Heterologous production of active form of beta-lytic protease by Bacillus subtilis and improvement of staphylolytic activity by protein engineering.
Most of the proteases classified into the M23 family in the MEROPS database exhibit staphylolytic activity and have potential as antibacterial agents. The M23 family is further classified into two subfamilies, M23A and M23B. Proteases of the M23A subfamily are thought to lack the capacity for self-maturation by auto-processing of a propeptide, which has been a challenge in heterologous production and application research. In this study, we investigated the heterologous expression, in Bacillus subtilis, of the Lysobacter enzymogenes beta-lytic protease (BLP), a member of the M23A subfamily. We found that B. subtilis can produce BLP in its active form. Two points were shown to be important for the production of BLP in B. subtilis. The first was that the extracellular proteases produced by the B. subtilis host are essential for BLP maturation. When the host strain was deficient in nine extracellular proteases, pro-BLP accumulated in the supernatant. This observation suggested that BLP lacks the capacity for self-maturation and that some protease from B. subtilis contributes to the cleavage of the propeptide of BLP. The second point was that the thiol-disulfide oxidoreductases BdbDC of the B. subtilis host are required for efficient secretory production of BLP. We infer that intramolecular disulfide bonds play an important role in the formation of the correct BLP conformation during secretion. We also achieved efficient protein engineering of BLP by utilizing the secretory expression system in B. subtilis. Saturation mutagenesis of Gln116 resulted in a Q116H mutant with enhanced staphylolytic activity. The minimum bactericidal concentration (MBC) of the wild-type BLP and the Q116H mutant against Staphylococcus aureus NCTC8325 was 0.75 μg/mL and 0.375 μg/mL, respectively, and the MBC against Staphylococcus aureus ATCC43300 was 6 μg/mL and 3 μg/mL, respectively. In this study, we succeeded in the secretory production of BLP in B. subtilis. To our knowledge, this work is the first report of the successful heterologous production of BLP in its active form, which opens up the possibility of industrial use of BLP. In addition, this study proposes a new strategy of using the extracellular proteases of B. subtilis for the maturation of heterologous proteins.


Ultrastructural localization of glycogen in the granulocytes of normal rabbit bone marrow.
The glycogen of rabbit granulocytes has been studied in glutaraldehyde and osmium tetroxide fixed bone marrow by the periodic acid-thiocarbohydrazide-silver proteinate procedure (PA-TCH-SP). The PA-TCH-SP procedure involved the staining of intracytoplasmic glycogen more densely than the routine lead citrate staining. The PA-TCH-SP procedure demonstrated the intracytoplasmic glycogen in all three kinds of granulocytes. Though a sequence of intensity was observed in each stage of cell maturation, intracytoplasmic glycogen increased generally in accordance with cell maturation in the granulocytes. Functional significance of the glycogen in the granulocytes was discussed in relation to its staining. A very weak reaction in the granules of the granulocytes was described in relation to their contents.


Management of hepatitis B in special populations.
Special populations infected with chronic HBV include those with decompensated cirrhosis, coinfections (HIV, HCV, HDV), hemodialysis and renal failure, immunosuppressed including transplant patients, children and women in pregnancy. These populations differ in their natural history and risk for liver-related complications, the indications for anti-HBV therapy as well as the recommendations regarding the HBV drugs used, duration of therapy and anticipated endpoints. Reflecting the special populations with substantive changes in management in recent years, this review focuses on HBV-HIV coinfected patients, immunosuppressed patients at risk for reactivation, liver transplant recipients and pregnant women. Management of women in the context of pregnancy and post-partum requires consideration of risks to mother and fetus/infant, including the risk of mother-to-child transmission. HBV-HIV coinfected patients require initiation of treatment concurrent with their HIV therapy and the HBV drugs used must by selected to minimize HIV and HBV resistance long-term. Increasing recognition of the risk for HBV reactivation with immunosuppressive therapy has led to recommendations to use prophylactic HBV therapy in patients with moderate to high risk of reactivation. Liver transplant recipients with HBV require life-long therapy to prevent or treat HBV infection but with current therapies, graft and patient survival are excellent.


Briarane diterpenoids isolated from gorgonian corals between 2011 and 2013.
The structures, names, bioactivities and references of 138 briarane-type diterpenoids, including 87 new compounds, are summarized in this review. All the briarane-type compounds mentioned in this review article were obtained from gorgonian corals including the genus Briareum, Dichotella, Junceella and Verrucella. Some of these compounds showed potential bioactivities.


Tudor-dimethylarginine interactions: the condensed version.
Biomolecular condensates (BMCs) can facilitate or inhibit diverse cellular functions. BMC formation is driven by noncovalent protein-protein, protein-RNA, and RNA-RNA interactions. Here, we focus on Tudor domain-containing proteins - such as survival motor neuron protein (SMN) - that contribute to BMC formation by binding to dimethylarginine (DMA) modifications on protein ligands. SMN is present in RNA-rich BMCs, and its absence causes spinal muscular atrophy (SMA). SMN's Tudor domain forms cytoplasmic and nuclear BMCs, but its DMA ligands are largely unknown, highlighting open questions about the function of SMN. Moreover, DMA modification can alter intramolecular interactions and affect protein localization. Despite these emerging functions, the lack of direct methods of DMA detection remains an obstacle to understanding Tudor-DMA interactions in cells.


Risk Factors for Malnutrition among Older Adults in the Emergency Department: A Multicenter Study.
Among older adults, malnutrition is common, often missed by healthcare providers, and influences recovery from illness or injury. To identify modifiable risk factors associated with malnutrition in older patients. Prospective cross-sectional multicenter study. 3 EDs in the South, Northeast, and Midwest. Non-critically ill, English-speaking adults aged ≥65 years. Random time block sampling was used to enroll patients. The ED interview assessed malnutrition using the Mini Nutritional Assessment Short-Form. Food insecurity and poor oral health were assessed using validated measures. Other risk factors examined included depressive symptoms, limited mobility, lack of transportation, loneliness, and medication side effects, qualified by whether the patient reported the risk factor affected their diet. The population attributable risk proportion (PARP) for malnutrition was estimated for each risk factor. In our sample (n = 252), the prevalence of malnutrition was 12%. Patient characteristics associated with malnutrition included not having a college degree, being admitted to the hospital, and residence in an assisted living facility. Of the risk factors examined, the PARPs for malnutrition were highest for poor oral health (54%; 95% CI 16%, 78%), food insecurity (14%; 95% CI 3%, 31%), and lack of transportation affecting diet (12%; 95% CI 3%, 28%). Results of this observational study identify multiple modifiable factors associated with the problem of malnutrition in older adults.


Effect of butyrate enemas on gene expression profiles and endoscopic/histopathological scores of diverted colorectal mucosa: A randomized trial.
A temporary stoma is often created to protect a distal anastomosis in colorectal surgery. Short-chain fatty acids, mainly butyrate, are the major fuel source for the epithelium and their absence in the diverted tract may produce mucosal atrophy and inflammation. To investigate whether the administration of sodium butyrate enemas (Naburen(©), Promefarm, Italy) could prevent mucosal inflammation and atrophy and affect gene expression profiles after ileo/colostomy. We performed a randomized, double-blind, placebo-controlled clinical trial, in patients with enterostomy performed for inflammatory bowel disease, colorectal cancer or diverticulitis. Twenty patients were randomly allocated to receive 30ml of sodium butyrate 600mmol/L (group A) or saline (group B), b.i.d. for 30 days. In group A endoscopic scores were significantly improved (p<0.01) while mucosal atrophy was reduced or unchanged; in group B mucosal atrophy was increased in 42.8% of patients. Despite the high dose of butyrate used, no short-chain fatty acids were detectable by gas chromatography-mass spectrometry in colorectal biopsies. Group A patients showed up-regulation of genes associated with mucosal repair such as Wnt signalling, cytoskeleton regulation and bone morphogenetic protein-antagonists. Butyrate enemas may prevent the atrophy of the diverted colon/rectum, thus improving the recovery of tissue integrity.


Kinetics of onset of rate-dependent effects of Class I antiarrhythmic drugs are important in determining their effects on refractoriness in guinea-pig ventricle, and provide a theoretical basis for their subclassification.
The kinetics of onset of rate-dependent depression of maximum rate of depolarisation (Vmax) of guinea-pig ventricular action potentials were studied for nine Class I anti-arrhythmic drugs using standard microelectrode techniques. The drugs were found to fall into three well-demarcated subgroups with "fast" (lignocaine, tocainide and mexiletine), "intermediate" (quinidine, disopyramide and procainamide) and "slow" (flecainide, encainide and lorcainide) kinetics. The "fast" drugs were found to share the ability to markedly prolong the effective refractory period (ERP) relative to the action potential duration (APD). The "slow" drugs had only minor effects on this parameter. The "intermediate" drugs produced small to moderate increases in ERP relative to APD but in addition significantly prolonged APD, which was shortened by the "fast" drugs. Thus, using the parameters of speed of onset of rate-dependent depression of Vmax and APD it was possible to subdivide the nine Class I drugs into three distinct subclasses.


[Protection against experimental infections in mice by an oral vaccine and its combined role when administered with antibiotics].
Immunomodulator with significantly modify the immunologic response of the host. The AA. studied the immunologic profile of an oral vaccine to protect the experimental infection in mice and its effect when it was administered with antibiotics. The mice infected with S. enteritidis were protected by the vaccine administered. Also in the group of mice treated with a vaccine and antibiotic combination, the mortality rate was lower than in the untreated groups.


Comparison of nickel-group metal cyanides and acetylides and their anions using anion photoelectron spectroscopy and density functional theory calculations.
The photoelectron spectra of NiCN-, PdCN-, PtCN-, HNiC2H-, Ni(C2H)2(-), PdC2H-, and PtC2H- are presented along with density functional theory calculations. Linear structures are predicted for all anions and neutrals. NiCN- and NiCN are predicted to have 3delta and 2delta ground states, respectively. HNiC2H- and Ni(C2H)2(-) are predicted to have 2delta and 2delta(g) anion and 3delta and 3pi(g) neutral ground states, respectively. The palladium and platinum cyanide and acetylides have 1sigma+ anion and 2sigma+ neutral ground states. Simulations generated from the calculated parameters are compared to observed spectra, and molecular orbital diagrams are presented to compare the bonding in these species.


