Evaluation of different cavitational reactors for size reduction of DADPS.
The present study deals with the size reduction based on the recrystallization (antisolvent approach using water) of 3,3'-Diamino Diphenyl Sulfone (DADPS) using different types of cavitational reactors as an alternative to the conventional process of mechanical size reduction, which is an energy intensive approach. Ultrasound was applied for fixed time specific to the reactors namely ultrasonic probes at different power dissipation levels and also ultrasonic bath. A High Speed Homogenizer was also used at varying speeds of rotation to establishing the efficacy for size reduction. The processed sample was analysed for particle size and morphology using particle size analyser and optical microscopy respectively. The final yield of recrystallization was also determined. The power density in W/L and power intensity in W/m2 calculated for each equipment has been used to establish efficacy for size reduction since all devices had dissimilar configurations. Based on the studies of varying power intensity of the different US equipment, it was established that larger the power intensity and power density, smaller was the resultant final particle size after treatment for same time. Among the various ultrasonic devices used, Sonics VCX750 probe yielded the best size reduction of 85.47% when operated at 40% amplitude for 60 min for a volume of 200 ml. A High Speed Homogenizer used at 7000 rpm gave 92.35% of size reduction in 15 min operation and also demonstrated the best energy efficiency. The work has elucidated the comparison of different cavitational devices for size reduction for the first time and presented the best reactors and conditions for the desired size reduction.


Immunosensor for extra-lab measurements based on liposome amplification and capillary migration.
A novel prototype immunosensing device has been developed which incorporates the simplicity of competitive immunochromatography with the rapid signal amplification capabilities of marker-loaded liposomes. An avidin capture zone provides direct readout of the analyte concentration.


TNF induces glycolytic shift in fibroblast like synoviocytes via GLUT1 and HIF1A.
TNF is a central cytokine in the pathogenesis of rheumatoid arthritis (RA). Elevated level of TNF causes local inflammation that affects immune cells and fibroblast-like synoviocytes (FLS). Nowadays, only 20-30% of patients experience remission after the standard of care therapy-antibodies against TNF. Interestingly, responders show reduced levels of GLUT1 and GAPDH, highlighting a potential link to cellular metabolism. The aim of the study was to investigate whether TNF directly affects the metabolic phenotype of FLS. Real-time respirometry displayed TNF-induced upregulation of glycolysis along with a modest increase of oxidative phosphorylation in FLS from healthy donors. In addition, TNF stimulation enhanced HIF1A and GLUT1 expression. The upregulation of HIF1A and GLUT1 reflects their enriched level in FLS from RA patients (RA-FLS). The inhibition of TAK1, HIF1a and hexokinase deciphered the importance of TNF/TAK1/HIF1A/glycolysis signaling axis. To prove that inhibition of glycolysis reduced the pathogenic phenotype, we showed that 2-deoxyglucose, a hexokinase inhibitor, partially decreased secretion of RA biomarkers. In summary, we identified a direct role of TNF on glycolytic reprogramming of FLS and confirmed the potency of immunometabolism for RA. Further studies are needed to evaluate the therapeutic impact especially regarding non-responder data.


Leukoaraiosis Severity Predicts Rate of Decline in Primary Progressive Aphasia.
The rate of decline in language in Primary Progressive Aphasia (PPA) is highly variable and difficult to predict at baseline. The severity of diffuse white matter disease (leukoaraiosis), a marker of overall brain health, may substantially influence the rate of decline. To test the hypothesis that leukoaraiosis is associated with a steeper decline in naming in PPA. In this longitudinal, observational study, 29 individuals with PPA (all variants) were administered the Boston Naming Test (BNT) at baseline and 1 year later. Two raters evaluated leukoaraiosis on baseline MRI, using the Cardiovascular Health Study scale. We evaluated the effects of leukoaraiosis severity, age, education, and baseline BNT on decline measured by change in BNT accuracy with multivariable linear regression. We also evaluated the effects of these variables on the dichotomized outcome of faster decline in BNT (worst 50%) versus slower decline (best 50%) using logistic regression. Together, leukoaraiosis, age, education, and baseline BNT score predicted change in BNT score (F(3, 25) = 8.12; p=0.0006). Change in BNT score was predicted by severity of leukoaraiosis (t =-3.81; p=0.001) and education (t= -2.45; p=0.022), independently of the other variables. When we dichotomized outcome into upper 50th percentile versus lower 50th percentile (faster decline), faster decline was predicted by all variables together (chi squared = 13.91; p = 0.008). However, only leukoaraiosis independently predicted outcome (OR=2.80; 95%CI: 1.11 to 7.03). For every 1 point increase on the CHS rating scale, there was 2.8 times higher chance of showing faster decline in naming. Severity of leukoaraiosis is associated with steeper decline in naming in PPA. This imaging marker can aide in prognosis and planning by caregivers and stratification of participants in clinical trials.


Atypical histiocytoid cells in fine-needle aspiration cytology of metastatic papillary thyroid carcinoma: A potential diagnostic pitfall.
Fine needle aspiration (FNA) cytology of cervical lymph nodes is an effective diagnostic tool to detect metastatic papillary thyroid carcinoma (PTC) when typical cytomorphologic features of PTC are observed. However, the presence of atypical histiocytoid cells (AHCs) due to cystic degeneration sometimes poses a diagnostic challenge. The purpose of this study was to evaluate the presence and cytomorphology of AHCs in metastatic PTC. We analyzed a total of 76 FNA cytological samples of cervical lymph nodes from 66 patients with metastatic PTC diagnosed during approximately 10-year period, from January 2010 to April 2020. Samples were either liquid based preparation (n = 53) or conventional smear (n = 23). AHCs were present in 38 (50%) of the 76 FNA cases and the remaining 38 cases showed classic PTC features. Among the 38 cases, eight displayed pure AHCs that constituted 10.5% of all the metastatic PTC in the lymph nodes. Pure AHCs were more commonly detected in the liquid based preparation (7/53, 13.2%) than the conventional smear (1/23, 4.3%). The remaining 30 cases had AHCs mixed with the characteristic PTC components. The presence of AHCs was found to be statistically associated with cystic background (p < .002). Metastatic PTC frequently exhibits cystic degeneration and the FNA cytology may not yield classic cytological features of PTC. Pure AHCs composed 10.5% of all cases and might be a potential pitfall for liquid based preparation in diagnosing metastatic PTC. The finding of AHCs within the cystic background should raise the concern of metastatic PTC.


