Are different station formats assessing different dimensions in multiple mini-interviews? Findings from the Canadian integrated French multiple mini-interviews.
Multiple mini-interviews (MMI) are used to assess non-academic attributes for selection in medicine and other healthcare professions. It remains unclear if different MMI station formats (discussions, role-plays, collaboration) assess different dimensions. Based on station formats of the 2018 and 2019 Integrated French MMI (IFMMI), which comprised five discussions, three role-plays and two collaboration stations, the authors performed confirmatory factor analysis (CFA) using the lavaan 0.6-5 R package and compared a one-factor solution to a three-factor solution for scores of the 2018 (n = 1438) and 2019 (n = 1440) cohorts of the IFMMI across three medical schools in Quebec, Canada. The three-factor solution was retained, with discussions, role-plays and collaboration stations all loading adequately with their scores. Furthermore, all three factors had moderate-to-high covariance (range 0.44 to 0.64). The model fit was also excellent with a Comparative fit index (CFI) of 0.983 (good if > 0.9), a Tucker Lewis index of 0.976 (good if > 0.95), a Standardized Root Mean Square Residual of 0.021 (good if < .08) and a Root Mean Square Error of 0.023 (good if < 0.08) for 2018 and similar results for 2019. In comparison, the single factor solution presented a lower fit (CFI = 0.819, TLI = 0.767, SRMR = 0.049 and RMSEA = 0.070). The IFMMI assessed three dimensions that were related to stations formats, a finding that was consistent across two cohorts. This suggests that different station formats may be assessing different skills, and has implications for the choice of appropriate reliability metrics and the interpretation of scores. Further studies should try to characterize the underlying constructs associated with each station format and look for differential predictive validity according to these formats.


[Brain photon emission tomography. Value of the corticocerebellar index and gammagraphic patterns in Alzheimer's disease and other diseases].
Brain single photon emission computed tomography (SPECT) with 99mTc-HMPAO is a diagnostic tool for evaluating regional cerebral blood flow. Recently, the diagnostic possibilities of the method are being investigated in some neurologic disorders, such as cerebrovascular accidents, seizures and dementia. This work has been carried out with 54 subjects, 9 healthy volunteers and 45 patients (31 dementia and 14 epileptics), in order to evaluate gammagraphic patterns and the utility of cortico/cerebellar activity indexes. An interesting diagnostic finding is a significant decrease (p less than 0.001) in perfusion of temporoparietal regions in the patients with Alzheimer's disease in relation with the healthy volunteers' group. We have not found significant changes in perfusion in the group of epileptic patients during the interictal phase. We conclude emphasizing the interest of the SPECT in the differential diagnosis of dementia.


Improved COVID-19 ICU admission and mortality outcomes following treatment with statins: a systematic review and meta-analysis.
Approximately 1% of the world population has now been infected by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19). With cases still rising and vaccines just beginning to rollout, we are still several months away from seeing reductions in daily case numbers, hospitalisations, and mortality. Therefore, there is a still an urgent need to control the disease spread by repurposing existing therapeutics. Owing to antiviral, anti-inflammatory, immunomodulatory, and cardioprotective actions, statin therapy has been considered as a plausible approach to improve COVID-19 outcomes. We carried out a meta-analysis to investigate the effect of statins on 3 COVID-19 outcomes: intensive care unit (ICU) admission, tracheal intubation, and death. We systematically searched the PubMed, Web of Science, Scopus, and ProQuest databases using keywords related to our aims up to November 2, 2020. All published observational studies and randomised clinical trials on COVID-19 and statins were retrieved. Statistical analysis with random effects modelling was performed using STATA16 software. The final selected studies (n = 24 studies; 32,715 patients) showed significant reductions in ICU admission (OR = 0.78, 95% CI: 0.58-1.06; n = 10; I 2 = 58.5%) and death (OR = 0.70, 95% CI: 0.55-0.88; n = 21; I 2 = 82.5%) outcomes, with no significant effect on tracheal intubation (OR = 0.79; 95% CI: 0.57-1.11; n = 7; I 2= 89.0%). Furthermore, subgroup analysis suggested that death was reduced further by in-hospital application of stains (OR = 0.40, 95% CI: 0.22-0.73, n = 3; I 2 = 82.5%), compared with pre-hospital use (OR = 0.77, 95% CI: 0.60-0.98, n = 18; I 2 = 81.8%). These findings call attention to the need for systematic clinical studies to assess both pre- and in-hospital use of statins as a potential means of reducing COVID-19 disease severity, particularly in terms of reduction of ICU admission and total mortality reduction.


Cemented versus uncemented hip replacement for fracture of the hip.
Review cemented versus uncemented hemi-arthroplasty hip replacement regarding morbidity and long term results. A literature review searching PubMed and Medline was done. Publications applicable to hip fractures treated by hip replacement or hemi-arthroplasty replacement were reviewed. Several articles compared cemented femoral stems to fracture fixation. There were few articles comparing cemented and uncemented stems. Some noted increased problems with uncemented stems but did consider design factors. Unreamed tapered stems may have may have fewer problems. Prospective studies comparing cemented and uncemented femoral stems are needed to determine the best form of fixation for patients having hip surgery following hip fracture. Tapered uncemented stems may offer as good a result as cemented stems, with less morbidity.


Design, synthesis and characterization of novel quinacrine analogs that preferentially kill cancer over non-cancer cells through the down-regulation of Bcl-2 and up-regulation of Bax and Bad.
Both quinacrine, which contains a 9-aminoacridine scaffold, and thiazolidin-4-one are promising anticancer leads. In an attempt to develop effective and potentially safe anticancer agents, we synthesized 23 novel hybrid compounds by linking the main structural unit of the 9-aminoacridine ring with the thiazolidin-4-one ring system, followed by examination of their anticancer effects against three human breast tumor cell lines and matching non-cancer cells. Most of the hybrid compounds showed good activities, and many of them possessed the preferential killing property against cancer over non-cancer cells. In particular, 3-[3-(6-chloro-2-methoxy-acridin-9-ylamino)-propyl]-2-(2,6-difluoro-phenyl)-thiazolidin-4-one (11; VR118) effectively killed/inhibited proliferation of cancer cells at IC50 values in the range of 1.2-2.4 μM. Furthermore, unlike quinacrine or cisplatin, compound 11 showed strong selectivity for cancer cell killing, as it could kill cancer cells 7.6-fold (MDA-MB231 vs MCF10A) to 14.7-fold (MCF7 vs MCF10A) more effectively than matching non-cancer cells. Data from flow cytometry, TUNEL and Western blot assays showed that compound 11 kills cancer cells by apoptosis through the down-regulation of Bcl-2 (but not Bcl-XL) survival protein and up-regulation of Bad and Bax pro-apoptotic proteins. Thus, compound 11 is a highly promising lead for an effective and potentially anticancer therapy.


Janus kinase (JAK) 2 V617F mutation in Asian Indians with cerebral venous thrombosis and without overt myeloproliferative disorders.
It is unclear whether the somatic JAK2V617F mutation, a marker for chronic myeloproliferative disorders (MPDs), is associated with cerebral venous thrombosis (CVT) in the absence of MPD. Our aim was to determine the prevalence and association of the JAK2V617F mutation among patients with CVT and without overt MPD. We investigated 372 CVT patients without features suggestive of MPD and 383 age- and gender-matched healthy controls, for the JAK2V617F mutation. Genotyping was done by polymerase chain reaction and restriction fragment length polymorphism. The heterozygous JAK2V617F mutation was present in 22 of 372 patients (5.9%) and 2 of 383 controls (0.5%). Logistic regression analysis showed this mutation to be an independent predictor of CVT after adjusting for the conventional risk factors (adjusted odds ratio: 5.47, 95% CI: 1.06-28.27, p=0.04). The mutation was more prevalent in men (p=0.005). Patients with JAK2V617F mutation were older (p=0.036), and had higher mean hemoglobin level (p<0.0001) than those without the mutation. Smokers with the mutation had 9.45-fold increased risk of CVT compared to non-smokers without the mutation (OR: 9.45, 95% CI: 1.17-76.02, p<0.0001). We conclude that the JAK2V617F mutation could contribute to increased risk of CVT in Indians. Larger studies in other ethnic populations are warranted before considering the inclusion of the JAK2V617F gene polymorphism into the routine diagnostic workup of CVT.


Color-stabilizing effect of lactate on ground beef is packaging-dependent.
Previous research on lactate-induced color stability in ground beef did not address the potential influence of packaging. The objective of the present study was to examine the effects of lactate on the color stability of ground beef patties stored in different modified atmosphere packaging (MAP) systems. Ground beef patties with either 2.5% potassium lactate or no lactate were packaged in vacuum (VP), high-oxygen MAP (HIOX; 80% O(2)+20% CO(2)), carbon monoxide MAP (CO; 0.4% CO+19.6% CO(2)+80% N(2)), or aerobic packaging (PVC) and stored for 0, 2, or 4 days at 2 degrees C. Lactate-treated patties were darker (P<0.05; lower L * values) than control patties. Surface redness (a * values) was greater (P<0.05) for lactate patties than the controls when stored in PVC, HIOX, and VP. However, lactate's effects on a * values were not evident when packaged in CO (P>0.05). The color-stabilizing effect of CO could have masked lactate's effect on surface redness. While lactate patties in PVC and VP demonstrated lower (P<0.05) discoloration than controls, no differences (P>0.05) existed between controls and lactate samples in CO and HIOX. Our results indicated that the effects of lactate on ground beef color are dependent on packaging.


Antidepressant use and cognitive decline in community-dwelling elderly people - The Three-City Cohort.
Cognitive impairment is very common in late-life depression, principally affecting executive skills and information processing speed. The aim of the study was to examine the effect of antidepressant treatment on cognitive performances over a 10-year period. The community-based cohort included 7381 participants aged 65 years and above. Five cognitive domains (verbal fluency, psychomotor speed, executive function, visuospatial skills and global cognition) were assessed up to five times over 10 years of follow-up. Treatment groups included participants under a specific antidepressant class at both baseline and the first follow-up and their follow-up cognitive data were considered until the last consecutive follow-up with a report of antidepressant use of the same class. Linear mixed models were used to compare baseline cognitive performance and cognitive decline over time according to antidepressant treatment. The models were adjusted for multiple confounders including residual depressive symptoms assessed by the Center for Epidemiologic Studies-Depression scale. At baseline, 4.0% of participants were taking antidepressants. Compared to non-users, tricyclic antidepressant users had lower baseline performances in verbal fluency, visual memory and psychomotor speed, and selective serotonin reuptake inhibitor users in verbal fluency and psychomotor speed. For the two other cognitive abilities, executive function and global cognition, no significant differences were found at baseline irrespective of the antidepressant class. Regarding changes over time, no significant differences were observed in comparison with non-users whatever the cognitive domain, except for a slight additional improvement over the follow-up in verbal fluency skills for tricyclic antidepressant users. In this large elderly general population cohort, we found no evidence for an association between antidepressant use and post-treatment cognitive decline over 10 years of follow-up in various cognitive domains.