Effects of diet type on incidence of spontaneous and 2-acetylaminofluorene-induced liver and bladder tumors in BALB/c mice fed AIN-76A diet versus NIH-07 diet.
Diet is a major influence on the responses of experimental animals to drugs, toxins, and carcinogens. Two diets used widely in toxicological and/or nutritional studies, and considered to be nutritionally adequate, were compared with respect to their influence on growth, body weight, lifespan, spontaneous neoplasia, and neoplastic responses to 2-acetylaminofluorene (2-AAF). Both sexes of weanling BALB/c mice were fed either a purified diet (AIN-76A) or a nonpurified, natural ingredient diet (NIH-07), with or without 2-AAF for up to 2 years. Dosages of 2-AAF were administered to males at 0, 20, 40, or 60 ppm in each diet and to females at 0, 100, 125, or 150 ppm. Each group consisted of 96 mice. In most instances, males and females fed purified diet (AIN-fed) gained weight more rapidly, attained higher maximum body weights, and died earlier than their non-purified diet (NIH-fed) counterparts. 2-AAF inhibited weight gain significantly only in AIN-fed females. Thus, females receiving 150 ppm 2-AAF gained little more than their NIH-fed counterparts. At the dosages used in males, 2-AAF did not induce liver neoplasia but the AIN diet was clearly associated with a higher spontaneous frequency of liver neoplasia than the NIH diet. Although 2-AAF induced liver tumors in females fed either diet at all dosages, a higher frequency and earlier appearance of liver tumors among AIN-fed females than their NIH-fed counterparts was apparent mainly at the lowest dosage. 2-AAF induced bladder neoplasia in both sexes.(ABSTRACT TRUNCATED AT 250 WORDS)


Bioactive compounds and therapeutic role of Brassica oleracea L. seeds in rheumatoid arthritis rats via regulating inflammatory signalling pathways and antagonizing interleukin-1 receptor action.
Rheumatoid arthritis (RA) is a chronic, progressive autoimmune disease characterized by aggressive and systematic polyarthritis. The present study aimed to isolate and identify the phenolic constituents in Brassica oleracea L. (Brassicaceae) seeds methanolic extract and evaluates its effect against rheumatoid arthritis in rats referring to the new therapy; interleukin-1 receptor antagonist (IL-1RA). The GC/MS profiling of the plant was determined. Arthritis induction was done using complete Freund's adjuvant. Arthritis severity was assessed by percentage of edema and arthritis index. IL-1 receptor type I gene expression, interleukin-1β (IL-1β), oxidative stress markers, protein content, inflammatory mediators, prostaglandin-E2 (PGE2), genetic abnormalities and the histopathological features of ankle joint were evaluated. For the first time twelve phenolic compounds had been isolated from the seeds extract. Treatment with extract and IL-1RA improved the tested parameters by variable degrees. RA is an irreversible disease, where its severity increases with the time of induction. Brassica oleracea L. seeds extract is considered as a promising anti-arthritis agent. IL-1 RA may be considered as an unusual therapeutic agent for RA disease. More studies are needed to consider the seeds extract as a nutraceutical agent and to recommend IL-1RA as a new RA drug.


Oil plant genomes: current state of the science.
Vegetable oils are an indispensable nutritional component of the human diet as well as important raw materials for a variety of industrial applications such as pharmaceuticals, cosmetics, oleochemicals, and biofuels. Oil plant genomes are highly diverse, and their genetic variation leads to a diversity in oil biosynthesis and accumulation along with agronomic traits. This review discusses plant oil biosynthetic pathways, current state of genome assembly, polyploidy and asymmetric evolution of genomes of oil plants and their wild relatives, and research progress of pan-genomics in oil plants. The availability of complete high-resolution genomes and pan-genomes has enabled the identification of structural variations in the genomes that are associated with the diversity of agronomic and environment fitness traits. These and future genomes also provide powerful tools to understand crop evolution and to harvest the rich natural variations to improve oil crops for enhanced productivity, oil quality, and adaptability to changing environments.


Effectiveness of first-generation HCV protease inhibitors: does HIV coinfection still play a role?
HIV/hepatitis C virus (HCV) coinfected patients are usually considered a difficult-to-treat population. The aim of this study was to assess the effectiveness of telaprevir-based and boceprevir-based treatments with respect to the HIV status. A prospective multicentre study was conducted among 22 Infectious Disease centres in Italy. Demographic, HIV and HCV related variables were collected, as well as data on HCV viral decay, sustained virologic response (SVR12) and grade 3-4 adverse events. Overall, 162 patients (24.7% HIV/HCV coinfected) received HCV treatment. Out of 145 evaluable patients, 57.2% achieved SVR12 (49.5% monoinfected, 78.9% coinfected). HIV coinfection was associated with a slight increase in the probability of SVR12 (adjusted odds ratio 1.66, 95% confidence interval 0.59-4.64, P=0.33). Premature discontinuation rates and adverse events were similar irrespective of HIV status, with the exception of skin reactions, which were more frequently in the HIV group. In a real-life setting, with a high proportion of cirrhotic and treatment-experienced patients, the overall SVR12 rate was 57.2%. HIV coinfection was not associated with impaired outcome.


Modulations of neurofilament axonal transport during the development of rabbit retinal ganglion cells.
We have compared the polypeptides undergoing axonal transport in the retinal ganglion cells of neonatal and adult rabbits, and have observed the following: (1) Representative polypeptides of five different adult transport groups are axonally transported from the time of birth. (2) Polypeptides of group IV (a group that includes actin and myosin) are transported two-fold more rapidly in neonates than in adults. (3) Two polypeptides, M (145K) and L (73K) that are components of neurofilaments and move with the fifth, slowest group of transported proteins, are transported approximately eight-fold more rapidly in neonatal rabbits than in adults. (4) H, a third group V polypeptide, that serves to crosslink neurofilaments, was not detected in the rabbit optic nerve until 12 days after birth. We consider the possibility that the late induction of the crosslinker precipitates a cytoskeletal "phase transition" that may be responsible for the developmental alterations in apparent transport velocities, and may have additional consequences for neuronal development.


Chemoprevention of cancer: selenium.
1. Selenium intake (in the form of selenite, selenate, selenomethionine, etc.) protects the organism against the action of some kinds of carcinogens. 2. People and animals having less Se in their blood are at a higher risk of acquiring cancer than those whose blood contains more of this element. 3. This chemopreventive action is probably due to antioxidant properties of Se, its involvements in the enzyme glutathione peroxidase as well as in the inhibition of enzymes converting carcinogens to their ultimate forms in the cell. 4. An intake of 150-300 micrograms of Se daily is considered to be adequate to protect the human organism without exhibiting the toxic properties of this element.


The melting curves of calf thymus-DNA are buffer specific.
The specific effects of salts (strong electrolytes) on biomolecular properties have been investigated for more than a century. By contrast, the specific role of pH buffers (weak electrolytes and their salts) has usually been ignored. Here, specific buffer effects on DNA thermal stability were evaluated by measuring the melting curve of calf thymus DNA through UV-vis spectroscopy. The study was carried out using phosphate, Tris, citrate and cacodylate buffers at fixed pH 7.4 at concentrations varying systematically in the range 1-600 mM. DNA stability increases with buffer concentration and is influenced specifically by buffer type. To interpret empirical data, a theoretical model was applied with parameters quantifying the impact of buffer on the DNA backbone charge. Comparing the buffer effects via buffer ionic strength rather than buffer concentration, we find that the buffers stabilize DNA in the order Tris > cacodylate > phosphate > citrate.


Two-dimensional TaC nanosheets on a reduced graphene oxide hybrid as an efficient and stable electrocatalyst for water splitting.
A novel highly active and stable HER catalyst containing two-dimensional TaC nanosheets hybridized with reduced graphene oxide (2D TaC-RGO) was prepared as an efficient and stable hydrogen evolution reaction catalyst.


Cancer genetic clinics: why do women who already have cancer attend?
Cancer patients attend oncogenetic clinics so that the existence of a genetic risk can be checked and the relatives informed. The aim of this study was to describe the expectations of cancer patients about genetic counselling and their beliefs about the aetiology of their disease. A survey based on self-administered questionnaires before and after the consultation was carried out on 115 women with breast/ovarian cancer who attended one of the six French participating clinics. In 59 cases (51%), the consultees' expectations focused on the preventive options available and in 86 cases (75%) on their offspring; 87 (76%) found the consultation informative. On average, the women rated heredity and diet as lower risk factors (P < 0.05) after the consultation than before. Heredity, stress and the environment were thought to be more decisive than diet, smoking and alcohol. 34 patients who seemed unlikely to have a genetic risk in the consultant's opinion thought heredity to be less relevant (P < 0.05) after the consultation than before. At the time of the survey, cancer patients accounted for at least half of the consultees attending oncogenetic clinics in France. They need to have the clinical specificities of their disease and its medical management explained. They attend mainly for their offspring's sake, whereas healthy clients attend for their own sake.


Hippocampal synaptotagmin-4 is correlated with impaired spatial learning and memory in SAMP8 mice.
The mechanism underlying age-related cognitive impairment remains unclear. To determine whether synaptotagmin (Syt)-1 and Syt-4 are involved in age-related cognitive impairment, we used a radial six-arm water maze (RAWM) to evaluate spatial learning and memory deficits in the senescence accelerated prone mouse 8. The Syt-1 and Syt-4 levels of different subregions of the dorsal hippocampus (DH) were detected through immunohistochemistry. The RAWM results revealed that 13- and 9-month-old mice exhibited longer latencies and more errors in both the learning and memory phases than 5-month-old mice. Similar results were observed in the comparison of 13-month-old mice to 9-month-old mice. Compared with the 9- and/or 5-month-old mice, the 13-month-old mice exhibited higher Syt-1 and Syt-4 levels in the majority of the DH subregions with the exception of Syt-1 in the dentate gyrus-hilus and Syt-4 in the dentate gyrus-hilus and cornu ammonis 1 pyramidal cell layer. With the exception of Syt-1 in the 9-month-old mice, the Syt-1 and Syt-4 levels in several DH subregions overall and in each group were significantly correlated with the performances on the RAWM. Therefore, the altered Syt-1 and Syt-4 levels in the different DH layers may have been involved in the impairments in spatial learning and memory during normal aging.


Prolonged survival in acute myelogenous leukaemia without maintenance chemotherapy.
46 adults with previously untreated acute myelogenous leukaemia who achieved complete remission with 6-thioguanine, cytarabine, and daunorubicin (TAD) received two courses of intensive consolidation chemotherapy. The first cycle consisted of 5-azacytidine and doxorubicin followed by a second consolidation cycle with TAD. Maintenance chemotherapy was not administered. Median remission duration was 14 months and 26% (95% confidence interval, 11%-41%) remained in continuous remission at 5 years. Actuarial 5 year survival was 31% (+/- 15%). Results were most favourable in patients who achieved complete remission within 60 days of chemotherapy being initiated. These data indicate that prolonged disease-free survival can be achieved in patients treated with intensive induction and consolidation treatment alone without maintenance chemotherapy.


