Base-promoted reactions of bridged ketones and 1,3- and 1,4-haloalkyl azides: competitive alkylation vs azidation reactions of ketone enolates.
The reactions of 1,3- and 1,4-haloalkyl azides with enolates of 2-norbornanone (and a ring-expanded analog) afford polycyclic 1,2,3-triazolines in good yields. The reaction occurs by the initial azidation of the ketone enolate, followed in order by triazoline formation and O-alkylation. An interesting element of this process is the preferential reaction of the alkyl azide with an enolate anion as opposed to the more familiar reaction of the alkyl halide (including Cl and I derivatives). Reactions of acyclic or monocyclic enolates generally lead to 1,2,3-triazoles but none of the alternative C-alkylation product.


Factors associated with non-beneficial treatments in end of life hospital admissions: a multicentre retrospective cohort study in Australia.
To quantitatively assess the factors associated with non-beneficial treatments (NBTs) in hospital admissions at the end of life. Retrospective multicentre cohort study. Three large, metropolitan tertiary hospitals in Australia. 831 adult patients who died as inpatients following admission to the study hospitals over a 6-month period in 2012. Odds ratios (ORs) of NBT derived from logistic regression models. Overall, 103 (12.4%) admissions involved NBTs. Admissions that involved conflict within a patient's family (OR 8.9, 95% CI 4.1 to 18.9) or conflict within the medical team (OR 6.5, 95% CI 2.4 to 17.8) had the strongest associations with NBTs in the all subsets regression model. A positive association was observed in older patients, with each 10-year increment in age increasing the likelihood of NBT by approximately 50% (OR 1.5, 95% CI 1.2 to 1.9). There was also a statistically significant hospital effect. This paper presents the first statistical modelling results to assess the factors associated with NBT in hospital, beyond an intensive care setting. Our findings highlight potential areas for intervention to reduce the likelihood of NBTs.


1,4-Pentenyne as a five-carbon synthon for efficient and selective syntheses of natural products containing 2,4-dimethyl-1-penten-1,5-ylidene and related moieties by means of Zr-catalyzed carboalumination of alkynes and alkenes.
Two highly efficient protocols for enantioselective synthesis of 2,4-dimethyl-1-penten-1,5-ylidene derivatives involve the combined use of the Zr-catalyzed methylalumination of alkynes (ZMA) and the Zr-catalyzed asymmetric carboalumination of alkenes (ZACA). The ZMA/ZACA protocol has been applied to the synthesis of a nafuredin intermediate 14 and a potential intermediate 18 for milbemycin beta 3, while the ZACA/ZMA protocol has been applied to the synthesis of a (-)-bafilomycin A(1) intermediate 25.


A retrospective study of two populations to test a simple rule for spirometry.
Chronic lung disease is common and often under-diagnosed. To test a simple rule for conducting spirometry we reviewed spirograms from two populations, occupational medicine evaluations (OME) conducted by Saint Louis and Wake Forest Universities at 3 sites (n = 3260, mean age 64.14 years, 95 % CI 58.94-69.34, 97 % men) and conducted by Wake Forest University preop clinic (POC) at one site (n = 845, mean age 62.10 years, 95 % CI 50.46-73.74, 57 % men). This retrospective review of database information that the first author collected prospectively identified rates, types, sensitivity, specificity and positive and negative predictive value for lung function abnormalities and associated mortality rate found when conducting spirometry based on the 20/40 rule (≥20 years of smoking in those aged ≥ 40 years) in the OME population. To determine the reproducibility of the 20/40 rule for conducting spirometry, the rule was applied to the POC population. A lung function abnormality was found in 74 % of the OME population and 67 % of the POC population. Sensitivity of the rule was 85 % for an obstructive pattern and 77 % for any abnormality on spirometry. Positive and negative predictive values of the rule for a spirometric abnormality were 74 and 55 %, respectively. Patients with an obstructive pattern were at greater risk of coronary heart disease (odds ratio (OR) 1.39 [confidence interval (CI) 1.00-1.93] vs. normal) and death (hazard ratio (HR) 1.53, 95 % CI 1.20-1.84) than subjects with normal spirometry. Restricted spirometry patterns were also associated with greater risk of coronary disease (odds ratio (OR) 1.7 [CI 1.23-2.35]) and death (Hazard ratio 1.40, 95 % CI 1.08-1.72). Smokers (≥ 20 pack years) age ≥ 40 years are at an increased risk for lung function abnormalities and those abnormalities are associated with greater presence of coronary heart disease and increased all-cause mortality. Use of the 20/40 rule could provide a simple method to enhance selection of candidates for spirometry evaluation in the primary care setting.


Systemic Racism and the Family Medical Leave Act (FMLA): Using Critical Race Theory to Build Equitable Family Leave Policies.
Past and current policies have led to the creation and sustainment of systemic racism. The Family and Medical Leave Act (FMLA) is a key contributor to sustaining health disparities for working Black women in the USA. Black women have a longstanding history of disadvantage and the current family leave policies make this demographic more vulnerable to economic hardship and eventually disparate health outcomes. Using data from the Family and Medical Leave Act in 2012 - Employee Survey (N = 1266), this study conducts logistic regression analyses to examine if this policy disparately benefits white men and white women compared to women of color. Respondents were categorized into leave takers (those who took family and medical leave as needed), leave needers (those who had an unmet need for leave), and employed only (those who neither needed nor took leave). As hypothesized, Black working women (vs. White working men) have the highest odds of having an unmet need for taking a leave followed by Latina women. In addition, Black working women (vs. White working men) had the highest odds of difficulty in making ends meet when they did take leave. The authors also conduct a policy analysis of the FMLA through a critical race theory (CRT) lens to offer policy recommendations, which deconstruct the role structural racism plays in the structure and implementation of the FMLA.


Mechanical embolectomy for acute ischemic stroke beyond six hours from symptom onset using MRI based perfusion imaging.
There is very limited data on the use of MRI based perfusion imaging to select patients with acute ischemic stroke and large vessel occlusion (LVO) for intraarterial therapy beyond 6h from onset. Our aim is to report the outcome of patients with acute ischemic stroke and large artery occlusion who presented beyond 6h from onset, had favorable MRI imaging profile, and underwent mechanical embolectomy. This is a single institution (Rhode Island Hospital) retrospective study between December 1st, 2015, and July 30th, 2016 that included patients with acute ischemic stroke and proximal LVO with CT ASPECTS of 6 or more and 6-24h from symptom onset who were assessed for mechanical embolectomy using MRI based perfusion imaging. Favorable imaging profile was defined based on prior studies as 1) DWI lesion volume (as defined as apparent diffusion coefficient<620×10-6mm2/s) of 70ml or less; 2) Penumbra volume (as defined by volume of tissue with Tmax>6s) of 15ml or greater; 3) A mismatch ratio of 1.8 or more; and 4) Volume of tissue with perfusion lesion with Tmax>10s is <100ml. Good outcome was defined as a 90-day mRS≤2. 41 patients met the inclusion criteria; 22 (53.7%) had favorable imaging profile and underwent mechanical embolectomy. The rate of good outcomes in this series was similar to that in a patient level pooled meta-analysis of the recent endovascular trials (63.6% vs. 46%, p=0.13). None of the patients in our cohort had symptomatic intracereberal hemorrhage. MRI perfusion based imaging may help select patients with acute ischemic stroke and proximal emergent LVO for embolectomy beyond the treatment window used in most endovascular trials. This provides compelling evidence for stroke centers to participate in ongoing trials using advanced imaging to study endovascular treatment in this patient population.


Assessing the Role of Trypsin in Quantitative Plasma and Single-Cell Proteomics toward Clinical Application.
Mass spectrometry-based bottom-up proteomics is rapidly evolving and routinely applied in large-scale biomedical studies. Proteases are a central component of every bottom-up proteomics experiment, digesting proteins into peptides. Trypsin has been the most widely applied protease in proteomics due to its characteristics. With ever-larger cohort sizes and possible future clinical application of mass spectrometry-based proteomics, the technical impact of trypsin becomes increasingly relevant. To assess possible biases introduced by trypsin digestion, we evaluated the impact of eight commercially available trypsins in a variety of bottom-up proteomics experiments and across a range of protease concentrations and storage times. To investigate the universal impact of these technical attributes, we included bulk HeLa cell lysate, human plasma, and single HEK293 cells, which were analyzed over a range of selected reaction monitoring (SRM), data-independent acquisition (DIA), and data-dependent acquisition (DDA) instrument methods on three LC-MS instruments. The quantification methods employed encompassed both label-free approaches and absolute quantification utilizing spike-in heavy-labeled recombinant protein fragment standards. Based on this extensive data set, we report variations between commercial trypsins, their source, and their concentration. Furthermore, we provide suggestions on the handling of trypsin in large-scale studies.


Outbreaks in distinct regions due to a single Klebsiella pneumoniae clone carrying a bla VIM-1 metallo-{beta}-lactamase gene.
From December 2004 to March 2005, 27 Klebsiella pneumoniae clinical isolates that were positive by the imipenem-EDTA double-disk synergy test and that exhibited a single macro-restriction pattern were recovered in two distinct Greek hospitals. The isolates carried a transferable bla(VIM-1) metallo-beta-lactamase gene in a class 1 integron. Reverse transcriptase PCR showed that the gene was similarly expressed in low- and high-level carbapenem-resistant isolates, indicating the existence of additional resistance mechanisms. The clonal spread of VIM-1-producing K. pneumoniae strains in distinct regions where up to now bla(VIM-2) and bla(VIM-4) alleles were common is worrisome.


[A frame shift mutation, Arg346fs mutation, is identified in cardiac myosin-binding protein C gene in a Chinese family with hypertrophic cardiomyopathy].
To explore the disease-causing gene mutation in Chinese with hypertrophic cardiomyopathy (HCM). The peripheral venous blood samples were collected from 5 HCM families without consanguinity, including 5 probands, 2 males and 3 females, 28 sporadic HCM patients, 18 males and 10 females, and 80 healthy controls. The exons in the functional regions of cardiac myosin-binding protein C (MYBPC3) were amplified with PCR and the amplified products were sequenced. A frame shift mutation-Arg346fs mutation in exon 13, the first mutation identified in Chinese-was discovered in one family with HCM. However, the members of the same HCM family with the Arg346fs mutation showed differences in phenotype and prognosis. Cardiac myosin-binding protein C (MYBPC3) may be one of the main disease-causing genes. The heterogeneity of phenotype suggests that multiple factors may be involved in the pathogenesis.


