Uptake of Pb(2+ )by a cyanobacterium belonging to the genus Synechocystis, isolated from East Kolkata Wetlands.
East Kolkata Wetlands is a conserved wetland utilizing sewage and garbage, generated by Kolkata Municipal Corporation area for cultivation purpose. Cyanobacteria are the photosynthetic prokaryotes having bioremedial capacity. We have isolated a cyanobacterium from the sewage recycling fish-pond of East Kolkata Wetlands. Partial sequence of 16S rDNA gene of the isolated strain showed 100% similarity with that of genus Synechocystis. Isolated strain and Synechocystis sp. PCC6803 survived up to 300 mug ml(-1) Pb(2+ )and growth was completely inhibited at 400 mug ml(-1) Pb(2+). All experiments were carried out with 100 mug ml(-1) Pb(2+) in which growth was the maximum. 91.67% of the total Pb(2+) got adsorbed to the outer surface of the cell and 1% of the total Pb(2+) entered the cell of the isolated strain as estimated by atomic absorption spectrometry, but in Synechocystis sp. PCC6803 72.72% adsorbed and 0.96% penetrated. Intracellular and periplasmic depositions of Pb(2+) were observed in both the strain. A filamentous structure developed outside the cell wall of the isolated cyanobacterium, but very little change was observed in Synechocystis sp. PCC6803. ZiaR-SmtB like regulator gene was expressed in both the strains after Pb(2+) induction. The cDNA sequence of ZiaR of the isolated cyanobacterium shows 100% homology with that of Synechocystis sp. PCC6803. Upon Pb(2+) induction, expression of SOD gene increased. cDNA sequence of the SOD gene from the isolated strain showed 98% homology with that of Synechocystis sp. PCC6803. Enzymatic activity of catalase and SOD was also increased. No DNA damage was monitored upon induction with Pb(2+).


Effects of perfluorodecanoic acid on hepatic indices of thyroid status in the rat.
Perfluorodecanoic acid (PFDA) alters the circulating level of thyroid hormones, but the physiological significance of this change at the target tissue remains to be defined. To this end, the activities of thyroid-responsive hepatic enzymes were examined in adult male rats 1 week after treatment with a single dose of PFDA (20, 40 or 80 mg/kg). Since PFDA treatment caused a dose-related reduction in feed intake, vehicle-treated rats pair-fed to their counterparts receiving PFDA were used to determine if any of the PFDA-induced alterations in enzyme activity were secondary to hypophagia. Following the administration of PFDA, L-glycerol-3-phosphate dehydrogenase, a liver mitochondrial enzyme sensitive to thyroid status, exhibited a modest increase in activity, whereas that of succinate dehydrogenase, a constitutive mitochondrial marker enzyme, was similar in both PFDA-treated rats and their pair-fed counterparts at all dose levels examined. Activity of cytosolic lactate dehydrogenase was also augmented modestly in livers of rats receiving PFDA. In contrast, activity of cytosolic malic enzyme, a thyroid-responsive enzyme, was increased markedly in PFDA-treated rats. Hepatic activity of glucose-6-phosphate dehydrogenase, which also responds to alterations in thyroid status, exhibited a modest increase with 20 and 40 mg/kg PFDA but was similar in both PFDA-treated rats and their pair-fed counterparts at the 80 mg/kg dose level. Absolute and relative liver mass was elevated in PFDA-treated rats at all dose levels in comparison to the appropriate vehicle-treated pair-fed animals. Total hepatic content of DNA was maintained in PFDA-treated rats at all dose levels, whereas a significant decrease in liver DNA was found in the vehicle-treated rats pair-fed to animals receiving 80 mg/kg PFDA. Following administration of PFDA, protein content per total liver was similar to that of their pair-fed counterparts. Thus, the pattern of activity of thyroid-responsive hepatic enzymes was not compatible with a functional shift toward a lessened thyroid status in rats treated with PFDA.


Sociodemographic factors and choice of oral anticoagulant in patients with non-valvular atrial fibrillation in Sweden: a population-based cross-sectional study using data from national registers.
The Swedish healthcare system aims to provide equal access to care to all residents yet evidence suggests that patients with low socioeconomic status are less likely to receive new drugs. Associations between sociodemographics and prescription of non-vitamin K antagonist oral anticoagulants (NOACs) as an alternative to warfarin in Sweden have not been investigated. We conducted a cross-sectional study using linked national registers in Sweden. The study population included oral anticoagulant naïve patients aged ≥18 years with non-valvular atrial fibrillation (NVAF) who filled a first prescription for a NOAC or warfarin from 01 December 2011 to 31 December 2014. Multivariable logistic regression was used to identify factors associated with the choice of anticoagulant treatment; adjusted odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. Among 68,056 patients with NVAF, 27.4% (N = 18,638) started treatment with a NOAC and 72.6% (N = 49,418) started on warfarin. Patients starting treatment with a NOAC were more likely to be highly educated (OR 1.37, 95% CI: 1.30-1.45), in the highest income quartile (OR 1.23, 95% CI: 1.16-1.31) and have a leading professional occupation (OR 1.41, 95% CI: 1.27-1.58). Patients residing in rural areas were half as likely to start treatment with a NOAC as those in urban areas (OR 0.48, 95% CI: 0.45-0.51). Among Swedish patients with NVAF, those with high socioeconomic status and urban residence were more likely to start preventative treatment with a NOAC than warfarin. Future research should explore reasons for these inequalities in NOAC treatment.


Fibrillin-1 genotype and risk of prevalent hypertension: a study in two independent populations.
Mutations in the fibrillin-1 gene are the cause of Marfan syndrome. We wanted to investigate the relationship between a mutation in this gene and risk of prevalent hypertension. In a cross-sectional study, the effect of a G-A substitution in intron 27 in the fibrillin-1 gene (rs11856553) on risk of prevalent hypertension was studied in two large population-based studies: the Health 2006 study, consisting of 3193 women and men, age 18-69 years, and the MONICA10 study, consisting of 2408 women and men, age 41-72 years. In 1646 MONICA10 participants, blood pressure (BP) was also measured by 24-h ambulatory recordings. Among the 3193 Health 2006 participants 23 had the G-A variant, and among the 2408 MONICA10 participants 18 had the G-A variant. In Health 2006, the odds ratio estimate (95% confidence intervals) for the G-A variant for risk of hypertension, defined as systolic (S) BP ≥ 140 mmHg or diastolic (D) BP ≥ 90 mmHg or on antihypertensive medicine, was 2.67 (1.14-6.18), p = 0.022. The corresponding figure for moderate to severe hypertension, defined as SBP ≥ 160 mmHg or DBP ≥ 100 mmHg, was 9.68 (4.24-22.12), p < 0.0001. In MONICA10, the odds ratio estimate (95% confidence intervals) for the G-A variant for risk of moderate to severe ambulatory hypertension, defined as 24-h mean SBP ≥ 150 mmHg or 24-h mean DBP ≥ 90 mmHg, was 5.73 (1.96-16.7), p = 0.0014. The G-A substitution in the fibrillin-1 gene (rs11856553) is a rare genetic variant that is associated with an increased risk of prevalent hypertension, particularly of moderate to severe prevalent hypertension.


Effects of aspirin on cardiovascular outcomes in patients with chronic kidney disease.
Patients with chronic kidney disease (CKD) carry a high cardiovascular (CV) risk. Since whether this risk is reduced by aspirin is unclear, we examined if the effect of aspirin on cardiovascular outcomes varied by baseline kidney function in a primary cardiovascular disease prevention trial. The International Polycap Study-3 (TIPS-3) trial had randomized people without previous cardiovascular disease to aspirin (75 mg daily) or placebo. We now examined aspirin versus placebo on cardiovascular events in participants grouped by estimated glomerular filtration rate (eGFR), using a threshold of 60 ml/min/1.73 m2, and by using tertiles of eGFR. The primary outcome was a composite of non-fatal myocardial infarction, non-fatal stroke or cardiovascular death. A total of 5712 participants were randomized with a mean follow-up of 4.6 years. Of these, 983 (17.2%) had an eGFR under 60 ml/min/1.73 m2 (mean eGFR 49 ml/min/1.73 m2) and 4,729 over 60 ml/min/1.73 m2 (mean 84 ml/min/1.73 m2). In participants with an eGFR under 60 ml/min/1.73 m2 there were 26 primary outcomes in 502 participants on aspirin and 39/481 on placebo (hazard ratio 0.57; 95% confidence interval 0.34-0.94). In participants with an eGFR over 60 ml/min/1.73 m2 there were 90 primary outcomes in 2357 participants on aspirin and 95/2372 on placebo (0.95; 0.71-1.27). With tertiles of eGFR under 70, 70-90, and over 90 ml/min/1.73 m2, risk reductions with aspirin for the primary outcome were larger at lower eGFR levels (0.62; 0.43-0.91) for the lowest tertile, (0.96; 0.62-1.49) for the middle, and (1.30; 0.77-2.18) for the highest tertile. Thus, our findings support aspirin may reduce cardiovascular events in people with moderate to advanced stage CKD.


The treatment of post-processing liquid from the hydrothermal carbonization of sewage sludge.
The liquid phase, being a major product of the hydrothermal carbonization of sewage sludge, is highly problematic due to numerous toxic compounds that make it impossible to dispose of without adequate purification. Therefore, this study is focused on the two groups of selected advanced methods of post-processing water derived from the hydrothermal carbonization process of sewage sludge. The first group included membrane processes, namely ultrafiltration, nanofiltration and double nanofiltration. The second included coagulation, ultrasonication and chlorination. Chemical and physical indicators were determined to confirm the validity of these treatment methods. The highest reduction values were found for double nanofiltration, which showed a spectacular decrease in the Chemical Oxygen Demand by 84.9 %, specific conductivity by 71.3 %, nitrate nitrogen by 92.4 %, phosphate phosphorus by 97.1 %, total organic carbon by 83.3 %, total carbon by 83.6 %, and inorganic carbon by 88.5 %, as compared to the liquid phase after hydrothermal carbonization. In the second group, for the largest number of parameters, the greatest reduction was achieved when 10 cm3/L of iron coagulant was added to the permeate from ultrafiltration. Additionally, COD decreased by 41 %, P-PO43- content by 78 %, phenol content by 34 %, TOC content by 97 %, TC content by 95 % and IC content by 40 %.


