Gene-environment-gut interactions in Huntington's disease mice are associated with environmental modulation of the gut microbiome.
Gut dysbiosis in Huntington's disease (HD) has recently been reported using microbiome profiling in R6/1 HD mice and replicated in clinical HD. In HD mice, environmental enrichment (EE) and exercise (EX) were shown to have therapeutic impacts on the brain and associated symptoms. We hypothesize that these housing interventions modulate the gut microbiome, configuring one of the mechanisms that mediate their therapeutic effects observed in HD. We exposed R6/1 mice to a protocol of either EE or EX, relative to standard-housed control conditions, before the onset of gut dysbiosis and motor deficits. We characterized gut structure and function, as well as gut microbiome profiling using 16S rRNA sequencing. Multivariate analysis identified specific orders, namely Bacteroidales, Lachnospirales and Oscillospirales, as the main bacterial signatures that discriminate between housing conditions. Our findings suggest a promising role for the gut microbiome in mediating the effects of EE and EX exposures, and possibly other environmental interventions, in HD mice.


Pollutant removal from dairy wastewater using live Azolla filiculoides in batch and continuous bioreactors.
Fast and proper treatment of dairy wastewater is necessary before discharging it to the environment. In this study, healthy Azolla filiculoides was used to remove pollutants, including phosphorus (P), sodium (Na), chemical oxygen demand (COD), biological oxygen demand (BOD), and total dissolved solids (TDS) of dairy effluent in batch, continuous system, as well as continuous with the slow stirring system. These systems were handmade. The maximum removal efficiency was related to the P, which obtained 66.25% after 12 h in the batch bioreactor system. The highest removal of 13.69% after 21 h was obtained for Na using continuous with a slow stirring method. The highest removal related to the COD and BOD was 33.53% and 29.93% after 18 h, respectively, in continuous with the slow stirring system. TDS removal was achieved 31.44% after 24 h using the batch system. The results of these three systems were compared with each other using a one-way analysis of variance (ANOVA). There was no significant difference between them. Azolla filiculoides is an abundant plant in northern nature that a biosystem was used for optimum usage. It can be used as an efficient, inexpensive, and affordable bioadsorbent for dairy wastewater treatment. PRACTITIONER POINTS: Live Azolla filiculoides was used to remove pollutants. P, Na, BOD, COD, and TDS were removed from dairy wastewater. Batch, continuous, and continuous with the slow stirring systems were used. Live Azolla was an efficient, inexpensive, and affordable bio-adsorbent for dairy wastewater treatment.


The heterogeneous mechanical properties of adolescent growth plate cartilage: A study in rabbit.
The growth plate is a cartilaginous tissue that functions to lengthen bones in children. When fractured, however, the growth plate can lose this critical function. Our understanding of growth plate fracture and mechanobiology is currently hindered by sparse information on the growth plate's microscale spatial gradients in mechanical properties. In this study, we performed microindentation across the proximal tibia growth plate of 9-week-old New Zealand White rabbits (n = 15) to characterize spatial variations in mechanical properties using linear elastic and nonlinear poroelastic material models. Mean indentation results for Hertz reduced modulus ranged from 380 to 690 kPa, with a peak in the upper hypertrophic zone and significant differences (p < 0.05) between neighboring zones. Using a subset of these animals (n = 7), we characterized zonal structure and extracellular matrix content of the growth plate through confocal fluorescent microscopy and Raman spectroscopy mapping. Comparison between mechanical properties and matrix content across the growth plate showed that proteoglycan content correlated with compressive modulus. This study is the first to measure poroelastic mechanical properties from microindentation across growth plate cartilage and to discern differing mechanical properties between the upper and lower hypertrophic zones. This latter finding may explain the location of typical growth plate fractures. The spatial variation in our reported mechanical properties emphasize the heterogeneous structure of the growth plate which is important to inform future regenerative implant design and mechanobiological models.


Chromatic assimilation measured by temporal nulling.
Chromatic assimilation is the shift in color appearance toward nearby light. Assimilation was measured using nearby light with time-varying chromaticity. This light induced time-varying assimilation within the test area. Assimilation was quantified by the amplitude of temporally varying test-area light--in counter-phase to the induced assimilation--required to null the assimilation. Unlike previous studies of assimilation, observers here judged only the steadiness of the test area, not its color. The inducing light was varied in luminance, temporal frequency and chromaticity. The measured assimilation could not be explained by only optical factors affecting receptoral quantal absorption. This implies a neural process contributes to assimilation. The nulling measurements showed also that assimilation was not induced independently within the L/M- and S-cone pathways.


Physical reservoir computing with origami and its application to robotic crawling.
A new paradigm called physical reservoir computing has recently emerged, where the nonlinear dynamics of high-dimensional and fixed physical systems are harnessed as a computational resource to achieve complex tasks. Via extensive simulations based on a dynamic truss-frame model, this study shows that an origami structure can perform as a dynamic reservoir with sufficient computing power to emulate high-order nonlinear systems, generate stable limit cycles, and modulate outputs according to dynamic inputs. This study also uncovers the linkages between the origami reservoir's physical designs and its computing power, offering a guideline to optimize the computing performance. Comprehensive parametric studies show that selecting optimal feedback crease distribution and fine-tuning the underlying origami folding designs are the most effective approach to improve computing performance. Furthermore, this study shows how origami's physical reservoir computing power can apply to soft robotic control problems by a case study of earthworm-like peristaltic crawling without traditional controllers. These results can pave the way for origami-based robots with embodied mechanical intelligence.


Gender differences in a cohort of major depressive patients: further evidence for the male depression syndrome hypothesis.
Previous studies have shown that major depressive patients may differ in several features according to gender, but the existence of a specific male depressive syndrome remains controversial. As part of the EPIDEP National Multisite French Study of 493 consecutive DSM-IV major depressive patients evaluated in at least two semi-structured interviews 1 month apart, 125 (27.7%) were of male gender, whereas 317 (72.3%) were female, after exclusion of bipolar I patients. Compared to women, men were more often married, had more associated mixed features, with more bipolar disorder NOS, more hyperthymic temperaments, and less depressive temperaments. Women had an earlier age at onset of depression, more depressive episodes and suicide attempts. A higher family loading was shown in men for bipolar disorder, alcohol use disorder, impulse control disorders and suicide, whereas their family loading for major depressive disorder was lower. Men displayed more comorbidities with alcohol use, impulse control, and cardiovascular disorders, with lower comorbidities with eating, anxiety and endocrine/metabolic disorders. The following independent variables were associated with male gender: hyperthymic temperament (+), alcohol use disorder (+), impulse control disorders (+), and depressive temperament (-). The retrospective design and the lack of specific tools to assess the male depressive syndrome. Study findings may lend support to the male depression syndrome concept and draw attention to the role of hyperthymic temperament, soft bipolarity as well as comorbidities as determinants of this syndrome. The latter could help recognize an entity which is probably underdiagnosed, but conveys a high risk of suicide and cardiovascular morbidity.


Possible role of NFkappaB in the embryonic vascular remodeling and the endothelial mesenchymal transition process.
The NFkappaB family of transcription factors, particularly the activated p50/p65 heterodimer, is expressed in vascular cells during intimal thickening formation when hemodynamic conditions are altered. Here, we report that p50, p65, IkappaBalpha and IKKalpha display different spatial and temporal patterns of expression and distribution during both chicken embryo aortic wall remodeling and intimal thickening development. Additionally, we show that both p50 and p65 were located in the nucleus of some mesenchymal cells expressing alpha-smooth muscle actin which are present in the spontaneous intimal thickening observed at embryonic days 12-14 of development. We also demonstrated that both NFkappaB subunits are present in monolayers of primary embryonic aortic endothelial cells attached to fibronectin and stimulated with complete medium. This study demonstrates for the first time the presence of activated NFkappaB during the remodeling of the embryonic aortic wall and the formation of intimal thickening, providing evidence that suggest a possible role for this transcription factor in the EndoMT process.


CAML is a p56Lck-interacting protein that is required for thymocyte development.
Calcium modulating cyclophilin ligand (CAML) is a ubiquitously expressed protein implicated in T cell signaling, although its mechanism and physiologic role in the immune system are unknown. We show here that CAML is essential for peripheral T cell development. Inactivation of CAML in mouse thymocytes lowered the numbers of double-positive and single-positive thymocytes, concomitant with reduced positive and enhanced negative selection. We found that CAML interacts with p56Lck and appears to regulate subcellular localization of the kinase in both resting and T cell receptor (TCR)-stimulated cells. CAML-deficient cells displayed enhanced p56lck and ZAP-70 phosphorylation and increased IL2 production and cell death after TCR stimulation, suggesting that CAML may act as a negative regulator of p56lck. Our data establish a novel role for CAML as an essential mediator of T cell survival during thymopoiesis and indicate that its loss deregulates p56Lck signaling.


Postoperative retinal break after 25-gauge transconjunctival sutureless vitrectomy: report of four cases.
A 25-gauge transconjunctival sutureless vitrectomy (TSV) has been reported effective. However, complications such as postoperative retinal detachment have been reported. In this study, we report four cases of retinal breaks found after 25-gauge TSV. In this study, we investigated factors contributing to occurrence of postoperative complications. Seventy-five patients (75 eyes) underwent 25-gauge TSV surgery at Kanazawa University hospital between April 2004 and September 2005. Postoperative follow-up monitoring was done for at least 3 months. The surgical charts were reviewed. Retinal breaks not accompanied by retinal detachment were noted postoperatively in four patients. All four of these patients had preoperative idiopathic macular holes. In all cases, there was no vitreous traction around the retinal break and photo coagulation was performed. One eye with age-related macular degeneration developed intraoperative rhegmatogenous retinal detachment. No other complications were observed during the intraoperative and postoperative periods. Upon performing 25-gauge TSV for macular hole repair, care should be taken to detect retinal breaks and retinal detachment intraoperatively and postoperatively.


Ten lessons about infants' everyday experiences.
Audio recorders, accelerometers, and cameras that infants wear throughout their everyday lives capture the experiences that are available to shape development. Everyday sensing in infancy reveals patterns within the everyday hubbub that are unknowable using methods that capture shorter, more isolated, or more planned slices of behavior. Here, we review ten lessons learned from recent endeavors that removed researchers from designing or participating in infants' experiences and instead quantified patterns that arose within infants' own spontaneously arising everyday experiences. The striking heterogeneity of experiences - there is no meaningfully "representative" hour of a day, instance of a category, interaction context, or infant - inspires next steps in theory and practice that embrace the complex, dynamic, and multiple pathways of human development.


