT-2 cell lines cultured in different laboratories. Not only Tax/Rex RNA and HBZ RNA, but also the transcriptional product for a specific defective provirus, were detectable in all three MT-2 cell lines. Because it has been reported that defective provirus is frequently detected in ATL cells, these results may be important in understanding the mechanism of HTLV-1 proviral polymorphism, which may be related to leukemogenesis. In addition, the large variation in integrated HTLV-1 proviruses makes it important for researchers to exercise caution in their assessment and interpretation of results using MT-2 cell lines.


Thymidylate synthase polymorphisms in genomic DNA as clinical outcome predictors in a European population of advanced non-small cell lung cancer patients receiving pemetrexed.
We studied whether thymidylate synthase (TS) genotype has an independent prognostic/predictive impact on a European population of advanced non-small cell lung cancer (NSCLC) patients receiving pemetrexed. Twenty-five patients treated with pemetrexed-based regimens were included. Genomic DNA was isolated prior to treatment. The variable number of tandem repeat (VNTR) polymorphisms, the G > C single nucleotide polymorphisms (SNP) and the TS 6-bp insertion/deletion (6/6) in the 3' untranslated region (UTR) polymorphisms were analyzed and correlated with overall response rate (ORR), progression-free survival (PFS), overall-survival (OS) and toxicity. The genotype +6/+6 predicted a higher ORR among active/former smokers compared to +6/-6 genotype (100% vs. 50%; p = 0.085). Overall, the 3R/3R genotype predicted a higher ORR (100%) over the rest VNTR polymorphisms (p = 0.055). The presence of 3R/3R genotype significantly correlated with a superior ORR in patients without EGFR activating mutations (100%) compared to 2R/2R, 2R/3R and 3R/4R genotype (77.8%, 33.3% and 0% respectively; p = 0.017). After a median follow-up of 21 months, a trend towards a better PFS, although not significant, was found among subjects showing 3R/3R polymorphisms (p = 0.089). A significantly superior OS was found in patients showing 3R/3R genotype rather than other VNTR polymorphisms (p = 0.019). No significant correlation with the toxicity was observed. In our series, 3R/3R polymorphism correlated with a superior OS. Also, this polymorphism, when associated to wild type EGFR, was related to a higher ORR to pemetrexed. Toxicity was not significantly correlated with a specific TS genotype.


Associations between sociodemographic and behavioural parameters and child development depending on age and sex: a cross-sectional analysis.
To explore environmental and individual factors that are associated with child development and to investigate whether the strength of these associations differs according to the age of the children. Cross-sectional study. This study was part of the LIFE Child study, a large cohort study conducted in Leipzig, Germany. 778 children aged between 0.5 and 6 years (48.6% girls, mean age=2.67 years). The outcomes were cognitive development, language development, body and hand motor skills, social-emotional development, and tracing skills, measured with a standardised development test. We analysed the associations between development and gestational age, socioeconomic status (SES), sex, behavioural difficulties, siblings, sleep duration, breastfeeding duration and overweight/obesity. We also tested for interactions between these variables and child age or sex. Higher gestational age (b ranging between 0.12 and 0.26) and higher SES (b ranging between 0.08 and 0.21) were associated with better outcomes in almost all developmental domains (all p<0.019). Children with older siblings had improved body and hand motor skills compared with children without older siblings (both b=0.55, all p<0.029). Boys had poorer scores than girls in body and hand motor skills and tracing (b=-0.45, -0.68 and -1.5, all p<0.019). Children with behavioural difficulties had significantly poorer outcomes in most developmental domains. Some of the associations with SES and sex were stronger in older than in younger children. Associations between gestational age and motor development were weaker in older children. We did not find significant associations between child development and sleep duration, breastfeeding duration or overweight/obesity. Some factors had a protective, others an adverse effect on development of children under 6 years of age. The effect of SES and sex increased, while the effect of gestational age decreased with age. NCT02550236.


Tegmentoreticular projections with special reference to the muscular atonia during paradoxical sleep in the cat: an HRP study.
Using the retrograde tracer technique with horseradish peroxidase (HRP), attempts were made to determine the cells of origin and the descending pathway of the tegmentoreticular projections in order to give an anatomical substrate for the physiological phenomenon of the postural atonia observed during paradoxical sleep (PS) in the cat. The HRP was injected into various parts of the pontomedullary reticular formation (RF) including the caudal raphe nuclei, nucleus (n.) reticularis gigantocellularis (Gc), n. reticularis magnocellularis (Mc), and other pontomedullary structures adjacent to the Mc. The results indicated that the HRP injection into the Mc, particularly its caudal and lateral two-thirds, resulted in specific labeling of cells located in an area just medial to the LCa together with those in the most medial part of the LCa. Bilateral lesions of these pontine structures have been reported to suppress the atonia otherwise observed during PS in the normal cat. In addition to the HRP labeled cells, we have also observed HRP filled fiber bundles directed to labeled cells in the medial part of the LCa and immediately adjacent tegmental RF area. The same course of HRP labeled fiber bundles was also observed together with HRP labeled cells in the Mc after HRP injections into the medial part of the LCa area, indicating the existence of an interconnection between the LCa area and the Mc. The location of the tegmentoreticular pathway corresponded to that of the lesions effective to suppress the muscular atonia during PS. HRP injections into the caudal medullar caudal to the Mc, on the other hand, resulted in no or almost no HRP labeled cells in the area medial to the LCa, in spite of the presence of HRP containing neurons in other parts of the pontomedullary RF areas, showing that the tegmentoreticular projections as described above terminate almost exclusively in the Mc.


A niche-based modeling approach to phytoplankton community assembly rules.
Six niche-based models proposed by Tokeshi, based on different assumptions of resource allocation by species, were fitted on phytoplankton relative abundance distributions, and potential environmental and biotic factors supporting the applicability of the fitted models were discussed. Overall 16 assemblages corresponding to different sampling times, various environmental conditions, and resource regimes within a year were fitted to the models. Phytoplankton biovolume was used as a measure of abundance, and a randomization test was applied to compare the model fit to the field data. The majority of the phytoplankton assemblages (11 of 16) were successfully described by the Random Fraction model, which is based on the theoretical assumption that resource is apportioned by the species in a random way. Only a few assemblages (three of 16), characterized by extremes in resource availability or disturbance, were not fitted by any of the models. The Random Fraction model in particular was rejected due to a steep slope during the first ranks, while the rest of the distribution remained relatively even, providing further evidence of resilience in phytoplankton communities. Although larger cells seem to have the potential to develop higher biomass, it seems that other factors, including the surface-to-volume ratio, counterbalance this advantage, resulting in a random-like behaviour in resource acquisition by phytoplankton, irrespective of cell size or species identity.