Differential effects of intranasal vaccination with recombinant NcPDI in different mouse models of Neospora caninum infection.
In this study, mice were vaccinated intranasally with recombinant N. caninum protein disulphide isomerase (NcPDI) emulsified in cholera toxin (CT) or cholera toxin subunit B (CTB) from Vibrio cholerae. The effects of vaccination were assessed in the murine nonpregnant model and the foetal infection model, respectively. In the nonpregnant mice, previous results were confirmed, in that intranasal vaccination with recNcPDI in CT was highly protective, and low cerebral parasite loads were noted upon real-time PCR analysis. Protection was accompanied by an IgG1-biased anti-NcPDI response upon infection and significantly increased expression of Th2 (IL-4/IL-10) and IL-17 transcripts in spleen compared with corresponding values in mice treated with CT only. However, vaccination with recNcPDI in CT did not induce significant protection in dams and their offspring. In the dams, increased splenic Th1 (IFN-γ/IL-12) and Th17 mRNA expressions was detected. No protection was noted in the groups vaccinated with recNcPDI emulsified in CTB. Thus, vaccination with recNcPDI in CT in nonpregnant mice followed by challenge infection induced a protective Th2-biased immune response, while in the pregnant mouse model, the same vaccine formulation resulted in a Th1-biased inflammatory response and failed to protect dams and their progeny.


Structural Factors in Health Care Associated With the Mental Health Needs of Black Women in California During the Perinatal Period.
To identify structural factors associated with the receipt of mental health care treatment among Black women in California during pregnancy and after childbirth. Secondary analysis of data from the population-based Listening to Mothers in California survey. The sample included 194 non-Latina Black women in the postpartum period. We used descriptive statistics, including differences between means and logistic regression, to conduct a series of bivariate analyses. Most respondents (84.4%, n = 163) reported symptoms of perinatal mood and anxiety disorders prenatally, and half (50% n = 97) reported symptoms of perinatal mood and anxiety disorders in the postpartum period. Only 12.3% to 14.6% of those who reported symptoms received mental health care treatment. Furthermore, 21.2% (n = 38) of respondents were not screened for postpartum depression. Respondents with private insurance coverage were more likely to report receipt of mental health care after childbirth (OR = 4.6; 95% confidence interval [1.5, 13.5]) compared to respondents with public insurance coverage. Our results suggest a high prevalence of unmet mental health needs among non-Latina Black women who lived in California during the perinatal period. Practitioners in clinical settings may be more likely to make referrals to mental health care for women with private insurance coverage in the postpartum period.


Myocardial metabolism of glutamate and left ventricular function in patients with coronary arterial disease.
Fractional myocardial extraction of glutamate, glutamine, ammonia, glucose and lactate was studied in 35 male patients during rest and atrial pacing. Fourteen patients had no coronary arterial disease. In 21 patients with coronary arterial disease and left ventricular dysfunction the increased myocardial extraction of glutamate at rest positively correlated with increased extraction of glucose, lactate and glutamine release, while it was inversely related to ammonia release. In 9 of these 21 patients pacing did not affect either left ventricular contractile function or myocardial metabolism of all studied compounds. In the other 12 patients pacing caused a decrease in left ventricular ejection fraction, velocity of circumferential fiber shortening and new regional wall motion abnormalities. A more pronounced pacing-induced left ventricular dysfunction was accompanied by myocardial lactate production and 2-fold decrease in myocardial glutamate extraction which was associated with the reduction of glutamine release and increased myocardial ammonia production. Possible relationships between alterations in myocardial glutamate metabolism and diminished ventricular performance have been reviewed. The results suggest the importance of myocardial glutamate extraction for the contractile function of human ischemic heart.


Longitudinal dynamics of the bovine udder microbiota.
In recent years, the number of studies concerning microbiota of the intramammary environment has increased rapidly due to the development of high-throughput sequencing technologies that allow mapping of microbiota without culturing. This has revealed that an environment previously thought to be sterile in fact harbours a microbial community. Since this discovery, many studies have investigated the microbiota of different parts of the udder in various conditions. However, few studies have followed the changes that occur in the udder microbiota over time. In this study, the temporal dynamics of the udder microbiota of 10 cows, five with a low somatic cell count (SCC, SCC < 100,000 cells/mL) and five with a high SCC (SCC > 100,000 cells/mL), were followed over 5 months to gather insights into this knowledge gap. Analysis of the temporal changes in the microbial composition of milk from udders with a low SCC revealed a dynamic and diverse microbiota. When an imbalance due to one dominating genus was recorded, the dominant genus quickly vanished, and the high diversity was restored. The genera dominating in the samples with a high SCC remained the dominant genera throughout the whole sampling period. These cows generally displayed a heightened SCC or an intramammary infection in at least one quarter though-out the sampling period. Our results show that the bovine udder has a diverse microbiota, and that the composition and diversity of this community affects udder health with regards to SCC. Understanding what influences the composition and stability of this community has important implications for the understanding, control, and treatment of mastitis.


Spontaneous expulsion of an intrabronchial sharp metallic foreign body and migration to the gastrointestinal tract at Muhimbili National Hospital: Case report and literature review.
Aspirated foreign bodies continue to pose challenges to Otorhinolaryngologists and are potentially life threatening thus an otorhinolaryngological emergency. The main stay of treatment of foreign bodies (FBs) in the tracheobronchial tree remains to be bronchoscopy while bearing in mind earlier and safer removal of such foreign bodies. Spontaneous expulsion of an Intrabronchial foreign body is a rare entity with few cases reported in the available literatures. We are reporting a rare case of a 3-year old male child who presented to otorhinolaryngology department with a 2-days history of foreign body inhalation (sharp metallic pin) prior admission which undergone spontaneous migration and went to be excreted in feaces after passing through the gastrointestinal tract. It is unwise, dangerous and inadvisable to wait for spontaneous expulsion in cases of intrabronchial foreign body but while preparing for endoscopy, a constant watch should be kept over the patient and every forceful bout of cough should be looked with suspicion of spontaneous expulsion and a danger of foreign body lodgment into subglottis during such rare but possible occurrence should be kept in mind. It's always worth to rule out the possibility of foreign body inhalation in children with sudden onset of difficulty in breathing to avoid diagnostic delays.


Copper(I)-Catalyzed Asymmetric Interrupted Kinugasa Reaction: Synthesis of α-Thiofunctional Chiral β-Lactams.
A copper(I)-catalyzed asymmetric, three-component interrupted Kinugasa reaction has been developed. Diverse chiral sulfur-containing chiral β-lactams with two consecutive stereogenic centers were synthesized in one step from readily available starting materials in good yields and with excellent diastereo- and enantioselectivity. The key is the interception of in situ formed chiral four membered copper(I) enolate intermediate with sulfur electrophiles.


Anti-neoplastic effects of interleukin-4.
Interleukin-4 (IL-4) is a cytokine, with potential anti-neoplastic effects. This study examined the effects of IL-4 on host anti-tumor responses in a murine model. C57/B16 mice (n = 40) were randomized to receive Lewis lung carcinoma (10(6) cells: right flank; sc) or saline, and sacrificed 10 days postinoculation for assessment of peritoneal macrophage (PMO) anti-tumor mechanisms [superoxide anion generation (O2-), tumor necrosis factor (TNF), and TNF-independent (P815) cytotoxicity], splenocyte mixed lymphocyte response (MLR) (Balb/c stimulator), and cytotoxic lymphocyte generation (CTL against P815). Cells were cultured +/- IL-4 (100 U/ml). In a second study, 20 mice received Lewis lung implants (sc) and were randomized on Day 21 to receive daily IL-4 (1000 U/mouse; ip) or saline. Tumor volumes and median survival were assessed. Tumor necrosis factor-independent cytotoxicity (O2-, MLR and CTL) was impaired in the tumor-bearing (TB) study group. Interleukin-4 administered to cultured cells from TB mice enhanced O2-, as well as MLR and CTL (P less than 0.01), and decreased TNF release but did not alter PM phi TNF-independent anti-tumor responses (P815). In vivo administration of IL-4 significantly decreased tumor growth (P less than 0.05) after 10 days of treatment and significantly prolonged median host survival (P less than 0.05). These findings indicate the therapeutic potential of IL-4 in the TB host which may function through downregulation of TNF production while potentiating certain T cell-dependent and independent anti-tumor immune mechanisms.


FOLFOX4 plus cetuximab treatment and RAS mutations in colorectal cancer.
The OPUS study demonstrated that addition of cetuximab to 5-fluorouracil, folinic acid and oxaliplatin (FOLFOX4) significantly improved objective response and progression-free survival (PFS) in the first-line treatment of patients with KRAS exon 2 wild-type metastatic colorectal cancer (mCRC). In patients with KRAS exon 2 mutations, a detrimental effect was seen upon addition of cetuximab to FOLFOX4. The current study reports outcomes in subgroups defined by extended RAS testing. Samples from OPUS study KRAS exon 2 wild-type tumours were reanalysed for other RAS mutations in four additional KRAS codons (exons 3-4) and six NRAS codons (exons 2-4) using BEAMing. A cutoff of ⩾5% mutant/wild-type sequences was selected to define RAS status; we also report an analysis using a cutoff based on the technical lower limit for mutation identification (0.1%). Other RAS mutations were detected in 31/118 (26%) evaluable patients. In the extended analysis of RAS wild-type tumours (n=87), objective response was significantly improved by addition of cetuximab to FOLFOX4 (58% versus 29%; odds ratio 3.33 [95% confidence interval 1.36-8.17]; P=0.0084); although limited by population size, there also appeared to be trends favouring the cetuximab arm in terms of PFS and overall survival in the RAS wild-type group compared with the RAS evaluable group. There was no evidence that patients with other RAS mutations benefited from cetuximab, but small numbers precluded precise estimations of treatment effects. In the combined population of patients with any RAS mutation (KRAS exon 2 or other RAS), a clear detrimental effect was associated with addition of cetuximab to FOLFOX4. Patients with RAS-mutant mCRC, as defined by mutations in KRAS and NRAS exons 2-4, derive no benefit and may be harmed by the addition of cetuximab to FOLFOX4. Restricting cetuximab administration to patients with RAS wild-type tumours will further tailor therapy to maximise benefit.


