Patterns of long-term care services use in a suburban municipality of Japan: a population-based study.
Increasing service use under the long-term care insurance (LTCI) system in Japan requires a comprehensive understanding of how the services are actually used. This study aimed to identify patterns of LTCI service use and to examine the characteristics of the patterns. We analyzed data from a population of 4,339 older adults living in the community who were certified as "Needing Care" and were using at least one LTCI service in a suburban municipality of Japan. We identified six patterns of service use using cluster analysis based on the amount of fees for LTCI services and compared characteristics among the clusters. The clusters were: 1) light use of care services (n = 1,852); 2) day care-centered (n = 1,071); 3) day care with rehabilitation-centered (n = 616); 4) home help-centered (n = 365); 5) short-stay respite service-centered (n = 246); and 6) compound uses of visiting services (n = 189). "Home help-centered" and "short-stay respite service-centered" clusters used a large number of fees, whereas "compound uses of visiting services" clusters did not despite their severe conditions. The "day care-centered (with rehabilitation)" classification included few people who needed medical procedures, likely due to the lack of medical facilities in those agencies. The results show the impact of social and medical factors on LTCI service use, suggesting possible difficulties in the socialization of care. The clusters could be used as typical service use patterns, providing a framework for further studies, such as those evaluating the services' effects. Geriatr Gerontol Int 2017; 17: 753-759.


Adverse events in the placebo arm of maintenance therapy trials in advanced ovarian cancer: A systematic review and meta-analysis.
Maintenance treatment is standard of care for front-line (FL) and platinum-sensitive recurrent ovarian cancer (PSROC) following response to chemotherapy. Adverse events (AEs) on maintenance therapies are common and usually attributable to investigational treatments but could also be unrelated. Randomised controlled trial (RCT) with blinded placebo design is the gold standard for determining the relative differences in efficacy and AEs between treatment arms. We performed a meta-analysis to quantify AE rates in placebo arms of RCTs to determine AEs not due to investigational agents. We performed an electronic search to identify eligible RCTs in FL and PSROC settings. Data from placebo arms were extracted and pooled using the inverse variance method to determine the risk of any AE, overall and specific grade 3 or higher (G ≥ 3) AEs, and AE-related treatment delay, reduction and discontinuation. We identified 13 eligible RCTs (FL, N = 8; PSROC, N = 5) with 2224 patients who received placebo (FL, N = 1541; PSROC, N = 683). The majority experienced an AE of any grade (FL, 93.0%; PSROC, 95.2%). Substantial proportions experienced G ≥ 3 AEs (FL, 14.6%; PSROC, 18.2%). In the FL setting, AEs led to treatment delay in 14.4%, dose reduction in 4.1% and discontinuation in 2.6%. Findings were similar for PSROC: 8.4%, 5.5% and 2.1%, respectively. AEs not due to investigational agents are common in ovarian cancer patients in maintenance therapy RCTs. Potential explanations include the nocebo effect, residual toxicities from previous treatment or underlying disease. Further research is required to identify better approaches to assessing AEs in this population.


Complex carbohydrate composition of large dense-cored vesicles from sympathetic nerve.
Highly purified noradrenergic, large, dense-cored vesicles were isolated from bovine sympathetic nerve endings by sucrose-D2O density gradient centrifugation. Their concentration of glycoprotein hexosamine and sialic acid was 6.6 and 3.9 mumol/100 mg lipid-free dry weight, respectively, values which are similar to those previously found in bovine chromaffin granules. However, whereas chromaffin granule glycoproteins are characterized by their high proportion of N-acetylgalactosamine-containing O-glycosidically-linked oligosaccharides (present in the chromogranins), such oligosaccharides accounted for only 17% of those in noradrenergic synaptic vesicle glycoproteins. Fractionation of N-3H-acetylated glycopeptides by sequential lectin affinity chromatography demonstrated that approximately two-thirds of the oligosaccharides were of the tri- and tetraantennary complex type, accompanied by 14% biantennary oligosaccharides and 3% high-mannose oligosaccharides. The vesicles had a relatively low concentration of chondroitin sulfate (less than 5% of that in chromaffin granules) but significant amounts of heparan sulfate (0.4 mumol N-acetylglucosamine/100 mg lipid-free dry weight). No hyaluronic acid was detected. The concentration of ganglioside sialic acid in the noradrenergic vesicles was approximately 1 mumol/100 mg lipid-free dry weight, which is significantly higher than that of a crude membrane mixture from which the vesicles were prepared; the ratio of N-acetyl- to N-glycolylneuraminic acid was 0.8. Several molecular species of gangliosides were detected by thin-layer chromatography, but most of these did not exactly comigrate with bovine brain gangliosides. Cholera toxin binding indicated that approximately half or less of the gangliosides belong to the gangliotetraose series.


A controlled trial of the effect of parenteral nutritional support on patients with respiratory failure and sepsis.
Energy and protein metabolism was studied in 11 septic patients receiving ventilatory support while on three different intravenous regimens. They received 5% dextrose in water (D5W), and one of two different regimens of parenteral nutritional support (PNS); either amino acid and dextrose (PNA) or amino acid and dextrose and lipid (PNB). All patients were given D5W and PNS in random order. The energy intake was targetted to exceed by 50% the measured metabolic rate. On D5W the mean measured energy expenditure was only 15.2% above the expected energy expenditure (p<0.02). A respiratory quotient of 0.75 while on D5W showed that in the absence of PNS the major part of energy requirements came from fat oxidation. In addition, on D5W these patients were in negative nitrogen and protein (synthesis-catabolism) balance. With PNS the metabolic rate rose significantly (p<0.02). While on PNA, the CO2 production was significantly higher than with PNB, and despite receiving all non-protein energy as glucose, the patients continued to oxidise fat to meet about 30% of their energy requirements. Continued fat oxidation was found to be associated with insulin resistance and high catecholamine levels, suggesting a cause and effect relationship. PNS caused an increase in protein (synthesis - catabolism) and nitrogen balances, and reduced leucine oxidation. The fall in leucine oxidation was greater on PNB than on PNA. Protein and nitrogen balances, expressed per gram of amino acid infused, were significantly better with PNB than PNA. It was concluded that insulin resistance may make fat an efficient source of energy.


Serum 5'-nucleotide phosphodiesterase as a predictor of hepatic metastases in gastrointestinal cancer.
Isoenzyme V of 5'-nucleotide phosphodiesterase (5'-NPD-V) is present in the peripheral sera of patients with hepatic metastases. A total of 122 patients underwent prospective serologic analysis followed by operation for primary tumors of the gastrointestinal tract and careful evaluation of the liver. A positive 5'-NPD-V assay was found in fifty-nine of sixty patients with liver metastases. A negative 5'-NPD-V assay was found in forty-three of sixty-two patients with no evidence of hepatic metastases. The accuracy of the test was 84 per cent, and the predictive value was 75 per cent. Serum 5'-NPD-V was abnormal significantly more frequently in patients with metastatic liver disease than were liver scans or carcinoembryonic antigen (CEA), alpha fetoprotein, serum glutamic oxalacetic transaminase (SGOT), and total serum bilirubin or serum alkaline phosphatase levels.


Global burden of transfusion in sickle cell disease.
Sickle cell disease (SCD) is the most common hereditary hemoglobinopathy. The underlying pathophysiology of the red blood cell (RBC) leads to pan-systemic complications which manifest at an early age. While curative and disease-modifying treatments exist for SCD, a key intervention in the management and treatment of SCD is RBC transfusion, which can alleviate or prevent many complications. SCD patients often require chronic RBC transfusion therapy which can result in complications, such as iron overload, alloimmunization and infection. In low- and middle-income countries (LMICs), SCD patients lack appropriate access to healthcare such as newborn screening, health education, prophylaxis for infection, and treatments to reduce both mortality and SCD-related adverse effects. Poor access to RBCs for transfusion, coupled with donated blood not meeting safety standards set by the World Health Organization, presents a significant barrier for patients requiring chronic transfusions in LMICs. Unmet needs associated with blood collection, blood component processing and recipient matching all pose a serious problem in many LMICs, although this varies depending on geographic location, political organizations and economy. This review aims to provide an overview of the global burden of SCD, focusing on the availability of current treatments and the burden of chronic RBC transfusions in patients with SCD.


An ultrastructural study of the effects of gossypol on the endometrium of the female rat.
Abnormal desmosomes were found in the endometrial epithelial cells of rats treated orally with gossypol acetic acid at a dose of 60 mg/kg/day for 30 days. Desmosomes in the endometrium of rats treated at 40 mg/kg/day were similar to those of controls. Abnormalities included an increase in desmosome number with prominent filamentous interconnections, asymmetry, disorganization of tonofilaments, missing tonofilaments, missing desmosomal plaques that did not appear to line up with those of the adjacent cell. It is thought that the antifertility actions of gossypol may be due to a disturbance of desmosome formation. This would cause a disruption of endometrial cell adhesion as well as an alteration in the microenvironment within cytoplasmic domains. These changes could lead to an endometrial environment unfavorable to fetal development.


Follow-up Care of Critically Ill Patients With Acute Kidney Injury: A Cohort Study.
To evaluate follow-up care of critically ill patients with acute kidney injury (AKI). Retrospective cohort study. Patients admitted to the intensive care unit (ICU) with AKI in Alberta, Canada from 2005 to 2018, who survived to discharge without kidney replacement therapy or estimated glomerular filtration rate <15 mL/min/1.73 m2. AKI (defined as ≥50% or ≥0.3 mg/dL serum creatinine increase). The primary outcome was the cumulative incidence of an outpatient serum creatinine and urine protein measurement at 3 months postdischarge. Secondary outcomes included an outpatient serum creatinine or urine protein measurement or a nephrologist visit at 3 months postdischarge. Patients were followed from hospital discharge until the first of each outcome of interest, death, emigration from the province, kidney replacement therapy (maintenance dialysis or kidney transplantation), or end of study period (March 2019). We used non-parametric methods (Aalen-Johansen) to estimate the cumulative incidence functions of outcomes accounting for competing events (death and kidney replacement therapy). There were 29,732 critically ill adult patients with AKI. The median age was 68 years (IQR, 57-77), 39% were female, and the median baseline estimated glomerular filtration rate was 72 mL/min/1.73 m2 (IQR, 53-90). The cumulative incidence of having an outpatient creatinine and urine protein measurement at 3 months postdischarge was 25% (95% CI, 25-26). At 3 months postdischarge, 64% (95% CI, 64-65) had an outpatient creatinine measurement, 28% (95% CI, 27-28) had a urine protein measurement, and 5% (95% CI, 4-5) had a nephrologist visit. We lacked granular data, such as urine output. Many critically ill patients with AKI do not receive the recommended follow-up care. Our findings highlight a gap in the transition of care for survivors of critical illness and AKI.