Body regional influences of L-menthol application on the alleviation of heat strain while wearing firefighter's protective clothing.
The purpose of this study was to investigate the influences of menthol application according to the amount of surface area on physiological and psychological heat strains, along with body regional influences. Male students underwent two stages of experiments: [Experiment 1] Cutaneous thermal threshold test at rest on eight body regions with/without a 0.8% menthol application at T (a) 28°C and 50% RH; [Experiment 2] Six exercise tests with/without a 0.8% menthol spray at T (a) 28°C and 40% RH, while wearing firefighter's protective clothing (No menthol, PC(NO); Face and neck menthol, PC(FN); Upper body menthol, PC(UP); Whole body menthol application, PC(WB)) or wearing normal clothing (No menthol, NC(NO); Upper body menthol, NC(UP)). Experiment 1 showed that menthol caused no significant influence on cutaneous warm thresholds, while menthol applications evoked earlier detection of cool sensations, especially on the chest (P = 0.043). Experiment 2 revealed that NC(UP), PC(UP) and PC(WB) caused lower mean skin temperature, especially with higher peripheral vasoconstrictions on the extremities at rest. During exercise, NC(UP), PC(UP) and PC(WB) induced greater and earlier increases in rectal temperatures (T (re)) and a delayed sweat response, but lessened psychological burdens (P < 0.05). Both physiological and psychological effects of PC(FN) were insignificant. For a composite analysis, individual Menthol Sensitivity Index at cooling in Experiment 1 had significant relationships with the threshold for T (re) increase and changes in heart rate in NC(UP) of Experiment 2 (P < 0.05). Our results indicate that menthol's topical influence is body region-dependent, as well as depending on the exposed body surface area.


Antioxidant inhibitors for cancer therapy.
Built-in cellular defense mechanisms play a major role in a tumor's protection against non-surgical antineoplastic therapies. Of these, the overexpression of antioxidants such as superoxide dismutase (SOD) may be the most important. Oxygen radicals are highly toxic, and have been implicated in various diseases, including carcinogenesis and aging. They produce a variety of pathological changes through lipid peroxidation and DNA damage. Therefore, treating free-radical-induced diseases with antioxidants has been an accepted therapeutic approach. Ironically, however, the underlying mechanism that most chemotherapeutic agents and ionizing radiation exert on tumor cell kill is not increased antioxidation but rather the production of more free radicals leading to irreversible tissue injury. A small increase in reactive oxygen species (ROS) following non-surgical antineoplastic therapies induces the expression of antioxidants such as SOD, but overproduction of ROS, conversely, exhausts the production of SOD and other adaptive antioxidant defenses. Based on these considerations, we hypothesize that the appropriate administration of antioxidant inhibitors and/or free-radical-generating compounds may be a useful strategy in the treatment of solid tumors.


Differential effects of the adenosine A₂A agonist CGS-21680 and haloperidol on food-reinforced fixed ratio responding in the rat.
Previous studies have shown that adenosine A(2A) receptors are colocalized with dopamine D(2) receptors on striatal neurons. Activation of these two receptors has antagonistic effects under a number of conditions suggesting that stimulation of adenosine A(2A) receptors may have behavioral effects resembling those produced by blockade of dopamine D(2) receptors, but this possibility has been investigated in a limited number of situations. We compared the effects of the adenosine A(2A) agonist CGS-21680 and the preferential D(2) dopamine antagonist haloperidol in a situation in which dopamine blockade produces a distinctive pattern of behavioral effects. Six rats were trained to lever press for food reward on a fixed ratio 15 schedule of reinforcement and then tested after being injected with various doses of CGS-21680 (0.064, 0.128, and 0.25 mg/kg) and haloperidol (0.25 and 0.1 mg/kg). Haloperidol produced a dose-dependent suppression of lever pressing with mean response rates declining across the duration of the test session. CGS-21680 also produced a dose-dependent suppression of responding, but this effect was not temporally graded, and responding was equivalently suppressed across the duration of the session. Additionally, CGS-21680 increased post-reinforcement pause duration to a much greater extent than did haloperidol. On this task, the behavioral effects of CGS-21680 do not resemble those produced by haloperidol. Several explanations of this discrepancy are possible, the most likely being that the observed behavioral effects of CGS-21680 result from an action at a site other than D(2) receptor-expressing striatal neurons.


Comparison of the practical diagnostic value of different tomographic movements.
The practical results of linear and circular tomography with angles of 6, 20, 30 and 45 degrees and spiral tomography were compared. The spiral proved to be suitable as a tomographic movement for different purposes. In zonography, circular movement with 6 degrees of deviation proved suitable. The linear movement presented no advantages when compared with the multidirectional movements.


Hyaluronic acid concentration in liver diseases.
The aim of this study was to evaluate the effect of liver diseases of different etiologies and clinical severity of liver cirrhosis on the serum level of hyaluronic acid. The results were compared with noninvasive markers of liver fibrosis: APRI, GAPRI, HAPRI, FIB-4 and Forn's index. Serum samples were obtained from 20 healthy volunteers and patients suffering from alcoholic cirrhosis (AC)-57 patients, non-alcoholic cirrhosis (NAC)-30 and toxic hepatitis (HT)-22. Cirrhotic patients were classified according to Child-Pugh score. Hyaluronic acid concentration was measured by the immunochemical method. Non-patented indicators were calculated using special formulas. The mean serum hyaluronic acid concentration was significantly higher in AC, NAC and HT group in comparison with the control group. There were significant differences in the serum hyaluronic acid levels between liver diseases, and in AC they were significantly higher than those in NAC and HT group. The serum hyaluronic acid level differs significantly due to the severity of cirrhosis and was the highest in Child-Pugh class C. The sensitivity, specificity, accuracy, positive and negative predictive values and the area under the ROC curve for hyaluronic acid and all non-patented algorithms were high and similar to each other. We conclude that the concentration of hyaluronic acid changes in liver diseases and is affected by the severity of liver cirrhosis. Serum hyaluronic acid should be considered as a good marker for noninvasive diagnosis of liver damage, but the combination of markers is more useful.


Comparison of mammary gland involution between 129S1 and C57BL/6 inbred mouse strains: differential regulation of Bcl2a1, Trp53, Cebpb, and Cebpd expression.
Genetic engineering has made the mouse an invaluable tool to address the function of individual genes in a targeted manner. Over the last decade it has become apparent that the genetic mouse strain background can significantly influence the phenotype of an engineered mouse. Therefore, it is essential to characterize the biology of the different wild-type background strains. In this study, we have compared mouse mammary gland involution in the 129S1 and C57BL/6 inbred strains and report significant differences at the molecular level with differential expression of Bcl2a1 (Bfl1), Trp53 (p53), Cebpb (C/EBP beta), and Cebpd (C/EBP delta). The C57BL/6 strain exhibits dynamic responses with induction of Trp53 and Cebpd and concomitant downregulation of Bcl2a1 during the first phase of involution. In contrast, expression of these genes does not change significantly in 129S1 mice. During the second phase, C57BL/6 glands contain more Cebpb than 129S1 glands. Nevertheless, involution proceeds morphologically with similar kinetics in both strains. The data demonstrate that the genetic response of mammary tissue varies significantly between 129S1 and C57BL/6. These results may provide a basis for the interpretation of strain-specific phenotypes in engineered mice and underline the importance of pure strains for large-scale expression studies with mutant mice.


Role of magnetic resonance imaging in the evaluation of diabetic foot with suspected osteomyelitis.
This study evaluated Magnetic Resonance Imaging (MRI) in infected diabetic foot ulcers. Sixteen diabetic patients underwent foot MRI between January 2006 and September 2007 for suspected unilateral osteomyelitis. Three of 16 patients showed radiographic changes due to Charcot neuropathic osteoarthropathy. Twelve of 16 patients also underwent MR angiography of the lower limbs for the purpose of planning surgical or endovascular treatment. The musculoskeletal and vascular MRI studies were retrospectively reviewed by three radiologists. The final diagnosis, based on clinical, imaging, microbiological and histological findings, was osteomyelitis in 13/16 cases. Foot MRI allowed a correct diagnosis in 15/16 patients, with 1 false positive result demonstrated by computed tomography (CT)-guided bone biopsy. MR angiography of the lower limbs was considered nondiagnostic in 5/12 patients in the infrapopliteal region owing to venous contamination. MRI has high sensitivity for the detection of osteomyelitis in the diabetic foot but lower specificity related to Charcot neuropathic osteoarthropathy. If diagnostic uncertainty persists, a bone biopsy is indicated. The inflammatory hyperaemia caused by the ulcer deteriorates the diagnostic quality of 40%-50% of MR angiography studies in the infrapopliteal region. In these cases, selective arteriography is appropriate, as it can be performed in the same session as angioplasty.


Autoionography.
A technique has been established for the autoradiography of beta-emitting radionuclides distributed on thin-layer chromatograms. The technique is derived from medical ionography and produces an electrostatic latent image of the distribution of radioactivity by using a planeparallel ionization chamber filled with a suitable gas. The latent image is formed on a highly insulating plastic sheet which covers one electrode of the ionization chamber and is made visible by methods employed in Xerography or related electrophotographic processes. An introduction to the theoretical basis of autoionography is presented and results of application of the technique are shown for prototype imaging chambers operating at pressures of from 1 to 100 atmospheres. The present sensitivity of autoionography compares favorably with that reported in the recent literature for film or film-fluorographic methods. An advantage of ionography is the simplicity and very low cost involved in producing each ionograph.


Effects of purine compounds on cholinergic nerves. Specificity of adenosine and related compounds on acetylcholine release in electircally stimulated guinea pig ileum.
The action of 21 purine compounds on the twitch response of the electrically stimulated guinea pig isolated ileum has been investigated. Adenosine and related compounds produced a dose-dependent depression of the response. Adenosine was the most potent and 2'-deoxyadenosine had one hundredth the potency of adenosine. Adenine, hypoxanthine, inosine, IMP, ITP, xanthine, xanthosine, XMP, XTP, guanine, GMP and GTP were ineffective at concentrations less than 1 mM. Adenosine (30 microgram) reduced the electrically induced ACh output from the ileal strips. The dose--depression curve for adenosine (0.1--30 microgram) was shifted to the right in the presence of xanthine derivatives and of these, theophylline was the most potent inhibitor of adenosine. On the other hand, dipyridamole (0.1--1 microgram) and hexobendine (0.1--1 microgram) shifted the curve to the left. They markedly inhibited 3H-adenosine uptake into the ileum. Theophylline (0.1 mM), dipyridamole (0.3 microgram) and hexobendine (0.3 microgram) did not affect tetrodotoxin-, adrenaline-, strychnine- and morphine-induced inhibition of the twitch response. The present investigations have revealed that adenosine and related compounds reduce ACh release from the intramural cholinergic nerves in the guinea pig ileum possibly in a specific manner (or through a specific receptor site) different from that of other inhibitors such as morphine.