Screening and prevalence of cardiac abnormalities on electro- and echocardiography in a large cohort of patients with mitochondrial disease.
In patients with primary mitochondrial disease (MD), screening with electrocardiogram (ECG) and transthoracic echocardiography (TTE) is warranted according to current guidelines as structural cardiac abnormalities are frequent. This study aims to evaluate the cardiac phenotype of a large Dutch cohort of patients with MD and investigates whether ECG alone is sufficient for predicting structural cardiac abnormalities on TTE. In this retrospective cohort study, genetically confirmed MD patients >18 years old with an available ECG and TTE were included. Newcastle Mitochondrial Disease Scale for Adults (NMDAS) scores were assessed. ECG's were evaluated for rhythm and conduction disorders, voltage criteria for left ventricular hypertrophy (LVH) and repolarization disorders. Echocardiographic evaluation included left and right ventricular volumes and function, and presence of LVH or concentric remodeling. In total, 200 MD patients were included with a median age of 45 years (IQR; 37-57) of whom 36% were male. Of all MD patients, 35% had abnormalities on ECG and 61% on TTE. Most frequent structural cardiac abnormalities on TTE were: global longitudinal strain > - 18% (54%), concentric remodeling (27%) and left ventricular (LV) ejection fraction <52% (14%). Patients with maternally inherited diabetes and deafness (MIDD) and mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) had the highest prevalence of ECG abnormalities (50% and 47%). TTE abnormalities were most prevalent in patients with MIDD (75%), followed by mitochondrial myopathy (MM) (55%), MELAS (47%) and Mitochondrial Epilepsy and Ragged Red Fibers (MERRF) (47%). MD patients with a high disease severity (NMDAS ≥21) had a higher prevalence of ECG abnormalities (44%, p = 0.039) and structural cardiac abnormalities (72%, p = 0.004) compared to patients with a NMDAS score of 11-20 and ≤ 10 (ECG: 34% and 19%; TTE: 63% and 39%). ECG abnormalities had a positive predictive value of 74% and a negative predictive value of 53% for structural cardiac abnormalities on TTE. MD patients frequently have cardiac involvement especially patients with MIDD, MELAS or high NMDAS score. ECG as sole screening parameter is insufficient to detect structural cardiac abnormalities.


Carbonic anhydrase activity in mammalian retina. Developmental aspects in altricial and precocial species.
Carbonic anhydrase activity has been studied during retina development in 2 mammalian species, guinea pig and rat, which differ for birth time and gestational period as being precocial and altricial respectively. For both species, the definitive pattern of enzyme distribution corresponds to the localization of the reaction product in the Müller glial cells at the level of nucleus, perikaryon, lateral processes, and end-feet. Only in the rat retina, staining has been observed also in some amacrine cells. The results of either in situ or extra situm investigations showed that, according to tissue maturity, in the precocial species, the definitive expression of carbonic anhydrase is reached at birth time. In the altricial species, on the contrary, maturity is very delayed and may be recognized at only the 12th d of postnatal life. Present findings confirm that carbonic anhydrase is a marker for the maturity of the retinal glial cells.


An optimized RNA extraction method for diverse leaves of Hawaiian Metrosideros, a hypervariable tree species complex.
The isolation of RNA from trees is challenging due to the interference of polyphenols and polysaccharides with downstream processes. Furthermore, many RNA extraction protocols are time consuming and involve hazardous chemicals. To address these issues, we aimed to develop a safe protocol for high-quality RNA extraction from diverse Metrosideros taxa representing a broad range of leaf toughness, pubescence, and secondary metabolites. We tested popular RNA isolation kits and protocols that were effective on other recalcitrant trees, including a broad range of optimization and purification steps. We optimized a protocol involving two silica-membrane column-based kits that yielded high-quantity RNA with an RNA integrity number >7 and without DNA contamination. All RNA samples were used successfully in a follow-on RNA-Seq experiment. We present an optimized high-throughput RNA extraction protocol that yielded high-quality and high-quantity RNA from three contrasting leaf phenotypes within a hyperdiverse woody species complex.


Pharmacological problems in the management of epilepsy in children.
Rational prescribing of anti-epilepsy drugs in children may be complicated by a number of problems, which include: (i) difficulties in arriving rapidly at a syndromic diagnosis, at least in some cases, with consequent uncertainties about therapeutic management; (ii) difficulties in evaluating drug response in young age groups, particularly with respect to subjective side-effects affecting cognitive function; (iii) the vulnerability of infants and children to specific aspects of drug toxicity, such as liver damage induced by valproic acid or behavioural disorders caused by barbiturates; and (iv) the need to adjust dosage to account for age-dependent pharmacokinetic changes. In particular, it is known that the rate of drug metabolism changes markedly during development. Metabolic drug elimination is often reduced at birth, but drug metabolizing enzymes mature rapidly and biotransformation in infants and children usually occurs at a faster rate than in adults. The elimination of drug which are excreted unchanged in urine appears to be less influenced by age in paediatric patients, though impairment in renal drug clearance may be seen in newborns. Monitoring of serum drug concentrations may be helpful for dosage adjustments, but it is not a substitute for careful clinical observation.


Evaluation of the capability of different chromatographic systems for the monitoring of thimerosal and its degradation products by high-performance liquid chromatography with amperometric detection.
Several liquid chromatographic systems using electrochemical detection on carbon electrodes were compared for the analysis of thimerosal and its degradation products, thiosalicylic acid and dithiodibenzoic acid. The studied separation systems included reversed-phase ion-suppressed chromatography, reversed-phase ion-pair chromatography and ion chromatography. Amperometry and coulometry were evaluated as electrochemical detection techniques. The best method for thimerosal determination in ophthalmic solutions in terms of selectivity and sensitivity was ion-pair chromatography.


Cuspal deflection and depth of cure in resin-based composite restorations filled by using bulk, incremental and transtooth-illumination techniques.
Restoration techniques affect shrinkage stress and depth of cure. The authors tested cuspal deflection and depth of cure resulting from the use of different techniques (bulk, incremental, bulk/transtooth illumination) and two resin-based composites (deep curing and conventional). The authors restored extracted teeth with deep-curing X-tra fil (VOCO, Cuxhaven, Germany) (by using bulk and incremental techniques) and Filtek Supreme Plus (3M ESPE, St. Paul, Minn.) (by using bulk, incremental and bulk/transtooth-illumination techniques). The sample size for each technique was five. They determined cuspal deflections as changes in buccal and lingual surfaces before and after restoration. To determine the extent of cure, they measured hardness 0.5 to 3.5 millimeters deep on the sectioned restorations. The authors found no difference in cuspal deflection between filling techniques within the same materials (P > .05). They found no difference in hardness for X-tra fil at any depth with either the bulk or the incremental technique (P > .05). Filtek Supreme Plus had higher hardness values at depths of less than 1.5 mm with the bulk/transtooth-illumination technique, whereas the bulk technique resulted in lower hardness values at depths of 2.0 mm and below (P < .05). Cuspal deflection was not affected by filling techniques. X-tra fil cured up to a depth of at least 3.5 mm; Filtek Supreme Plus had lower curing values below a depth of 2 mm. The transtooth-illumination technique improved curing depth for restorations placed in bulk. When using resin-based composite restorative materials, clinicians should be more concerned about the effect of filling techniques on curing depth than about how these techniques affect shrinkage stresses.


Integration in descending motor pathways controlling the forelimb in the cat. 4. Corticospinal inhibition of forelimb motoneurones mediated by short propriospinal neurones.
A previously described inhibitory trisynaptic cortico-motoneuronal pathway (Illert et al., 1976a) was analysed in order to identify the two relay stations. Intracellular recording was made from motoneurones to elbow muscles. Corticospinal fibres were stimulated in the contralateral medullary pyramid. Pyramidal IPSPs were abolished by a transection of the corticospinal tract in C2 but remained after a corresponding lesion in C5. After a C5 lesion pyramidal volleys facilitated transmission in the Ia inhibitory pathway with a time course suggesting disynaptic excitatory action on the Ia inhibitory interneurones. The trisynaptic pyramidal IPSPs were depressed by volleys in the appropriate recurrent motor axon collaterals as would be expected if these IPSPs were mediated by Ia inhibitory interneurones. It is concluded that trisynaptic cortico-motoneuronal inhibition is evoked by consecutive activation of propriospinal neurones in C3--C4 and segmental Ia inhibitory interneurones.


Fabrication of FOX-7 quasi-three-dimensional grids of one-dimensional nanostructures via a spray freeze-drying technique and size-dependence of thermal properties.
1,1-Diamino-2,2-dinitroethylene (C(2)H(4)N(4)O(4), FOX-7) quasi-three-dimensional (3D) grids, a promising high-energy-density material with superior sensitivity properties, were synthesized by a spray freeze-drying technique. The FOX-7 3D grids were constructed from one-dimensional nanostructures. The sizes and structures of the FOX-7 3D grids strongly depend on the concentration of the aqueous solution of FOX-7. A possible formation mechanism of this structure was proposed in detail. Thermal analysis reveals that decrease in average particle sizes of FOX-7 grids results in a lower decomposition temperature and a much higher decomposition rate, which is in agreement with those reported about inorganic nanomaterials.


Popliteal venotomy during posterior cruciate ligament reconstruction in the setting of a popliteal artery bypass graft.
Injury to the vascular structures in the popliteal fossa during arthroscopic cruciate ligament reconstruction can be limb threatening or even life threatening. We present the first report, to our knowledge, of an isolated injury to a popliteal vein during arthroscopic posterior cruciate ligament reconstruction. Unfortunately, the venotomy led to cardiopulmonary arrest and flash pulmonary edema in this patient. Preoperative planning is paramount to assess risk of injury to vascular structures, which may be increased in patients who have had prior procedures on the affected knee. Furthermore, vascular surgery consultation preoperatively after a magnetic resonance angiogram or venogram and avoiding the use of epinephrine in the arthroscopy fluid should be considered when performing these higher-risk procedures.


A tribute to David Triggle.
"A gentleman and a scholar" is how many would characterize David Triggle. His insightful, thoughtful approaches to professional pursuits, both personal research and collaborative relationships, stand out by any measure. He has shaped students, colleagues, and whole fields, calcium ion channels and ligands being most representative of the latter. In recent years, he has expanded his contributions to important commentaries on politics and social challenges in the sciences. David is the rare intellect able to do all this and more, as outlined herein.


Study of Cytokine Profile of Cultured "Early" and "Late" Endothelial Progenitor Cells in Peripheral Blood of Chronic Heart Failure Patients after Mobilization Course with Granulocyte Colony-Stimulating Factor.
The effect of cell culturing protocol with various adhesion proteins and different culture time on the profile of cytokine and growth factors produced by endothelial progenitor cells harvested after mobilization with granulocyte colony-stimulating factor was examined in patients with chronic heart failure. The endothelial progenitor cells cultured on fibronectin or gelatin produced a broad and overall similar spectrum of cytokines and growth factors, the levels of which depended on the culture time. On culture day 16, the cells grown on fibronectin diminished the production of cytokines and growth factors (IL-10, IL-18, IL-8, erythropoietin, and VEGF), while the cells grown on gelatin down-regulated the synthesis of TNF-α, IL-8, and erythropoietin, although they up-regulated the production of IL-10, IL-18, and VEGF.