Manganese dioxide driven the carbon and nitrogen transformation by activating the complementary effects of core bacteria in composting.
This study revealed core bacterial metabolic mechanisms involved in carbon (C) and nitrogen (N) in composting with adding MnO2. Two tests (control group (CK), adding MnO2 (M)) were performed. The results indicated that the MnO2 accelerated the transformation of carbon and nitrogen in composting. Core bacteria involved in the C and N conversion were identified, the complementarity effects of core bacteria were stimulated in M composting. Additionally, the influence of core bacteria on the C and N conversion could be divided into two pathways in M composting. One was that core bacteria promoted C and N conversion by accelerating the flow of amino acids into the tricarboxylic acid cycle. Another was that the complementarity effects of core bacteria increased the overall bacterial diversity, which contributed to C and N conversion. These findings showed that the addition of MnO2 to composting was a promising application to treat agricultural organic waste.


Viral Contagion and Anti-Terrorism: Notes on Medical Emergency, Legality and Diplomacy.
The dominant imagery in current international relations seems to betray the emergence of an imperialist imaginary that differs markedly from an earlier one. This paper traces the main outlines of this emerging imaginary that has left notions of Empire as spheres of integrative production firmly behind, and is now geared towards imagining Empire as a complete, organic body of free-but-organic-and-therefore-orderly flows that however needs to be kept intact by means of epidemiological interventions aimed at excluding or neutralizing viral entities. Dealing with terrorism, or invading states that allegedly breed them, in this imaginary, is first and foremost a matter of medical necessity and urgency. The legal and diplomatic 'logic' of UN resolutions (Resolution 1441 for example), in this imaginary space, can only be imagined as being of secondary importance. Cooperation and `cosmopolitan' negotiation, as alternatives, disappear in this imaginary that projects an imperialist globalism of epidemiological purity.


Choice of anesthetic agents for peribulbar anesthesia.
To determine the effectiveness of various combinations of lidocaine, epinephrine, and hyaluronidase with bupivacaine, a prospective, randomized, masked study on 117 patients having cataract extraction under local anesthesia was undertaken. All patients were given a 9 ml peribulbar block by one surgeon, and a graded assessment of analgesia and akinesia was made in a masked fashion one hour later. A mixture using all these agents gave significantly better results than any of the combinations (P = .001). No single agent was shown to be the major determinant of effectiveness. The result suggests a synergistic effect found only when all the agents are combined.


Limb salvage procedure for neoplasms about the knee by spherocentric total knee arthroplasty and autogenous autoclaved bone grafting.
Spherocentric total joint arthroplasty was performed for treatment of neoplasm in 15 patients. The average follow-up period was 30 months. In nine of the patients concomitant autoclaved autologous bone implants were also prepared from the resected specimens. The results were satisfactory in ten patients and unsatisfactory in five. One patient had an infection that required amputation. One patient with osteosarcoma had a recurrence at 20 months and was treated by amputation. Poor results were caused by stem failure in two patients and by component loosening in one patient. Total joint arthroplasty combined with autoclaved bone implantation is a useful limb salvage procedure for resected neoplasms about the knee.


Mawangdui-Guidance Qigong Exercise for patients with chronic non-specific low back pain: Study protocol of a randomized controlled trial.
Worldwide, there is a high frequency of chronic non-specific low back pain (CNLBP), which is a significant public health concern. The etiology is complicated and diverse, and it includes a number of risk factors such as diminished stability and weak core muscles. Mawangdui-Guidance Qigong has been employed extensively to bolster the body in China for countless years. However, the effectiveness of treating CNLBP has not been assessed by a randomized controlled trial (RCT). In order to verify the results of the Mawangdui-Guidance Qigong Exercise and examine its biomechanical mechanism, we intend to perform a randomized controlled trial. Over the course of 4 weeks, 84 individuals with CNLBP will be randomly assigned to receive either Mawangdui-Guidance Qigong Exercise, motor control exercise, or medication (celecoxib). Electromyographic data, including muscle activation time, iEMGs, root mean square value (RMS) and median frequency (MF), will be the main outcomes. The Japanese Orthopedic Association (JOA) Score, the Mcgill Pain Questionnaire (MPQ), beta-endorphin, and substance P are examples of secondary outcomes. At the start of treatment and 4 weeks later, all outcomes will be evaluated. SPSS version 20.0 (SPSS Inc., Chicago, IL, USA) will be used for all of the analysis. The prospective findings are anticipated to offer an alternative treatment for CNLBP and provide a possible explanation of the mechanism of Mawangdui-Guidance Qigong Exercise on CNLBP. The Sichuan Regional Ethics Review Committee on Traditional Chinese Medicine has given the study approval (Approval No. 2020KL-067). It has also registered at the website of China Clinical Trial Center Registration. The application adheres to the Declaration of Helsinki's tenets (Version Edinburgh 2000). Peer-reviewed papers will be used to publicize the trial's findings. ClinicalTrials.gov, identifier ChiCTR2000041080.


A novel biphenyl diester derivative, AB38b, inhibits glioblastoma cell growth via the ROS-AKT/mTOR pathway.
AB38b is a novel biphenyl diester derivative synthesized in our laboratory, and it has been shown to improve the pathology of nephropathy and encephalopathy in diabetic mice. Glioblastoma (GBM) is the most lethal brain tumor, without effective drugs to date. The present study aims at investigating the role of AB38b in GBM growth and revealing the underlying molecular mechanisms. We found that AB38b administration showed a dose- and time-dependent inhibition on cell proliferation in multiple immortalized and primary GBM cell lines, but it had no significant effects on human astrocyte cell line. More importantly, AB38b blocked cell cycle progression, induced early apoptosis, decreased the activity of AKT/mTOR pathway, and increased the generation of reactive oxygen species (ROS) in GBM cells. Interestingly, antioxidant treatments could reverse the AB38b-mediated abovementioned effects; overexpression of constitutively active AKT could partially rescue the suppressive effects of Ab38b on GBM cell proliferation. In addition, AB38b administration inhibited the tumor growth, decreased the activity of AKT/mTOR pathway, and prolonged the survival time in GBM animal models, without any adverse influences on the important organs. These findings suggest that AB38b exerts anti-glioma activity via elevating the ROS generation followed by inhibiting the activity of AKT/mTOR pathway.


Alternatives Exert Higher Health Risks than Bisphenol A on Indo-Pacific Humpback Dolphins.
The detrimental effects of bisphenol (BP) exposure are a concern for vulnerable species, Indo-Pacific humpback dolphins (Sousa chinensis). To investigate the characteristics of BP profiles and their adverse impact on humpback dolphins, we assessed the concentrations of six BPs, including bisphenol A (BPA), bisphenol S (BPS), bisphenol F (BPF), bisphenol AF (BPAF), bisphenol B (BPB), and bisphenol P (BPP) in blubber (n = 26) and kidney (n = 12) of humpback dolphins stranded in the Pearl River Estuary, China. BPS accounted for the largest proportion of the total bisphenols (∑BPs) in blubber (55%) and kidney (69%). The concentration of ∑BP in blubber was significantly higher than that in the kidney and liver. The EC50 values of five BPA alternatives were lower than those of BPA in humpback dolphin skin fibroblasts (ScSF) and human skin fibroblasts (HSF). ScSF was more sensitive to BPS, BPAF, BPB, and BPP than HSF. The enrichment pathway of BPA was found to be associated with inflammation and immune dysregulation, while BPP and BPS demonstrated a preference for genotoxicity. BPA, BPP, and BPS, which had risk quotients (RQs) > 1, were found to contribute to subhealth and chronic disease in humpback dolphins. According to the EC50-based risk assessment, BPS poses a higher health risk than BPA for humpback dolphins. This study successfully evaluated the risks of bisphenols in rare and endangered cetacean cell lines using a noninvasive method. More in vivo and in field observations are necessary to know whether the BPA alternatives are likely to be regrettable substitutions.


[Effect of aflatoxin on the serum profile and antibody formation in chickens].
Experiments were carried out to follow up the effect of aflatoxin on the production of hemagglutinating antibodies in birds vaccinated against Newcastle disease and the changes in the serum profile. Birds that had been given a feed mixture with 560 and 640 mcg per kg for 20 days showed a lower titer of hemagglutinating antibodies and a drop of the alpha1, alpha2, beta1, gamma2-globulin fractions as well as a rise of the albumin and gamma1-globulin fractions. The liver and kidneys of the treated birds showed dystrophic changes.


Short-term outcomes of reduced-port laparoscopic surgery versus conventional laparoscopic surgery for total gastrectomy: a single-institute experience.
The efficacy of reduced-port laparoscopic surgery (RLS) for total gastrectomy remains unclear. This study focused on evaluating the short-term outcomes of RLS compared with conventional laparoscopic surgery (CLS) for total gastrectomy. One hundred and ten patients who underwent completed laparoscopic total gastrectomy for gastric cancer between September 2018 and June 2022 were retrospectively collected and classified into two groups (65 CLS and 45 RLS) according to different operation approach. Twenty-four RLS cases underwent single-incision plus two ports laparoscopic surgery (SILS + 2) and twenty-one underwent single-incision plus one port laparoscopic surgery (SILS + 1). Surgical outcomes, pain intensity, cosmetic and postoperative morbidity, and mortality were compared between groups. The overall incidence of postoperative complications was similar between the CLS group and the RLS group (16.9% vs. 8.9%, P = 0.270). It was also comparable in the Clavien-Dindo classification (P = 0.774). However, compared with the CLS group, the RLS group had a significantly shorter total length of incision (5.6 ± 1.0 cm vs. 7.1 ± 0.7 cm, P = 0.000); shorter time to first ambulation (24.9 ± 5.9 h vs. 27.6 ± 5.0 h, P = 0.009), flatus (3.0 ± 0.8 d vs. 3.5 ± 1.0 d, P = 0.022) and oral intake (4.0 ± 1.6 d vs. 6.1 ± 5.1 d, P = 0.011); lower white blood cell count on the third day after the operation (9.8 ± 4.0*109/L vs. 11.6 ± 4.7*109/L, P = 0.037); and lower visual analogue scale score on postoperative days 1 and 3(3.0 ± 0.7 vs. 3.3 ± 0.7, P = 0.044 and 0.6 ± 0.7 vs. 1.6 ± 0.6, P = 0.000 respectively). On the other hand, it didn't find any difference in short-term outcomes between the SILS + 2 group and the SILS + 1 group (P > 0.05). But the proximal resection margin was longer in the SILS + 2 group than in the SILS + 1 group (2.6 ± 0.7 cm vs. 1.5 ± 0.9 cm, P = 0.046) in patients with adenocarcinoma of the esophagogastric junction (AEG). RLS for total gastrectomy is a feasible and safe technique when performed by an experienced laparoscopic surgeon. Moreover, compared with SILS + 1, SILS + 2 might have some advantages in AEG patients.