Social distancing as a protective barrier against bullying actions among schoolchildren during the COVID-19 pandemic.
Violence in the work or school environment is becoming a public health problem. Bullying in this scenario is characterized by a set of aggressive, repetitive, intentional behaviors which occur without evident motivation and affects countless young people daily. This study aimed to verify the incidence of bullying cases of elementary and high school students during the COVID-19 pandemic, describing the reasons for this victimization from an emic view; in addition, to compare associated factors such as nutritional status and body image between victims and non-victims of bullying. This is a non-probabilistic descriptive design involving 115 students regularly enrolled in elementary and high school in public schools in the city of Dourados-MS, Brazil. The results indicated an incidence of 20.9% of victims, with verbal aggression (swearing, nicknames, gossip) and social exclusion being the most recurrent. A total of 78.2% of the victim students did not suffer bullying during social distancing, and 87.3% felt safer in their homes. The rate of overweight and obesity was similar between victims and non-victims, similar to the body perception result. This study indicated that social distancing during the COVID-19 pandemic was a protective barrier in school bullying actions.


Two copper-containing proteins from white and gray matter of brain.
The procedure for the isolation of two water soluble copper-containing proteins from the white and gray matter of bovine brain is described. One of the proteins, cerebrocuprein I, is superoxide dismutase; and three molecular forms of this enzyme are to be found in brain. The other protein present in gray and white matter is devoid of superoxide dismutase and amine oxidase activities. The amino acid composition, molecular weight, isoelectric point and copper content of this protein were determined. The effect of some agents, pH and thermal treatment of the optical and EPR spectra of the protein were also studied. The copper of the protein may be removed and the holoprotein reconstituted again from apoprotein and copper. The results obtained led to the conclusion that in brain a new copper protein is discovered, which is named neurocuprein.


Cross-validation of the factor structure of the Toronto Alexithymia Scale.
The Toronto Alexithymia Scale (TAS) is a self-report measure of the alexithymia construct. In previous studies with college students, the TAS demonstrated excellent psychometric properties including a 4-factor structure theoretically congruent with the alexithymia construct. The present study attempted to cross-validate the factor structure of the TAS with samples of normal adults, psychiatric outpatients and college students. Congruence coefficients comparing the similarity of the factor structures for these three samples indicated good congruence for all four factors. The results provide further support for the validity of both the TAS and the alexithymia construct. In addition, the results provide evidence of the applicability of the scale to normal adult and clinical samples.


Global time trends of perceived loneliness among adolescents from 28 countries in Africa, Asia, and the Americas.
Perceived loneliness in adolescence is associated with a plethora of adverse outcomes. However, data on its temporal trends are scarce. Therefore, we aimed to examine the temporal trend of perceived loneliness among school-going adolescents aged 12-15 years from 28 countries in Africa, Asia, and the Americas, where temporal trends of loneliness are largely unknown. Cross-sectional data from the Global School-based Student Health Survey 2003-2017 were analyzed. Perceived loneliness referred to feeling lonely most of the time or always in the past 12 months. Crude linear trends of perceived loneliness by country were assessed by linear regression models. Data on 180,087 adolescents aged 12-15 years were analyzed [Mean (SD) age 13.7 (1.0) years; 51.4 % females]. The overall prevalence of perceived loneliness was 10.7 %. Among the 28 countries included in the study, significant increasing and decreasing trends were observed in six counties each, with stable trends found in 16 countries. The most drastic increase and decrease were observed in Egypt between 2006 (7.9 %) and 2011 (14.3 %), and in Samoa between 2011 (23.3 %) and 2017 (8.0 %), respectively. Stable trends with high prevalence across time were also common. Our data suggest that perceived loneliness among adolescents is a global phenomenon, which has seen little improvement if any in recent years. It would be prudent to implement nationwide policies to combat loneliness globally.


Effects of serotonin agonists on operant behavior in the squirrel monkey: quipazine, MK-212, trifluoromethylphenylpiperazine, and chlorophenylpiperazine.
The behavior of squirrel monkeys was studied under fixed-interval (FI) schedules with responding maintained either by food presentation or by termination of stimuli correlated with impending electric shock delivery (stimulus-shock termination). The 5-HT agonists m-trifluoromethylphenylpiperazine (TFMPP), m-chlorophenylpiperazine (mCPP), and 6-chloro-2(l-piperazinyl)pyrazine (MK-212) decreased responding under both the food and shock schedules (0.3-5.6 mg/kg). These decreases in responding were blocked by the nonselective 5-HT antagonists methysergide and mianserin (0.3, 1.0 mg/kg), but not by the selective 5-HT2 antagonists ketanserin (0.3-1.7 mg/kg) or pirenperone (0.001-0.1 mg/kg). Quipazine (0.3-5.6 mg/kg) decreased responding under the food schedule, and this effect was blocked by both the nonselective and selective 5-HT2 antagonists. This pattern of antagonism suggests that the decreases in responding produced by quipazine involve significant actions at 5-HT2 sites, whereas those produced by TFMPP, mCPP, and MK-212 do not. In contrast to the decreases in responding seen with the food schedules, quipazine produced moderate increases in responding under the shock schedules. Moreover, these increases in responding were not blocked by methysergide or mianserin, but instead were enhanced. The results with antagonists suggest that certain behavioral effects of quipazine are probably due to actions at 5-HT2 sites, whereas similar effects of TFMPP, mCPP, and MK-212 are more related to actions at other 5-HT receptor subtypes.


Mandibular advancement device use in obstructive sleep apnea: ORCADES study 5-year follow-up data.
Mandibular advancement devices (MADs) are an alternative to continuous positive airway pressure for the management of obstructive sleep apnea (OSA). The ORthèse d'avanCée mAndibulaire dans le traitement en DEuxième intention du SAHOS sévère (ORCADES) study is investigating the long-term effectiveness of MAD therapy in patients with OSA who refused or were intolerant of continuous positive airway pressure. Five-year follow-up data are presented. Data were available in 172 of 331 patients treated with a custom-made computer-aided design/computer-aided manufacturing biblock MAD (Narval CC; ResMed, Saint-Priest, France). The primary end point was treatment success (≥50% decrease in apnea-hypopnea index from baseline). Five-year treatment success rates were 52% overall and 25%, 52%, and 63%, respectively, in patients with mild, moderate, or severe OSA. This reflects a decline over time vs 3-6 months (79% overall) and 2 years (68%). Rates declined in all patient subgroups but to the greatest extent in patients with mild OSA. The slight worsening of respiratory parameters over time was not associated with any relevant changes in sleepiness and symptoms. Moderate or severe OSA at baseline, treatment success at 3-6 months, and no previous continuous positive airway pressure use were significant independent predictors of 5-year treatment success on multivariate analysis. No new safety signals emerged during long-term follow-up. The proportion of patients using their MAD for ≥4 h/night on ≥4 days/wk was 93.3%; 91.3% of patients reported device use of ≥6 h/night at 5 years. At 5-year follow-up, 96.5% of patients reported that they wanted to continue MAD therapy. Long-term MAD therapy remained effective after 5 years in >50% of patients, with good levels of patient satisfaction and adherence. Vecchierini MF, Attali V, Collet JM, et al. Mandibular advancement device use in obstructive sleep apnea: ORCADES study 5-year follow-up data. J Clin Sleep Med. 2021;17(8):1695-1705.


Mesocolonic lymphangioma: a case report with immunoperoxidase and electron microscopic studies.
A 14 yr old girl presented with a large cystic mass in the transverse mesocolon which was completely excised. Cystic lymphangioma was diagnosed, based on the specific histologic, immunoperoxidase and ultrastructural findings.


Exploring wheat-based management strategies to balance agricultural production and environmental sustainability in a wheat-maize cropping system using the DNDC model.
Faced with the great challenge of food demand and environmental pollution, optimizing agricultural practices can potentially balance food security and environmental protection. In this study, the DeNitrification-DeComposition (DNDC) model was applied to explore the effect of wheat-based management strategies on crop productivity and greenhouse gas emissions in the wheat-maize system. The DNDC model was tested against crop yield, daily nitrous oxide (N2O) fluxes, and cumulative N2O emissions determined from field measurements in a typical winter wheat-summer maize cropping system. Model evaluations demonstrated a good agreement between the observations and simulated crop yield (4.4%≤NRMSE≤8.0%), daily N2O fluxes (0.68 ≤ d ≤ 0.88), and cumulative N2O emissions (4.9%≤NRMSE≤11.9%). By adopting sensitivity analysis, the DNDC model then assessed the impacts on crop yield and cumulative N2O emissions of multiple management practices from the winter wheat season. Delaying the sowing date from October 7 to November 4 reduced annual yield by 1.9%, while cumulative N2O emissions were increased by 10.4%. Furthermore, postponing the supplementary irrigation date from April 1 to May 20 decreased annual yield by 2.4% without affecting cumulative N2O emissions. An N fertilizer rate of 120-150 kg N ha-1 was able to reduce N usage and cumulative N2O emissions without sacrificing annual yield. Despite an improvement in the annual yield at the 0-30 cm tillage depth by 2.9%, cumulative N2O emissions increased by 11.6%. The results suggest that sowing in early October, applying supplementary irrigation in early April, an N fertilizer rate of 120-150 kg N ha-1, and no-tillage from the winter wheat season can improve crop yield and mitigate N2O emissions. This is conducive to the synergism of agricultural production and environmental sustainability.


Efficacy of bromovinyldeoxyuridine in the treatment of herpes simplex virus and varicella-zoster virus eye infections.
As has been established in rabbits, (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU) is superior to 5-iodo-2'-deoxyuridine (IDU) in the topical treatment of epithelial HSV-1 (herpes simplex virus type 1) keratitis, and superior to 5-trifluoromethyl-2'-deoxyuridine (TFT) in the topical treatment of deep stromal HSV-1 keratitis and HSV-1 uveitis. BVDU 0.1% eye drops have also proven efficacious in the treatment of patients with dendritic corneal ulcers, geographic corneal ulcers and stromal keratitis, and combined treatment of BVDU 0.1% eye drops with oral BVDU at 375 mg/day for 5 days led to a prompt healing of keratouveitis and skin lesions in patients with ophthalmic herpes zoster.


