Retrospective analysis of the effectiveness of functional endoscopic sinus surgery in the treatment of adult chronic rhinisinusitis refractory to medical treatment.
Chronic rhinosinusitis (CRS) is a common disease that restricts the quality of life of millions of involved patients. The aim of the study was to evaluate how functional endoscopic sinus surgery (FESS) modifies patients symptom profile and to also confirm that FESS is the modality of treatment in patients with refractory CRS. The study was retrospective analysis. 105 patients with symptoms of CRS were included in the study (between August 2006 to July 2009). Patients were assessed for CRS symptoms preoperatively and postoperatively using grading symptoms. Statistical analysis using Chi square test. Leading symptom of CRS was nasal obstruction followed by headache. Furthermore patients reported of anosmia, facial pressure, postnasal drip, purulent nasal discharge, halitosis, dental pain, cough, earache. None of the patients had fever as their complaint. After a postoperative followup of 6 months there was improvement in the symptoms. All minor symptoms had 100% improvement. Nasal obstruction responded best, next followed by (all symptoms P value <0.001). An overall improvement of 86.66% was recorded. The restriction of quality of life in patients with CRS is mainly caused by these symptoms, which can be improved in excellent fashion by FESS in majority of the patients.


Effect of exogenous nitric oxide on antioxidative system and S-nitrosylation in leaves of Boehmeria nivea (L.) Gaud under cadmium stress.
Cadmium (Cd)-induced growth inhibition is one of the primary factors limiting phytoremediation effect of Boehmeria nivea (L.) Gaud in contaminated soil. Sodium nitroprusside (SNP), a donor of nitric oxide (NO), has been evidenced to alleviate Cd toxicity in many plants. However, as an important mechanism of NO in orchestrating cellular functions, S-nitrosylation is still poorly understood in its relation with Cd tolerance of plants. In this study, higher exogenous NO levels were found to coincide with higher S-nitrosylation level expressed as content of S-nitrosothiols (SNO). The addition of low concentration (100 μM) SNP increased the SNO content, and it simultaneously induced an alleviating effect against Cd toxicity by enhancing the activities of superoxide dismutase (SOD), ascorbate peroxidase (APX), and glutathione reductase (GR) and reduced the accumulation of H2O2 as compared with Cd alone. Application of S-nitrosoglutathione reductase (GSNOR) inhibitors dodecanoic acid (DA) in 100 μM SNP group brought in an extra elevation in S-nitrosylation level and further reinforced the effect of SNP. While the additions of 400 μM SNP and 400 μM SNP + 50 μM DA further elevated the S-nitrosylation level, it markedly weakened the alleviating effect against Cd toxicity as compared with the addition of 100 μM SNP. This phenomenon could be owing to excess consumption of glutathione (GSH) to form SNO under high S-nitrosylation level. Therefore, the present study indicates that S-nitrosylation is involved in the ameliorating effect of SNP against Cd toxicity. This involvement exhibited a concentration-dependent property.


Management of marmosets for biomedical research.
The management of a successful breeding colony of common marmosets, Callithrix jacchus, is described, including details of treatment during the conditioning period after arrival from the wild. Methods are described for the collection of blood, urine, and vaginal washings. Suggestions are made for improving the conditions of importation of these animals from South America.


Heparinizable graft copolymers from chlorosulphonated polyethylene with poly(amido-amine) segments.
The synthesis and the physical characterization of three graft copolymers (PES/PAA) obtained from chlorosulphonated polyethylene (PECS) and three different secondary amino end-capped poly(amido-amine)s are reported. The properties of these heparinizable materials appear to be suitable for constructing prosthetic devices for biomedical use. The heparin adsorbing ability and the stability of the complex with heparin of the three copolymers have been evaluated, by means of biological tests, as activated Partial Thromboplastin Time (PTT) and Thrombin Time (TT).


Air-side ammonia stripping coupled to anaerobic digestion indirectly impacts anaerobic microbiome.
Air-side stripping without a prior solid-liquid phase separation step is a feasible and promising process to control ammonia concentration in thermophilic digesters. During the process, part of the anaerobic biomass is exposed to high temperature, high pH and aerobic conditions. However, there are no studies assessing the effects of those harsh conditions on the microbial communities of thermophilic digesters. To fill this knowledge gap, the microbiomes of two thermophilic digesters (55°C), fed with a mixture of pig manure and nitrogen-rich co-substrates, were investigated under different organic loading rates (OLR: 1.1-5.2 g COD l-1 day-1 ), ammonia concentrations (0.2-1.5 g free ammonia nitrogen l-1 ) and stripping frequencies (3-5 times per week). The bacterial communities were dominated by Firmicutes and Bacteroidetes phyla, while the predominant methanogens were Methanosarcina sp archaea. Increasing co-substrate fraction, OLR and free ammonia nitrogen (FAN) favoured the presence of genera Ruminiclostridium, Clostridium and Tepidimicrobium and of hydrogenotrophic methanogens, mainly Methanoculleus archaea. The data indicated that the use of air-side stripping did not adversely affect thermophilic microbial communities, but indirectly modulated them by controlling FAN concentrations in the digester. These results demonstrate the viability at microbial community level of air side-stream stripping process as an adequate technology for the ammonia control during anaerobic co-digestion of nitrogen-rich substrates.


Propolis extract and oregano essential oil as biofungicides for garlic seed cloves: in vitro assays and synergistic interaction against Penicillium allii.
This study aimed to evaluate in vitro individual and combined antifungal activity of propolis extract (PE) and oregano essential oil (OEO) against Penicillium allii, causal agent of blue mould disease. The chemical characterization of both products was also included. Chromatographic analysis of PE and OEO confirmed the presence of bioactive compounds. The antifungal susceptibility assays showed that PE and OEO were highly active against the mycelial growth and conidial germination of P. allii. PE and OEO MICs were 12·5 and 1·5 μl ml-1 , respectively. The MFCs of these products were 50 and 3·1 μl ml-1 , respectively. PE acted mainly through diffusion, while OEO acted by a mixed contribution of vapour and diffusion. Synergism and additive effect between both products were found in some combination ratios. PE and OEO, both natural products with different chemical composition, have a strong antifungal activity against P. allii and show a favourable interaction causing synergism. The results of this study indicated the potential use of PE combined with OEO as a non-conventional strategy towards the formulation of a biofungicide to control blue mould disease in garlic seed-cloves.


Simultaneous determination of tazarotene, clindamycin phosphate and their active metabolites in Bama mini-pig skin by LC-MS/MS: Application to the development of a tazarotene/clindamycin phosphate cream.
Topical tazarotene combined with clindamycin phosphate can significantly improve the adherence and outcomes for the treatment of acne vulgaris than monotherapy, a novel tazarotene (0.05%)/clindamycin phosphate (1.2%) cream is thus developed. However, the pharmacokinetics and potential interaction of tazarotene and clindamycin phosphate in skin when formulated together remain unknown, which should be investigated to assess this novel cream. In the present work, a sensitive and rapid LC-MS/MS method for simultaneous determination of tazarotene, clindamycin phosphate and their active metabolites tazarotenic acid, clindamycin in Bama mini-pig skin was developed and reported for the first time. After pretreatment of the skin samples, the analytes were well separated on a Hypersil BDS C8 column (4.6 × 100 mm, 2.4 μm) using 0.2% (v/v) formic acid-0.1% (w/v) ammonium acetate water solution and acetonitrile as mobile phase in linear gradient elution. Quantification of tazarotene, clindamycin phosphate and their active metabolites tazarotenic acid, clindamycin was conducted under positive electrospray ionization mode using multiple reactions monitoring detection. The LC-MS/MS method was fully validated and then applied to the dermal pharmacokinetic study of the tazarotene/clindamycin phosphate cream. According to the obtained results, tazarotene and clindamycin phosphate did not have any drug-drug interaction when they were formulated together in the cream for topical application. Their absorption and metabolism features in the skin were also characterized, which can support the clinical medication regimen of tazarotene/clindamycin phosphate cream.


The Serendipitous Story of Sildenafil: An Unexpected Oral Therapy for Erectile Dysfunction.
The serendipitous discovery of sildenafil (Viagra [sildenafil citrate]) as a treatment for erectile dysfunction (ED) is one of the most fascinating drug development stories of our time. When sildenafil was approved by the U.S. Food and Drug Administration in 1998, it revolutionized the treatment protocol for men with ED, once considered a psychological issue or an inevitable part of aging. To review the discovery of sildenafil and its role in changing the field of sexual medicine in the context of the epidemiology and history of treatment for ED. For this narrative review, a literature search was conducted to identify essential articles and was supplemented by author observations from a historical perspective. A broad overview of ED and its past, current, and future treatments. ED is a prevalent condition for which medical treatment had been limited to genitally localized interventions, including surgery, vacuum pumps, injectable therapies, and intraurethral suppositories. The discovery of sildenafil provided a safe, oral pharmacotherapy for the treatment of ED, sparking greater understanding of the science behind ED and its role in men's overall health. The approval of sildenafil initiated a global conversation about ED that had profound implications for patients, methods of clinical practice, and academic sexual medicine. These changes will catalyze continued advances in ED treatment. Goldstein I, Burnett AL, Rosen RC, et al. The serendipitous story of sildenafil: an unexpected oral therapy for erectile dysfunction. Sex Med Rev 2019;7:115-128.


Results of laser treatment-PRP to the diabetic retinopathy.
Diabetic retinopathy-(DR) presents the most aggressive form of the retinopathy that has progressive movement and often it ends with optic-atrophic blindness end includes heavy complications unless carried out by laser pan-retinal-photocoagulation. The aim of this study was analyzing the diabetic retinopathy and impact of the PRP laser treatment, proposition of the precautious as well to managing the complications and PDR prevention. In this study were presented the treatment results of diabetic retinopathy treated in the Eye's Clinic in Prishtina, during the period of time (2004-2009). There were examined and diagnosed 42 patients with DR of whom 24 males or (57.14%) and 18 females or (42.85%). In 18 patients or (27%) we have had improvement, in 35 cases or (53%) stabilization and 13 cases or (20%) worsening of state after laser treatment with PRP to DR. The most frequently complications were vitreous hemorrhage in 5 cases or (38.46%) and blindness in 3 cases or (23.07%). There have been used statistical methods of processing and analysis according to the WHO standards. We consider that through an advanced education and research programs for inovative projects that meet criterias of our strategic targets to protecting the retina and optic-nerv by understanding DR and PDR and developing a better laser treatment and accurately monitoring of DM, we can manage to prevent complications and heavy consequences of DR. In order to achieve this aim we have to work hard to standardized protocols.