Effective communication of drug safety information to patients and the public: a new look.
Recent parallel developments in the fields of medicine and the social sciences are providing us with new insights and resources that have the potential for improving the effectiveness of drug safety communication and decision-making. These developments include medicine's new look at patient safety with its emphasis on complex adaptive systems, education's new appreciation for learning as an internal change process and risk communication's evolving recognition that relevant knowledge may not be the exclusive property of 'experts'. Eight principles are drawn from this analysis: there cannot be a safer drug until there is a safer system;all stakeholders are equal partners and have an equal voice in all deliberations;paternalism must be eliminated;the expertise for determining acceptable benefit and risk is dispersed throughout society;patients and all stakeholders serve as both teachers and learners;all stakeholders are involved in the identification of their learning needs, processes and evaluation of outcomes;in a complex adaptive system all individual actions are interconnected and;patients must be involved in the continuous feedback and redesign of the evolving drug safety information system. The conclusion is that we are not asking the right questions; 'what information should we communicate?' and 'how do we communicate more effectively?' should be reframed to ask 'how do we provide an equal voice for patients with the other stakeholders in the determination and communication of benefit-risk information?' Some patients are not waiting. The International Alliance of Patient Organizations (IAPO), the Database of Individual Patient Experience (Dipex) and the Self-Help Group Clearinghouse are examples of international patient driven efforts to actively participate in their own care. The author suggests that the emerging discipline of inter-active management can contribute methodologies for creating citizenship models to generate the collective wisdom and translate it into action. A future research agenda calls for creating new models of public accountability that support these evolving systems of engaging the entire community in benefit-risk determination, communication and management.


Haemophilus influenzae abscess presenting as an asymptomatic lung mass.
We report the radiographic and computed tomographic findings in an asymptomatic patient who had a Haemophilus influenzae lung abscess. The diagnosis was made by Gram's staining and culture of abscess material obtained by transthoracic needle aspiration. The radiographic abnormalities cleared after specific antimicrobial therapy.


Computational design and modeling of nanobodies toward SARS-CoV-2 receptor binding domain.
The ongoing pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global health concern and pose a serious threat to humanity. There is an urgent need for developing therapeutic drugs and (or) biologics to prevent the spread of the virus. The life cycle of SARS-CoV-2 shows that the virus enters host cells by first binding to angiotensin-converting enzyme 2 (ACE2) through its spike protein receptor-binding domain (RBD). Therefore, blocking the binding between of ACE2 and SARS-CoV-2 RBD can inhibit the virus infection in the host cells. In this study, by grafting the complementarity-determining regions (CDRs) of developed SARS-CoV, MERS-CoVs specific neutralizing antibodies (nAbs) include monoclonal antibodies (mAbs) as well as SARS-CoV-2 mAbs onto a known stable nanobody (Nb) scaffold, and a total of 16 Nbs sequences were designed. Five Nbs, namely CS01, CS02, CS03, CS10, and CS16, were selected based on the free energy landscape of protein docking verified by the recently reported Nb-RBD cocrystal structures. CS01, CS02, and CS03 occupied the ACE2 binding site of RBD, while CS10 and CS16 were proposed to inhibit the interaction between RBD and ACE2 through an allosteric mechanism. Based on the structures of the five Nbs in complex with RBD, seven brand-new Nbs with enhanced binding affinities (CS02_RD01, CS03_RD01, CS03_RD02, CS03_RD03, CS03_RD04, CS16_RD01, and CS16_RD02) were generated by redesign of residues on the interface of the five Nbs contact with SARS-CoV-2 RBD. In addition, the identified "hot spots" on the interface of each complex provide useful information to understand the binding mechanism of designed Nbs to SARS-CoV-2 RBD. In sum, the predicted stabilities and high binding affinities of the 11 (re)designed Nbs indicating the potential of the developed computational framework in this work to design effective agents to block the infection of SARS-CoV-2.


Manipulating Electric Double Layer Adsorption for Stable Solid-Electrolyte Interphase in 2.3 Ah Zn-Pouch Cells.
Constructing a reliable solid-electrolyte interphase (SEI) is imperative for enabling highly reversible zinc metal (Zn0 ) electrodes. Contrary to conventional "bulk solvation" mechanism, we found the SEI structure is dominated by electric double layer (EDL) adsorption. We manipulate the EDL adsorption and Zn2+ solvation with ether additives (i.e. 15-crown-5, 12-crown-4, and triglyme). The 12-crown-4 with medium adsorption on EDL leads to a layer-structured SEI with inner inorganic ZnFx /ZnSx and outer organic C-O-C components. This structure endows SEI with high rigidness and strong toughness enabling the 100 cm2 Zn||Zn pouch cell to exhibit a cumulative capacity of 4250 mAh cm-2 at areal-capacity of 10 mAh cm-2 . More importantly, a 2.3 Ah Zn||Zn0.25 V2 O5 ⋅n H2 O pouch cell delivers a recorded energy density of 104 Wh Lcell -1 and runs for >70 days under the harsh conditions of low negative/positive electrode ratio (2.2 : 1), lean electrolyte (8 g Ah-1 ), and high-areal-capacity (≈13 mAh cm-2 ).


Generation of Protein Inhibitors for Validation of Cancer Drug Targets Identified in Functional Genomic Screens.
Functional genomic screens can identify several proteins as potential targets for drug development in cancer. Typically, these drug targets are validated with pharmacological inhibition using small molecules. Given that chemical inhibitors do not exist for a many of these proteins, several promising candidates often remain unexplored. In this chapter, we describe methods for generating protein-based inhibitors of intracellular targets using phage display. This is a scalable and inexpensive approach that can be applied to several protein targets identified in genetic screens. We describe methods for expression of target proteins, construction of phage-display libraries and selection of binding proteins. These synthetic binding proteins can block natural protein interactions within the cancer cell and act as inhibitors. Protein inhibitors have utility in validation of drug targets and can also guide small-molecule drug development.


Microvasculature in the small portal tracts in idiopathic portal hypertension. A morphological comparison with other hepatic diseases.
The morphology of the microvasculature in the small portal tracts was examined in normal livers, idiopathic portal hypertension (IPH) and other hepatic diseases. The microvasculature examined was arbitrary divided into two groups: that near the limiting plate and that within portal tracts, particularly around bile ducts. Based on comparisons of histology, immunohistochemistry and vascular casts, it is suggested that the former corresponded to inlet venules and the latter to distributing portal veins and peribiliary capillary plexus. Both of these microvasculatures were positive for Ulex europaeus lectin I, and (infrequently and weakly) for factor VIII-related antigen. Morphometry disclosed that inlet venules were reduced in number in IPH compared with normal livers and that distributing portal veins, peribiliary capillary plexus and inlet venules were increased in extrahepatic portal obstruction, chronic active hepatitis and extrahepatic obstructive cholestasis. We believe that the change in the microvasculature reflects abnormal microcirculation in the small portal tracts, and that the reduction of inlet venules plays an important role in the development of portal hypertension in IPH.


Impact of ibuprofen and peroxisome proliferator-activated receptor gamma on emotion-related neural activation: A randomized, placebo-controlled trial.
Nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen have shown initial promise in producing antidepressant effects. This is perhaps due to these drugs being peroxisome proliferator-activated receptor gamma (PPARγ) agonists, in addition to their inhibition of cyclooxygenase enzymes. Some, albeit mixed, evidence suggests that PPARγ agonists have antidepressant effects in humans and animals. This double-blind, placebo-controlled, pharmacologic functional magnetic resonance imaging (ph-fMRI) study aimed to elucidate the impact of ibuprofen on emotion-related neural activity and determine whether observed effects were due to changes in PPARγ gene expression. Twenty healthy volunteers completed an emotional face matching task during three fMRI sessions, conducted one week apart. Placebo, 200 mg, or 600 mg ibuprofen was administered 1 h prior to each scan in a pseudo-randomized order. Peripheral blood mononuclear cells were collected at each session to isolate RNA for PPARγ gene expression. At the doses used, ibuprofen did not significantly change PPARγ gene expression. Ibuprofen dose was associated with decreased blood oxygen level-dependent (BOLD) activation in the dorsolateral prefrontal cortex and fusiform gyrus during emotional face processing (faces-shapes). Additionally, PPARγ gene expression was associated with increased BOLD activation in the insula and transverse and superior temporal gyri (faces-shapes). No interaction effects between ibuprofen dose and PPARγ gene expression on BOLD activation were observed. Thus, results suggest that ibuprofen and PPARγ may have independent effects on emotional neurocircuitry. Future studies are needed to further delineate the roles of ibuprofen and PPARγ in exerting antidepressant effects in healthy as well as clinical populations.


MCU-induced mitochondrial calcium uptake promotes mitochondrial biogenesis and colorectal cancer growth.
Mitochondrial calcium uniporter (MCU) has an important role in regulating mitochondrial calcium (Ca2+) homeostasis. Dysregulation of mitochondrial Ca2+ homeostasis has been implicated in various cancers. However, it remains unclear whether MCU regulates mitochondrial Ca2+ uptake to promote cell growth in colorectal cancer (CRC). Therefore, in the present study the expression of MCU in CRC tissues and its clinical significance were examined. Following which, the biological function of MCU-mediated mitochondrial Ca2+ uptake in CRC cell growth and the underlying mechanisms were systematically evaluated using in in vitro and in vivo assays, which included western blotting, cell viability and apoptosis assays, as well as xenograft nude mice models. Our results demonstrated that MCU was markedly upregulated in CRC tissues at both the mRNA and protein levels. Upregulated MCU was associated with poor prognosis in patients with CRC. Our data reported that upregulation of MCU enhanced the mitochondrial Ca2+ uptake to promote mitochondrial biogenesis, which in turn facilitated CRC cell growth in vitro and in vivo. In terms of the underlying mechanism, it was identified that MCU-mediated mitochondrial Ca2+ uptake inhibited the phosphorylation of transcription factor A, mitochondrial (TFAM), and thus enhanced its stability to promote mitochondrial biogenesis. Furthermore, our data indicated that increased mitochondrial Ca2+ uptake led to increased mitochondrial production of ROS via the upregulation of mitochondrial biogenesis, which subsequently activated NF-κB signaling to accelerate CRC growth. In conclusion, the results indicated that MCU-induced mitochondrial Ca2+ uptake promotes mitochondrial biogenesis by suppressing phosphorylation of TFAM, thus contributing to CRC cell growth. Our findings reveal a novel mechanism underlying mitochondrial Ca2+-mediated CRC cell growth and may provide a potential pharmacological target for CRC treatment.