Large-scale diet tracking data reveal disparate associations between food environment and diet.
An unhealthy diet is a major risk factor for chronic diseases including cardiovascular disease, type 2 diabetes, and cancer1-4. Limited access to healthy food options may contribute to unhealthy diets5,6. Studying diets is challenging, typically restricted to small sample sizes, single locations, and non-uniform design across studies, and has led to mixed results on the impact of the food environment7-23. Here we leverage smartphones to track diet health, operationalized through the self-reported consumption of fresh fruits and vegetables, fast food and soda, as well as body-mass index status in a country-wide observational study of 1,164,926 U.S. participants (MyFitnessPal app users) and 2.3 billion food entries to study the independent contributions of fast food and grocery store access, income and education to diet health outcomes. This study constitutes the largest nationwide study examining the relationship between the food environment and diet to date. We find that higher access to grocery stores, lower access to fast food, higher income and college education are independently associated with higher consumption of fresh fruits and vegetables, lower consumption of fast food and soda, and lower likelihood of being affected by overweight and obesity. However, these associations vary significantly across zip codes with predominantly Black, Hispanic or white populations. For instance, high grocery store access has a significantly larger association with higher fruit and vegetable consumption in zip codes with predominantly Hispanic populations (7.4% difference) and Black populations (10.2% difference) in contrast to zip codes with predominantly white populations (1.7% difference). Policy targeted at improving food access, income and education may increase healthy eating, but intervention allocation may need to be optimized for specific subpopulations and locations.


Species-related difference in calcium accumulation by cardiac mitochondria.
1. Mitochondria isolated from the ventricles of Cavia porcellus, Mesocricetus auratus, Rattus rattus and Mus musculus accumulate calcium in an energy-linked process. 2. Measurements of the initial velocity of accumulation by dual-wavelength spectrophotometry show species-dependent variation, with Cavia demonstrating the fastest rate and Rattus the slowest rate of accumulation. 3. Total amount of calcium accumulated per unit protein varied in a manner similar to rate of accumulation, with Cavia accumulating the greatest amount of calcium and Rattus the least.


Relationship between energy demand, financial development, and carbon emissions in a panel of 101 countries: "go the extra mile" for sustainable development.
The objective of the study is to examine the impact of energy demand on carbon emissions in mediation of financial development and economic growth in a panel of 101 countries by using the time series data from 1995 to 2018. The study employed dynamic GMM estimator in order to reduce possible endogeneity in the given model. Further, the study used Granger causality and innovation accounting matrix (IAM) to find the causal relationships and variance error shocks between the variables. The results show that energy demand and FDI inflows increase carbon emissions, while financial development decreases carbon emissions across countries. Moreover, the results confirmed the inverted U-shaped relationship between income and emissions with a turning point of US$43,500. Among 101 countries, only 13 countries hold environmental Kuznets curve (EKC) hypothesis as their per capita income surpassed the stated turning point, while the remaining countries exhibit "race to the bottom" hypothesis. The feedback relationship is established between (i) income and carbon emissions, (ii) money supply and carbon emissions, and (iii) FDI inflows and energy demand across countries, whereas one-way linkages found in (i) carbon emissions to money supply, (ii) energy demand to money supply, (iii) money supply to FDI inflows and income, and (iv) energy demand to income across countries. The IAM analysis shows that energy demand, FDI inflows, and money supply will likely to increase carbon emissions, while money supply will decrease carbon emissions over a time horizon.


Tuberculosis and human immunodeficiency virus infection.
Mycobacterium tuberculosis infects one third of the world's population, and tuberculosis remains one of the most common infectious diseases of humans. From a global perspective, tuberculosis may be one of the most common HIV-related opportunistic infections. HIV immunosuppression has had a dramatic influence on the epidemiology, natural history and clinical presentation of tuberculosis. Treatment is highly effective for drug susceptible tuberculosis and has been shown to have a significant impact on resistant, especially multidrug-resistant, tuberculosis if started promptly. Directly observed therapy and rigorous adherence to infection control principles have helped control the tuberculosis epidemic in the United States.


How does Nephroblastomatosis impact the prognosis of unilateral Wilms tumor?
We aimed to explore whether Nephroblastomatosis (Nbm) has an effect on the prognosis of Wilms tumor (WT), and compare the relapse-free survival (RFS) and overall survival (OS) after surgery of WT patients with or without Nbm. We retrospectively analyzed the clinical data of children with WT admitted to our department from April 2010 to September 2021. The enrolled patients were divided into two groups according to whether they were combined with Nbm histologically or not, the Nbm group for patients accompany with Nbm and the non-Nbm group for pure WT. All patients underwent a standardized comprehensive treatment according to National Wilms Tumor Study 5. Clinical variables, pathological results, and the prognosis were collected during follow-up. A total of 345 patients were finally enrolled in this study, of which 299 patients in the non-Nbm group and 46 patients in the Nbm group. Univariate Cox analysis revealed that Nbm was not the risk factor of either OS or RFS. The difference of postoperative RFS (P = 0.66) and OS (P = 0.68) between two groups was not significant. Subgroup analysis revealed that the RFS and OS between the non-Nbm group and the Nbm group had no statistical difference under the condition of same stage (low grade and high grade), same histology (favorable histology and unfavorable histology), same surgical approach (nephrectomy and nephron-sparing surgery), with or without lymph node metastasis (P > 0.05). Although Nbm had a strong correlation with the occurrence of WT, a combined Nbm did not increase the risk of metastasis and poor prognosis of WT. After complete surgical resection followed by standardized treatment, the long-term RFS and OS were not different from pure WT. IEC-C-006-A04-V.06 retrospectively registered.


Transthyretin stability is critical in assisting beta amyloid clearance- Relevance of transthyretin stabilization in Alzheimer's disease.
The absence of transthyretin (TTR) in AD mice decreases brain Aβ clearance and reduces the low-density lipoprotein receptor-related protein 1 (LRP1). It is possible that neuroprotection by TTR is dependent on its tetramer structural stability, as studies using TTR mutants showed that unstable L55P TTR has low affinity for Aβ, and TTR tetrameric stabilizers such as iododiflunisal ameliorate AD features in vivo. We firstly investigated TTR folding status in human plasma measuring the resistance to urea denaturation. The importance of TTR stability on Aβ internalization was studied in human cerebral microvascular endothelial (hCMEC/D3) and hepatoma cells (HepG2), by flow cytometry. To investigate the fate of Aβ at the blood-brain barrier, Aβ efflux from hCMEC/D3 cells seeded on transwells was measured using ELISA. Further, to assess Aβ colocalization with lysosomes, Lysotracker was used. Moreover, levels of LRP1 were assessed in the liver and plasma of mice with different TTR backgrounds or treated with iododiflunisal. We showed that TTR stability is decreased in AD and that WT TTR and drug-stabilized L55P TTR are able to increase uptake of Aβ. Furthermore, measurement of Aβ efflux showed that stable or stabilized TTR increased Aβ efflux from the basolateral to the apical side. Moreover, HepG2 cells incubated with Aβ in the presence of WT TTR, but not L55P TTR, showed an increased number of lysosomes. Further, in the presence of WT TTR, Aβ peptide colocalized with lysosomes, indicating that only stable TTR assists Aβ internalization, leading to its degradation. Finally, we demonstrated that only stable TTR can increase LRP1 levels. TTR stabilization exerts a positive effect on Aβ clearance and LRP1 levels, suggesting that TTR protective role in AD is dependent on its stability. These results provide relevant information for the design of TTR-based therapeutic strategies for AD.


Incidence of persistent lymphopenia in people with multiple sclerosis on dimethyl fumarate.
Dimethyl fumarate (DMF) is a disease modifying therapy (DMT) used in the management of Multiple Sclerosis (MS). Lymphopenia occurs in approximately 30% of people receiving this medication. The recently revised Summary of Product Characteristics (SPC) recommends increased monitoring or cessation of this medication in the context of persistent lymphopenia, because of an increased risk of progressive multifocal leukoencephalopathy (PML). It is therefore important for clinicians and patients to be aware of the frequency of persistent, moderate-severe lymphopenia in order to make informed decisions regarding drug choice and safety monitoring. We reviewed medical records of 156 people with MS (PwMS) started on DMF between 2014 and 2020, who received at least 6 months of treatment, in order to identify the incidence and duration of persistent lymphopenia. Ten were excluded due to missing data. In 146 patients, treated for 30.7 months (mean), 16 (11%) were found to experience persistent moderate lymphopenia (0.5-0.7 × 109/L) and 5 (3%) experienced persistent severe lymphopenia (<0.5 × 109/L). Of the 5 patients with persistent severe lymphopenia, 3 discontinued DMF. Two cases stopped directly due to SPC recommendations and after 6-months no further DMTs were initiated. Treatment was withdrawn in a further case due to lack of efficacy. Two cases remained on DMF as their persistent severe lymphopenia predated SPC revision. Mean times to persistent moderate and severe lymphopenia were 10.6 months and 25.5 months respectively. Increased age was a predictor for persistent lymphopenia (B = 0.071, p = 0.004) while sex, and previous DMT were not.


Nfe2l1 deficiency mitigates streptozotocin-induced pancreatic β-cell destruction and development of diabetes in male mice.
Streptozotocin (STZ) is a pancreatic β cell-specific toxicant that is widely used to generate models of diabetes in rodents as well as in the treatment of tumors derived from pancreatic β cells. DNA alkylation, oxidative stress and mitochondrial toxicity have been recognized as the mechanisms for STZ-induced pancreatic β cell damage. Here, we found that pancreatic β cell-specific deficiency of nuclear factor erythroid-derived factor 2-related factor 1 (NFE2L1), a master regulator of the cellular adaptive response to a variety of stresses, in mice led to a dramatic resistance to STZ-induced hyperglycemia. Indeed, fifteen days subsequent to last dosage of STZ, the pancreatic β cell specific Nfe2l1 knockout [Nfe2l1(β)-KO] mice showed reduced hyperglycemia, improved glucose tolerance, higher plasma insulin and more intact islets surrounded by exocrine acini compared to the Nfe2l1-Flox control mice with the same treatment. Immunohistochemistry staining revealed a greater amount of insulin-positive cells in the pancreas of Nfe2l1(β)-KO mice than those in Nfe2l1-Flox mice 15 days after the last STZ injection. In line with this observation, both isolated Nfe2l1(β)-KO islets and Nfe2l1-deficient MIN6 (Nfe2l1-KD) cells were resistant to STZ-induced toxicity and apoptosis. Furthermore, pretreatment of the MIN6 cells with glycolysis inhibitor 2-Deoxyglucose sensitized Nfe2l1-KD cells to STZ-induced toxicity. These findings demonstrated that loss of Nfe2l1 attenuates pancreatic β cells damage and dysfunction caused by STZ exposure, partially due to Nfe2l1 deficiency-induced metabolic switch to enhanced glycolysis.