Induction techniques that reduce redistribution hypothermia: a prospective, randomized, controlled, single blind effectiveness study.
While much effort has been devoted to correcting intraoperative hypothermia, less attention has been directed to preventing redistribution hypothermia. In this study, we compared three different anesthetic induction techniques to standard IV propofol inductions (control) in their effect on reducing redistribution hypothermia. Elective, afebrile patients, age 18 to 55 years, were randomly assigned to one of four groups (n = 50 each). Group "INH/100" was induced with 8% sevoflurane in 100% oxygen, Group "INH/50" with 8% sevoflurane in 50% oxygen and 50% nitrous oxide, Group "PROP" with 2.2 mg/kg propofol, and Group "Phnl/PROP" with 2.2 mg/kg propofol immediately preceded by 160 mcg phenylephrine. Patients were maintained with sevoflurane in 50% nitrous oxide and 50% oxygen in addition to opioid narcotic. Forced air warming was used. Core temperatures were recorded every 15 min after induction for 1 h. Compared to control group PROP, the mean temperatures in groups INH/100, INH/50, and Phnl/PROP were higher 15, 30, 45 and 60 min after induction (p < 0.001 for all comparisons), averaging between 0.39 °C and 0.54 °C higher. In group PROP, 60% of patients had at least one temperature below 36.0 °C in the first hour whereas only 16% did in each of groups INH/100, INH/50, and Phnl/PROP (p < 0.0001 in each group compared to PROP). In this effectiveness trial, inhalation inductions with sevoflurane or with prophylactic phenylephrine bolus prior to propofol induction reduced the magnitude of redistribution hypothermia by an average of 0.4 to 0.5 °C in patients aged 18 to 55 years. Retrospectively registered on clinical-trials.gov as NCT02331108 , November 20, 2014.


Safety of rapid administration of flumazenil in patients with ischaemic heart disease.
The purpose of this study was to determine if higher (36 micrograms.kg-1) doses of flumazenil (a new benzodiazepine (BZ) antagonist) produced an effect on haemodynamics. Twelve patients with class III-IV angina were entered into this double-blind randomised placebo-controlled study. BZ were withheld for 2 weeks prior to surgery. Patients were placed on an ambulatory monitor 18 h prior to surgery to record changes in heart rate rhythm and ST segment changes. The patients were given secobarbital 100-200 mg and morphine 0.12 mg.kg-1 90 min prior to surgery. Flumazenil or placebo was given in divided doses every 3 min (1 mg, 1 mg, 1 mg). Complete haemodynamic profiles were obtained at baseline and 2 min following each injection of flumazenil. Flumazenil produced a minimal but statistically significant reduction in systolic blood pressure (147 +/- 13.9 to 137 +/- 18.4 mmHg) and diastolic blood pressure (74 +/- 14.8 to 67 +/- 13 mmHg). There was no consistent effect on heart rate, pulmonary capillary wedge pressure or cardiac index. We conclude that flumazenil is safe when administered in relatively high doses to patients with ischaemic heart disease who have not received benzodiazepines.


Cingulate impairments in ADHD: Comorbidities, connections, and treatment.
The entire cingulate cortex is engaged in the structure/function abnormalities found in attention-deficit/hyperactivity disorder (ADHD). In ADHD, which is the most common developmental disease, impaired impulse control and cognition often trace to anterior midcingulate cortex (aMCC) in Go/No-go tests, decoding and reading, the Stroop Color and Word Test, and the Wisconsin Card Sorting Test (WCST), with volume deficits in anterior cingulate cortex (ACC) and posterior midcingulate cortex (pMCC). Volumes in pMCC correlate positively with the WCST and negatively with total and nonperseverative errors on the WCST. Activation and connectivity on N-back tests show connections for high and low spatial working memory, but patients have increased activation in PCC and decreased connectivity between MCC and PCC for high load. Students struggle in class due to malfunctioning aMCC, pregenual anterior cingulate cortex (pACC), and dorsal posterior cingulate cortex (dPCC), and to core deficits in response/task switching in aMCC. Gene mutations are found in the DA transporter and DA4 and DA5 receptors. Methylphenidate decreases hyperactivity in aMCC. The DA system is controlled by cholinergic receptors in the daMCC and genetics show nAChR mutations in alpha 3, 4, and 7 receptors. At 25 years, a modified Eriksen flanker/No-go task and voxel-based morphometry (VBM) show prenatal smoking, lifetime smoking at 13 years, and novelty seeking. Prenatal exposure to nicotine exhibits weaker responses in aMCC during cognitive tasks for hyperactivity/impulsiveness but not inattention. AZD1446 (ɑ4β2 nAChR agonist) improves the Groton Maze task due to high nAChR in dPCC/RSC engaged in spatial orientation. Environmental factors associated with childhood ADHD relate to pesticides, organochlorine, and air pollutants. Network connection segregation shows increased amygdala local nodal, but decreased ACC and PCC connections, reflecting emphasis on local periamygdala connections at the expense of cortical connections. Thus, ADHD children/adolescents respond impulsively to the significance of stimuli without having cortical inhibition. Finally, controls show negative relationships between aMCC and the default mode network, and ADHD compromises this relationship, showing decreased connectivity between ACC and precuneus/PCC.


Multielement analysis of metal-binding proteins in cytosol fractions.
The distribution of 24 elements among the cytosol protein fractions was determined for specimens of the bivalve mollusc Macoma balthica obtained from three estuarine locations subject to varying levels of metal pollution and on specimens of Rangia cuneata from three areas subject to varying degrees of thermal pollution. Of the 24 elements examined 15 occurred at levels above detection limits and in association with one or more of four distinct protein fractions. Levels of Ag and Cu associated with high molecular weight proteins and with "metallothionein-like" proteins permitted identification of those Macoma balthica specimens exposed to the greatest degree of metal stress.


Rib fractures in infants: red alert! The clinical features, investigations and child protection outcomes.
To examine clinical features, investigation methods and outcomes of infants with rib fractures. All infants aged 2 years or younger who presented over a 5-year period with documented rib fractures were identified from the medical records database of a tertiary referral paediatric hospital and data collected by retrospective chart review. Additional data regarding notifications and placements were obtained from the Department of Families Youth and Community Care, Queensland. Rib fractures were attributed to child abuse in 15 of 18 infants identified. The initial presentation in the abused infants was most often as a result of intracranial pathology and limb fractures. In four cases the rib fractures were incidental findings when abuse had not been suspected. Bone scintigraphy revealed eight previously undetected rib injuries in four cases. In three cases of abuse, the rib fractures were an isolated finding. Three of the infants with inflicted rib injuries were discharged home. In one such infant a significant re-injury occurred. Three returned home with implicated adults no longer in residence, and nine spent a mean period of 12 months in foster care. Rib fractures in infancy are usually caused by severe physical abuse. Accidental rib fractures are rare in infants and result from massive trauma. Rib fractures, multiple or single, may occur in isolation in abused infants. The implications of such injuries must be recognized to ensure appropriate, safe and consistent child protection outcomes. Bone scintigraphy is more sensitive than radiographs in the detection of acute rib fractures and should be performed in all cases of suspected infant abuse.


Analysis of correlated data in human biomonitoring studies. The case of high sister chromatid exchange frequency cells.
Sister chromatid exchange (SCE) analysis in peripheral blood lymphocytes is a well established technique that aims to evaluate human exposure to toxic agents. The individual mean value of SCE per cell had been the only recommended index to measure the extent of this cytogenetic damage until the early 1980's, when the concept of high frequency cells (HFC) was introduced to increase the sensitivity of the assay. All statistical analyses proposed thus far to handle these data are based on measures which refer to the individual mean values and not to the single cell. Although this approach allows the use of simple statistical methods, part of the information provided by the distribution of SCE per single cell within the individual is lost. Using the appropriate methods developed for the analysis of correlated data, it is possible to exploit all the available information. In particular, the use of random-effects models seems to be very promising for the analysis of clustered binary data such as HFC. Logistic normal random-effects models, which allow modelling of the correlation among cells within individuals, have been applied to data from a large study population to highlight the advantages of using this methodology in human biomonitoring studies. The inclusion of random-effects terms in a regression model could explain a significant amount of variability, and accordingly change point and/or interval estimates of the corresponding coefficients. Examples of coefficients that change across different regression models and their interpretation are discussed in detail. One model that seems particularly appropriate is the random intercepts and random slopes model.


An overview of meta-analyses on radiomics: more evidence is needed to support clinical translation.
To conduct an overview of meta-analyses of radiomics studies assessing their study quality and evidence level. A systematical search was updated via peer-reviewed electronic databases, preprint servers, and systematic review protocol registers until 15 November 2022. Systematic reviews with meta-analysis of primary radiomics studies were included. Their reporting transparency, methodological quality, and risk of bias were assessed by PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) 2020 checklist, AMSTAR-2 (A MeaSurement Tool to Assess systematic Reviews, version 2) tool, and ROBIS (Risk Of Bias In Systematic reviews) tool, respectively. The evidence level supporting the radiomics for clinical use was rated. We identified 44 systematic reviews with meta-analyses on radiomics research. The mean ± standard deviation of PRISMA adherence rate was 65 ± 9%. The AMSTAR-2 tool rated 5 and 39 systematic reviews as low and critically low confidence, respectively. The ROBIS assessment resulted low, unclear and high risk in 5, 11, and 28 systematic reviews, respectively. We reperformed 53 meta-analyses in 38 included systematic reviews. There were 3, 7, and 43 meta-analyses rated as convincing, highly suggestive, and weak levels of evidence, respectively. The convincing level of evidence was rated in (1) T2-FLAIR radiomics for IDH-mutant vs IDH-wide type differentiation in low-grade glioma, (2) CT radiomics for COVID-19 vs other viral pneumonia differentiation, and (3) MRI radiomics for high-grade glioma vs brain metastasis differentiation. The systematic reviews on radiomics were with suboptimal quality. A limited number of radiomics approaches were supported by convincing level of evidence. The evidence supporting the clinical application of radiomics are insufficient, calling for researches translating radiomics from an academic tool to a practicable adjunct towards clinical deployment.