IgG Fc-binding protein positively regulates the assembly of pore-forming protein complex βγ-CAT evolved to drive cell vesicular delivery and transport.
Cell membranes form barriers for molecule exchange between the cytosol and the extracellular environments. βγ-CAT, a complex of pore-forming protein BmALP1 (two βγ-crystallin domains with an aerolysin pore-forming domain) and the trefoil factor BmTFF3, has been identified in toad Bombina maxima. It plays pivotal roles, via inducing channel formation in various intracellular or extracellular vesicles, as well as in nutrient acquisition, maintaining water balance, and antigen presentation. Thus, such a protein machine should be tightly regulated. Indeed, BmALP3 (a paralog of BmALP1) oxidizes BmALP1 to form a water-soluble polymer, leading to dissociation of the βγ-CAT complex and loss of biological activity. Here, we found that the B. maxima IgG Fc-binding protein (FCGBP), a well-conserved vertebrate mucin-like protein with unknown functions, acted as a positive regulator for βγ-CAT complex assembly. The interactions among FCGBP, BmALP1, and BmTFF3 were revealed by co-immunoprecipitation assays. Interestingly, FCGBP reversed the inhibitory effect of BmALP3 on the βγ-CAT complex. Furthermore, FCGBP reduced BmALP1 polymers and facilitated the assembly of βγ-CAT with the biological pore-forming activity in the presence of BmTFF3. Our findings define the role of FCGBP in mediating the assembly of a pore-forming protein machine evolved to drive cell vesicular delivery and transport.


Clinical Presentation of Alpha-Gal Syndrome in Pediatric Gastroenterology and Response to Mammalian Dietary Elimination.
Alpha-gal syndrome is an immunoglobulin E (IgE)-mediated delayed hypersensitivity reaction to nonprimate mammalian products, which has a newly established gastrointestinal (GI) phenotype in adults. We assessed the GI presentation and treatment response in children. This is a retrospective study of patients presenting in a pediatric gastroenterology clinic tested for alpha-gal IgE. Forty of 199 patients (20%) tested had a positive alpha-gal-specific IgE, with 77.5% reporting GI symptoms in isolation. Of the 30 that attempted dietary elimination, 8 (27%) experienced full resolution of symptoms. Alpha-gal syndrome can present with isolated GI symptoms in children.


Regional quantitative determination of lactate in brain sections. A bioluminescent approach.
Regional lactate distribution in brain was assessed quantitatively in coronal sections using a bioluminescent technique. This bioluminescence can be induced by covering freeze-dried and heat-inactivated brain sections with a frozen solution containing enzymes and coenzymes both for lactate-dependent NADH formation and NADH-dependent bioluminescence, which was recorded photographically. Quantification and density coding of bioluminescent images were carried out by utilizing the regression coefficients of the correlation between the optical density of bioluminescent pictures and the lactate content measured in tissue samples. Regional quantitative lactate images were obtained from brain tissue taken from brain tumors or after experimental cerebral ischemia.


Sagittal imbalance influences outcome of vertebroplasty in patients with osteoporotic vertebral compression fracture.
The correlation between sagittal balance of the spine and clinical outcome after vertebroplasty (VP) in patients with osteoporotic vertebral compression fractures (OVCF) is poorly investigated. We analysed the clinical outcome of patients with OVCF undergoing VP taking into account sagittal balance. The primary endpoint was the change in axial back pain, disability and health-related quality-of-life using Visual Analogue Scale (VAS), Oswestry Disability Index (ODI) and SF-36, respectively, in correlation to the parameters that define sagittal balance (SVA). Radiographic assessment included full spine standing lateral films. Imaging and clinical data were collected pre- and post-procedure at 1, 3 and 12 months. 51 patients were included presenting a total of 113 OVCF. 30 patients (60.7%) had multiple OVCF. Comparing the evolution of VAS and ODI throughout the follow-up it does not seem that there are significant differences in their behaviour between the SVA>50mm and the SVA<50mm groups (p>0.05). On the contrary, pre-VP SF-36 scores showed worst results in the SVA>50mm group in the physical functioning (PF) section (p<0.05) and in the physical component score (PCS) (p<0.05). These differences were maintained until 3 months of follow-up in the case of the PCS and until the end of follow-up in the case of the PF (p<0.05). Patients with a SVA>50mm showed a slower recovery of their quality-of-life after VP for OVCF, but without significant differences with respect to pain or disability, when compared patients with SVA<50mm.


Optimizing the soft independent modeling of class analogy (SIMCA) using statistical prediction regions.
The ultimate goal of a one-class classifier like the "rigorous" soft independent modeling of class analogy (SIMCA) is to predict with a certain confidence probability, the conformity of future objects with a given reference class. However, the SIMCA model, as currently implemented often suffers from an undercoverage problem, meaning that its observed sensitivity often falls far below the desired theoretical confidence probability, hence undermining its intended use as a predictive tool. To overcome the issue, the most reported strategy in the literature, involves incrementing the nominal confidence probability until the desired sensitivity is obtained in cross-validation. This article proposes a statistical prediction interval-based strategy as an alternative strategy to properly overcome this undercoverage issue. The strategy uses the concept of predictive distributions sensu stricto to construct statistical prediction regions for the metrics. Firstly, a procedure based on goodness-of-fit criteria is used to select the best-fitting family of probability models for each metric or its monotonic transformation, among several plausible candidate families of right-skewed probability distributions for positive random variables, including the gamma and the lognormal families. Secondly, assuming the best-fitting distribution, a generalized linear model is fitted to each metric data using the Bayesian method. This method enables to conveniently estimate uncertainties about the parameters of the selected distribution. Propagating these uncertainties to the best-fitting probability model of the metric enables to derive its so-called posterior predictive distribution, which is then used to set its critical limit. Overall, the evaluation of the proposed approach on a diversity of real datasets shows that it yields unbiased and more accurate sensitivities than existing methods which are not based on predictive densities. It can even yield better specificities than the strategy that attempts to improve sensitivities of existing methods by "optimizing" the type 1 error, especially in low sample sizes' contexts.


DLX6-AS1 activated by H3K4me1 enhanced secondary cisplatin resistance of lung squamous cell carcinoma through modulating miR-181a-5p/miR-382-5p/CELF1 axis.
Cisplatin (CDDP) based chemotherapy is widely used as the first-line strategy in treating non-small cell lung cancer (NSCLC), especially lung squamous cell carcinoma (LUSC). However, secondary cisplatin resistance majorly undermines the cisplatin efficacy leading to a worse prognosis. In this respect, we have identified the role of the DLX6-AS1/miR-181a-5p/miR-382-5p/CELF1 axis in regulating cisplatin resistance of LUSC. qRT-PCR and Western blot analysis were applied to detect gene expression. Transwell assay was used to evaluate the migration and invasion ability of LUSC cells. CCK-8 assay was used to investigate the IC50 of LUSC cells. Flow cytometry was used to test cell apoptosis rate. RNA pull-down and Dual luciferase reporter gene assay were performed to evaluate the crosstalk. DLX6-AS1 was aberrantly high expressed in LUSC tissues and cell lines, and negatively correlated with miR-181a-5p and miR-382-5p expression. DLX6-AS1 expression was enhanced by H3K4me1 in cisplatin resistant LUSC cells. Besides, DLX6-AS1 knockdown led to impaired IC50 of cisplatin resistant LUSC cells. Furthermore, DLX6-AS1 interacted with miR-181a-5p and miR-382-5p to regulate CELF1 expression and thereby mediated the cisplatin sensitivity of cisplatin resistant LUSC cells. DLX6-AS1 induced by H3K4me1 played an important role in promoting secondary cisplatin resistance of LUSC through regulating the miR-181a-5p/miR-382-5p/CELF1 axis. Therefore, targeting DLX6-AS1 might be a novel way of reversing secondary cisplatin resistance in LUSC.