Antibodies and cytokines independently protect against pneumonic plague.
Yersinia pestis causes pneumonic plague, an exceptionally virulent disease for which we lack a safe and effective vaccine. Antibodies specific for the Y. pestis F1 and LcrV proteins can protect mice against pulmonary Y. pestis infection. We demonstrate that neutralizing tumor necrosis factor-alpha (TNFalpha) and gamma-interferon (IFNgamma) abrogates this protection at sub-optimal levels of F1- or LcrV-specific antibody, but not at optimal levels. Moreover, we demonstrate that endogenous TNFalpha and IFNgamma confer measurable protection in the complete absence of protective antibodies. These findings indicate that antibodies and cytokines independently protect against pneumonic plague and suggest that surrogate assays for plague vaccine efficacy should consider both the level of vaccine-induced antibody and the capacity of vaccine recipients to produce TNFalpha and IFNgamma upon exposure to Y. pestis.


Biological and phylogenetic characterization of Fusarium oxysporum complex, which causes yellows on Brassica spp., and proposal of F. oxysporum f. sp. rapae, a novel forma specialis pathogenic on B. rapa in Japan.
Although the causal agent of yellows of Brassica rapa (turnip, pak choi, and narinosa) in Japan was reported in 1996 to be Fusarium oxysporum f. sp. conglutinans, this classification has remained inconclusive because of a lack of detailed genetic and pathogenic studies. Therefore, we analyzed the taxonomic position of this organism using Japanese isolates of F. oxysporum complex obtained from diseased individuals of various B. rapa subspecies. Phylogenetic analyses using partial sequences of the rDNA intergenic spacer region and the mating-type gene (MAT1-1-1alpha-box) showed that B. rapa and cabbage isolates belong to different monophyletic clades that separated at early evolutionary stages. Additionally, correlations were observed between the molecular phylogeny and the vegetative compatibility groups. Isolates from turnip, komatsuna, and narinosa (B. rapa group) did not show pathogenicity against cabbage or broccoli (B. oleracea group), although they caused severe symptoms on their original host species. In contrast, cabbage isolates had significantly higher (P = 0.05) virulence on B. oleracea than on B. rapa crops. Our results indicate that F. oxysporum complex isolates from B. rapa and B. oleracea are not only phylogenetically distinct but also differ in host specificity. Therefore, we propose a novel forma specialis, F. oxysporum f. sp. rapae, which causes yellows on B. rapa, including turnip, komatsuna, pak choi, and narinosa.


New diagnostic strategy using narrow-band imaging (NBI) during laparoscopic surgery for patients with colorectal cancer.
Accurate tumor stage diagnosis during laparoscopic surgery remains difficult. We clarify the impact of new diagnostic strategy using narrow-band imaging (NBI) during laparoscopic surgery for colorectal cancer compared with other strategies. We defined angiogenesis (Ag) and fibrosis (Fib) grades using NBI laparoscopy (lap-NBI), and assessed the clinicopathological features associated with these grades for 67 patients with colorectal cancer who underwent surgery. We assessed vessel density and gray scale with computer software. NBI-Ag-grade and NBI-Fib-grade of the serosal surface of cancer lesions and peritoneal nodules correlated with vessel density and gray scale of those assessed by Image J computer software. NBI-Fib-grades of liver nodules also correlated with gray scale. NBI-Ag- grade and Fib-grade of the serosal surface of cancer lesions correlated with pathological depth of invasion. These NBI grades of pathological metastatic peritoneal nodules were higher than those of pathologically benign peritoneal nodules. NBI- Fib grades of pathological metastatic liver nodules were higher than those of pathologically benign liver nodules. In multivariate analysis, lap-NBI was associated with different diagnosis for T3, T4 and non-T3, and non-T4. Moreover, lap-NBI was associated with different diagnosis for T4 and non-T4. Predictive value for T4 by lap-NBI showed high sensitivity (85%) specificity (87%), positive predictive value (74%), negative predictive value (93%), and overall accuracy (87%). Sensitivity and overall accuracy of lap-NBI was superior to that of other diagnostic modalities. We clarified the usefulness of the new diagnostic strategy using lap-NBI during laparoscopic surgery for colorectal cancer in comparison with other strategies.


Adoptive Immunotherapy via Donor Lymphocyte Infusions following Allogeneic Hematopoietic Stem Cell Transplantation for Myelofibrosis: A Real-World, Retrospective Multicenter Study.
Allogeneic hematopoietic cell transplantation (allo-HCT) remains the sole curative option for myelofibrosis (MF). Relapse remains a significant problem, however, occurring in up to 20% to 30% of cases. Donor lymphocyte infusion (DLI) represents a potentially effective strategy for relapse prevention and management, but the optimal timing based on measurable residual disease/chimerism analyses and the choice of regimen remain undetermined. We performed a retrospective real-world analysis of a multicenter cohort of MF allo-HCT recipients from 8 European transplantation centers who received DLI between 2005 and 2022. Response was assessed using International Working Group-Myeloproliferative Neoplasms Research and Treatment-defined response criteria, and survival endpoints were estimated using the Kaplan-Meier estimator and log-rank test. The study included 28 patients with a median age of 58 years and a Karnofsky Performance Status of >80. The majority of patients had Dynamic International Prognostic Scoring System-plus intermediate-2 or high-risk disease at the time of allo-HCT. In vivo T cell depletion was used in 20 patients (71.2%), with 19 of the 20 receiving antithymocyte globulin. The indication for DLI was either "preemptive" (n = 15), due to a decrease in recipient chimerism (n = 13) or molecular relapse (n = 2), or "therapeutic" (n = 13) for clinician-defined hematologic/clinical relapse. No patient received DLI prophylactically. The median time of DLI administration was 23.4 months post allo-HCT. Of the 16 patients receiving multiple DLIs, 12 were part of a planned escalating dose regimen. The median follow-up from the time of first DLI was 55.4 months. The responses to DLI were complete response in 9 patients, partial response in 1 patient, and clinical improvement in 6 patients. Chimerism levels improved in 16 patients, and stable disease was reported in 5 patients. No response or progression was reported in 7 patients. DLI-induced acute graft-versus-host disease (aGVHD) was reported in 11 patients (39%), with grade III-IV aGVHD in 7 (25%). The median overall survival from the time of first DLI was 62.6 months, and the cumulative incidence of relapse/progression after first DLI was 30.8% at 6 months. This study highlights that good response rates can be achieved with DLI even after frank relapse in some patients in a cohort in which other treatment options are very limited. More prospective studies are warranted to identify the optimal DLI regimen and timing to improve patient outcomes.