5'-Nitro-indirubinoxime, an indirubin derivative, suppresses metastatic ability of human head and neck cancer cells through the inhibition of Integrin β1/FAK/Akt signaling.
Head and neck cancer is a malignant cancer and has the high infiltrative potential leading to metastasis. The objective of the study was to investigate the effects of 5'-nitro-indirubinoxime (5'-NIO), an indirubin derivative, on metastasis of head and neck cancer cells and to explore the underlying molecular mechanisms involved in this process. After treatment of head and neck cancer cells with 5'-NIO, cell metastatic behaviors such as colony formation, invasion, and migration were inhibited in a concentration-dependent manner. 5'-NIO inhibited the beta1 Integrin/FAK/Akt pathway which can then facilitate invasion and/or migration of cancer cells through the extracellular matrix (ECM). Moreover, treatment of head and neck cancer cell with Integrin β1 siRNA or FAK inhibitor effectively inhibited the invasion and migration, suggesting their regulatory role at invasiveness and migratory of head and neck cancer cells. In vivo CAM assay, treatment with 5'-NIO reduced the angiogenesis in FaDu cells xenograft fertilized chicken eggs, primarily by inhibiting expression of VEGF. We conclude that 5'-NIO inhibits the metastatic ability of head and neck cancer cells by blocking the Integrin β1/FAK/Akt pathway.


Cu-Mediated Amination of (Hetero)Aryl C-H bonds with NH Azaheterocycles.
Direct synthesis of N-(hetero)arylated heteroarenes has been realized through Cu-mediated C-N coupling of NH azaheterocycles with aryl C-H bonds under aerobic conditions. This method features a broad scope of both heterocyclic arenes (pyridine, quinoline, pyrazole, imidazole, furan, thiophene, benzofuran, and indole) and NH azaheterocycles (imidazole, pyrazole, indole, azindole, purine, indazole, benzimidazole, pyridone, carbazole), providing a versatile method for the synthesis of pharmaceutically important N-(hetero)arylated heteroarenes. The versatility of this reaction was further demonstrated through late-stage modification of marketed drugs and the synthesis of a key intermediate for accessing a class of angiotensin II receptor 1 antagonists.


Percutaneous aspiration and sclerotherapy of a giant simple hepatic cyst causing obstructive jaundice: A case report and review of literature.
Giant simple hepatic cysts causing intrahepatic duct dilatation and obstructive jaundice are uncommon. A variety of measures with different clinical efficacies and invasiveness have been developed. Nonsurgical management, such as percutaneous aspiration and sclerotherapy, is often applied. The case is a 39-year-old female with a 5-mo history of cutaneous and scleral icterus, loss of appetite, and dark urine. Lab tests showed jaundice and liver function abnormalities. Imaging revealed a giant simple hepatic cyst obstructing the intrahepatic bile ducts. A combination of percutaneous catheter aspiration and lauromacrogol sclerotherapy was successfully performed and the effects were satisfactory with the size of cyst decreasing from 13.7 cm × 13.1 cm to 3.0 cm × 3.0 cm. Further literature review presented the challenges of managing giant simple hepatic cysts that cause obstructive jaundice and compared the safety and efficacy of a combination of percutaneous aspiration and lauromacrogol sclerotherapy with other management strategies. Giant simple hepatic cysts can cause obstructive jaundice, and a combination of percutaneous catheter aspiration and sclerotherapy with lauromacrogol are suggested to treat such cases.


Biosynthesis, processing, and secretion of M and Z variant human alpha 1-antitrypsin.
The Z genetic variant of human alpha 1-antitrypsin (alpha 1AT) is associated with decreased serum alpha 1AT levels, hepatic inclusion bodies, and an increased risk of lung and liver disease. We studied the biosynthesis, processing, and secretion of normal and Z variant alpha 1AT in cell-free translation systems, reconstituted in vitro processing systems, and in the Xenopus oocyte secretory system. Human liver mRNA was prepared from normal subjects (PiMM) and from individuals homozygous for alpha 1AT deficiency (PiZZ). Cell-free translation resulted in the synthesis of 49,000-Da preproteins with a 23-amino acid signal sequence. The genetic variants were synthesized at comparable levels and could be distinguished on the basis of charge. The majority of the amino acids in the ZZ signal peptide were identified and found to be the same as those comprising the MM signal sequence. These proteins were co-translationally processed with similar efficiency by dog pancreas microsomes, producing 52,000-Da glycoproteins which were completely translocated across the endoplasmic reticulum membrane. When the human liver RNA preparations were injected into Xenopus oocytes, both of the alpha 1AT variants were synthesized intracellularly and alpha 1AT was detected in the medium of all oocytes injected with MM RNA. However, the Z variant accumulated within the microsomal vesicles of the cell and was undetectable or present at decreased levels in the medium. We conclude that the single amino acid substitution in the Z variant of alpha 1AT does not affect its synthesis or co-translational processing but that it strongly affects its transport from the rough endoplasmic reticulum through the secretory pathway.


Ureterosigmoidostomy: an outdated approach to bladder exstrophy?
Long-term results among 46 children with ureterosigmoidostomy are presented. The indication for ureterosigmoidostomy had been bladder exstrophy in 40 patients, incontinent epispadias in 5 and neurogenic bladder dysfunction in 1. Of the 40 patients with bladder exstrophy 8 had undergone ureterosigmoidostomy after failure of other types of urinary tract reconstruction (6 had upper tract dilatation before ureterosigmoidostomy). Three patients with previously damaged upper urinary tracts required early postoperative conversion because of severely increasing kidney dilatation. Three other patients required conversion after a mean of 10 years to preserve kidney function. One patient died after 16 years of a cause not related to ureterosigmoidostomy. The remaining 39 patients were alive with a functioning ureterosigmoidostomy after a mean followup of 14.7 years. The daytime continence rate was 97.4% (38 of 39 patients) and the complete continence rate was 92.3% (36 of 39). Except for 1 tubular adenoma that was removed successfully during routine colonoscopy, no bowel neoplasia has been observed. None of the 45 living patients has renal insufficiency.


Nighttime sleep benefits the prospective component of prospective memory.
Studies suggest that sleep benefits event-based prospective memory, which involves carrying out intentions when particular events occur. Prospective memory has a prospective component (remembering that one has an intention), and a retrospective component (remembering when to carry it out). As effects of sleep on retrospective memory are well established, the effect of sleep on prospective memory may thus be due exclusively to an effect of sleep on its retrospective component. Therefore, the authors investigated whether nighttime sleep improves the prospective component of prospective memory, or a retrospective component, or both. In a first session, participants performed an event-based prospective-memory task (that was embedded in an ongoing task) 3 minutes after forming an intention and, in a second session, 12 hours after forming an intention. The sessions were separated by either nighttime sleep or daytime wakefulness. The authors disentangled prospective-memory performance into its retrospective and prospective components via multinomial processing tree modeling. There was no effect of sleep on the retrospective component, which may have been due to a time-of-day effect. The prospective component, which is the component unique to prospective memory, declined less strongly after a retention interval filled with sleep as compared with a retention interval filled with wakefulness. A hybrid interaction suggested that refreshed attention after sleep may account for this effect, but did not support the consolidation of the association between the intention and its appropriate context as a mechanism driving the effect.


Graphene from amorphous titanium carbide by chlorination under 200 °C and atmospheric pressures.
The synthesis of graphene via decomposition of SiC has opened a promising route for large-scale production of graphene. However, extremely high requirements for almost perfectly ordered crystal SiC and harsh process conditions such as high temperatures (>1200 °C) and ultra-high vacuum are two significant challenges hindering its wide use to synthesize graphene by decomposition of SiC. Here, we show that the readily available precursor of carbides, amorphous TiC (a-Ti(1-x)C(x)), can be transformed into graphene nanosheets (GNS) with tunable layers by chlorination method at very low temperatures (200 °C) and ambient pressures. Moreover, freestanding GNS can be achieved by stripping off GNS from the surface of resulting particles. Therefore, our strategy, the direct transformation of a-Ti(1-x)C(x) into graphene, is simple and expected to be easily scaled up.


Novel, highly potent systemic glucokinase activators for the treatment of Type 2 Diabetes Mellitus.
Glucokinase (GK, hexokinase IV) is a unique hexokinase that plays a central role in mammalian glucose homeostasis. Glucose phosphorylation by GK in the pancreatic β-cell is the rate-limiting step that controls glucose-stimulated insulin secretion. Similarly, GK-mediated glucose phosphorylation in hepatocytes plays a major role in increasing hepatic glucose uptake and metabolism and possibly lowering hepatic glucose output. Small molecule GK activators (GKAs) have been identified that increase enzyme activity by binding to an allosteric site. GKAs offer a novel approach for the treatment of Type 2 Diabetes Mellitus (T2DM) and as such have garnered much attention. We now report the design, synthesis, and biological evaluation of a novel series of 2,5,6-trisubstituted indole derivatives that act as highly potent GKAs. Among them, Compound 1 was found to possess high in vitro potency, excellent physicochemical properties, and good pharmacokinetic profile in rodents. Oral administration of Compound 1 at doses as low as 0.03mg/kg led to robust blood glucose lowering efficacy in 3week high fat diet-fed mice.


Lipemic and lipoproteinemic effects of natural and synthetic androgens in humans.
Testosterone cypionate administration in weight-trained subjects reduced serum high-density lipoprotein cholesterol (HDL-C) levels without affecting the total cholesterol (Total-C)/HDL-C ratio. Nandrolone decanoate administration also reduced HDL-C levels, but elevated the Total-C/HDL-C ratio. These findings could not be attributed to changes in exercise patterns, dietary intake, or alcohol consumption. It is concluded that the synthetic androgen employed in this study produced a worsening of potential lipid-related risk factors for ischemic heart disease and that exogenous testosterone has a much less pronounced effect on such risk factors.


Is follow-up still mandatory more than 5 years after surgery for colorectal cancer?
The aim of this study was to assess if to prolong follow-up (FU) more than 5 years after surgery for colorectal cancer (CRC) is justified or not. Patients who underwent surgery for a CRC before 2013 and without any tumor recurrence (or synchronous metastases) during the first 5 years after surgery were identified from our database and included. Between 1996 and 2012, 121 patients operated for rectal (RC) (median of FU of 84 months; range 60-211) and 97 with colonic cancer (CC) (median of FU of 78 months; range 60-139), without any tumor recurrence (or synchronous metastases) during the first 5 years after surgery, presented a late tumor recurrence: 13/121 RC (10.7%) versus 2/97 CC (2.1%) (p = 0.014); 8/13 recurrences in RC (61.5%) were observed after neoadjuvant radiochemotherapy, and 9/13 (69.2%) in pN0 tumors. Among the 13 recurrences, 3 had both local and metastatic recurrences (23%), 5 an isolated local recurrence (38.5%) and 5 an isolated metastatic recurrence (38.5%). After surgery for CC, the 2 recurrences were observed in patients with T3N0 tumors. After surgery for a CRC, in patients without tumor recurrence during the first 5 years after surgery, follow-up after 5 years must be continued in rectal cancer patients because of a 10.7% rate of late recurrence. On the opposite, after surgery for colon cancer the 2% rate of late recurrence after 5 years suggested that only patients with pT3-T4 colonic cancer could probably be followed more than 5 years after surgery.