Effect of modulation of PPAR-γ activity on Kupffer cells M1/M2 polarization in the development of non-alcoholic fatty liver disease.
Abnormal lipid-mediated hepatic inflammatory-immune dysfunction and chronic low grade inflammation play an important role in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Macrophage polarization is an important mechanism for the regulation of inflammatory response. Since PPAR-γ has emerged as a master regulator of macrophage polarization, we aimed to investigate the lipid-induced macrophage/Kupffer cell polarization in vivo and in vitro, and explore the association between PPAR-γ activity and macrophages M1/M2 polarization shifting. Here we showed that long-term high-fat diet increased Kupffer cells content with M1-predominant phenotype and increasing production of pro-inflammatory cytokines. Saturated fatty acids polarized Kupffer cells/macrophages to an M1-predominant phenotype while n-3 PUFA polarized Kupffer cells/macrophages to an M2 phenotype, which was associated with activation of NF-κB signal pathway and PPAR-γ respectively. Furthermore, up-regulation of PPAR-γ shifted lipid-induced macrophages polarization from M1-predominant phenotype to M2 phenotype. Macrophages polarization switch was associated with the interaction between PPAR-γ and NF-κBp65 signal pathway. Rosiglitazone restored high-fat diet-induced imblance of Kupffer cells M1/M2 polarization and alleviated hepatic steatosis as well as local pro-inflammatory response. These findings suggest that manipulation of PPAR-γ activity has the potential to balance lipid-induced M1/M2 macrophage/Kupffer cell polarization, and leading to prevent the development of NAFLD.


Cation-independent mannose 6-phosphate and 78 kDa receptors for lysosomal enzyme targeting are located in different cell compartments.
The distribution of the cation-independent mannose 6-phosphate and 78 kDa receptors was studied in postnuclear subcellular fractions from two rat liver cell lines. ELISA assays revealed that the mannose 6-phosphate receptor is enriched in the light buoyant Percoll fractions that contain Golgi structures and early endosomes. Most of the 78 kDa receptor is localized in a heavy fraction at the bottom of the Percoll gradient and smaller amounts in the endosomal fractions. The high-density compartment is denser than lysosomes, contains LAMP2 but not LIMPII or acid hydrolases, and is not disrupted with glycyl-l-phenylalanine 2-naphthylamide, a substrate for cathepsin C that selectively disrupts lysosomes. Immunofluorescence microscopy studies indicate no colocalization of the 78 kDa receptor with the mannose 6-phosphate receptor or LIMPII. Mannose 6-phosphate-independent endocytosed beta-glucuronidase was found in the lysosomal, the early and late endosomal fractions. These fractions were immunoadsorbed in columns containing antibodies against the 78 kDa receptor. Only the endocytosed beta-glucuronidase present in the early and late endosomal fractions is associated to immunoadsorbed vesicles. In these vesicles, LAMP2 was detected but no LIMPII or the mannose 6-phosphate receptor. Results obtained suggest that the 78 kDa receptor is found along the endocytic pathway, but in vesicles different from the cation-independent mannose 6-phosphate receptor.


groEL is a suitable genetic marker for detecting Vibrio parahaemolyticus by loop-mediated isothermal amplification assay.
A groEL gene-based loop-mediated isothermal amplification (LAMP) assay was developed to detect Vibrio parahaemolyticus in contaminated seafood and water. The assay was optimized and conducted at 63°C for 40 min using Bacillus stearothermophilus (Bst) DNA polymerase, large fragment. Amplification was analysed via multiple detection methods, including opacity, formation of white precipitate, DNA intercalating dyes (ethidium bromide and SYBR Green I), metal ion-binding indicator dye, calcein, and 2% agarose gel electrophoresis. A characteristic ladder-like band pattern on agarose gel and the desired colour changes when using different dyes were observed in positive cases, and these were species-specific for V. parahaemolyticus when compared with other closely related Vibrio spp. The limit of detection (LoD) of this assay was 100 fg per reaction, 100-fold higher than that for conventional polymerase chain reaction (PCR). When tested on artificially contaminated seafood and seawater, the LoDs of the LAMP assay were 120 and 150 fg per reaction respectively, and those of conventional PCR were 120 and 150 pg per reaction respectively. Based on our results, the groEL gene-based LAMP assay is rapid, specific, sensitive, and reliable for detecting V. parahaemolyticus, and it could be used in field diagnosis. The loop-mediated isothermal amplification (LAMP) assay using groEL gene (an abundant, highly conserved gene and member of the groESL chaperone gene family) provided rapid, species-specific and highly sensitive method for detecting Vibrio parahaemolyticus, the leading causal agent of seafood-borne diseases worldwide. Moreover, groEL LAMP revealed high efficiency than conventional PCR assay for V. parahaemolyticus using template both from pure culture and artificially contaminated seafood and water, which indicated the applicability in the field and environmental screening purpose for the organism.


The Efficacy Mechanism of Epigallocatechin Gallate against Pre-Eclampsia based on Network Pharmacology and Molecular Docking.
Pre-eclampsia (PE), a pregnancy complication, affects 3-5% of all pregnancies worldwide and is the main cause of maternal and perinatal morbidity. However, there is no drug which can clearly slow this disease progression. Epigallocatechin gallate (EGCG), a natural compound extracted from green tea, has been found to enhance the treatment efficacy of oral nifedipine against pregnancy-induced severe PE. This study aims to clarify the potential targets and pharmacological mechanisms of EGCG in treatment of PE. We used Traditional Chinese Medicine Systems Pharmacology database and Gene Cards database to obtain 179 putative target proteins of EGCG, 550 PE-related hub genes and 39 intersecting targets between EGCG and PE. By using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses, we got the gene entries and enrichment pathways closely related to the intersecting targets. The top 10 enrichment pathways were pathway in cancer, proteoglycans in cancer, HIF-1 signaling pathway, AGE-RAGE signaling pathway in diabetic complications, TNF signaling pathway, bladder cancer, hepatitis B, IL-17 signaling pathway, toxoplasmosis, PI3K-Akt signaling pathway. Furthermore, compound-target-pathway (CTP) and protein-protein interaction (PPI) network analysis were employed to explore the interaction of the top twelve targets for EGCG in treating PE. Molecular docking analysis showed combinations between these targets and EGCG, and the interaction between EGCG and the targets IL-6 and EGFR was confirmed by using molecular dynamic simulation. In conclusion, these findings hint the underlying mechanism of EGCG in the treatment of PE and point out directions in further studies on PE.