Pathological findings associated with Dipetalonema spp. (Spirurida, Onchocercidae) infection in two species of Neotropical monkeys from Brazil.
Among vector-borne helminths, filarioids of the genus Dipetalonema (Spirurida: Onchocercidae) localize in several tissues and body cavities of several animal species, causing mild to moderate lesions. The pathological findings associated with Dipetalonema spp. infection in Neotropical monkeys from southern Brazil are herein described, along with a fatal case due to filarial polyserositis and entrapment of an intestinal segment. At necropsy, nematodes were observed in abdominal and thoracic cavities, or in the pericardium of 37 (31.3%) out of the 118 individuals examined (i.e., 35 Alouatta guariba clamitans and two Sapajus nigritus). In addition, at histology, 27.0% of positive animals presented microfilarie (inside blood vessels of lung, spleen, liver, and brain) and 8.1% presented adult nematodes in the heart, lung, and liver. In two cases, cross-sections of filarioids were associated with areas of epicardial thickening with intense fibrosis and pyogranulomatous inflammation in the brain, heart, liver, lungs, or spleen. The DNA fragment was amplify using the cox1 gene, sequenced and analyzed to identify the nematode species collected; presence of Wolbachia was assessed in the filarioids using the 16S rRNA gene. At BLAST analysis of the cox1 gene, 10 sequences showed 91.7% nucleotide identity with Dipetalonema gracile, and two with D. gracile (98.5%) and Dipetalonema graciliformis (98.3%). Phylogenetic analyses clustered sequences of the cox1 obtained in this study in two clades corresponding with the host species. Wolbachia sp. endosymbiont was detected in four samples. Data herein reported provide a description of pathological lesions associated with the infection by Dipetalonema spp., suggesting that they may cause disease in Neotropical monkeys. In addition, a better understanding of diversity and biology of Dipetalonema spp. in South America is needed to assess the impact they may cause in native non-human primates from Brazil.


Small rainfall events: An ecological role in semiarid regions.
Small precipitation events account for a large proportion of the precipitation received in semiarid regions, and their potential ecological importance has previously been ignored. We investigated the effect of a small rainfall event (5 mm) upon Bouteloua gracilis, the dominant grass species of the central and southern Great Plains of North America. An effect of a small event on leaf water potential and leaf conductance to water vapor was observed in less than 12 h and lasted for up to two days.The remarkable short response time of Bouteloua gracilis to a rainfall stimulus enables this species to utilize small events and, therefore, may influence its persistence as a dominant species in the steppe region.We proposed response times to be one of the major species characteristics determining capacity for utilizing different portions of the water resource of the region. We suggest that small precipitation events are ecologically significant and a qualitatively distinct resource for ecosystems in semiarid regions.


Molecular characteristics of Neisseria meningitidis isolated during an outbreak in a jail: association with the spread and distribution of ST-4821 complex serogroup C clone in China.
To characterize the meningococcal strains isolated from cases and close contacts with meningococcal disease associated with an outbreak in a jail in May 2010 by investigating the national distribution of hyperinvasive ST-4821 serogroup C clone associated with this outbreak. The cases were described based on the clinical symptoms and laboratory results. Pharyngeal swabs were cultured for N. meningitidis from men in the jail. Meningococcal isolates were identified by serogrouping, pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing (MLST), respectively. Four hundred and sixteen serogroup C N. meningitidis strains were collected from 27 provinces between 2003 and 2010 for a nationwide survey and analyzed by PFGE and MLST. Three persons in a jail system were infected with invasive N. meningitidis serogroup C. All isolates tested had matching PFGE patterns and belonged to the multilocus sequence type (ST) 4821 clonal complex. All 47 N. meningitidis strains were identified from the pharyngeal swabs of 166 peoples in the jail, and 26 of them belonged to ST-4821 serogroup C clone, and 90.14% (375/416) serogroup C strains identified in the nationwide survey belonged to the ST-4821 complex. The ST-4821 serogroup C clone was spread nationwide, distributed in 24 provinces, especially in eastern provinces between 2003 and 2010. Endemic transmission and carriage rate of ST-4821 serogroup C clone are high in this jail system. The ST-4821 serogroup C clone is spreading in China and nationwide distributed despite the existence of some effective vaccines.


Ureteral reimplantation by the transverse advancement technique.
When the transverse advancement technique of ureteral reimplantation is used the submucosal tunnel is made transversely across the base of the bladder. This method was used for reimplantation of 131 ureters in 92 children. The results indicate that the transverse advancement technique is adaptable to virtually any situation requiring ureteral reimplantation and is a simple, safe and reliable procedure for prevention of reflux.


Lymphocyte function tests in cirrhotic patients under treatment with spironolactone and potassium canrenoate.
This controlled study in cirrhotic patients investigated whether two antialdosteronic steroids, spironolactone (100-200 mg/day; n = 12 patient pairs) and potassium canrenoate (50-100 mg/day, n = 32 patient pairs) which are reported to bind to intracellular membranes and modify cytochrome P-450, could also produce nuclear changes. The model used was the response of peripheral lymphocytes to blastogenic agents by studying lymphocyte sub-populations. No changes occurred in the B- and T-lymphocyte sub-populations or in the helper and suppressor sub-types. The response to the blastogenic agents, phytohaemagglutinin and purified protein derived from mycobacteria, did not change significantly from before entry into the study to the follow-up (18.1 +/- 2.9 months). All control patients (n = 44 patient pairs) had slightly greater mitogenic activity compared with patients treated with spironolactone; no difference was found when control patients were compared with patients given potassium canrenoate. The difference between spironolactone and potassium canrenoate might be due to toxicity caused by the thio group of spironolactone. Overall, however, both drugs may be regarded as safe, in terms of effects on lymphatic tissue, occurring during the course of cirrhosis.


Safety of duodenal ampullectomy for benign periampullary tumors.
Surgical resection, such as pancreaticoduodenectomy (PD), is used for treatment of benign periampullary tumors, but high morbidity and mortality resulting from PD can be a huddle. The aim of this study is to suggest a safe and less invasive procedure for treatment of benign periampullary tumors. From January 2001 to September 2016, 31 patients with ampulla of Vater (AOV) tumors were reviewed retrospectively. Patients who were confirmed with malignancy through biopsy were excluded, except for one patient with malignancy and multiple underlying diseases. To investigate the safety and availability of transduodenal ampullectomy (TDA), TDA and endoscopic papillectomy (EP) were compared. There was no significant difference in the occurrence of complications between the TDA group and EP group (p=0.145), and the resection margins were negative in both groups. There was no recurrence in patients who had TDA, while one patient had a recurrence after EP. This study suggests that TDA is as safe as EP for treating benign periampullary tumors.


Intercountry assessment of the impact of severe premenstrual disorders on work and daily activities.
We explored the effects of premenstrual symptoms in women suffering from moderate-to-severe premenstrual syndrome/premenstrual dysphoric disorder (PMS/PMDD) on work productivity, absenteeism, and daily life activities in a large, worldwide exploratory study. Women aged 15-45 years from 19 countries in North America, Latin America, Europe, Asia, and Australia were screened for suspected PMS and PMDD and invited to participate in this 2-month web-based survey. Overall, 4,032 women completed all administered questionnaires and represent the analysis set. Women suffering from moderate-to-severe PMS/PMDD had increased work absenteeism and work productivity impairment due to premenstrual symptoms relative to those with mild PMS/no perceived symptoms.


Aging and age related stresses: a senescence mechanism of intervertebral disc degeneration.
Intervertebral disc (IVD) degeneration is a complicated process that involves both age-related change and tissue damage caused by multiple stresses. In a degenerative IVD, cellular senescence accumulates and is associated with reduced proliferation, compromised self-repair, increased inflammatory response, and enhanced catabolic metabolism. In this review, we decipher the senescence mechanism of IVD degeneration (IVDD) by interpreting how aging coordinates with age-related, microenvironment-derived stresses in promoting disc cell senescence and accelerating IVDD. After chronic and prolonged replication, cell senescence may occur as a natural part of the disc aging process, but can potentially be accelerated by growth factor deficiency, oxidative accumulation, and inflammatory irritation. While acute disc injury, excessive mechanical overloading, diabetes, and chronic tobacco smoking contribute to the amplification of senescence-inducing stresses, the avascular nature of IVD impairs the immune-clearance of the senescent disc cells, which accumulate in cell clusters, demonstrate inflammatory and catabolic phenotypes, deteriorate disc microenvironment, and accelerate IVDD. Anti-senescence strategies, including telomerase transduction, supply of growth factors, and blocking cell cycle inhibitors, have been shown to be feasible in rescuing disc cells from early senescence, but their efficiency for disc regeneration requires more in vivo validations. Guidelines dedicated to avoiding or alleviating senescence-inducing stresses might decelerate cellular senescence and benefit patients with IVD degenerative diseases.


Two-stage (posterior and anterior) surgical treatment using posterior spinal instrumentation for pyogenic and tuberculotic spondylitis.
A retrospective analysis was performed of the clinical outcomes of patients with pyogenic or tuberculotic spondylitis who were treated with two-stage surgery (first stage: placement of posterior instrumentation; second stage: anterior debridement and bone grafting). To evaluate the clinical outcomes of the abovementioned two-stage surgical treatment for pyogenic or tuberculotic spondylitis. Although several methods of surgical treatment for pyogenic and tuberculotic spondylitis have been reported, there have been few reports of two-stage surgical treatment. Eight patients (7 male, 1 female) with pyogenic or tuberculotic spondylitis (pyogenic: 6; tuberculotic: 2) were treated by two-stage surgery (first: placement of posterior instrumentation, second: anterior debridement and bone graft). Age at the time of surgery was 63.5 +/- 9.91 years (average +/- SD) (range: 47 to 77 years). Most of the patients had systemic problems, such as pneumonia, diabetes mellitus, or chronic renal failure. First, posterior spinal instrumentation was placed. Then, anterior debridement and bone grafting were performed. Patients were evaluated before and after surgery in terms of pain level, hematologic parameters, neurologic status, and Barthel index. Average duration of surgery for both procedures was less than 4 hours. Changes in the pain level, blood parameters, and Barthel index demonstrated significant clinical improvement in all patients. Posterior wound infection occurred in two patients who were in poor general condition. This two-stage surgical treatment for pyogenic or tuberculotic spondylitis provided satisfactory results and can also be used in patients who are in poor general condition.


[Choice of the mode of intubation and decompression of the small intestine in acute obstruction].
On the basis of case records analysis of 370 patients from 1107 with acute small bowel obstruction (ASBO) treated in hospital, the authors have classified methods of intubation and decompression of the small bowel and modes of the use of decompression probe. Classification of clinical course of ASBO is proposed for substantiation of application of various modes of intubation and decompression depending on the progression stage of ASBO and medical technology for treatment of such kind of patients.


Allergic fungal rhinosinusitis: a review.
Allergic fungal rhinosinusitis (AFRS) is a relatively new and incompletely understood clinical entity with characteristic clinical, radiographic, and histopathologic findings. AFRS is often misdiagnosed. Recognition and understanding of this unique disease will lead to efficient diagnosis and treatment of this curable process. The following is a review, conducted via a PubMed English language search, of the current diagnosis, pathogenesis, and treatment of AFRS. AFRS is an immune-modulated disease entity. The Bent and Kuhn diagnostic criteria are the standard for diagnosis of this disease that occurs because of an incompletely understood allergic mechanism. Multimodality treatment relies heavily on surgical therapy along with corticosteroid use and immunotherapy. AFRS is a unique disease process that differs from other forms of sinusitis and as such requires that physicians understand its diagnosis and management to provide care for patients with this condition.