Pharmacokinetics of pralidoxime chloride in the rat.
The pharmacokinetics of pralidoxime chloride (2-PAM) was studied in rats. Different groups of rats were given an intramuscular injection of 2-PAM at one of three doses (20, 40, or 80 mg/kg). This range of doses is used commonly in studies concerned with the efficacy of 2-PAM against poisoning by potent organophosphorus inhibitors of cholinesterase enzyme. Individual, sequential blood samples were collected during the course of the experiment. From these blood samples the plasma concentrations of 2-PAM were determined over time for each animal. Next the relationship of plasma concentration to time was expressed in terms of a standard pharmacokinetic model. Estimates of various pharmacokinetic parameters were calculated using an open, one-compartment model: volume of distribution (Vd), maximal plasma concentration (Cmax), elimination rate constant (k10), absorption rate constant (k01), area under the curve (AUC) and clearance (CL). Of the pharmacokinetic estimates, only Cmax and AUC were found to be statistically significant (p less than 0.0001) when compared across all the doses; these pharmacokinetic estimates were highly correlated with doses with r = 0.998 and r = 0.997, respectively. However, when AUC and Cmax were normalized by dividing through by dose, no significant differences were found in the transformed data. The results of this study in rat indicate that the pharmacokinetics of 2-PAM is linearly related to dose in a range employed in therapeutic studies of 2-PAM.


Survival of Left-to-Right Shunt Repair in Children with Pulmonary Arterial Hypertension at a Tertiary Hospital in a Low-to-Middle-Income Country.
In low-to-middle-income countries, repair of the left-to-right shunts congenital heart disease (CHD) are often done with existing pulmonary arterial hypertension (PAH). Long-term outcomes data of this condition in either low-to-middle or high-income countries are limited. We conducted a study to evaluate the outcomes of children with PAH related to left-to-right shunt CHD who underwent surgical or transcatheter repair. All cases of PAH related to left-to-right shunt CHD repairs from 2015-2018 were retrospectively reviewed with additional new patients who underwent repair within our study period (2019-2020). Cases with complex congenital heart disease and incomplete hemodynamic echocardiography or catheterization measurements were excluded. Kaplan-Meier curves, log-rank test, Cox regression with Firth's correction and restricted mean survival time were used for survival analysis. Of the 118 patients, 103 patients were enrolled and 15 patients were excluded due to complex congenital heart disease and missing hemodynamic measurements prior to repair. Overall, median age at intervention was 44 months, mPAP mean was 43.17 ± 16.05 mmHg and Pulmonary Vascular Resistance index (PVRi) mean was 2.84 ± 2.09 (WU.m2). Nine patients died after repair. The survival rate for patients with PAH-CHD at 1 day, 30 days and 1400 days (4 years) was 96.1%, 92.1%, and 91.0% respectively. Patients with persisting PAH after correction had -476.1 days (95% confidence interval [CI]: -714.4, -237,8) shorter survival over 4 years of follow up compared to patients with reversed PAH. PVRi was found to be the influencing covariate of the difference of restricted mean survival time between these groups. In low-to-middle income settings, with accurate PAH reversibility assessment prior to intervention, repair of left-to-right shunt CHD with existing PAH in children has a favourable outcome. Inferior survival is found in patients with persistence of PAH. PVRi at baseline predicts between-group survival difference.


The Arg473Cys-neuroligin-1 mutation modulates NMDA mediated synaptic transmission and receptor distribution in hippocampal neurons.
Synapses mediate communication between neurons, thus playing a fundamental role in information processing in the CNS. Neuroligins form a family of heterophilic synaptic cell adhesion molecules, and neuroligin 1 (NL1) has been shown to be involved in the formation of excitatory synapses and have been suggested to associate indirectly with NMDA receptors by common binding to PSD95. A mutation in neuroligin 3 (Arg451Cys-NL3, human sequence numbering) identified in autistic patients is associated with altered spine density and has reduced binding capacity for its presynaptic partner beta-neurexin. Here, we investigated the role of NL1 and the homologous NL1 mutation Arg473Cys-NL1 (R473C-NL1) in excitatory synaptic transmission and NMDA receptor distribution. We demonstrate that R473C-NL1, when expressed in cultured hippocampal neurons, can induce a dramatic increase in NMDA current amplitude and that this change is accompanied by NMDA receptor clustering in the postsynaptic cell.


Simultaneous polarographic determination of 2-nitrophenol and 4-nitrophenol by differential pulse polarography method and support vector regression.
A differential pulse polarography (DPP) for the simultaneous determination of 2-nitrophenol and 4-nitrophenol was proposed. It was found that under optimum experimental conditions (pH = 5, scan rate = 5 mV/s, pulse amplitude = -50 mV), 2-nitrophenol and 4-nitrophenol had well-defined polarographic reduction waves with peak potentials at -317 and -406 mV, respectively. In the mixture of two compounds overlapping polarographic peaks were observed. In this study, support vector regression (SVR) was applied to resolve the overlapped polarograms. Furthermore, a comparison was made between the performance of SVR and partial least square (PLS) on data set. The results demonstrated that SVR is a better well-performing alternative for the analysis and modeling of DPP data than the commonly applied PLS technique. The proposed method was used for the determination of 2-nitrophenol and 4-nitrophenol in industrial waste water.


Accelerated degradation of cellulose in silkworm excrement by the interaction of housefly larvae and cellulose-degrading bacteria.
The environmental pollution caused by silkworm (Bombyx mori) excrement is prominent, and rich in refractory cellulose is the bottleneck restricting the efficient recycling of silkworm excrement. This study was performed to investigate the effects of housefly larvae vermicomposting on the biodegradation of cellulose in silkworm excrement. After six days, a 58.90% reduction of cellulose content in treatment groups was observed, which was significantly higher than 11.5% of the control groups without housefly larvae. Three cellulose-degrading bacterial strains were isolated from silkworm excrement, which were identified as Bacillus licheniformis, Bacillus amyloliquefaciens, and Bacillus subtilis based on 16S rRNA gene sequence analysis. These three bacterial stains had a high cellulose degradation index (HC value ranged to between 1.86 and 5.97 and FPase ranged from 5.07 U/mL to 7.31 U/mL). It was found that housefly larvae increased the abundance of cellulose-degrading bacterial genus (Bacillus and Pseudomonas) by regulating the external environmental conditions (temperature and pH). Carbohydrate metabolism was the bacterial communities' primary function during vermicomposting based on the PICRUSt. The results of Tax4Fun indicated that the abundance of endo-β-1,4-glucanase and exo-β-1,4-glucanase increased rapidly and maintained at a higher level in silkworm excrement due to the addition of housefly larvae, which contributed to the accelerated degradation of cellulose in silkworm excrement. The finding of this investigation showed that housefly larvae can significantly accelerate the degradation of cellulose in silkworm excrement by increasing the abundance of cellulose-degrading bacterial genera and cellulase.


Quality control in laboratory investigations on Schistosoma mansoni in St. Lucia, West Indies. Maintenance of artificial prevalence as a laboratory aid.
A method is described of maintaining an apparent S. mansoni prevalence rate of 10% in an area estimated to have a natural rate of below 5% following two chemotherapy campaigns. To sustain interest and therefore accuracy among microscopists engaged on screening, known S. mansoni-positive stools were seeded, without their knowledge, among those collected in the field. The problems of achieving a desired level of seeding, and of a possible further dimension of the scheme are discussed.


Simple and rapid determination of enflurane in human tissues using gas chromatography and gas chromatography-mass spectrometry.
A simple, rapid and reliable method was devised to determine the levels of enflurane in human tissues, using gas chromatography and gas chromatography-mass spectrometry. 1,4-Dioxane was used as an internal standard (I.S.). Enflurane and the I.S. were extracted from 0.25 g of body tissues using an automatic headspace sampler and 1 ml of headspace gas was injected into the gas chromatograph. Enflurane was analyzed qualitatively by gas chromatography-mass spectrometry and quantitatively by gas chromatography with a flame-ionization detector. The calibration curves in all tissues examined were linear in the concentration range 1-100 microg/0.25 g. The lower limit of detection was 200-300 ng/0.25 g. The accuracy and precision of this method were evaluated at two different concentrations, 1 and 20 microg/0.25 g. The coefficient of variation ranged from 3.4-13.4%. We used this method to determine the presence of enflurane in tissues from an autopsied individual who died suddenly during extirpation of a malignant tumor.


Statistical Evaluations of Variations in Dairy Cows' Milk Yields as a Precursor of Earthquakes.
Previous studies have provided quantitative data regarding unusual animal behavior prior to earthquakes; however, few studies include long-term, observational data. Our previous study revealed that the milk yields of dairy cows decreased prior to an extremely large earthquake. To clarify whether the milk yields decrease prior to earthquakes, we examined the relationship between earthquakes of various magnitudes and daily milk yields. The observation period was one year. In the results, cross-correlation analyses revealed a significant negative correlation between earthquake occurrence and milk yields approximately three weeks beforehand. Approximately a week and a half beforehand, a positive correlation was revealed, and the correlation gradually receded to zero as the day of the earthquake approached. Future studies that use data from a longer observation period are needed because this study only considered ten earthquakes and therefore does not have strong statistical power. Additionally, we compared the milk yields with the subionospheric very low frequency/low frequency (VLF/LF) propagation data indicating ionospheric perturbations. The results showed that anomalies of VLF/LF propagation data emerged prior to all of the earthquakes following decreases in milk yields; the milk yields decreased earlier than propagation anomalies. We mention how ultralow frequency magnetic fields are a stimulus that could reduce milk yields. This study suggests that dairy cow milk yields decrease prior to earthquakes, and that they might respond to stimuli emerging earlier than ionospheric perturbations.


A Bayesian approach to the probability of coronary heart disease subject to the -308 tumor necrosis factor-α SNP.
We study the correlation of the occurrence of coronary heart disease (CHD) with the presence of the single-nucleotide polymorphism (SNP) at the -308 position of the tumor necrosis factor alpha (TNF-α) gene. We also consider the influence of the occurrence of type 2 diabetes (t2DM). Using Bayesian inference, we first pursue a bottom-up approach to compute the working hypothesis and the probabilities derivable from the data. We then pursue a top-down approach by modelling the signal pathway that causally connects the SNP with the emergence of CHD. We compute the functional form of the probability of CHD conditional on the presence of the SNP in terms of both the statistical and biochemical properties of the system. From the probability of occurrence of a disease conditional on a given risk factor, we explore the possibility of extracting information on the pathways involved in the occurrence of the disease. This is a first study that we want to systematise into a comprehensive formalism to be applied to the inference of the mechanism connecting the risk factors to the disease.