RAGE signaling is required for AMPA receptor dysfunction in the hippocampus of hyperglycemic mice.
Diabetes in humans has been associated for a long time with cognitive dysfunction. In rodent animal models, cognitive dysfunction can manifest as impaired hippocampal synaptic plasticity. Particular attention has been concentrated on the receptor for advanced glycation end products (RAGE), which is implicated in multiple diabetic complications involving the development of vascular and peripheral nerve abnormalities. In this study, we hypothesize that RAGE signaling alters glutamate receptor function and expression, impairing synaptic transmission in the hippocampus. Using preparations of hippocampal slices from male mice, we show a RAGE-dependent decrease in long-term potentiation (LTP) and an increase in paired-pulse facilitation (PPF) following streptozotocin (STZ)-induced diabetes. Consistently, in hippocampal cultures from male and female neonatal mice, high glucose caused a RAGE-dependent reduction of AMPA- but not NMDA-evoked currents, and an increase in cytosolic reactive oxygen species (ROS). Consistently, when cultures were co-treated with high glucose and the RAGE antagonist FPS-ZM1, AMPA-evoked currents were unchanged. Hippocampi from STZ-induced hyperglycemic wild type (WT) mice showed increased RAGE expression concomitant with a decrease of both expression and phosphorylation (Ser 831 and 845) of the AMPA GluA1 subunit. We found these changes correlated to activation of the MAPK pathway, consistent with decreased pJNK/JNK ratio and the JNK kinase, pMEK7. As no changes in expression or phosphorylation of regulatory proteins were observed in hippocampi from STZ-induced hyperglycemic RAGE-KO mice, we report a RAGE-dependent impairment in the hippocampi of hyperglycemic WT mice, with reduced AMPA receptor expression/function and LTP deficits.


Lipid characterization of seed oils from high-palmitic, low-palmitoleic, and very high-stearic acid sunflower lines.
Information obtained in recent years regarding the enzymes involved in FA synthesis can now be applied to develop novel sunflower lines by incorporating enzymes with specific characteristics into lines with a defined background. We have generated three highly saturated mutant lines in this way and characterized their FA content. The new high-palmitic, low-palmitoleic lines CAS-18 and CAS-25, the latter on a high-oleic background, have been selected from the high-stearic mutant CAS-3 by introducing a deficient stearic acid desaturase in a high-palmitic background from the previously developed mutant lines CAS-5 and CAS-12, respectively. As such, the desaturation of palmitic acid and the synthesis of palmitoleic acid and its derivatives (asclepic and palmitolinoleic acids) were reduced in these high-palmitic lines, increasing the stearic acid content. Likewise, introducing a FA thioesterase from a high-palmitic line (e.g., CAS-5) into the high-stearic CAS-3 increased the stearic acid content from 27 to 32% in the new high-stearic line CAS-31. As previously described in high-palmitic lines, high growth temperatures did not reduce the linoleic acid content of the oil. Furthermore, the FA composition of TAG, DAG, and phospholipids was modified in these lines. Besides a high degree of saturation, the TAG from these new vegetable oils have a low content of saturated FA in the sn-2 position. The alpha asymmetric coefficient obtained also indicates that the saturated FA are asymmetrically distributed within the TAG molecules. Indeed, the disaturated TAG content rose from 31.8 to 48.2%. These values of disaturated TAG are the highest to date in a temperate oilseed.


Cryo-EM structure of the entire FtsH-HflKC AAA protease complex.
The membrane-bound AAA protease FtsH is the key player controlling protein quality in bacteria. Two single-pass membrane proteins, HflK and HflC, interact with FtsH to modulate its proteolytic activity. Here, we present structure of the entire FtsH-HflKC complex, comprising 12 copies of both HflK and HflC, all of which interact reciprocally to form a cage, as well as four FtsH hexamers with periplasmic domains and transmembrane helices enclosed inside the cage and cytoplasmic domains situated at the base of the cage. FtsH K61/D62/S63 in the β2-β3 loop in the periplasmic domain directly interact with HflK, contributing to complex formation. Pull-down and in vivo enzymatic activity assays validate the importance of the interacting interface for FtsH-HflKC complex formation. Structural comparison with the substrate-bound human m-AAA protease AFG3L2 offers implications for the HflKC cage in modulating substrate access to FtsH. Together, our findings provide a better understanding of FtsH-type AAA protease holoenzyme assembly and regulation.


Progesterone modulates pro-inflammatory cytokine expression profile after spinal cord injury: Implications for neuropathic pain.
Neuropathic pain is a frequent complication of spinal cord injury (SCI), still refractory to conventional treatment. Glial cell activation and cytokine production contribute to the pathology of central neuropathic syndromes. In this study we evaluated the effects of progesterone, a neuroactive steroid, on pain development and the spinal expression of IL-1β, its receptors (IL-1RI and IL-1RII) and antagonist (IL-1ra), IL-6 and TNFα, and NR1 subunit of NMDAR. Our results show that progesterone, by modulating the expression of pro-inflammatory cytokines and neuronal IL-1RI/NR1 colocalization, emerges as a promising agent to prevent chronic pain after SCI.


[Total reconstruction of the lower lid by the Mustardé's technic].
The total lower lid loss reconstructive technique of Mustardé is reported. The technique is presented step by step. The morphological and aesthetic results and the low incidence of complications are discussed.


Celastrol: A lead compound that inhibits SARS-CoV-2 replication, the activity of viral and human cysteine proteases, and virus-induced IL-6 secretion.
The global emergence of coronavirus disease 2019 (COVID-19) has caused substantial human casualties. Clinical manifestations of this disease vary from asymptomatic to lethal, and the symptomatic form can be associated with cytokine storm and hyperinflammation. In face of the urgent demand for effective drugs to treat COVID-19, we have searched for candidate compounds using in silico approach followed by experimental validation. Here we identified celastrol, a pentacyclic triterpene isolated from Tripterygium wilfordii Hook F, as one of the best compounds out of 39 drug candidates. Celastrol reverted the gene expression signature from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected cells and irreversibly inhibited the recombinant forms of the viral and human cysteine proteases involved in virus invasion, such as Mpro (main protease), PLpro (papain-like protease), and recombinant human cathepsin L. Celastrol suppressed SARS-CoV-2 replication in human and monkey cell lines and decreased interleukin-6 (IL-6) secretion in the SARS-CoV-2-infected human cell line. Celastrol acted in a concentration-dependent manner, with undetectable signs of cytotoxicity, and inhibited in vitro replication of the parental and SARS-CoV-2 variant. Therefore, celastrol is a promising lead compound to develop new drug candidates to face COVID-19 due to its ability to suppress SARS-CoV-2 replication and IL-6 production in infected cells.


Quinidine-induced allergic granulomatous angiitis: an unusual cause of acute renal failure.
A case of systemic allergic-type vasculitis after the administration of quinidine and digoxin is described. The renal biopsy findings are unique in that they describe an arteritis with eosinophilic infiltration and non-caseating granulomata. We believe quinidine is the antigen that was responsible for the reported findings.


Resveratrol decreases the insoluble Aβ1-42 level in hippocampus and protects the integrity of the blood-brain barrier in AD rats.
Our previous studies demonstrated resveratrol (Res) administration protected Alzheimer's disease (AD) rats from developing memory decline by anti-oxidation. Beta-amyloid peptide 1-42 (Aβ1-42) is not only the primary protein component of senile plaques in AD but also is believed to play an important part in its pathology. Increasing evidence has shown neuroinflammation and the integrity of the blood-brain barrier (BBB) is closely related to the pathogenesis of AD. The aim of the present study is to further elucidate whether Res prevents AD rats from inflammation induced by Aβ1-42 and protects the integrity of BBB. Rats were divided into six groups: (1) ovariectomized (OVX)+D-galactose (D-gal) 100mg/kg group (OVX+D-gal); (2-4) OVX, D-gal and Res 20, 40 and 80 mg/kg treated groups; and (5) OVX, D-gal and estradiol valerate 0.8 mg/kg treated group (ET); (6) Sham control group. 12 weeks later, Res 40 and 80 mg/kg treatment exhibited a significant decrease of Aβ1-42 compared with the OVX+D-gal rats of hippocampus, which was accompanied by decreased expression of advanced glycation endproducts (RAGE), matrix metalloprotein-9 (MMP-9), nuclear factor kappaB (NF-κB) and the increase of Claudin-5. These results suggest that Res is useful not only in protecting OVX+D-gal rats from neuroinflammation mediated by Aβ1-42 by decreasing the expression of NF-κB but also the integrity of BBB by increasing Claudin-5 and decreasing RAGE, MMP-9.


Dissociation of processing time and awareness by the inattentional blindness paradigm.
Consciousness researchers are interested in distinguishing between mental activity that occurs with and without awareness (i.e., explicit versus implicit processes). The inattentional blindness (IB) paradigm is an excellent tool for this question because it permits the independent manipulation of processing time and awareness. In the present study, we show that implicit texture segregation can occur during inattentional blindness, provided that the texture is exposed for a sufficient duration. In contrast, a Simon effect does not occur during inattentional blindness, even with similar exposure duration of the critical stimulus. This reveals a dissociation between processing time and awareness, consistent with the possibility of separate processing streams for explicit and implicit visual perception.


Retrospective chart review of patient socioeconomic status and language preference associated with live video telehealth in a pediatric dermatology practice.
Pediatric teledermatology rapidly expanded with the COVID-19 pandemic, and the impacts of this expansion on patients' access to care have not yet been entirely defined. In this retrospective study of 3027 patients in an academic pediatric dermatology practice, patients who identified as having a primary language other than English were less likely to access pediatric dermatology care during the COVID lockdown. This study did not identify a significant or meaningful difference in age, geography, socioeconomic status, ethnicity, or race between patients who were offered pediatric dermatology care that was either in-person or via synchronous telehealth. These findings are overall reassuring that there were not major disparities in telehealth utilization during the COVID shelter-in-place mandate, although highlight the need for institutions to ensure systems are in place to enhance telehealth access for patients with non-English primary language.