Virtual Reality Zoo Therapy for Alzheimer's Disease Using Real-Time Gesture Recognition.
Alzheimer's disease affects almost ten million people every year. Negative emotions such as frustration and anxiety can have impact on brain capability in terms of memory functions. Alzheimer's patients experience more negative emotions than healthy older adults. Non-pharmacological treatment such as animal therapy could help Alzheimer patient but has restrictions and requirements. We propose a Virtual Reality Zoo Therapy system in which the patients are immersed in a virtual environment and can interact with animals using their hands. With the immersive experience of virtual reality (VR), patients feel that they are in a real therapy room and can freely interact with animals. This system is controlled by an intelligent agent which tracks the patients' emotions using electroencephalography and commands the animals according to their hand gesture and emotions. Experiments have been done and preliminary results show that it is possible to predict patients' hand gesture and interpret them in order to interact with virtual animals and the Zoo Therapy system can reduce the negative emotions.


Vancomycin-loaded electrospun polycaprolactone/nano-hydroxyapatite membrane for the treatment of blood infections.
Nowadays, because of the resistance of bacteria to antibiotics, researchers are trying to make new antibiotics or sometimes even bring them back into the treatment cycle so that they could eliminate the bacteria's resistance. On the other hand, the use of nanofibers has become widespread in many fields for their unique properties and convenient design. The present study focuses on the production of hydrophobic nanofibers to absorb the bacteria and their toxins from the bloodstream that contains the infection. Many bacterial surfaces have hydrophobic surfactant properties due to hydrophobic surface protein. According to the principle of binding two hydrophobic molecules to each other in an aqueous medium, the nanofibers are designed to physically absorb the bacteria. The use of antibiotics in the study can remove some unattached bacteria. In addition, using nanofiber manufacturing techniques can reduce the resistance of bacteria to antibiotics. The construction of the desired membrane can be used in subsequent studies as a replacement membrane for dialysis filters.


Movement of heparins across rat gastric mucosa is dependent on molecular weight and pH.
Movement of unfractionated (UFH) and low molecular weight heparins (LMWHs) through gastric mucosa was compared to determine effect of molecular weight on absorption. Rat gastric mucosa, mounted in an Ussing chamber, was bathed in oxygenated Kreb's buffer, containing mannitol on the mucosal (lumen) at pH 7.4 or 4, and glucose on the serosal side (circulation) at pH 7.4. Heparins (10 mg/ml) were added to the mucosal side. Potential difference (PD), resistance, and short circuit current (Isc), were determined. Buffers and tissues were extracted to measure heparin by gel electrophoresis. PD increased on heparin addition and following a lag period, that was longer for UFH at pH 7.4 and LMWHs at pH 4.0, returned to baseline. Isc increased slightly for UFH at pH 4.0 but significantly for LMWHs at pH 7.4. More UFH or LMWHs were recovered from serosal buffers at pH 4.0 and pH 7.4 respectively. Results suggest UFH and LMWHs cross gastric mucosa faster, and active transport is involved, at pH 4.0 and pH 7.4, respectively. Decreasing heparin size, increases movement through gastric mucosa at mucosal buffer pH 7.4 but not pH 4.0. The stomach environment may favor UFH absorption while the intestine environment favors LMWH absorption.


A new peptide docking strategy using a mean field technique with mutually orthogonal Latin square sampling.
The theoretical prediction of the association of a flexible ligand with a protein receptor requires efficient sampling of the conformational space of the ligand. Several docking methodologies are currently available. We propose a new docking technique that performs well at low computational cost. The method uses mutually orthogonal Latin squares to efficiently sample the docking space. A variant of the mean field technique is used to analyze this sample to arrive at the optimum. The method has been previously applied to explore the conformational space of peptides and identify structures with low values for the potential energy. Here we extend this method to simultaneously identify both the low energy conformation as well as a 'high-scoring' docking mode. Application of the method to 56 protein-peptide complexes, in which the length of the peptide ligand ranges from three to seven residues, and comparisons with Autodock 3.05, showed that the method works well.


HLA supratypes in an Italian population.
A supratype analysis of a North Italian population was performed, using 16 polymorphisms in the HLA region spanning the HLA-A-DP segment. Fourteen supratypes were identified, mostly corresponding to those found in other Caucasoid populations. The degree of their conservation both within the B-DR/DQ region and in the regions telomeric and centromeric from HLA-A and DP was evaluated and linkage disequilibria among several DR and DP alleles were identified. Notably, the degree of association with DP increased when the DR marker was part of a conserved B-DR/DQ supratype. These data are relevant to the definition of the genetic structure of the population and to the prediction of probabilities of histocompatibility matching between unrelated individuals.


Resistance and functional training reduces knee extensor position fluctuations in functionally limited older adults.
The purpose of this study was to determine the effect of task-specificity on knee extensor steadiness adaptations in functionally limited older adults. Twenty-four functionally limited older adults (74.6+/-7.6 years: 22 women, 2 men) completed a 10-week control period followed by 10 weeks (2 days/week) of resistance (RT), functional (FT) (practicing everyday tasks, i.e., chair rises) or functional + resistance (FRT) training, which featured both shortening and lengthening movements. During testing, subjects performed a steady isometric [10, 25, 50% of maximal voluntary contraction (MVC)] and shortening/lengthening (5, 30, 65% of MVC) knee extensor contractions. There were no steadiness (isometric, shortening or lengthening contractions) changes in the control period and no adaptations in isometric steadiness due to training. RT induced a 37% reduction in shortening fluctuations at 5% of MVC and 35% reduction in lengthening fluctuations at both 30% and 65% of MVC. FRT induced a 60% reduction in shortening fluctuations at 30% of MVC. No adaptations in dynamic steadiness were observed in the FT group. Further analysis indicated that those who were the least steady at baseline showed the greatest training effects during isometric (RT: R (2)=0.25, FRT: R (2)=0.49, FT: R (2)=0.38), shortening (RT: R (2)=0.36, FRT: R (2)=0.36, FT: R (2)=0.35) and lengthening (RT: r (2)=0.29, FRT: r (2)=0.44) contractions. In conclusion, steadiness improvements in groups performing resistance exercise, without a concomitant improvement in the FT group, supports a role for task-specificity in explaining steadiness adaptations, particularly for unsteady older adults.


Nanoparticulate Mineralized Collagen Scaffolds and BMP-9 Induce a Long-Term Bone Cartilage Construct in Human Mesenchymal Stem Cells.
Engineering the osteochondral junction requires fabrication of a microenvironment that supports both osteogenesis and chondrogenesis. Multiphasic scaffold strategies utilizing a combination of soluble factors and extracellular matrix components are ideally suited for such applications. In this work, the contribution of an osteogenic nanoparticulate mineralized glycosaminoglycan scaffold (MC-GAG) and a dually chondrogenic and osteogenic growth factor, BMP-9, in the differentiation of primary human mesenchymal stem cells (hMSCs) is evaluated. Although 2D cultures demonstrate alkaline phosphatase activity and mineralization of hMSCs induced by BMP-9, MC-GAG scaffolds do not demonstrate significant differences in the collagen I expression, osteopontin expression, or mineralization. Instead, BMP-9 increases expression of collagen II, Sox9, aggrecan (ACAN), and cartilage oligomeric protein. However, the hypertrophic chondrocyte marker, collagen X, is not elevated with BMP-9 treatment. In addition, histologic analyses demonstrate that while BMP-9 does not increase mineralization, BMP-9 treatment results in an increase of sulfated glycosaminoglycans. Thus, the combination of BMP-9 and MC-GAG stimulates chondrocytic and osteogenic differentiation of hMSCs.


The use of prolonged bladder distension in the treatment of intractable urinary incontinence in females with detrusor instability.
Fifty patients suffering from detrusor instability who failed to respond to anticholinergic treatment were treated with prolonged bladder distension. Twelve months after treatment 9 were symptom free, 15 improved and 26 remained symptomatically unchanged. Extraperitoneal bladder rupture occurred in 2 patients.


Prophylactic antibiotics in obstetrics and gynecology.
Studies throughout the world demonstrate the effectiveness of prophylactic antibiotics in vaginal hysterectomy and cesarean section. Febrile morbidity is reduced by more than one half, and pelvic infections are reduced one third to one fifth, respectively. Prophylactic antibiotics are most beneficial in high-risk cesarean section, such as in patients in labor and with ruptured membranes. In abdominal hysterectomy, the effect of prophylactic antibiotics is less pronounced, and the results of the individual studies are more controversial. Prophylactic antibiotics are commonly used in extensive oncologic surgery, infertility surgery, and in other procedures, but data for adequate evaluation are lacking. First- and second-generation cephalosporins are the antibiotics most frequently used. In vaginal hysterectomies, a single preoperative dose, and in cesarean section, three perioperative doses seem to be adequate. Infections occurring despite prophylactic antibiotics are often caused by resistant organisms.


Ligustrazine prevents basilar artery remodeling in two-kidney-two-clip renovascular hypertension rats via suppressing PI3K/Akt signaling.
In the present study, we used a two-kidney-two-clip (2k2c) stroke-prone renovascular hypertension rat model (RHRSP) to investigate the protective effects of ligustrazine (TMP) on cerebral arteries and to examine PI3K/Akt pathway behavior under this protection. The cerebral artery remodeling was induced by 2k2c-induced renovascular hypertension. Brain basilar artery tissues were isolated and their histological changes were detected through H&E and EVG staining, α-SMA IHC staining, and transmission electron microscopy at four, eight, and twelve weeks after 2k2c surgery, both with and without TMP treatment. Meanwhile, the ET-1, Ang II, and NO levels in basilar arteries and plasma were determined. Furthermore, the PTEN expression and the activation of PI3K/Akt in basilar artery tissues were detected through IHC and Western Blot. In addition, the primary basilar artery smooth muscle cells (BASMCs) were cultured and TMP protection of BASMCs stimulated with ET-1/Ang II in the presence or absence of insulin-like growth factor 1 (IGF-1) was determined. TMP attenuated basilar artery remodeling, decreased ET-1 and Ang II levels and increased NO level in basilar arteries and plasma of RHRSP rats. Moreover, TMP reduced BASMCs proliferation upon ET-1/Ang II stimulation. We also found that TMP could effectively suppress the activation of PI3K/Akt in 2k2c-RHRSP rat basilar artery and ET-1/Ang II stimulated BASMCs. Most importantly, IGF-1, as an activator of PI3K/Akt, could damage the protective effect of TMP. TMP exerts its protective effects and prevents basilar artery remodeling in RHRSP rats at least partly through the inhibition of PI3K/Akt pathway.