Clinical, laboratory and therapeutic aspects of platelet-type von Willebrand disease.
Platelet-type von Willebrand disease (PT-VWD), or pseudo-VWD, is a rare inherited platelet disorder characterized by an increased affinity of the platelet membrane glycoprotein Ibalpha receptor for normal von Willebrand factor leading to characteristic platelet hyperaggregability. As PT-VWD shares most of the clinical and laboratory features of subtype 2B VWD, the differential diagnosis between these two inherited bleeding disorders requires either platelet-mixing or molecular genetic studies. In this review, the main clinical, laboratory and therapeutic characteristics of PT-VWD are concisely reported.


Urogenital sinus abnormalities in the female patient.
Three patients with a urogenital sinus and 1 with a cloaca presented with complex diagnostic and therapeutic anomalies. A classification of these and other vaginal anomalies is based on the theory that they all represent an arrest in normal embryological development. Six categories are described, including vaginal agenesis, urogenital sinus, vaginal atresia, vaginal septa, vaginal stenosis and cloaca.


Development of an enzyme-modified carbon paste electrode for determining inhibitors of lipoxygenase.
In this study, a 15-lipoxygenase-modified carbon paste electrode (15-LOX-MCPE) was developed in connection with the help of voltammetry, which can be used as an assay system for screening drugs with inhibiting lipoxygenase (LOX) activity. The influence of different experimental conditions (LOX loading of carbon paste, pH, type of buffer system etc.) was investigated in order to optimise the biosensing device. The best composition of the biosensor is 30% paraffin oil, 68% graphite powder and 2% LOX. The optimised voltammetric measurement medium is Sörensen/NaOH (0.1M, pH 9.0) using linoleic acid as a substrate. Under these conditions the hydroperoxy linoleic acid is formed, which can be oxidised at a potential of +0.9 V versus Ag/AgCl/3M KCl. The applicability of the LOX biosensor as assay of lipoxygenase inhibitors was successfully tested with nordihydroguaiaretic acid, zileuton and fenleuton, which are well known inhibitors of LOX.


Intensive care unit to unit capacity transfers are associated with increased mortality: an observational cohort study on patient transfers in the Swedish Intensive Care Register.
Transfers from one intensive care unit (ICU) to another ICU are associated with increased length of intensive care and hospital stay. Inter-hospital ICU transfers are carried out for three main reasons: clinical transfers, capacity transfers and repatriations. The aim of the study was to show that different ICU transfers differ in risk-adjusted mortality rate with repatriations having the least risk. Observational cohort study of adult patients transferred between Swedish ICUs during 3 years (2016-2018) with follow-up ending September 2019. Primary and secondary end-points were survival to 30 days and 180 days after discharge from the first ICU. Data from 75 ICUs in the Swedish Intensive Care Register, a nationwide intensive care register, were used for analysis (89% of all Swedish ICUs), covering local community hospitals, district general hospitals and tertiary care hospitals. We included adult patients (16 years or older) admitted to ICU and subsequently discharged by transfer to another ICU. Only the first admission was used. Exposure was discharge to any other ICU (ICU-to-ICU transfer), whether in the same or in another hospital. Transfers were grouped into three predefined categories: clinical transfer, capacity transfer, and repatriation. We identified 15,588 transfers among 112,860 admissions (14.8%) and analysed 11,176 after excluding 4112 repeat transfer of the same individual and 300 with missing risk adjustment. The majority were clinical transfers (62.7%), followed by repatriations (21.5%) and capacity transfers (15.8%). Unadjusted 30-day mortality was 25.0% among capacity transfers compared to 14.5% and 16.2% for clinical transfers and repatriations, respectively. Adjusted odds ratio (OR) for 30-day mortality were 1.25 (95% CI 1.06-1.49 p = 0.01) for capacity transfers and 1.17 (95% CI 1.02-1.36 p = 0.03) for clinical transfers using repatriation as reference. The differences remained 180 days post-discharge. There was a large proportion of ICU-to-ICU transfers and an increased odds of dying for those transferred due to other reasons than repatriation.


The transmembrane domain of caveolin-1 exhibits a helix-break-helix structure.
Caveolin is an integral membrane protein that is found in high abundance in caveolae. Both the N- and C- termini lie on the same side of the membrane, and the transmembrane domain has been postulated to form an unusual intra-membrane horseshoe configuration. To probe the structure of the transmembrane domain, we have prepared a construct of caveolin-1 that encompasses residues 96-136 (the entire intact transmembrane domain). Caveolin-1(96-136) was over-expressed and isotopically labeled in E. coli, purified to homogeneity, and incorporated into lyso-myristoylphosphatidylglycerol micelles. Circular dichroism and NMR spectroscopy reveal that the transmembrane domain of caveolin-1 is primarily α-helical (57-65%). Furthermore, chemical shift indexing reveals that the transmembrane domain has a helix-break-helix structure which could be critical for the formation of the intra-membrane horseshoe conformation predicted for caveolin-1. The break in the helix spans residues 108 to 110, and alanine scanning mutagenesis was carried out to probe the structural significance of these residues. Our results indicate that mutation of glycine 108 to alanine does not disrupt the structure, but mutation of isoleucine 109 and proline 110 to alanine dramatically alters the helix-break-helix structure. To explore the structural determinants further, additional mutagenesis was performed. Glycine 108 can be substituted with other small side chain amino acids (i.e. alanine), leucine 109 can be substituted with other β-branched amino acids (i.e. valine), and proline 110 cannot be substituted without disrupting the helix-break-helix structure.


Mutational Status and Clinical Outcomes Following Systemic Therapy with or without Focal Radiation for Resected Melanoma Brain Metastases.
Brain metastases occur frequently in advanced melanoma and traditionally require surgery and radiation therapy. New evidence demonstrates that systemic therapies are effective for controlling metastatic melanoma brain metastases. This study evaluated outcomes after resection of melanoma brain metastases treated with systemic therapy, with or without focal radiotherapy. All patients received immunotherapy or BRAF/MEK inhibitors preoperatively or in the immediate 3 months postoperatively. Resection cavity failure, distant central nervous system progression, and adverse radiation effects were reported in the presence and absence of focal radiotherapy using the Kaplan-Meier method. Between 2011 and 2020, 37 resection cavities in 29 patients met criteria for analysis. Of lesions, 22 (59%) were treated with focal radiotherapy, and 15 (41%) were treated with targeted therapy or immunotherapy alone. The 12- and 24-month freedom from local recurrence was 64.8% (95% confidence interval [CI] 42.1%-99.8%) and 46.3% (95% CI 24.5%-87.5%), respectively, for systemic therapy alone and 93.3% (95% CI 81.5%-100%) at both time points for focal radiotherapy (P = 0.01). On univariate analysis, focal radiotherapy was the only significant factor associated with reduction of local recurrence risk (hazard ratio 0.10, 95% CI 0.01-0.85; P = 0.04). There were no significant differences in central nervous system progression-free survival or overall survival between patients who received systemic therapy plus focal radiotherapy compared with systemic therapy alone. BRAF mutation status was reviewed for either the brain metastasis (n = 9 patients, 31%) or the primary site (n = 20 patients, 69%), and patients harboring BRAFV600E mutations had worse progression-free survival (P = 0.043). Focal radiotherapy with systemic therapy for resected melanoma brain metastases significantly decreased resection cavity recurrence compared with systemic therapy alone. BRAF mutation status correlated with poorer outcomes.


Physicochemical characterisation, molecular docking, and drug-likeness evaluation of hypotensive peptides encrypted in flaxseed proteome.
In this study, hypotensive peptides derived from mature flaxseed protein sequences were predicted in silico using BIOPEP-UWM with nine proteases, three each from digestive, plant and microbial sources. The physicochemical properties of 2256 ACE-inhibitory peptides and 267 renin-inhibitory peptides (including seven (7) peptides with dual inhibitory activities against both ACE and renin enzymes) were assessed in silico using the 'Peptides' package of R. The hypotensive peptides showed relatively low molecular weight (mol. wt.) range (132 = mol. wt. ≤ 442 Da); broad range of isoelectric point (3.61 = pI ≤ 12.50); both high (>2) and low (≤2) Boman indices, and a variety of hydrophobicity indices (hydrophilic, hydrophobic and amphipathic properties). Following this, the seven peptides with dual ACE and renin inhibitory activities were selected for molecular docking with the respective enzyme receptors. The binding energies of the seven hypotensive peptides with ACE and renin respectively ranged from -36.82 to -25.94 kJ/mol, and -33.05 to -27.61 kJ/mol; and compared well with values recorded for inhibitor drugs, captopril (-26.78 kJ/mol) and aliskiren (-34.73 kJ/mol). The seven peptides inhibited ACE through hydrogen bonds, electrostatic and hydrophobic interactions; and renin, mainly through hydrogen bonds and hydrophobic interactions. In silico prediction of adsorption, digestion, metabolism, excretion and toxicity (ADME/Tox) profile based on physicochemical properties and Lipinski's rule-of-five showed that the peptides were non-toxic and had desirable drug-like properties (flexibility, lipophilicity, molecular weight, gastrointestinal absorption, and bioavailability). This study provides insight into the molecular interactions of hypotensive peptides with their physiological targets, and the potential to develop the bioactive peptides from flaxseed proteins.


Induction of neurogenin-1 expression by sonic hedgehog: Its role in development of trigeminal sensory neurons.
We have examined the roles of signaling molecules in the mechanisms underlying the induction of neurogenin (ngn)-1 expression. ngn-1 is a basic helix-loop-helix (bHLH) transcription factor, which is essential for the specification of trigeminal sensory neurons. Semiquantitative reverse transcriptase-polymerase chain reaction using cranial explants in organ cultures showed that sonic hedgehog (Shh) promotes ngn-1 expression. This promoting activity was not observed in other signaling molecules examined. The promotion of ngn-1 expression by Shh, furthermore, was inhibited by cyclopamine, a specific inhibitor of Shh signaling. Shh did not affect the expression of ngn-2, a bHLH transcription factor that plays an important role in the specification of epibranchial placode-derived sensory neurons. The expression levels of ngn-1 and ngn-2 decreased after fibroblast growth factor-2 treatment. These results suggest that Shh induces ngn-1 expression specifically and that expression of ngn-1 and ngn-2 is regulated by different mechanisms. The induction of ngn-1 expression by Shh suggests that this signaling molecule participates in the specification of trigeminal sensory neurons. We therefore examined the effect of Shh on the development of these neurons. Immunostaining using anti-ngn-1 demonstrated that Shh promotes ngn-1 expression in trigeminal neural crest cells. Trigeminal neural crest cells are derived from the posterior mesencephalon and the most-anterior rhombencephalon, and they contain a subset of precursors of trigeminal sensory neurons. Moreover, a subpopulation of trigeminal neural crest cells expressed the Shh receptor Patched. The number of cells that express Brn3a, a POU-domain transcription factor that plays an important role in differentiation of sensory neurons, also increased with Shh treatment. Our data suggest that Shh signaling is involved in the specification of trigeminal sensory neurons through the induction of ngn-1 expression. Furthermore, Shh promotes the differentiation of neural crest cells into trigeminal sensory neurons.