Enhanced Telehealth Home-Monitoring Intervention for Vulnerable and Frail Patients after Cardiac Surgery (THE-FACS Pilot Intervention Study).
Frail cardiac surgery patients have an increased risk of worse postoperative outcomes. The purpose of this study was to evaluate the implementation of a novel Telehealth Home monitoring Enhanced-Frailty And Cardiac Surgery (THE-FACS) intervention and determine its impact on clinical outcomes in frail patients post-cardiac surgery. Frail/vulnerable patients defined by Edmonton Frailty Scale (EFS > 4) undergoing cardiac surgery were prospectively enrolled (November 2019 -March 2020) at the New Brunswick Heart Centre. Exclusion criteria included age < 55 years, emergent status, minimally invasive surgery, lack of home support, and > 10-days postoperative hospital stay. Following standard training on THE-FACS, participants were sent home with a tablet device to answer questions about their health/recovery and measure blood pressure for 30-consecutive days. Transmitted data were monitored by trained cardiac surgery follow-up nurses. Patients were contacted only if the algorithm based on the patient's self-collected data triggered an alert. Patients who completed the study were compared to historical controls. The primary outcome of interest was to determine the number of patients that could complete THE-FACS; secondary outcomes included participant/caregiver satisfaction and impact on hospital readmission. We identified 86 eligible (EFS > 4), out of 254 patients scheduled for elective cardiac surgery during the study period (vulnerable: 34%). The patients who consented to participate in THE-FACS (64/86, 74%) had a mean age of 69.1 ± 6.4 years, 25% were female, 79.7% underwent isolated Coronary Artery Bypass Graft (CABG) and median EFS was 6 (5-8). 29/64 (45%) were excluded post-enrollment due to prolonged hospitalization (15/64) or requirement for hospital-to-hospital transfer (12/64). Of the remaining 35 patients, 21 completed the 30-day follow-up (completion rate:60%). Reasons for withdrawal (14/35, 40%) were mostly due to technical difficulties with the tablet. Hospital readmission, although non-significant, was reduced in THE-FACS participants compared to controls (0% vs. 14.3%). A satisfaction survey revealed > 90% satisfaction and ~ 67% willingness to re-use a home monitoring device. THE-FACS intervention can be used to successfully monitor vulnerable patients returning home post-cardiac surgery. However, a significant number of frail patients could not benefit from THE-FACS given prolonged hospitalization and technological challenges. Our findings suggest that despite overall excellent satisfaction in participants who completed THE-FACS, there remain major challenges for wide-scale implementation of technology-driven home monitoring programs as only 24% completed the study.


Protein S-Leu17Pro disrupts the hydrophobicity of its signal peptide causing a proteasome-dependent degradation.
Protein S is a vitamin K-dependent glycoprotein with important anticoagulant, fibrinolytic, anti-inflammatory, anti-apoptotic, and cytoprotective functions. Congenital protein S deficiency is an autosomal dominant thrombophilia due to protein S gene (PROS1) variations. Our group identified a variation in PROS1 that translates into protein S deficiency: c.50 T > C (p.Leu17Pro). Here, we investigated the mechanisms by which this variation results in protein S deficiency. The effect of L17P substitution on protein S signal peptide was predicted by in silico (a computational prediction technique) analysis of hydrophobicity and signal peptide cleavage. Recombinant protein S was overexpressed in HEK293 and COS-7 cells. Intracellular kinetics and extracellular secretion of recombinant protein S-L17P were analyzed by western blotting and immunocytochemistry. In silico hydrophobicity analysis showed that protein S-L17P had disrupted hydrophobic status in the h-region of its signal peptide. Under normal culture conditions, recombinant protein S -L17P was not detected in either transfectant cell lysates or medium. Upon treatment with a proteasome inhibitor, recombinant protein S-L17P was clearly detected in the cell lysate, but not in the culture medium. Recombinant protein S-L17P did not undergo post-translational modification with N-glycosylation, suggesting that the nascent polypeptide of recombinant protein S-L17P is not transported to the endoplasmic reticulum lumen, but is mislocalized to the cytosol. PROS1-L17P variation translates into protein S deficiency. Protein S-L17P causes its cytosolic mislocalization resulting in its proteasome-dependent degradation.


Avian spinal cord chimeras. Further studies on the neurological syndrome affecting the chimeras after birth.
These experiments bring new information concerning the immunological status after birth of quail----chick spinal cord chimeras. Such birds have been produced using recipient flocks of chickens different from those in our previous experiments. The breakdown of tolerance after hatching has been recorded and found to vary with the origin of the embryos. Chickens of broiler JA 657 strain and of a white leghorn strain raised in Japan started to exhibit signs of neural graft rejection later in life than the white leghorn chickens from a French breeder used in our previous studies. As previously described, in two animals, long-term tolerance was observed only for allogeneic chick----chick neural tube grafts. In one chimera the neurological syndrome resulting from rejection was reversible, and no signs of immune attack of the grafted central nervous tissue could be detected at sacrifice. This and other observations reported in this article strongly support the contention that the host immune response to foreign neural tissues starts in peripheral nerves and ganglia where no blood-brain barrier exists rather than in the spinal cord. A humoral response of the host against non-polymorphic quail antigens present on fibroblasts was observed in all birds at the time of rejection.


Annual variations of black carbon over the Yangtze River Delta from 2015 to 2018.
In this study, the black carbon (BC) measurements in the atmosphere of Nanjing, China were continuously conducted from 2015 to 2018 using a Model AE-33 aethalometer. By combining dataset of PM2.5, PM10, CO, NO2, SO2, O3 and meteorological parameters, the temporal variations and the source apportionment of BC were given in this study. The results showed that the PM2.5 mass concentrations decreased in Nanjing, with an average annual rate of variation of 6.50 μg/(m3⋅year). Differently, the annual average concentrations of BC increased with an average annual variation rate of 214.71 ng/(m3⋅year). The seasonal variations showed the pattern of BC mass concentrations in winter > autumn > spring > summer. The diurnal variations of BC mass concentrations showed a double-peak in all four seasons. The first peak occurred at approximately 7:00 in spring, summer and autumn and around 8:00 in winter. The second peak took place after 18:00. The average AAE (absorption Ångström exponent) was 1.26 with a maximum of 1.35 during wintertime and the lowest (1.12) during summertime. In addition, the AAE was smaller in the daytime than that at night, with a minimum occurring between 13:00 and 14:00. BC and visibility show a good power-function relationship at different humidity levels. The average values of the visibility thresholds of the BC mass concentrations in spring, summer, autumn and winter were 1.326, 5.522, 1.340 and 0.708 μg/m3, respectively. The greater the relative humidity, the smaller the visibility threshold for the BC mass concentrations was.


Perspectives - Social Change from the Inside Out. From Fixation to Foundation. From Competition to Change.
After a brief overview of the author's journey as a humanitarian and researcher, this article offers an introduction in the why, how, and what of a new multidisciplinary paradigm to understand (and improve) human behavior at the individual and collective levels called POZE. The logic of POZE underpins five books that appear at Palgrave/Springer in 2020/21. It is based on the understanding that human existence results from four dimensions, soul, heart, mind, and body, which find their expression in aspirations, emotions, thoughts, and sensations. Through their four-dimensionality individuals are symmetrical to the four dimensions that shape the society, which they are part of. Individuals are the micro entity of a four-dimensional collective reality that encompasses communities and institutions in the meso-dimension, and countries and economies in the macro-dimension. Altogether micro, meso and macro are integral parts of the meta dimension, Planet Earth; the latter also includes non-anthropocentric aspects such as Nature. POZE provides insights about the multiple dynamics that shape our individual and collective experience. Moreover, it provides practical guidance to optimize the interplay between them. As a result of this understanding, it posits that change is possible. Moving towards a fair inclusive world, characterized by a life of quality for everyone 1) is at reach; 2) is achievable; 3) involves everyone as both a right-holder and duty-bearer; and 4) is to the benefit of everyone. POZE has four meanings: it i) translates as 'inner peace' from Haitian Creole, country where the dynamic began in 2017; ii) is an acronym that encompasses the four core concepts of the paradigm (Purpose, Om, Zoom, Expression); iii) is a representation of the four outcomes of the logic (Perspective, Optimization, Zenith, Exposure); finally it iv) stands for an exercise to nurture inner peace daily (Pause, Observe, Zoom in, Experience). These will be explored further in the article.


Source, temporal variation and health risk of volatile organic compounds (VOCs) from urban traffic in harbin, China.
The main of this work investigated the levels, emission sources, and associated health risks of ambient volatile organic compounds (VOCs) closed urban traffic trunk from June 2017 to November 2018. The seasonal variation trend for total VOCs (TVOCs) concentrations was autumn > winter > summer > spring. During the daily fluctuations in summer, the TVOC concentrations appeared to be the highest at midnight and the lowest at 14:00. In spring, autumn, and winter, the concentrations of TVOCs reached the highest levels at 06:00 and dropped to the lowest levels at 14:00 to 15:00; then, the levels increased after 20:00. Aromatics were the most important types of ambient VOCs for the formation of secondary organic aerosols (SOAs). The Positive Matrix Factorization (PMF) source analysis indicated that the traffic emission accounted for 28.9% of TVOCs, followed by combustion (24.7%), industrial (21.3%), gasoline volatilization (12.4%), and solvent (11.7%) sources. Carcinogenic and non-carcinogenic risks via inhalation exposure to the selected 10 toxic VOCs may be of more concern for residents nearby traffic trunk in Harbin in autumn.


Portable fluid circuit device containing printed silicone microvessels as a training aid for arterial microanastomosis.
Anastomosis of the microvessels requires high-level skills and extensive basic training. This study was performed to introduce and evaluate an inexpensive laboratory device as a training aid. Micro-tubes of 0.8 mm inner diameter and 0.5/0.8 mm wall thickness mimicking human vein/artery were printed from a silicon-containing hydrogel using three-dimensional printing technology. The hydrogel components are optimized to render the printed tubes biomechanical features resembling the blood vessels of a living organism. These artificial vessels were connected to a pump for fluid flow, simulating the blood circulation. Forty medical interns were assigned to two equal groups. The 20 interns in group A practiced anastomosis using the training aid for a total of 10 hours over 5 days. The 20 interns in group B practiced anastomosis using the traditional gum pieces and silicone tubes. Then, all interns performed anastomosis on rat carotid arteries, and their performance was scored by a team of five experienced maxillofacial surgeons. The average success score and time required for anastomosis were compared between the two groups. The mean success score of group A was significantly higher than that of group B (0.83 ± 0.12 vs 0.64 ± 0.10, P < 0.001). The mean anastomosis time of group A was significantly shorter than that of group B (10.2 ± 1.1 vs 17.2 ± 1.4 minutes, P < 0.001). This training device for vessel microanastomosis is an inexpensive, practical, and effective tool for use in laboratories and also reduces the use of animals.