Effects of melatonin on performance testing in patients with seasonal affective disorder.
Psychomotor performance and memory were assessed in 6 patients with seasonal affective disorder following one week of daily administration of oral melatonin. No effect was noted on either vigilance or memory testing, but reaction time on a simple visual/tactile task was significantly reduced. Identical testing following a week of placebo administration showed no changes from baseline. Clinical status was monitored by both observer and self ratings; no clinical changes were detected that could account for the performance difference. The reaction time finding is in contrast to a previous report of a reaction time increase following melatonin administration. We discuss the possibility that this discrepancy is due to different dosages of melatonin administered or to the effects of melatonin on circadian rhythms of performance.


(2-Chloro-3,5-dinitro-phen-yl)(piperidin-1-yl)methanone.
In the title compound, C(12)H(12)ClN(3)O(5), the piperidine ring adopts a chair conformation. One of the nitro groups is almost coplanar with the aromatic ring [O-N-C-C = -1.4 (2)°], whereas the other one is significantly twisted out of the ring plane [O-N-C-C = 34.7 (2)°]. The crystal packing is stabilized by inter-molecular π-π stacking inter-actions with centroid-centroid distances of 3.579 (3) Å.


Bilateral simulataneous kidney tumors of dissimilar cell type: a case report with emphasis on operative approach.
The first reported case of bilateral, simultaneous renal tumors of dissimilar cell type treated in a living patient is presented. The operative approach is outlined to support single in situ operative procedures in young patients. A second look laparotomy at 1 year and a creatinine clearance of 60 ml. per minute at 2 years substantiate our enthusiasm for this approach to bilateral renal lesions.


A Boxed Warning for Montelukast: The FDA Perspective.
The U.S. Food and Drug Administration (FDA) became aware of postmarketing reports of neuropsychiatric adverse events with Singulair (montelukast) use in 2007. Over the years, the FDA has conducted reviews of the clinical trial safety data, focused analyses of postmarketing reports, and reviews of the published literature. These activities have resulted in successive labeling updates and public communications. However, there has been continued concern among stakeholders about the risk of neuropsychiatric events and the lack of awareness among prescribers and patients/caregivers. On the basis of these concerns, the FDA embarked on another comprehensive review and also conducted a new observational study using claims data in the Sentinel Distributed Database. In September 2019, the FDA held a public Advisory Committee meeting to discuss its review and solicit recommendations from the panel regarding labeling and communication strategies. After careful consideration of the available data and feedback received during the FDA Advisory Committee meeting, the FDA required a boxed warning and a revision specifically for the allergic rhinitis indication to reserve use of montelukast to patients who have an inadequate response or intolerance to alternative therapies. Based on benefit-risk considerations, the asthma indication was not changed. To provide insight into the process and rationale for the required labeling changes, we provide an overview of the decision-making framework we used.


Association of maternal HDL2-c concentration in the first trimester and the risk of large for gestational age birth.
Maternal lipid levels during pregnancy are critical for fetal development. Recent studies revealed that high-density lipoprotein cholesterol (HDL-c) levels during pregnancy were negatively correlated with birthweight. High-density lipoprotein 2 cholesterol (HDL2-c) is one of the major subclasses of HDL-c, and its relationship with birthweight is unclear. Association of HDL2-c concentration in the first trimester and risk of large for gestational age (LGA) was explored. This study recruited pregnant women who registered in Fuxing Hospital from October 2018 to January 2020, had regular obstetric examinations during pregnancy, and delivered between June 2019 and September 2020. Finally, 549 participants were recruited for the study. Maternal demographic characteristics and venous blood were collected at the 6th-14th gestational week, and serum total cholesterol (TC), triglyceride (TG), HDL-c, HDL2-c, high-density lipoprotein 3 cholesterol (HDL3-c), and low-density lipoprotein cholesterol (LDL-c) concentrations were detected. Neonatal characteristics were collected at delivery. A logistic regression model was used to explore the relationship between the first trimester HDL2-c concentration and LGA incidence. A nomogram was developed, and the performance was evaluated with a concordance index. Seventy-five mothers delivered LGA infants, and the LGA incidence was 13.66%. LGA mothers had significantly lower serum HDL-c and HDL2-c concentrations than appropriate for gestational age (AGA) mothers. A logistic regression model showed that HDL2-c concentration was negatively correlated with LGA risk (odds ratio (OR) = 0.237, 95% confidence intervals (CI): 0.099-0.567, P = 0.001) when adjusted for age, prepregnancy body mass index (BMI), and parity. A nomogram was generated using all these risk factors. The area under the curve (AUC) was 0.663 (95% CI: 0.593-0.732). Maternal HDL2-c concentration in the first trimester was negatively correlated with the risk of LGA.


Regeneration of motor axons in crayfish limbs: distal stump activation followed by synaptic reformation.
Severed distal stumps of limb motor axons in the crayfish Procambarus clarkii remain ultrastructurally intact for at least 2-3 ms after being severed from their cell body. Initial regeneration of a motor axon is associated with the appearance of up to 200 small profiles (satellite axons) having no glial sheath adjacent to the large surviving stump for about 1 cm distal to the lesion at 4-5 wks postoperatively. These satellite axons are seen 2-4 cm distally at the target muscles 3-4 ms postoperatively. By 14-15 ms postoperative, the motor sheaths from the lesion site to the target muscles contain small axonal processes having thick glial sheaths. Behavioral tests show that some axons that are reconnected to the CNS at 4-5 wks may not be connected at 14-15 ms, whereas other axons not connected by 3-4 ms may be connected at 14-15 ms when the original distal stumps have degenerated. We suggest that all these data can best be explained by the view that motor axons in crayfish limbs initially regenerate via activation of the surviving distal stump by satellite axons which grow out from proximal stump. In most cases, these satellite axons continue to activate the surviving distal stump as they slowly grow to the target muscle. Eventually the satellite axons reform synapses on the target muscle and the original distal stump degenerates.


Some distinctions between flavin-containing and cytochrome P450 monooxygenases.
This minireview summarizes information concerning the differences and similarities of the human flavin-containing- (FMO, E.C. 184.108.40.206) and the cytochrome P450-monooxygenases (CYP, E.C. 22.214.171.124). Human FMO oxygenates soft nucleophiles. CYP mainly catalyzes C-H abstraction but also oxidizes nitrogen- and sulfur-containing compounds. Both FMO and CYP generally convert lipophilic compounds into more hydrophilic metabolites. The mechanism by which each monooxygenase operates is quite distinct. Sometimes, CYP or FMO bioactivate chemicals to reactive metabolites but to date, drug toxicity thus far observed in the clinic is mainly the result of CYP-dependent oxidation. Both FMO and CYP possess genetic variability that may contribute to inter-individual variability observed for drug metabolism. In contrast to CYP, FMO is not induced or readily inhibited and potential adverse drug-drug interactions are minimized for drugs prominently metabolized by FMO. These properties may provide advantages in drug design, and by incorporating FMO detoxication pathways into drug candidates, more drug-like materials may emerge.


Mutations in TLR4 signaling that lead to increased susceptibility to infection in humans: an overview.
In this overview, we will present current information on known mutations in the TLR4 signaling pathway that have been associated with increased susceptibility to disease. To date, mutations in the extracellular domain of TLR4 itself, IRAK-4, NEMO (IKK gamma), and I kappa B alpha have been identified and profoundly affect the host response to infection.


Clinical impact of pharmacist-led antibiotic stewardship programs in outpatient settings in the United States: A scoping review.
To provide an overview of the impact of pharmacist interventions on antibiotic prescribing and the resultant clinical outcomes in an outpatient antibiotic stewardship program (ASP) in the United States. Reports on studies of pharmacist-led ASP interventions implemented in US outpatient settings published from January 2000 to November 2020 and indexed in PubMed or Google Scholar were included. Additionally, studies documented at the ClinicalTrials.gov website were evaluated. Study selection was based on predetermined inclusion criteria; only randomized controlled trials, observational studies, nonrandomized controlled trials, and case-control studies conducted in outpatient settings in the United States were included. The primary outcome was the observed differences in antibiotic prescribing or clinical benefits between pharmacist-led ASP interventions and usual care. Of the 196 studies retrieved for full-text review, a cumulative total of 15 studies were included for final evaluation. Upon analysis, we observed that there was no consistent methodology in the implementation of ASPs and, in most cases, the outcome of interest varied. Nonetheless, there was a trend toward improvement in antibiotic prescribing with pharmacist interventions in ASPs compared with that under usual care (P < 0.05). However, the results of these studies are not easily generalizable. Our findings suggest a need for a consistent approach for the practical application of outpatient pharmacist-led ASPs. Managed care organizations could play a significant role in ensuring the successful implementation of pharmacist-led ASPs in outpatient settings.


Chronic pain is common and worsens daytime sleepiness, insomnia, and quality of life in veterans with obstructive sleep apnea.
Chronic noncancer pain (CP) commonly co-occurs with obstructive sleep apnea (OSA) and may contribute to greater symptom burden. The study aims were to (1) characterize CP among veterans with OSA and (2) examine differences in sleepiness (Epworth Sleepiness Scale), insomnia symptoms (Insomnia Severity Index), and quality of life (Short Form Health Survey-20) in veterans with OSA with or without pre-existing CP. An observational, cross-sectional, study of 111 veterans with newly diagnosed, untreated OSA was conducted. Descriptive statistics characterized the sample and comorbid CP outcomes. Regression analyses were performed to investigate associations between self-reported CP and sleep-related symptoms or quality of life while controlling for potential confounders. CP was reported by 69.5% (95% confidence interval: 61.8%, 76.2%) of participants. Having CP was associated with increased Epworth Sleepiness Scale (12.7 ± 5.5 vs 10.2 ± 5.2; P = .021) and Insomnia Severity Index scores (18.1 ± 6.2 vs 13.7 ± 7.4; P = .002), and worse quality of life across all Short Form Health Survey-20 domains. There is a high prevalence of CP among veterans with OSA and symptom burden is higher in patients with OSA and CP. Future investigations should address symptom response and burden to OSA treatment in comorbid OSA and CP to guide outcome expectancies and residual OSA symptom treatment plans. Saconi B, Kuna ST, Polomano RC, Compton PA, Keenan BT, Sawyer AM. Chronic pain is common and worsens daytime sleepiness, insomnia, and quality of life in veterans with obstructive sleep apnea. J Clin Sleep Med. 2023;19(6):1121-1132.