Centralized anterior bone plug results in less graft extrusion in patients undergoing medial meniscus allograft transplantation following anterior cruciate ligament reconstruction.
This study was performed to analyze the effect of anterior bone plug positioning on clinical and radiological outcomes in patients undergoing medial meniscus allograft transplantation (M-MAT) following anterior cruciate ligament reconstruction (ACLR). Data from 24 patients who underwent M-MAT following meniscectomy and ACLR from November 2008 to June 2017 were retrospectively investigated. Patients were divided into either the centrally positioned group (group C) or the medially positioned group (group M) based on the location of the anterior bone plug for M-MAT. Clinical and radiographic follow-up was performed at two years postoperatively. International Cartilage Repair Society (ICRS) grades of chondral lesion, graft extrusion, and meniscus signal intensity were evaluated by magnetic resonance imaging (MRI) at one year postoperatively. There were no significant differences in demographics including follow-up time of two years between the two groups. There were no significant differences in postoperative subjective International Knee Documentation Committee (IKDC), Lysholm, and Tegner scores between groups. Furthermore, there were no significant differences in osteoarthritis progression or ICRS grade on MRI. However, group C showed significantly less absolute graft extrusion (P = .008) and relative graft extrusion (P < .0001) on one-year follow-up MRI, relative to group M. Meniscus signal intensity tended to be better in group C, although this difference was not statistically significant (P = .092). The centrally positioned group showed significantly less graft extrusion on MRI compared to the medially positioned group; however, there were no statistically significant differences in clinical outcomes between the two groups.


Classification and regression tree-based prediction of 6-mercaptopurine-induced leucopenia grades in children with acute lymphoblastic leukemia.
The rationale of the current study was to develop 6-mercaptopurine (6-MP)-mediated hematological toxicity prediction model for acute lymphoblastic leukemia (ALL) therapeutic management. A total of 96 children with ALL undergoing therapy with MCP-841 protocol were screened for all the ten exons of TPMT, exon 2, exon 3 and intron 2 of ITPA using bidirectional sequencing. This dataset was used to construct prediction models of leucopenia grade by constructing classification and regression trees (CART) followed by smart pruning. The developed CART model indicated TPMT*12 and TPMT*3C as the key determinants of toxicity. TPMT int3, int4 and int7 polymorphisms exert toxicity when co-segregated with one mutated allele of TPMT*12 or TPMT*3C or ITPA exon 3. The developed CART model exhibited 93.6% accuracy in predicting the toxicity. The area under the receiver operating characteristic curve was 0.9649. TPMT *3C and TPMT*12 are the key determinants of 6-MP-mediated hematological toxicity while other variants of TPMT (int3, int4 and int7) and ITPA ex2 interact synergistically with TPMT*3C or TPMT*12 variant alleles to enhance the toxicity. TPMT and ITPA variants cumulatively are excellent predictors of 6-MP-mediated toxicity.


Awareness, practices, and myths related to coronavirus disease-19 among rural people in Kolar District, South India: A community-based mixed-methods study.
Capturing the baseline information on awareness, practices, and prevailing myths related to the ongoing coronavirus disease-19 (COVID-19) pandemic in rural India will help in planning interventions to improve the health literacy on COVID-19. The aim of the study was to assess the level of awareness, practices, and myths regarding COVID-19 among rural population of Kolar district in South India. A concurrent mixed-methods study with a quantitative community-based cross-sectional analytical design and a qualitative phenomenological design was conducted in five randomly selected villages during June 2020. A prevalidated and pretested semi-structured questionnaire was administered to one adult in the households selected using systematic random sampling to capture the sociodemographic details and their awareness, practices, and myths related to COVID-19. The supervisors additionally and concurrently used a nonparticipant observation technique to record the real-time behaviors and preventive practices adopted by the villagers. Quantitative analysis was done using STATA and included multivariable regression analysis, and the association was reported using prevalence rates along with their 95% confidence intervals (CIs). Qualitative analysis was done manually as per discussion and concordance among supervisors and reported as categories along with supporting statements. Among the 298 respondents, "poor awareness" was seen in 128 (43.0%, 95% CI: 37.5%-48.6%). Among the responders, 89 (29.9%) believed in the myth that "Corona disease is due to God's wrath or curse." The field observations were categorized under three categories - "avoidance of masks," "nonexistent social distancing," and "rampant spitting." About two in five villagers were found to have "poor awareness" to COVID, and practices related to COVID were found to be largely unsatisfactory. Lower level of education and belonging to nuclear family were associated with "poor awareness." Various myths were identified that has to be debunked on priority basis by the government, especially targeting the people having low level of education in rural India.


Treatment of patients with advanced nonsmall cell lung carcinoma using docetaxel and gemcitabine plus granulocyte-colony stimulating factor.
A combination regimen comprised of docetaxel, gemcitabine, and granulocyte-colony stimulating factor (G-CSF) was studied in patients with advanced nonsmall cell lung carcinoma (NSCLC) to determine its antitumor efficacy and tolerance. Thirty-four patients with advanced measurable NSCLC (3 patients with Stage IIIB and 31 patients with Stage IV disease) were treated with an intravenous combination chemotherapy regimen comprised of docetaxel, 80 mg/m(2), on Day 1 and gemcitabine, 1000 mg/m(2), on Days 1 and 10; G-CSF, 5 microg/kg, was administered subcutaneously between Days 2 and 8. Treatment cycles were repeated every 3 weeks. All patients were evaluable for toxicity and response assessment. A total of 163 courses was administered. Objective tumor response was noted in 17 patients (50%; 95% confidence interval, 32. 5-67.5%), including 2 complete responses (6%) and 15 partial responses (44%). There was no change in 10 patients (29%) and 7 patients developed progressive disease. The median duration of response was 6.5 months (range, 3-15 months) and the median time to disease progression for all patients was 6.8 months (range, 1.8-18 months). The median overall survival time was 13.0 months (range, 2. 5-23+ months) with a 1-year survival rate of 55.8%. Myelosuppression was the most frequently encountered adverse reaction, although World Health Organization Grade 3 or 4 leukocytopenia and/or granulocytopenia occurred in only 18% and 24% of patients, respectively. Other toxicities generally were mild to moderate, and always fully reversible. With a response rate of 50% and a median survival time of 13 months, the drug combination described in the current study appears to have significant activity against advanced metastatic NSCLC. Due to its fairly good tolerance and ease of administration, further investigation of this regimen appears warranted.


Myostatin blockade with a fully human monoclonal antibody induces muscle hypertrophy and reverses muscle atrophy in young and aged mice.
Loss of skeletal muscle mass and function in humans is associated with significant morbidity and mortality. The role of myostatin as a key negative regulator of skeletal muscle mass and function has supported the concept that inactivation of myostatin could be a useful approach for treating muscle wasting diseases. We generated a myostatin monoclonal blocking antibody (REGN1033) and characterized its effects in vitro using surface plasmon resonance biacore and cell-based Smad2/3 signaling assays. REGN1033 was tested in mice for the ability to induce skeletal muscle hypertrophy and prevent atrophy induced by immobilization, hindlimb suspension, or dexamethasone. The effect of REGN1033 on exercise training was tested in aged mice. Messenger RNA sequencing, immunohistochemistry, and ex vivo force measurements were performed on skeletal muscle samples from REGN1033-treated mice. The human monoclonal antibody REGN1033 is a specific and potent myostatin antagonist. Chronic treatment of mice with REGN1033 increased muscle fiber size, muscle mass, and force production. REGN1033 prevented the loss of muscle mass induced by immobilization, glucocorticoid treatment, or hindlimb unweighting and increased the gain of muscle mass during recovery from pre-existing atrophy. In aged mice, REGN1033 increased muscle mass and strength and improved physical performance during treadmill exercise. We show that specific myostatin antagonism with the human antibody REGN1033 enhanced muscle mass and function in young and aged mice and had beneficial effects in models of skeletal muscle atrophy.


Immune defense mechanisms against a systemic bacterial infection in the cat flea (Ctenocephalides felis).
A significant amount of work has been devoted towards understanding the cellular and humoral immune responses in arthropod vectors. Although fleas (Siphonaptera) are vectors of numerous bacterial pathogens, few studies have examined how these insects defend themselves from infection. In this study, we investigated the immune defense mechanisms in the hemocoel of cat fleas (Ctenocephalides felis), currently the most important flea pest of humans and many domestic animals. Using model species of bacteria (Micrococcus luteus, Serratia marcescens, and Escherichia coli), we delivered a systemic infection and measured the following: antimicrobial activity of hemolymph, levels of free radicals resulting from the induction of oxidase-based pathways, number of circulating hemocytes, phagocytosis activity of circulating hemocytes, and in vivo bacteria killing efficiency when phagocytosis activity is limited. Our results show that the antimicrobial activity of flea hemolymph increases in response to certain species of bacteria; yet, a systemic infection with the same bacterial species did not influence levels of hydrogen peroxide (H2O2), a reactive intermediate of oxygen, at the same time. Additionally, the number of circulating hemocytes increases in response to E. coli infection, and these cells display strong phagocytic activity against this bacterium. Moreover, limiting phagocytosis by injecting polystyrene beads subsequently increases flea susceptibility to E. coli infection when compared to injury controls; however, impairing the cellular immune response itself did not increase flea susceptibility to infection when compared to untreated fleas. Overall, this work yields significant insight into how fleas interact with bacterial pathogens in their hemocoel, and suggests that cellular and humoral immune responses cooperate to combat systemic bacterial infections.


Phenotypic variability in a Spanish family with a Caveolin-3 mutation.
We report a Spanish family affected from a late onset, hand-involved and autosomal dominant distal myopathy associated to Caveolin-3 mutation. Signs of muscle hyperexcitability and hyperckemia were observed in the youngest relatives but not motor symptoms. Neurological examination was performed in all members of the family. Muscle biopsy sample was taken from the proband and DNA genomics was amplified for the two exons of Cav-3 by the polymerase chain reaction (PCR) in all the affected members and in three asymptomatic relatives. Signs of muscle hyperexcitability and hyperckemia were observed in the affected members from early ages. Cav-3 expression was greatly reduced in the sarcolemma of the proband's muscle. Genetic studies revealed a G --> A transition at nucleotide position 80 in exon 1 of the Cav-3 gene (c.80G>A), generating a Arg --> Gln change at codon 27 (p.R27Q) of the amino acid chain in heterozygous state, while no mutation was found in unaffected members. Signs of muscle hyperexcitability and hyperckemia at early ages may predict the development of a late onset autosomal dominant hand-involved myopathy associated to Cav-3 mutation in the family reported herein.