Psychological Predictors of Postconcussive Symptoms Following Traumatic Injury.
To determine the contribution of demographics, injury type, pain, and psychological factors on postconcussive symptoms. Recently injured (n = 54) and noninjured (n = 184) adults were recruited from a hospital emergency department or the community. Thirty-eight individuals met the diagnostic criteria for a mild traumatic brain injury and 16 individuals received treatment for a minor traumatic non-brain injury. Standardized tests were administered to assess 4 postconcussion symptom types and theorized predictors including a "physiogenic" variable (injury type) and "psychogenic" variables (symptoms of anxiety, depression, and stress) within 1 month of the injury. In the injured sample, after controlling for injury type, demographics, and pain (chronic and current), a hierarchical regression analysis revealed that the combination of psychological symptoms predicted affective (F10,42 = 2.80, P = .009, Rchange = 0.27) but not other postconcussion symptoms types. Anxiety (β = .48), stress (β = .18), and depression (β = -.07) were not statistically significant individual predictors (P > .05). Cognitive and vestibular postconcussion symptoms were not predicted by the modeled factors, somatic sensory postconcussion symptoms were predicted by demographic factors only, and the pattern of predictors for the symptom types differed for the samples. Traditional explanatory models do not account for these findings. The predictors are multifactorial, different for injured versus noninjured samples, and symptom specific.


Annexin V and vesicle membrane electroporation.
The method of membrane electroporation (ME) has been used as an analytical tool to quantify the effect of membrane curvature on transient electric pore formation, and on the adsorption of the protein annexin V (M(r)= 35,800) to the outer surface of unilamellar lipid vesicles (of radii 25 < or = a/nm < or = 200). Relaxation kinetic studies using optical membrane probes of the diphenylhexatriene type suggest that electric pore formation is induced by ionic interfacial polarization causing entrance of the (more polarizable) water into the lipid bilayer membrane yielding (hydrophobic and hydrophilic) pore states with a mean stationary pore radius rp = 0.35 (+/-0.05) nm. Extent and rate of ME, compared at the same induced transmembrane voltage, were found to decrease both with increasing vesicle radius and with increasing protein concentration. This 'inhibitory' effect of annexin V is apparently allosteric and saturates at about [ANT]sat = 4 microM annexin V for vesicles of a = 100 nm at 1 mM total lipid concentration, 0.13 mM total Ca2+ concentration and at T = 293 K. Data analysis in terms of Gibbs area-difference-elasticity energy suggests that the bound annexin V reduces the gradient of the lateral pressure across the membrane. At [ANT]sat, about 20% of the vesicle surface is covered by the bound protein, but it is only 0.01% of the surface of the outer lipid leaflet in which a part of the protein, perhaps the aromatic residue of the tryptophan (W 187), is inserted. Insertion leads to a denser packing of the lipid molecules in the outer membrane leaflet. As a consequence, the radius of the electropores in the remaining membrane part, not covered by annexin V decreases (rp/nm = 0.37, 0.36 and 0.27) with increasing adsorption of the protein ([ANT] = 0, 2 and 4 microM, respectively).


[Post-transplantation diabetes mellitus in kidney recipients].
Post-transplantation diabetes mellitus is defined as diabetes that is diagnosed in grafted patients. It affects 20 to 30 % of kidney transplant recipients, with a high incidence in the first year. The increasing age at transplantation and the rising incidence of obesity may increase its prevalence in the next years. Post-transplantation diabetes mellitus is associated with poor outcomes, such as mortality, cardiovascular events or graft dysfunction. Its occurrence is mainly related to immunosuppressive agents, affecting both insulin secretion and sensibility. Immunosuppressants may be iatrogenic, and as such, induce an early and transient diabetes. They may also precociously determine a permanent diabetes, acting here as a promoting factor in patients proned to the development of type 2 diabetes. Lastly, they may behave, far from transplantation, as an additional risk factor for type 2 diabetes. The screening, management and prognosis of these different subtypes of post-transplantation diabetes mellitus will be different.


Epi Info™: Now an Open-source application that continues a long and productive "life" through CDC support and funding.
ABOUT THE AUTHORS: Enrique Nieves Jr is the Acting Director of the Division of Integrated Surveillance Systems and Services (DISSS), National Center for Public for Health Informatics (NCPHI), Coordinating Center for Health information and Service (CCHIS), Centers for Disease Control and Prevention (CDC), Atlanta, USA. Jay Jones is a BearingPoint Consultant to the CDC/NCPHI Division of Alliance Management and Consultation (DAMC), National Center for Public for Health Informatics (NCPHI), Coordinating Center for Health information and Service (CCHIS), Centers for Disease Control and Prevention (CDC), Atlanta, USA.


Human perceptual learning: the effect of pre-exposure schedule depends on task demands.
The effects of the pre-exposure schedule (concurrent, intermixed, and blocked) to two similar visual stimuli were assessed in three different tasks. Participants were more accurate identifying one of two pre-exposed stimuli as the target by means of same/different judgments after concurrent than intermixed or blocked pre-exposures. Regardless of pre-exposure schedule, participants were accurate in identifying the same target stimulus in a subsequent multiple choice task. However, the other pre-exposed stimulus was incorrectly chosen as the target in a greater proportion after blocked than intermixed or concurrent pre-exposure. Finally, participants who received the blocked schedule showed a greater ability to construct the target in a puzzle test than those who received a concurrent or intermixed schedule. These results suggest that the effect of pre-exposure schedule may depend on task-specific demands. But all these results might be explained by a selective attention mechanism like that proposed by Gibson (1969) to account for perceptual learning.


Tadalafil solid dispersion formulations based on PVP/VA S-630: Improving oral bioavailability in rats.
Here, solid dispersion (SD) techniques were utilized to improve the oral bioavailability of tadalafil (TDF). Poly(vinyl pyrrolidone-covinyl acetate) (PVP/VA S-630; 60% VP and 40% VA; MW 50,000) SD formulations were previously found to improve the solubility and dissolution (%) of TDF. The effect of various weak acids and bases on SD formulations was also investigated herein. PVP/VA S-630 SD formulations in combination with weak acids and bases increased the apparent solubility of TDF. After 1h, the apparent solubility of PVP/VA S-630 SD formulations with MgO, meglumine, and tartaric acid were significantly higher by 387.0±4.17, 376.8±9.88, and 308.8±4.17μg/mL, respectively, than those of SD formulations without weak acids and bases (166.8±0.50μg/mL). The dissolution (%) of SD formulations with weak acids was under 60%; however, the dissolution (%) of those containing MgO, meglumine, and NaHCO3 was over 80% in distilled water (specifically 85.6%, 89.9%, and 91.6%, respectively). The optimal SD formulation contained meglumine (B-2); both its apparent solubility after 24h and dissolution (%) were the highest among all SD formulations. The B-2 SD formulation showed no toxicity in Caco-2 cells after 24h. The area under the concentration-time curve (AUClast) and peak plasma concentration (Cmax) of the orally administered B-2 SD formulation was greater than that with Cialis® powder in rats. We conclude that the B-2 SD formulation significantly improves the apparent solubility and dissolution (%) of TDF over that of commercially available products (i.e., Cialis®). Moreover, the B-2 SD formulation improves the relative bioavailability (BA) of TDF (21.9%) over that of Cialis®.


[A study of nucleic acids and protein metabolism during the first six days of the cephalic regeneration of Eisenia foetida (Sav.)].
1. During the first six days of cephalic regeneration of Eisenia foetida several successive metabolic stages have been found as follows: a first and short stimulation of protein synthesis (from the 6th to the 16th hour), a first and short stimulation of RNA synthesis (from the 12th to the 36th hour), a second stimulation of protein synthesis, larger than the first and continuous (beginning at the 16th hour), a second, long and continuous stimulation of RNA synthesis (beginning at the 48th hour) and finally the S phase. 2. The regeneration is totally stopped by the RNA synthesis inhibitors (actinomycin D and 5-fluorouracil) when added during the first RNA stimulation (0-36 hours). If added after the 36th hour the same inhibitors give mostly delay or anomalies in regeneration. Same results are obtained when animals are treated during 48 hours before operation. 3. The use of protein synthesis inhibitors (puromycin and cycloheximide) for short times does not stop regeneration, but gives anomalies and long delays in regeneration. 4. An urea soluble fraction (and specially proteins with smaller molecular weight) is preferentially synthesized during the first stimulation of protein synthesis. It is postulated that these proteins are characteristic of the early phase of cellular activation. 5. The RNA synthesized during the first three days is polydispersed. The RNAs formed at 0, 24, 48 and 72 hours are mostly of ribosomal and transfer type. Nevertheless an increased synthesis of the heaviest fractions and those between 18 S and 4-5 S peaks, occurs at the 16th hour (beginning of the first RNA synthesis stimulation). An increased production of heavy RNA is also noticed at 36 hours before the beginning of the second RNA synthesis stimulation.


Fungal isolation and identification from parrot excreta in northeast Iran: A threat to human health.
One of the environmental sources of pathogenic fungi is parrot droppings. Thus, this work aimed to investigate fungal contamination in parrots' droppings. Seventy-nine parrot droppings including Cockatiel, Cockatoo, Green check conure, Love bird, Budgerigar, African grey parrot, Alexandrine parakeet, Amazon parrot, Yellow crown parakeet, and Macaw were sampled, and suspended 1:10 in saline solution and then 0.5 mL of supernatant was cultured. The fungi were identified by standard mycological techniques. Fungal contamination was detected in 66 samples (83.54%) out of 79 samples. Yeast and mould fungi were respectively isolated from 44 samples (55.69%) and 36 samples (45.56%) out of 79 samples. Overall 105 fungal isolates were isolated from parrot excreta. Cryptococcus neoformans (17.14%), Rhizopus spp. (10.47%), Rhodotorula spp. and Aspergillus niger (6.66%), and Penicillium spp. (5.71%) were the most fungi isolated from faecal samples. The evidence from this study suggests that the rate of fungal contamination in parrots' excreta was high. Keeping parrots in the house and their close contact with humans can double the importance of these contaminations and provide the basis for the transmission of contamination to humans. Therefore, the accumulations of parrot faeces for long periods suggest a potential threat to public health.


Construction of high-performance electrode materials of NiCo2O4 nanoparticles encapsulated in ultrathin N-doped carbon nanosheets for supercapacitors.
Highly dispersed nitrogen doped carbon (N-C) is decomposed by 2-methylimidazole (C4H6N2) and is used as a composite material with nickel cobaltite (NiCo2O4). The N-C and NiCo2O4 composites are obtained by a one-step hydrothermal method and subsequent calcination. In addition, N-C is used to control the morphology and structure of NiCo2O4 to obtain excellent capacitor materials. The N-C/NiCo2O4 electrode shows an excellent specific capacitance of 157.97 mA h g-1 (1263.75 F g-1) at 1 A g-1. Herein, we successfully develop a N-C/NiCo2O4//AC asymmetric supercapacitor (ASC), which is prepared using N-C/NiCo2O4 as a cathode coupled with activated carbon (AC) as an anode at a voltage of 1.6 V. The prepared N-C/NiCo2O4//AC device shows an excellent volumetric energy density of 66.44 mW h kg-1. The promising performance of N-C/NiCo2O4//AC illustrated its potential for portable supercapacitor applications.