Added clinical value of applying myocardial deformation imaging to assess right ventricular function.
Right heart dysfunction has been found to be a strong prognostic factor predicting adverse outcome in various cardiopulmonary diseases. Conventional echocardiographic measurements can be limited by geometrical assumptions and impaired reproducibility. Speckle tracking-derived strain provides a robust quantification of right ventricular function. It explicitly evaluates myocardial deformation, as opposed to tissue Doppler-derived strain, which is computed from tissue velocity gradients. Right ventricular longitudinal strain provides a sensitive tool for detecting right ventricular dysfunction, even at subclinical levels. Moreover, the longitudinal strain can be applied for prognostic stratification of patients with pulmonary hypertension, pulmonary embolism, and congestive heart failure. Speckle tracking-derived right atrial strain, right ventricular longitudinal strain-derived mechanical dyssynchrony, and three-dimensional echocardiography-derived strain are emerging imaging parameters and methods. Their application in research is paving the way for their clinical use.


A chemical derivatization based UHPLC-LTQ-Orbitrap mass spectrometry method for accurate quantification of short-chain fatty acids in bronchoalveolar lavage fluid of asthma mice.
Recent studies have demonstrated the important role of short-chain fatty acids (SCFAs) in the maintenance of homeostasis of respiratory immunity. However, there is still no report focus on the determination of SCFAs level in bronchoalveolar lavage fluid (BALF), the most common sample used for screening biomarkers of the pulmonary diseases. Herein, an ultra-high-performance liquid chromatography with LTQ-Orbitrap mass spectrometer (UHPLC-LTQ-Orbitrap) oriented 3-nitrophenylhydrazine (3-NPH)-based derivatization method was developed for the quantification of SCFAs in BALF. To achieve accurate quantitation, d4-acetate was used as internal standard to compensate for the matrix effects. Method validation showed a good linearity (R2 > 0.9992) with wide concentration range, and the intra-day and inter-day precision for determination of eight SCFAs in BALF samples was ≤ 14.79%. The quantitation accuracy, assessed by relative recoveries, ranged from 90% to 110% for target SCFAs at three concentration levels. Matrix effects ranged from 85% to 115%, and the lower limits of quantification of these targeted SCFAs were varied from 3 to 24 nmol/L. The SCFAs-targeted method was then applied to determine the changed levels in BALF samples from OVA-induced asthma mice and normal mice. In addition, the universality of our developed method was also demonstrated by determining the SCFAs concentrations in feces, serum and lung tissue samples from asthma and normal mice. These results indicate that 3-NPH derivatization based UHPLC-LTQ-Orbitrap provides accurate view of global SCFAs alternation in different samples, giving a support to deduce the origin of SCFAs in lung. The present study is of great importance for understanding the role of SCFAs in modulation of host metabolism and immunity.


Toll-like receptors and interferon associated immune factors responses to spring viraemia of carp virus infection in common carp (Cyprinus carpio).
Pattern recognition receptor (PRR) toll-like receptors (TLRs), antiviral agent interferon (IFN) and the effector IFN stimulated genes (ISGs) play a fundamental role in the innate immune response against viruses among all vertebrate classes. Common carp is a host for spring viraemia of carp virus (Rhabdovirus carpio, SVCV), which belong to Rhabdoviridae family. The present in-vivo experiment was conducted to investigate the expression of these innate immune factors in early phase as well as during recovery of SVCV infection by real-time quantitative reverse transcriptase polymerase chain reaction. A less lethal SVCV infection was generated in common carp (Cyprinus carpio) and was sampled at 3, 6, 12 h post infection (hpi), 1, 3, 5, 7 and 10 days post infection (dpi). At 3 hpi, the SVCV N gene was detected in all three fish and all three fish showed a relative fold increase of TLR2, TLR3 and TLR7, IFNa1, ISG15 and Vig1. Viral copies rapidly increased at 12 hpi then remained high until 5 dpi. When viral copy numbers were high, a higher expression of immune genes TLR2, TLR3, TLR7, IFNa1, IFNa2, IFNa1S, IFN regulatory factor 3 (IRF3), IRF7, interleukin 1β (IL1β), IL6, IL10, ADAR, ISG15, Mx1, PKR and Vig1 were observed. Viral copies were gradually reduced in 5 to 10 dpi fish, and also the immune response was considerably reduced but remained elevated. A high degree of correlation was observed between immune genes and viral copy number in each of the sampled fish at 12 hpi. The quick and prolonged elevated expression of the immune genes indicates their crucial role in survival of host against SVCV.


Role of Amino Acid Transporter SNAT1/SLC38A1 in Human Melanoma.
The tumor metabolism is an important driver of cancer cell survival and growth, as rapidly dividing tumor cells exhibit a high demand for energetic sources and must adapt to microenvironmental changes. Therefore, metabolic reprogramming of cancer cells and the associated deregulation of nutrient transporters are a hallmark of cancer cells. Amino acids are essential for cancer cells to synthesize the necessary amount of protein, DNA, and RNA. Although cancer cells can synthesize glutamine de novo, most cancer cells show an increased uptake of glutamine from the tumor microenvironment. Especially SNAT1/SLC38A1, a member of the sodium neutral amino acid transporter (SNAT) family, plays an essential role during major net import of glutamine. In this study, we revealed a significant upregulation of SNAT1 expression in human melanoma tissue in comparison to healthy epidermis and an increased SNAT1 expression level in human melanoma cell lines when compared to normal human melanocytes (NHEMs). We demonstrated that functional inhibition of SNAT1 with α-(methylamino) isobutyric acid (MeAIB), as well as siRNA-mediated downregulation reduces cancer cell growth, cellular migration, invasion, and leads to induction of senescence in melanoma cells. Consequently, these results demonstrate that the amino acid transporter SNAT1 is essential for cancer growth, and indicates a potential target for cancer chemotherapy.


Trends in cardiovascular admissions and procedures for people with and without diabetes in England, 1996-2005.
The aim of this study was to compare 10-year trends in admissions, with and without diabetes recorded, for myocardial infarction, angina, stroke, percutaneous coronary interventions (PCI) and coronary artery bypass graft (CABG). We used national hospital-activity data in England collected between 1996 and 2005 and compared trends in admissions, after adjusting for age, sex and area-level deprivation. Overall, there was a modest fall in the number of admissions for angina and little change in the numbers of admissions for myocardial infarction (MI) and stroke. From 1996/1997 to 2005/2006, the numbers of admissions with diabetes recorded rose for each of MI, angina and stroke; the proportion of admissions with type 2 diabetes recorded rose from 7.2% to 13.9% for MI, from 6.7% to 15.3% for angina and from 6.2% to 11.3% for stroke. Over the 10-year period, after adjusting for age, sex and deprivation, the number of admissions for CABG rose about threefold; for PCI, the number of admissions with diabetes recorded rose 15-fold, compared with a fourfold increase in the number of admissions with diabetes not recorded. We found significant increases in the numbers of admissions with type 2 diabetes recorded for major cardiovascular events and procedures, which has important financial and public-health implications. Better prevention of type 2 diabetes in at-risk patients and aggressive cardiovascular risk-factor management in current patients with diabetes is needed.