Iron Fenton oxidation of 2'-deoxyguanosine in physiological bicarbonate buffer yields products consistent with the reactive oxygen species carbonate radical anion not the hydroxyl radical.
Product analysis from the iron Fenton oxidation of 2'-deoxyguanosine found reactions in bicarbonate buffer yield 8-oxo-2'-deoxyguanosine and spiroiminodihyantoin consistent with CO3˙-. Reactions in phosphate buffer furnished high yields of sugar oxidation products consistent with HO˙. These observations change the view of DNA oxidation products from the iron-Fenton reaction.


Antituberculosis drug resistance and anonymous HIV surveillance in tuberculosis patients in Botswana, 2002.
Two surveys undertaken in Botswana in the 1990s have recorded low rates of antituberculosis drug resistance, despite a three-fold rise in tuberculosis since 1989. We undertook a third survey to determine both trends since 1995 and HIV prevalence in tuberculosis patients in Botswana. Sputum specimens were obtained from patients nationwide in 2002 who also underwent anonymous, rapid HIV testing by use of Oraquick. Of 2200 sputum smear-positive patients and 219 previously treated patients with suspected recurrent tuberculosis, 1457 (60%) were infected with HIV. Resistance to at least one drug in new patients rose from 16 (3.7%) isolates in 1995 to 123 (10.4%; p<0.0001) in 2002. Interventions for tuberculosis control are urgently needed in Botswana to prevent further emergence of drug resistance.


Acute liver failure in Still's disease relapse during pregnancy: case report and discussion of a possible trigger role of DILI.
Still's disease is a rare systemic inflammatory disease with frequent but generally mild liver involvement. The most common cause of acute liver failure in western countries is drug-induced liver injury, while it has rarely been reported in subjects suffering from Still's disease. We report a case of a young woman presenting with SD reactivation in pregnancy and acute liver failure after delivery with a possible triggering role of drug induced liver injury. The prompt recognition of Still's disease reactivation allowed early introduction of steroid therapy and resolution of the clinical picture. We discuss potential factors precipitating ALF in this case, and implications for the diagnosis and management of such patients.


The effects of plasma viscosity in thromboembolic events among patients with essential thrombocytosis: A case-control study.
Essential thrombocythemia (ET) is an entity of classic Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs), characterized by thrombocytosis with megakaryocytic hyperplasia where in the thrombocytes are increased with abnormal function.Thrombotic events are seen frequently and represent the main cause of morbidity and mortality in patients with MPNs, mainly polycythemia vera and ET. This study has aimed to research the effects of clonally increased thrombocytes on plasma viscosity (PV) levels among patients with ET and the relationship between PV and thromboembolism history, according to the hypotheses about the effects of PV in thromboembolic events among patients with ET. A total of 55 patients were enrolled in the study group, 18 of who had been newly diagnosed with ET according to 2016 World Health Organization criteria and had not previously been treated. 37 of them had already been diagnosed with ET and had been treated. There were 47 healthy volunteers in the control group. 5 cc blood samples were taken from the patients into tubes including an anticoagulant to measure their PV levels. PV of the control group was found to be lower than in the study group and both each patient groups (p < 0.05). No relationship was found between the patient groups in terms of PV (p = 0.404). The mean PV levels of the 16 patients with a history of thromboembolism and the 39 patients with no such history were 2.42±0.17 cP and 2.33±0.20 cP, respectively. The mean PV levels were found to be similar according to their history of thromboembolism in all patient groups and in treated patients (p = 0.572 vs p = 0.991). We have found that PV levels were increased in clonally increased thrombocytes in patients with ET when compared with the control group. This is the first study in this field according to our knowledge.


Diverse populations of intrinsic cholinergic interneurons in the mouse olfactory bulb.
Cholinergic activities affect olfactory bulb (OB) information processing and associated learning and memory. However, the presence of intrinsic cholinergic interneurons in the OB remains controversial. As a result, morphological and functional properties of these cells are largely undetermined. We characterized cholinergic interneurons using transgenic mice that selectively mark choline acetyltransferase (ChAT)-expressing cells and immunolabeling. We found a significant number of intrinsic cholinergic interneurons in the OB. These interneurons reside primarily in the glomerular layer (GL) and external plexiform layer (EPL) and exhibit diverse distribution patterns of nerve processes, indicating functional heterogeneity. Further, we found these neurons express ChAT and vesicular acetylcholine transporter (VAChT), but do not immunoreact to glutamatergic, GABAergic or dopaminergic markers and are distinct from calretinin-expressing interneurons. Interestingly, the cholinergic population partially overlaps with the calbindin D28K-expressing interneuron population, revealing the neurotransmitter identity of this sub-population. Additionally, we quantitatively determined the density of VAChT labeled cholinergic nerve fibers in various layers of the OB, as well as the intensity of VAChT immunoreactivity within the GL, suggesting primary sites of cholinergic actions. Taken together, our results provide clear evidence showing the presence of a significant number of cholinergic interneurons and that these morphologically and distributionally diverse interneurons make up complex local cholinergic networks in the OB. Thus, our results suggest that olfactory information processing is modulated by dual cholinergic systems of local interneuron networks and centrifugal projections.


Effects of straw mulching combined with nitrogen application on soil organic matter content and atrazine digestion.
To explore the response of atrazine (AT) degradation rate, soil organic matter (SOM) distribution and the relationship between them to straw mulching and nitrogen application, field experiments were conducted to study the distribution of SOM content and AT degradation rate under different straw returning modes combined with nitrogen fertilization in 2 years in Hetao Irrigation District. No (N0), low (NL), medium (NM), and high (NH) levels of N fertilization were incorporated into the soil combined with the surface coverage straw (Treatment BN0, BNL, BNM, BNH, respectively) and the deeply buried straw (Treatment SN0, SNL, SNM, SNH, respectively). The traditional cultivation was used as a control treatment (Treatment CK). The results showed that SOM content of Treatment B was accumulated in 0~20 cm soil layer. The largest SOM content of Treatments B in 0~20 cm soil layer was found in BNH treatment, with an average increase of 14.2% and 24.1% significantly when compared with those in CK and SNH (P < 0.05), respectively. The SOM content of Treatments B increased with the increase of nitrogen application and decreased with the deepening of soil depth. The SOM content of Treatment S was accumulated in the soil layer (20~40 cm and 40~60 cm) near the inter-layer. With the increase of nitrogen application and depth of soil layer, the SOM content increased firstly and then decreased. SNM had the largest SOM content in the soil layer of 20~40 cm and 40~60 cm, with an average increase of 82.6% and 67.7% when compared with Treatment CK (P < 0.05). In the soil layer over 60 cm, there was no significant difference in SOM content of different straw returning methods under the same nitrogen level (P > 0.05). Straw returning methods and nitrogen application level significantly affected AT digestion rate and digestion half-life, with significant differences among treatments (P < 0.05). It found that treatment SNM had the highest digestion rate and the shortest half-life of AT. Compared with Treatment CK, the digestion rate of Treatment SNM was increased by 5.3% on average, and the half-life was shortened by 3.9 days on average. Single regression and stepwise regression analysis of the half-life of AT degradation and SOM content in different soil layers (0~20 cm and 20~40 cm) showed that the degradation of AT was greatly affected by SOM content of 20~40 cm soil layer. Based on the comprehensive analysis, the effect of straw deep burial combined with medium nitrogen application rate (Treatment SNM) was best, which could achieve the goal of increasing SOM content and shortening the half-life of AT digestion. The research provided a technical support for straw resource utilization, alleviated AT pollution and improved farmland ecological environment in Hetao Irrigated District.


Significance of intra-nodular vessel sign in differentiating benign and malignant pulmonary ground-glass nodules.
The presence of pulmonary vessels inside ground-glass nodules (GGNs) of different nature is a very common occurrence. This study aimed to reveal the significance of pulmonary vessels displayed in GGNs in their diagnosis and differential diagnosis. A total of 149 malignant and 130 benign GGNs confirmed by postoperative pathological examination were retrospectively enrolled in this study. There were significant differences in size, shape, nodule-lung interface, pleural traction, lobulation, and spiculation (each p < 0.05) between benign and malignant GGNs. Compared with benign GGNs, intra-nodular vessels were more common in malignant GGNs (67.79% vs. 54.62%, p = 0.024), while the vascular categories were similar (p = 0.663). After adjusting the nodule size and the distance between the nodule center and adjacent pleura [radius-distance ratio, RDR], the occurrences of internal vessels between them were similar. The number of intra-nodular vessels was positively correlated with nodular diameter and RDR. Vascular changes were more common in malignant than benign GGNs (52.48% vs. 18.31%, p < 0.0001), which mainly manifested as distortion and/or dilation of pulmonary veins (61.19%). The occurrence rate, number, and changes of internal vessels had no significant differences among all the pre-invasive and invasive lesions (each p > 0.05). The incidence of internal vessels in GGNs is mainly related to their size and the distance between nodule and pleura rather than the pathological nature. However, GGNs with dilated or distorted internal vessels, especially pulmonary veins, have a higher possibility of malignancy.


Selective embolization of the superior vesical artery for the treatment of a severe retroperitoneal pelvic haemorrhage following Endo-Stitch sacrospinous colpopexy.
Pelvic haemorrhage is a rare but important complication that may follow sacrospinous fixation of the vaginal vault. When such complication occurs, packing and clipping of the involved artery is often suggested as the first-line treatment, while arterial embolization is considered only after failure of surgery. In this report, we describe the successful super-selective embolization of a variant of the superior vesical artery in a patient who underwent Endo-Stitch sacrospinous colpopexy. Based on our experience, we suggest that when a well-trained radiological staff is available, endovascular embolization is an effective and less invasive option.


Mechanics of Rouleau formation.
The formation of rouleau of red blood cells is considered from the standpoint of adhesion theory. With the use of the elastic properties of the red blood cell membrane obtained from previous work, the strain energy of the red blood cell in rouleau formation has been computed. The surface energy of adhesion for the bonding of two red blood cells is then computed from the variation of this strain energy. Computed cell shapes agree well with experiments.