Postcolonial partnerships: deep sea research, media coverage and (inter)national narratives on the Galathea Deep Sea Expedition from 1950 to 1952.
The Danish Galathea Deep Sea Expedition between 1950 and 1952 combined scientific and official objectives with the production of national and international narratives distributed through the daily press and other media. Dispatched by the Danish government on a newly acquired naval ship, the expedition undertook groundbreaking deep sea research while also devoting efforts to showing the flag, public communication of science, and international cooperation. The expedition was conceived after the war as a way in which to rehabilitate Denmark's reputation internationally and to rebuild national pride. To this end, the expedition included an onboard press section reporting the expedition to the Danish public and to an international audience. The press section mediated the favourable, post-war and postcolonial image of Denmark as an internationalist, scientific, modernizing and civilizing nation for which the expedition planners and many others were hoping. The expedition, therefore, was highly relevant to, indeed fed on, the emerging internationalist agenda in Denmark's foreign policy. Bringing out these aspects of the historical context of the expedition, this paper adds important perspectives to our knowledge about the expedition in particular and, more generally, about scientific exploration in the immediate post-war and postcolonial period.


Long-term discontinuation of warfarin in a patient with HeartMate 3 left ventricular assist device without complication.
A 38-year-old woman with peripartum cardiomyopathy underwent placement of a HeartMate 3 (HM3) left ventricular assist device (LVAD). Postoperatively, she refused warfarin therapy and was maintained on aspirin monotherapy for 19 months. She did not experience thrombotic or thromboembolic complications associated with lack of oral vitamin K antagonist anticoagulation. Our patient represents the longest reported duration of a patient with HM3 LVAD maintained without warfarin without evidence of thrombotic or thromboembolic events.


Tryptophan hydroxylase-1 gene variants associate with a group of suicidal borderline women.
Alterations in the serotonin (5-HT) system have been related to impulsive aggression and suicidal behavior, common features of the borderline personality disorder (BPD). Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in 5-HT biosynthesis. Two isoforms are known, TPH-1 and TPH-2. TPH-1 has been correlated to various psychiatric and behavioral disorders by gene polymorphism association studies. We aimed to determine whether specific TPH-1 haplotypes associate with BPD. A case-control design was employed. The control group included 98 women without psychiatric history. In all, 95 patients were included, all Caucasian women with a BPD diagnosis who had attempted suicide at least twice during their lifetime. Exclusion criteria were: (i) substance dependence; (ii) dementia or other irreversible organic brain syndromes; (iii) psychotic disorders or major depressive illness with melancholic features; (iv) life-threatening eating disorders. Six single-nucleotide polymorphisms (SNPs) were found at significant linkage disequilibrium across 23 kb of the TPH-1 gene in both patients and controls, suggesting a haplotype block structure. While no individual SNP showed association, several haplotypes associated with the BPD group. In particular, one six-SNP haplotype was absent from the control group while representing about one-quarter of all haplotypes in the BPD group (corrected P<<10(-5)). A 'sliding window' analysis attributed the strongest disease association to haplotype configurations located between the gene promoter and intron 3. We conclude that TPH-1 associates with BPD in suicidal women. Our data support the expectation that haplotype analysis is superior to single locus analysis in gene-disease, case-control association studies.


Necrotizing fasciitis caused by Vibrio vulnificus: first published infection acquired in Turkey is the second time a strain is isolated in Germany.
Vibrio vulnificus, a marine vibrio, has recently been recognized as a potential human pathogen. It causes human infections with mortality rates up to 60%. Until 1991, most human isolations were reported from the USA, Japan and Taiwan. The second strain isolated in Germany is documented and a significant case of V. vulnificus infection acquired in Turkey is published for the first time.


Biological activity and biotechnological aspects of locked nucleic acids.
Locked nucleic acid (LNA) is one of the most promising new nucleic acid analogues that has been produced under the past two decades. In this chapter, we have tried to cover many of the different areas, where this molecule has been used to improve the function of synthetic oligonucleotides (ONs). The use of LNA in antisense ONs, including gapmers, splice-switching ONs, and siLNA, as well as antigene ONs, is reviewed. Pharmacokinetics as well as pharmacodynamics of LNA ONs and a description of selected compounds in, or close to, clinical testing are described. In addition, new LNA modifications and the adaptation of enzymes for LNA incorporation are reviewed. Such enzymes may become important for the development of stabilized LNA-containing aptamers.


Field performance of cyphenothrin: an integrated insecticide strategy against German cockroaches (Dictyoptera: Blatellidae).
Resistance to organophosphorous and carbamate insecticides amongst German cockroaches is widely reported. Cyphenothrin EC, a new synthetic pyrethroid was evaluated in cookhouses in an urban area, with the aim of exploring alternate control option against the German cockroach Blatella germanica. Three cookhouses were selected by simple random sampling method, two for treatment and one as control. The impact of treatment on cockroach infestation was monitored weekly by visual assessment sampling technique. Cyphenothrin brought about 95 to 97.5% reduction in cockroach infestation by the end of six weeks post-treatment. The study reports the efficacy of cyphenothrin in the control of German cockroaches and recommends an "Integrated insecticide strategy" for the control of cockroaches in urban cookhouses.


Challenges in the Development of Drug/Device and Biologic/Device Combination Products in the United States and European Union: A Summary From the 2013 DIA Meeting on Combination Products.
Compared with single-entity treatments, multientity or combination products have the potential to provide enhanced therapeutic utility. Because they involve components that would normally be overseen by different branches of health authorities (eg, different FDA centers), they raise numerous scientific, regulatory, policy, and review management challenges. This article summarizes the current status of the evolving combination product development landscape and potential options to address key challenges facing combination product developers. Continued collaboration and transparency among regulators, combination product developers, and other stakeholders is essential to streamlining the global combination product development and review process to ensure the availability of high-quality new products that are being used in a way that is safe and effective.


Microfluidic intestinal organoid-on-a-chip uncovers therapeutic targets by recapitulating oxygen dynamics of intestinal IR injury.
Increasing evidence demonstrates that mammals have different reactions to hypoxia with varied oxygen dynamic patterns. It takes ∼24 h for tri-gas incubator to achieve steady cell hypoxia, which fails to recapitulate ultrafast oxygen dynamics of intestinal ischemia/reperfusion (IR) injury. Inspired from the structure of native intestinal villi, we engineered an intestinal organoid chip embedded with engineered artificial microvessels based on co-axial microfluidic technology by using pH-responsive ZIF-8/sodium alginate scaffold. The chip was featured on: (i) eight times the oxygen exchange efficiency compared with the conventional device, tri-gas incubator, (ii) implantation of intestinal organoid reproducing all types of intestinal epithelial cells, and (iii) bio-responsiveness to hypoxia and reoxygenation (HR) by presenting metabolism disorder, inflammatory reaction, and cell apoptosis. Strikingly, it was found for the first time that Olfactomedin 4 (Olfm4) was the most significantly down-regulated gene under a rapid HR condition by sequencing the RNA from the organoids. Mechanistically, OLFM4 played protective functions on HR-induced cell inflammation and tissue damage by inhibiting the NF-kappa B signaling activation, thus it could be used as a therapeutic target. Altogether, this study overcomes the issue of mismatched oxygen dynamics between in vitro and in vivo, and sets an example of next-generation multisystem-interactive organoid chip for finding precise therapeutic targets of IR injury.


A simplified method of 85Kr measurement for dating young groundwaters.
The technique of gas extraction from water and gas sample preparation for 85Kr low-level measurements was further developed to improve its applicability to isotope-hydrological "age" determinations of young groundwaters. A water sample of about 200 L is flushed with helium to extract the dissolved gases. Krypton is separated from the extracted gas mixture by repeated adsorption on charcoal, fractionated desorption and subsequent gas chromatography. The detection limit for a 10,000 min counting time in a 10 mL counter containing the krypton (15 microL) and methane as counting gas corresponds to 25 mBq 85Kr per mL (STP) krypton or 2.5% of the mean atmospheric 85Kr activity concentration in the year 1990.


Identification of chlorfenvinphos toxicity in a municipal effluent in Sydney, New South Wales, Australia.
Acute toxicity in a municipal sewage treatment plant in Sydney, New South Wales, Australia, was traced to chlorfenvinphos, an organophosphorous pesticide. Toxicity identification evaluation procedures led to the tentative identification of chlorfenvinphos as the toxic contaminant in the sample. Subsequent analytical verification revealed 0.95 microg/L of chlorfenvinphos in the effluent sample, and spiking studies confirmed that it accounted for the observed toxicity. The 48-h median lethal concentration of chlorfenvinphos to Ceriodaphnia dubia averaged 0.28 microg/L (n = 4). Source-control measures were effective at eliminating chlorfenvinphos and associated toxicity from the discharge.


Oxygen, Metabolism, and Regeneration: Lessons from Mice.
The discovery that the Murphy Roths Large (MRL) mouse strain is a fully competent, epimorphic tissue regenerator, proved that the machinery of regeneration was preserved through evolution from hydra, to salamanders, to mammals. Such concepts have allowed translation of the biology of amphibians, and their ability to regenerate, to a mammalian context. We identified the ancient hypoxia-inducible factor (HIF)-1α pathway, operating through prolyl hydroxylase domain proteins (PHDs), as a central player in mouse regeneration. Thus, the possibility of targeting PHDs or other HIF-1α modifiers to effectively recreate the amphibian regenerative state has emerged. We posit that these regenerative pathways are critical in mammals. Moreover, the current approved use of PHD inhibitors in the clinic should allow fast-track translation from mouse studies to drug-based regenerative therapy in humans.