The electron spin relaxation of the electron acceptors of photosystem I reaction centre studied by microwave power saturation.
Photosystem I particles from spinach were reduced by illumination at 77 K. Under these conditions the one-electrom transfer from P-700 resulted in a reduction of only one acceptor molecule of the reaction centre. The EPR signals at g=2.05, 1.94 and 1.86 were attributed to reduced centre A and the smaller signals at g=2.07, 1.92 and 1.89 to reduced centre B. Reduction of both centres by dithionite in the dark lead to signals at g=2.05, 1.99, 1.96, 1.94, 1.92 and 1.89. Thus, the features at g=2.07 and 1.86 disappeared and new signals at g=1.99 and 1.96 were observed. From the spectral changes it followed that the iron-sulphur centres A and B interact magnetically. Temperature dependent EPR spectra demonstrated a faster electron spin relaxation of centre A than of centre B. These conclusions were corroborated using microwave power saturation of the respective EPR signals. The saturation data of the fully reduced centres A and B could not be fitted using the saturation equation for a one-electron spin system. The magnetic interaction between the (4Fe-4S) CENTRes of the electron acceptors A and B resulted in saturation properties which are simular to those of the 2(4Fe-4S) ferredoxin from Clostridium pasteurianum. For centre X a high proportion of homogeneous broadening of the EPR lines was inferred from the inhomogeneity parameter (b=1.83). It was, therefore, concluded that centre X is most probably an anion radical of chlorophyll. From the low temperature necessary for observing the EPR signal of centre X followed that the drastic relaxation enhancement has to be attributed to a magnetic interaction of the anion radical with iron.


Extraordinary parasite multiplication rates in human malaria infections.
For pathogenic organisms, faster rates of multiplication promote transmission success, the potential to harm hosts, and the evolution of drug resistance. Parasite multiplication rates (PMRs) are often quantified in malaria infections, given the relative ease of sampling. Using modern and historical human infection data, we show that established methods return extraordinarily - and implausibly - large PMRs. We illustrate how inflated PMRs arise from two facets of malaria biology that are far from unique: (i) some developmental ages are easier to sample than others; (ii) the distribution of developmental ages changes over the course of infection. The difficulty of accurately quantifying PMRs demonstrates a need for robust methods and a subsequent re-evaluation of what is known even in the well-studied system of malaria.


Childhood epidermolysis bullosa acquisita: report of a Chinese case.
Epidermolysis bullosa acquisita (EBA) is a rare, acquired, subepidermal blistering disease characterized by autoantibodies directed against type VII collagen, the major component of anchoring fibrils. We report a 5-year-old Chinese boy who presented with extensive lesions consisting of disseminated pruritic vesicles and tense blisters. The diagnosis of EBA was confirmed by histopathology, immunofluorescence, and immunoblotting analysis. The disease was controlled with a combination of prednisone and dapsone.


Percutaneous transluminal balloon valvuloplasty of congenital pulmonary valve stenosis, with a special report on infants and neonates.
Fifty-six percutaneous transluminal balloon valvuloplasty procedures were performed in 51 patients suffering from congenital pulmonary valve stenosis. The patients ranged in age from 1 day to 60 years (mean 6.9 years); 21 were infants less than 1 year of age, including 8 neonates. The peak systolic pressure gradient was greater than 50 mm Hg (mean 81.5) in 47 cases, and less than 50 mm Hg (mean 34.6) in 9. Valvuloplasty enabled a reduction in the mean right ventricular peak systolic pressure from 93.1 to 51.6 mm Hg (p less than 0.001), the mean transvalvular gradient from 73.4 to 27.0 mm Hg (p less than 0.001) and the mean right ventricular pressure expressed as a percent of systemic pressure from 99.5 to 52.0% (p less than 0.001). In infants and neonates, the mean right ventricular pressure expressed as a percent of systemic pressure decreased from 117.3 to 64.4% (p less than 0.001). In 23 patients, follow-up cardiac catheterization at 1 to 17 months revealed a significant change in the right ventricular systolic pressure, which decreased from 54.0 to 46.7 mm Hg (p less than 0.05), and in the peak systolic pressure gradient, which decreased from 27.3 to 22.6 mm Hg (p less than 0.05). Valvuloplasty is an effective procedure in relieving pulmonary stenosis in patients of all ages, including neonates.


Long-term outcome of a cuffed expanded PTFE graft for hemodialysis vascular access.
Development of venous outflow stenosis has been a major obstacle in maintaining the patency of dialysis vascular grafts. In the present study, we retrospectively analyzed the long-term results of cuffed expanded polytetrafluoroethylene (ePTFE) and non-cuffed (standard) ePTFE grafts placed for hemodialysis access. A total of 67 patients who underwent placement of either cuffed (n = 41) or standard (n = 26) ePTFE grafts were retrospectively analyzed. There were no significant differences between the two groups with regard to age, gender, cause of end-stage renal disease, and anatomic placement of the graft. Endpoints consisted of primary (without any intervention) and secondary (with radiological or surgical intervention) graft patency rates at 1-3 years. There was a trend toward better primary graft patency rates in the cuffed versus the standard ePTFE: 37.7% vs. 25.7% at 1 year, 35% vs. 10.3% at 2 years, 28% vs. 5.1% at 3 years, respectively (p = 0.086, Kaplan-Meier). Secondary patency rates in the cuffed group were significantly superior (p = 0.047) to those in the standard group (81.8% vs. 56.1% at 1 year, 61.8% vs. 46.3% at 2 years, 51.5% vs. 33.1% at 3 years, respectively). Thrombosis as a cause of complete graft failure was significantly higher (34%) in the standard group than in the cuffed group (9%) (p = 0.0125). Compared to the standard ePTFE, the cuffed ePTFE graft provided better long-term outcome, especially in terms of secondary patency rates after radiological intervention.


From etiology and pathogenesis to therapy of multiple sclerosis.
The Author describes the histopathologic picture of the Multiple Sclerosis and Experimental Allergic Encephalitis and discusses some etiopathogenetic hypotheses elaborating on the immunogenetic and immunopathological aspects. The therapeutical problem is analyzed in all its various facets: cortisone derivatives, immunosuppressive products and reabilitation therapy aiming simultaneously at motion reeducation and at individual and group psycotherapy.