Structure and flow calculation of cake layer on microfiltration membranes.
Submerged membrane bioreactors (SMBR) are widely used in wastewater treatment. The permeability of a membrane declines rapidly because of the formation of a cake layer on the membrane surface. In this paper, a multiple staining protocol was conducted to probe the four major foulants in the cake layer formed on a filtration membrane. Fluorescent images of the foulants were obtained using a confocal laser scanning microscope (CLSM). The three dimensional structure of the cake layer was reconstructed, and the internal flow was calculated using computational fluid dynamics (CFD). Simulation results agreed well with the experimental data on the permeability of the cake layer during filtration and showed better accuracy than the calculation by Kozeny-Carman method. β-d-Glucopyranose polysaccharides and proteins are the two main foulants with relatively large volume fractions, while α-d-glucopyranose polysaccharides and nucleic acids have relatively large specific surface areas. The fast growth of β-d-glucopyranose polysaccharides in the volume fraction is mainly responsible for the increase in cake volume fraction and the decrease in permeability. The specific area, or the aggregation/dispersion of foulants, is less important to its permeability compared to its volume fraction.


Long-term health-related quality of life for disease-free esophageal cancer patients.
Health-related quality of life (HRQL) has been studied extensively during the first year following esophagectomy, but little is known about HRQL in long-term survivors. The aim of this study was to investigate HRQL in patients alive at least 1 year after surgical resection for esophageal cancer using validated European Organisation for Research and Treatment of Cancer (EORTC) quality of life (QOL) questionnaires (QLQ). Eligible patients, without known disease recurrence and at least 1 year after esophagectomy, were identified from a prospectively maintained database. Patients completed general (QLQ-C30) and esophageal cancer-specific (QLQ-OES18, OG25) questionnaires. A numeric score (0-100) was computed in each conceptual area and compared with validated cancer (n = 1031) and age-matched (n = 7802) healthy populations using two-tailed unpaired t-tests. A cohort of 80 patients had pretreatment scores recorded. Altogether, 132 of 156 eligible patients (84%) completed the self-rated questionnaire, 105 (67.3%) were men, and the mean age was 62 years (range 29-84 years). The mean time since esophagectomy was 70.3 months (12-299 months). Global health status was significantly reduced at least 1 year after esophagectomy (mean ± SD score 48.4 ± 18.6) when compared with patients with esophageal cancer prior to treatment (55.6 ± 24.1) and the general population (71.2 ± 22.4) (p < 0.0001). In a prospective cohort of eighty patients, symptoms related to swallowing difficulty, reflux, pain, and coughing significantly decreased in the long term (p < 0.0001). The degree of subjective swallowing dysfunction was highly correlated with a poor QOL (Spearman's ρ = 0.508, p < 0.01). Global health status remains significantly reduced in long-term survivors after esophagectomy compared with population controls, and swallowing dysfunction is highly associated with this compromised QOL.


Autonomic cardiac regulation after general anesthesia in children.
General anesthesia dramatically decreases the activity of the autonomic nervous system. Most of the hypnotic agents used to induce anesthesia inhibit sympathetic cardiovascular regulation and baroreflex control in a dose-dependent manner, lowering cardiac adaptability during the operation. The consequence of this effect in children during and after surgery has never been studied to date. The aim of this study was to follow the variations in autonomic cardiac indices in children younger than 8 years old after general anesthesia (6-24 hours) in programmed surgery. A prospective descriptive monocentric study of 44 children under 8 years old who underwent scheduled surgery at our hospital center (Saint-Étienne University Hospital, France) was performed between June 1, 2016 and November 1, 2016. Heart rate variability was monitored for 24 hours using Holter-ECG devices and the resulting data were interpreted using linear and nonlinear analyses. Compared to baseline thresholds before surgery, all heart rate variability indices decreased dramatically during general anesthesia. After awakening, a slight reduction in sympathetic activity persisted 6 hours after surgery, but all measurements of sympathetic and parasympathetic activity had returned to baseline thresholds 12 hours after the operation. Twenty-four hours after surgery, some parameters had increased above the corresponding baseline levels. Autonomic nervous function normalizes rapidly (within 12 hours) in prepubertal children. This study indicates that general anesthesia does not seem to increase the long-term risk of autonomic dysfunction in these patients.


Calcium-mediated inhibition of glucuronide production by epinephrine in the perfused rat liver.
Rates of production of p-nitrophenyl glucuronide by isolated perfused livers from fed or fasted phenobarbital-treated rats were estimated by monitoring the concentration of glucuronide in the effluent perfusate. Infusion of epinephrine decreased the steady state level of p-nitrophenyl glucuronide by about 39% (half-maximal inhibition at approximately 5 microM). This result was unexpected because epinephrine activated glycogenolysis and elevated hepatic UDP-glucuronic acid contents. The effect of epinephrine can be attributed to its interaction with alpha-adrenergic receptors, since the inhibition of glucuronide production by epinephrine was reversed by an alpha-antagonist (phentolamine) but not by a beta-antagonist, propranolol. Since alpha-adrenergic agonists increase the cytosolic free calcium concentration, we investigated the possibility that the decrease in glucuronide production elicited by epinephrine was mediated by calcium. Removal of calcium from the perfusion fluid diminished the inhibition of glucuronide production by epinephrine, while increasing extracellular calcium from 0 to 150 microM restored the inhibition in a dose-dependent manner. In the presence of extracellular calcium, glucuronide production was inhibited by the addition of the calcium ionophore A23187 or angiotensin II, a hormone which increases cytosolic calcium. Concentrations of ionized calcium comparable to physiological intracellular levels (0.1-2 microM) increased microsomal beta-glucuronidase activity by 50 to 100% but had no effect on microsomal glucuronosyl-transferases . These results indicate that activation of hepatic alpha-adrenergic receptors increases cytosolic calcium which stimulates microsomal beta-glucuronidase activity. This decreases net glucuronide formation by the liver. In support of this hypothesis, rates of glucuronide production were unaffected by epinephrine in perfused livers from beta-glucuronidase-deficient C3H/HeJ mice.


Expression of cdc25B and cdc25A in medullary thyroid carcinoma: cdc25B expression level predicts a poor prognosis.
Cdc25B and cdc25A phosphatases are prominent stimulators of cell cycle progression and have been suggested to play oncogenic roles. In this study, we immunohistochemically investigated the expression of these phosphatases in medullary thyroid carcinoma. Cdc25B was positive in 35.8% of cases examined. Its positivity was linked only to patient age. However, patients with cdc25B-positive tumors showed a significantly worse disease-free survival rate (P=0.0210) than those with cdc25B-negative tumors. Cdc25A was positive in only 17.2% of cases and was not related to clinicopathological parameters or prognosis. These findings suggest that cdc25B can be regarded as having prognostic significance and as a novel marker of biologically aggressive characteristics in this carcinoma.


Measurement of Cu and Zn adsorption onto surficial sediment components: new evidence for less importance of clay minerals.
Clay minerals in surficial sediment samples, collected from the Songhua River in China, were separated via sedimentation after removal of Fe/Mn oxides and organic materials; Cu and Zn adsorption onto the sediment components was then evaluated. Clay minerals were examined via X-ray diffraction and scanning electron microscopy. Clay minerals were found to consist mainly of illite, kaolinite, chlorite and an illite/smectite mixed layer. Non-clay minerals were dominated by quartz and orthoclase. The retention of Cu and Zn by clay minerals was 1.6 and 2.5 times, respectively, greater than that of the whole, untreated surficial sediment. Compared to the other critical components in sediments related to metal sorption (Mn oxides, Fe oxides and organic materials), the adsorption capacity of clay minerals was found to be relatively lower on a unit mass basis. These data suggest that, although clay minerals may be important in the adsorption of heavy metals to aquatic sediments, their role is less significant than Fe/Mn oxides and organic materials.


Many Unaware of Link between HPV and Some Cancers.
Public awareness of the link between the human papillomavirus (HPV) and cervical cancer has declined over the past several years. The findings also reveal low awareness of HPV's connection with other cancers, including anal, oral, and penile, highlighting an urgent need for educational campaigns targeting medical professionals and the public.


The complete mitochondrial genome of Thrinchus schrenkii (Orthoptera: Caelifera, Acridoidea, Pamphagidae).
Complete nucleotide sequences of mitochondrial genome (mitogenome) of Thrinchus schrenkii (Orthoptera: Acridoidea: Pamphagidae) were determined. It is 15672 bp in length and contains 71.2% A+T. All T. schrenkii protein-coding sequences except for the cytochrome oxidase subunit I (COI) start with a typical ATN codon. Instead, CCG, which is a rare but possible initiation codon, is located at the initiation context of COI. The usual termination codons (TAA and TAG) were found from 12 PCGs. However, the ND5 had incomplete termination codon (T). All tRNA genes could be folded into the typical cloverleaf secondary structure, excluding tRNASer(AGN) which forms another structure according to the Steinberg-Cedergren tertiary structure. The sizes of the large and small ribosomal RNA genes are 1319 and 848 bp, respectively. The A+T content of the A+T-rich region is 78.7%, which is the lowest among the known mitogenome of Acridoidea.


Screen-detected versus interval cancers: Effect of imaging modality and breast density in the Flemish Breast Cancer Screening Programme.
To investigate if direct radiography (DR) performs better than screen-film mammography (SF) and computed radiography (CR) in dense breasts in a decentralized organised Breast Cancer Screening Programme. To this end, screen-detected versus interval cancers were studied in different BI-RADS density classes for these imaging modalities. The study cohort consisted of 351,532 women who participated in the Flemish Breast Cancer Screening Programme in 2009 and 2010. Information on screen-detected and interval cancers, breast density scores of radiologist second readers, and imaging modality was obtained by linkage of the databases of the Centre of Cancer Detection and the Belgian Cancer Registry. Overall, 67% of occurring breast cancers are screen detected and 33% are interval cancers, with DR performing better than SF and CR. The interval cancer rate increases gradually with breast density, regardless of modality. In the high-density class, the interval cancer rate exceeds the cancer detection rate for SF and CR, but not for DR. DR is superior to SF and CR with respect to cancer detection rates for high-density breasts. To reduce the high interval cancer rate in dense breasts, use of an additional imaging technique in screening can be taken into consideration. • Interval cancer rate increases gradually with breast density, regardless of modality. • Cancer detection rate in high-density breasts is superior in DR. • IC rate exceeds CDR for SF and CR in high-density breasts. • DR performs better in high-density breasts for third readings and false-positives.