Lipoic acid modified antimicrobial peptide with enhanced antimicrobial properties.
RIWVIWRR-NH2 (Bac8c) is a natural antimicrobial peptide (AMP) exhibiting great antibacterial activity against Gram-negative and Gram-positive bacteria. In this work, lipoic acid was used as a fatty acid hydrophobic ligand to modify Bac8c (LA-Bac8c) to further improve its antimicrobial properties. Minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) assays showed that LA-Bac8c exhibited lower MIC (MBC) values against Staphylococcus aureus (S. aureus) and methicillin-resistant Staphylococcus aureus (MRSA) than Bac8c. Similar results were reflected in the antibiofilm activity towards S. aureus and MRSA, and LA-Bac8c showed better activity to the biofilm which has been formed or is being formed. In addition to this, the obvious interaction between bacteria/biofilm and LA-Bac8c was observed by microscopy. LA-Bac8c displayed strong membrane depolarization and outer membrane permeabilizing ability, and the cell membrane treated with LA-Bac8c was destroyed to the leakage of bacteria cellular components. All these data indicated LA-Bac8c could be used as a useful antimicrobial peptide with wide application prospect.


[Autologous transfusion of blood deep frozen in the interim in childhood].
In the report we describe a method of reducing the number of transfusions of heterologous blood in patients with a surgical correction of chest walls. In 71 children between 2 and 17 years of age, 10-15% of total blood volume were withdrawn 3-4 weeks before the operation, deep frozen and thawed at the appropriate time to be ready for retransfusion. This arrangement reduced the need of heterologous blood significantly from 18.6% (prior to the introduction of the method) to 4.2%.


The recovery trajectory of adolescent social defeat stress-induced behavioral, (1)H-MRS metabolites and myelin changes in Balb/c mice.
Adolescent exposure to social stress precipitates emotion-related disorders and affects the development and function of medial prefrontal cortex (mPFC). However, this adversity-induced behavioral and neurological changes remain not fully explored. Adolescent Balb/c mice were subjected to intermittent social defeat stress during postnatal days 28 to 42. Proton magnetic resonance spectroscopy ((1)H-MRS) measurements, behavioral tests and immunohistochemistry were performed one day or 3 weeks after the last stress episode. Defeated mice exhibited hypoactivity and social avoidance with the latter lasting into the early adulthood, while the anxiety level was unchanged. Social defeat experience lead to temporary decreases in the levels of total creatines (Cr + pCr) and Glx (Glu + Gln), but a delayed increase of N- acetylaspartate (NAA) levels. These alternations were accompanied with a persistent reduction of myelin basic protein expression although the number of mature oligodendrocyte did not change. These findings provide evidence that adolescent adverse social experience permanently impairs the emotion-related behavioral performance and induces biochemical and molecular changes in the brain which at least lasts into early adulthood, thus enhancing our understanding of the neurobiology of social defeat stress. Our finding also implicates that NAA signals on MRS may reflect myelin status.


Fluorescence correlation spectroscopy and its application to the characterization of molecular properties and interactions.
Fluorescence correlation spectroscopy (FCS) utilizes temporal fluctuations in fluorescence emission to extract quantitative measures of inter- or intramolecular dynamics or molecular motions of probe molecules, which occur on submicrosecond to second timescales. In typical experiments, one can readily obtain the probe's diffusion coefficient and concentration from small volumes of sample. Recent FCS applications have yielded information on interactions of the probe with changing or structured solvent, binding with other molecules, photophysical or conformational changes in the probe, polymerization, and other changes in the dynamics of the probe. In cross-correlation mode FCS promises to attract more applications as the technique can monitor interactions in a system with two or more probes with different fluorophores.


Racial differences in the major clinical symptom domains of bipolar disorder.
Across clinical settings, black individuals are disproportionately less likely to be diagnosed with bipolar disorder compared to schizophrenia, a traditionally more severe and chronic disorder with lower expectations for remission. The causes of this disparity are likely multifactorial, ranging from the effects of implicit bias, to developmental and lifelong effects of structural racism, to differing cultural manifestations of psychiatric symptoms and distress. While prior studies examining differences have found a greater preponderance of specific psychotic symptoms (such as persecutory delusions and hallucinations) and a more dysphoric/mixed mania presentation in Black individuals, these studies have been limited by a lack of systematic phenotypic assessment and small sample sizes. In the current report, we have combined data from two large multi-ethnic studies of bipolar disorder with comparable semi-structured interviews to investigate differences in symptoms presentation across the major clinical symptom domains of bipolar disorder. In the combined meta-analysis, there were 4423 patients diagnosed with bipolar disorder type I, including 775 of self-reported as Black race. When symptom presentations were compared in Black versus White individuals, differences were found across all the major clinical symptom domains of bipolar disorder. Psychotic symptoms, particularly persecutory hallucinations and both persecutory and mood-incongruent delusions, were more prevalent in Black individuals with bipolar disorder type I (ORs = 1.26 to 2.45). In contrast, Black individuals endorsed fewer prototypical manic symptoms, with a notably decreased likelihood of endorsing abnormally elevated mood (OR = 0.44). Within depression associated symptoms, we found similar rates of mood or cognitive related mood symptoms but higher rates of decreased appetite (OR = 1.32) and weight loss (OR = 1.40), as well as increased endorsement of initial, middle, and early-morning insomnia (ORs = 1.73 to 1.82). Concurrently, we found that black individuals with BP-1 were much less likely to be treated with mood stabilizers, such as lithium (OR = 0.45), carbamazepine (OR = 0.37) and lamotrigine (OR = 0.34), and moderately more likely to be on antipsychotic medications (OR = 1.25). In two large studies spanning over a decade, we found highly consistent and enduring differences in symptoms across the major clinical symptom domains of bipolar disorder. These differences were marked by a greater burden of mood-incongruent psychotic symptoms, insomnia and irritability, and fewer prototypical symptoms of mania. While such symptoms warrant better recognition to reduce diagnostic disparities, they may also represent potential targets of treatment that can be addressed to mitigate persistent disparities in outcome.


Biological and Clinical Insight from Analysis of the Tumor B-Cell Receptor Structure and Function in Chronic Lymphocytic Leukemia.
The B-cell receptor (BCR) is essential to the behavior of the majority of normal and neoplastic mature B cells. The identification in 1999 of the two major CLL subsets expressing unmutated immunoglobulin (Ig) variable region genes (U-IGHV, U-CLL) of pre-germinal center origin and poor prognosis, and mutated IGHV (M-CLL) of post-germinal center origin and good prognosis, ignited intensive investigations on structure and function of the tumor BCR. These investigations have provided fundamental insight into CLL biology and eventually the mechanistic rationale for the development of successful therapies targeting BCR signaling. U-CLL and M-CLL are characterized by variable low surface IgM (sIgM) expression and signaling capacity. Variability of sIgM can in part be explained by chronic engagement with (auto)antigen at tissue sites. However, other environmental elements, genetic changes, and epigenetic signatures also contribute to the sIgM variability. The variable levels have consequences on the behavior of CLL, which is in a state of anergy with an indolent clinical course when sIgM expression is low, or pushed towards proliferation and a more aggressive clinical course when sIgM expression is high. Efficacy of therapies that target BTK may also be affected by the variable sIgM levels and signaling and, in part, explain the development of resistance.


PACdb: PolyA Cleavage Site and 3'-UTR Database.
The PolyA Cleavage Site and 3'-UTR Database (PACdb) is a web-accessible database that catalogs putative 3'-processing sites and 3'-UTR sequences for multiple organisms. Sites have been identified primarily via expressed sequence tag-genome alignments, enabling delineation of both the specificities and heterogeneity of 3'-processing events. By web browser or CGI: PACdb: http://harlequin.jax.org/pacdb/; AtPACdb: http://harlequin.jax.org/atpacdb/. Available online at http://harlequin.jax.org/pacdb/supplemental.php.


The Project ENABLE Cornerstone randomized controlled trial: study protocol for a lay navigator-led, early palliative care coaching intervention for African American and rural-dwelling advanced cancer family caregivers.
Family caregivers play a vital, yet stressful role in managing the healthcare needs and optimizing the quality of life of patients with advanced cancer, from the time they are newly diagnosed until end of life. While early telehealth palliative care has been found to effectively support family caregivers, little work has focused on historically under-resourced populations, particularly African American and rural-dwelling individuals. To address this need, we developed and are currently testing Project ENABLE (Educate, Nurture, Advise, Before Life Ends) Cornerstone, a lay navigator-led, early palliative care coaching intervention for family caregivers of African American and rural-dwelling patients with newly diagnosed advanced cancer. This is a 2-site, single-blind, hybrid type I implementation-effectiveness trial of the Cornerstone intervention versus usual care. Cornerstone is a multicomponent intervention based on Pearlin's Stress-Health Process Model where African American and/or rural-dwelling family caregivers of patients with newly diagnosed advanced cancer (target sample size = 294 dyads) are paired with a lay navigator coach and receive a series of six, brief 20-60-min telehealth sessions focused on stress management and coping, caregiving skills, getting help, self-care, and preparing for the future/advance care planning. Subsequent to core sessions, caregivers receive monthly follow-up indefinitely until the patient's death. Caregiver and patient outcomes are collected at baseline and every 12 weeks until the patient's death (primary outcome: caregiver distress at 24 weeks; secondary outcomes: caregiver: quality of life and burden; patient: distress, quality of life, and healthcare utilization). Implementation costs and the intervention cost effectiveness are also being evaluated. Should this intervention demonstrate efficacy, it would yield an implementation-ready model of early palliative care support for under-resourced family caregivers. A key design principle that has centrally informed the Cornerstone intervention is that every caregiving situation is unique and each caregiver faces distinct challenges that cannot be addressed using a one-size-fits all approach. Hence, Cornerstone employs culturally savvy lay navigator coaches who are trained to establish a strong, therapeutic alliance with participants and tailor their coaching to a diverse range of individual circumstances. ClinicalTrials.gov NCT04318886 . Registered on 20 March, 2020.