Circulating endothelial progenitor cell deficiency contributes to impaired arterial elasticity in persons of advancing age.
Reduced arterial elasticity is a hallmark of ageing in healthy humans and appears to occur independently of coexisting disease processes. Endothelial-cell injury and dysfunction may be responsible for this fall in arterial elasticity. We hypothesized that circulating endothelial progenitor cells (EPCs) are involved in endothelial repair and that lack of EPCs contributes to impaired arterial elasticity. A total of 56 healthy male volunteers were divided into young (n=26) and elderly (n=30) groups. Large and small artery elasticity indices were noninvasively assessed using pulse wave analysis. The number of circulating EPCs was measured by using flow cytometry. Cells demonstrating DiI-acLDL and FITC-ulex lectin double-positive fluorescence were identified as EPCs. C1 large artery elasticity and C2 small artery elasticity indices were significantly reduced in the elderly group compared with the young group (11.73+/-1.45 vs 16.88+/-1.69 ml/mm Hg x 10, P<0.001; 8.40+/-1.45 vs 10.58+/-1.18 ml/mm Hg x 100, P<0.001, respectively). In parallel, the number of circulating EPCs was significantly reduced in the elderly group compared with the young group (0.13+/-0.02 vs 0.17+/-0.04%, P<0.05). The number of circulating EPCs correlated with C1 large and C2 small artery elasticity indices (r=0.47, P<0.01; r=0.4, P<0.01). The present findings suggest that the fall in circulating EPCs with subsequently impaired endothelial-cell repair and function contributes to reduced arterial elasticity in humans with ageing. The decrease in circulating EPCs may serve as a surrogate biologic measure of vascular function and human age.


BET in hematologic tumors: Immunity, pathogenesis, clinical trials and drug combinations.
The bromodomain and extra-terminal (BET) proteins act as "readers" for lysine acetylation and facilitate the recruitment of transcriptional elongation complexes. BET protein is associated with transcriptional elongation of genes such as c-MYC and BCL-2, and is involved in the regulation of cell cycle and apoptosis. Meanwhile, BET inhibitors (BETi) have regulatory effects on immune checkpoints, immune cells, and cytokine expression. The role of BET proteins and BETi in a variety of tumors has been studied. This paper reviews the recent research progress of BET and BETi in hematologic tumors (mainly leukemia, lymphoma and multiple myeloma) from cellular level studies, animal studies, clinical trials, drug combination, etc. BETi has a promising future in hematologic tumors, and future research directions may focus on the combination with other drugs to improve the efficacy.


COVID-19 and distribution centres operations: The impacts and countermeasures.
COVID-19 has wreaked havoc on supply chains. This is particularly true for distribution centres as they struggle to bounce back amid the COVID-19 outbreak. While much literature has recently emerged on supply chain disruption, studies pertaining to the impacts of COVID-19 on distribution centres and the countermeasures taken to mitigate such impacts are elusive and mute. Our study fills this important gap in the supply chain literature. This study employs a multiple-case methodology and conducts 40 semi-structured interviews with senior managers/executives from eight distribution centres in the United Arab Emirates. Our results exhibit that COVID-19 is adversely affecting the distribution centres in at least six distinct ways. For instance, distribution centres are encountering limited staff availability, inventory shortage, destabilized supply chains, excessive inventory, limited capacity and surge in demand. Results also demonstrate six corresponding strategies employed by distribution centres to mitigate the impact. For example, distribution centres enhance warehouse automation, increase hands-on inventory, reshoring manufacturing, use scalable processes and an automation retrieval system, and finally employ a picking strategy. Distribution centres can use the findings provided in this study. Particularly, they can learn how COVID-19 affects them and what corresponding strategies they should adopt to stay strong during this pandemic. This study demystifies its contribution to theory and practice alongside limitations and future research directions.


Vincristine sulfate liposome injection: a guide to its use in refractory or relapsed acute lymphoblastic leukemia.
Adult patients with acute lymphoblastic leukemia frequently relapse or are refractory to conventional treatments. The vincristine sulfate liposome injection (Marqibo(®)) encapsulates the drug in a liposome composed of sphingomyelin and cholesterol to improve tumor drug exposure. At a dose of 2.25 mg/m(2) once weekly, this formulation was associated with an overall response rate of 35 % in adults with Philadelphia chromosome-negative relapsed or refractory disease. There were no new or unexpected toxicities.


Prevalence of depression in an elderly community sample: a comparison of GMS-AGECAT and DSM-IV diagnostic criteria.
Prevalence rates of depression based on the GMS-AGECAT system are markedly higher than rates of major depression diagnosed using DSM-III and DSM-III-R criteria. Interpreting this finding is difficult since AGECAT diagnostic criteria have not been published. We conducted a survey in Edmonton, Canada, in which 1119 community residents aged 65 years or older were administered the Geriatric Mental State (GMS) questionnaire. Depression was diagnosed using AGECAT and also according to criteria for DSM-IV major depression and minor depression. We identified 57 items in the GMS relating to major and minor depression which were then grouped into dysphoric, somatic and cognitive categories. The relationship of these symptoms to AGECAT depression was investigated by recording symptoms to absent (nullifying) and recalculating the number of AGECAT cases. Data were weighted to reflect the underlying population. There were 143 cases of AGECAT depression (prevalence rate = 11.4%), 14 cases of major depression (prevalence rate = 0.86%) and 44 cases of minor depression (prevalence rate = 3.6%). Of the 154 subjects with either AGECAT or DSM-IV depression, only 47 (31%) were depressed according to both diagnostic systems. Nullifying all dysphoric symptoms reduced the number of AGECAT cases to eight, whereas nullifying somatic and cognitive symptoms reduced the numbers of cases only to 138 and 142, respectively. By themselves, dysphoric symptoms accounted for 77 of the 143 cases of AGECAT depression, while somatic and cognitive symtpoms alone accounted for no cases. AGECAT depression is more inclusive than DSM-IV major or minor depression and AGECAT case status is determined mainly by the proportion of dysphoric symptoms.


[Experimental studies on the effect of the immunosuppressant FK-506 on penetrating keratoplasty rejection model in rats].
To study the immunosuppressive effects of FK-506 on allogeneic transplantation in a rat model. Inbred strain Lou rats were used as recipients, and F344 rats were used as donors. Subconjunctival injection of FK-506 0.1 mg/kg and cyclosporine A (CsA) 3 mg/kg were administered respectively for 2 weeks, and the grafts were inspected by clinical evaluation. The group receiving FK-506 had a significant delay in allograft rejection with mean survival time (22.1 +/- 5.17) days vs. (18.4 +/- 1.4) days for the CsA group and (12.1 +/- 2.13) days for the control group (P < 0.01). It is indicated that FK-506 would be a useful drug to suppress corneal graft rejection.