Efficacy and safety of Zolpidem in the treatment of insomnia disorder for one month: a meta-analysis of a randomized controlled trial.
A meta-analysis of a randomized placebo-controlled trial was used to evaluate the effectiveness and safety of Zolpidem in the treatment of insomnia disorder for one month. Searched from PubMed, EMBASE, MEDLINE, PsycINFO, Cochrane Central Register of Controlled Trials and web of science from inception to May 13, 2021. In addition, we also searched ClinicalTrials.gov trials register to obtain relevant research and related data. Include all randomized controlled trials that meet the criteria. The primary efficacy outcome were total sleep time and sleep latency. The secondary outcome was wake-time after sleep onset. And to evaluate the safety of Zolpidem in the treatment of insomnia. Total of 6 randomized placebo-controlled trials involving 1068 patients with insomnia disorder were included in our study. Our analysis results showed that compared with placebo, zolpidem treatment for one month was more effective in increasing the total sleep time of patients with insomnia disorder, reducing sleep latency and improving sleep quality. There was no significant statistical difference between the two groups in the amount of change in the wake after sleep onset. Meanwhile, there was no significant statistical difference in adverse events between Zolpidem and placebo after one month of treatment. Our meta-analysis showed that zolpidem is an effective and safe therapy option to treat insomnia disorder for one month. However, when using zolpidem to treat insomnia, its effect on sleep structure should be considered. In the future, large-scale clinical trials are needed to compare the effectiveness and safety of zolpidem in the treatment of insomnia from subjective and objective indicators combined with zolpidem on sleep structure.


Quantifying alternative polyadenylation in RNAseq data with LABRAT.
Alternative polyadenylation (APA) generates transcript isoforms that differ in their 3' UTR content and may therefore be subject to different regulatory fates. Although the existence of APA has been known for decades, quantification of APA isoforms from high-throughput RNA sequencing data has been difficult. To facilitate the study of APA in large datasets, we developed an APA quantification technique called LABRAT (Lightweight Alignment-Based Reckoning of Alternative Three-prime ends). LABRAT leverages modern transcriptome quantification approaches to determine the relative abundances of APA isoforms. In this manuscript we describe how LABRAT produces its calculations, provide a step-by-step protocol for its use, and demonstrate its ability to quantify APA in single-cell RNAseq data.


How much time is needed in clinical practice to reach a diagnosis of clinically established Parkinson's disease?
The implementation of accepted clinical diagnostic criteria has improved the accuracy of a clinical diagnosis of Parkinson's disease (PD). Time frames of 3-10 years have been empirically proposed to reach a diagnosis of clinically established PD. We explored the time to a Final Clinical Diagnosis (FCD) and the factors that predict faster diagnoses in patients presenting with parkinsonism and/or tremor between 2009 and 2015 at our tertiary center. All patients underwent a standardized workout process to reach a FCD, which included an acute levodopa challenge (LDC) after the first visit. Among the 326 patients included, 215 (66%) received a FCD within the first six months after the LDC. A FCD was reached in 95% and 100% of patients in 33 and 108 months, respectively. PD was the FCD in 196 patients (60.1%). The FCD was reached faster in patients with a positive response to levodopa and when the FCD was PD. The time needed to reach a final diagnosis in the clinical setting was 2.75 years in 95% of patients presenting initially with parkinsonism and/or tremor. Patients with positive responses to levodopa at the LDC, benefited from shorter delays until the FCD.


Neurodegenerative disorders mimicking progressive supranuclear palsy: a report of three cases.
Progressive supranuclear palsy (PSP) is rarely confused with other parkinsonian disorders once the vertical gaze palsy appears. Corticobasal degeneration is the most common differential diagnostic entity. We describe three cases diagnosed during life as PSP but found to have another neurologic disorder at autopsy. No explanation for the gaze palsies was found in any case.


CD138- Plasmablastic Lymphoma: A Multi-institutional Study and Review of the Literature.
Plasmablastic lymphoma (PBL) is a rare aggressive lymphoma, usually positive for CD138 and frequently occurring in the oral cavity of human immunodeficiency virus (HIV) patients. Up to 10% of cases are negative for CD138 and diagnostically very challenging. To investigate the appropriate approach to diagnose CD138- plasmablastic lymphoma and avoid misdiagnosis. We studied 21 cases of CD138- PBL from multiple large institutes in the United States and 21 cases from the literature. CD138- PBLs were positive for different B/plasma cell markers at various percentages: MUM1 (94.4%; 34 of 36), OCT2 (70.6%; 12 of 17), immunoglobulin light chains (68.8%; 22 of 32), CD38 (68.4%; 13 of 19), CD79a (34.2%; 13 of 38), and PAX5 (15.6%; 5 of 32), suggesting that MUM1, OCT2, immunoglobulin light chains, and CD38 are useful markers to help establish the lineage. A total of 83% of cases (30 of 36) were extraoral lesions. Extraoral lesions showed much lower Epstein-Barr virus (EBV) infection rates (16 of 30; 53.3%) and had worse prognosis. MYC was positive in 80% (8 of 10) of EBV+ cases and 40% (2 of 5) EBV- cases, indicating the importance of MYC in pathogenesis, especially in EBV+ cases. Our study emphasizes that CD138- PBLs tend to be extraoral lesions, with much lower EBV infection rates, and diagnostically very challenging. Accurate diagnosis requires a thorough investigation and workup by using appropriate markers.


Dendrimer biocompatibility and toxicity.
The field of biomedical dendrimers is still in its infancy, but the explosion of interest in dendrimers and dendronised polymers as inherently active therapeutic agents, as vectors for targeted delivery of drugs, peptides and oligonucleotides, and as permeability enhancers able to promote oral and transdermal drug delivery makes it timely to review current knowledge regarding the toxicology of these dendrimer chemistries (currently under development for biomedical applications). Clinical experience with polymeric excipients, plasma expanders, and most recently the development of more 'classical polymer'-derived therapeutics can be used to guide development of "safe" dendritic polymers. Moreover, in future it will only ever be possible to designate a dendrimer as "safe" when related to a specific application. The so far limited clinical experience using dendrimers make it impossible to designate any particular chemistry intrinsically "safe" or "toxic". Although there is widespread concern as to the safety of nano-sized particles, preclinical and clinical experience gained during the development of polymeric excipients, biomedical polymers and polymer therapeutics shows that judicious development of dendrimer chemistry for each specific application will ensure development of safe and important materials for biomedical and pharmaceutical use.


Generation of arbitrary spatially variant polarization beams with a trapezoid Sagnac interferometer.
We present a flexible approach to generate arbitrary vector beams with a trapezoid Sagnac interferometer. With the interferometer, the different orders of two orthogonally polarized beams from computer-generated holograms coincide with each other in Fourier spectrum domain, and coaxially combine into the vector beams. This approach provides convenient way to experimentally study the properties of vector beams with complex polarization.


Striving towards environmental sustainability: how natural resources, human capital, financial development, and economic growth interact with ecological footprint in China.
On the economic side, China has attained rapid development; yet, the ecological aspects pose threats to its sustainable development. The nexus between economic growth, natural resources, human capital, and financial development has an important inference for the environment, and therefore, this endeavor examines the influence of said variables on the ecological footprint in China via adopting the novel dynamic simulated ARDL approach by utilizing the data from 1985 to 2018. The outcomes of the analysis confirm that natural resources and financial development have a considerable positive short- and long-run relation with the ecological footprint. Besides, this depicts that natural resources and financial development lead to an upsurge in ecological footprint in China. Furthermore, human capital also upsurges the negative influence on the environment. Economic growth also upsurges the ecological footprint; however, the outcomes also yielded an interesting insight lending credence to the existence of the environmental Kuznets curve in China. So, it is important to offer awareness sessions to the community as well as to human resources working in different sectors regarding the significance of sustainability by giving training related to the reduction of the excessive consumption of scarce resources. Moreover, a watchful deliberation must be given while implementing strategies about sustainability concerning the specified factors and their potential impact on ecological footprints so that the targets of Sustainable Development Goals 7, 8, and 13 could be accomplished by the Chinese economy.


Enclathration of morpholinium cations by Dianin's compound: salt formation by partial host-to-guest proton transfer.
In spite of partial deprotonation upon inclusion of morpholine, Dianin's compound maintains its well-known clathrate structure in the solid state.


SeSaMe: Metagenome Sequence Classification of Arbuscular Mycorrhizal Fungi-associated Microorganisms.
Arbuscular mycorrhizal fungi (AMF) are plant root symbionts that play key roles in plant growth and soil fertility. They are obligate biotrophic fungi that form coenocytic multinucleated hyphae and spores. Numerous studies have shown that diverse microorganisms live on the surface of and inside their mycelia, resulting in a metagenome when whole-genome sequencing (WGS) data are obtained from sequencing AMF cultivated in vivo. The metagenome contains not only the AMF sequences, but also those from associated microorganisms. In this study, we introduce a novel bioinformatics program, Spore-associated Symbiotic Microbes (SeSaMe), designed for taxonomic classification of short sequences obtained by next-generation DNA sequencing. A genus-specific usage bias database was created based on amino acid usage and codon usage of a three consecutive codon DNA 9-mer encoding an amino acid trimer in a protein secondary structure. The program distinguishes between coding sequence (CDS) and non-CDS, and classifies a query sequence into a genus group out of 54 genera used as reference. The mean percentages of correct predictions of the CDS and the non-CDS test sets at the genus level were 71% and 50% for bacteria, 68% and 73% for fungi (excluding AMF), and 49% and 72% for AMF (Rhizophagus irregularis), respectively. SeSaMe provides not only a means for estimating taxonomic diversity and abundance but also the gene reservoir of the reference taxonomic groups associated with AMF. Therefore, it enables users to study the symbiotic roles of associated microorganisms. It can also be applicable to other microorganisms as well as soil metagenomes. SeSaMe is freely available at www.fungalsesame.org.


On the phylogeny of Mustelidae subfamilies: analysis of seventeen nuclear non-coding loci and mitochondrial complete genomes.
Mustelidae, as the largest and most-diverse family of order Carnivora, comprises eight subfamilies. Phylogenetic relationships among these Mustelidae subfamilies remain argumentative subjects in recent years. One of the main reasons is that the mustelids represent a typical example of rapid evolutionary radiation and recent speciation event. Prior investigation has been concentrated on the application of different mitochondrial (mt) sequence and nuclear protein-coding data, herein we employ 17 nuclear non-coding loci (>15 kb), in conjunction with mt complete genome data (>16 kb), to clarify these enigmatic problems. The combined nuclear intron and mt genome analyses both robustly support that Taxidiinae diverged first, followed by Melinae. Lutrinae and Mustelinae are grouped together in all analyses with strong supports. The position of Helictidinae, however, is enigmatic because the mt genome analysis places it to the clade uniting Lutrinae and Mustelinae, whereas the nuclear intron analysis favors a novel view supporting a closer relationship of Helictidinae to Martinae. This finding emphasizes a need to add more data and include more taxa to resolve this problem. In addition, the molecular dating provides insights into the time scale of the origin and diversification of the Mustelidae subfamilies. Finally, the phylogenetic performances and limits of nuclear introns and mt genes are discussed in the context of Mustelidae phylogeny. Our study not only brings new perspectives on the previously obscured phylogenetic relationships among Mustelidae subfamilies, but also provides another example demonstrating the effectiveness of nuclear non-coding loci for reconstructing evolutionary histories in a group that has undergone rapid bursts of speciation.