Preparation and investigation of sustained drug delivery systems using an injectable, thermosensitive, in situ forming hydrogel composed of PLGA-PEG-PLGA.
In situ gelling systems are very attractive for pharmaceutical applications due to their biodegradability and simple manufacturing processes. The synthesis and characterization of thermosensitive poly(D,L-lactic-co-glycolic acid) (PLGA)-polyethylene glycol (PEG)-PLGA triblock copolymers as in situ gelling matrices were investigated in this study as a drug delivery system. Ring-opening polymerization using microwave irradiation was utilized as a novel technique, and the results were compared with those using a conventional method of polymerization. The phase transition temperature and the critical micelle concentration (CMC) of the copolymer solutions were determined by differential scanning calorimetry and spectrophotometry, respectively. The size of the micelles was determined with a light scattering method. In vitro drug release studies were carried out using naltrexone hydrochloride and vitamin B12 as model drugs. The rate and yield of the copolymerization process via microwave irradiation were higher than those of the conventional method. The copolymer structure and concentration played critical roles in controlling the sol-gel transition temperature, the CMC, and the size of the nanomicelles in the copolymer solutions. The rate of drug release could be modulated by the molecular weight of the drugs, the concentration of the copolymers, and their structures in the formulations. The amount of release versus time followed zero-order release kinetics for vitamin B12 over 25 days, in contrast to the Higuchi modeling for naltrexone hydrochloride over a period of 17 days. In conclusion, PLGA-PEG1500-PLGA with a lactide-to-glycolide ratio of 5:1 is an ideal system for the long-acting, controlled release of naltrexone hydrochloride and vitamin B12.


Cancer Treatment-Induced Bone Loss (CTIBL): State of the Art and Proper Management in Breast Cancer Patients on Endocrine Therapy.
About 70-80% of early breast cancer (BC) patients receive adjuvant endocrine therapy (ET) for at least 5 years. ET includes in the majority of cases the use of aromatase inhibitors, as upfront or switch strategy, that lead to impaired bone health. Given the high incidence and also the high prevalence of BC, cancer treatment-induced bone loss (CTIBL) represents the most common long-term adverse event experimented by patients with hormone receptor positive tumours. CTIBL is responsible for osteoporosis occurrence and, as a consequence, fragility fractures that may negatively affect quality of life and survival expectancy. As recommended by main international guidelines, BC women on aromatase inhibitors should be carefully assessed for their fracture risk at baseline and periodically reassessed during adjuvant ET in order to early detect significant worsening in terms of bone health. Antiresorptive agents, together with adequate intake of calcium and vitamin D, should be administered in BC patients during all course of ET, especially in those at high risk of osteoporotic fractures, as calculated by tools available for clinicians. Bisphosphonates, such as zoledronate or pamidronate, and anti-RANKL antibody, denosumab, are the two classes of antiresorptive drugs used in clinical practice with similar efficacy in preventing bone loss induced by aromatase inhibitor therapy. The choice between them, in the absence of direct comparison, should be based on patients' preference and compliance; the different safety profile is mainly related to the route of administration, although both types of drugs are manageable with due care, since most of the adverse events are predictable and preventable. Despite advances in management of CTIBL, several issues such as the optimal time of starting antiresorptive agents and the duration of treatment remain unanswered. Future clinical trials as well as increased awareness of bone health are needed to improve prevention, assessment and treatment of CTIBL in these long-term survivor patients.


Notch signaling plays a crucial role in cancer stem-like cells maintaining stemness and mediating chemotaxis in renal cell carcinoma.
Cancer stem cells (CSCs) are correlated with the initiation, chemoresistance and relapse of tumors. Notch pathway has been reported to function in CSCs maintenance, but whether it is involved in renal cell carcinoma (RCC) CSCs maintaining stemness remain unclear. This study aims to explore the effect of Notch pathway on stemness of CSCs in RCC and the underlying mechanisms. The CD133+/CD24+ cells were isolated from RCC ACHN and Caki-1 cell line using Magnetic-activated cell sorting and identified by Flow cytometry analysis. RT-PCR and immunoblot analyses were used for determining the stemness maker expression. The effect of Notch pathway on function of CSCs was assessed by self-renewal ability, chemosensitivity, invasive and migratory ability tumorigenicity in vivo using soft agar colony formation assay, sphere-forming assay, MTT assay, Transwell assay. Here, we found that the sorted CD133+/CD24+cells possessed elevated stemness maker CTR2, BCL-2, MDR1, OCT-4, KLF4, compared with parental cells, as well as enhanced self-renewal ability, stronger resistance to cisplatin and sorafenib, increased invasion and migration, and higher tumorigenesis in vivo, suggesting the CD133+/CD24+ cells have the stem-like characteristics of CSCs and thus identified as RCC CSCs. Then the enhanced notch1, notch2, Jagged1, Jagged2, DLL1 and DLL4 expression were detected in RCC CSCs and blockage of Notch1 or notch2 using pharmacological inhibitor MRK-003 or its endogenous inhibitor Numb resulted in loss of its stemness features: self-renewal, chemoresistance, invasive and migratory potential, and tumorigenesis in vivo. Moreover, it is confirmed that overexpression of notch1 up-regulated CXCR4 inRCC CSCs and augmented SDF-1-induced chemotaxis in RCC CSCs in vitro, which could be rescued when treatment of CXCR4 inhibitor, suggesting that notch signaling promotes the chemotaxis of RCC CSCs by SDF-1/CXCR4 axis. Our results provide a new mechanism of RCC CSCs maintaining stemness via notch pathway as well as a potential therapeutic target in human RCC.


Quality and patient satisfaction after ambulatory laparoscopic management of non-severe and uncomplicated gallbladder pathology.
Ambulatory laparoscopic cholecystectomy (ALC) reduces the use of hospital beds and benefits the patient by returning home sooner. Therefore, it is important to evaluate the degree of patient satisfaction. A controlled clinical trial was designed to assess the efficacy, safety, and satisfaction of ALC, compared to the usual laparoscopic cholecystectomy (ULC). Efficacy and safety were evaluated based on; recovery of the oral route, spontaneous urination, gas channeling, presence of pain, nausea, vomiting, bleeding, pain, penrose expense. Satisfaction was explored through an adaptation of the SATISCORE questionnaire. We included 71 patients, 38 from the experimental group (ALC) and 33 from the control group (ULC). There was a higher proportion of women, average age at the fifth decade, and a similar distribution of comorbidities. In safety and efficacy, the results were similar. In the survey, the ALC group showed an 89.5% high degree of satisfaction. There was a good postoperative recovery in both groups as they reincorporated earlier, identified in a better satisfaction index referred by the patient. The ALC is as effective and safe as ULC, so it can be considered as the new "gold standard" for the surgical management of uncomplicated biliary pathology.