The long-distance flight behavior of Drosophila supports an agent-based model for wind-assisted dispersal in insects.
Despite the ecological importance of long-distance dispersal in insects, its mechanistic basis is poorly understood in genetic model species, in which advanced molecular tools are readily available. One critical question is how insects interact with the wind to detect attractive odor plumes and increase their travel distance as they disperse. To gain insight into dispersal, we conducted release-and-recapture experiments in the Mojave Desert using the fruit fly, Drosophila melanogaster We deployed chemically baited traps in a 1 km radius ring around the release site, equipped with cameras that captured the arrival times of flies as they landed. In each experiment, we released between 30,000 and 200,000 flies. By repeating the experiments under a variety of conditions, we were able to quantify the influence of wind on flies' dispersal behavior. Our results confirm that even tiny fruit flies could disperse ∼12 km in a single flight in still air and might travel many times that distance in a moderate wind. The dispersal behavior of the flies is well explained by an agent-based model in which animals maintain a fixed body orientation relative to celestial cues, actively regulate groundspeed along their body axis, and allow the wind to advect them sideways. The model accounts for the observation that flies actively fan out in all directions in still air but are increasingly advected downwind as winds intensify. Our results suggest that dispersing insects may strike a balance between the need to cover large distances while still maintaining the chance of intercepting odor plumes from upwind sources.


Hippo/YAP signaling pathway protects against neomycin-induced hair cell damage in the mouse cochlea.
The Hippo/Yes-associated protein (YAP) signaling pathway has been shown to be able to maintain organ size and homeostasis by regulating cell proliferation, differentiation, and apoptosis. The abuse of aminoglycosides is one of the main causes of sensorineural hearing loss (SSNHL). However, the role of the Hippo/YAP signaling pathway in cochlear hair cell (HC) damage protection in the auditory field is still unclear. In this study, we used the YAP agonist XMU-MP-1 (XMU) and the inhibitor Verteporfin (VP) to regulate the Hippo/YAP signaling pathway in vitro. We showed that YAP overexpression reduced neomycin-induced HC loss, while downregulated YAP expression increased HC vulnerability after neomycin exposure in vitro. We next found that activation of YAP expression inhibited C-Abl-mediated cell apoptosis, which led to reduced HC loss. Many previous studies have reported that the level of reactive oxygen species (ROS) is significantly increased in cochlear HCs after neomycin exposure. In our study, we also found that YAP overexpression significantly decreased ROS accumulation, while downregulation of YAP expression increased ROS accumulation. In summary, our results demonstrate that the Hippo/YAP signaling pathway plays an important role in reducing HC injury and maintaining auditory function after aminoglycoside exposure. YAP overexpression could protect against neomycin-induced HC loss by inhibiting C-Abl-mediated cell apoptosis and decreasing ROS accumulation, suggesting that YAP could be a novel therapeutic target for aminoglycosides-induced sensorineural hearing loss in the clinic.


Protocol for the isolation, sequencing, and analysis of the gut phageome from human fecal samples.
The phage-bacteria interactions in the gut microbiome are critical for health and disease, but viruses of the human gut microbiome are poorly understood. Here, we present a simple and cost-efficient protocol for collecting viral-like particles (VLPs) from human fecal samples. We describe VLPs quantification using epifluorescence and TEM microscopy, followed by DNA sequencing and bioinformatics analysis. This protocol characterizes the gut phageome in normal-weight and obese children with metabolic syndrome. It is also suitable to conduct high-throughput studies for other diseases. For complete details on the use and execution of this profile, please refer to Bikel et al. (2021).


Protein engineering of CYP105s for their industrial uses.
Cytochrome P450 enzymes belonging to the CYP105 family are predominantly found in bacteria belonging to the phylum Actinobacteria and the order Actinomycetales. In this review, we focused on the protein engineering of P450s belonging to the CYP105 family for industrial use. Two Arg substitutions to Ala of CYP105A1 enhanced its vitamin D3 25- and 1α-hydroxylation activities by 400 and 100-fold, respectively. The coupling efficiency between product formation and NADPH oxidation was largely improved by the R84A mutation. The quintuple mutant Q87W/T115A/H132L/R194W/G294D of CYP105AB3 showed a 20-fold higher activity than the wild-type enzyme. Amino acids at positions 87 and 191 were located at the substrate entrance channel, and that at position 294 was located close to the heme group. Semi-rational engineering of CYP105A3 selected the best performing mutant, T85F/T119S/V194N/N363Y, for producing pravastatin. The T119S and N363Y mutations synergistically had remarkable effects on the interaction between CYP105A3 and putidaredoxin. Although wild-type CYP105AS1 hydroxylated compactin to 6-epi-pravastatin, the quintuple mutant I95T/Q127R/A180V/L236I/A265N converted almost all compactin to pravastatin. Five amino acid substitutions by two rounds of mutagenesis almost completely changed the stereo-selectivity of CYP105AS1. These results strongly suggest that the protein engineering of CYP105 enzymes greatly increase their industrial utility. This article is part of a Special Issue entitled: Cytochrome P450 biodiversity and biotechnology, edited by Erika Plettner, Gianfranco Gilardi, Luet Wong, Vlada Urlacher, Jared Goldstone.


Cholinesterase in serum and low density lipoprotein of hyperlipidemic patients.
Cholinesterase activity in the low density lipoprotein fraction of serum is increased in types IIa, IIb and IV hyperlipoproteinemic patients, whereas only types IIb and IV show increases in serum cholinesterase activity. In obese patients, cholinesterase activity is increased both in the serum and low density lipoprotein fraction only when hyperlipidemia is present. Cholinesterase activity is also found to increase in proportion with increases in low density lipoprotein, cholesterol, and triglycerides both in the serum and low density lipoprotein fraction. We suggest on the basis of these findings that cholinesterase has a function in lipid and lipoprotein metabolism.


Maxillofacial and oral surgery in patients with thrombophilia: safe territory for the oral surgeon? A single-center retrospective study.
The aim of this study was to analyze patients with thrombophilia who underwent oral and/or maxillofacial surgery at our center. We performed a retrospective analysis of patients with hereditary or acquired thrombophilia who had undergone oral/maxillofacial surgery between January 1, 2000 and December 31, 2019. Data regarding demographic and patient characteristics, surgical treatment modalities, antithrombotic therapies, and complications were analyzed. A total of 76 eligible patients (26 male, 50 female) were included in this study, with a mean follow-up period of 3.8 months (range, 0-51 months). The mean age at time of surgery was 44.7 ± 19.4 years. Seven different hereditary and acquired thrombophilia were identified: factor V Leiden (n = 31; 40.8%), prothrombin G20210A mutation (n = 5; 6.6%), protein C deficiency (n = 4; 5.3%), protein S deficiency (n = 11; 14.5%), antiphospholipid syndrome (n = 10; 13.2%), hyperhomocysteinemia (n = 8; 10.5%), and elevated factor VIII (n = 2; 2.6%). Complications occurred in 9 patients (11.8%) and included postoperative infections (n = 6; 7.9%) and postoperative bleeding (n = 3; 3.9%). Our data suggest that oral and/or maxillofacial surgery in patients with a confirmed diagnosis of thrombophilia is not associated with a burden of thrombosis or high complication rates. Furthermore, we formulated a guideline for preoperative antithrombotic therapy for patients with thrombophilia undergoing oral and/or maxillofacial surgery.


Safety and Activity of Programmed Cell Death 1 Versus Programmed Cell Death Ligand 1 Inhibitors for Platinum-Resistant Urothelial Cancer: A Meta-Analysis of Published Clinical Trials.
Programmed death 1/ligand 1 (PD-1/L1) inhibitors have acceptable antitumor activity in patients with platinum-resistant urothelial cancer (UC). However, the reliability and comparability of the antitumor activity, safety profiles and survival outcomes of different immune checkpoint inhibitors are unknown. Our objective was to compare the clinical efficacy and safety of anti-PD-1/PD-L1 therapies in platinum-resistant UC patients. We reviewed the published trials from the PubMed, Embase and Cochrane Library databases up to August 2020. A well-designed mirror principle strategy to screen and pair trial characteristics was used to justify indirect comparisons. The primary end point was the objective response rate (ORR). The safety profile and survival outcomes were also evaluated. The restricted mean survival time (RMST) up to 12 months was calculated. Eight studies including 1,666 advanced or metastatic UC patients (1,021 patients with anti-PD-L1 treatment and 645 patients with anti-PD-1 treatment) met the study criteria. The ORRs of anti-PD-1 and PD-L1 therapy were 22% (95% CI, 18%-25%) and 15% (95% CI, 13%-17%) with all studies combined. The proportions of the treated population with a confirmed objective response (I2 = 0; P = 0.966; HR, 1.60; 95% CI, 1.23-2.07; P < 0.001) and disease control (I2 = 30.6%; P = 0.229; HR, 1.35; 95% CI, 1.10-1.66; P = 0.004) were higher with anti-PD-1 therapy than with anti-PD-L1 therapy. The treatment-related adverse events (AEs) (I2 = 78.3%; P = 0.003; OR, 1.09; 95% CI, 0.65-1.84; P = 0.741) and grade 3-5 treatment-related AEs (I2 = 68.5%; P = 0.023; OR, 1.69; 95% CI, 0.95-3.01; P = 0.074) of anti-PD-1 therapy were comparable to those of anti-PD-L1 therapy. The RMST values at the 12-month follow-up were 9.4 months (95% CI,: 8.8-10.0) for anti-PD-1 therapy and 9.3 months (95% CI, 8.8-9.7) for anti-PD-L1 therapy (z = 0.26, P = 0.794). There was no significant difference between patients in the anti-PD-1 and anti-PD-L1 groups (12-month overall survival (OS): 43% versus 42%, P = 0.765. I2 = 0; P = 0.999; HR, 0.95; 95% CI, 0.83-1.09; P = 0.474). The results of our systematic comparison suggest that anti-PD-1 therapy exhibits better antitumor activity than anti-PD-L1 therapy, with comparable safety profiles and survival outcomes. These findings may contribute to enhanced treatment awareness in patients with platinum-resistant UC.