The effect of l-thyroxine treatment on sexual function and depressive symptoms in men with autoimmune hypothyroidism.
Thyroid autoimmunity and mild hypothyroidism in women seem to be associated with sexual dysfunction and depressive symptoms. Data concerning similar associations in men are limited. The aim of this study was to investigate sexual functioning and depressive symptoms in men with autoimmune hypothyroidism. The study population consisted of three groups: men with autoimmune overt hypothyroidism (group A), men with autoimmune subclinical hypothyroidism (group B) and healthy euthyroid males without thyroid autoimmunity (group C). Apart from measuring serum levels of thyrotropin and free thyroid hormones and thyroid antibody titers, all included patients completed a questionnaires evaluating male sexual function (International Index of Erectile Function-15: IIEF-15) and assessing the presence and severity of depressive symptoms (Beck Depression Inventory-Second Edition - BDI-II) before and after 6 months of levothyroxine treatment. Men with overt hypothyroidism obtained lower scores in all five domains of IIEF-15, while men with subclinical hypothyroidism only in erectile function. The total BDI-II score was higher in groups A than in groups B and C, as well as higher in group B than in group C. L-thyroxine improved erectile function and normalized intercourse satisfaction, orgasmic function, sexual desire and overall satisfaction in group A, as well as normalized erectile function in group B. In group A, L-thyroxine reduced, while in group B tended to reduce total BDI-II. The obtained results suggest that autoimmune hypothyroidism in men is characterized by sexual and mood disturbances and that hypothyroid patients with sexual dysfunction and depressive symptoms benefit from L-thyroxine treatment.


A rare case of tetralogy of Fallot with unusual blood supply to the left lung.
We present a rare case of tetralogy of Fallot with absence of the leaflets of the pulmonary valve and anomalous blood supply of the left lung from the transverse aortic arch. Although embryologic considerations would suggest that the anomalous vessel is not the arterial duct, there was a good response to prostaglandin therapy.


[Effect of an educational admission program for patients at the conservative phase of chronic kidney disease (CKD)].
We have been conducting a 1-week educational admission program for patients at the conservative phase of chronic kidney disease (CKD) since 2006. In this study we evaluated the effect of the program. We retrospectively reviewed 469 patients who could be followed for 12 months after a 1-week educational admission program for CKD out of a total of 700 patients who attended the program between October 2006 and April 2012. We compared the rates of decrease in renal function before and after the program. In addition, we divided the patients into two groups of diabetic nephropathy and non-diabetic nephropathy. We compared the rate of decrease in renal function in each group. The rate of decrease in renal function 12 months after discharge was improved compared with that 6 months before admission. (before: 0.316 mL/min/1.73 m2/month; after: 0.001 mL/min/1.73 m2/month.) The rate of decrease in renal function 6 months before admission of the diabetic nephropathy group was 72.3 times faster than that of the non-diabetic nephropathy group. However, the rate of decrease in renal function 12 months after admission was improved in both groups. It was revealed that the educational admission program is effective for preserving the renal function on patients at the conservative phase of CKD.


Association of certain Ia allotypes with the occurrence of chronic lymphocytic leukemia. Recognition by a monoclonal anti-Ia reagent of a susceptibility determinant not in the DR series.
The Ia antigen allospecificities of individuals with B type chronic lymphocytic leukemia differed significantly from those of a control population. A monoclonal antibody, IVD12, directed to a MB3-1ike determinant, reacted with 92.5 percent of the individuals with leukemia and yielded the greatest positive relative risk, 13.5. A lower degree of positive association was found with the presence of the MT2 determinant. In contrast, the low observed frequency of the MT1/MB1 determinant among leukemic individuals was associated with the most significant negative relative risk, -8.1. Among HLA- DR specificities, the relative risk associated with the presence of DR5 was positive while that with DR2 was negative.


Design of biorefineries towards carbon neutrality: A critical review.
The increase in worldwide demand for energy is driven by the rapid increase in population and exponential economic development. This resulted in the fast depletion of fossil fuel supplies and unprecedented levels of greenhouse gas in the atmosphere. To valorize biomass into different bioproducts, one of the popular and carbon-neutral alternatives is biorefineries. This system is an appropriate technology in the circular economy model. Various research highlighted the role of biorefineries as a centerpiece in the carbon-neutral ecosystem of technologies of the circular economy model. To fully realize this, various improvements and challenges need to be addressed. This paper presents a critical and timely review of the challenges and future direction of biorefineries as an alternative carbon-neutral energy source.


How experienced alpine-skiers cope with restrictions of ankle degrees-of-freedom when wearing ski-boots in postural exercises.
The present study investigates the mechanisms underlying changes in postural strategy that occur to compensate for mechanical ankle joint restrictions induced by wearing ski-boots during postural exercises. Fourteen experienced skiers were asked to stand as still as possible in a stable (STA) posture and in 2 postures with instability in the medio/lateral and antero/posterior (ML and AP postures) direction. Postural tasks were performed with eyes open or closed and while wearing or not wearing ski-boots. The electromyographic (EMG) activity of representative lower limb muscles and positions of centre-of-foot pressure (COP) were recorded and analyzed. Our results illustrated enhanced postural performances with ski-boots in the STA posture, whereas postural performances remained unchanged when wearing ski-boots in the ML and AP postures. Analysis of COP sways in the frequency domain did not illustrate any modification in the contribution of different neuronal loops when the study subjects wore ski-boots. EMG showed that the mechanical effects of wearing ski-boots were compensated by changes in postural strategy through the reorganization of muscle coordination, made possible by inherent redundancies in the human body. The preservation of postural performances, despite restrictions of ankle degrees-of-freedom induced by ski-boots, emphasizes the subjects' capacity to exploit the additional support provided by ski-boots by adequately adjusting muscle coordination to control posture in different balance conditions.


Comparison between the Icelandic and Dutch forms of hereditary cerebral amyloid angiopathy.
Hereditary cerebral amyloid angiopathy has been described in Icelandic and Dutch families. Although the clinical manifestations show similarities, biochemical characterization revealed that amyloid in the Icelandic patients consists of cystatin C and in the Dutch patients of beta-protein. Both diseases are caused by a single base mutation leading to the same amino acid (viz. glutamine). Furthermore, both cystatin C and the beta-protein precursor are protease inhibitors. Therefore, the mechanism of amyloidogenesis may be similar in both diseases. A comparison of clinical, pathological, genetic, and biochemical aspects of these two types of hereditary cerebral amyloid angiopathy is presented.


One-year mortality in displaced intracapsular hip fractures and associated risk: a report of Chinese-based fragility fracture registry.
The purpose of this registry-based retrospective study was to investigate the risk factors related to one-year mortality in displaced intracapsular fragility hip fracture patients. Patients were screened from the Fragility Fracture Registry. Inclusion criterion was displaced intracapsular hip fracture patients with atypical or pathological fractures excluded. One-year mortality was investigated against risk factors including age, gender, past medical history, pre-fracture mobility (PFM), pre-operation ASA grade, delayed surgery over 48 h, post-surgical complications, and length of stay at acute orthopedic ward (LOS). A total of 1050 patients were included for further analysis. Gross one-year mortality was 14.9%. One-year mortality was significantly higher in patients who received non-operative treatment and those who received surgery but delayed over 48 h after admission (both p < 0.001). Male gender (OR = 2.708), advanced age (OR = 1.359), higher risk ASA grades (III to V) (OR = 1.990), past history of gastrointestinal disease (OR = 1.671), and renal impairment (OR = 1.984) were related to higher one-year mortality. The mortality of patients in PFM grade 3 and LOS group 3 was significantly higher (OR = 2.240 and 1.722, respectively). Higher age, male gender, past gastrointestinal disease and renal impairment, ASA grade over 3, indoor confined pre-fracture ambulatory, and stay at hospital over 15 days were risk factors related to higher one-year mortality in surgically treated displaced intracapsular hip fracture patients. A multi-disciplinary approach is advised to patients identified with these risks factors and co-managed by orthopedic surgeons, geriatricians, and fracture liaison nurses.


Amplified Cancer Immunotherapy of a Surface-Engineered Antigenic Microparticle Vaccine by Synergistically Modulating Tumor Microenvironment.
Efficient cancer vaccines not only require the co-delivery of potent antigens and highly immunostimulatory adjuvants to initiate robust tumor-specific host immune response but also solve the spatiotemporal consistency of host immunity and tumor microenvironment (TME) immunomodulation. Here, we designed a biomaterials-based strategy for converting tumor-derived antigenic microparticles (T-MPs) into a cancer vaccine to meet this conundrum and demonstrated its therapeutic potential in multiple murine tumor models. The internal cavity of T-MPs was employed to store nano-Fe3O4 (Fe3O4/T-MPs), and then dense adjuvant CpG-loaded liposome arrays (CpG/Lipo) were tethered on the surface of Fe3O4/T-MP through mild surface engineering to get a vaccine (Fe3O4/T-MPs-CpG/Lipo), demonstrating that co-delivery of Fe3O4/T-MPs and CpG/Lipo to antigen presenting cells (APCs) could elicit strong tumor antigen-specific host immune response. Meanwhile, vaccines distributed in the TME could reverse infiltrated tumor-associated macrophages into a tumor-suppressive M1 phenotype by nano-Fe3O4, amazingly induce abundant infiltration of cytotoxic T lymphocytes, and transform a "cold" tumor into a "hot" tumor. Furthermore, amplified antitumor immunity was realized by the combination of an Fe3O4/T-MPs-CpG/Lipo vaccine and immune checkpoint PD-L1 blockade, specifically inhibiting ∼83% of the progression of B16F10-bearing mice and extending the median survival time to 3 months. Overall, this study synergistically modulates the tumor immunosuppressive network and host antitumor immunity in a spatiotemporal manner, which suggests a general cell-engineering strategy tailored to a personalized vaccine from autologous cancer cell materials of each individual patient.


Establishment of a two-step purification scheme for tag-free recombinant Taiwan native norovirus P and VP1 proteins.
The protruding (P) domain of the major capsid protein VP1 of norovirus (NoV) is the crucial element for immune recognition and host receptor binding. The heterologous P protein expressed by Pichia pastoris self-assembles into P particles. However, tag-free NoV protein purification schemes have rarely been reported due to the low isoelectric point of NoV proteins, which leads to highly competitive binding between the target protein and yeast host cell proteins at alkaline pH. In this study, a two-step purification scheme based on surface histidines and the charge on the NoV GII.4 strain P protein was developed. Using HisTrap and ion exchange chromatography, the P protein was directly purified, with a recovery of 28.1% and purity of 82.1%. Similarly, the NoV capsid protein VP1 was also purified using HisTrap and gel filtration chromatography based on native surface histidines and self-assembly ability, with 20% recovery and over 90% purity. Dynamic light scattering and transmission electron microscopy analyses of the purified NoV P revealed that most of these small P particles were triangle-, square- and ring-shaped, with a diameter of approximately 14 nm, and that the purified NoV VP1 self-assembles into particles with a diameter of approximately 47 nm. Both the purified NoV P and VP1 particles retained human histo-blood group antigen-binding ability, as evidenced by a saliva-binding assay.