Obstructive sleep apnoea: longer respiratory event lengths in patients with heart failure.
This study investigated the effect of heart failure on respiratory patterns in patients with obstructive sleep apnoea (OSA). 39 patients with established OSA (apnoea/hypopnoea index (AHI) >10 events·h(-1)) and either with heart failure (New York Heart Association (NYHA) class II and III, left ventricular-ejection fraction (LVEF) ≤40%; n=26, age mean ± SD 67 ± 9 years) or without heart failure (LVEF ≥50%, N-terminal pro-brain naturic peptide <400 pg·mL(-1); n=13, age 73 ± 6 years) underwent simultaneous right- and left-heart catheterisation within 12 h of cardiorespiratory polygraphy recording. Respiratory patterns of OSA were significantly longer in OSA patients with heart failure versus without heart failure, including mean ± SD cycle length (46.0 ± 10.0 versus 37.8 ± 10.6 s; p=0.024), ventilation length (25.4 ± 6.3 versus 21.3 ± 7.1 s; p=0.044), apnoea length (20.5 ± 4.9 versus 16.5 ± 3.9 s; p=0.013), time-to-peak ventilation (10.6 ± 3.0 versus 8.3 ± 2.5 sc; p=0.021) and circulatory delay (28.5 ± 7.5 versus 22.6 ± 3.7 s; p=0.005). Positive and robust correlations were found between some of these parameters and the degree of congestion in heart failure: cycle length (r=0.53; p=0.006), ventilation length (r=0.55; p=0.004) and time-to-peak ventilation (r=0.47; p=0.015) all increased with a rise in pulmonary capillary wedge pressure. Respiratory patterns in OSA appear to be dependent on cardiac function, with an increase in event lengths as cardiac function decreases. In patients with heart failure, some of these events correlate with the degree of pulmonary congestion.


Cholesterol reducer and thrombolytic therapy in acute ischemic stroke patients.
Specific clinical risk factors may contribute to improving or worsening neurological functions in acute ischemic stroke (AIS) patients pre-treated with a combined cholesterol reducer and recombinant tissue plasminogen activator (rtPA) therapy. In this study, clinical risk factors associated with good or poor presenting neurological symptoms in ischemic stroke patients with prior cholesterol reducer use, specifically a statin and rtPA therapy was investigated. Retrospective data for baseline clinical and demographic data for patients with AIS taking cholesterol reducers prior to rtPA treatment from January 2010 to June 2016 in a regional stroke center was analyzed. Improving (NIHSS score ≤ 7) or worsening (NIHSS score > 7) of neurologic functions were the determined measures of treatment outcome. Multivariate logistic regression models identified demographic and clinical factors associated with worsening or improving neurologic functions. Adjusted multivariate analysis showed that in an AIS population with a combined rtPA and cholesterol reducer medication history, increasing age (OR = 1.032, 95% CI, 1.015-1.048, P < 0.001) and atrial fibrillation (OR = 1.859, 95% CI, 1.098-3.149, P = 0.021) demonstrated a likely association with worsening neurologic functions, while direct admission (OR = 0.411, 95% CI, 0.246-0.686, P = 0.001) and being Caucasian (OR = 0.496, 95% CI, 0.297-0.827, P = 0.007) showed an association with improving or progressing neurologic functions. A prior cholesterol reducer, namely a statin, plus rtPA combination may be associated with worsening neurological function for elderly AIS patients with atrial fibrillation, while Caucasians directly admitted to a neurology unit are more likely to show an association with progress or improvements in neurologic functions. While combining statin with rtPA treatment may facilitate worsening neurologic functions in elderly AIS patients with atrial fibrillation, they should not be denied of this therapy. The decision to combine statin and rtPA for AIS patients with atrial fibrillation can be done after clinical stabilization following appropriate clinical management.


Transcriptional regulation of the human factor IX promoter by the orphan receptor superfamily factor, HNF4, ARP1 and COUP/Ear3.
A study of the human clotting factor IX promoter by DNase I footprinting and gel shifts in vitro, and by functional analysis of HepG2 cells in vivo, suggests that the liver-enriched transcription factor, HNF4, is involved in transactivating two cis-acting elements, i.e. X (nucleotides -15 to +3) and Y (nucleotides +15 to +36), in addition to the well-known element centred around nucleotide -20. Other members of the orphan receptor superfamily, e.g. ARP1 and COUP/Ear3, repress the factor IX promoter possibly by competition with HNF4 binding sites in the X and Y elements, but probably not at the -20 element. Mutations at -6 in the promoter, similar to those found in patients with haemophilia B, hinder HNF4 binding and transactivation of the X element, suggesting that impaired HNF4 binding contributes to the down-regulation of the factor IX expression in these patients, but is unlikely to be the only factor involved.


Contrary effects of sphingosine-1-phosphate on expression of α-smooth muscle actin in transforming growth factor β1-stimulated lung fibroblasts.
Transforming growth factor-β1 (TGFβ1) plays a pivotal role in fibrosis in various organs including the lung. Following pulmonary injury, TGFβ1 stimulates conversion of fibroblasts to myofibroblasts that are mainly characterized by up-regulation of α-smooth muscle actin (αSMA) expression, and the resulting excess production of extracellular matrix proteins causes fibrosis with loss of alveolar function. The present study was undertaken to define the role of the sphingosine-1-phosphate (S1P) pathway in TGFβ1-induced expression of αSMA in human fetal lung fibroblasts, HFL1 cells. Analysis of mRNA revealed the existence of S1P(1), S1P(2), and S1P(3) receptor mRNAs. Treatment with TGFβ1 increased sphingosine kinase (SphK) activity and S1P(3) receptor mRNA at 24h after stimulation, and pharmacological data showed the involvement of sphingomyelinase, SphK, and S1P(3) receptor in the TGFβ1-induced up-regulation of αSMA with and without serum. Treatment with pertussis toxin and S1P(1) receptor antagonist W146 enhanced αSMA expression by TGFβ1/serum, and S1P decreased and increased αSMA levels with and without serum, respectively. TGFβ1 increased cyclooxygenase-2 expression in a manner dependent on serum and the sphingomyelinase/SphK pathway, and the response was decreased by pertussis toxin. Prostaglandin E(2), formed by TGFβ1/serum stimulation, decreased the TGFβ1-induced expression of αSMA via EP prostanoid receptor. These data suggest that S1P formed by TGFβ1 stimulation has diverse effects on the expression of αSMA, inhibition via the S1P(1) receptor-mediated and serum-dependent expression of cyclooxygenase-2 and the resulting formation of prostaglandin E(2), and stimulation via the S1P(3) receptor in a serum-independent manner.


Molecular control of gut formation in the spider Parasteatoda tepidariorum.
The development of a digestive system is an essential feature of bilaterians. Studies of the molecular control of gut formation in arthropods have been studied in detail in the fruit fly Drosophila melanogaster. However, little is known in other arthropods, especially in noninsect arthropods. To better understand the evolution of arthropod alimentary system, we investigate the molecular control of gut development in the spider Parasteatoda tepidariorum (Pt), the primary chelicerate model species for developmental studies. Orthologs of the ectodermal genes Pt-wingless (Pt-wg) and Pt-hedgehog (Pt-hh), of the endodermal genes, Pt-serpent (Pt-srp) and Pt-hepatocyte-nuclear factor-4 (Pt-hnf4) and of the mesodermal gene Pt-twist (Pt-twi) are expressed in the same germ layers during spider gut development as in D. melanogaster. Thus, our expression data suggest that the downstream molecular components involved in gut development in arthropods are conserved. However, Pt-forkhead (Pt-fkh) expression and function in spiders is considerably different from its D. melanogaster ortholog. Pt-fkh is expressed before gastrulation in a cell population that gives rise to endodermal and mesodermal precursors, suggesting a possible role for this factor in specification of both germ layers. To test this hypothesis, we knocked down Pt-fkh via RNA interference. Pt-fkh RNAi embryos not only fail to develop a proper gut, but also lack the mesodermal Pt-twi expressing cells. Thus, in spiders Pt-fkh specifies endodermal and mesodermal germ layers. We discuss the implications of these findings for the evolution and development of gut formation in Ecdysozoans.


Presence of atopy in first-degree relatives as a predictor of a female proband's depression: results from the Northern Finland 1966 Birth Cohort.
Recent investigations suggest a common genetic rather than environmental cause to explain the association between IgE-mediated atopic allergies and depression. Taking into account psychosocial confounding factors, we investigated separately and at the epidemiologic level the effects of maternal, paternal, and sibling atopy on the cumulative incidence of a child's depression. We used an unselected, genetically homogenous, general population birth cohort of 12,058 live-born children in Finland. The 31-year prospective follow-up included questionnaire information on atopic disorders of the cohort members' parents and siblings. The probands' own atopic conditions were evaluated by means of skin prick tests, and information on lifetime depression diagnoses was gleaned from postal questionnaires and national hospital discharge registers. Potential confounders were mother's parity, father's social class, maternal smoking during pregnancy, proband's regular daily smoking, and proband's dwelling place. Total variable information was available from 4068 cohort members. Among female probands, the presence of atopy in parents was the strongest predictor for lifetime depression (P <.001), and sibling atopy and parental atopy were the strongest predictors for hospital-treated depression (P =.018 and P =.036, respectively). After controlling for confounders, it was noticed that maternal atopy increased a female proband's risk of lifetime depression up to 1.9-fold (odds ratio, 1.9; 95% CI, 1.1-3.0). The corresponding risk increased over 4-fold if parental-maternal atopy was combined with proband's own atopy. Our findings suggest that maternal inheritance could be a significant causative factor in the association between atopy and depression of female probands.


Tolerance mechanisms in maize identified through phenotyping and transcriptome analysis in response to water deficit stress.
Water deficit is a key limiting factor for maize (Zea mays L.) productivity. Elucidating the molecular regulatory networks of stress tolerance is crucial for genetic enhancement of drought tolerance. Two genotypes of maize contrasting in their yield response to water deficit were evaluated for tolerance traits of water relations, net CO2 assimilation rate, antioxidative metabolism and grain yield in relation to the expression levels, based on transcription profiling of genes involved in stress signaling, protein processing and energy metabolism to identify functional tolerance mechanisms. In the genotype SNJ201126 upregulation of calcium mediated signaling, plasma membrane and tonoplast intrinsic proteins and the membrane associated transporters contributed to better maintenance of water relations as evident from the higher relative water content and stomatal conductance at seedling and anthesis stages coupled with robust photosynthetic capacity and antioxidative metabolism. Further the protein folding machinery consisting of calnexin/calreticulin (CNX/CRT) cycle was significantly upregulated only in SNJ201126. While the down regulation of genes involved in photosystems and the enzymes of carbon fixation led to the relative susceptibility of genotype HKI161 in terms of reduced net CO2 assimilation rate, biomass and grain yield. Our results provide new insight into intrinsic functional mechanisms related to tolerance in maize. The online version contains supplementary material available at 10.1007/s12298-021-01003-4.