Further delineation of the Simpson-Golabi-Behmel (SGB) syndrome.
The Simpson-Golabi-Behmel syndrome is an X-linked condition characterized by pre- and postnatal overgrowth, "coarse" face, postaxial polydactyly, midline defects, and psychomotor development ranging from normal to mildly retarded. We report on an additional sporadic patient with novel manifestations, contributing to a more thorough delineation of this syndrome.


A green microwave method for synthesizing a more stable phthalazin-1-ol isomer as a good anticancer reagent using chemical plasma organic reactions.
Conventional synthesis of the phthalazine has already allowed affording the phthalazin-1-one phthalazin-1-ol dynamic equilibrium that decreases the anticancer activity due to diminishing the concentration of the phthalazin-1-ol product. Nowadays, pure phthalazin-1-ol (5) can be gaining by using green microwave tools that increase the power of the phthalazine nucleus as an anticancer drug. A microscopic thermal kinetic parameter like activation energy and the pre-exponential factor of the chemical plasma organic reactions affording pure phthalazin-1-ol (5) is calculated by using DFT simulation is obtained. Then we fed these parameters into the exact Arrhenius model to evaluate the distribution of chemical equilibrium conditions for producing phthalazin-1-ol. The proposed novel models that matching between microscopic and macroscopic show that the thermal stability of the equivalent temperature of phthalazin-1-ol is more stable than phthalazinone-1-one (4) in case of using plasma organic effect (green microwave) at 485 K. The structures of the prepared compounds were explained by physical and spectral data like FT-IR, 1H-NMR. Moreover, the theoretical calculations of Gibbs entropy of the phase transfer confirmed the equilibrium state of phthalazin-1-ol with the experimental result is achieved. Briefly, we introduce a good study for obtaining more stable phthalazin-1-ol isomer by using a green microwave method which is considered as good anticancer reagents of phenolic group (OH) and p-propenyl-anisole precursor as anise oil analogous.


Equilibria for the relative motion of three heavy spheres in Stokes fluid flow.
Dynamics of three identical solid spheres falling under gravity in low-Reynolds-number fluid flow is investigated. Stationary solutions are found. Their stability is discussed. Phase portraits for two types of symmetric motions are calculated.


A two-colour multiplexed lateral flow immunoassay system to differentially detect human malaria species on a single test line.
Malaria continues to impose a tremendous burden in terms of global morbidity and mortality, yet even today, a large number of diagnoses are presumptive resulting in lack of or inappropriate treatment. In this work, a two-colour lateral flow immunoassay (LFA) system was developed to identify infections by Plasmodium spp. and differentiate Plasmodium falciparum infection from the other three human malaria species (Plasmodium vivax, Plasmodium ovale, Plasmodium malariae). To achieve this goal, red and blue colours were encoded to two markers on a single test line of strips, for simultaneous detection of PfHRP2 (red), a marker specific for P. falciparum infection, and pLDH (blue), a pan-specific marker for infections by all species of Plasmodium. The assay performance was first optimized and evaluated with recombinant malarial proteins spiked in washing buffer at various concentrations from 0 to 1000 ng mL-1. The colour profiles developed on the single test line were discriminated and quantified: colour types corresponded to malaria protein species; colour intensities represented protein concentration levels. The limit of detection (the lowest concentrations of malaria antigens that can be distinguished from blank samples) and the limit of colour discrimination (the limit to differentiate pLDH from PfHRP2) were defined for the two-colour assay from the spiked buffer test, and the two limits were 31.2 ng mL-1 and 7.8 ng mL-1, respectively. To further validate the efficacy of the assay, 25 human whole blood frozen samples were tested and successfully validated against ELISA and microscopy results: 15 samples showed malaria negative; 5 samples showed P. falciparum positive; 5 samples showed P. falciparum negative, but contained other malaria species. The assay provides a simple method to quickly identify and differentiate infection by different malarial parasites at the point-of-need and overcome the physical limitations of traditional LFAs, improving the multiplexing potential for simultaneous detection of various biomarkers.


Effects of whey protein and leucine supplementation on insulin resistance in non-obese insulin-resistant model rats.
Whey protein (WP) has been reported to reduce body weight gain and improve glucose metabolism in obese individuals. This study aims to assess and compare the effects of WP and its hydrolysate-leucine (Leu) supplementation in non-obese, insulin-resistant (IR) rat models, particularly the effects on insulin sensitivity, lipid profile, and antioxidant activity. Wistar rats were fed a diet consisting of 38.5% fat for 12 wk and 51.3% fat for an additional 4 wk to establish non-obese IR rats. The IR rats were then switched to regular AIN-93 diet containing 0% WP, 5% WP, 15% WP or 1.6% Leu for 8 wk. The Leu content was the same in the 15% WP and 1.6% Leu groups based on high-performance liquid chromatography. The IR rats' body weight, fasting blood glucose, fasting insulin, and homeostasis model assessment-insulin resistance were measured before and after supplementation. An oral glucose tolerance test was performed after supplementation. Body composition, plasma concentrations of the lipids profile, and antioxidant index also were analyzed. No significant difference was observed in body weight, energy intake, and fasting blood glucose in the non-obese IR rats at the end of the experiment. Compared with the 0% WP group, the fasting insulin and homeostasis model assessment-insulin resistance significantly decreased in the 15% WP and 1.6% Leu groups. Furthermore, the blood glucose area under the curve of the oral glucose tolerance test was significantly less in the 15% WP and 1.6% Leu groups. There were no differences in the lipids profile, except for the increase in the high-density lipoprotein cholesterol in the 15% WP and 1.6% Leu groups. For the antioxidant index, the 15% WP group had significantly increased plasma levels for total antioxidation capacity, superoxide dismutase, and glutathione, and a decreased malondialdehyde concentration. The 1.6% Leu group was shown to have the same effect as the 15% WP group, except for the glutathione. Our findings demonstrate that the supplementation of WP and Leu may improve IR and antioxidant stress without resulting in changes in body weight and energy intake in non-obese IR rats.