Lateral Wedge Insoles for Reducing Biomechanical Risk Factors for Medial Knee Osteoarthritis Progression: A Systematic Review and Meta-Analysis.
Lateral wedge insoles are intended to reduce biomechanical risk factors of medial knee osteoarthritis (OA) progression, such as increased knee joint load; however, there has been no definitive consensus on this topic. The aim of this systematic review and meta-analysis was to establish the within-subject effects of lateral wedge insoles on knee joint load in people with medial knee OA during walking. Six databases were searched from inception until February 13, 2015. Included studies reported on the immediate biomechanical effects of lateral wedge insoles during walking in people with medial knee OA. Primary outcomes of interest relating to the biomechanical risk of disease progression were the first and second peak external knee adduction moment (EKAM) and knee adduction angular impulse (KAAI). Eligible studies were pooled using random-effects meta-analysis. Eighteen studies were included with a total of 534 participants. Lateral wedge insoles resulted in a small but statistically significant reduction in the first peak EKAM (standardized mean difference [SMD] -0.19; 95% confidence interval [95% CI] -0.23, -0.15) and second peak EKAM (SMD -0.25; 95% CI -0.32, -0.19) with a low level of heterogeneity (I(2) = 5% and 30%, respectively). There was a favorable but small reduction in the KAAI with lateral wedge insoles (SMD -0.14; 95% CI -0.21, -0.07, I(2) = 31%). Risk of methodologic bias scores (quality index) ranged from 8 to 13 out of 16. Lateral wedge insoles cause small reductions in the EKAM and KAAI during walking in people with medial knee OA. Current evidence demonstrates that lateral wedge insoles appear ineffective at attenuating structural changes in people with medial knee OA as a whole and may be better suited to targeted use in biomechanical phenotypes associated with larger reductions in knee load.


Optimality in forward dynamics simulations.
This paper discusses a methodology and an algorithm for the analysis of dynamics of bio-mechanical systems, and in particular of optimal movement patterns between initial and target configurations. The basic formulation utilizes a finite element time discretization and establishes a large set of equations in displacements and forces. These are solved simultaneously for the whole time interval considered. The algorithm allows different optimization criteria for the movement, based on either the smoothness of the movement or the minimization of needed controls or control rates. It is primarily aimed at musculoskeletal simulations with either the joint resultant moments or the redundant muscular tensions as unknowns. Kinetic and kinematic constraints can be introduced for the obtained movement. Examples show that the obtained results are strongly dependent on the optimality criterion used. Systematic usage of the algorithm can improve knowledge about optimal motion planning.


α-Synuclein arginylation in the human brain.
Alpha-synuclein (α-syn) exhibits pathological misfolding in many human neurodegenerative disorders. We previously showed that α-syn is arginylated in the mouse brain and that lack of arginylation leads to neurodegeneration in mice. Here, we tested α-syn arginylation in human brain pathology using newly derived antibodies in combination with Western blotting, biochemical assays, and experiments in live neurons. We found that α-syn was arginylated in the human brain on E46 and E83, two sites previously implicated in α-syn pathology and familial cases of Parkinson's disease. The levels of arginylation in different brain samples ranged between ~ 3% and ~ 50% of the total α-syn pool, and this arginylation nearly exclusively concentrated in the subcellular α-syn fraction that sedimented at low centrifugation speeds and appeared to be simultaneously targeted by multiple posttranslational modifications. Arginylated α-syn was less susceptible to S129 phosphorylation and pathological aggregation in neurons. The arginylation level inversely correlated with the overall α-syn levels and with patient age, suggesting a possible causal relationship between arginylation decline and α-syn-dependent neuropathology. We propose that α-syn arginylation constitutes a potential neuroprotective mechanism that prevents its abnormal accumulation during neurodegeneration and aging in the human brain.


Basophils and their effector molecules in allergic disorders.
Basophils are the rarest granulocytes which represent <1% of peripheral blood leukocytes. Basophils bear several phenotypic similarities to tissue-resident mast cells and therefore had been erroneously considered as blood-circulating mast cells. However, recent researches have revealed that basophils play nonredundant roles in allergic inflammation, protective immunity against parasitic infections and regulation of innate and acquired immunity. Basophils are recruited to inflamed tissues and activated in an IgE-dependent or IgE-independent manner to release a variety of effector molecules. Such molecules, including IL-4, act on various types of cells and play versatile roles, including the induction and termination of allergic inflammation and the regulation of immune responses. Recent development of novel therapeutic agents has enabled us to gain further insights into basophil biology in human disorders. In this review, we highlight the recent advances in the field of basophil biology with a particular focus on the role of basophils in allergic inflammation. Further studies on basophils and their effector molecules will help us identify novel therapeutic targets for treating allergic disorders.


Scintigraphic imaging using 99mTc-labeled PEG liposomes allows early detection of experimental invasive pulmonary aspergillosis in neutropenic rats.
The value of scintigraphic imaging using 99mTc labeled poly(ethyleneglycol) (PEG) -liposomes for detecting invasive pulmonary aspergillosis at different stages of the disease was investigated in a rat model. At 24, 48, 72, 120 and 168 h after fungal inoculation scintigraphic images were obtained and biodistribution of the radiolabel was determined. Findings were compared with serum galactomannan detection and other parameters of progression of fungal infection. At 48 h liposomal uptake in the infected left lung was increased significantly and 82% of the scintigraphic images was assessed positive. Serum galactomannan was only detected at 72 h and later. Liposomal uptake in the infected left lung increased over time and was significantly correlated with both the size of the pulmonary hemorrhagic lesion and the levels of circulating galactomannan. It was concluded that scintigraphic imaging using 99mTc-PEG-liposomes allows early detection of invasive pulmonary aspergillosis in this model, and that liposomal uptake in the infected lung was strongly associated with the severity of the disease.


[Study on the effect of extract of Chinese chive seed in warming kidney and enhancing yang].
To explore the effect of extract from Chinese chive seed in warming kidney and enhancing yang. The influence of extract from Chinese chive seed on the erection of penis of was investigated in adult male rats with experimental insufficiency of the kidney-yang produced by both removal of double spermaries and high dose of hydrocortisone. The extract of Chinese chive seed enhanced the responsiveness of the penis of emasculate rats to outside stimulus, promoted the resistance of the emasculated rats to cold and tiredness and increased autonomous activity. The extract of Chinese chive seed has the effect of warming kidney and enhancing yang.


Evaluation of genotoxic effects induced by exposure to antineoplastic drugs in lymphocytes and exfoliated buccal cells of oncology nurses and pharmacy employees.
The continuous introduction of new antineoplastic drugs and their use as complex mixture emphasize the need to carry out correct health risk assessment. The aim of this study was to evaluate genotoxic effects of antineoplastic drugs in nurses (n=25) and pharmacy technicians (n=5) employed in an oncology hospital. The nurses administered antineoplastic drugs in the day-care hospital (n=12) and in the wards (n=13), and pharmacy technicians prepared the drugs in the central pharmacy. We performed the micronucleus (MN) test with lymphocytes and exfoliated buccal cells and conducted traditional analysis of chromosomal aberrations (CA). Thirty healthy subjects were selected as controls. Monitoring of surface contamination with cyclophosphamide, 5-fluorouracil, ifosfamide, cytarabine, and gemcitabine showed the presence of detectable levels only for cyclophosphamide, 5-fluorouracil and ifosfamide. In addition, we measured the 5-fluorouracil metabolite alpha-F-betaalanine in the urine of all subjects and found significant concentrations only in 3 out of 25 nurses. The micronucleus assay with lymphocytes did not show significant differences between exposed and control groups, while the same test with exfoliated buccal cells found higher values in nurses administering antineoplastic drugs than in pharmacy employees. In the CA analysis, we detected in exposed groups a significant increase (about 2.5-fold) of structural CA, particularly breaks (up to 5.0-fold). Our results confirm the genotoxic effect of antineoplastic drugs in circulating blood lymphocytes. Moreover, in exfoliated buccal cells the data show more consistent genetic damage induced during administration of the antineoplastic drugs than during their preparation. The data also stress the use of this non-invasive sampling, to assess occupational exposure to mixture of chemicals at low doses.


Control of iron metabolism in bacteria.
Bacteria depend upon iron as a vital cofactor that enables a wide range of key metabolic activities. Bacteria must therefore ensure a balanced supply of this essential metal. To do so, they invest considerable resourse into its acquisition and employ elaborate control mechanisms to eleviate both iron-induced toxitiy as well as iron deficiency. This chapter describes the processes that bacteria engage in maintaining iron homeostasis. The focus is Escherichia coli, as this bacterium provides a well studied example. A summary of the current status of understanding of iron management at the 'omics' level is also presented.


CK2 phospho-independent assembly of the Tel2-associated stress-signaling complexes in Schizosaccharomyces pombe.
An evolutionarily conserved protein Tel2 regulates a variety of stress signals. In mammals, TEL2 associates with TTI1 and TTI2 to form the Triple T (TTT: TEL2-TTI1-TTI2) complex as well as with all the phosphatidylinositol 3-kinase-like kinases (PIKKs) and the R2TP (Ruvbl1-Ruvbl2-Tah1-Pih1 in budding yeast)/prefoldin-like complex that associates with HSP90. The phosphorylation of TEL2 by casein kinase 2 (CK2) enables direct binding of PIHD1 (mammalian Pih1) to TEL2 and is important for the stability and the functions of PIKKs. However, the regulatory mechanisms of Tel2 in fission yeast Schizosaccharomyces pombe remain largely unknown. Here, we report that S. pombe Tel2 is phosphorylated by CK2 at Ser490 and Thr493. Tel2 forms the TTT complex with Tti1 and Tti2 and also associates with PIKKs, Rvb2, and Hsp90 in vivo; however, the phosphorylation of Tel2 affects neither the stability of the Tel2-associated proteins nor their association with Tel2. Thus, Tel2 stably associates with its binding partners irrespective of its phosphorylation. Furthermore, the Tel2 phosphorylation by CK2 is not required for the various stress responses to which PIKKs are pivotal. Our results suggest that the Tel2-containing protein complexes are conserved among eukaryotes, but the molecular regulation of their formation has been altered during evolution.


1,25-Dihydroxyvitamin D stimulation of specific membrane proteins in chick intestine.
Vitamin D-deficient chicks were injected intracardially with physiological doses of 1,25-dihydroxycholecalciferol (1,25-(OH)2D3) and the formation of intestinal brush-border proteins was followed in vitro. Within 4 h of receiving the hormone the incorporation of radioactive leucine into at least two proteins in the brush-borders was increased. The apparent molecular weights of these proteins were 45 000 and 84 000. The change in the synthesis of these proteins was followed with time and compared with the concomitant changes in intestinal calcium transport. The relationship of these changes is such that there is a strong possibility that the proteins are involved in calcium absorption.