Energy Status of Lymphocytes in Children with Bronchial Asthma of Various Severity in Comparison with Frequently Ill and Healthy Children.
We studied disturbances of cellular energy exchange as one of the leading factors in the development of chronic inflammation in asthma. Comparison of the indicators of mitochondrial respiration and glycolysis in lymphocytes of children with bronchial asthma of different severity, children from the group of frequently ill, and conditionally healthy children showed that the degree of impaired energy metabolism correlates with the severity of the disease. In mild and compensated course of bronchial asthma, as well as in the group of frequently ill children, an increase in the activity of oxidative phosphorylation was observed, which was also accompanied by support in the form of glycolysis activation. This suggests that the energy supply mechanisms are preserved. In more serious cases (moderate bronchial asthma), mitochondrial respiration was hyperactivated with suppression or even absence of glycolysis in some cells. In children with severe bronchial asthma, depression of all studied dehydrogenases was observed, which is probably an unfavorable prognostic sign. These results make it possible to determine the indications for the choice of basic therapy drugs and can serve as a prognostic marker of the severity of the course of the disease.


Oxygen self-enriched nanoplatform combined with US imaging and chemo/photothermal therapy for breast cancer.
Oxygen-saturated perfluorohexane-cored, cisplatin (Pt)-decorated hollow gold nanospheres (Pt-HAuNS-PFH@O2) have been synthesized for ultrasound (US) imaging-guided tumor treatment depending on chemo/photothermal therapy, relief of hypoxia, and photothermal induced US contrast signal. Both NIR laser-induced hyperthermia generation by gold nanospheres and acidity triggered release of Pt resulted in high toxicity after internalization by breast cancer cells. According to ex vivo immunofluorescence investigation and in vivo pharmacodynamic studies on MDA-MB-231 tumor bearing mice, the susceptibility of tumors to Pt-HAuNS-PFH@O2 was improved by the relief of hypoxia. In addition, US imaging under different conditions verified the amplified US contrast property of Pt-HAuNS-PFH@O2 by the heat-dependent liquid-gas conversion of PFH. Overall, Pt-HAuNS-PFH@O2 can be promisingly used as an oxygen self-enriched nanoplatform for US imaging-guided chemo/photothermal therapy.


ZIC2 promotes colorectal cancer growth and metastasis through the TGF-β signaling pathway.
ZIC2 is involved in the tumor progression of many types of cancers. The role of ZIC2 in the metastasis of colorectal cancer and its mechanism are not yet clear. In this study, we found that high ZIC2 expression was not only associated with poor prognosis, relapse-free survival and advanced metastasis but was also an independent prognostic factor in colorectal cancer patients. Moreover, ZIC2 knockdown inhibited cell proliferation, migration and invasion, while the upregulation of ZIC2 had the opposite effect in vitro. ZIC2 overexpression induced TGF-β1 expression and increased Smad3 phosphorylation. The carcinogenic effects of elevated ZIC2 expression can be eliminated by interfering with the TGF-β1 receptor with inhibitors. This further verified the promoting effect of ZIC2 on the TGF-β signaling pathway. In vivo experiments have also confirmed that ZIC2 can promote liver metastases of colorectal cancer. The results suggest that ZIC2 is associated with poor prognosis and relapse-free survival in colorectal cancer patients. Moreover, ZIC2 promoted colorectal cancer progression and metastasis by activating the TGF-β signaling pathway. Hence, ZIC2 is expected to be a new therapeutic and prognostic target for colorectal cancer in the future.


Identification of U11snRNA as an endogenous agonist of TLR7-mediated immune pathogenesis.
The activation of innate immune receptors by pathogen-associated molecular patterns (PAMPs) is central to host defense against infections. On the other hand, these receptors are also activated by immunogenic damage-associated molecular patterns (DAMPs), typically released from dying cells, and the activation can evoke chronic inflammatory or autoimmune disorders. One of the best known receptors involved in the immune pathogenesis is Toll-like receptor 7 (TLR7), which recognizes RNA with single-stranded structure. However, the causative DAMP RNA(s) in the pathogenesis has yet to be identified. Here, we first developed a chemical compound, termed KN69, that suppresses autoimmunity in several established mouse models. A subsequent search for KN69-binding partners led to the identification of U11 small nuclear RNA (U11snRNA) as a candidate DAMP RNA involved in TLR7-induced autoimmunity. We then showed that U11snRNA robustly activated the TLR7 pathway in vitro and induced arthritis disease in vivo. We also found a correlation between high serum level of U11snRNA and autoimmune diseases in human subjects and established mouse models. Finally, by revealing the structural basis for U11snRNA's ability to activate TLR7, we developed more potent TLR7 agonists and TLR7 antagonists, which may offer new therapeutic approaches for autoimmunity or other immune-driven diseases. Thus, our study has revealed a hitherto unknown immune function of U11snRNA, providing insight into TLR7-mediated autoimmunity and its potential for further therapeutic applications.


Interferon-λ at the Center of the Storm.
Type I and III interferons (IFNs) drive effective antiviral functions but differentially affect tissue homeostasis. Using mouse models of severe inflammation, Broggi et al. and Major et al. report in Science that type III IFNs disrupt epithelial cell proliferation and differentiation in the lung.


Interdependence of attachment styles and relationship quality in parent-adolescent dyads.
The current study examined how attachment styles of parents and adolescents may jointly influence the quality of their relationship. Parent-adolescent (Ndyads = 77) pairs were recruited from a Midwestern town in the United States. The mean of adolescents' age was 16.25. Both members reported their attachment styles, relationship closeness, and relationship discord. The Actor-Partner Interdependence Model (APIM) showed that both members' attachment avoidance was associated with self-report lower levels of closeness. Parents' attachment anxiety was related to relationship discord. Parents with higher avoidant attachment reported lower closeness when adolescents were higher in avoidant attachment. Higher parents' anxious attachment was related to higher relationship closeness when adolescents were higher on anxious attachment. Such an association was negative when adolescents had lower anxious attachment. Higher parents' anxious attachment was related to greater discord when adolescents were lower on anxiety attachment. This study reveals the complex dyadic dynamics of relationship quality in parent-adolescent pairs.


Do lower nitrogen fertilization levels require breeding of different types of cultivars in triticale?
The comparably low genotype-by-nitrogen level interaction suggests that selection in early generations can be done under high-input conditions followed by selection under different nitrogen levels to identify genotypes ideally suited for the target environment. Breeding high-yielding, nitrogen-efficient crops is of utmost importance to achieve greater agricultural sustainability. The aim of this study was to evaluate nitrogen use efficiency (NUE) of triticale, investigate long-term genetic trends and the genetic architecture, and develop strategies for NUE improvement by breeding. For this, we evaluated 450 different triticale genotypes under four nitrogen fertilization levels in multi-environment field trials for grain yield, protein content, starch content and derived indices. Analysis of temporal trends revealed that modern cultivars are better in exploiting the available nitrogen. Genome-wide association mapping revealed a complex genetic architecture with many small-effect QTL and a high level of pleiotropy for NUE-related traits, in line with phenotypic correlations. Furthermore, the effect of some QTL was dependent on the nitrogen fertilization level. High correlations of each trait between N levels and the rather low genotype-by-N-level interaction variance showed that generally the same genotypes perform well over different N levels. Nevertheless, the best performing genotype was always a different one. Thus, selection in early generations can be done under high nitrogen fertilizer conditions as these provide a stronger differentiation, but the final selection in later generations should be conducted with a nitrogen fertilization as in the target environment.


Routine Therapeutic Drug Monitoring of Dabigatran: Experience at a Tertiary Center.
A liquid chromatography-mass spectrometry assay to determine plasma dabigatran concentrations has been available for routine clinical use at our tertiary institutions since 2017. The aim of the study was to describe (1) the use of the assay over time; (2) the indications for testing; and (3) subsequent dabigatran prescribing decisions. Patients for whom dabigatran concentrations were measured were identified using the laboratory database, and clinical data were extracted from the associated electronic health records. There were 233 samples in 24 months. The use of dabigatran increased over time, with a mean (95% confidence interval) increase of +0.5 (0.3-0.7) samples per month. Dabigatran concentrations ranged from <1 to 1060 mcg/L. The main reasons for testing were uncertainty about impact on renal function and drug interactions (39%), to inform prescribing decisions after thromboembolic or bleeding events (21%), and for investigation following dose-adjustment (16%). Dabigatran dose was changed after 30% (68/233) of assay results. The clinical use of the dabigatran assay has increased, with almost one-third of results associated with a subsequent change in dabigatran prescribing.


Non-invasive monitoring of blood volume during hemodialysis: its relation with post-dialytic dry weight.
Hemodialysis has a profound effect on fluid balance. Since fluid is initially withdrawn from the intravascular compartment, blood volume will decrease rapidly. A fluid shift (refill) from the overhydrated interstitium towards the intravascular compartment counteracts hypovolemia. Underestimation of postdialytic dry weight will cause interstitial dehydration and consequently a low refill capacity. This can cause hypovolemia-induced hypotension, a serious problem in the daily practice of hemodialysis: during one out of three sessions a hypotensive episode occurs. Clinical criteria to estimate post-dialytic dry weight are insensitive. We have developed non-invasive methods to estimate dry weight and changes in blood volume (BV) more accurately. The aim of this study was to investigate the relation between hydration state of the patient and changes in BV during treatment. Therefore, 37 hemodialysis patients were divided into three groups according to their post-dialytic extracellular fluid volume (EFV), which was measured by means of the non-invasive conductivity method: de- (N = 11), normo- (N = 18), and overhydrated (N = 8). Using an on-line optical reflection method, changes in BV were measured continuously during hemodialysis. BV decrease, corrected for ultrafiltration, was stronger in the dehydrated (4.4 +/- 1.5%/liter) than in the normohydrated (3.3 +/- 1.5%/liter) and overhydrated (2.7 +/- 1.9%/liter) groups. In the dehydrated group, the frequency of hypotensive episodes (48.5 +/- 20.2%) was significantly greater compared to the normohydrated (20.5 +/- 23.5%) or overhydrated (6.5 +/- 6.5%) group, P < 0.005.(ABSTRACT TRUNCATED AT 250 WORDS)


Epidemiology of heartworm: what is happening in South America and Mexico?
Canine heartworm has been known to exist in the Americas for more than 150 years (1847), and the first South American report was published approximately 30 years later (1875). The first human case was reported in 1887 and the first feline case in 1921. Coincidently, these two reports were from Brazil, where most surveys of the disease during the past two decades have been conducted in dogs. Feline cases are seldom found in the South American literature, although feline heartworm disease has been reported in Venezuela and Brazil. The prevalence in Mexico seems to be stable over the past 10 years (7.3-7.5%). Only 5 of the 13 South American countries have reported on canine heartworm infection prevalence. In Argentina, the national prevalence ranges from 3.5 to 12.7%; however, there was a much higher prevalence (17.7 and 23.5%) reported for two sections of Buenos Aires. In Lima, Peru, the prevalence is 4.35%, and Colombia reports 3.8-4.8% of dogs are infected. No infections were detected in 1056 dogs sampled in Chile. In Brazil, the national prevalence has declined from 7.9% in 1988 to 2% in 2001. The downward trend observed for canine heartworm in Brazil suggests that multiple pressures may be affecting the nematode transmission, including a possible decrease in mosquito vector population due to better control programs, reduction of transmission due to effective chemoprophylaxis, reduction of microfilaremic dog populations with the off-label use of injectable ivermectin, or reduction of the reproductive capacity of worms from tetracyclines used to control ehrlichiosis. Survey of a large population of captured mosquitoes indicated the most frequent species captured were vectors of heartworms (Aedes taeniorhynchus (73.9%), Aedes scapularis (20%) and Culex quinquefasciatus (2.5%), suggesting that the composition of the mosquito population is not a critical factor in the decrease in heartworm infections in dogs in South America.