Production of insulin-like growth factor-II (MSA) by endoderm-like cells derived from embryonal carcinoma cells: possible mediator of embryonic cell growth.
The present study was carried out to determine if an insulin-like growth factor (IGF) type activity might be produced by embryonal carcinoma-derived cells. The cell line used to condition growth medium for the isolation of secreted growth factors was a newly established Dif 5 cell type. Dif 5 cells are a differentiated endoderm-like cell type derived from F9 embryonal carcinoma cells (which possess properties similar to mouse embryonic stem cells) following extensive exposure to retinoic acid. When growth medium conditioned by Dif 5 cells is chromatographed on Sephadex G-75 in 1 M acetic acid two peaks of activity are observed which compete for specific [125I]iodo multiplication stimulating activity (MSA) binding to PYS cells. MSA is the rat homologue of human IGF-II. The high molecular weight fraction (Mr approximately 60K) apparently corresponds to IGF-binding protein as determined by its ability to bind [125I]iodo-MSA. The low molecular weight fraction (Mr approximately 8K) is biologically active as this fraction stimulates [3H]thymidine incorporation into serum-starved chick embryo fibroblasts. Radioimmunoassay data indicate that the IGF-like activity produced by Dif 5 cells is more closely related to IGF-II than to IGF-I. Undifferentiated embryonal carcinoma stem cell lines (F9, Nulli, and PCC4) produced little of this MSA-like activity, while PYS-2 (parietal endoderm-like) cells produced about 16 ng MSA/10(6) cells/24 hr as determined by radioimmunoassay. Dif 5 and PSA-5E (visceral endoderm-like) cells, are found to secrete significant amounts of MSA into the growth medium (30-50 ng MSA/10(6) cells/24 hr). These findings offer further support to a proposal that MSA (IGF-II) produced by endoderm cells, particularly visceral endoderm, may serve as an early embryonic growth factor.


An Exploratory Mixed Methods Study of Diabetes self-management in Blind Americans.
This study used mixed methods to investigate the experiences of 33 participants who are blind (PWB) and have diabetes in managing their diabetes, support (or lack thereof) from their health care providers, and diabetes distress as PWB. Participants most frequently reported barriers to check blood glucose (55%), maintaining a healthy diet (45%), and distress due to their intersectional status of having blindness and diabetes. Those who mentioned intersectional distress of managing diabetes as a PWB tended to be Braille illiterate and less likely to use mobility tools that are symbolic of blindness (e.g., white cane, guide dog). These results illuminate heterogenous characteristics of PWB with diabetes, an understudied population of public health significance, to be considered when setting priorities for diabetes self-management support and health care coverage policy.


Preparation and application of peptide molecularly imprinted material based on mesoporous metal-organic framework.
In this study, a new molecularly imprinted material, MIP@UiO-66-NH2, was synthesized with glutathione (GSH) as template and mesoporous metal organic framework (UiO-66-NH2) as matrix. The molecularly imprinted polymer was modified on the surface and into the pores of the UiO-66-NH2 by surface molecular imprinting method with thin polymer layer. Based on high specific surface area (1091.93 m2 g-1) and appropriate pore size (35 nm) of the ordered mesoporous UiO-66-NH2, the adsorption capacity for GSH reached 94.43 mg g-1, and the adsorption equilibrium could be achieved within 30 min. The adsorption isotherm data of MIP@UiO-66-NH2 could be described well by Freundlich model and the kinetic data complied well with pseudo-second-order model. In addition, the MIP@UiO-66-NH2 showed low adsorption capacity to GSH structural analogs (QL-cys = 6.51 mg g-1), suggesting great selectivity for GSH recognition. Finally, the MIP@UiO-66-NH2 was successfully applied for selective separation of GSH from BSA, skim milk and egg white tryptic digest.


Retinal melatonin and dopamine in seasonal affective disorder.
The author describes how phototherapy may treat seasonal affective disorder (SAD) by stimulating the production of retinal dopamine and suppressing the production of retinal melatonin. This hypothesis offers a framework in which winter-induced retinal dopamine deficiency or retinal melatonin overactivity may cause SAD and by which light reverses this syndrome. This hypothesis is consistent with recent data indicating that phototherapy in SAD acts specifically through the eyes.


The polyhydroxyalkanoate (PHA) synthase 1 of Pseudomonas sp. H9 synthesized a 3-hydroxybutyrate-dominant hybrid of short- and medium-chain-length PHA.
Pseudomonas sp. H9 (H9), an environmental strain isolated from a riverbank soil sample collected in southern Taiwan, is Gram-negative and shares a 99 % sequence identity to Pseudomonas putida KT2440 based on 16S rRNA gene analysis. H9 produced novel polyhydroxyalkanoates (PHA) including a hybrid PHA, comprised of 3-hydroxyvalerate (37 mol%) and medium-chain-length (MCL) monomers from valerate, as well as a 3-hydroxyhexanoate-dominant (93 mol%) MCL-PHA from hexanoate. Next-generation sequencing analysis showed H9 had a typical class II PHA operon, consisted of phaC1H9-phaZH9-phaC2H9, in which phaC1H9 was the sole active PHA synthase in H9. Deletion of phaC1H9 gene led to a complete loss of its PHA accumulation capability. Knockout of phaC2H9 gene, in contrast, affected neither bacterial growth nor PHA accumulation. When co-expressed with the phaAB genes of Ralstonia eutropha H16 in the PHA mutant strain Pseudomonas sp. H9ΔC1, phaC1H9 synthesized a hybrid PHA consisted of 3-hydroxybutyrate (3HB) (75 mol%) and MCL-monomers, confirmed in analyses using hot-acetone fractionation and 13C-NMR spectroscopy. As a novel PHA synthase, PhaC1H9 possesses a broad substrate specificity to synthesize a hybrid of SCL- and MCL-PHA, known to have many mechanical properties for potential applications.


The role of arthroscopy in the problem total knee replacement.
Fourteen patients were retrospectively reviewed to examine the role of arthroscopy in the diagnosis and treatment of the problem total knee arthroplasty (TKA), and to define parameters for indications, techniques, and results. All patients had undergone a previous TKA, and postoperatively had problems with pain and/or range of motion. Routine evaluation failed to reveal sepsis or aseptic loosening. Arthroscopy was used to evaluate and treat certain specific conditions. The arthroscope was successful in removing loose bodies, correcting patella subluxation with an arthroscopic lateral release, excising a symptomatic pseudomeniscus, and releasing intraarticular adhesions to improve motion and relieve pain. The postoperative knee score improved 73%. Arthroscopy is a valuable tool to evaluate a painful TKA, and can be used to treat certain conditions that would otherwise require an arthrotomy. The rehabilitation time is easier on the patient and much quicker. Arthroscopy of a TKA does not compromise any future procedures. However, it remains a technically demanding procedure whose indications and expectations are still being defined.