Granulomas obstruct lymphatics in all layers of the intestine in Crohn's disease.
After an earlier study defining immunolabeled lymphoid follicles, obstructed lymphatics, and granulomas of the diseased ilea of 24 Crohn's disease patients, we chose to trace the lymphatics of these cases and 10 additional by serial sectioning. Particular attention was given to establishing physical continuity between granuloma-obstructed lymphatics and lymphatics with 'lymphocytic thrombi'. Formalin-fixed paraffin-embedded tissue blocks from resected diseased ilea and proximal colons from 34 patients were reviewed. Patients were 13 men and 21 women, aged 14-60 years. Duration of disease ranged from 1 month to 10 years. Immunohistochemistry employed D2-40 antibody to label lymphatics and anti-CD68 to label granulomas. Twenty-nine of the 34 (85%) resection tissues had lymphangectasia, in mucosa, submucosa, and subserosa. In 53% of the specimens, lymphatics of the various layers were obstructed by granulomas that filled the lumina. In 44%, 15/34, there were also distended lymphatics that were totally plugged with lymphocytes. In 10 of the 15, serial sections revealed continuity between the lymphocyte-plugged lymphatics and the endolymphatic granulomatous obstruction downstream. In 5 of the cases, D2-40 immunostaining revealed redundant lymphatic endothelium interwoven with the granuloma cells. Granulomas totally obstruct lymphatics in all layers of the intestine in Crohn's disease. Upstream of these obstructions, lymphatics are distended with lymphocytes. The degree and extent of this potentially irreversible 'lymphangitis nodosa' have undoubtedly confounded treatment regimens and clinical trials. There currently are no imaging methods to demonstrate the lymphangitis, nor treatments to resolve it.


Electronic deoxyribonucleic acid (DNA) microarray detection of viable pathogenic Escherichia coli, Vibrio cholerae, and Salmonella typhi.
An electronic deoxyribonucleic acid (DNA) microarray technique was developed for detection and identification of viable Escherichia coli O157:H7, Vibrio cholerae O1, and Salmonella typhi. Four unique genes, the E. coli O157 lipopolysaccharide (LPS) gene (rfbE) and H7 flagellin gene (fliC), the V. cholerae O1 LPS gene (rfbE), and the S. typhi LPS gene (tyv), were chosen as the targets for detection. These targets were selectively amplified from mRNA of viable cells using reverse transcription polymerase chain reaction (RT-PCR) and detected using the electronic DNA microarray technique. Specific captures and reporters were designed and examined for selective detection and correct identification of the target pathogens. The technique was able to detect as few as 2-150 cells of E. coli O157:H7. The co-presence of six other common bacteria and a parasite at 10- and 1000-fold higher concentrations than the target E. coli O157:H7 did not interfere with the specific detection. Comparative analysis of live and heat-killed E. coli O157:H7 cells showed that the technique only responded to the viable cells and not to the dead cells. Thus, the integration of RT-PCR of specific mRNA with the electronic DNA microarray technique enables specific and sensitive detection of viable target cells. This technique is potentially useful for high throughput screening of multiple pathogenic bacteria in different samples.


Fibrin D-dimer, tissue-type plasminogen activator, von Willebrand factor, and risk of incident stroke in older men.
Abnormalities in blood coagulation and the fibrinolytic system have been associated with increased risk of stroke, but few prospective studies have studied the associations in older adults. We have examined the associations between fibrin D-dimer, tissue-type plasminogen activator, and von Willebrand factor (vWF) and risk of stroke in older men and examined their predictive roles separately in normotensive and hypertensive men. Prospective study of 3358 men aged 60 to 79 years with no previous diagnosis of myocardial infarction or stroke and without atrial fibrillation followed-up for an average of 9 years, during which there were 187 incident stroke events. Increased levels of D-dimer and vWF were associated with significantly increased risk of major stroke events after adjustment for potential confounders, including systolic blood pressure (adjusted hazard ratios and 95% confidence interval per standard deviation increase in D-dimer and vWF were 1.24 [95% confidence interval, 1.08-1.44] and 1.25 [95% confidence interval, 1.09-1.45], respectively). No associations were seen with tPA after adjustment. The positive associations between D-dimer and vWF and incident stroke remained after additional adjustment for markers of inflammation (C-reactive protein, IL-6). D-dimer was associated with stroke in both normotensive and hypertensive men; vWF showed stronger associations in normotensive than in hypertensive men (test for interaction: P=0.52 for D-dimer; P<0.01 for vWF). Fibrin D-dimer and vWF are associated with increased risk of stroke in older men. These associations were not explained by their associations with inflammation. D-dimer may be a useful marker to identify those at high risk for stroke among hypertensive men.


Substance P in primary afferent neurons of the female rat reproductive system.
The amount of substance P-immunoreactivity (SP-I) was studied in the female rat reproductive organs (uterus, cervix, vagina and ovary) in the diestrous and estrous stages of the estrous cycle, after ovariectomy and on days 7, 14 and 19 of pregnancy. The concentration of SP-I (pmol X g-1 tissue) was generally highest in the vagina followed by cervix, uterus and ovary. SP-I concentrations in all reproductive organs were significantly higher following ovariectomy but significantly lower during pregnancy compared to concentrations from intact rats. There were no significant differences in the total content of SP-I per organ during the estrous cycle, after ovariectomy or during pregnancy (cervix, vagina). SP-I concentrations were markedly reduced in the reproductive organs of adult rats treated with capsaicin as neonates. This led to the conclusion that SP in reproductive organs is present in primary afferent fibers. The findings indicate that the number of SP-I containing primary afferent fibers in the female reproductive organs are stable elements neither increasing nor decreasing in response to changing hormonal levels or to the tissue growth and differentiation occurring during the estrous cycle or pregnancy.


Are lymphocytes concerned with our definition of idiotypes?
For some, idiotypes are interesting as markers of individual molecules, providing the basis for a taxonomy of B- and T-cell clones. For us, idiotypes are components of a larger network structure of variable regions, and their shapes are of significance because they establish connectivity. Each unique specificity per se is less interesting, for it is interchangeable without altering network organization. These issues are critical for delineating concepts of autoimmunity and for choosing between 'nonspecific' and 'targeted' approaches of immunoglobulin therapy in autoimmune diseases.


Comparison of quantitative flow ratio and fractional flow reserve with myocardial perfusion scintigraphy and cardiovascular magnetic resonance as reference standard. A Dan-NICAD substudy.
Quantitative flow ratio (QFR) and fractional flow reserve (FFR) have not yet been compared head to head with perfusion imaging as reference for myocardial ischemia. We aimed to compare the diagnostic accuracy of QFR and FFR with myocardial perfusion scintigraphy (MPS) or cardiovascular magnetic resonance (CMR) as reference. This study is a predefined post hoc analysis of the Dan-NICAD study (NCT02264717). Patients with suspected coronary artery disease by coronary computed tomography angiography (CCTA) were randomized 1:1 to MPS or CMR and were referred to invasive coronary angiography with FFR and predefined QFR assessment. Paired data with FFR, QFR and MPS or CMR were available for 232 vessels with stenosis in 176 patients. Perfusion defects were detected in 57 vessel territories (25%). For QFR and FFR the diagnostic accuracy was 61% and 57% (p = 0.18) and area under the receiver operating curve was 0.64 vs. 0.58 (p = 0.22). Stenoses with absolute indication for stenting due to diameter stenosis > 90% by visual estimate were not classified as significant by either QFR or MPS/CMR in 21% (7 of 34) of cases. The diagnostic performance of QFR and FFR was similar but modest with MPS or CMR as reference. Comparable performance levels for QFR and FFR are encouraging for this pressure wire-free diagnostic method.


Natural variation in expression of genes associated with carotenoid biosynthesis and accumulation in cassava (Manihot esculenta Crantz) storage root.
Cassava (Manihot esculenta Crantz) storage root provides a staple food source for millions of people worldwide. Increasing the carotenoid content in storage root of cassava could provide improved nutritional and health benefits. Because carotenoid accumulation has been associated with storage root color, this study characterized carotenoid profiles, and abundance of key transcripts associated with carotenoid biosynthesis, from 23 landraces of cassava storage root ranging in color from white-to-yellow-to-pink. This study provides important information to plant breeding programs aimed at improving cassava storage root nutritional quality. Among the 23 landraces, five carotenoid types were detected in storage root with white color, while carotenoid types ranged from 1 to 21 in storage root with pink and yellow color. The majority of storage root in these landraces ranged in color from pale-to-intense yellow. In this color group, total β-carotene, containing all-E-, 9-Z-, and 13-Z-β-carotene isomers, was the major carotenoid type detected, varying from 26.13 to 76.72 %. Although no α-carotene was observed, variable amounts of a α-ring derived xanthophyll, lutein, was detected; with greater accumulation of α-ring xanthophylls than of β-ring xanthophyll. Lycopene was detected in a landrace (Cas51) with pink color storage root, but it was not detected in storage root with yellow color. Based on microarray and qRT-PCR analyses, abundance of transcripts coding for enzymes involved in carotenoid biosynthesis were consistent with carotenoid composition determined by contrasting HPLC-Diode Array profiles from storage root of landraces IAC12, Cas64, and Cas51. Abundance of transcripts encoding for proteins regulating plastid division were also consistent with the observed differences in total β-carotene accumulation. Among the 23 cassava landraces with varying storage root color and diverse carotenoid types and profiles, landrace Cas51 (pink color storage root) had low LYCb transcript abundance, whereas landrace Cas64 (intense yellow storage root) had decreased HYb transcript abundance. These results may explain the increased amounts of lycopene and total β-carotene observed in landraces Cas51 and Cas64, respectively. Overall, total carotenoid content in cassava storage root of color class representatives were associated with spatial patterns of secondary growth, color, and abundance of transcripts linked to plastid division. Finally, a partial carotenoid biosynthesis pathway is proposed.


Chemical composition and bile acid binding activity of products obtained from amaranth (Amaranthus cruentus) seeds.
Cardiovascular diseases are currently the greatest cause of mortality in the world, and dislipidemia is appearing as one of the most important risk factors. The binding of bile acids (BAs) has been hypothesized as a possible mechanism by which dietary fibers lower blood cholesterol levels. Besides the fibers, other components in the amaranth seeds may be related to this hypocholesterolemic effect. The objective of the present study was to evaluate the BA binding capacity of some products obtained from defatted amaranth flour (DAF) and from the amaranth protein concentrate (APC). The alkaline residue, rich in fibers (8.6%), presented the lowest binding activity for the BAs tested, with the exception of glycocholic acid. The DAF showed intermediary binding activity for all the BAs tested, although similar to that of the APC for deoxycholic acid, and to that of the amaranth protein hydrolysate (APH) for taurocholic acid. The DAF and APC showed binding activity for secondary bile acids toxic to the intestinal mucus. From the results, amaranth products were shown to have the ability to bind BAs, but it was not possible to affirm whether the main component responsible for this activity was the proteins, fibers or eventually some other non-evaluated component.