Targets for adapting intravenous iron dose in hemodialysis: a proof of concept study.
Intravenous iron is widely used to control anemia in dialysis patients and limits costs related to erythropoiesis-stimulating agents (ESA). Current guidelines do not clearly set upper limits for serum ferritin (SF) and transferrin saturation (TSAT). International surveys such as the Dialysis Outcomes and Practice Patterns Study (DOPPS) showed that this lack of upper limits potentially led nephrologists to prescribe iron infusions even for patients with a high SF. Recent publications have suggested a risk of short- and long-term adverse effects related to iron overload. We conducted a proof of concept study to assess the impact of reducing intravenous iron administration. In a prospective 8-month study conducted in a hospital dialysis unit, we assessed the impact of a strategy designed to reduce iron infusions. Instead of the usual strategy targeting 30-50% TSAT irrespective of SF, intravenous iron was administered if and only if TSAT was below 20% and SF below 200 μg/L. Routine practices for ESA remained unchanged: hemoglobin target 10-12 g/dL; ESA delivered monthly and dose corrected by 25% as necessary; ESA discontinued temporarily if hemoglobin >13 g/dL; methoxy polyethylene glycol-epoetin beta generally used. Tests were ordered monthly to monitor hemoglobin. Intravenous iron was administered weekly and ESA monthly. Baseline and 6-month TSAT, SF and hemoglobin levels were compared. Six-month data were available for 45 patients (31 M/14 F; 67.6 ± 14.0 y; 53.9 ± 85.7 months on dialysis). Patients experienced the following comorbidities: ischemic heart disease (n = 29, 44%), diabetes mellitus (n = 14; 31%), malignant disease (n = 11; 24%), transplantation (n = 11; 24%) and severe heart failure (n = 6; 13%). The mean weekly dose of iron declined from 77.8 ± 87.6 to 24.4 ± 52.9 mg per patient (p = 0.0003). SF decreased from 947.7 ± 1056.4 to 570.7 ± 424.4 μg/L (p = 0.0001), and TSAT from 41.5 ± 22.4 to 32.6 ± 13.7% (p = 0.01). Hemoglobin levels remained stable (11.13 ± 1.05 vs. 11.00 ± 1.16 g/dL, p = 0.54) as did ESA dose (126.4 ± 91.9 vs. 108.2 ± 112.7 μg/28 days, p = 0.07). Our study suggests that a regular hemoglobin level can be maintained using regular ESA doses combined with intravenous iron doses adapted to TSAT and SF thresholds lower than those used in routine practice. This strategy reduces the risk of iron overload.


Quantitation of synergism of arabinosylcytosine and cladribine against the growth of arabinosylcytosine-resistant human lymphoid cells.
This report presents a quantitative analysis of the synergistic interaction of arabinosylcytosine (araC) and cladribine (CdA) in human H9-lymphoid cell lines sensitive and resistant to araC (H9-araC cells). H9-araC cells obtained by cultivation of H9 cells in the presence of 0.5 microM arabinosylcytosine (araC) had lower deoxycytidine kinase (dCK) than the parental cell line. The IC50 values of araC and CdA calculated by using median-effect analysis and CalcuSyn software were: 0.55 microM and 1.16 microM for CdA and 0.0058 microM and 3.5 microM for araC in H9 and H9-araC cells, respectively. These values were reduced to 0.10 microM and 0.38 microM for CdA and to 0.004 microM and to 0.77 microM for araC when the drugs were used in combination. Computerized simulation of dose reduction index (DRI) indicated that at 50-99% growth inhibition levels, the doses of araC could be reduced by 2.0 to 11.9-fold and 2.9 to 5.3-fold and the doses of CdA by 5.9 and 183.7-fold and 3.1 to 164.8-fold in H9 and H9-araC cells, respectively, when the drugs are used in combination. Assessment by combination index (CI) analysis showed that the combination exhibited moderate to strong synergistic lympho-cytotoxic effects. CdA metabolic studies (influx and activation) in the presence of deoxyadenosine, deoxycytidine, or araC suggested that CdA enters cells by a deoxyadenosine-inhibitable transport system, which is different than that of araC and deoxycytidine transport system. Thus, in addition to the known mechanisms, other mechanisms might be involved in the metabolism of CdA. The demonstration that araC and CdA combinations exert synergistic cytotoxicity even in the resistant cells raises hope that such a combination may be useful in tumors that were found resistant to these drugs.


Detection of early cardiac disease manifestation in propionic acidemia - Results of a monocentric cross-sectional study.
In propionic acidemia (PA) myocardial involvement is common and includes development of cardiomyopathy, life-threatening acute heart failure, and acquired long-QT syndrome. We sought to investigate which echocardiographic parameters of left ventricular systolic and diastolic function indicate early cardiac disease manifestation in PA. This is a prospective observational study (cross-sectional design) in a Tertiary Medical Care Center. Individuals with confirmed PA were enrolled and the following cardiac investigations were performed in all study individuals: echocardiographic measurements of systolic and diastolic left ventricular (LV) function (LV fractional shortening (LV-FS), LV ejection fraction by biplane modified Simpson's (LV-EF), mitral annular plane systolic excursion (MAPSE), LV global longitudinal strain (LV-GLS) by speckle tracking echocardiography (STE), pulsed Doppler analyses of mitral valve (MV) inflow velocities (MV E/A) and MV deceleration time (DT-E), tissue doppler imaging (TDI) of the mitral annulus (MV E/e'), and LV myocardial performance index (LV-MPI)). LV and left atrial (LA) diameters were assessed. 12‑lead electrocardiograms (ECG) were recorded and corrected QT intervals (QTc) calculated. Clinical phenotype and laboratory parameters at the time of cardiac investigation were assessed. Besides descriptive analyses we analyzed frequency, onset, and combinations of echocardiographic and ECG data as well as their correlations with clinical and biochemical findings. The effects of 'age at visit' and LV functional parameters on QTc were analyzed with multiple regression. A total of 18 patients with confirmed PA were enrolled. Median age at PA onset was 6 days (range 1-357 days). Median age at visit for cardiac evaluation was 13.1 years (range 0.6-28.1 years). LV-GLS was abnormal in 72.2%, LV-EF in 61.1%, MAPSE in 50%, MV E/e' in 44.4%, LV-MPI in 33.3%, LV-FS in 33.3%, and MV E/A in 27.8%. In cases with normal or near normal LV-FS, LV-GLS was pathological in 5/10, LV-EF in 4/10, and MAPSE in 3/10. The probability of developing LV dysfunction - systolic and diastolic - increases with age. LV-MPI is a reliable parameter to indicate systolic LV-dysfunction in combination with a dilated LV, i. e. dilated cardiomyopathy (DCM) in PA. Multiple regression reveals a significant positive association between LV diameters and QTc. Abnormal LV-GLS significantly correlates with reduced muscle strength, muscle tone and/or abnormal gross motor function. Our data suggests a high prevalence of cardiac disease manifestation in PA, considerably higher than in previous studies, where only LV-FS was used to assess LV function. Usage of advanced echocardiographic techniques, such as LV-GLS assessment, may allow for early detection of subtle LV dysfunction in PA, and may lead to timely cardiac treatment but also consideration of liver transplantation to prevent development of manifest cardiac complications.


Simultaneous liver and colorectal resections are safe for synchronous colorectal liver metastasis.
The optimal surgical strategy for the treatment of synchronous resectable colorectal liver metastasis has not been defined. The aims of this study were to review our experience with synchronous colorectal metastasis and to define the safety of simultaneous versus staged resection of the colon and liver. From September 1984 through November 2001, 240 patients were treated surgically for primary adenocarcinoma of the large bowel and synchronous hepatic metastasis. Clinicopathologic, operative, and perioperative data were reviewed to evaluate selection criteria, operative methods, and perioperative outcomes. One hundred thirty-four patients underwent simultaneous resection of a colorectal primary and hepatic metastasis in a single operation (Group I), and 106 patients underwent staged operations (Group II). Simultaneous resections tend to be performed for right colon primaries (p < 0.001), smaller (p < 0.01) and fewer (p < 0.001) liver metastases, and less extensive liver resection (p < 0.001). Complications were less common in the simultaneous resection group, with 65 patients (49%) sustaining 142 complications, compared with 71 patients (67%) sustaining 197 complications for both hospitalizations in the staged resection group (p < 0.003). Patients having simultaneous resection required fewer days in the hospital (median 10 days versus 18 days, p = 0.001). Perioperative mortality was similar (simultaneous, n = 3; staged, n = 3). Simultaneous colon and liver resection is safe and efficient in the treatment of patients with colorectal cancer and synchronous liver metastasis. By avoiding a second laparotomy, the overall complication rate is reduced, with no change in operative mortality. Given its reduced morbidity, shorter treatment time, and similar cancer outcomes, simultaneous resection should be considered a safe option in patients with resectable synchronous colorectal metastasis.