Association of Gene Polymorphisms of Some Endothelial Factors with Stent Reendothelization after Elective Coronary Artery Revascularization.
Restenosis remains the main complication after percutaneous coronary interventions in patients with coronary heart disease. The causes of its development include, in particular, genetic factors. We studied polymorphic loci of genes encoding endothelin-1 (EDN1 rs5370), endothelin-1 receptor (EDNRA rs5333), endothelin-converting enzyme (ECE1 rs1076669), and endothelial NO synthase (eNOS rs1549758, eNOS rs1799983, and eNOS rs2070244) in the context of in-stent restenosis development. It was found that the analyzed polymorphisms of the endothelin system genes were more significant for patients aged ≥ 65 years, while the polymorphic loci of the endothelial NO synthase gene (eNOS rs1799983 and eNOS rs1549758) were predominantly associated with time of in-stent restenosis. The obtained results can be useful for comprehensive assessment of the restenosis risk factors and the choice of optimal treatment for patients with coronary heart disease before elective surgical intervention.


Surgical treatment of Achilles tendinitis by decompression of the retrocalcaneal bursa and the superior calcaneal tuberosity.
Initial nonoperative treatment of pain at the Achilles tendon, often referred to as "tendinitis," is not always successful. Surgical treatment is effective for patients with insertional tendinitis unrelieved by nonoperative measures. Retrospective cohort study. Thirty-five patients (41 feet) who had painful Achilles tendon syndrome unrelieved by 6 months of nonoperative measures were treated surgically. The technique consisted of a single incision along the lateral border of the Achilles tendon. The dissection exposed the retrocalcaneal bursa and fat pad, which were completely excised along with any scarred and thickened paratenon. A partial calcaneal exostectomy of the tubercle was performed. At a minimum follow-up of 20 months (average, 39), the patients' pain scores (rated from 0 to 6) improved from 4.7 (SD, 1.1) preoperatively to 1.5 (SD, 1.3); 90% had complete or significant relief of symptoms, 10% felt improved, and none felt unchanged or worse. Surgical treatment of chronic Achilles tendon pain with resection of the prominent tuberosity, complete debridement of the bursa, excision of thickened, scarred paratenon, and removal of accessible calcific deposits within the tendon is an effective treatment.


Effect of Biliary Tract Invasion with Obstructive Jaundice on the Prognosis of Patients With Unresectable Hepatocellular Carcinoma.
Biliary tract invasion (BTI) is associated with poor outcomes in patients with hepatocellular carcinoma (HCC). However, the presence of a BTI is a neglected variable for staging in the current guidelines. This study aimed to explore the effects of BTI with obstructive jaundice on the prognosis of patients with unresectable HCC. We retrospectively included 205 patients initially diagnosed with unresectable HCC who presented with obstructive jaundice due to BTI between January 2010 and June 2021. BTI was classified into four types according to the location of the biliary obstruction. Both clinical and treatment factors that affect median overall survival (mOS) were analyzed. The mOS of patients with Barcelona Clinic Liver Cancer (BCLC) stages B, C, and D was 9.2 months, 3.4 months, and 1.8 months, respectively (p<.001). The mOS of BTI type I patients was superior to that of BTI type II patients (7.1 months vs. 3.2 months, p=.002). Patients who underwent successful biliary drainage had a longer mOS than those who underwent unsuccessful biliary drainage (10.4 months vs. 2.9 months, p<.001). In the multivariate analysis, BTI type I (p=.009), successful biliary drainage (p=.005), and HCC treatment (p<.001) were significant favorable prognostic factors that affected patient survival. HCC patients with BTI type II may have a poorer prognosis than those with BTI type I. Effective biliary drainage and anti-cancer treatment may provide survival benefits to these patients. A more detailed staging system for HCC based on the state of BTI is needed.


Antibacterial potential of some Saudi honeys from Asir region against selected pathogenic bacteria.
Honey is a nutrient rich natural product and has been utilized as traditional and complementary medicine since ancient times. In this study, antibacterial activity of Sider (Ziziphus spina-christi), Dharm (Lavandula dentata), and Majra (Hypoestes forskaolii) honey samples collected from Asir region of Saudi Arabia was in vitro evaluated at 80% and 50% w/v concentrations against five pathogenic bacteria i.e. Escherichia coli, Proteus mirabilis, Staphylococcus aureus, Shigella flexneri, and Staphylococcus epidermidis. Well diffusion assays to measure the average zone of inhibition (ZOI) and minimum inhibitory concentration (MIC) values were employed in the experiments. All the tested honey samples showed antibacterial activity in a dose-dependent manner. Sider and Dharm exhibited a good antibacterial activity at high concentrations while, Majra honey of Apis mellifera jemenitica and of Apis florea showed comparatively low antibacterial activity. The average MIC values of Sider, Dhram from Rijal Alma, Dharm from Al-Souda, Majra (A.m. jemenitica), and Majra (A. florea) honey against all tested bacteria were 22%, 16%, 18%, 32%, and 28% (v/v) respectively. Dharm and Sider honeys showed better antibacterial activity than Majra honey. Saudi honey can be considered as a promising future antimicrobial agent and should be further investigated as an alternative candidate in the management of resistant bacterial pathogens.


Review of local soft tissue recurrence of breast cancer irradiated with and without actinomycin-D.
Between 1962 and 1973, regionally recurrent breast cancer was treated in 156 patients by irradiation alone or irradiation with concurrent actinomycin-D. Thirty-two patients were entered into a randomized trial, and 124 patients were retrospectively reviewed. Local control with irradiation alone was achieved in 48 of 80 patients (60%) and in 60 of 76 patients (79%) treated with irradiation and actinomycin-D (p less than .05). Results were remarkably similar in the randomized and retrospective series.


Interfacial ferroelectricity by van der Waals sliding.
Despite their partial ionic nature, many layered diatomic crystals avoid internal electric polarization by forming a centrosymmetric lattice at their optimal van-der-Waals stacking. Here, we report a stable ferroelectric order emerging at the interface between two naturally-grown flakes of hexagonal-boron-nitride, which are stacked together in a metastable non-centrosymmetric parallel orientation. We observe alternating domains of inverted normal polarization, caused by a lateral shift of one lattice site between the domains. Reversible polarization switching coupled to lateral sliding is achieved by scanning a biased tip above the surface. Our calculations trace the origin of the phenomenon to a subtle interplay between charge redistribution and ionic displacement, and provide intuitive insights to explore the interfacial polarization and its unique "slidetronics" switching mechanism.


Effects of corneal cross-linking on contrast sensitivity, visual acuity, and corneal topography in patients with keratoconus.
To assess the effects of corneal collagen cross-linking (CXL) on contrast sensitivity (CS), visual acuity, and corneal topography investigating possible predictors of efficacy. Sixty-eight eyes of 34 patients with progressive keratoconus were enrolled in this prospective study. CXL was performed in one eye and the other eye was left untreated as a control. CS, best spectacle-corrected visual acuity (BSCVA), simulated keratometry in the steepest meridian (SimK-s), mean power in the central 3-mm zone (C-MP), mean power in the paracentral 3- to 5-mm zone (P-MP), maximum keratometric power in the central zone (C-Kmax), and maximum keratometric power in the paracentral zone (P-Kmax) were evaluated at baseline, 40 days, 3 months, 6 months, 1 year, and after 2 years of follow-up. Treated eyes showed an improvement (P < 0.001) of +0.16 logCS and -0.16 logarithm of the minimum angle of resolution (logMAR) and a reduction in SimK-s of -0.61 diopter (D), C-Kmax -1.11 D, P-Kmax -0.99 D, C-MP -0.39 D, and P-MP -0.30 D. Of the treated eyes, 43.3% had a decrease in C-Kmax greater than 1 D, 50% by 0 to 0.99 D, and 6.7% had an increase of up to +0.89 D. Treated eyes with keratometric apex in the central 3-mm zone (CKA) improved BSCVA -0.19 logMAR and CS +0.19 logCS; whereas in treated eyes with paracentral keratometric apex (PKA), the improvement was -0.13 logMAR and +0.16 logCS. CXL with riboflavin and UV-A improved CS and inhibited the progression of keratoconus. As a predictor of treatment efficacy, eyes with CKA showed greater improvement in BSCVA after CXL when compared with eyes with PKA.


VvSNAT1 overexpression enhances melatonin production and salt tolerance in transgenic Arabidopsis.
Melatonin (N-acetyl-5-methoxytryptamine) plays important roles in the regulation of development and the response to biotic and abiotic stresses in plants. Serotonin-N-acetyltransferase (SNAT) functions as a key catalytic enzyme involved in melatonin biosynthesis. In this study, the candidate gene VvSNAT1 (SNAT isogene) was isolated from grape (Vitis vinifera L. cv. Merlot). Tissue-specific expression and external treatment revealed that VvSNAT1 is a salt-inducible gene that is highly expressed in leaves. Subcellular localisation results revealed that VvSNAT1 was located in the chloroplasts, which is similar to other plant SNAT proteins. Ectopic overexpression of VvSNAT1 in Arabidopsis resulted in increased melatonin production and salt tolerance. Transgenic Arabidopsis overexpressing VvSNAT1 exhibited enhanced growth and physiological performance, including a lower degree of leaf wilting, higher germination rate, higher fresh weight, and longer root length under salt stress. Moreover, overexpression of VvSNAT1 in Arabidopsis protected cells from oxidative damage by reducing the accumulation of malondialdehyde (MDA) and hydrogen peroxide (H2O2). These results indicate that VvSNAT1 positively responds to salt stress. Our results provide a novel perspective for VvSNAT1 to improve salt tolerance, mediated by melatonin accumulation, plant growth promotion and oxidative damage reduction.


Amsorb Plus and Drägersorb Free, two new-generation carbon dioxide absorbents that produce a low compound A concentration while providing sufficient CO2 absorption capacity in simulated sevoflurane anesthesia.
The properties of two new-generation CO(2) absorbents, Amsorb Plus (Armstrong Medical, Coleraine, UK) and Drägersorb Free (Drager, Lubeck, Germany), were compared with those of Amsorb (Armstrong Medical) and Sodasorb II (W.R. Grace, Lexington, MA, USA). The concentration of compound A produced by each absorbent was determined in a low-flow circuit containing sevoflurane, and the CO(2) absorption capacity of the absorbent was measured. The circuit contained 1000 g of each absorbent and had a fresh gas (O(2)) flow rate of 1 l.min(-1) containing 2% sevoflurane. CO(2) was delivered to the circuit at a flow rate of 200 ml.min(-1). The maximum concentrations of compound A were 2.2 +/- 0.0, 2.3 +/- 0.3, 2.2 +/- 0.2, and 23.5 +/- 1.5 ppm (mean +/- SD) for Amsorb Plus, Drägersorb Free, Amsorb, and Sodasorb II, respectively. The maximum concentration of compound A for Sodasorb II was significantly higher than those for the other absorbents (P < 0.01). The CO(2) absorption capacities (time taken to reach an inspiratory CO(2) level of 2 mmHg) were 1023 +/- 48, 1074 +/- 36, 767 +/- 41, and 1084 +/- 54 min, respectively, and the capacity of Amsorb was significantly lower than that of the other absorbents (P < 0.01). The new-generation carbon dioxide absorbents, Amsorb Plus and Drägersorb Free, produce a low concentration of compound A in the circuit while showing sufficient CO(2) absorption capacity.