The remnant orchiectomy.
We examined and characterized the histological features of remnant testicular tissue distal to the internal inguinal ring in boys who underwent exploration for a nonpalpable testis. The medical records and histology of 48 boys (50 remnants) who underwent exploration for a nonpalpable testis during a 10-year period were reviewed in detail. Remnant tissue was characterized by evidence of ischemia and necrosis (scar, calcification, hemosiderin and hyalinization) suggestive of a vascular accident. Viable germ cells were identified in 5 remnants. A 10% incidence of viable germ cells in remnant testicular tissue warrants exploration and removal of all remnant tissue in boys who undergo exploration for a nonpalpable testis.


CD4+CD25(high) Treg cells in peripheral blood during remission and exacerbation of allergic asthma in children.
To determine the percentage of CD4+CD25(high) Treg cells in peripheral bloodCD4+ T cells of allergic asthmatic children during disease remission and exacerbation. Peripheral blood mononuclear cells (PBMC) and serum samples were collected from 6- to 11-year-old children with mild-to-moderate allergic asthma (n = 34)and from healthy controls (n = 15). CD4+CD25(high) T cells in PBMC were detected by flow cytometry. Total and specific IgE in serum were analysed by enzyme-amplified chemiluminescence, and IL-2 was measured by ELISA. There was no significant difference in CD4+CD25(high) T-cell proportions between asthmatic children in exacerbation and remission as compared with controls.CD4+CD25(high) T-cell percentages were not correlated with total and specific IgE. IL-2 was elevated in both disease remission and exacerbation but did not correlate significantly with CD4+CD25(high) T-cell percentages. CD4+CD25(high) T-cell proportion in the peripheral blood of total CD4+T cells is not reduced in children with allergic IgE-mediated asthma and does not differ between disease remission and exacerbation.


Parkinson's disease patients combined with constipation tend to have higher serum expression of microRNA 29c, prominent neuropsychiatric disorders, possible RBD conversion, and a substandard quality of life.
The symptom of constipation has been confirmed as an early diagnose criteria for Parkinson's disease (PD). Furthermore, evidences suggest that pathogenesis of PD initiates in gut, rather than brain. If so, identifying biomarkers for constipation in PD might have potentials to assist early diagnosis and initial treatment. We first identified that microRNA 29c (miR-29c) was dysregulated both in PD and constipation patients through bioinformatics analysis. Then, serological analysis of the expression of miR-29c in 67 PD patients with constipation (PD-C), 51 PD patients without constipation (PD-NC), and 50 healthy controls (HC) was carried out by qPCR. Demographic and clinical features were also compared. Patients in PD-C group were further classified into two groups: those with prodromal stage constipation (PD-C-Pro) (n = 36) and those with clinical stage constipation (PD-C-Clinic) (n = 31), to explore their different characteristics. The levels of miR-29c in PD-C group were higher than that in PD-NC group, both higher than HC group. PD-C-Pro group's miR-29c levels were statistically higher compared with PD-C-Clinic group's. What is more, PD-C group had higher scores of MDS-UPDRS-I, NMSS, NMSS3, NMSS4, NMSS6, NMSS9, SCOPA-AUT, HAMD, HAMA, RBDSQ, CSS, and PACQOL compared with PD-NC party. Relative to the PD-C-Clinic, patients in PD-C-Pro group had higher MDS-UPDRS-I, NMSS, NMSS3, HAMD, and HAMA scores, and were more likely to have RBD. Our results indicated that miR-29c seems to be an underlying cause for developing constipation in patients with PD and PD-C identifies a group of patients with more severe non-motor impairment, prominent neuropsychiatric disorders, and possible RBD conversion as well as a substandard quality of life. We further confirmed that there is a close relationship between symptoms representing the same pathological origin, especially constipation and RBD.


A newly identified linear epitope on non-RBD region of SARS-CoV-2 spike protein improves the serological detection rate of COVID-19 patients.
Serological test is helpful in confirming and tracking infectious diseases in large population with the advantage of fast and convenience. Using the specific epitope peptides identified from the whole antigen as the detection antigen is sensitive and relatively economical. The development of epitope peptide-based detection kits for COVID-19 patients requires comprehensive information about epitope peptides. But the data on B cell epitope of SARS-CoV-2 spike protein is still limited. More importantly, there is a lack of serological data on the peptides in the population. In this study, we aimed to identify the B cell epitope peptides of spike protein and detect the reactivity in serum samples, for further providing data support for their subsequent serological applications. Two B cell linear epitopes, P104 and P82, located in non-RBD region of SARS-CoV-2 S protein were identified by indirect ELISA screening of an overlapping peptide library of the S protein with COVID-19 patients' convalescent serum. And the peptides were verified by testing with 165 serum samples. P104 has not been reported previously; P82 is contained in peptide S21P2 reported before. The positive reaction rates of epitope peptides S14P5 and S21P2, the two non-RBD region epitopes identified by Poh et al., and P82 and P104 were 77.0%, 73.9%, 61.2% and 30.3%, respectively, for 165 convalescent sera, including 30 asymptomatic patients. Although P104 had the lowest positive rate for total patients (30.3%), it exhibited slight advantage for detection of asymptomatic infections (36.7%). Combination of epitopes significantly improved the positive reaction rate. Among all combination patterns, (S14P5 + S21P2 + P104) pattern exhibited the highest positive reaction rate for all patients (92.7%), as well as for asymptomatic infections (86.7%), confirming the feasibility of P104 as supplementary antigen for serological detection. In addition, we analyzed the correlation between epitopes with neutralizing antibody, but only S14P5 had a medium positive correlation with neutralizing antibody titre (rs = 0.510, P < 0.01). Our research proved that epitopes on non-RBD region are of value in serological detection especially when combination more than one epitope, thus providing serological reaction information about the four epitopes, which has valuable references for their usage.


Conservation biology: the many ways to protect biodiversity.
Protecting hotspots of marine species richness may not be an effective strategy to conserve biodiversity because these sites do not coincide with hotspots of functional and phylogenetic diversity.


Histamine in cancer immunology and immunotherapy. Current status and new perspectives.
Cancer is the second leading cause of death globally and its incidence and mortality are rapidly increasing worldwide. The dynamic interaction of immune cells and tumor cells determines the clinical outcome of cancer. Immunotherapy comes to the forefront of cancer treatments, resulting in impressive and durable responses but only in a fraction of patients. Thus, understanding the characteristics and profiles of immune cells in the tumor microenvironment (TME) is a necessary step to move forward in the design of new immunomodulatory strategies that can boost the immune system to fight cancer. Histamine produces a complex and fine-tuned regulation of the phenotype and functions of the different immune cells, participating in multiple regulatory responses of the innate and adaptive immunity. Considering the important actions of histamine-producing immune cells in the TME, in this review we first address the most important immunomodulatory roles of histamine and histamine receptors in the context of cancer development and progression. In addition, this review highlights the current progress and foundational developments in the field of cancer immunotherapy in combination with histamine and pharmacological compounds targeting histamine receptors.