Impacts of algal organic matter and humic substances on microcystin-LR removal and their biotransformation during the biodegradation process.
The application of bioaugmentation (i.e., injection of contaminant-degrading microorganisms) has shown its potential to remove harmful cyanotoxins like microcystin-LR (MC-LR) from drinking water sources. However, the natural organic matter (NOM) present in both natural and engineered water systems might affect the bacterial biodegradation of MC-LR. Therefore, for the successful application of bioaugmentation for MC-LR removal in water treatment, it is important to understand NOM effects on MC-LR biodegradation. In this study, the impact of NOM [algal organic matter (AOM) and humic substances (HS)] on MC-LR biodegradation was evaluated in the presence of varying concentrations of NOM by monitoring MC-LR biodegradation kinetics. The changes in NOM composition during MC-LR biodegradation were also characterized by a five-component Parallel factor (PARAFAC) model using 336 excitation-emission matrix (EEM) spectra collected at different sampling points. Our results showed decreases in MC-LR biodegradation rate of 1.6-and 3.4-fold in the presence of AOM and HS, respectively. The expression of the functional mlrA gene exhibited a similar trend to the MC-LR degradation rate at different NOM concentrations. EEM-PARAFAC analyses and NOM molecular size fractionation results indicated a relatively greater production of terrestrial humic-like components (57%) and a decrease of protein-like components. Two-dimensional correlation spectroscopy (2D-COS) analyses further confirmed that low molecular weight protein-like components were initially utilized by bacteria, followed by the formation of higher molecular weight humic-like components, likely due to microbial metabolism.


Current recommendations for cancer surveillance in Gorlin syndrome: a report from the SIOPE host genome working group (SIOPE HGWG).
Gorlin syndrome (MIM 109,400), a cancer predisposition syndrome related to a constitutional pathogenic variation (PV) of a gene in the Sonic Hedgehog pathway (PTCH1 or SUFU), is associated with a broad spectrum of benign and malignant tumors. Basal cell carcinomas (BCC), odontogenic keratocysts and medulloblastomas are the main tumor types encountered, but meningiomas, ovarian or cardiac fibromas and sarcomas have also been described. The clinical features and tumor risks are different depending on the causative gene. Due to the rarity of this condition, there is little data on phenotype-genotype correlations. This report summarizes genotype-based recommendations for screening patients with PTCH1 and SUFU-related Gorlin syndrome, discussed during a workshop of the Host Genome Working Group of the European branch of the International Society of Pediatric Oncology (SIOPE HGWG) held in January 2020. In order to allow early detection of BCC, dermatologic examination should start at age 10 in PTCH1, and at age 20 in SUFU PV carriers. Odontogenic keratocyst screening, based on odontologic examination, should begin at age 2 with annual orthopantogram beginning around age 8 for PTCH1 PV carriers only. For medulloblastomas, repeated brain MRI from birth to 5 years should be proposed for SUFU PV carriers only. Brain MRI for meningiomas and pelvic ultrasound for ovarian fibromas should be offered to both PTCH1 and SUFU PV carriers. Follow-up of patients treated with radiotherapy should be prolonged and thorough because of the risk of secondary malignancies. Prospective evaluation of evidence of the effectiveness of these surveillance recommendations is required.


Complications in surface replacement arthroplasty of the hip: experience with the Paltrinieri-Trentani prosthesis.
A method of surface replacement arthroplasty of the hip joint is described for use in selected patients, often in the younger age group. One hundred and forty patients were reviewed after a mean interval of four years. Seventy-two per cent were graded 5 or 6 on the Charnley scale, the remainder had symptoms due to femoral neck fracture or loosening of the prosthetic components. In the main the bad results were attributed to incorrect patient selection or technical imperfections with the operative technique. The advantages of the operation are no alteration in the relationship of the femoral head, neck and acetabulum and minimal interference with the surrounding muscle and soft tissues. The amount of implanted material is reduced and no entry is made into the femoral medullary canal, which facilitates any further revision surgery that may be necessary.


Combined transarterial chemoembolization and radiofrequency ablation for subphrenic versus nonsubphrenic hepatocellular carcinoma: a propensity score matched study.
To compare therapeutic outcomes of combined transarterial chemoembolization (TACE) and radiofrequency ablation (RFA) treatment for small hepatocellular carcinoma (HCC) in subphrenic versus nonsubphrenic locations by propensity score matching. This retrospective study included 293 patients with single HCC (≤ 3 cm) ineligible for ultrasound-guided RFA who received iodized oil TACE and subsequent RFA between June 2010 and January 2017. The patients were divided into two groups according to the tumor location: subphrenic (n = 99) and nonsubphrenic (n = 194). Subphrenic HCC was defined as a tumor abutting the diaphragm. Local tumor progression (LTP) and overall survival (OS) rates were compared by propensity score matching. Procedure-related complications were also assessed. Matching yielded 93 matched pairs of patients. In the matched cohorts, cumulative 1-, 3-, and 5-year LTP rates were 5.4%, 12.1%, and 12.1% in the subphrenic group and 1.1%, 7.5%, and 8.6% in the nonsubphrenic group, respectively, with no significant differences (p = 0.278). Corresponding OS rates were 100%, 80.2%, and 71.3% in the subphrenic group and 97.9%, 88.1%, and 75.6% in the nonsubphrenic group, respectively, with no significant differences (p = 0.308). The subphrenic location was not a significant risk factor for LTP and OS in multivariate analysis. There were no significant differences in complication rates between the two groups (p > 0.05). The therapeutic outcomes of combined TACE and RFA for small subphrenic HCC were similar to those for nonsubphrenic HCC. The combination therapy seems to be an effective and safe method in treating small subphrenic HCC.


The Impact of Social Determinants of Health on Gender Disparities Within Respiratory Medicine.
Gender is the centerpiece to an individual's understanding of self and encompasses many behavioral, social, and cultural arenas; its broad scope means that it also intersects many social determinants of health. Multiple examples of social determinants highlighted in this article, including income, education, occupation, domestic exposures, and cultural norms such as sexual identity, are critical factors that contribute to ongoing respiratory disparities between genders. Each of these social factors can have disparate impact on patients of differing genders. Understanding and addressing social determinants of health between genders is an essential first step toward achieving respiratory health equity.


Haemorrhagic pericarditis and cardiac tamponade during chronic haemodialysis.
Three cases of uraemic haemorrhagic pericarditis observed during haemodialysis treatment are described. The condition is explained with uraemic toxicosis, cyclic heparinaemia resulting from dialysis, deficient thrombocyte function, and decreased capillary resistance. The clinical appearance of haemorrhagic pericarditis was not typical in any of the cases. Two patients died, while in one patient partial pericardiectomy was performed with success.


Massive hemoperitoneum following suprapubic bladder aspiration.
Hemoperitoneum in the newborn is usually a result of visceral injury from birth trauma. This report describes an as yet unreported complication of massive hemoperitoneum following suprapubic bladder aspiration.


Mathematics and complex systems.
Contemporary researchers strive to understand complex physical phenomena that involve many constituents, may be influenced by numerous forces, and may exhibit unexpected or emergent behavior. Often such "complex systems" are macroscopic manifestations of other systems that exhibit their own complex behavior and obey more elemental laws. This article proposes that areas of mathematics, even ones based on simple axiomatic foundations, have discernible layers, entirely unexpected "macroscopic" outcomes, and both mathematical and physical ramifications profoundly beyond their historical beginnings. In a larger sense, the study of mathematics itself, which is increasingly surpassing the capacity of researchers to verify "by hand," may be the ultimate complex system.


A critical review of complications in non-surgical rhinoplasty and their management.
In recent years, there has been a rise in non-surgical rhinoplasty (NSR) due to its minimally invasive approach. As with all procedures, NSR can result in complications. Although rare, the consequences of complications can result in a devastating outcome and therefore an evidence-based approach to enable the recognition and management of NSR complications is required. This paper aims to review and appraise current literature to determine the evidence base for complications experienced with NSR including their causes and management. A systematic review was conducted using a PRISMA methodology. The PubMed and WebofScience databases were queried. Papers relating to the three most commonly used filler materials; hyaluronic acid (HA), calcium hydroxyapatite and collagen were collated. Four hundred and ninety studies were identified in the initial literature search and after applying an inclusion and exclusion criteria, 12 papers were included. The results of this literature review showed a paucity of high-level evidence which may indicate underreporting of NSR complications. Although treatment is not always effective, it is clear that early recognition and treatment favors better outcomes with the potential for complete resolution in some cases. Immediate availability of hyaluronidase is important when undertaking NSR with HA as this review showed early use was critical in the management of serious complications such as vascular occlusion.


Mapping of optimal CD8 T cell epitopes.
Defining the optimal epitope of a CD8 T cell response towards a certain antigen is a multistep procedure that requires the performance of peptide truncation design, ELISPOT peptide titration assays, and assessing the HLA class I restriction of the defined epitope via intracellular cytokine staining assays with B cell lines and epitope-specific CD8 T cell lines.


Transcatheter aortic valve implantation: the evolution of prostheses, delivery systems and approaches.
It is two decades since the first report of transcatheter implantation of a stented aortic valve in an animal. The first implantation of a transcatheter aortic valve in a human was accomplished just one decade ago dramatically demonstrating the promise and feasibility of this new therapy. Over the past 10 years, there have been rapid developments in valves, delivery systems and technical approaches. Today, transcatheter valve implantation is a technical possibility for the great majority of patients with aortic stenosis. The next 10 years may well see this become the dominant therapy for aortic stenosis.