Treatment of Cancer-Associated Retinopathy: A Systematic Literature Review.
Systematic literature review of treatment efficacy of previously used protocols in treating patients with proven cancer-associated retinopathy (CAR). There is no universally accepted treatment algorithm for CAR and visual prognosis is very poor. We describe a patient with CAR with dramatic improvement in vision after treatment with high doses of corticosteroids followed by plasma exchange (PLEX) and present results of a systematic literature review of treatment efficacy of previously used protocols in treating patients with proven CAR. We describe a 70-year-old man with CAR who demonstrated dramatic improvement in vision after treatment with high doses of systemic corticosteroids followed by 7 sessions of PLEX. We then report the results of a systematic review of all previously published English literature discussing visual outcomes of various treatment regimens used for patients with antibody-proven CAR. The index patient is a rare case of CAR with sustained significant improvement in vision after treatment with high doses of corticosteroids followed by PLEX. The systematic review identified 28 antibody-proven cases of CAR, 27 of which were treated with steroids, which resulted in varying degrees of improvement in visual acuity in 59% (16 of 27). The time from symptom onset to initiation of treatment and the dose of steroids did not influence the visual outcome. Three patients were also treated with PLEX in addition to steroids, and 2 of 3 patients demonstrated improvement in vision; however, there was no difference in visual outcome in patients treated with steroids only versus those treated with steroids + PLEX. Treatment with steroids or steroids + PLEX resulted in some improvements in visual acuity in 59% of patients. Removal of antirecoverin antibodies with PLEX can arrest the immune attack on the photoreceptors and potentially improve visual function; thus, it should be considered in addition to steroids. Further studies with larger cohorts are needed to establish a treatment protocol and further determine the effectiveness of the different approaches. The author(s) have no proprietary or commercial interest in any materials discussed in this article.


The inhibition by ionophores in vitro of an Enterococcus-like pathogen of rainbow trout, Oncorhynchus mykiss.
Streptococcosis is a major disease of several fish species in Australia, Japan and South Africa. The minimum inhibitory concentration of some ionophores (lasalocid, monensin, narasin and salinomycin) was determined in vitro for an Enterococcus-like species pathogenic for rainbow trout (Oncorhynchus mykiss) in Australia. Forty isolates of the fish pathogen were tested, together with control strains of Staphylococcus aureus ATCC 29213, Enterococcus faecalis ATCC 29212 and Streptococcus bovis ATCC 9809. The minimum inhibitory concentrations (MIC) of erythromycin, the drug of choice for controlling streptococcosis, ranged between 0.1 and 0.8 microgram/ml whereas the MIC values for the ionophores ranged between 0.2 and 1.5 micrograms/ml. Of the ionophores tested, narasin was the most inhibitory (0.2-0.4 microgram/ml), while monensin was the least inhibitory (0.4-1.5 micrograms/ml). Salinomycin was marginally more inhibitory (0.4-0.8 microgram/ml) than lasalocid (0.8 microgram/ml).


Satellite cells surrounding axotomised rat dorsal root ganglion cells increase expression of a GFAP-like protein.
Segments of sciatic nerve, 8-10 mm long, were removed from the left thigh of adult Sprague-Dawley rats. One day to 6 weeks after operation the animals were killed and the 4th and 5th lumbar dorsal root ganglia dissected out on both the operated and the unoperated side. A monoclonal and two polyclonal antibodies to glial fibrillary acidic protein (GFAP) were used to localize GFAP-like molecules in cryostat sections of the ganglia by means of indirect immunofluorescence. Expression of GFAP in satellite cells, demonstrable by the binding of polyclonal antibodies, had increased noticeably by three days post operation and remained at a high level throughout the remaining period of the experiment. Whereas on the unoperated side only about 15% of the neurons in the ganglia were surrounded by GFAP-positive satellite cells, on the operated side about 88% of the neurons were surrounded by GFAP-positive cells. Satellite cells could not be labelled with the monoclonal antibodies to GFAP.


Metformin overdose with a resultant serum pH of 6.59: survival without sequalae.
Metformin, widely used in the treatment of diabetes mellitus, is known to cause lactic acidosis in both therapeutic use and after an overdose. We report the case of a 40-year-old woman who claimed to have ingested between 75 and 100 grams of metformin and subsequently developed severe lactic acidosis. She eventually developed a peak serum lactate level of 40.0 mmol/L and a serum pH nadir of 6.59 and became obtunded, hypotensive, and hypothermic. After aggressive supportive therapy with mechanical ventilation, vasopressor agents, sodium bicarbonate, and hemodialysis, her metabolic derangements steadily improved and she made a complete recovery without any residual sequelae. Her admission serum metformin concentration was later determined to be 160 microg/mL (therapeutic range is 1-2 microg/mL). There are several case reports and case series describing lactic acidosis secondary to metformin ingestion, although the exact mechanism remains unclear. The overall management of metformin overdose is reviewed. This case represents the largest reported amount of ingested metformin, the lowest serum pH, and the highest serum lactate concentration in any intentional metformin overdose survivor in the literature. Despite potentially lethal metabolic derangements, such patients can survive with aggressive supportive care.


Psychiatric drugs impact mitochondrial function in brain and other tissues.
Mitochondria have been linked to the etiology of schizophrenia (SZ). However, studies of mitochondria in SZ might be confounded by the effects of pharmacological treatment with antipsychotic drugs (APDs) and other common medications. This review summarizes findings on relevant mitochondria mechanisms underlying SZ, and the potential impact of psychoactive drugs including primarily APDs, but also antidepressants and anxiolytics. The summarized data suggest that APDs impair mitochondria function by decreasing Complex I activity and ATP production and dissipation of the mitochondria membrane potential. At the same time, in the brains of patients with SZ, antipsychotic drug treatment normalizes gene expression modules enriched in mitochondrial genes that are decreased in SZ. This indicates that APDs may have both positive and negative effects on mitochondria. The available evidence suggests three conclusions i) alterations in mitochondria functions in SZ exist prior to APD treatment, ii) mitochondria alterations in SZ can be reversed by APD treatment, and iii) APDs directly cause impairment of mitochondria function. Overall, the mechanisms of action of psychiatric drugs on mitochondria are both direct and indirect; we conclude the effects of APDs on mitochondria may contribute to both their therapeutic and metabolic side effects. These studies support the hypothesis that neuronal mitochondria are an etiological factor in SZ. Moreover, APDs and other drugs must be considered in the evaluation of this pathophysiological role of mitochondria in SZ. Considering these effects, pharmacological actions on mitochondria may be a worthwhile target for further APD development.


A prospective study of the microbiological environment of the genitourinary tract in Hong Kong Chinese women during pregnancy.
Microbiological colonization of the genitourinary tract in pregnancy is associated with an increased risk of preterm labour and delivery. In our population, the risk of preterm labour is relatively low, and the purpose of this study was to examine the microbiological environment of the genitourinary tract to determine whether it differed from that reported in populations where the rate of preterm delivery is higher. A prospective study was made in 367 unselected women between 16 and 24 weeks' gestation. Although the rate of colonization with Candida species was higher than in most other studies (30.2%), colonization with Gardnerella, Group B Streptococcus, Trichomonas and Chlamydia was uncommon (1.9%, 0.8%, 0.6% and 3.5% respectively). Significant bacteriuria was also uncommon, occurring in only 4.9% of cases. The results of this study confirmed a relatively low incidence of colonization of the genitourinary tract in this population of women with a low incidence of preterm delivery. These findings suggest that low levels of colonization may be related to a low incidence of preterm delivery in our patients.


The role of epicardial and pericoronary adipose tissue radiomics in identifying patients with non-ST-segment elevation myocardial infarction from unstable angina.
This study aimed to ascertain if the radiomics features of epicardial adipose tissue (EAT) and pericoronary adipose tissue (PCAT) based on coronary computed tomography angiography (CCTA) could identify non-ST-segment elevation myocardial infarction (NSTEMI) from unstable angina (UA). This retrospective case-control study included 108 patients with NSTEMI and 108 controls with UA. All patients were separated into training cohort (n = 116), internal validation cohort 1 (n = 50), and internal validation cohort 2 (n = 50) based on the time order of admission. The internal validation cohort 1 used the same scanner and scan parameters as the training cohort, while the internal validation cohort 2 used different canners and scan parameters than the training cohort. The EAT and PCAT radiomics features selected by maximum relevance minimum redundancy (mRMR) and least absolute shrinkage and selection operator (LASSO) were adopted to build logistic regression models. Finally, we developed an EAT radiomics model, three vessel-based (right coronary artery [RCA], left anterior descending artery [LAD], and left circumflex artery [LCX]) PCAT radiomics models, and a combined model by combining the three PCAT radiomics models. Discrimination, calibration, and clinical application were employed to assess the performance of all models. Eight radiomics features of EAT, sixteen of RCA-PCAT, fifteen of LAD-PCAT, and eighteen of LCX-PCAT were selected and used to construct radiomics models. The area under the curves (AUCs) of the EAT, RCA-PCAT, LAD-PCAT, LCX-PCAT and the combined models were 0.708 (95% CI: 0.614-0.802), 0.833 (95% CI:0.759-0.906), 0.720 (95% CI:0.628-0.813), 0.713 (95% CI:0.619-0.807), 0.889 (95% CI:0.832-0.946) in the training cohort, 0.693 (95% CI:0.546-0.840), 0.837 (95% CI: 0.729-0.945), 0.766 (95% CI: 0.625-0.907), 0.675 (95% CI: 0.521-0.829), 0.898 (95% CI: 0.802-0.993) in the internal validation cohort 1, and 0.691 (0.535-0.847), 0.822 (0.701-0.944), 0.760 (0.621-0.899), 0.674 (0.517-0.830), 0.866 (0.769-0.963) in the internal validation cohort 2, respectively. Compared with the RCA-PCAT radiomics model, the EAT radiomics model had a limited ability to discriminate between NSTEMI and UA. The combination of the three vessel-based PCAT radiomics may have the potential to distinguish between NSTEMI and UA.


Temozolomide-perillyl alcohol conjugate induced reactive oxygen species accumulation contributes to its cytotoxicity against non-small cell lung cancer.
Temozolomide-perillyl alcohol conjugate (TMZ - POH), a novel temozolomide analog, was reported to play a cytotoxic role in triple-negative breast cancer and TMZ-resistant gliomas. In a current study we had demonstrated how TMZ - POH also exhibited its cytotoxicity against non-small cell lung cancer (NSCLC), the most common type of lung cancer, as evidence from cell/tumor proliferation inhibition, G2/M arrest, DNA damage and mitochondrial apoptosis. Importantly, TMZ - POH's cytotoxicity is closely related to reactive oxygen species (ROS) accumulation because it can be reversed by two ROS scavengers, catalase (CAT) and N-acetyl-L-cysteine (NAC). TMZ - POH induces mitochondrial transmembrane potential (MTP) decrease and ROS accumulation, in turn activates mitogen-activated protein kinase (MAPKs) signaling and mitochondrial apoptosis, and then exerts its cytotoxicity, thus proposing TMZ - POH as a potential therapeutic candidate for NSCLC.