Toward personalized immunotherapy in sepsis: The PROVIDE randomized clinical trial.
The state of immune activation may guide targeted immunotherapy in sepsis. In a double-blind, double-dummy randomized clinical study, 240 patients with sepsis due to lung infection, bacteremia, or acute cholangitis were subjected to measurements of serum ferritin and HLA-DR/CD14. Patients with macrophage activation-like syndrome (MALS) or immunoparalysis were randomized to treatment with anakinra or recombinant interferon-gamma or placebo. Twenty-eight-day mortality was the primary endpoint; sepsis immune classification was the secondary endpoint. Using ferritin >4,420 ng/mL and <5,000 HLA-DR receptors/monocytes as biomarkers, patients were classified into MALS (20.0%), immunoparalysis (42.9%), and intermediate (37.1%). Mortality was 79.1%, 66.9%, and 41.6%, respectively. Survival after 7 days with SOFA score decrease was achieved in 42.9% of patients of the immunotherapy arm and 10.0% of the placebo arm (p = 0.042). Three independent immune classification strata are recognized in sepsis. MALS and immunoparalysis are proposed as stratification for personalized adjuvant immunotherapy. Clinicaltrials.gov registration NCT03332225.


A Double-Blind, Randomized, Placebo-Controlled Clinical Study of Trofinetide in the Treatment of Rett Syndrome.
This study aimed to determine the safety and tolerability of trofinetide and to evaluate efficacy measures in adolescent and adult females with Rett syndrome, a serious and debilitating neurodevelopmental condition for which no therapies are available for its core features. This was an exploratory, phase 2, multicenter, double-blind, placebo-controlled, dose-escalation study of the safety and tolerability of trofinetide in 56 adolescent and adult females with Rett syndrome. Subjects were randomly assigned in a 2:1 ratio to 35 mg/kg twice daily of trofinetide or placebo for 14 days; 35 mg/kg twice daily or placebo for 28 days; or 70 mg/kg twice daily or placebo for 28 days. Safety assessments included adverse events, clinical laboratory tests, vital signs, electrocardiograms, physical examinations, and concomitant medications. Efficacy measurements were categorized into four efficacy domains, which related to clinically relevant, phenotypic dimensions of impairment associated with Rett syndrome. Both 35 mg/kg and 70 mg/kg dose levels of trofinetide were well tolerated and generally safe. Trofinetide at 70 mg/kg demonstrated efficacy compared with placebo based on prespecified criteria. Trofinetide was well tolerated in adolescent and adult females with Rett syndrome. Although this study had a relatively short duration in a small number of subjects with an advanced stage of disease, consistent efficacy trends at the higher dose were observed in several outcome measures that assess important dimensions of Rett syndrome. These results represented clinically meaningful improvement from the perspective of the clinicians as well as the caregivers.


Signaling and transacting factors in the transcriptional inhibition of gonadotropin releasing hormone gene by human chorionic gonadotropin in immortalized hypothalamic GT1-7 neurons.
We recently demonstrated that immortalized GT1-7 neurons co-express luteinizing hormone (LH)/human chorionic gonadotropin (hCG) receptor and gonadotropin releasing hormone (GnRH) genes. Treatment of GT1-7 neurons with LH/hCG resulted in a transcriptional inhibition of GnRH gene. In the present study, we investigated the signaling and transacting factors involved in the action of hCG. Eight-bromo-cyclic AMP can mimic the down-regulating action of hCG on GnRH mRNA levels. H-89, a protein kinase (PK) A inhibitor, but not bisindolylmaleimide, a PKC inhibitor, blocked the down- regulating actions of hCG as well as of 8-bromocyclic AMP. Treatment with the PKA inhibitor alone modestly decreased GnRH mRNA levels suggesting that PKA signaling also controls the basal expression of the GnRH gene. The direct measurement of PK activities revealed that hCG treatment of GT1-7 neurons increased the PKA but not the PKC activity. New protein synthesis is required for the down-regulating action of hCG on GnRH mRNA levels. Since some of the new proteins could be nuclear transcription or transacting factors, we investigated the effects of hCG on cyclic AMP response element binding protein (CREB), c-Fos and c-Jun protein levels. Treatment of GT1-7 neurons with hCG resulted in an increase of 43 kDa phosphorylated CREB, 50 kDa c-Fos and 40 kDa c-Jun proteins compared to the corresponding controls. The kinetics of increases were different and in all cases the increases of the proteins preceded the decrease of GnRH mRNA levels. In summary, PKA signaling and transacting factors such as CREB, Fos and Jun are probably involved in transcriptional inhibition of GnRH gene by hCG in GT1-7 neurons.


Quantification of BSA-loaded chitosan/oligonucleotide nanoparticles using reverse-phase high-performance liquid chromatography.
Therapeutic proteins are administered subcutaneously because of their instability in the gastrointestinal tract. Current research suggests that polymeric-based nanoparticles, microparticles and liposomes are ideal nanocarriers to encapsulate proteins for disease management. In order to develop a successful drug delivery system, it is crucial to determine drug release profile and stability. However, the non-active excipients in polymeric formulations can influence the quantification of proteins in analytical techniques. This study investigated the effect of nine common polymers on quantification of bovine serum albumin (BSA) using RP-HPLC method. The technique offers advantages such as short analytical time, high accuracy and selectivity. In the meantime, the technique can be employed to separate proteins including BSA, insulin and pigment epithelium-derived factor (PEDF). Furthermore, the RP-HPLC method was applied to quantify the drug release pattern of a novel BSA-loaded nanoparticulate formulation in simulated gastric and intestinal fluids. The nanoparticles were formulated by natural polymer (chitosan) and oligonucleotide (Dz13Scr) using complex coacervation. The prepared particles were found to have small size (337.87 nm), low polydispersity index (0.338) and be positively charged (10.23 mV). The in vitro drug release patterns were characterised using the validated RP-HPLC method over 12 h. Graphical abstract .


Whole Exome Sequencing Uncovers Germline Variants of Cancer-Related Genes in Sporadic Pheochromocytoma.
Pheochromocytomas (PCCs) show the highest degree of heritability in human neoplasms. However, despite the wide number of alterations until now reported in PCCs, it is likely that other susceptibility genes remain still unknown, especially for those PCCs not clearly syndromic. Whole exome sequencing of tumor DNA was performed on a set of twelve PCCs clinically defined as sporadic. About 50% of PCCs examined had somatic mutations on the known susceptibility VHL, NF1, and RET genes. In addition to these driver events, mutations on SYNE1, ABCC10, and RAD54B genes were also detected. Moreover, extremely rare germline variants were present in half of the sporadic PCC samples analyzed, in particular variants of MAX and SAMD9L were detected in the germline of cases wild-type for mutations in the known susceptibility genes. Additional somatic passenger mutations can be associated with known susceptibility VHL, NF1, and RET genes in PCCs, and a wide number of germline variants with still unknown clinical significance can be detected in these patients. Therefore, many efforts should be aimed to better define the pathogenetic role of all these germline variants for discovering novel potential therapeutic targets for this disease still orphan of effective treatments.