Anlotinib exerts potent antileukemic activities in Ph chromosome negative and positive B-cell acute lymphoblastic leukemia via perturbation of PI3K/AKT/mTOR pathway.
Despite advances in the development of novel targeted therapies, the need for B-ALL alternative treatments has not been met. Anlotinib could blunt the proangiogenic activity of VEGFR, PDGFR, and FGFR, and has shown strong antitumor activities across multiple tumors. However, anlotinib cytotoxicity against B-ALL has not ever been evaluated, thus prompting us to initiate this study. Expression2Kinases program was used to identify potential treatment targets. Cell viability and apoptosis were determined by CCK-8 and Annexin V/PI staining kit, respectively. qRT-PCR and Western blotting were utilized to investigate the molecular mechanisms. In vivo antileukemia activity of Anlotinib was evaluated in a Ph+ B-ALL patient-Derived Xenograft (PDX) model. Compared with treatment-naive B-ALL cases, RR B-ALL patients had higher activities in the VEGF/VEGFR signaling and the PI3K/AKT/mTOR pathway. Exposure of Ph- and Ph+ B-ALL cells to anlotinib resulted in significant cell viability reduction, apoptosis enhancement, and cell cycle arrest at G2/M phase. Importantly, anlotinib treatment led to remarkably decreased leukemia burdens and extended the survival period in a Ph+ B-ALL PDX model. Blockade of the role of the proangiogenic mediators, comprising VEGFR2, PDGFR-beta, and FGFR3, played a critical role in the cytotoxicity of anlotinib against Ph- and Ph+ B-ALL. Moreover, anlotinib dampened the activity of PI3K/AKT/mTOR pathway that resides in the convergence of the three mentioned proangiogenic signals. This work provides impressive preclinical evidence of anlotinib against Ph- and Ph+ B-ALL and raises a rationale for future clinical evaluation of this drug in the management of Ph- and Ph+ B-ALL.


Adaptation of a 96-well plate larval migration inhibition test for measuring the sensitivity of cyathostomins to macrocyclic lactone anthelmintics.
The use of macrocyclic lactone drugs for control of equine cyathostomins is threatened by increasing levels of resistance. Detection of changes in drug sensitivity is important for effective and sustainable management of cyathostomins, however, at present such detection relies on the use of the faecal egg count reduction test, which is known to be an insensitive method. The present study therefore aimed to examine the use of a 96-well plate larval migration inhibition test for detection of resistance to macrocyclic lactone drugs in cyathostomins. We optimised conditions for migration of larvae, and examined the effects of larval storage time on drug dose responses. The modified test was able to define the sensitivity of cyathostomin isolates to ivermectin and eprinomectin in terms of dose response curves, and IC50 and IC95 values. The IC95 showed much greater consistency than the IC50 with larvae that had been stored for different periods prior to the test. Comparisons between two isolates, which had both been defined previously as susceptible using faecal egg count reduction tests, showed more variation at the IC50 compared to the IC95. Limitations of the test included the degree of variation in control-well migration despite optimisation of migration incubation conditions, and the need to incorporate a method to determine the species composition of the larval populations to account for possible species differences in drug sensitivity among cyathostomins. Validation of the technique on reference susceptible and resistant isolates of known species composition is still required.


Routine day-case laparoscopic cholecystectomy.
A prospective study was carried out to assess the feasibility of performing true day-case laparoscopic surgery in a district general hospital. All patients admitted consecutively under the care of one surgeon for laparoscopic cholecystectomy were included in the study. Selection criteria for a day-case procedure included an American Society of Anesthesiologists grade of I or II and the availability of a responsible carer at home. Patients were discharged 4-6 h after surgery with a standard analgesia pack and a contact number for advice. All patients were contacted by telephone on the day after discharge. A postal questionnaire was sent to the first 100 patients to assess satisfaction with the day-case process. Of 357 patients admitted for laparoscopic cholecystectomy over a 24-month period, 154 (43.1 per cent) were operated on as day cases on a morning theatre list. Twenty-two patients required an overnight stay (14.3 per cent), three because of conversion to an open procedure. One patient was readmitted for neck pain. Eighty-two (92.1 per cent) of 89 patients were either satisfied or very satisfied with the day-case procedure. This study has demonstrated a low rate of overnight stay (14.3 per cent) and readmission (1.9 per cent), and a high degree of patient satisfaction for day-case laparoscopic cholecystectomy.


Why does the Chinese public accept evolution?
A substantial proportion of Chinese nationals seem to accept evolution, and the country is sometimes held up to show that the sorry state of evolution acceptance in the United States is not inevitable. Attempts to improve evolution acceptance generally focus on improving communication, curricular reform, and even identifying cognitive mechanisms that bias people against evolution. What is it that the Chinese scientific community did so well, and can it be generalized? This paper argues that evolution acceptance in China has a very specific history, one that other countries are very unlikely to emulate. We show that the interactions among science, education, mass media, social and political movements, and ideological arguments about evolution greatly influenced the Chinese public's understanding and acceptance of evolution. We find that it was not just formal education, but many more ideologically motivated methods of evolution exposure that contributed to the high rate of acceptance. But since the purpose of evolution dissemination has moved beyond merely teaching biology, the Chinese public persists with substantial misunderstandings of the theory. Thus, bottom line percentage of acceptance figures can be misleading; the details and the history really matter.


Comparative analysis of the VIDAS Toxo IgG IV assay in the detection of antibodies to Toxoplasma gondii.
A new serological test, Vidas Toxo IgG IV, has been developed with antigens obtained from tachyzoites cultured on cells. Vidas Toxo IgG IV replaces Vidas Toxo IgG II by offering a more standardized antigenic production and a lower number of indeterminate results while retaining equivalent sensitivity and specificity.


Adverse reactions to biologic agents: focus on autoimmune disease therapies.
In recent years, a growing number of biologic agents have become available for the treatment of various autoimmune, neoplastic, cardiovascular, infectious, allergic, and other conditions. Their introduction has resulted in marked clinical improvements for many patients. Nevertheless, a variety of adverse reactions have been observed with these agents. Because many biologic agents affect key components of sundry physiologic processes, a number of important adverse reactions might be considered mechanism based. Other adverse reactions relate to the agent rather than the target, including hypersensitivity reactions. As a means of exploring the spectrum of potential adverse effects related to biologic agents and their mechanisms, this review will focus on the experience to date with biologic agents used for the treatment of autoimmune disorders. An understanding of the spectrum and types of reactions possible with biologic agents, as well as the mechanisms underlying such reactions, will help clinicians use them optimally.


Model-based registration of preprocedure MR and intraprocedure US of the lumbar spine.
Epidural and spinal needle insertions, as well as facet joint denervation and injections are widely performed procedures on the lumbar spine for delivering anesthesia and analgesia. Ultrasound (US)-based approaches have gained popularity for accurate needle placement, as they use a non-ionizing, inexpensive and accessible modality for guiding these procedures. However, due to the inherent difficulties in interpreting spinal US, they yet to become the clinical standard-of-care. A novel statistical shape [Formula: see text] pose [Formula: see text] scale (s [Formula: see text] p [Formula: see text] s) model of the lumbar spine is jointly registered to preoperative magnetic resonance (MR) and US images. An instance of the model is created for each modality. The shape and scale model parameters are jointly computed, while the pose parameters are estimated separately for each modality. The proposed method is successfully applied to nine pairs of preoperative clinical MR volumes and their corresponding US images. The results are assessed using the target registration error (TRE) metric in both MR and US domains. The s [Formula: see text] p [Formula: see text] s model in the proposed joint registration framework results in a mean TRE of 2.62 and 4.20 mm for MR and US images, respectively, on different landmarks. The joint framework benefits from the complementary features in both modalities, leading to significantly smaller TREs compared to a model-to-US registration approach. The s [Formula: see text] p [Formula: see text] s model also outperforms our previous shape [Formula: see text] pose model of the lumbar spine, as separating scale from pose allows to better capture pose and guarantees equally-sized vertebrae in both modalities. Furthermore, the simultaneous visualization of the patient-specific models on the MR and US domains makes it possible for clinicians to better evaluate the local registration accuracy.


Nighttime kidney transplantation is associated with less pure technical graft failure.
To minimize cold ischemia time, transplantations with kidneys from deceased donors are frequently performed during the night. However, sleep deprivation of those who perform the transplantation may have adverse effects on cognitive and psychomotor performance and may cause reduced cognitive flexibility. We hypothesize that renal transplantations performed during the night are associated with an increased incidence of pure technical graft failure. A retrospective analysis of data of the Dutch Organ Transplant Registry concerning all transplants from deceased donors between 2000 and 2013 was performed. Nighttime surgery was defined as the start of the procedure between 8 p.m. and 8 a.m. The primary outcome measure was technical graft failure, defined as graft loss within 10 days after surgery without signs of (hyper)acute rejection. Of 4.519 renal transplantations in adult recipients, 1.480 were performed during the night. The incidence of pure technical graft failure was 1.0 % for procedures started during the night versus 2.6 % for daytime surgery (p = .001). In a multivariable model, correcting for relevant donor, recipient and graft factors, daytime surgery was an independent predictor of pure technical graft failure (p < .001). Limitation of this study is mainly to its retrospective design, and the influence of some relevant variables, such as the experience level of the surgeon, could not be assessed. We conclude that nighttime surgery is associated with less pure technical graft failures. Further research is required to explore factors that may positively influence the performance of the surgical team during the night.


A facile route to prepare cellulose-based films.
Cellulose is the most abundant renewable and biodegradable material available in nature. Its insoluble character in water as well as common organic and inorganic liquids, however, curtails the wholesome utility. The continuous rise for biodegradable products based on cellulose coupled with its intrinsic ability to form a viable substitute for the petroleum-based materials necessitates the critical need for solubilizing the cellulose. Herein, we demonstrate the feasibility of ZnCl2 solutions, especially the 64-72% concentrations, to dissolve cellulose. FTIR results suggest that Zn(2+) ions promote Zn⋯O3H interactions, which in-turn weaken the intrinsic O3H⋯O5 hydrogen bonds that are responsible for strengthening the cellulose chains. Interestingly, Ca(2+) ions promote interactions among the Zn-cellulose chains leading to the formation of nano fibrils and yield gelling solutions. The tensile strength of the Ca(2+) added Zn-cellulose films increases by around 250% compared to the Zn-cellulose films. Overall, utilization of inorganic salt solutions to solubilize and crosslink cellulose is cost-effective, recyclable and certainly stands out tall among the other available systems. More importantly, the proposed protocol is simple and is a "green" process, and thus its large-scale adaptability is quite feasible. We strongly believe that the outcome opens up a new window of opportunities for cellulose in the biomedical, pharmaceutical, food and non-food applications.