New polymeric membrane cadmium(II)-selective electrodes using tripodal amine based ionophores.
Fabrication of PVC membrane electrodes incorporating selective neutral carriers for Cd(2+) was reported. The ionophores were designed to have different topologies, donor atoms and lipophilicity by attaching tripodal amine (TPA) units to the lipophilic anthracene (ionophore I) and p-tert-butylcalix[4]arene (ionophores II, III and IV). The synthesized ionophores were incorporated to the plasticized PVC membranes to prepare Cd(II) ion selective electrodes (ISEs). The membrane electrodes were optimized by changing types and amounts of ionic sites and plasticizers. The selectivity of the membranes fabricated from the synthesized ionophores was evaluated, the relationship between structures of ionophores and membrane characteristics were explored. The ionophore IV which composed of two opposites TPA units on the calix[4]arene compartment showed the best selectivity toward Cd(2+). The best membrane electrode was fabricated from ionophore IV (10.2 mmol kg(-1)) with KTpClPB (50.1 mol% related to the ionophore) as an ion exchanger incorporated in the DOS plasticized PVC membrane (1:2; PVC:DOS). The Cd-ISE fabricated from ionophore IV exhibited good properties with a Nernstian response of 29.4±0.6 mV decade(-1) of activity for Cd(2+) ions and a working concentration range of 1.6×10(-6)-1.0×10(-2)M. The sensor has a fast response time of 10s and can be used for at least 1 week without any divergence in potential. The electrode can be used in the pH range of 6.0-9.0. The proposed electrodes using ionophores III and IV were employed as a probe for determining Cd(2+) from the oxidation of CdS QDs solution and the real treatment waste water sample with excellent results.


Cytosine-phosphate-guanine oligodeoxynucleotides regulate the cell cycle, apoptosis, and steroidogenesis of mouse ovarian granulosa cells by targeting inhibin alpha (1 ~ 32) fragments.
Cytosine-phosphate-guanine oligodeoxynucleotides (CpG-ODNs), which exist in vertebrate, bacterial, and viral genomes, are regarded as strong immune adjuvants. To date, the biological activities of CpG-ODNs in reproduction remain unknown. Here, we investigated the effects of CpG-ODNs on the cell cycle, apoptosis, and steroidogenesis in mouse granulosa cells (mGCs), in combination with inhibin alpha (1 ~ 32) fragments. mGCs were transfected with pEGFP (containing green fluorescent protein, as a control), pEGISI (containing inhibin alpha (1 ~ 32) fragments), or pEGISI-CpG-ODNs (containing inhibin alpha (1 ~ 32) fragments and CpG-ODNs motifs) plasmid for 48 h in vitro. Our results showed that the mRNA and protein expression levels of inhibin alpha were downregulated in mGCs transfected with pEGISI-CpG-ODNs, compared to those transfected with pEGISI. Flow cytometry demonstrated that pEGISI-CpG-ODNs transfection promoted cell proliferation (for example, increasing the number of cells in S and G2 phases) and decreased apoptosis, compared to pEGISI transfection. The present study also indicated that the expression of cell cycle-related genes (cyclin D2, cyclin D3, cyclin E1, Cdk2, and Cdk6) was increased, while the expression of apoptosis-related factors (Fas, FasL, caspase-8, and caspase-3) decreased after pEGISI-CpG-ODNs treatment. Additionally, pEGISI-CpG-ODNs reversed the effect of pEGISI on the secretion of estradiol in mGCs, which was further validated by upregulating the levels of its synthesis-related factors (StAR, Cyp11a1, and 17β-HSD II). Nevertheless, pEGISI-CpG-ODNs or pEGISI did not affect the concentration of progesterone nor changed the expression levels of its synthesis-related factors (3β-HSD I and Cyp19a1). In conclusion, this study demonstrated that CpG-ODNs may affect the cell cycle, apoptosis, and steroidogenesis by targeting the effects of inhibin alpha (1 ~ 32) fragments, supporting the potential role of CpG-ODNs in the development of granulosa cells.


Intramedullary nail holes laser indicator, a non-invasive technique for interlocking of intramedullary nails.
Interlocking of intramedullary nails is a challenging procedure in orthopedic trauma surgery. Numerous methods have been described to facilitate this process. But they are exposed patient and surgical team to X-rays or involves trial and error. An accurate and non-invasive method has been provided to easily interlocking intramedullary nails. By transferring a safe visible light inside the nail, a drilling position appears which use to drilling bone toward the nail hole. The wavelength of this light was obtained from ex-vivo spectroscopy on biological tissues which has optimal transmission, reflectance, and absorption properties. Moreover, animal and human experiments were performed to evaluate performance of the proposed system. Ex-vivo performance experiments were performed successfully on two groups of cow and sheep samples. Output parameters were procedure time and drilling quality which there were significant differences between the two groups in procedure time (P < 0.05). But no significant differences were observed in drilling quality (P > 0.05). Moreover, an In-vivo performance experiment was performed successfully on a middle-aged man. To compare the provided method, targeting-arm, and free-hand techniques, two human experiments were performed on a middle-aged and a young man. The results indicate the advantage of the proposed technique in the procedure time (P < 0.05), while the drilling quality is equal to the free-hand technique (P = 0.05). Intramedullary nail holes laser indicator is a safe and accurate method that reduced surgical time and simplifies the process. This new technology makes it easier to interlocking the intramedullary nail which can have good clinical applications.


Glycolysis in human erythrocytes containing elevated concentrations of 2, 3-P2-glycerate.
In studies on the mechanism of the inhibitory effect of 2, 3-diphosphoglycerate on glycolysis in human erythrocytes, the following results were obtained: 1) Glucose consumption and lactate production are reduced by 70 and 40 per cent relative to normal erythrocytes in red blood cells containing five times the normal amount of 2, 3, -P2-glycerate ("high-diphosphoglycerate" cells) at an extracellular pH of 7.4. The marked dependency of glycolysis on the extracellular pH observed in normal erythrocytes is almost completely lost in the "high-diphosphoglycerate" cells. 2) About 50 per cent of the inhibition of glycolysis in "high-diphosphoglycerate" cells can be accounted for by the 2, 3-P2-glycerate-induced decrease of the red-cell pH. This fall of the red-cell pH which occurs as a conswquence of the Donnan effect of the non-pentrating 2, 3-P2-glycerate anion leads to a reduction of the glycolytic rate due to the properties of the enzyme phosphofructokinase. 3) The remaining part of the inhibitory effect must be attributed to an inhibition by 2, 3-P2-glycerate of glycolytic enzymes. From measurements of glycolytic rates and of the concentrations of glycolytic intermediates in the absence and presence of methylene blue it is concluded that the hexokinase reaction is inhibited by an elevation of 2, 3-P2-glycerate concentration in "high-diphosphoglycerate" cells suggests that also the enzyme pyruvate kinase is inhibited by 2, 3-P2-glycerate. 4) The dependencies of net-change of 2, 3-P2-glycerate concentration on the red-cell pH are identical in normal and "high-diphosphoglycerate" cells indicating that the balance between formation and decomposition of 2, 3-P2-glycerate is the same in erythrocytes with normal and very high compositions of 2, 3-P2-glycerate.


Efficacy and Safety of PD-1/PD-L1 Inhibitors in Advanced Hepatocellular Carcinoma: A Systematic Review and Meta-analysis.
Programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) inhibitors have been increasingly employed for the treatment of various cancers in clinical practice. This study aimed to systematically evaluate the efficacy and safety of PD-1/PD-L1 inhibitors for advanced hepatocellular carcinoma (HCC). PubMed, EMBASE, Cochrane library, Web of Science, and Abstracts of American Society of Clinical Oncology proceedings databases were searched. Objective response rate (ORR), disease control rate (DCR), median progression-free survival (PFS), median overall survival (OS), and incidence of adverse events (AEs) and drug withdrawal were pooled. Odds ratio (OR) and hazard ratio (HR) were calculated to analyze the difference in the ORR, DCR, PFS, and OS between groups. Among the 14,902 initially identified papers, 98 studies regarding use of PD-1/PD-L1 inhibitors in advanced HCC were included. Based on different criteria of response in solid tumors, the pooled ORR, DCR, and median PFS was 16-36%, 54-74%, and 4.5-6.8 months, respectively. The pooled median OS was 11.9 months. Compared to multitarget tyrosine kinase inhibitors (TKIs), PD-1/PD-L1 inhibitors monotherapy significantly increased ORR (OR 2.73, P < 0.00001) and OS (HR 0.97, P = 0.05), and PD-1/PD-L1 inhibitors combined with TKIs significantly increased ORR (OR 3.17, P < 0.00001), DCR (OR 2.44, P < 0.00001), PFS (HR 0.58, P < 0.00001), and OS (HR 0.58, P < 0.00001). The pooled incidence of all-grade AEs, grade ≥ 3 AEs, and drug withdrawal was 71%, 25%, and 7%, respectively. On the basis of the present systematic review and meta-analysis, PD-1/PD-L1 inhibitors should be the preferred treatment choice for advanced HCC owing to their higher antitumor effect and improved outcomes.


Short-term suppression of Aedes aegypti using genetic control does not facilitate Aedes albopictus.
Under permit from the National Biosafety Commission for the use of genetically modified organisms, releases of a genetically engineered self-limiting strain of Aedes aegypti (OX513A) were used to suppress urban pest Ae. aegypti in West Panama. Experimental goals were to assess the effects on a coexisting population of Ae. albopictus and examine operational parameters with relevance to environmental impact. Ae. albopictus populations were shown to be increasing year upon year at each of three study sites, potentially reflecting a broader-scale incursion into the area. Ae. albopictus abundance was unaffected by a sustained reduction in Ae. aegypti by up to 93% through repeated releases of OX513A. Males accounted for 99.99% of released OX513A, resulting in a sustained mating fraction of 75%. Mean mating competitiveness of OX513A was 0.14. The proportion of OX513A in the local environment decreased by 95% within 25 days of the final release. There was no evidence for species replacement of Ae. aegypti by Ae. albopictus over the course of this study. No unintentional environmental impacts or elevated operational risks were observed. The potential for this emerging technology to mitigate against disease outbreaks before they become established is discussed.


From classroom theory to clinical practice: evaluating the impact of a post-registration course.
This paper is concerned with the translation of bioscience theory into clinical practice. The empirical data form part of an action research study undertaken to investigate the clinical outcomes of the bioscience component of a post-registration, day release diploma in nursing taught in a higher education institution. Evidence for the impact of the course on patient care was collected by academic diary, questionnaire and interview. The triangulated data indicated that by adapting the pedagogic interpretation of the biosciences, it is possible to bridge the theory-practice gap. As a result, some nurses related the substance of the lessons to their patients, in order to bring about improvements in care. This paper examines the reasons behind the successes and failures of this continuing professional education initiative.