Gefitinib plus tremelimumab combination in refractory non-small cell lung cancer patients harbouring EGFR mutations: The GEFTREM phase I trial.
A phase I open-label multicentre study was initiated to evaluate the association of tremelimumab with gefitinib in EGFR-mutant NSCLC patients who progressed after first-generation EGFR-TKI. Here we provide the efficacy data from the entire cohort. Patients with advanced EGFR-mutant NSCLC with progression after response to EGFR-TKI were enrolled. Study treatment was gefitinib 250 mg daily and tremelimumab at 3 dose levels: 3, 6 and 10 mg/kg IV Q4W for 6 cycles followed by Q12W until progression or unacceptable toxicity. The primary objective was safety and tolerability, and to establish a RP2D. Between January 2014 and July 2015, 27 patients (21 in the escalating dose cohort and 6 in expansion cohort) received at least one dose of tremelimumab. DLTs occurred in 4 patients: 1 at 3 mg/kg (one grade 3 diarrhoea), 1 at 6 mg/kg (one grade 3 diarrhoea) and 2 at 10 mg/kg (one grade 3 diarrhoea and one grade 3 AST/ALT increase) of tremelimumab. Grade 3 TRAE occurred in 22 patients (81%), most frequently diarrhoea (30%) and ALT/AST increase (15%). Stable disease was the best overall response in 72% patients, with median PFS of 2.2 months (95% CI, 1.8-4.2). All patients discontinued treatment, most frequently due to disease progression (63% of patients). The recommended dose of tremelimumab in combination with gefitinib in EGFR-mutant NSCLC patients was 3 mg/kg. The gastrointestinal toxicity and the limited efficacy data prevented further evaluation of this combination. (GEFTREM; clinical trial number NCT02040064).


Critical Rationalism and Trust in Science.
In this paper, I consider whether the critical rationalist philosophy of science may provide a rationale for trusting scientific knowledge. In the first part, I refer to several insights of Karl Popper's social and political philosophy in order to see whether they may be of help in offsetting the distrust of science spawned by the COVID-19 pandemic. In the second part, I address the more general issue of whether the theoretical principles of the critical rationalist philosophy of science may afford a foundation for building trust in science. Both parts of the discussion, confined for the sake of the argument largely to the repudiation of the concept of good reasons for considering a theory to be true, imply that this question would have to be answered negatively. Against this, I argue that such a conclusion is based on a misconception of the nature of scientific knowledge: critical rationalism views science as a cognitive regime which calls for bold theories and at the same time demands a rigorous and continuous distrust towards them, and it is precisely this attitude that should be adopted as a compelling argument for trusting science.


Incidence of medication-related osteonecrosis of the jaw in patients treated with both bone resorption inhibitors and vascular endothelial growth factor receptor tyrosine kinase inhibitors.
Several case reports and small case series have suggested a higher incidence of medication-related osteonecrosis of the jaw (MRONJ) in patients treated concomitantly with bone resorption inhibitors (BRIs) and vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs), as compared to patients treated with BRIs alone. We aimed to assess ONJ-incidence in patients exposed concomitantly to BRIs and VEGFR-TKIs. We reviewed the records of all patients who received VEGFR-TKIs concomitantly with BRIs. Patients, who were treated with BRIs without VEGFR-TKI, served as a control group. Endpoints of the study were total MRONJ-incidence, MRONJ-incidence during the first and second year of exposure, and time-to-ONJ-incidence. Ninety patients were treated concomitantly with BRIs and VEGFR-TKIs with a median BRI-exposure of 5.0 months. Total MRONJ-incidence was 11.1%. During the first year of BRI-exposure (with a median concomitant exposure of 4.0 months), 6 out of 90 patients (6.7%) developed a MRONJ, compared to 1.1% in the control group (odds ratio 5.9; 95%CI 2.0-18.0; p = 0.0035). In Kaplan-Meier estimates, time-to-ONJ-incidence was significantly shorter in patients treated with BRIs and VEGFR-TKIs compared to BRIs alone (hazard ratio 9.5; 95%CI 3.1-29.6; p < 0.0001). MRONJs occurred earlier in patients treated concomitantly compared to patients treated with BRIs only (after a median exposure of 4.5 and 25.0 months, respectively; p = 0.0033). With a global MRONJ-incidence of 11%, patients receiving concomitant treatment with VEGFR-TKIs and BRIs have a five to ten times higher risk for development of MRONJ compared to patients treated with BRIs alone.


[Progress and changes in the treatment of shaft fractures of the femur and tibia].
The historical development of the treatment of shaft fractures is outlined. Nowadays there is a number of possibilities for the treatment of shaft fractures: conservative and surgical methods. Operative treatment can be done with screws and plates, with intramedullary or interlocking nailing, and with external fixators. The advantages and risks of the various methods are explained. We should now no longer ask what the best method is for any fracture, but rather what method will provide the best prospects of healing in a particular pattern of injury.


Plasma and urine elastase alpha-1-proteinase inhibitor levels in neonatal urinary tract infection.
To examine whether plasma or urine elastase alpha(1)-proteinase inhibitor (E-alpha(1)-PI) levels could be used as a diagnostic marker of urinary tract infection (UTI) in neonates. Plasma and urine E-alpha(1)-PI levels were measured by immunoassay in 23 neonates with UTI at the time of admission and 72 h after the onset of treatment and in 10 'normal' neonates (i.e. with trivial problems). Additionally E-alpha(1)-PI plasma levels were measured in 15 neonates with septicemia. E-alpha(1)-PI plasma levels did not differ between normal neonates and those with UTI. Urine E-alpha(1)-PI levels were significantly higher in neonates with UTI on admission compared to normal neonates. A significant decrease in urine E-alpha(1)-PI levels was noticed 72 h after the onset of treatment in all but 2 neonates in whom infection persisted. In this study, we have found that the urine E-alpha(1)-PI concentration at a cutoff level of 48 microg/l had a sensitivity of 83%, a specificity of 90%, a positive predictive value of 95% and a negative predictive value of 69% for the diagnosis of neonatal UTI. Elevated levels of E-alpha(1)-PI in urine seem to be a useful tool for the diagnosis of UTI in neonates (even in those that have already been started on antibiotics) and possibly a valuable marker for early recognition of treatment failure.