Newcastle disease virus infection induces activation of the NLRP3 inflammasome.
Inflammatory responses are important aspects of the innate immune system during virus infection. We found that Newcastle disease virus can induce inflammasome activation in the human macrophage-like cell line THP-1. Viral replication was required for inflammasome activation, and small hairpin RNA knockdown experiments indicated that IL-1β secretion was mediated by the NLRP3 inflammasome. We also verified the results in LPS-primed bone marrow-derived macrophages (BMDMs) from NLRP3-deficient and wild type mice. NDV is considered to be a promising oncolytic virus. Stimulating the immune system has been proposed as a key mechanism of oncolytic specificity, and the inflammasome appears to be an important mechanism by which NDV is controlled. Knockdown of inflammasome components or chemical inhibition of caspase-1 activity shows that cell survival was augmented and benefited NDV replication. This study shows that NLRP3 inflammasome activation is an innate cellular response to NDV infection and offers insights into the oncolytic specificity of NDV.


Gram-scale synthesis of nitrogen-doped carbon dots from locusts for selective determination of sunset yellow in food samples.
Locust powder was converted into water-soluble fluorescent nitrogen-doped carbon dots (N-CDs) with gram-scale yield through a self-exothermic reaction between nitric acid and diethylenetriamine (DETA) within 10 min. The morphology, elemental information, and optical properties of the N-CDs were characterized using high-resolution transmission electron microscopy, X-ray photoelectron spectroscopy, and Fourier-transform infrared, ultraviolet-visible and fluorescence spectroscopy. Spectroscopic investigation indicated that the fluorescence emission behaviour of N-CDs is excitation wavelength dependent, with the strongest emission peak at 470 nm using a 390 nm excitation wavelength. The strong absorption peak of sunset yellow (SY) at 482 nm overlaps substantially with the blue emission peak (470 nm) of N-CDs. This enables the fluorescence emission of N-CDs to be obviously quenched by SY through the inner filter effect. There was a good linear relationship between the fluorescence quenching degree and the concentrations of SY within the range 0.5-40 μM. The detection limit of developed fluorescence assay for SY is 28 nM, and the relative standard deviation is 2.3% (c = 10 μM). The N-CDs derived from locusts by the self-exothermic reaction are highly selective and sensitive fluorescent probes for SY, which were applied to the fluorescence sensing of SY in different food samples with satisfactory results.


Biomolecule-mimetic nanomaterials for photothermal and photodynamic therapy of cancers: Bridging nanobiotechnology and biomedicine.
Nanomaterial-based phototherapy has become an important research direction for cancer therapy, but it still to face some obstacles, such as the toxic side effects and low target specificity. The biomimetic synthesis of nanomaterials using biomolecules is a potential strategy to improve photothermal therapy (PTT) and photodynamic therapy (PDT) techniques due to their endowed biocompatibility, degradability, low toxicity, and specific targeting. This review presents recent advances in the biomolecule-mimetic synthesis of functional nanomaterials for PTT and PDT of cancers. First, we introduce four biomimetic synthesis methods via some case studies and discuss the advantages of each method. Then, we introduce the synthesis of nanomaterials using some biomolecules such as DNA, RNA, protein, peptide, polydopamine, and others, and discuss in detail how to regulate the structure and functions of the obtained biomimetic nanomaterials. Finally, potential applications of biomimetic nanomaterials for both PTT and PDT of cancers are demonstrated and discussed. We believe that this work is valuable for readers to understand the mechanisms of biomimetic synthesis and nanomaterial-based phototherapy techniques, and will contribute to bridging nanotechnology and biomedicine to realize novel highly effective cancer therapies.


Multi-decadal oscillations of surface temperatures and the impact on temperature increases.
The last IPCC assessment report indicated that natural climate variability could temporarily amplify or obscure anthropogenic climate change on decadal time scales. Here we analyse global mean surface temperatures in terms of such long-period variations. We find two main oscillations, a strong oscillation with a period of about 70 years and an amplitude of about 0.09 K and a quasi-bidecadal oscillation with an amplitude of about 0.06 K. The strong oscillation shows large hemispheric differences. In the Northern hemisphere the period is longer and the amplitude is larger (about 82 years and 0.18 K) compared to the Southern hemisphere (about 47 years and 0.065 K). No obvious hemispheric differences are observed for the quasi-bidecadal oscillation. Such long-period oscillations can strengthen or weaken the temperature increase if the oscillation positively or negatively adds to the underlying long-term trend.


Appropriate and inappropriate use of dronedarone in 2013.
Dronedarone is a multichannel blocking antiarrhythmic agent that has been shown to prevent atrial fibrillation/flutter (AF/AFl) recurrences in several multi-center trials. In the ANDROMEDA trial, dronedarone treatment increased mortality and cardiovascular hospitalizations patients with decompensated heart failure. In the ATHENA trial, dronedarone was used in elderly high risk patients with paroxysmal or persistent AF/AFl, excluding those with advanced heart failure, cardiovascular hospitalizations were significantly reduced. Dronedarone increased mortality and cardiovascular hospitalizations in a different patient group with permanent AF/AFl. Although organic toxicity from the drug is very rare, post-marketing data has reported rare hepatic toxicity associated with dronedarone use. Current guidelines position dronedarone as a front-line antiarrhythmic in many patients with AF/Fl. However, dronedarone should not be used in patients with advanced heart failure or in permanent AF. Clinical trial results have helped us define appropriate and inappropriate candidates for dronedarone.


Cardiovascular risk prediction model for Omanis with type 2 diabetes.
To date, no cardiovascular risk assessment tool has been developed specifically for any Arabian population including Omanis. This study aims to develop a suitable cardiovascular risk prediction model in the form of a statistical equation, for Omanis with type 2 diabetes. A sample of 2039 patients with type 2 diabetes selected from primary care settings in the Aldakhiliyah Province of Oman were involved in a retrospective cohort study. All patients were free of cardiovascular disease at baseline (in 2009-2010) and were followed up until: 1) their first cardiovascular event occurred; 2) the patient died, or 3) the end of the data collection in December 2015. Among the total sample, 192 cardiovascular disease events were recorded within a mean follow-up period of 5.3-year. The 5-year probability of a cardiovascular event was given as 1-0.9991Exp∑XiBi, where Exp ∑XiBi (hazard ratio)=Exp (0.038 age+0.052 DM duration+0.102 HbA1c+0.201 total cholesterol+0.912 albuminuria [1 if present]+0.166 hypertension [1 if present]+0.005 BMI). The first cardiovascular risk prediction tool in the Arab world was developed in this study. It may be used to estimate the 5-year cardiovascular risk among Omanis with type 2 diabetes in order to plan patient management and preventive measures. However, further validation studies are required to determine the accuracy of the model.


Stem cell-laden hydrogel bioink for generation of high resolution and fidelity engineered tissues with complex geometries.
Recently, 3D bioprinting has been explored as a promising technology for biomedical applications with the potential to create complex structures with precise features. Cell encapsulated hydrogels composed of materials such as gelatin, collagen, hyaluronic acid, alginate and polyethylene glycol have been widely used as bioinks for 3D bioprinting. However, since most hydrogel-based bioinks may not allow rapid stabilization immediately after 3D bioprinting, achieving high resolution and fidelity to the intended architecture is a common challenge in 3D bioprinting of hydrogels. In this study, we have utilized shear-thinning and self-healing ionically crosslinked oxidized and methacrylated alginates (OMAs) as a bioink, which can be rapidly gelled by its self-healing property after bioprinting and further stabilized via secondary crosslinking. It was successfully demonstrated that stem cell-laden calcium-crosslinked OMA hydrogels can be bioprinted into complicated 3D tissue structures with both high resolution and fidelity. Additional photocrosslinking enables long-term culture of 3D bioprinted constructs for formation of functional tissue by differentiation of encapsulated human mesenchymal stem cells.


Spontaneous insertion and partitioning of alkaline phosphatase into model lipid rafts.
Several cell surface eukaryotic proteins have a glycosylphosphatidylinositol (GPI) modification at the C-terminal end that serves as an anchor to the plasma membrane and could be responsible for the presence of GPI proteins in rafts, a type of functionally important membrane microdomain enriched in sphingolipids and cholesterol. In order to understand better how GPI proteins partition into rafts, the insertion of the GPI-anchored alkaline phosphatase (AP) was studied in real-time using atomic force microscopy. Supported phospholipid bilayers made of a mixture of sphingomyelin-dioleoylphosphatidylcholine containing cholesterol (Chl+) or not (Chl-) were used to mimic the fluid-ordered lipid phase separation in biological membranes. Spontaneous insertion of AP through its GPI anchor was observed inside both Chl+ and Chl- lipid ordered domains, but AP insertion was markedly increased by the presence of cholesterol.


Gangrenous, hemorrhagic, bullous cellulitis associated with pseudomonas aeruginosa in a patient with Waldenström's macroglobulinemia.
Patients with Waldenström's macroglobulinemia may manifest several types of skin lesions. We present our experience with a patient with the disease that adds to the literature on the topic. A 57-year-old man with history of multiple sclerosis and Waldenström's macroglobulinemia was admitted to the intensive care unit in shock. His family members reported that the patient had complained of fever and the gradual development of gangrenous, hemorrhagic, bullous cellulitis lesions on the abdomen and lower extremities for 7 days prior to his admission to the hospital. Pseudomonas aeruginosa was isolated from fluid specimens collected from the cutaneous lesions. Appropriate antimicrobial treatment including continuous intravenous administration of meropenem (6 g every 24 h) led to the cure of the infection. We postulate that the underlying Waldenström's macroglobulinemia contributed to the pathophysiology of the development of the rare skin manifestations of the infection observed in our patient.


Klenkia terrae resistant to DNA extraction in germ-free mice stools illustrates the extraction pitfall faced by metagenomics.
Over the past decade, metagenomics has become the preferred method for exploring complex microbiota such as human gut microbiota. However, several bias affecting the results of microbiota composition, such as those due to DNA extraction, have been reported. These bias have been confirmed with the development of culturomics technique. In the present study, we report the contamination of a gnotobiotic mice unit with a bacterium first detected by gram staining. Scanning electron microscopy and transmission electron microscopy permitted to detect a bacterium with a thick cell wall. However, in parallel, the first attempt to identify and culture this bacterium by gene amplification and metagenomics of universal 16S rRNA failed. Finally, the isolation in culture of a fastidious bacterium not detected by using universal PCR was successfully achieved by using a BCYE agar plate with CO2 atmosphere at 30 °C. We performed genome sequencing of this bacterium using a strong extraction procedure. The genomic comparison allowed us to classify this bacterium as Klenkia terrae. And finally, it was also detected in the stool and kibble that caused the contamination by using specific qPCR against this bacterium. The elucidation of this contamination provides additional evidence that DNA extraction could be a bias for the study of the microbiota. Currently, most studies that strive to analyze and compare the gut microbiota are based on metagenomics. In a gnotobiotic mice unit contaminated with the fastidious Actinobacteria Klenkia terrae, standard culture, 16S rRNA gene amplification and metagenomics failed to identify the micro-organism observed in stools by gram-staining. Only a procedure based on culturomics allowed us to identify this bacterium and to elucidate the mode of contamination of the gnotobiotic mice unit through diet.