Simultaneously improving the activity and thermostability of a new proline 4-hydroxylase by loop grafting and site-directed mutagenesis.
trans-Proline 4-hydroxylases (trans-P4Hs) hydroxylate free L-proline to trans-4-hydroxy-L-proline (trans-4-Hyp) is a valuable chiral synthon for important pharmaceuticals such as carbapenem antibiotics. However, merely few microbial trans-P4Hs have been identified, and trans-4-Hyp fermentations using engineered Escherichia coli strains expressing trans-P4Hs are usually performed at temperatures below 37 °C, which is likely due to poor stability and low activities. In the present study, a new trans-P4H from uncultured bacterium esnapd13 (UbP4H) with potential in the fermentative production of trans-4-Hyp at 37 °C was reported. In order to enhance the activity and thermostability of UbP4H, the replacement of its putative "lid" loop in combination with site-directed mutagenesis was performed. Consequently, four loop hybrids were designed by substituting a loop of UbP4H (A162-K178) with the corresponding sequences of four other known trans-P4Hs, respectively. Among them, UbP4H-Da exhibited a doubled activity when compared to the wild type (81.6 ± 1.9 vs. 40.4 ± 4.6 U/mg) but with reduced thermostability (t1/2, 11 vs. 47 min). Meanwhile, 10 single variants were designed through sequence alignments and folding free energy calculations. Three best point substitutions were respectively combined with UbP4H-Da, resulting in UbP4H-Da-R90G, UbP4H-Da-E112P, and UbP4H-Da-A260P. UbP4H-Da-E112P exhibited a 1.8-fold higher activity (85.2 ± 0.6 vs. 46.6 ± 4.0 U/mg), a 7.6-fold increase in t1/2 (359 vs. 47 min), and a 3 °C rise in Tm (46 vs. 43 °C) when compared to UbP4H. The fed-batch fermentations of trans-4-Hyp at 37 °C using trans-4-Hyp producing chassis cells expressing UbP4H or its variants were evaluated, and a 3.3-fold increase in trans-4-Hyp titer was obtained for UbP4H-Da-E112P (12.9 ± 0.1 vs. 3.9 ± 0.0 g/L for UbP4H). These results demonstrate the potential application of UbP4H-Da-E112P in the industrial production of trans-4-Hyp.


A Technique to Minimize Aerosolization During Percutaneous Tracheostomy in COVID-19 Patients.
The SARS-CoV-2 pandemic has caused respiratory failure in many patients. With no effective treatment or vaccine, prolonged mechanical ventilation is common in survivors. Timing and performance of tracheostomy, for both patient and surgical team safety, remains a question. Here within, we report our experience with percutaneous dilatational tracheostomy with modification to minimize aerosolization. A modified percutaneous dilatational tracheostomy technique is described. The technique was performed on 10 patients in the surgical intensive care unit. Ten patients underwent percutaneous dilatational tracheostomy. There were 7 males, and the average age for the group was 60.8 years. The average number of ventilator days before the operation was 26.3. All procedures were successful, and no patient had any procedure-related complications. The procedure described was successful in our patient population. We believe that this approach is safe for patients with coronavirus disease 2019 and limits aerosolization during the operation. Level IV, case series.


Pharmacokinetics of etomidate associated with prolonged i.v. infusion.
Plasma concentrations of etomidate have been measured in six patients who required intermittent positive pressure ventilation following surgery. There was an approximately linear relationship between the plasma concentration and the rate of infusion of etomidate. The drug exhibited linear pharmacokinetics over a 10-fold variation in plasma concentration. The decrease in the plasma concentration after discontinuing the infusion was consistent with a three-compartment pharmacokinetic model. The plasma terminal half-life was found to be about 5.5 h, and the clearance calculated to be 0.025 litre kg-1 min-1.


Spontaneous abortion in cattle after consumption of Hesperocyparis (Cupressus) macrocarpa (Hartw.) Bartel and Cupressus arizonica (Greene) needles in Uruguay.
An outbreak of cattle abortion associated with the consumption of Hesperocyparis (Cupressus) macrocarpa and Cupressus arizonica needles has been reported in Uruguay. Twenty-five of 125 pregnant heifers in late-term pregnancy aborted after being introduced into a paddock containing numerous H. macrocarpa, C. arizonica and Casuarina cunninghamiana trees. There were no significant macroscopic or histological findings in the two fetuses analyzed. Abortifacient labdane acids were detected in the needles of H. macrocarpa (1.68%, D.W.) and C. arizonica (0.36%, D.W.) but none were found in C. cunninghamiana.


On the presence of different populations of pinealocytes in the mammalian pineal gland.
The different categories of cells described by many authors in the pineal gland of mammals have been critically considered. In some mammalian species, two different populations of pinealocytes have been observed. To each of these populations a specific secretory process can be attributed. One is characterized by the formation of granular vesicles originating from the Golgi apparatus, the other by the formation of material directly from the cisterns of the granular endoplasmic reticulum. Both of these secretory processes appear to be also present in the pineal of the mole, the hedgehog, and the rat, mammals in which generally only one population of pinealocytes has been described. The physiological consequences of these findings have been discussed.


Tobacco Rattle Virus-Based Silencing of Enoyl-CoA Reductase Gene and Its Role in Resistance Against Cotton Wilt Disease.
A Tobacco rattle virus (TRV)-based virus-induced gene silencing assay was employed as a reverse genetic approach to study gene function in cotton (Gossypium hirsutum). This approach was used to investigate the function of the Enoyl-CoA reductase (GhECR) gene in pathogen defense. Amino acid sequence alignment of Arabidopsis ECR with homologous sequence from G. hirsutum, G. arboreum, G. herbaceum and G. barbadense showed that ECRs are highly conserved among these species. TRV-based silencing of GhECR gene in G. hirsutum induced a cell death/necrotic lesion-like phenotype. Reverse transcription polymerase chain reaction (RT-PCR) and real-time quantitative PCR showed reduced GhECR mRNA levels in TRV inoculated plants. Three isolates of Verticillium dahliae (V. dahliae) and Fusarium oxysporum f. sp. vasinfectum (FOV) were used to infect GhECR-silenced plants. Out of 6 races of 2 pathogens, down regulation of GhECR gene resulted in reduced resistance. This is the first report showing that cotton GhECR gene is involved in resistance to different strains of V. dahliae and FOV.


Enumeration of S-phase cells in normal rat liver by immunohistochemistry using bromodeoxyuridine-antibromodeoxyuridine system.
The visualization of incorporation sites of the thymidine analog bromodeoxyuridine (BrdU) into DNA, detected by immunocytochemistry, has been proposed as an index of the percentage of S-phase cells in a variety of tissues and as an easy, less expensive alternative to autoradiography. This technique has not yet been applied to the study of physiological cell renewal in the normal liver. In the present study, results obtained with this method in the liver of normal young adult rats is reported. BrdU was administered in vivo and subsequent incorporation was detected by the PAP technique using monoclonal anti-BrdU antibodies. The nuclei exhibiting a positive reaction within the liver were few and accounted for about 0.45% of all hepatocytes. Positive cells were located preferentially in zone 1, which contained 82.7% of the labeled cells. Zone 2 contained 15.4%, while only 1.9% of the labeled cells were found in zone 3. Positive-staining Kupffer cell nuclei were rare (about 0.5% of all Kupffer cells) and were distributed randomly in the hepatic lobule. These findings provide quantitative data about hepatocyte renewal in the normal liver in the absence of a growth stimulus. The simplicity and the reproducibility of this technique suggests that further application of this method in situations assessing hepatic regeneration are indicated.


Variability of the 5'-end of the large subunit rDNA and presence of a new short class of rRNA in Rhizobiaceae.
A highly variable region of DNA was found between positions 115 and 388 (Escherichia coli numeration) of the large subunit (ls) rRNA genes of 55 rhizobial and agrobacterial strains. In each case this heterogeneity was accompanied by the presence of a new rRNA species approximately 130 bp long. This novel rRNA species corresponded to the 5'-end of the ls rRNA genes. An additional rRNA processing site was located in the central region of the remaining ls rRNA of many of the Rhizobium leguminosarum and Rh. etli strains, and in all of the agrobacteria studied, excepting the type strain of Agrobacterium vitis NCPPB 3554 and Agrobacterium sp. strain ChAg4.


Clinical significance of lymphatic invasion in the esophageal region in patients with adenocarcinoma of the esophagogastric junction.
The lymphatic flow around the esophagogastric junction is complicated. Therefore, it is unclear whether lymphatic invasion in the esophageal region (eLI) and in the gastric region (gLI) in patients with adenocarcinoma of the esophagogastric junction (AEG) equally affect the incidence of lymph node metastases (LNM), and consequently, survival. We retrospectively reviewed clinicopathological data of 175 patients with AEG between January 2008 and July 2017. Risk factors for LNM and impacts of eLI or gLI on survival outcomes were investigated. eLI was identified in 34% of the patients (59/175). By multivariate analysis, eLI was associated with an increased risk of both mediastinal LNM (odds ratio [OR] = 2.98, 95% confidence interval [CI]: 1.26-7.05) and abdominal LNM (OR = 5.44, 95% CI: 1.95-15.20). The 5-year overall survival for patients with eLI (53%) was significantly worse than for patients without eLI (76%) (hazard ratio = 2.45, 95% CI: 1.37-10.01). gLI was not selected in either of these analyses. Positive eLI was strongly associated with mediastinal and abdominal LNM and worse survival in patients with AEG compared with gLI. In the histopathological examination, it seems to make sense to assess eLI and gLI separately.


Biowaiver Monograph for Immediate-Release Solid Oral Dosage Forms: Isavuconazonium Sulfate.
A Biopharmaceutics Classification System (BCS)-based biowaiver monograph is presented for isavuconazonium sulfate. A BCS-based biowaiver is a regulatory option to substitute appropriate in vitro data for in vivo bioequivalence studies. Isavuconazonium sulfate is the prodrug of isavuconazole, a broad-spectrum azole antifungal indicated for invasive fungal infections. While the prodrug can be classified as a BCS Class III drug with high solubility but low permeability, the parent drug can be classified as a BCS Class II drug with low solubility but high permeability. Interestingly, the in vivo behavior of both is additive and leads isavuconazonium sulfate to act like a BCS class I drug substance after oral administration. In this work, experimental solubility and dissolution data were evaluated and compared with available literature data to investigate whether it is feasible to approve immediate release solid oral dosage forms containing isavuconazonium sulfate according to official guidance from the FDA, EMA and/or ICH. The risks associated with waiving a prodrug according to the BCS-based biowaiver guidelines are reviewed and discussed, noting that current regulations are quite restrictive on this point. Further, results show high solubility but instability of isavuconazonium sulfate in aqueous media. Although experiments on the dissolution of the capsule contents confirmed 'very rapid' dissolution of the active pharmaceutical ingredient (API) isavuconazonium sulfate, its release from the commercial marketed capsule formulation Cresemba is limited by the choice of capsule shell material, providing an additional impediment to approval of generic versions via the BCS-Biowaiver approach.