Inequity in health. A case study.
This article presents a particular case of inequity in health, that of two types of Israeli urban settlement: development towns and veteran towns. Inequity in health is demonstrated by the varying levels of resources allocated to each type of community, by the differences in health-care utilization (process), and by the diversity of external factors affecting the two categories of towns. Despite the existence of almost universal health insurance coverage in Israel, it is shown that inhabitants of less privileged development towns are more prone to inequitable health outcomes with respect to the wealthier populations living in veteran towns. This case illustrates an integrated approach to inequity in health, including the health-care system structure, utilization patterns, and the socio-demographic-economic background of different strata.


[Predictability of Gleason score and reduction time (tau) of prostatic volume after castration for the prognosis of prostatic cancer].
The efficacy of the reduction time (tau) after castration as a prognostic factor was examined by comparing to Gleason score. The change of prostatic volume after castration was observed from the castration to 3 months after in 24 cases of prostatic cancer. Prostatic volume was examined by transrectal ultrasonography of the prostate. Survival curves was calculated by Kaplan-Meier method. Differences among survival curves were analyzed using Cox-Mantel test. tau had a close relationship to the prognosis of each case (Wilcoxon test: p < 0.05, Cox-Mantel test: p < 0.05). Gleason score had a weak relationship to prognosis (Wilcoxon test: N. S., Cox-Mantel test: p < 0.05). tau was efficient as prognostic factor compared to Gleason score.


Malignant Left Ventricular Outflow Tract Obstruction: A Reason to Operate?
A 57-year-old man with high-grade synovial sarcoma was found to have cardiac involvement of his malignancy. Intracardiac tumor resulted in dynamic left ventricular outflow tract obstruction and severe mitral regurgitation. He underwent mitral valve replacement and had no cardiovascular symptoms at 1-year follow-up. (Level of Difficulty: Intermediate.).


The Interaction between Macrophages and Triple-negative Breast Cancer Cells Induces ROS-Mediated Interleukin 1α Expression to Enhance Tumorigenesis and Metastasis.
Triple-negative breast cancer (TNBC) has higher mortality than non-TNBC because of its stronger metastatic capacity. Increasing studies reported that TNBC tumors had more macrophage infiltration than non-TNBC tumors, which promoted the metastasis of TNBC cells. However, how TNBC cells become more malignant after interacting with macrophages is less reported. In this study, it is observed that when TNBC cells are co-cultured with macrophages, they display higher viability and stronger metastatic ability than non-TNBC cells. Mechanistic studies reveal that TNBC cells acquired these abilities via interactions with macrophages in three phases. First, within 12 h of co-culture with macrophages, some TNBC cells have significantly elevated levels of reactive oxygen species (ROS), which upregulate interleukin 1α (IL1α) expression in ERK1/2-c-Jun- and NF-κB-dependent manners at 24-48 h. Second, the secreted IL1α bound to IL1R1 activates the ERK1/2-ZEB1-VIM pathway which increases metastasis. Third, IL1α/IL1R1 facilitates its own synthesis and induces the expression of IL1β and IL8 at 72-96 h through the MKK4-JNK-c-Jun and NF-κB signaling pathways. Moreover, a higher level of IL1α is positively correlated with more macrophage infiltration and shorter overall survival in breast cancer patients. Thus, reducing ROS elevation or downregulating IL1α expression can serve as new strategies to decrease metastasis of TNBC.


Investigating the potential of functionalized MCM-41 on adsorption of Remazol Red dye.
The modification of MCM-41 was performed with 3-aminopropropyltrimethoxysilane. The structural order and textural properties of the synthesized materials were studied by X-ray diffraction, Fourier transform infrared spectroscopy, thermogravimetry/differential thermogravimetry, nitrogen adsorption, and desorption analysis. The adsorption capacity of NH2-MCM-41 was studied with Remazol Red dye. The following parameters were studied in the adsorption process: pH, temperature, adsorbent dosage, and initial concentration. The desorption process was studied in different concentrations of NaOH solutions. The Freundlich isotherm model was found to be fit with the equilibrium isotherm data. Kinetics of adsorption follows the modified Avrami rate equation. The maximum adsorption capacity was estimated to be 45.9 mg g(-1), with removal of the dye of 99.1%. The NH2-MCM-41 material exhibited high desorption capacity with 98.1%.


Endoscopic management of choledochocele. A case report and review of the English literature.
Choledochocele or type III choledochal cyst is a rare lesion of the biliary tree. It may be of acquired or congenital etiology and can assume one of two anatomic variants. Either the common bile duct and the pancreatic duct enter the choledochocele together, or it is formed by the common bile duct alone with the pancreatic duct entering as a separate opening. The most frequent presenting symptoms are abdominal pain, pancreatitis, and jaundice. Traditional therapy has been either marsupialization of the cyst into the duodenum or complete surgical excision. This paper cites the eighth patient reported in the English-language literature whose choledochocele was treated endoscopically. It is the authors' opinion that either an endoscopic papillotomy or an endoscopic fistulotomy with extension of the incision over the cyst is the simpler and preferred method of treatment.


One-pot fabrication of sacchachitin for production of TEMPO-oxidized sacchachitin nanofibers (TOSCNFs) utilized as scaffolds to enhance bone regeneration.
One-pot fabrication of sacchachitin (SC) for mass-production was developed and optimized by selecting KOH as alkaline agent in depigmentation step and utilizing NaClO2 as bleaching agent in subsequent step in the same pot. Overall yield of one-pot-fabricated SC was up to 35 %w/w of initial weight with a fibrous texture soft enough for mechanical disintegration into SC nanofibers (SCNFs) and better dispersion for producing TEMPO-oxidized SCNFs (T033SC). Both SCNFs and T033SC could form a 3D gelatinous scaffold into which MC3T3-E1 cells were attracted. Higher calcium-trapping ability of T033SC resulting from a greater extent of carboxylate groups provided an excellent bone regeneration environment that resulted in better outcomes of bone regeneration in a femur defect rat model compared to those with SCNFs possessed fewer carboxylate groups. In conclusion, biomaterial scaffolds based on TEMPO-oxidized SCNFs produced from one-pot fabricated SC showed great potential for bone regeneration due to unique physical and chemical properties.


Carotid and vertebral-basilar transient ischemic attacks: effect of anticoagulants, hypertension, and cardiac disorders on survival and stroke occurrence--a population study.
A population of 199 patients from Rochester, MN, was followed from the time of their first carotid or vertebral-basilar transient ischemic attack (TIA). Patients treated with anticoagulants had no significant difference in survival from untreated patients. Among patients with carotid TIA who received anticoagulants, the net probability of stroke was slightly but not significantly lower than in untreated patients. The difference favoring treated patients with vertebral-basilar TIA was significant starting at three months. The rate of intracranial hemorrhage was higher higher among all patients receiving anticoagulant treatment than among untreated patients and was significantly higher among those 55 to 74 years old. Almost all the hemorrhages occurred after a year or more of anticoagulant treatment and in patients more than 65 years old. Patients with high diastolic blood pressure had a significantly higher net probability of stroke than did patients with lower blood pressure and those receiving antihypertensive drugs. By implication, treatment of hypertension was effective in preventing stroke in patients with TIA. Linear discriminant analysis and actuarial analysis indicated that diastolic blood pressure and anticoagulant therapy were the only factors that influenced stroke occurrence. There was no suggestion that previous myocardial infarction, angina pectoris, valvular heart disease, cardiac arrhythmia, or congestive heart failure--individually or in combination--influenced the occurrence of stroke or survival.


Methamphetamine and poly-substance use among gym-attending men who have sex with men in New York City.
Methamphetamine and other drug use has been documented among men who have sex with men (MSM). Patterns of use may be influenced by point of recruitment into these studies. The aim of this study is to describe patterns of methamphetamine and other drug use and to delineate psychosocial and demographic factors which accompany these patterns of use in a sample of MSM attending gyms in New York City. Active recruitment strategies were implemented to ascertain a sample of 311 MSM. Participants completed a one-time survey regarding both health risks and health promotion. Methamphetamine use in the last 6 months was reported by 23.8% of men. Inhalation and smoking were the most common modes of administration, and 84% of men reported more than one mode of use. Study participants also indicated a variety of other substances used, including but not limited to alcohol, inhalant nitrates, and 3,4 methylenedioxymethamphetamine (MDMA). Compared to nonusers, methamphetamine users were more likely to report being black or Latino, depressed, HIV-positive, perceiving more benefits of unprotected sex, and understanding masculinity in sexual terms. These data suggest that health-risk behaviors are common among MSM who are regularly using a gym and are indicative of the complexities of health issues for this segment of the population.


Anorexia nervosa following sexual harassment on the internet: a case report.
Sexual abuse may be a risk factor for the development of anorexia nervosa. No information is available on sexual abuse through the Internet and its connection to the development of eating disorders. We report on a case of an adolescent female with the diagnosis of anorexia nervosa, whose symptomatology correlated significantly with an incident of sexual harassment experienced via the Internet. A case of on-line harassment suffered without off-line follow-up is reported to have led to a restrictive type of anorexia nervosa, where the symptomatology was connected to a "computer scatology" like persecution of our patient. A causal connection of the on-line sexual harassment suffered and development of eating disorder is reported.


A lost generation.
The funding policies of the NIH have made it increasingly difficult for young researchers to procure research funds. This threatens to drive a whole generation of young people away from careers in basic biomedical research.


A clinical and stress radiographical follow-up investigation after Jones' operation for replacing the anterior cruciate ligament.
Measurements have been made on knee radiographs exposed during stress displacement by controlled hydraulic forces using a specially designed apparatus. This accurately records the amount of anterior and posterior tibial displacement (drawer sign) and the degree of medial and lateral collateral ligament laxity on radiographs. The findings in 25 patients have been analysed following the Jones' procedure for the repair of the anterior cruciate ligaments. The operative results were judged to be completely successful in 72% of patients and the value of stress radiographic measurements is discussed.


Relapsed acute lymphoblastic leukemia: current status and future opportunities.
Significant improvements in primary therapy for childhood acute lymphoblastic leukemia (ALL) have led to dramatic increases in cure rates over the past few decades. Relapsed ALL, however, remains more common than new diagnoses of many common pediatric malignancies. Outcomes for patients with relapsed ALL remain poor, especially for patients with early bone marrow relapse. However, most relapse patients do achieve a second complete remission, followed by therapeutic options including further chemotherapy and hematopoietic stem cell transplant. The level of minimal residual disease after achieving second remission or before transplant may predict outcomes. The substantial likelihood of achieving second remission with familiar drug combinations may discourage participation in formal relapse studies. The high likelihood of achieving a third remission may discourage participation in single-agent trials of new drugs, despite the critical need for novel agents with activity against resistant disease that may improve outcomes for recurrent ALL.