Presence of proteolipid protein in coelacanth brain myelin demonstrates tetrapod affinities and questions a chondrichthyan association.
The protein and glycoprotein compositions of CNS myelin from the living coelacanth (Latimeria chalumnae) were analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. An unglycosylated component of 25 kilodaltons showed substantially stronger immunoblot reactivity with antibodies against mammalian proteolipid protein (PLP) than lungfish glycosylated PLP. DM-20 (intermediate protein) was not detectable in either fish. The presence of unglycosylated PLP in CNS myelin of the actinistian coelacanth contradicts an association with cartilaginous fishes but supports tetrapod affinities closer than those of lungfish.


Ph1-negative eosinophilic leukaemia with trisomy 8. Case report and review of cytogenetic studies.
A case of eosinophilic leukaemia of the mature cell type in a 73-year-old man is described. Bone marrow chromosomes were studied in direct preparations on 3 occasions. With the G- and Q-banding techniques an extra chromosome number 8 was observed in all metaphases. There was no Ph1-chromosome. Therapy with vincristine and prednisone produced remissions but the course of the disease was accelerated. Review of the literature and study of the present case suggests that eosinophilic leukaemia like CGL may be divided into a Ph1-positive and a Ph1-negative group. In both groups karyotype abnormalities may be present and might herald a downhill course.


Poorly differentiated hepatocellular carcinoma: resection is equivalent to transplantation in patients with low liver fibrosis.
Organ allocation criteria for liver transplantation focus on tumor size and multifocality while tumor differentiation and existing liver damage are omitted. This study analyzes the impact of hepatocellular carcinoma (HCC) grade and liver fibrosis comparing resection (SX) to transplantation (LT). The National Cancer Database was queried between 2004 and 2016 for solitary HCC meeting Milan criteria undergoing SX vs LT. Two groups were created: low fibrosis (LF) vs high fibrosis (HF) and stratified by grade. Cox multivariable regression models, Kaplan-Meier survival analyses and log-rank tests were performed. 1515 patients were identified; 780 had LT and 735 had SX. Median overall survival (mOS) was 39.7 months; LT mOS was 47.9 months vs SX mOS of 34.9 months (P < .001). Multivariate analysis revealed SX, no chemotherapy, longer hospital stays, and age to be associated with worse survival. However, while transplantation conferred survival benefit for well-moderately differentiated tumors, SX vs LT did not impact survival for poorly differentiated HCC in LF patients, independent of tumor size. HCC differentiation and liver fibrosis, but not size, synergistically determine efficacy of SX vs LT. Therefore, current HCC transplantation criteria should incorporate tumor grade or liver fibrosis for optimal organ allocation.


Ginkgolide B produced endophytic fungus (Fusarium oxysporum) isolated from Ginkgo biloba.
To screen the presence of ginkgolide B-producing endophytic fungi from the root bark of Ginkgo biloba, a total of 27 fungal isolates, belonging to 6 different genus, were isolated from the internal root bark of the plant Ginkgo biloba. The fungal isolates were fermented on solid media and their metabolites were analyzed by TLC. The obtained potential ginkgolides-producing fungus, the isolate SYP0056 which was identified as Fusarium oxysporum, was successively cultured in the liquid fermentation media, and its metabolite was analyzed by HPLC. The ginkgolide B was successfully isolated from the metabolite and identified by HPLC/ESI-MS and (13)C-NMR. The current research provides a new method to produce ginkgolide B by fungal fermentation, which could overcome the natural resource limitation of isolating from the leaves and barks of the plant Ginkgo biloba.


A preliminary validation of a nutritional risk measure for the elderly.
We used data from a two-stage random sample of 401 noninstitutionalized elderly individuals residing in 18 census tracts in south-central metropolitan St. Louis to establish the reliability and validity of a 16-item nutritional risk measure. Reliability analysis yielded a Cronbach's alpha of 0.603. Concurrent predictive validity was demonstrated by the prediction of physician, emergency room, and hospital use. Individuals with high scores displayed a consistent pattern of higher rates of known nutrition-related problems and their sequelae than did those with low scores, providing evidence of known groups validity. Statistical correlations with components of an established theoretical model of the elderly's health and illness behavior demonstrate preliminary support for construct validity. The advantages of our nutritional risk measure include its ease of administration and telephone portability.


Neural correlates of manual action language: Comparative review, ALE meta-analysis and ROI meta-analysis.
Despite decades of research, the nature of the involvement of the motor system in action language processing is still controversial, and little is known about how processing action language relates to observing, imaging and executing motor actions. This study combines a systematic review of the literature, an ALE meta-analysis and a region-of-interest (ROI) meta-analysis to provide the first complete (qualitative and quantitative) account of the motor-related functional network involved in action language processing in comparison to activation reported during motor observation, motor imagery and motor execution. The review of the literature revealed that the methodology of action language studies differed considerably from the methodology of other motor-related processes which may have contributed to blurring the interpretations over the years. The ALE and ROI meta-analyses showed that the functional network of action language was more similar to observation than imagery and finally execution, following a motor gradation. Overall, our results point towards a more cognitive, as opposed to purely motoric, involvement of the motor system during action language processing.


Impact of Landscape Fire Smoke Exposure on Patients With Asthma With or Without Laryngeal Hypersensitivity.
Individuals with asthma experienced severe and prolonged symptoms after the Australian 2019 to 2020 landscape fire. Many of these symptoms, such as throat irritation, occur in the upper airway. This suggests that laryngeal hypersensitivity contributes to persistent symptoms after smoke exposure. This study examined the relationship between laryngeal hypersensitivity and symptoms, asthma control, and health impacts on individuals exposed to landscape fire smoke. The study was a cross-sectional survey of 240 participants in asthma registries who were exposed to smoke during the 2019 to 2020 Australian fire. The survey, completed between March and May 2020, included questions about symptoms, asthma control, and health care use, as well as the Laryngeal Hypersensitivity Questionnaire. Daily concentration levels of particulate matter less than or equal to 2.5 μm in diameter were measured over the 152-day study period. The 49 participants with laryngeal hypersensitivity (20%) had significantly more asthma symptoms (96% vs 79%; P = .003), cough (78% vs 22%; P < .001), and throat irritation (71% vs 38%; P < .001) during the fire period compared with those without laryngeal hypersensitivity. Participants with laryngeal hypersensitivity had greater health care use (P ≤ .02), more time off work (P = .004), and a reduced capacity to participate in usual activities (P < .001) during the fire period, as well as poorer asthma control during the follow-up (P = .001). Laryngeal hypersensitivity is associated with persistent symptoms, reports of lower asthma control, and increased health care use in adults with asthma who were exposed to landscape fire smoke. Management of laryngeal hypersensitivity before, during, or immediately after landscape fire smoke exposure might reduce the symptom burden and health impact.


Huntingtin triplet-repeat locus is stable under long-term Fen1 knockdown in human cells.
The influence of Fen1 loss on trinucleotide-repeat expansion varies between species. In yeast, loss or haploinsufficiency of the Fen1 homolog Rad27 leads to triplet expansion. In mice, haploinsufficiency of Fen1 leads to expansion of a Huntingtin locus CAG repeat. However, no expansion was seen of a (CTG)(n).(CAG)(n) repeat in a Myotonic dystrophy type 1 (DM1) knock-in model. In contrast, in Drosophila, a SCA7 CAG90 repeat was completely stable in a series of strains with mutations of DNA repair genes, among them PCNA, MutS and Fen1. In light of the apparent species dependence of triplet expansion, we have investigated in human cells the effect of Fen1 loss on the Huntingtin CAG repeat. We constructed a cell line, Fen-Rex, which in a reversible manner allows regulation of endogenous Fen1 expression, by using RNA interference (RNAi). Keeping the Fen1 protein knocked down 10-fold over 27 successive cell passages (10(17)-fold expansion in total) and measuring the Huntingtin triplet expansion by both length profiling of PCR products on PAGE gels, and cloning and sequencing of the repeat region, we find the Huntingtin locus completely stable. Our results argue against a role for Fen1 in triggering Huntingtin triplet expansion in human cells.


Two cases of lupus vulgaris in childhood and review of the clinical challenges.
Lupus vulgaris (LV) is the most common form of cutaneous tuberculosis (TB) in Europe, nevertheless the overall incidence is low. It constitutes about 1.5% of all extra-pulmonary cases worldwide. A slight raise in TB incidence rates among children was recently registered in Germany, which can be explained by the increased immigration. We present 2 cases of immigrated children who were diagnosed with Lupus vulagris, both clinically and histopathologically. Although the symptoms and the duration of the skin lesions were very different, both patients had a non-healing skin ulceration.In our cases cultures of the skin biopsy were positive for Mycobacterium tuberculosis and the lesions showed marked improvement in response to antituberculous treatment. In the first patient, it took 6 years between occurrence of skin lesions and final diagnosis. The second patient had an extracutaneous focus, namely abdominal TB. We report our experience and emphasize on recent advances in the diagnosis and treatment of paediatric skin TB.


An easy and quick implantation procedure for the measurement of myocardial wall thickness using sonomicrometry.
Ultrasonic techniques for the measurement of ventricular dimensions are widely used in acute and chronic experiments. Implantation of ultrasonic crystals is associated with reversible and irreversible myocardial damage which might limit the interpretation of the obtained results, in particular during acute experiments. We therefore developed a sonomicrometric device which can be easily and quickly implanted, and thus reduces the reversible myocardial damage induced by prolonged surgical implantation.


Active conformation of some arylpiperazine postsynaptic 5-HT(1A) receptor antagonists.
The synthesis and pharmacological properties of novel conformationally restricted arylpiperazine (2b-4b) or 1,2,3,4-tetrahydroisoquinoline (5b and 6b) derivatives of the known, flexible 5-HT(1A) receptor ligands 2a-6a (K(i)=0.95-7 nM) with different intrinsic activities are reported. Replacement of a tetramethylene chain with a 1e,4e-disubstituted cyclohexane ring in the structure of flexible ligands resulted in insignificant diminution of the 5-HT(1A) receptor affinity in the case of 2b-4b (K(i)=15-52 nM), whereas derivatives 5b and 6b were practically inactive (K(i)>1354 nM). The results of in vivo behavioural tests showed that 2a and 3a acted as postsynaptic 5-HT(1A) receptor partial agonists. Like the flexible 4a, the new rigid compounds 2b-4b showed features of postsynaptic 5-HT(1A) receptor antagonists. Since all possible conformations of the constrained compounds belong to an extended family--as indicated by molecular modelling studies--our hypothesis that such conformations are responsible for the blockade of postsynaptic 5-HT(1A) receptors has been confirmed. Determination of regions explored by terminal amide, or imide and hydrocarbon groups of the restricted compounds as well as the results of in vitro and in vivo studies allowed us to discuss the bioactive conformations of flexible ligands.