M1 macrophage-derived exosomes and their key molecule lncRNA HOTTIP suppress head and neck squamous cell carcinoma progression by upregulating the TLR5/NF-κB pathway.
Exosomes serve as a crucial mode of communication between tumor-associated macrophages (TAMs) and cancer cells. This study attempted to explore the function of M1-derived exosomes and clarify their specific mechanism in head and neck squamous cell carcinoma (HNSCC). Moreover, the functional roles of M1-derived exosomes and their key molecule long noncoding RNA (lncRNA) HOXA transcript at the distal tip (HOTTIP) in HNSCC were investigated by conducting a series of in vitro and in vivo experiments. The dual-luciferase test was utilized to clarify the binding capacities between HOTTIP/mRNA and miRNAs. Accordingly, HOTTIP was found to be upregulated in M1-derived exosomes. Meanwhile, the in vitro experiments indicated that M1 exosomes suppressed proliferation, migration and invasion but induced apoptosis of cancer cells. This function was noted to be enhanced by HOTTIP-overexpressed M1 exosomes but was weakened by HOTTIP-knockdown ones, indicating that HOTTIP serves as a key molecule in M1 exosomes. Therefore, the function of HOTTIP in cancer cells was explored, for which overexpression of HOTTIP was found to inhibit proliferation, migration and invasion but induced apoptosis of cancer cells in vitro. A mechanism study further showed that M1 exosomes and HOTTIP activated the TLR5/NF-κB signaling pathway by competitively sponging miR-19a-3p and miR-19b-3p. Furthermore, cancer cells expressing HOTTIP were noted to induce the polarization of both local M1 and M2 macrophages; however, M1 exosomes were observed to reprogram local TAMs into M1 macrophages. More importantly, both cancer cells expressing HOTTIP and M1 exosomes reeducated circulating monocytes to express the M1 phenotype. The corresponding data demonstrated that the M1 exosomal lncRNA HOTTIP suppresses HNSCC progression by upregulating the TLR5/NF-κB signaling pathway through competitively sponging miR-19a-3p and miR-19b-3p. In particular, M1 exosomes and HOTTIP induce the polarization of M1 in circulating monocytes, thus providing novel insight into HNSCC immunotherapy.


Design, synthesis and evaluation of nitric oxide releasing derivatives of 2,4-diaminopyrimidine as novel FAK inhibitors for intervention of metastatic triple-negative breast cancer.
To search for novel medicines for intervention of triple-negative breast cancer (TNBC), a series of phenylsulfonyl furoxan-based 2,4-diaminopyrimidine derivatives (8a-t) were designed and synthesized based on blocking FAK-mediated signaling pathways through both kinase-dependent and -independent manners. The most active compound 8f not only significantly inhibited FAK kinase activity (IC50 = 27.44 nM), displayed potent inhibitory effects on the proliferation (IC50 = 0.126 μM), invasion and migration of MDA-MB-231 cells, superior to the most widely studied FAK inhibitor, TAE226, bearing 2,4-diaminopyrimidine, but also released high levels of NO, contributing to blockage of FAK mediated-signaling pathways by upregulating of p53 as well as suppressing the Y397 phosphorylation and its downstream effectors, including p-Akt, MMP-2, and MMP-9 via kinase-independent manner, leading to apoptosis induction and decrease of FAs and SFs in TNBC cells. Importantly, 8f inhibited the lung metastasis of TNBC in vivo. Together, 8f may serve as a promising candidate for the treatment of metastatic TNBC.


The Dundee University Scottish Keratoconus Study II: a prospective study of optical and surgical correction.
To investigate and correlate optical correction, and progression to penetrating keratoplasty (PKP), with the corneal, refractive, topographic and familial characteristics of subjects with keratoconus, within the Tayside region of Scotland. Prospective, observational, longitudinal study design. Two hundred subjects with keratoconus were enrolled into the Dundee University Scottish Keratoconus Study (DUSKS) and were assessed during a 4-year period using standardised clinical assessment, computerised corneal topography and questionnaires. Keratoconic subjects in this study wore rigid contact lenses (90.6%) for longer than 12 hours per day (81%), 7 days a week (91%) and achieved a very good level of Snellen visual acuity (97%, > or =6/9). Corneal staining was observed in the majority of corneas (71%), although only a small percentage of subjects reported major problems of: discomfort (18%), hyperaemia (16%), or the lens falling out (4%). Poor visual acuity was the main reason (79%) for undergoing PKP usually in the latter part of the third decade of life, approximately a decade after diagnosis. During the study period 4% of eyes progressed to PKP. Only a small percentage of eyes (9.5%) required no visual correction postoperatively. The main mode of visual rehabilitation for keratoconus was rigid contact lenses, which were mostly worn successfully with good visual acuity. During the study period a small minority of keratoconics progressed to corneal graft surgery. It is advisable to emphasise that postoperatively refractive correction will be required in the majority of these cases.


Modulation of acyl and des-acyl ghrelin on autonomic and behavioral thermoregulation in various ambient temperatures.
Maintenance of body temperature (Tb) at various ambient temperatures (Ta) during fasting is important for homeotherms. Fasting decreases Tb in thermoneutral and cold conditions and facilitates thermoregulatory behavior in the cold in rats; however, the mechanism is unknown. We focused on ghrelin, a hormone secreted by the stomach during fasting, in two circulatory forms: acyl ghrelin (AG) and des-acyl ghrelin (DAG). AG is called active ghrelin, while DAG, the non-active ghrelin, was unknown for a long time before its many functions were recently clarified. In the present review, we present the modulation of AG and DAG on autonomic and behavioral thermoregulation at various Ta and discuss the differences between their modulation on thermoregulation. AG decreases Tb in thermoneutral and cold conditions but does not affect the thermoregulatory behavior of rodents in cold conditions. The DAG decreases Tb in thermoneutral and hot conditions, but it does not affect Tb and facilitates the thermoregulatory behavior of rodents in the cold. These findings indicate that the actions of AG and DAG on thermoregulation are similar in thermoneutral conditions but are different in cold conditions.


External support factors utilized by patients in coping with cancer: a European perspective.
The article presents the results of research on psychosocial aspects of living with cancer in the Slovak Republic focusing on hospitalized and outpatient cancer patients in treatment during the curative stage of the disease. Assessing cancer patient's interest in receiving help from individual members of a multidisciplinary team was a part of the research. The research was done through a questionnaire designed to focus on individual psychosocial aspects of cancer treatment. The research sample included 67 hospitalized patients and 61 outpatients. Execution of research was conducted in the individual clinical workplaces. When calculating the interest of cancer patients in spiritual counseling during oncological treatment, hospitalized patients indicated significant interest (p = .014). Similarly, hospitalized patients indicated more interest in using psychological counseling (p = .040) as well as in consultation with the social worker with a significant difference of (p = .017). Interest in the aid of a physical therapist was exhibited more significantly with hospitalized patients (p = .000). Significant interest in hospitalized patients using additional members of the multidisciplinary team was statistically significant (p = .017). Outpatient cancer patients indicated significant interest in finding information about medical conditions on the Internet (p = .000). For items addressing an interest in meeting people with cancer in self-help groups, there was no significant difference between outpatient and hospital patients (p = .298) as with talking to other patients who had cancer (p = .207). External support factors are important in helping patients cope with cancer. Health professionals can help patients mitigate the various difficulties associated with cancer.


The effectiveness of supplemental oxygen during exercise training in patients with chronic obstructive pulmonary disease who show severe exercise-induced desaturation: a protocol for a meta-regression analysis and systematic review.
Supplemental oxygen during exercise training is used to increase the training effect of an exercise program in patients with chronic obstructive pulmonary disease (COPD) who show exercise-induced desaturation. Exercise-induced desaturation is not clearly defined in the guidelines; however, it is generally defined in clinical studies as a decrease in SpO2 of more than 4% from rest or a decrease to less than 88% during exercise. Although some meta-analyses examined the effectiveness of supplemental oxygen during exercise training, these studies concluded that it does not further improve exercise tolerance compared to exercise training alone. However, supplemental oxygen during exercise training may be effective in improving exercise tolerance in COPD patients with severe exercise-induced desaturation. Therefore, this study will be performed to elucidate the effectiveness of supplemental oxygen during exercise training and the relationship between its effectiveness and severity of exercise-induced desaturation at baseline. We will first assess the effectiveness of supplemental oxygen during exercise training in COPD. The main outcome is the change in exercise tolerance before and after the intervention, indicated by the 6-min walking distance, the walking distance, or the walking time in incremental shuttle walking test, and analyzed as the standardized mean difference (SMD). The quality and risk of bias in individual studies will be assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system and risk-of-bias tool (RoB ver.2). If statistical heterogeneity in terms of the effectiveness of exercise tolerance is shown, we will conduct meta-regression analyses to examine the association between the effectiveness of exercise training with supplemental oxygen and severity of exercise-induced desaturation at baseline. One strength of this study is that it is a systematic review with meta-regression analysis to elucidate the effectiveness of supplemental oxygen during exercise training in patients with COPD who show severe exercise-induced desaturation. Furthermore, we will assess the severity of exercise-induced desaturation for which exercise training with supplemental oxygen is effective, the influence of acute effects at baseline, and the effect of supplemental oxygen on adverse events. Registration number, UMIN000039960.


Genotype evaluation of cowpea seeds (Vigna unguiculata) using 1H qNMR combined with exploratory tools and solid-state NMR.
The ultimate aim of this study was to apply a non-targeted chemometric analysis (principal component analysis and hierarchical clustering analysis using the heat map approach) of NMR data to investigate the variability of organic compounds in nine genotype cowpea seeds, without any complex pre-treatment. In general, both exploratory tools show that Tvu 233, CE-584, and Setentão genotypes presented higher amount mainly of raffinose and Tvu 382 presented the highest content of choline and least content of raffinose. The evaluation of the aromatic region showed the Setentão genotype with highest content of niacin/vitamin B3 whereas Tvu 382 with lowest amount. To investigate rigid and mobile components in the seeds cotyledon, 13C CP and SP/MAS solid-state NMR experiments were performed. The cotyledon of the cowpea comprised a rigid part consisting of starch as well as a soft portion made of starch, fatty acids, and protein. The variable contact time experiment suggests the presence of lipid-amylose complexes.


Halothane-induced decrease in experimental myocardial ischemia in the non-failing canine heart.
The effect of halothane on net myocardial oxygen balance of ischemic myocardium was studied in the non-failing canine heart. Myocardial ischemia was produced by repeated reversible occlusions of a coronary artery; the severity of ischemia was estimated by summating ST-segment elevations (sigma ST) obtained by epicardial ECG mapping at 15 to 18 sites. Control measurements were obtained before and after administration of halothane (0.75 per cent) to six dogs with chloralose-urethane basal anesthesia. Halothane was associated with significant decreases of systemic arterial pressure (P less than .001), heart rate (P less than .01), and the product of systolic arterial pressure X heart rate (P less than .01), an indirect index of myocardial oxygen consumption, while left atrial pressure remained unchanged at normal levels. sigmaST during occlusion was less (P less .001) during halothane (26.5 +/- 7.4 (SD) mv) than before (36.6 +/- 5.4 mv) or after (34.4 +/- 8.2 mv) its administration. Thus, halothane decreased the severity of experimentally-induced myocardial ischemia in the non-failing canine heart. The data suggest that, in the absence of ventricular failure, halothane influences the relationship between myocardial oxygen supply and demand in a favorable direction when coronary blood flow is limited.