Safety and Survival Rates Associated With Ablative Stereotactic Radiotherapy for Patients With Oligometastatic Cancer: A Systematic Review and Meta-analysis.
The oligometastatic paradigm postulates that patients with a limited number of metastases can be treated with ablative local therapy to each site of disease with curative intent. Stereotactic ablative radiotherapy (SABR) is a radiation technique that has become widely used in this setting. However, prospective data are limited and are mainly from single institutional studies. To conduct a meta-analysis to characterize the safety and clinical benefit of SABR in oligometastatic cancer. A comprehensive search was conducted in PubMed/MEDLINE, Embase, Cochrane Database of Systematic Reviews, and Cumulative Index to Nursing and Allied Health Literature on December 23, 2019, that included prospective clinical trials and review articles that were published within the past 15 years. Inclusion criteria were single-arm or multiarm prospective trials including patients with oligometastatic cancer (ie, ≤5 sites of extracranial disease), and SABR was administered in less than or equal to 8 fractions with greater than or equal to 5 Gy/fraction. The Population, Intervention, Control, Outcomes and Study Design; Preferred Reporting Items for Systematic Reviews and Meta-analyses; and Meta-analysis of Observational Studies in Epidemiology methods were used to identify eligible studies. Study eligibility and data extraction were reviewed by 3 authors independently. Random-effects meta-analyses using the Knapp-Hartung correction, arcsine transformation, and restricted maximum likelihood method were conducted. Safety (acute and late grade 3-5 toxic effects) and clinical benefit (1-year local control, 1-year overall survival, and 1-year progression-free survival). Twenty-one studies comprising 943 patients and 1290 oligometastases were included. Median age was 63.8 years (interquartile range, 59.6-66.1 years) and median follow-up was 16.9 months (interquartile range, 13.7-24.5 months). The most common primary sites were prostate (22.9%), colorectal (16.6%), breast (13.1%), and lung (12.8%). The estimate for acute grade 3 to 5 toxic effect rates under the random-effects models was 1.2% (95% CI, 0%-3.8%; I2 = 50%; 95% CI, 3%-74%; and τ = 0.20%; 95% CI, 0.00%-1.43%), and the estimate for late grade 3 to 5 toxic effects was 1.7% (95% CI, 0.2%-4.6%; I2 = 54%; 95% CI, 11%-76%; and τ = 0.25%; 0.01%-1.00%). The random-effects estimate for 1-year local control was 94.7% (95% CI, 88.6%-98.6%; I2 = 90%; 95% CI, 86%-94%; and τ = 0.81%; 95% CI, 0.36%-2.38%]). The estimate for 1-year overall survival was 85.4% (95% CI, 77.1%-92.0%; I2 = 82%; 95% CI, 71%-88%; and τ = 0.72%; 95% CI, 0.30%-2.09%) and 51.4% (95% CI, 42.7%-60.1%; I2 = 58%; 95% CI, 17%-78%; and τ = 0.20%; 95% CI, 0.02%-1.21%) for 1-year progression-free survival. In this meta-analysis, SABR appears to be relatively safe in patients with oligometastatic cancer with clinically acceptable rates of acute and late grade 3 to 5 toxic effects less than 13% and with clinically acceptable rates of 1-year local control overall survival, and progression-free survival. These findings are hypothesis generating and require validation by ongoing and planned prospective clinical trials.


Correction: Palladium(II)-catalyzed vinylic geminal double C-H activation and alkyne annulation reaction: synthesis of pentafulvenes.
Correction for 'Palladium(II)-catalyzed vinylic geminal double C-H activation and alkyne annulation reaction: synthesis of pentafulvenes' by Jyotshna Phukon et al., Chem. Commun., 2020, 56, 1133-1136, https://doi.org/10.1039/C9CC09564K.


Passive biaxial mechanical properties of isolated canine myocardium.
Excised sheets of canine myocardium were subjected to cyclic loading and unloading in the predominant fibre and cross-fibre directions to determine passive mechanical properties. Myocardium under biaxial loading exhibits both non-linear elasticity and viscoelasticity with some strain-rate dependence in the position of the stress-strain relations, but very little rate dependence in the area enclosed by the loading and unloading portions of the stress-strain loops. Fibre and cross-fibre directions demonstrate anisotropic behaviour, with both the degree and direction of the anisotropy being dependent upon the region of the heart from which specimens are obtained. In the same specimen biaxial as compared with uniaxial loading yields different interpretations as to the material properties.


Sustained antibody persistence for at least 15 years after a booster vaccination against tick-borne encephalitis following different primary vaccination schedules: Third 5-year follow-up.
Vaccination is the best mode of protection against tick-borne encephalitis (TBE) and its sequelae. The duration of protection and the optimal interval of repeat booster doses are still debated. The current study evaluated the persistence of the antibody response 11-15 years after a first booster vaccination following different primary vaccination schedules with a TBE vaccine (Encepur Adults, manufactured by Bavarian Nordic, previously by GSK). This phase IV, open-label, mono-centric extension study enrolled adults who had received (at ≥ 12 years of age) primary vaccination with one of three randomly assigned TBE vaccine schedules (rapid [group R], conventional [group C], or accelerated conventional schedule [group A]) followed by a booster dose 3 years later. The antibody response was measured annually from 11 to 15 years post-booster using a TBE virus neutralization test (NT). An NT titer of ≥ 10 was considered as a clinically meaningful threshold and surrogate for protection. In total, 194 participants were enrolled and included in the per-protocol set; 188 completed the study. The percentage of participants with an NT titer ≥ 10 was 100% in group R and 99.0% in group A at all visits and ranged from 100% (year 11) to 95.8% (year 15) in group C. NT geometric mean titers were similar in the three study groups (181-267 in group R, 142-227 in group C, 141-209 in group A). NT geometric mean titers also remained high among participants ≥ 50 years old (98-206) and ≥ 60 years old (91-191) across study groups and time points. This study showed neutralizing antibody persistence for at least 15 years after a first booster dose of the Encepur Adults TBE vaccine in all age groups evaluated, regardless of which primary vaccination schedule was given to adolescents or adults. Trialregistry: ClinicalTrials.gov: NCT03294135.


B-cell activating factor (BAFF) and its receptors' expression in pediatric nephrotic syndrome is associated with worse prognosis.
Immune pathogenesis of nephrotic syndrome (NS) is not completely understood. We aimed to evaluate the expression of B-cell activating factor (BAFF) and its receptors in renal samples from pediatric NS patients and its relationship with renal function survival. We conducted an ambispective study on 33 patients with pediatric NS. Immunohistochemistry for BAFF, TACI, BCMA and BR3 was performed. Markers were evaluated on podocytes and interstitial inflammatory infiltrates (III). We performed Kaplan-Meier curves to describe renal function survival according to markers' expression. Thirty-three NS patients were included. Minimal change disease was seen in 21 (63.6%) patients, and focal segmental glomerulosclerosis in 12 (36.4%). BAFF was found in podocytes (18.2% of samples) and III (36.4% of samples), BAFF-R in one sample, TACI in 4 (podocytes and III), and BCMA in 5 samples of podocytes and 7 of III. BAFF on podocytes and III was associated with worst renal function at follow-up; those patients had 25% probability of having GFR >90 mL/min/1.73m2, versus 84.9% when absent (p = 0.0067). Patients with BAFF in III had 42.9% probability of having GFR>90 mL/min/1.73 m2, versus 94.1% when absent (p = 0.0063). BAFF expression in renal biopsies could be a prognostic factor for renal function.


Soil phosphorus forms and their variations in selected paddy soils of Iran.
Fractionation of soil phosphorus (P) can provide useful information for assessing the risk of soil P as the potential sources of eutrophication in aquatic systems. Little information exists on P forms in paddy soils of Isfahan Province in central Iran, where P fertilizers have been continuously applied for at least 45 years. The objectives of this study were to investigate concentrations and proportions of P forms in paddy soils and correlate the content of P forms with basic soil properties. Soil samples from three paddy sites were obtained, and soil P forms were determined by a modified Hedley fraction method. Results show that the total P concentrations ranged from 288 to 850 mg kg(-1) and were enriched in site 1. In all sites, the rank order of P fractions was HCl-P (CARB-P) > residual-P (RES-P) > NaOH-P (Fe-Al-P) > KCl-P (EXCH-P), indicating that Ca compounds are the main soil components contributing to P retention in these calcareous paddy soils. The EXCH-P represented on average < 1 % of the total P, while the Fe-Al-P ranged 3.3-18 %. The CARB-P showed considerable contribution (63.6-85.6 %) to the total P. The Pearson correlation matrix indicated that Fe-Al-P only was positively correlated with total P, but did not show any significant correlations with other soil geochemical properties. Calcium-bound P fraction was significantly correlated with the clay, silt, cation exchange capacity, and total P.


Hypertriglyceridemia Thalassemia Syndrome: Common Disease, Uncommon Association.
Hypertriglyceridemia has been rarely described with thalassemia, an entity called hypertriglyceridemia-thalassemia syndrome. The authors describe a young infant diagnosed with thalassemia major with severe hypertriglyceridemia. The presence of severe hypertriglyceridemia in this child which rapidly resolved after transfusion, probably suggests a self limited mechanism which may not require therapy. Though hypertriglyceridemia has been reported with hemolytic anemias, the mechanism is unclear. This case illustrates that thalassemia may be associated with hypertriglyceridemia; once familial and secondary causes are ruled out, clinicians may wait for spontaneous resolution before considering specific therapy.


Electrokinetic ion transport through unsaturated soil: 1. Theory, model development, and testing.
An electromigration transport model for non-reactive ion transport in unsaturated soil was developed and tested against laboratory experiments. This model assumed the electric potential field was constant with respect to time, an assumption valid for highly buffered soil, or when the electrode electrolysis reactions are neutralized. The model also assumed constant moisture contents and temperature with respect to time, and that electroosmotic and hydraulic transport of water through the soil was negligible. A functional relationship between ionic mobility and the electrolyte concentration was estimated using the chemical activity coefficient. Tortuosity was calculated from a mathematical relationship fitted to the electrical conductivity of the bulk pore water and soil moisture data. The functional relationship between ionic mobility, pore-water concentration, and tortuosity as a function of moisture content allowed the model to predict ion transport in heterogeneous unsaturated soils. The model was tested against laboratory measurements assessing anionic electromigration as a function of moisture content. In the test cell, a strip of soil was spiked with red dye No 40 and monitored for a 24-h period while a 10-mA current was maintained between the electrodes. Electromigration velocities predicted by the electromigration transport model were in agreement with laboratory experimental results. Both laboratory-measured and model-predicted dye migration results indicated a maximum transport velocity at moisture contents less than saturation due to competing effects between current density and tortuosity as moisture content decreases.