[Not Available].
The murine thymoma cell line EL-4 was used as an in vitro T-cell model to assess the immunomodulating effect of pure Ochratoxin A (OTA) and an Aspergillus ochraceus raw toxin preparation. Cytokine production (IL-2, IL-4, IL-5, IL-6) and cell viability of PMA-stimulated EL-4 cells were investigated in the presence of OTA. The cytotoxic effect of the raw toxin could be observed at lower concentrations than pure OTA. The IC50 values were 3 µg/ml and 11 µg/ml, respectively. Increasing concentrations of both OTA preparations caused an inhibition of cytokine production, but the inhibition effect of the raw toxin was stronger than of pure OTA. This is supposed to be the effect of further up to now not characterized substances in the raw toxin. Differences in the susceptibility of the mechanisms of production and regulation of each cytokine are indicated by the different concentrations for inhibition effects. Both toxin preparations showed also stimulating effects on some cytokines (IL-2 and IL-6) while others (IL-4 and IL-5) were depressed at these OTA concentrations. This indicates the immunomodulating properties of the toxin.


Answer justification in medical decision support systems based on Bayesian classification.
Answer justification refers to the ability of a computer program to explain how or why it arrived at a particular conclusion. This paper presents a new method for automated answer justification that is suitable for use in computer-supported decision aids in medicine which are based on Bayesian classification. The factors most responsible for the relative ordering of posterior probabilities of outcomes are identified by analyzing the prior and conditional probabilities used to generate them. This approach is illustrated using a computer decision aid for stroke classification and is seen to produce understandable and clinically plausible explanations.


Protein Modelling and Molecular Docking Analysis of Fasciola hepatica β-Tubulin's Interaction Sites, with Triclabendazole, Triclabendazole Sulphoxide and Triclabendazole Sulphone.
Fasciola hepatica is a globally distributed trematode that causes significant economic losses. Triclabendazole is the primary pharmacological treatment for this parasite. However, the increasing resistance to triclabendazole limits its efficacy. Previous pharmacodynamics studies suggested that triclabendazole acts by interacting mainly with the β monomer of tubulin. We used a high-quality method to model the six isotypes of F. hepatica β-tubulin in the absence of three-dimensional structures. Molecular dockings were conducted to evaluate the destabilization regions in the molecule against the ligands triclabendazole, triclabendazole sulphoxide and triclabendazole sulphone. The nucleotide binding site demonstrates higher affinity than the binding sites of colchicine, albendazole, the T7 loop and pβVII (p < 0.05). We suggest that the binding of the ligands to the polymerization site of β-tubulin can lead a microtubule disruption. Furthermore, we found that triclabendazole sulphone exhibited significantly higher binding affinity than other ligands (p < 0.05) across all isotypes of β-tubulin. Our investigation has yielded new insight on the mechanism of action of triclabendazole and its sulphometabolites on F. hepatica β-tubulin through computational tools. These findings have significant implications for ongoing scientific research ongoing towards the discovery of novel therapeutics to treat F. hepatica infections.


On the relation between extended forms of the sinusoidal perfusion and of the convection-dispersion models of hepatic elimination.
Two models of hepatic elimination, the distributed sinusoidal perfusion model, and the convection-dispersion model, are extended and then compared for first order kinetics in the steady-state. The sinusoidal perfusion model is extended by the inclusion of intrahepatic sites of mixing between sinusoids. The degree of such mixing is estimated for taurocholate elimination by isolated perfused rat livers by a comparison of anatomical and kinetic estimates of uptake heterogeneity, using previously published data. The dispersion model is generalized by the inclusion of distributions of enzyme activity along the flow. Direct comparison of the two models in the limit in which the degree of dispersion is small, allows the flow-dependence of the dispersion coefficient to be determined, thereby greatly extending the explanatory power of the convection-dispersion model. Finally, the effect of intrahepatic mixing sites on uptake by Michaelis-Menten kinetics is quantified in terms of the distributed sinusoidal perfusion model, with results which may be applicable to capillary beds in general.


Dolomite used in phosphate water treatment: Desorption processes, recovery, reuse and final disposition.
Desorption is a method that contributes to two important aspects for the sustainability of the water treatments that involve adsorption processes: a) the regeneration of the adsorbent making it reusable in several efficient cycles and, b) the recovery of the adsorbate. In previous studies, it was shown that dolomite constituted an efficient adsorbent of phosphates from aqueous solutions. Once the adsorbent saturation is achieved, it becomes useless for further uses, generating waste, a new environmental problem if it could not be properly disposed. In this work, the main objectives were to study the phosphate desorption process for the recovery and reuse of dolomite and to evaluate the possibilities of a final disposal of exhausted dolomite for agricultural soil improvement and applying the desorbed phosphate as fertilizer. The most efficient agent for the desorption process was 1 M NH4Cl. Ultrasound evidenced a negative effect on desorption. The pseudo-second order model fitted better the experimental data and the equilibrium time was 30 min. Up to four efficient adsorption-desorption cycles were obtained. Phosphate bioavailability of exhausted dolomite was assessed with autochthonous microorganisms. The obtained extracts were used in Lactuca sativa growth experiments, establishing that they are not phytotoxic and otherwise, could promote the vegetal growth.


Regional glycine receptor binding in the p,p'-DDT myoclonic rat model.
Abnormal glycinergic neurotransmission has been implicated in the pathophysiology of DDT-induced myoclonus. To examine the role of glycine receptors in the DDT model, was measured [3H]strychnine receptor binding in brainstem and spinal cord in the rat after acute administration of DDT. The highest dose of DDT tested significantly increased both Bmax (20%) and Kd (57%) of glycine sites in spinal cord but not brainstem compared to vehicle-treated controls at 4 h. Lower DDT doses, which also induced myoclonus, had no significant effects on [3H]strychnine specific binding. In vitro, 10(-7) DDT did not displace [3H]strychnine binding in naive rat spinal cord, but higher doses could not be studied due to poor solubility of DDT under the assay conditions. These data suggest that only a maximal dose of DDT has significant though mixed effects on parameters of [3H]strychnine binding in spinal cord which are not correlated with the onset of myoclonus.


Treatment of a urinoma and a post-traumatic pseudoaneurysm using selective arterial embolization.
We report a case of severe renal trauma giving rise to a pseudoaneurysm of a renal branch artery and a large urinoma secondary to fracture of a calix disconnected from the rest of the collecting system. Both conditions were successfully treated using selective arterial embolization.


Incarceration and adult weight gain in the National Survey of American Life (NSAL).
The United States has the unenviable distinction of having both the highest obesity rate among Organisation for Economic Co-operation and Development (OECD) member countries and the highest incarceration rate in the world. Further, both are socially patterned by race/ethnicity and socioeconomic position. Incarceration involves various health behaviors that could influence adult weight trajectory. We evaluated the associations between history and duration of adult incarceration and weight gain using the National Survey of American Life (N=6082 adults residing in the 48 contiguous states between February 2001 and March 2003). We propensity score-matched individuals to control for the probability of having a history of incarceration. To examine the relation between prior incarceration and adult weight gain, we fit gender-stratified generalized estimating equations controlling for propensity of incarceration history, age, education, income, race/ethnicity, and marital status. For males (N=563), incarceration was associated with about a 1.77 kg/m(2) lower gain in body mass index (BMI) during adulthood, after adjusting for age, education, income, race/ethnicity, and marital status in addition to the propensity of having a history of incarceration (95% CI: -2.63, -0.92). For females (N=286), no significant overall relationship was found between a history of incarceration and adult weight gain. In subgroup analyses among those with an incarceration history, we found no overall association between duration of incarceration and adult weight gain in men or women. In sensitivity analyses, neither tobacco smoking nor parity changed the results. The results of this study indicate that incarceration is associated with a lower transition of weight gain in males, but not in females..


Demyelination: a failure of cell communication?
A hypothesis is proposed that demyelination in both the CNS and PNS involves a failure of cell communication between the axon and oligodendrocyte/Schwann cell, as a primary event. The site of communication is assumed to be the paranodal myelin loop-axolemma membrane complex. It is postulated that "cross-talk" between the two cell types can be interrupted, and hence demyelination initiated, by pathophysiological changes in either the axon or myelinating cell. Experimental evidence in support of the hypothesis is cited in so far as it exists.


Association of Metformin Treatment with Risk for Death in Diabetic Patients with Concomitant Gastric Cancer.
Despite the existing guideline's recommendation of metformin therapy as the initial approach for managing diabetes mellitus (DM), there remains a scarcity of comprehensive documentation regarding metformin's impact on outcomes that are important for patients. The objective of this study was to assess the potential impact of metformin treatment on the risk of death in individuals diagnosed with both gastric cancer and pre-existing diabetes mellitus (DM); Design, Setting, and Participants: The study made use of a dataset encompassing nationwide health insurance claims, allowing for a retrospective analysis of all patients with a history of gastric cancer diagnosis (classified under International Classification of Diseases 10th Revision code: C16.X) spanning from 1 January 2002 to 31 December 2012. The primary objective was to observe death within a 5-year follow-up period. The study population comprised 63,664 individuals who fell into two categories: those treated with metformin (n = 29,548) and those who did not receive metformin treatment (n = 34,116). This classification was based on the initial treatment allocation following the diagnosis of gastric cancer. Metformin treatment, comorbidities, concurrent medication, and procedural information. All-cause death, disease-specific death, cardiovascular death. During the 5-year follow-up period, the metformin treatment group exhibited a lower cumulative incidence of all-cause death (27.5%) in comparison to the group not receiving metformin treatment (32.8%). Furthermore, the relative hazards for all-cause death were significantly reduced in the metformin treatment group (HR: 0.80, 95% CI 0.78-0.82), indicating a lower risk of death when compared to the non-metformin group. In addition, metformin treatment was associated with lower occurrences of disease-specific death (related to gastric cancer) and cardiovascular death when compared to the group not undergoing metformin treatment. The findings demonstrated that the use of metformin was effective at improving prognosis among gastric cancer patients documented with prior DM. In this population-based cohort study, metformin treatment was associated with reduced risk of mortality.