Potential risks of viral infections in xenotransplantation.
The shortage of cadaveric human organs for transplantation may, be alleviated by the use of xenografts as a therapeutic option for end-stage organ failure. Successful attempts have been made to prevent rejection of xenograft tissues in humans. The potential spread of animal-derived pathogens to the xenograft recipient is a complication of xenotransplantation, which must be addressed. This can be complicated further by, the presence of new pathogens, new clinical syndromes, and altered behaviour of these organisms in the immunocompromised recipient. There is concern over the possible activation of latent viruses, including retroviruses, from xenograft tissues. This paper discusses the possible dangers of transmission of animal viruses to humans via xenotransplantation.


Comparison of Patient Satisfaction and Safety Outcomes for Postoperative Telemedicine vs Face-to-Face Visits in Urology: Results of the Randomized Evaluation and Metrics Observing Telemedicine Efficacy (REMOTE) Trial.
There is a need to better understand the role of postoperative care via telemedicine (TM). We evaluated patient satisfaction and outcomes of postoperative face-to-face (F2F) versus TM visits for adult ambulatory urological surgeries in an urban academic center. Methods:This was a prospective, randomized controlled trial. At surgery, patients undergoing ambulatory endoscopic procedures or open surgery were randomized 1:1 to a postoperative F2F or TM visit. After the visit, a telephone survey assessing satisfaction was administered. Primary outcome was patient satisfaction; secondary outcomes were time and cost savings, and 30-day safety outcomes. Results:A total of 197 patients were approached; 165 (83%) consented and were randomized-76 (45%) to F2F and 89 (54%) to TM cohorts. There were no significant differences in baseline demographics between the cohorts. Both cohorts were equally satisfied with their postoperative visit (F2F 98.6% vs TM 94.1%, p=0.28) and found their visit to be an acceptable form of health care (F2F 100% vs TM 92.7%, p=0.06). The TM cohort saved a significant amount of time (TM 66.2% spent <15 minutes vs F2F 43.1% spent 1-2 hours, p <0.0001) and money (44.1% TM saved $5-$25 vs 43.1% F2F spent $5-$25, p=0.041) associated with travel. There were no significant differences in 30-day safety outcomes between the cohorts. Conclusions:TM for postoperative visits after ambulatory adult urological surgery saves patients time and money without compromising satisfaction or safety. TM should be offered as an alternative to F2F for routine postoperative care for certain ambulatory urological surgeries.


Are all data useful? Inferring causality to predict flows across sewer and drainage systems using directed information and boosted regression trees.
As more sensor data become available across urban water systems, it is often unclear which of these new measurements are actually useful and how they can be efficiently ingested to improve predictions. We present a data-driven approach for modeling and predicting flows across combined sewer and drainage systems, which fuses sensor measurements with output of a large numerical simulation model. Rather than adjusting the structure and parameters of the numerical model, as is commonly done when new data become available, our approach instead learns causal relationships between the numerically-modeled outputs, distributed rainfall measurements, and measured flows. By treating an existing numerical model - even one that may be outdated - as just another data stream, we illustrate how to automatically select and combine features that best explain flows for any given location. This allows for new sensor measurements to be rapidly fused with existing knowledge of the system without requiring recalibration of the underlying physics. Our approach, based on Directed Information (DI) and Boosted Regression Trees (BRT), is evaluated by fusing measurements across nearly 30 rain gages, 15 flow locations, and the outputs of a numerical sewer model in the city of Detroit, Michigan: one of the largest combined sewer systems in the world. The results illustrate that the Boosted Regression Trees provide skillful predictions of flow, especially when compared to an existing numerical model. The innovation of this paper is the use of the Directed Information step, which selects only those inputs that are causal with measurements at locations of interest. Better predictions are achieved when the Directed Information step is used because it reduces overfitting during the training phase of the predictive algorithm. In the age of "big water data", this finding highlights the importance of screening all available data sources before using them as inputs to data-driven models, since more may not always be better. We discuss the generalizability of the case study and the requirements of transferring the approach to other systems.


Suggested guidelines for the use of emergency tests in clinical biochemistry.
We have discussed the need for guidelines as a means of reducing out-of-hours investigations in clinical biochemistry, and suggest protocols that can be modified to suit local needs.


Endoscopic closure of bronchopleural fistulas using a tissue adhesive.
Bucrylate tissue adhesive has been found to be effective in achieving closure of surgically created bronchopleural fistulas in dogs. Success was obtained with both endoscopic and direct application. Clinical application of this method in one patient was successful [unpublished observations]. We believe that the speed, low risk, and cost-effectiveness of this approach justifies its further use in these difficult situations.


Hydronidone ameliorates liver fibrosis by inhibiting activation of hepatic stellate cells via Smad7-mediated degradation of TGFβRI.
Liver fibrosis is a wound-healing reaction that eventually leads to cirrhosis. Hydronidone is a new pyridine derivative with the potential to treat liver fibrosis. In this study, we explored the antifibrotic effects of hydronidone and its potential mode of action. The anti-hepatic fibrosis effects of hydronidone were studied in carbon tetrachloride (CCl4 )- and 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)- induced animal liver fibrosis. The antifibrotic mechanisms of hydronidone were investigated in hepatic stellate cells (HSCs). The antifibrotic effect of hydronidone was further tested after Smad7 knockdown in HSCs in mouse models of fibrosis. In animal models, hydronidone attenuated liver damage and collagen accumulation, and reduced the expression of fibrosis-related genes. Hydronidone decreased the expression of fibrotic genes in HSCs. Impressively, hydronidone significantly upregulated Smad7 expression and promoted the degradation of transforming growth factor β receptor I (TGFβRI) in HSCs and thus inhibited the TGFβ-Smad signalling pathway. Specific knockdown of Smad7 in HSCs in vivo blocked the antifibrotic effect of hydronidone. Hydronidone ameliorates liver fibrosis by inhibiting HSCs activation via Smad7-mediated TGFβRI degradation. Hydronidone is a potential drug candidate for the treatment of liver fibrosis.


Building Anesthesia Capacity in the Developing World.
Over two-thirds of the world's population do not have access to safe surgical and anesthetic care. Barriers to care include a lack of specialty trained personnel and unavailability of essential operating room resources. Aid efforts with the greatest impact focus on forming partnerships between high- and low-income communities, with the goal of creating self-sustaining programs run by local communities. Together these partnerships can work to build local capacity and expand the trained workforce by educating local providers.


Deconstructing COVID Time.
This essay explores the problem of trust and truth in states of emergency. Drawing on Giorgio Agamben's theory of biopolitics and his objections to political managerialism I argue that the real problem exposed by the pandemic was not a lack of trust in authority but an unscientific and uncritical attachment to expertise.