Relative informativeness of quantifiers used in syllogistic reasoning.
Three experiments tested a possible resolution of the probability heuristics model (PHM) of syllogistic reasoning proposed by Chater and Oaksford (1999), with their experimental results apparently showing that the generalized quantifier few was not as informative as suggested theoretically. Modifying the interpretation of few to take into account the distinction between positive and negative quantifiers (Moxey & Sanford, 1993) indicated two orderings over the quantifiers all, most, few, some, none, and some...not that are more consistent with the results. Experiments 1-3 tested these orderings empirically by having participants rank whether a quantifier applied to a particular probabilistic state of affairs. Experiments 1 and 2 showed that participants agreed on when a quantifier applied and that the empirically derived informativeness orderings were consistent with the proposed modifications of the order. Experiment 3 showed that this finding was robust even when response competition was eliminated.


Beyond Glioma: The Utility of Radiomic Analysis for Non-Glial Intracranial Tumors.
The field of radiomics is rapidly expanding and gaining a valuable role in neuro-oncology. The possibilities related to the use of radiomic analysis, such as distinguishing types of malignancies, predicting tumor grade, determining the presence of particular molecular markers, consistency, therapy response, and prognosis, can considerably influence decision-making in medicine in the near future. Even though the main focus of radiomic analyses has been on glial CNS tumors, studies on other intracranial tumors have shown encouraging results. Therefore, as the main focus of this review, we performed an analysis of publications on PubMed and Web of Science databases, focusing on radiomics in CNS metastases, lymphoma, meningioma, medulloblastoma, and pituitary tumors.


The relationship between knee extension strength and lower extremity functions in nursing home residents with dementia.
To assess the relationships between knee extension strengths and lower extremity functions in subjects with dementia and to predict lower extremity functions using knee extension strength. Fifty-four nursing home residents with dementia were enrolled in the study. The strength of the knee extensor was measured using a hand-held dynamometer. To predict lower extremity functions, subjects were classified into two groups: those who could dress their lower body, toilet, transfer to bed/toilet/shower and walk independently, and those who required assistance. Knee extension strength was compared between the two groups. Logistic regression analysis showed that the strength of the knee extensor muscles was a significant predictor of the ability to dress the lower body (odds ratio, 109.90; 95% CI, 7.60-1589.49), toileting (odds ratio, 18.29; 95% CI, 2.41-138.84), transferring to bed/toilet/shower (odds ratio, 39.70; 95% CI, 4.51-349.08), and gait performance (odds ratio, 12.77; 95% CI, 2.30-70.77). The curve of the negative and positive predictive values indicated that a cutoff score of 0.8 Nm/kg would provide the best balance for dressing the lower body and toileting; 1.2 Nm/kg for transferring to bed/toilet/shower; and 0.6 Nm/kg for gait performance. Knee extension strength was significantly related to the lower extremity functions in people with dementia. Moreover, threshold levels of strength existed that could predict lower extremity dysfunctions in people with dementia.


Targeting Bcl-xL is a potential therapeutic strategy for extranodal NK/T cell lymphoma.
Extranodal natural killer/T cell lymphoma, nasal type (ENKTL) is an aggressive lymphoid malignancy with a poor prognosis and lacks standard treatment. Targeted therapies are urgently needed. Here we systematically investigated the druggable mechanisms through chemogenomic screening and identified that Bcl-xL-specific BH3 mimetics effectively induced ENKTL cell apoptosis. Notably, the specific accumulation of Bcl-xL, but not other Bcl-2 family members, was verified in ENKTL cell lines and patient tissues. Furthermore, Bcl-xL high expression was shown to be closely associated with worse patient survival. The critical role of Bcl-xL in ENKTL cell survival was demonstrated utilizing selective inhibitors, genetic silencing, and a specific degrader. Additionally, the IL2-JAK1/3-STAT5 signaling was implicated in Bcl-xL dysregulation. In vivo, Bcl-xL inhibition reduced tumor burden, increased apoptosis, and prolonged survival in ENKTL cell line xenograft and patient-derived xenograft models. Our study indicates Bcl-xL as a promising therapeutic target for ENKTL, warranting monitoring in ongoing clinical trials by targeting Bcl-xL.


Social dominance in monkeys: Lack of effect on ethanol self-administration during schedule induction.
Nonhuman primate models of alcohol use disorder (AUD) frequently utilize schedule-induced polydipsia to initiate ethanol drinking. Previous research has demonstrated that specific characteristics of drinking during the final phase of induction, in which monkeys consume 1.5 g/kg of ethanol per day, can predict whether monkeys become heavy or light drinkers when they subsequently have free access to ethanol (22 hours per day; Baker, Farro, Gonzales, Helms, & Grant, 2017; Grant et al., 2008). A monkey's position in the social dominance hierarchy is another factor associated with ethanol drinking in nonhuman primates; lower social status is associated with higher ethanol intakes. In the present study, characteristics of drinking during induction were measured in 12 male cynomolgus monkeys living in three established social groups (4 monkeys per group). All monkeys were induced to consume water, then increasing doses of ethanol (0.5, 1.0, and 1.5 g/kg) for 30 sessions per dose using a 300-s fixed-time schedule of food pellet delivery. Drinking sessions occurred five days per week and monkeys were group-housed on the other two days. Contrary to our hypothesis that subordinate monkeys would show characteristics of drinking during the last phase of induction that were predictive of later heavy drinking, no significant differences were observed between dominant and subordinate monkeys in any phase of induction. When ethanol availability was subsequently increased to 22 hours per day for 5 weeks, the intakes of subordinate- and dominant-ranked monkeys diverged, with higher intakes on average in subordinates. Several factors unique to the conditions of induction may have obscured any influence of social rank, including the limited duration of sessions and limited maximal ethanol intake. The data support the conclusion that the effects of social rank on ethanol consumption require unrestricted access to ethanol.


Morphological polymorphism of Trypanosoma copemani and description of the genetically diverse T. vegrandis sp. nov. from the critically endangered Australian potoroid, the brush-tailed bettong (Bettongia penicillata (Gray, 1837)).
The trypanosome diversity of the Brush-tailed Bettong (Bettongia penicillata), known locally as the woylie, has been further investigated. At a species level, woylies are critically endangered and have declined by 90% since 1999. The predation of individuals made more vulnerable by disease is thought to be the primary cause of this decline, but remains to be proven. Woylies were sampled from three locations in southern Western Australia. Blood samples were collected and analysed using fluorescence in situ hybridization, conventional staining techniques and microscopy. Molecular techniques were also used to confirm morphological observations. The trypanosomes in the blood of woylies were grouped into three morphologically distinct trypomastigote forms, encompassing two separate species. The larger of the two species, Trypanosoma copemani exhibited polymorphic trypomastigote forms, with morphological phenotypes being distinguishable, primarily by the distance between the kinetoplast and nucleus. The second trypanosome species was only 20% of the length of T. copemani and is believed to be one of the smallest recorded trypanosome species from mammals. No morphological polymorphism was identified for this genetically diverse second species. We described the trypomastigote morphology of this new, smaller species from the peripheral blood of the woylie and proposed the name T. vegrandis sp. nov. Temporal results indicate that during T. copemani Phenotype 1 infections, the blood forms remain numerous and are continuously detectable by molecular methodology. In contrast, the trypomastigote forms of T. copemani Phenotype 2 appear to decrease in prevalence in the blood to below molecular detectable levels. Here we report for the first time on the morphological diversity of trypanosomes infecting the woylie and provide the first visual evidence of a mixed infection of both T. vegrandis sp. nov and T. copemani. We also provide supporting evidence that over time, the intracellular T. copemani Phenotype 2 may become localised in the tissues of woylies as the infection progresses from the active acute to chronic phase. As evidence grows, further research will be necessary to investigate whether the morphologically diverse trypanosomes of woylies have impacted on the health of their hosts during recent population declines.


Maternal hypercalcemia as a possible cause of unexplained fetal polyhydramnion: a case series.
This study was undertaken to present a possible association between maternal hypercalcemia and fetal polyhydramnion. Five cases of maternal hypercalcemia were diagnosed with otherwise unexplained fetal polyhydramnion. Cases are outlined; maternal and fetal/neonatal investigation, treatment, and outcome are presented. Fetal polyhydramnion was identified sonographically (mean amniotic fluid index = 32 +/- 11.3 cm). Maternal hypercalcemia (mean 12.8 +/- 1.1 mg/dL) led to the diagnosis of primary hyperparathyroidism. Of the 5 women, 4 underwent parathyroidectomy. One had a hypercalcemic crisis and intrauterine fetal demise. Neonatal hypercalcemia of remaining infants was documented (mean 13 +/- 1 mg/dL), with subsequent hypocalcemia in 1 of the neonates. All mothers and the 4 live neonates were discharged in good condition. We suggest that fetuses exposed to a hypercalcemic environment may have polyuria develop similar to adult hypercalcemic polyuria, leading to fetal polyhydramnion. Maternal serum calcium levels may be part of the investigation in otherwise unexplained polyhydramnion, as maternal hypercalcemia may threaten the health of both mother and fetus.


Comparison of autologous and heterologous bone graft stability effects for filling maxillary bone gap after Le Fort I osteotomy.
The amount of postoperative maxillary relapse of two different bone graft materials after Le Fort I osteotomy were compared in this study. The aim of this study is to compare postoperative maxillary relapse rates using heterologous and autologous graft materials after Le Fort I osteotomy. A total of 80 patients who had developmental malocclusion were analyzed retrospectively in this study. Twenty nine (36.2%) and 51 (63.8%) patients underwent Le Fort I osteotomy, and Le Fort I and bilateral sagittal split ramus osteotomy (two-jaw surgery), respectively. Forty two (52.5%) maxillary bone gaps were filled with heterologous bone grafts (group A) and 38 (47.5%) were filled with autologous bone grafts (group B) after Le Fort I osteotomy. The cephalometric graphics and measurements were taken before (T1), 1 week after (T2), and 1 year after (T3) the surgery. The results were documented and determined by the Dolphin imaging 10.5 (Dolphin Imaging, Chatsworth, Calif.) computer program for skeletal relapse. Whether or not the relationship between group A's and B's maxillary relapse rates was evaluated in the postoperative period. It was observed that both graft materials have positive effects on maxillary relapse rate in the postoperative period. When the groups are compared to each other, the relapse rates were similar between group A (8.3%) and group B (10.8%) (p>0.05). Heterologous bone graft material (Osteoplant®-Flex) is thought to be a good alternative to autologous grafts in decreasing the relapse rates and reducing the morbidity of the donor area of the patients who underwent Le Fort I osteotomy.