Proabsorptive properties of forskolin: disposition of glycine, leucine and lysine in rat jejunum.
The effects of forskolin on mucosal cyclic AMP levels and active transport of glycine, L-lysine and L-leucine were studied in rat jejunum in vitro. Furthermore, the effects on lysine and glycine incorporation into mucosal protein and on mucosal cell volume were investigated. Elevation of intestinal mucosal cyclic AMP to threefold control levels by 10 mumol 1(-1) forskolin was accompanied by increased absorption of glycine (+33%), L-leucine (+72%) and L-lysine (+188%), as determined in a three compartment model suitable to measure active transport. Increased intracellular accumulation could be demonstrated for lysine as a transport substrate. Accordingly, using a dual label method, calculated values for uphill transport of lysine at the site of the brush border membrane were markedly enhanced. Forskolin up to 10 mumol 1(-1) had no effects on the fraction of lysine or glycine incorporated into TCA-precipitable proteins of jejunal absorptive cells. Serosal to mucosal transfer, as well as basolateral entry into mucosal cells remained unchanged for all three amino acids. Likewise, intracellular fluid space, calculated from distribution spaces for 14C-inulin and 3H2O as well as the response of cellular volume to an osmotic gradient were not affected by forskolin. As comparable stimulatory effects of forskolin on active hexose transport were reported earlier, it is suggested that forskolin - known to inhibit sodium-coupled fluid absorption - may stimulate active transport by enhancing sodium availability for sodium dependent intestinal cotransporters in general.


Expanded Radialenes: Modular Synthesis and Characterization of Cross-Conjugated Enyne Macrocycles.
Stepwise palladium-catalyzed cross-coupling between terminal alkynes and vinyl triflates afforded the first cross-conjugated enyne macrocycles constructed of 3-alkylidene-1-propynyl [-C≡C-C(=CR2)-] building blocks, namely, the expanded radialene 1 and the hybrid radialene 2.


Comparison of intravenous ketorolac at three doses for treating renal colic in the emergency department: A noninferiority randomized controlled trial.
Ketorolac tromethamine is a nonsteroidal anti-inflammatory drug (NSAID) that is extensively used for the management of renal colic in the emergency department (ED). It has been proposed that ketorolac is used at doses above its analgesic ceiling with no more advantages and increased risk of adverse effects. In this study, we compared the analgesic effects of three doses of intravenous ketorolac in patients with renal colic. This noninferiority, randomized, double-blind clinical trial evaluated the analgesic efficacy of three doses of intravenous ketorolac (10, 20, and 30 mg) in adult patients presenting to the ED with renal colic. Exclusion criteria consisted of age > 65 years, active peptic ulcer disease, acute gastrointestinal hemorrhage, renal or hepatic insufficiency, NSAID hypersensitivity, pregnancy or breastfeeding, unstable vital signs, and patients who had received analgesics in the past 24 hours. Pain was recorded every 15 minutes from baseline up to 60 minutes, and the primary outcome was pain reduction at 30 minutes. If patients still required additional pain medications at 30 minutes, they would receive 0.1 mg/kg intravenous morphine sulfate as a rescue analgesic. A total of 165 subjects enrolled in this study, 55 in each group. The median visual analog scale score in 30 minutes was improved from 90 at baseline to 40 among subjects who were randomized to 30-mg group. This improvement was 40 and 50 mm in 20- and 10-mg ketorolac treatment arms, respectively, with no significant difference between the three doses (p < 0.05). Secondary outcomes showed similar rescue analgesic administration and adverse effects. There was no serious adverse event. Ketorolac at 10-, 20-, and 30-mg doses can produce similar analgesic efficacy in renal colic.


Allogeneic hematopoietic SCT for alpha-mannosidosis: an analysis of 17 patients.
Alpha-mannosidosis is a rare lysosomal storage disease. Hematopoietic SCT (HSCT) is usually recommended as a therapeutic option though reports are anecdotal to date. This retrospective multi institutional analysis describes 17 patients that were diagnosed at a median of 2.5 (1.1-23) years and underwent HSCT at a median of 3.6 (1.3-23.1) years. In all, 15 patients are alive (88%) after a median follow-up of 5.5 (2.1-12.6) years. Two patients died within the first 5 months after HSCT. Of the survivors, two developed severe acute GvHD (>=grade II) and six developed chronic GvHD. Three patients required re-transplantation because of graft failure. All 15 showed stable engraftment. The extent of the patients' developmental delay before HSCT varied over a wide range. After HSCT, patients made developmental progress, although normal development was not achieved. Hearing ability improved in some, but not in all patients. We conclude that HSCT is a feasible therapeutic option that may promote mental development in alpha-mannosidosis.


CRT diagnosis of pulmonary disease: influence of monitor brightness and room illuminance on observer performance.
Using a 21-in. cathode ray tube (CRT) monitor (2048 x 2560 x 8bits), six radiologists interpreted 12 images with interstitial lung disease under six conditions of CRT luminance (50 and 400 cd/m(2)) and room illuminance (20, 120 and 480lx), and 10 radiologists interpreted 25 images with pulmonary nodules under nine conditions of CRT luminance (50, 200 and 500 cd/m(2)) and room illuminance (20, 120 and 480lx). Observer's performance for interstitial disease was relatively better at 120lx. Four hundred and eighty lux illuminance with 50 cd/m(2) CRT luminance, which degraded the detectability of pulmonary nodule significantly (p<0.05), should be avoided for clinical use.


Diagnostic ability of magnification endoscope with narrow-band imaging in screening esophagogastroduodenoscopy.
Magnifying endoscopy with narrow-band imaging (M-NBI) is useful for the optical diagnosis of gastrointestinal neoplasms. However, the utility of M-NBI in screening esophagogastroduodenoscopy (EGD) is unclear. We aimed to evaluate the diagnostic ability of the magnification endoscope (ME) in screening EGD for a population with a low prevalence of upper gastrointestinal cancers. Overall, 4887 asymptomatic examinees without a history of laryngopharyngeal and/or upper gastrointestinal neoplasms who underwent opportunistic screening EGD between April 2011 and December 2017 were enrolled in this retrospective study. The examinees were categorized into two groups depending on whether screening EGD was performed using ME (ME group) or not (non-ME group). Using a propensity score-matched analysis, the diagnostic ability of EGD was compared between the two groups. In total, 1482 examinees (30%) were allocated to the ME group and 3405 (70%) to the non-ME group. Thirty-five epithelial neoplasms were detected in 30 examinees (0.6%). The groups were matched for baseline characteristics (1481 pairs). Both groups showed no significant difference in the epithelial neoplasm detection rate (0.8% vs. 0.3%; P = 0.14). The biopsy rate was significantly lower in the ME group than in the non-ME group (12% vs. 15%; P = 0.003). The positive predictive value (PPV) for biopsy was significantly higher in the ME group than in the non-ME group (6.6% vs. 2.8%; P = 0.048). Using an ME for screening EGD in an apparently healthy, asymptomatic population could reduce unnecessary biopsies by improving PPV for biopsy without decreasing the epithelial neoplasm detection rate.


Relative hypoxia of the extremities in Fabry disease.
A purine degradation study, thermography and near infrared spectroscopy of the extremities were performed on 2 young males with Fabry disease and 2 healthy controls. Two-minute semi-ischemic forearm exercise caused a distinct increase in lactate in all subjects, but venous hypoxanthine and ammonia were greatly increased only in the Fabry patients, suggesting a relatively hypoxic state of the extremities. Limb thermograms of the patients revealed glove and stocking type disturbance at rest. Poor recovery of the skin temperature of the hands and forearms after exercise was observed in the patients, but the sharp increase in oxygenated hemoglobin after total ischemia was found to be normal or near infrared spectroscopy. Neurotropin showed an analgesic effect, i.e. a strong and selective heat-productive action on the painful lesions, and suppressed the hypoxanthine level after exercise in 1 patient. Although the pathophysiology of the pain in Fabry disease has not been clearly elucidated, a relatively hypoxic state with peripheral hypothermia might play an important role in triggering of a painful attack or chronic burning paresthesia.


Top-down effects of raptor predation on northern bobwhite.
Understanding how predators affect prey species is a central endeavor in applied ecology. Game birds are a culturally and economically important group of birds throughout the world. Specifically, northern bobwhite (Colinus virginianus) is an imperiled game bird native to North America that has declined precipitously over the past 65 years. Concurrently, raptor populations increased substantially as a result of pesticide bans and legal protections. However, relationships between raptors and bobwhites are not well-understood because of limited long-term data. We analyzed long-term raptor survey and bobwhite survival datasets from 2008 to 2018 to determine if oscillations in raptor abundance affected bobwhite survival. We used a novel open multi-species dynamics hierarchical distance sampling model to estimate the abundance of raptors. We used a known-fate survival model to determine if variation in raptor abundance affected bobwhite survival. We had multiple working hypotheses regarding biological relationships between raptor abundance and bobwhite survival. Raptors affected bobwhites in every biological season but were more influential in the breeding season and late winter supporting the notion of bobwhite behavior and raptor migration were driving observed patterns. Our results suggest that even in areas with abundant habitat, predators exert top-down influences on vital rates suggesting similar or greater influences on populations under poor habitat conditions.


Intravenous quinidine in congestive cardiomyopathy.
Eight male patients with compensated congestive cardiomyopathy received single 300-mg doses of intravenous quinidine by 15-min infusion. Left ventricular (LV) performance was evaluated by echocardiography at multiple points in time during the next 24 h. Quinidine kinetics and protein binding were determined from multiple serum samples drawn for up to 36 h after dosage. LV function was not impaired. Instead, quinidine transiently increased ejection fraction (mean: +39%) and rate of circumferential shortening (mean: +46%). Endsystolic and end-diastolic LV internal diameter likewise were decreased (means: -13% and -7%). Blood pressure and ventricular rate were not significantly altered. Compared to 8 healthy controls matched for age, sex, and weight, quinidine volume of distribution among patients was smaller (means: 2.27 vs 1.90 l/kg), as was total quinidine clearance (3.49 vs 2.84 ml/min/kg); however, differences were not statistically significant. Well-controlled, slow intravenous infusion of quinidine does not impair LV performance and is safe for patients with compensated congestive cardiomyopathy. However, such patients may have reduced quinidine clearance and hence require lower doses than expected based on age and weight.