Interfused core-shell heterogeneous graphene/MXene fiber aerogel for high-performance and durable electromagnetic interference shielding.
Flexible, lightweight, and durable electromagnetic interference (EMI) shielding materials are urgently required to solve the increasingly serious electromagnetic radiation pollution. Transition metal carbides/nitrides (MXenes) are promising candidates for EMI shielding materials because of their excellent metallic electrical conductivity. However, MXenes are highly susceptible to oxidization when exposed to wet environments, leading to the loss of their functional properties and degradation of reliability and stability. Herein, an interfused core-shell heterogeneous reduced graphene oxide (rGO)/MXene aerogel (GMA) is designed for the first time via coaxial wet spinning and freeze-drying. The fabricated GMAs exhibit excellent EMI shielding performance, and the EMI shielding effectiveness (SE) and specific EMI SE can be up to 83.3 dB and 3119 dB·cm3/g, respectively, which is higher than most carbon-based and MXene-based aerogels and foams. More importantly, GMAs have only a 17.4 % degradation in EMI shielding performance after 120 days due to the protection of hydrophobic graphene sheath, exhibiting superior EMI shielding durability to its MXene film counterpart. Moreover, the hydrophobic GMAs exhibit good oil/water separation and thermal insulation performance. The interfused core-shell GMAs are highly promising for applications in durable EMI shielding, thermal insulation, oil/water separation and sensors, etc.


Effect of Limosilactobacillus reuteri ZJF036 on Growth Performance and Gut Microbiota in Juvenile Beagle Dogs.
This experiment investigated the effects of Limosilactobacillus reuteri ZJF036 on growth performance, serum biochemical parameters, and gut microbiota in beagle dogs. Sixteen 75 ± 5-day-old healthy male beagles (4.51 ± 1.37 kg) were randomly divided into two groups; the experimental group (L1) and the control group (L0), and then fed with or without a basal diet containing L. reuteri ZJF036 (109 CFU/g), respectively. The results showed that there was no significant difference in daily weight gain between the two groups (P > 0.05). However, we found that L. reuteri ZJF036 decreased Chao1 index and ACE index and increased the relative abundance of Firmicutes and Fusobacteria (P < 0.05) compared to the L0 group. In addition, we also found that the ratio of Firmicutes to Bacteroidetes was decreased in L1 group. Furthermore, the relative abundance of Lactobacillus increased, while that of Turicibacter and Blautia decreased in L1 group (P < 0.05). In conclusion, L. reuteri ZJF036 appeared to regulate the intestinal microbiota of beagle dogs. This study revealed the potential use of L. reuteri ZJBF036 as a probiotic supplement for beagle dogs.


Blood pressure in children with diabetes mellitus.
Blood pressure measurements were evaluated in 151 children aged 2-19 years old with insulin-dependent diabetes mellitus (DM) of a duration of few months to 15 1/2 years. Compared with a reference group, the diabetic children had lower diastolic blood pressure (DBP) shortly after start of DM. There was no difference for the systolic blood pressure (SBP). After duration of diabetes of 5 years there were no significant differences in SBP and only significantly lower DBP in girls (median difference 5 mmHg, p less than 0.01), while the difference in boys is insignificant (median difference 2 mmHg, p = 0.32). In a model describing the intraindividual variation in blood pressure and its dependence on age, weight and height it was found that age was insignificant when weight and height were included. For DBP height was also insignificant when weight was included. For the 9 children with retinal microaneurysms the average SBP was significantly higher than expected for diabetic children of that weight and height.


Transcriptome analysis of the salivary glands of Nephotettix cincticeps (Uhler).
The green rice leafhopper (GRH), Nephotettix cincticeps, is one of the most important pests of rice in temperate Asian countries. GRH, a vascular feeder, secretes watery and gelling saliva in the process of feeding on phloem and xylem sap. It is known that GRH saliva contains several bioactive proteins, including enzymes such as laccase and beta-glucosidase. In this study, we performed transcriptome analysis of salivary glands of GRH using Illumina paired-end sequencing. Of 51,788 assembled contigs, 16,017 (30.9%) showed significant similarity to known proteins in the NCBI nr database, while 34,978 (67.5%) could not be annotated by similarity search, Pfam, or gene ontology (GO). Contigs (905) with predicted signal peptides and no putative transmembrane domains are suggested to represent secreted protein coding genes. Among the 76 most highly expressed putative secretory protein contigs, 68 transcripts were found to be salivary gland-specific or at least -dominant, but not expressed in stomach or Malpighian tubules. However, 45 of the 68 transcripts were unknown proteins. These findings suggest that most of the GRH transcripts encoding secreted proteins expressed in salivary glands are species and/or tissue specific. Our results provide a fundamental list of genes involved in GRH-Poaceae host plant interactions including successful feeding and plant pathogen transmission.


Patterns of premature newborns' sleep-wake states before and after nursing interventions on the night shift.
To examine patterns of behavioral states of premature newborns before and after nursing interventions. Secondary analysis of videotaped data, using a repeated measures design. 1 8-bed neonatal intensive- and intermediate-care unit in a 400-bed suburban teaching hospital. Forty medically stable premature newborns with an average postconceptional age of 32.79 weeks at the time of testing. Behavioral states measured by observations of videotape recordings. Five-hour observations of behavioral states revealed that newborns showed more quiet sleep, F (2, 38) = 5.65, p = .023, and fewer waking episodes, F (2, 38) = 14.4, p = .001, in the 30 minutes after nursing interventions than in the 30 minutes before. This repeated measures ANOVA analysis accounted for effects of caffeine or theophylline. Neither the frequency nor the duration of nursing interventions predicted duration or frequency of behavioral states before or after interventions. Some newborns experience waking outside the context of nursing interventions. For medically stable newborns, nursing interventions are generally followed by sleep, possibly indicating satiety after feeding or significant energy expenditure. The findings also may suggest that some newborns show anticipation of feeding by waking, although 50% of the newborns did not experience any waking prior to interventions. Further research is needed to examine associations between specific types of nursing interventions and newborn behavioral responses, as well as the relationship of behavioral state patterns and newborn development.


Genetic causes of acute encephalopathy in adults: beyond inherited metabolic and epileptic disorders.
Acute encephalopathy is a widely used term, implying a rapidly progressive multifocal or diffuse brain dysfunction, caused by acute structural disturbance or a myriad of metabolic, toxic, epileptic, or infection-related factors. Apart from the more common acquired causes, a broad range of rare inherited disorders may produce spells of encephalopathy in adulthood, posing diagnostic challenges to clinicians. Among the latter, neurometabolic disorders and epileptic syndromes constitute typical examples. Interestingly, certain genetic entities have the potential to provoke episodic changes of cognition, via alternative, neither metabolic nor epileptic, mechanisms. Our aim is to provide a short and focused overview of their clinicoradiological features and potential pathophysiology. As the neurogenetic landscape is rapidly evolving, it is important to be familiar with these chameleons, in order to provide swift diagnosis and proper genetic counselling.


Association of ITM2A rs1751094 polymorphism on X chromosome in Korean pediatric patients with autoimmune thyroid disease.
Autoimmune thyroid disease (AITD) manifests with a female predominance, and much attention has been directed towards the integral membrane protein 2 A (ITM2A) gene located on the X chromosome. In a study of 166 pediatric patients with autoimmune thyroid disease (AITD), the ITM2A rs1751094 single-nucleotide polymorphism (SNP) was genotyped. The sample comprised 143 females and 23 males, with 67 patients diagnosed with Hashimoto chronic thyroiditis (HD) and 99 with Graves' disease (GD). In the 99 GD patients, 49 (49.5%) exhibited thyroid-associated ophthalmopathy (TAO). Among the 85 GD patients, 70.6% (60/85) were considered intractable GD. The results were compared to those from 198 healthy Korean individuals, including 97 females and 101 males. The frequency of the rs1751094 C allele and CC/AC genotype were higher in AITD, GD and HD patients compared to controls, while the frequency of the A allele and AA genotype were lower. The results were more pronounced in female AITD and GD patients compared to male patients. The association was also found in intractable GD and TAO patients. Target SNP fits Hardy-Weinberg equilibrium. These findings indicate that the ITM2A gene polymorphism on the X chromosome may contribute to the immunological basis of female-predominant AITD in Korean children.


Potential for phytoremediation of neonicotinoids by nine wetland plants.
Broad-spectrum insecticides such as neonicotinoids tend to accumulate and detrimentally impact natural ecosystems. Accordingly, we aimed to assess the neonicotinoid phytoremediation abilities of nine wetland plant species commonly used in constructed wetland systems: Acorus calamus, Typha orientalis, Arundo donax, Thalia dealbata, Canna indica, Iris pseudacorus, Cyperus alternifolius, Cyperus papyrus and Juncus effusus. We assessed their removal of six neonicotinoids and explored the mechanisms responsible for the observed removal in a 28-day experiment. The planted systems effectively removed the neonicotinoids, with removal efficiencies of 9.5-99.9%. Compared with the other neonicotinoids, imidacloprid, thiacloprid and acetamiprid were most readily removed in the planted systems. C. alternifolius and C. papyrus exhibited the best removal performance for all six neonicotinoids. Based on our assessment of mass balance, the main removal processes were biodegradation and plant accumulation. Plants can enhance neonicotinoid removal through enhancing biodegradation. The differences in transport and accumulation behaviors may be related to plant species and physicochemical properties of neonicotinoids. Further research is merited on the toxicity of neonicotinoids to plants and microorganisms and the metabolic pathways by which neonicotinoids are broken down in wetland systems.


Perceptions, practices and barriers to reporting of adverse drug reactions among HIV infected patients and their doctors in 3 public sector hospitals of the Ethekwini Metropolitan, Kwa-Zulu Natal: a cross sectional and retrospective analysis.
Adverse drug reactions (ADRs) remain a global public health concern. Pharmacovigilance practises are essential in ensuring patients safety and post drug marketing surveillance. This study aimed to describe practices, perceptions and barriers towards ADR reporting practices amongst People Living with HIV/AIDS (PLWHA), who are on Highly Active Anti-Retroviral Therapy (HAART) and their doctors. The study took place at 3 public sector hospitals. The first phase of the study was a quantitative cross-sectional study using a closed ended questionnaire that was given to PLWHA. Phase two was a retrospective analysis of these patients' medical files, whilst phase 3 included a descriptive statistics to determine the frequencies and percentages for variables such as ADR reporting practices by doctors. Spontaneous reporting, was evident with 202 patients (48%) indicating that they reported experiencing ADRs to their doctors. Ten doctors (77%) indicated that they received PV training. Eight (62%) doctors indicated that the completed ADR reporting forms were submitted to the pharmacy manager in the hospital for forwarding to the regulatory authority, with 2 (15%) indicating that they submitted directly to the South African Health Products Regulatory Authority. Four (31%) doctors stated that the system of reporting ADRs is ineffective with the majority of the doctors 12 (92%) responding that the reporting of ADRs is very important/critical. A barrier cited by 4 patients (0.9%) for non-reporting of their ADRs was transport cost. Whilst doctors' barriers included reporting being time consuming (31%), and a lack of availability of reporting forms (31%). Patients and doctors are reporting ADRs but more education and easier reporting process should be available to strengthen the knowledge and reporting of ADRs. Doctors agree that it is critical to report ADRs. Electronic reporting should be encouraged to lessen the time it takes to report ADRs.