Survival response of Bacteriovorax in surface biofilm versus suspension when stressed by extremes in environmental conditions.
The Bacteriovorax, previously in the genus Bdellovibrio, are prokaryotes that prey upon many Gram-negative bacteria. They are ubiquitous in salt-water environments and have been reported to have a strong association with biofilms. The purpose of this study was to test the hypothesis that this association affords protection for the Bacteriovorax and enhances their survival in nature when exposed to extreme environmental conditions. Experiments were designed to compare their survival in biofilms versus in suspension when exposed to extremes in salinity and temperature. Natural mixed-population biofilms generated in moderate-salinity (16 per thousand) Patuxent River water and containing Bacteriovorax were exposed to drastic changes in salinity by placing in low-salinity (1 per thousand) river water and salt-free (no measurable salinity) distilled water for up to 14 days. In a separate trial, the biofilm was exposed to extremes in temperature, 5 degrees C and 35 degrees C, for up to 12 weeks in aquarium mesocosms. Simultaneously, suspensions of the Bacteriovorax were exposed to the same extremes in salinity and temperature as biofilms. The results revealed that the Bacteriovorax typically were able to survive for a week or longer while in association with biofilms than when in suspension. These results are consistent with observations from nature and establish that biofilms are important in the survival and ecology of the Bacteriovorax.


Bioartificial liver: implanted artificial cells microencapsulated living hepatocytes increases survival of liver failure rats.
Suspension of living hepatocytes were microencapsulated inside 300 micron mean diameter alginate artificial cells. The galactosamine fulminant hepatic failure rat model was used. 48 hours after the injection of galactosamine, grade II coma hepatic failure rats were divided into pairs. One of the pair was randomly chosen for the control group, and the other for the treated group. Each rat in the control group received one peritoneal injection of microcapsules containing no hepatocytes. Each rat in the treated group received one peritoneal injection of microcapsules containing hepatocytes. The survival of the treated group is significantly higher than the control group.


Efficacy and safety of fingolimod in Hispanic patients with multiple sclerosis: pooled clinical trial analyses.
The disease characteristics of multiple sclerosis (MS) appear to differ between Hispanic and Caucasian patients, with Hispanic patients having a younger age at onset, and a higher prevalence of optic nerve and spinal cord involvement. Fingolimod, the first-in-class oral sphingosine 1-phosphate receptor modulator approved for the treatment of relapsing MS, has been shown to significantly reduce annualized relapse rates (ARRs), lesion-based magnetic resonance imaging (MRI) activity, confirmed disability, and brain volume loss, compared with placebo or intramuscular interferon beta-1a (IFNβ-1a IM) in randomized, double-blind, controlled clinical studies. Here, the efficacy and safety profile of fingolimod in Hispanic patients was compared to that observed in the overall study populations. This was a post hoc analysis of relapses and safety data for Hispanic patients with relapsing-remitting MS (RRMS) randomized to receive daily fingolimod 0.5 mg, weekly IFNβ-1a IM (30 mg) or placebo, in the phase 3, controlled FREEDOMS, FREEDOMS II, and TRANSFORMS fingolimod studies. The ARR was estimated for each treatment group; only relapses that were confirmed by an independent examining neurologist were included in these analyses. Safety assessments included the incidence of adverse events and serious adverse events. Eligible Hispanic patients aged 18-55 years (n=181) had been treated as follows: fingolimod 0.5 mg (n=89), IFNβ-1a IM (n=65), and placebo (n=27). Hispanic patients treated with fingolimod for up to 2 years had lower ARRs (ARR: 0.22, 95% confidence interval [CI]: 0.14-0.35) than those receiving placebo (ARR: 0.46, 95% CI: 0.24-0.88) or IFNβ-1a IM (ARR: 0.34, 95% CI: 0.18-0.63), with relative reductions of 52% and 35%, respectively. A transient decrease in heart rate that started to attenuate 6 h after fingolimod administration was observed, consistent with the well-characterized pharmacologic effect following fingolimod treatment initiation. No cases of symptomatic bradycardia were reported in Hispanic patients. The incidence of first-degree atrioventricular block was low and similar across all treatment groups (3.1-4.5%). The safety profile of fingolimod in Hispanic patients was consistent with that reported in the overall population of each study. Overall, this study demonstrates that fingolimod is efficacious and well tolerated in Hispanic patients with RRMS.


Identification of lncRNA-Protein Interactions by CLIP and RNA Pull-Down Assays.
The emerging data indicates that long noncoding RNAs (lncRNAs) are involved in fundamental biological processes, and their deregulation may lead to oncogenesis and other diseases. LncRNA fulfil its biological functions at least in part by interacting with distinctive proteins. Here, we described two methods to identify the direct or indirect interactions between lncRNA and proteins: cross-linking and immunoprecipitation (CLIP) and RNA pull-down assay. CLIP methods enable yield a list of lncRNAs that directly interact target protein in living cells, whereas immunoprecipitation of biotin-labeled RNA (RNA pull-down) assay represents a method for identification of proteins that directly and indirectly bind with a particular target lncRNA of interest.


Effects of parenteral nutrition with lipids on the human liver. An electron-microscopic study.
The ultrastructural findings in the Kupffer cells of a liver biopsy of a 5-week-old baby, who had received repeated i.v. administration of Intralipid (10%) in a dose of 20 ml/kg body weight/day for 12 days, are presented. Heterophagocytosis of free lipid droplets occurs by invagination of the Kupffer cell membrane. Large, solitary or conglomerated fat droplets surrounded by a membrane (lipophagosomes) are present within the hypertrophic and most active Kupffer cells. Small, round or elongated dark bodies (primary lysosomes) are linked with and/or seem to fuse with these lipophagosomes. In addition, smaller phagosomes almost completely surrounded by a dark small rim and a less electron-dense center probably represent (further stages of the lysosomal breakdown. The latter is also expressed by the condensation from the periphery towards the center of the original lipid droplets enclosed within the lysosomes. Angular inclusion bodies, build up of lipid remnants and a granular matrix of medium electron density, constitute far advanced stages of lysosomal digestion and represent the development or transformation of the phagocytosed lipids into lipogenous pigments. On the electron-microscopic level a distinction between lipofuscin granules and ceroid pigment can hardly be made at that stage. These pigment granules can be found in various amounts within the Kupffer cells and can stay there for a long time. This accumulation probably inhibits the clearance capacity of the cellular elements of the hepatic reticuloendothelial system. The hepatocytes and spaces of Disse seem not to be directly involved in the process of fat phagocytosis and breakdown as summarized above.


Immunological studies on peroxynitrite modified human DNA.
Peroxynitrite (ONOO(-)) is a strong and potent oxidizing and nitrating agent, formed by rapid reaction of two highly reactive, nitric oxide and superoxide anion. The action of peroxynitrite generated by synergistic action of diethylamine NONOate (a nitric oxide donor) and 1,4-hydroquinone (a superoxide donor), on human placental DNA was monitored by ultraviolet and fluorescence spectroscopy, melting temperature studies, S1 nuclease digestibility and alkaline agarose electrophoresis. The peroxynitrite modified human DNA (ONOO(-)-DNA) was found to be highly immunogenic in rabbits inducing high titre immunogen specific antibodies. However, the induced antibodies exhibited appreciable cross-reactivity with various polynucleotides and nucleic acids. The data demonstrate that the antibodies, though cross-reactive, preferentially bind ONOO(-)-modified epitopes on DNA. Visual detection of immune complex formation with native and ONOO(-)-DNA reiterated preferential binding with modified human DNA. DNA modified by ONOO(-) presents unique epitopes which may be one of the factors for the induction of autoantibodies in cancer patients.


Long-term enteral arginine supplementation in rats with intestinal ischemia and reperfusion.
The effects of short-term enteral arginine supplementation on intestinal ischemia-reperfusion (IR) injury have been widely studied, especially the ischemic preconditioning supplementation. The aim of this study was to investigate the effects of long-term intra-duodenal supplementation of arginine on intestinal morphology, arginine-associated amino acid metabolism, and inflammatory responses in rats with intestinal IR. Male Wistar rats with or without three hours of ileal ischemia underwent duodenal cannulation for continuous infusion of formula with 2% arginine or commercial protein powder for 7 d. The serological examinations, plasma amino acid and cytokine profiles, and intestinal morphology were assessed. Intestinal IR injury had significant impacts on the decreases in circulating red blood cells, hemoglobin, ileum mass, and villus height and crypt depth of the distal jejunum. In addition, arginine supplementation decreased serum cholesterol and increased plasma arginine concentrations. In rats with intestinal IR injury, arginine supplementation significantly decreased serum nitric oxide, plasma citrulline and ornithine, and the mucosal protein content of the ileum. These results suggest that long-term intra-duodenal arginine administration may not have observable benefits on intestinal morphology or inflammatory response in rats with intestinal ischemia and reperfusion injury. Therefore, the necessity of long-term arginine supplementation for patients with intestinal ischemia and reperfusion injury remains questionable and requires further investigation.


Longitudinal anterior knee laxity related to substantial tibial tunnel enlargement after anterior cruciate ligament revision.
Allograft and bioabsorbable screw use in anterior cruciate ligament (ACL) revision surgery is common. However, both allograft and bioabsorbable screws have been associated with immunologic reactions that lead to tunnel enlargement. Long-term studies examining tibial tunnel enlargement in this population are currently not available. We report a case of severe tibial and femoral tunnel enlargement 6.5 years after ACL revision surgery with anterior tibialis and semitendinosus allograft and bioabsorbable screw fixation. Longitudinal knee arthrometer data, knee examination with the patient under anesthesia, and arthroscopic inspection of the graft showed minimal effects of severe tunnel enlargement on anterior knee laxity and graft integrity. To our knowledge, this is the first case report of a longitudinal assessment of anterior knee laxity associated with severe tunnel enlargement. Surgeons should be aware of this condition and the clinical consequences that may accompany bone tunnel enlargement after ACL surgery.