Antimicrobial resistance patterns of Campylobacter from feedlot cattle*.
This study examined 448 Campylobacter strains isolated in 1999 and 2000 from US feedlot cattle for resistance to 12 antimicrobials. Isolates were tested for antimicrobial susceptibility using the E-test method. Approximately 60% (n = 267) were resistant to one or more antimicrobials, and 19.6% (n = 88) were resistant to two or more antimicrobials. Of the Campylobacter jejuni isolates, 49.1% (n = 187) were resistant to tetracycline, 10.2% (n = 39) were resistant to nalidixic acid, 8.4% were resistant to trimethoprim/sulfamethoxazole, and 1.8% (n = 7) were resistant to ciprofloxacin. Resistance to any of the other eight antimicrobials was 1.3% or less, but 14.4% (n = 55) were resistant to two or more antimicrobials. In the Campylobacter coli group, 65.7% (n = 44) were resistant to tetracycline, 52.2% (n = 35) were resistant to trimethoprim/sulfamethoxazole, 22.4% (n = 15) were resistant to nalidixic acid, and 9.0% (n = 6) were resistant to ciprofloxacin. Resistance to any of the remaining eight antimicrobials was 3.0% or less, although 49.3% (n = 33) were resistant to two or more antimicrobials. Although antimicrobials are widely used in US feedlot cattle production, our results demonstrate generally low levels of resistance to a broad range of commonly used antimicrobials relative to other recent studies. Resistance data on Campylobacter isolated from this major US livestock commodity is lacking. This overview enhances current knowledge and provides a basis for further studies.


Humoral immune response of foals to experimental infection with Rhodococcus equi.
Humoral immune response to Rhodococcus equi in experimentally infected foals was studied with the enzyme-linked immunosorbent assay (ELISA) method. Class-specific antibodies were measured by ELISA in the sera of foals after intratracheal or oral inoculation with R. equi ATCC 6939 or T 48 and in the lung washings of a foal after intratracheal inoculation or of normal horses. After intratracheal or oral inoculation with R. equi, serum antibodies were first detected in immunoglobulin G (IgG) followed by IgM and IgA classes, but significant levels of IgM and IgA developed only in the foal infected intratracheally with R. equi T 48. Only the foal infected intratracheally with T 48 developed pneumonia. Anti-R. equi IgG and IgA antibodies appeared in lung washings of the intratracheally infected foal. There were differences in the antibody response to R. equi among the intratracheally infected foals, the orally infected foal and the naturally infected foal. These results suggest that the humoral immune response to R. equi may be affected by the type of R. equi strain and the route and extent of R. equi exposure.


Evaluation of the mechanism of action of albendazole on adult rat lungworm (Angiostrongyluscantonensis).
Albendazole is considered the anthelmintic of choice for the management of rat lungworm disease (neuroangiostrongyliasis), due to its broad spectrum of nematocidal activity and its ability to cross the blood-brain barrier. Albendazole binds to β-tubulins, preventing their polymerization into microtubules, thereby corrupting the cascade of cell division at metaphase, which ultimately leads to the death of individual cells and eventually the death of the parasite. Inhibition of microtubule formation will also hinder the axoplasmic transport system, affecting the neuronal activities of the parasite. While this mechanism has been explicated in other parasitic and non-parasitic nematodes, it has never been evaluated in Angiostrongylus cantonensis. This study evaluates the antimitotic effects of albendazole sulphoxide (active metabolite) on the microtubules of adult A. cantonensis using the tubulin polymerization assay and measures its effects on worm viability using the colorimetric MTT assay. Three different concentrations of albendazole (62.5 μM, 250 μΜ, and 1 mM) were evaluated. We saw a statistically significant dose-dependent reduction in the band intensity of polymerized tubulins (or microtubules) (P = 0.019), suggesting that albendazole imparts its antimitotic effect in a dose-dependent manner. Similarly, our MTT assay showed a dose-dependent decrease in formazan intensity (proportional to cell viability), suggesting that the rate of nematocidal activity of albendazole is also proportional to its concentration. In compiling the results from both these experiments, a correlation between the microtubule assembly and worm viability is evident.


Novel CCR1 antagonists with oral activity in the mouse collagen induced arthritis.
Cinnamides as novel CCR1 antagonist chemotypes are described with high affinity to human and rodent receptors. A1B1 and A4B7 showed oral activity in the mouse collagen induced arthritis.


Azole Derivatives: Recent Advances as Potent Antibacterial and Antifungal Agents.
Azoles are the famous and widespread scaffold in the pharmaceutical industry due to their wide range of activities, high efficacy, good tolerability, and oral availability. Furthermore, azole derivatives have attracted attention as potent antimicrobial agents. The purpose of this review is to provide an overview of pharmacological aspects of the main scaffolds of azoles, including imidazole, benzimidazole, triazole, and tetrazole, which possess antimicrobial activity, reported from 2016 to 2020, as well as all of our publication in this field. In addition, we discuss the relationship between structure and activity and molecular docking studies of the azole derivatives to provide critical features and valuable information for the synthesis of novel azole compounds with desirable biological activities. The presented structures in this review have been tested against several bacteria and fungi, such as E. coli and C. albicans, which have been common in all of these studies. A comparison of the reported MIC for tested compounds showed fluconazole base structures as the most active antifungal agents, and triazole derivatives bearing nitrophenyl and coumarin moieties to have the most dominant antibacterial activity. Triazole and imidazole scaffolds are more important for designing antimicrobial compounds than other azole derivatives, like benzimidazole or tetrazole. All the most active compounds were observed to fulfill the Lipinski rule.


Two-year clinical outcomes of triple therapy with photodynamic therapy, anti-vascular endothelial growth factor agent, and triamcinolone acetonide for neovascular age-related macular degeneration.
To analyze the 2-year treatment outcomes of triple therapy with standard-fluence photodynamic therapy (PDT), intravitreal injection of ranibizumab (IVR)/aflibercept (IVA), and sub-tenon injection of triamcinolone acetonide (STTA) for neovascular age-related macular degeneration (nAMD) in Japanese patients. A retrospective, clinical case-series study. Forty-four eyes of 44 patients with treatment-naïve nAMD followed for more than 24 months were evaluated. Initial treatment was given with triple therapy and retreatment with IVR/IVA as a pro re nata regimen. Best-corrected visual acuity (BCVA), central retinal thickness (CRT), the number of treatments, and intraocular pressure elevation were analyzed. The mean age was 73.3 ± 10.0 years. The mean BCVA significantly improved from 0.61 ± 0.30 at baseline to 0.50 ± 0.46 at 24 months (p = 0.034). CRT significantly improved from 373 ± 162 μm at baseline to 200 ± 107 μm at 24 months (p < 0.001). The number of treatments given during the 2-year treatment period was 2.7 ± 1.8. No retreatments were necessary in 18 of 44 eyes (40.9%), with no significant difference between IVR (46.4%) or IVA (31.3%) used during the 2-year follow-up of triple therapy (p = 0.51). Four eyes (9.1%) temporarily required glaucoma eye drop treatments. In nAMD patients, induction treatment with triple therapy resulted in approximately 40% of the patients requiring no retreatment for 2 years. The type of anti-VEGF agents used made no difference in the results.


The outcomes of lung transplantation in patients with bronchiectasis and antibody deficiency.
Lung transplantation is an established treatment for end-stage bronchiectasis. A proportion of patients with bronchiectasis have an associated antibody deficiency. This group benefits from immunoglobulin replacement therapy, but the outcome of lung transplantation is not known. We conducted a retrospective observational study of all who received a transplant for bronchiectasis at our unit. We compared the survival after transplant, number of infective and rejection episodes, and the change in forced expiratory volume in 1 second (FEV1). Five of the 37 patients identified with bronchiectasis had an antibody deficiency that required immunoglobulin replacement therapy. Actuarial survival was similar in the 2 groups, being 81% at 12 months in the Bronchiectasis Group and 80% in the Antibody Deficiency Group. The FEV1 at 12 months after transplantation was similar in each group, with a predicted mean +/- SD FEV1 of 83.7% +/- 24.2% in those with bronchiectasis and 83.0% +/- 30.4% in those with antibody deficiency as well. The infection and rejection rates in the first year after transplantation were lower in the Antibody Deficiency Group. Infection episodes per 100 patient-days for bronchiectasis alone were 0.90 vs 0.53 and rejection episodes per 100 patient-days were 0.59 vs 0.24. There was no evidence that transplant recipients with bronchiectasis and antibody deficiency have a worse prognosis than those with bronchiectasis alone.


More is needed-Thousands of loci are required to elucidate the relationships of the 'flowers of the sea' (Sabellida, Annelida).
Sabellida is a well-known clade containing tube-dwelling annelid worms with a radiolar crown. Iterative phylogenetic analyses over three decades have resulted in three main clades being recognized; Fabriciidae, Serpulidae and Sabellidae, with Fabriciidae proposed as the sister group to Serpulidae. However, relationships within Sabellidae have remained poorly understood, with a proliferation of genera. In order to obtain a robust phylogeny with optimal support, we conducted a large-scale phylogenomic analysis with 19 new sabellid transcriptomes for a total of 21 species. In contrast to earlier findings based on limited DNA data, our results support the position of Fabriciidae as sister taxon to a Sabellidae + Serpulidae clade. Our large sampling within Sabellidae also allows us to establish a stable phylogeny within this clade. We restrict Sabellinae to a subclade of Sabellidae and broaden the previously monotypic Myxicolinae to include Amphicorina and Chone. We tested the robustness of species tree reconstruction by subsampling increasing numbers of genes to uncover hidden support of alternative topologies. Our results show that inclusion of more genes leads to a more stable topology with higher support, and also that including higher divergence genes leads to stronger resolution.


Response to dietary dilution in an omnivorous freshwater turtle: implications for ontogenetic dietary shifts.
Several species of freshwater turtles in the family Emydidae undergo an ontogenetic dietary shift; as juvenile turtles mature, they change from a primarily carnivorous to a primarily herbivorous diet. It has been hypothesized that this shift results from an unfavorable ratio of gut capacity to metabolic rate that prevents small reptiles from processing adequate volumes of plant material to meet their energetic demands. Effects of dietary dilution on intake were evaluated in two size classes of red-eared sliders (Trachemys scripta elegans) to test whether small reptiles have a lower capacity to compensate for low-quality diets through increased intake than do larger conspecifics. Artificial diets with an inert diluent were offered to two size classes of turtles, and mass-specific intakes of dry matter, energy, and nitrogen were calculated. Both small (28.7+/-4.9 g body mass, mean mass+/-SD) and large (1,230+/-94 g body mass) turtles compensated for dietary dilution and maintained constant energy and nitrogen intakes on diets with lower energy content than common aquatic plants. Thus, body size did not affect the ability to respond to nutritional dilution, which suggests that processing limitations imposed by small body size do not constrain juveniles from adopting an herbivorous diet.