Severity of infection following the introduction of new infection control measures for medical abortion.
In response to concerns about serious infections following medical abortion, in early 2006 the Planned Parenthood Federation of America changed the route of misoprostol administration from vaginal to buccal and required either routine antibiotic coverage or universal screening and treatment for chlamydia; in July 2007, the Planned Parenthood Federation of America began requiring routine antibiotic coverage for all medical abortions. We previously reported a pronounced drop in the rate of serious infections following the adoption of these new infection control measures. Our objective in this study was to assess whether the degree of severity of the serious infections differed in the three infection control groups (vaginal misoprostol and no antibiotics; buccal misoprostol and screen-and-treat method; buccal misoprostol and routine antibiotics) or, equivalently, to assess whether the declines in rates of serious infections after the adoption of new infection control measures differed across the degree of severity categories. Of particular importance is whether the new infection control measures selectively reduced the least severe serious infections but did not diminish the rate of the most severe infections. We performed a retrospective analysis assessing the degree of severity of infections before infection controls were implemented and after each of the two new measures was adopted: buccal administration of antibiotics with either screen-and-treat method or routine antibiotic coverage. We ranked the severity of infection from 1 (when treatment occurred in an emergency department) to 4 (when death occurred). We compared the distributions of the severity of serious infections in the three infection control groups (none; buccal misoprostol and screen-and-treat method; buccal misoprostol and routine antibiotics) or, equivalently, assessed whether the declines in rates of serious infections after the adoption of new infection control measures differed across the degree of severity categories using the Jonckheere-Terpstra test for a doubly ordered 4 × 3 table. The distribution of infection by severity was the same for all three infection control groups. Likewise, when the two new infection control groups--buccal misoprostol plus either screen-and-treat method or routine antibiotics--were combined, the distribution of infection by severity was the same before and after the new measures were implemented. The pronounced decline in the rate of serious infections occurred in each category of severity.


180° congenital penile torsion with distal hypospadias mistaken for an epispadias: Optimal outcome with tubularized incised plate urethroplasty and dartos flap rotation.
Severe penile torsion of 180° associated with hypospadias is a rare entity. Knowledge of penile anatomy and pathology are necessary as the diagnosis could be missed. We report a case of severe 180° penile torsion with distal hypospadias that was mistaken for an epispadias which was corrected with surgery. Tubularized incised plate urethroplasty and dartos flap rotation provided satisfactory result for this association.


Inhibition of reflex epilepsy by (+/-)-N-n-propylnorapomorphine.
In baboons, Papio papio, spontaneously showing photosensitive epilepsy, myoclonic responses to intermittent photic stimulation were reduced or abolished for up to four hours by (+/-)-N-n-propylnorapomorphine (NPA) 0.05-0.2 mg/kg body weight, given i.v. In animals pretreated with allyglycine, 200 mg/kg, a transient abolition of myoclonic responses followed NPA, 0.2 mg/kg. In DBA/2 mice, seizures following auditory stimulation were attenuated or abolished by NPA 0.025-0.1 mg/kg given intraperitoneally (ED50 for abolition of clonic phase = 0.032 mg/kg). The ED50 for pentylenetetrazol seizures in MF 1 mice was not altered by NPA 0.25 mg/kg.


Function and regulation of hepatic and intestinal fatty acid binding proteins.
Two structurally different fatty acid binding proteins (FABP) have been isolated from rat liver and small intestinal epithelium. hFABP is a 14 184 Da protein found in abundance in both liver and small intestine, whereas gFABP (15 063 Da) is abundantly present only in small intestine. This review discusses studies which have provided insight into the physiological functions of these proteins. These include analyses of endogenous and exogenous ligand binding to FABP in vitro; examination of the modulating effect of FABP preparations on enzyme activities in vitro; exploration of relationships between alterations in cytosolic FABP content in response to hormonal, pharmacological, and dietary manipulations and changes in the rates of cellular fatty acid uptake and utilization; and studies of hFABP turnover and the mechanisms of FABP regulation. These experiments provide compelling evidence for a broad role of the FABPs in the transport, utilization and cellular economy of free fatty acids in the liver and small intestine, and also in protecting several aspects of cellular function against the modulatory effects of fatty acids, fatty acyl-CoA esters, and other ligands. Studies of FABP regulation also suggest a role in long-term rather than short-term modulation of hepatic fatty acid metabolism and indicate that hFABP and gFABP may perform different functions in the small intestine.


Early fusion outcome after surgical treatment of single-level and multi-level pyogenic spondylodiscitis: experience at a level 1 center for spinal surgery-a single center cohort study.
Retrospective single center cohort study. Spinal instrumentation in combination with antibiotic therapy is a treatment option for acute or chronic pyogenic spondylodiscitis (PSD). This study compares the early fusion outcome for multi-level and single-level PSD after urgent surgical treatment with interbody fusion in combination with fixation. This is a retrospective cohort study. Over a 10 year period at a single institution, all surgically treated patients received surgical debridement, fusion und fixation of the spine to treat PSD. Multi-level cases were either adjacent to each other on the spine or distant. Fusion rates were assessed at 3 and 12 months after surgery. We analyzed demographic data, ASA status, duration of surgery, location and length of spine affected, Charlson comorbidity index (CCI), and early complications. A total of 172 patients were included. Of these, 114 patients suffered from single-level and 58 from multi-level PSD. The most frequent location was the lumbar spine (54.0%) followed by the thoracic spine (18.0%). The PSD was adjacent in 19.0% and distant in 81.0% of multi-level cases. Fusion rates at the 3 month follow-up did not differ among the multi-level group (p = 0.27 for both adjacent and distant sites). In the single-level group, sufficient fusion was achieved in 70.2% of cases. Pathogen identification was possible 58.5% of the time. Surgical treatment of multi-level PSD is a safe option. Our study demonstrates that there was no significant difference in early fusion outcomes between single-level and multi-level PSD, whether adjacent or distant.


Modulation of Fgf8 activity during vertebrate brain development.
In recent years much emphasis has been placed on investigation of the precise control of FGF signaling during brain development. Such control is achieved in part by regulatory elements that determine the domains and levels of expression of genes coding for the diverse FGF ligands via specific molecular signaling pathways. There is new knowledge on the operation of such mechanisms in regions of the neural tube involved in the correct patterning of adjacent territories (known as secondary organizers of neural tube pattern). In the present minireview we intend to summarize recent evidence and emerging conclusions on potent modulators that govern the activity of Fgf8 signals in the developing vertebrate brain, focusing our attention on the best known secondary organizer, the isthmic organizer.


Complement activation triggers metalloproteinases release inducing cervical remodeling and preterm birth in mice.
Inflammation is frequently linked to preterm delivery (PTD). Here, we tested the hypothesis that complement activation plays a role in cervical remodeling and PTD. We studied two mouse models of inflammation-induced PTD. The first model was induced by vaginal administration of lipopolysaccharide (LPS) and the second one by administration of progesterone antagonist RU486. Increased cervical C3 deposition and macrophages infiltration and increased serum C3adesArg and C5adesArg levels were observed in both models when compared to gestational age matched controls. A significant increase in collagen degradation, matrix metalloproteinase 9 (MMP-9) activity and tissue distensibility was observed in the cervix in both models. Mice deficient in complement receptor C5a did not show increased MMP-9 activity and cervical remodeling and did not deliver preterm in response to LPS or RU486, suggesting a role for C5aR in the cervical changes that precede PTD. In vitro studies show that macrophages release MMP-9 in response to C5a. Progesterone diminished the amount of C5aR on the macrophages surface, inhibited the release of MMP-9 and prevented PTD. In addition, macrophages depletion also prevented cervical remodeling and PTD in LPS-treated mice. Our studies show that C5a-C5aR interaction is required for MMP-9 release from macrophages, and the cervical remodeling that leads to PTD. Complement inhibition and supplementation with progesterone may be good therapeutic options to prevent this serious pregnancy complication.


Pressure natriuresis in isolated kidneys from hypertension-prone and hypertension-resistant rats (Dahl rats).
Dahl described a strain of rats with genetically controlled propensities for hypertension. Chronic excess salt feeding increased blood pressure in sensitive (s) rats, whereas resistant rats (R) remain normotensive. We tested the pressure natriuretic function (urinary sodium excretion versus perfusion pressure) in isolated kidneys perfused with a cellular medium: in sodium-restricted normotensive sensitive (S0) and resistant (R0) animals; in sensitive rats receiving a high-salt diet for 3 weeks (S3): and in both S and R animals exposed to excess sodium for 7 weeks (R7 and S7). The aim of these studies was to determine if a preset alteration of the pressure natriuretic function might be present in S animals prior to the development of hypertension. Systolic blood pressure in S0, S3, and S7 animals were 123 +/- 4, 136 +/- 2, and 162 +/- 4 mm Hg, respectively, whereas that of R0 and R7 were 121 +/- 5 and 126 +/- 5 mm Hg. An increase of the perfusion pressure of isolated kidneys from 105 to 185 mm Hg in stepwise fashion resulted in a pressure natriuresis whose slope was similar in R0 and S0 animals. Of interest was that the pressure natriuretic function slope of kidneys from R0 (low sodium) and R7 (high sodium) rats was as predicted by the Guyton system analysis of normal blood pressure control Micropuncture of the proximal nephrons demonstrated that the origin of the natriuresis resulted from a site beyond the accessible proximal tubule. Results from S7 kidneys contrasted with all others in that the natriuretic response was depressed (P less than 0.01), which resulted from significantly lower filtration rates at higher perfusion pressures. We concluded (1) in normal R rats, the pressure natriuretic function is that predicted by the Guyton hypothesis, (2) Dahl S animals have no preset abnormality of this function until hypertension is present for some time, and (3) a depression of the pressure natriuretic function may aggravate hypertension in S rats once high blood pressure has persisted.