Using mindfulness-based therapeutic interventions in psychiatric nursing practice--part I: Description and empirical support for mindfulness-based interventions.
Finding effective nursing interventions for the treatment of mental illness is a major concern for advanced practice psychiatric nurses (APPN). Increasingly, innovative psychotherapeutic treatment modalities are being used for the treatment of individuals with serious mental illness. One such innovative approach, mindfulness-based therapeutic interventions, has been shown to relieve distress for individuals with medical and psychiatric illnesses. In part one of this two-part article, the investigators describe principle concepts of mindfulness, review current research in the usefulness of mindfulness practice for treatment of psychiatric illnesses, and outline the theoretical basis for this treatment modality, including mindfulness-based cognitive therapy (MBCT). In Part II, the writers detail the therapy phases of MBCT and present a clinical case in which an advance practice psychiatric nurse integrates mindfulness-based psychotherapeutic approaches into her treatment. This clinical case may inform future clinical nursing research and advanced psychiatric nursing practice.


10-20-30 training increases performance and lowers blood pressure and VEGF in runners.
The present study examined the effect of training by the 10-20-30 concept on performance, blood pressure (BP), and skeletal muscle angiogenesis as well as the feasibility of completing high-intensity interval training in local running communities. One hundred sixty recreational runners were divided into either a control group (CON; n = 28), or a 10-20-30 training group (10-20-30; n = 132) replacing two of three weekly training sessions with 10-20-30 training for 8 weeks and performance of a 5-km run (5-K) and BP was measured. VO2max was measured and resting muscle biopsies were taken in a subgroup of runners (n = 18). 10-20-30 improved 5-K time (38 s) and lowered systolic BP (2 ± 1 mmHg). For hypertensive subjects in 10-20-30 (n = 30), systolic and diastolic BP was lowered by 5 ± 4 and 3 ± 2 mmHg, respectively, which was a greater reduction than in the non-hypertensive subjects (n = 102). 10-20-30 increased VO2max but did not influence muscle fiber area, distribution or capillarization, whereas the expression of the pro-angiogenic vascular endothelial growth factor (VEGF) was lowered by 22%. No changes were observed in CON. These results suggest that 10-20-30 training is an effective and easily implemented training intervention improving endurance performance, VO2max and lowering BP in recreational runners, but does not affect muscle morphology and reduces muscle VEGF.


SLC6A4 polymorphisms modulate the efficacy of a tryptophan-enriched diet on age-related depression and social cognition.
In a placebo controlled study we sought to determine if a four-weeks tryptophan-enriched diet is able to improve age-related depression or social cognitive impairment, depending on polymorphisms located in the promoter region of Solute Carrier Family 6 Member 4 (SLC6A4), also known as serotonin transporter (SERT1) gene. 91 young volunteers (age: 21 ± 2 yrs) and 127 above 50 years old (58 ± 6 yrs) healthy volunteers completed the study. Participants from the placebo and tryptophan group followed the same protocol. Before starting the study blood samples, to measure serotonin-transporter-linked polymorphic region (5-HTTLPR) and rs25531 polymorphisms, were collected. In addition, before and after completing the study urine samples (to measure 5-hydroxyindolacetic acid (5-HIAA) were taken, while psychological questionnaires (to assess depression and social cognition levels), and a one week dietary record (to calculate the tryptophan (TRP) intake) were assessed. The triallelic approach of SLC6A4 showed that in S'S´ subjects there was a positive correlation between TRP intake and 5-HIAA levels. Age of participants, SLC6A4 genotype, and experimental condition were important factors contributing to the outcome of depression and social cognition. 5-HTTLPR and rs25531 polymorphisms play a key role in the response to the TRP- based nutritional intervention, improving only age-related depressive symptoms and empathy in S'S´ subjects who have a higher risk to show signs of depression during their lifetime.


Suppressed neural complexity during ketamine- and propofol-induced unconsciousness.
Ketamine and propofol have distinctively different molecular mechanisms of action and neurophysiological features, although both induce loss of consciousness. Therefore, identifying a common feature of ketamine- and propofol-induced unconsciousness would provide insight into the underlying mechanism of losing consciousness. In this study we search for a common feature by applying the concept of type-II complexity, and argue that neural complexity is essential for a brain to maintain consciousness. To test this hypothesis, we show that complexity is suppressed during loss of consciousness induced by ketamine or propofol. We analyzed the randomness (type-I complexity) and complexity (type-II complexity) of electroencephalogram (EEG) signals before and after bolus injection of ketamine or propofol. For the analysis, we use Mean Information Gain (MIG) and Fluctuation Complexity (FC), which are information-theory-based measures that quantify disorder and complexity of dynamics respectively. Both ketamine and propofol reduced the complexity of the EEG signal, but ketamine increased the randomness of the signal and propofol decreased it. The finding supports our claim and suggests EEG complexity as a candidate for a consciousness indicator.


Levamisole: as adjuvant to cyclic chemotherapy in breast cancer.
The addition of levamisole, administered in adjunctive manner between the cycles of conventional high dose chemotherapy in patients with hormone resistant end state breast cancer substantially improved the survival of treated patients. Analysis of this double-blind study in 60 such patients suggests that improvement in remission status and survival is related to better tolerability of such cytotoxic therapy as regards both specific and nonspecific cytotoxicity. This improved tolerability enabled patients to receive higher doses of cytotoxic drugs over a shorter time period resulting in an improved remission rate and ultimate survival.


Deep learning for standardized, MRI-based quantification of subcutaneous and subfascial tissue volume for patients with lipedema and lymphedema.
To contribute to a more in-depth assessment of shape, volume, and asymmetry of the lower extremities in patients with lipedema or lymphedema utilizing volume information from MR imaging. A deep learning (DL) pipeline was developed including (i) localization of anatomical landmarks (femoral heads, symphysis, knees, ankles) and (ii) quality-assured tissue segmentation to enable standardized quantification of subcutaneous (SCT) and subfascial tissue (SFT) volumes. The retrospectively derived dataset for method development consisted of 45 patients (42 female, 44.2 ± 14.8 years) who underwent clinical 3D DIXON MR-lymphangiography examinations of the lower extremities. Five-fold cross-validated training was performed on 16,573 axial slices from 40 patients and testing on 2187 axial slices from 5 patients. For landmark detection, two EfficientNet-B1 convolutional neural networks (CNNs) were applied in an ensemble. One determines the relative foot-head position of each axial slice with respect to the landmarks by regression, the other identifies all landmarks in coronal reconstructed slices using keypoint detection. After landmark detection, segmentation of SCT and SFT was performed on axial slices employing a U-Net architecture with EfficientNet-B1 as encoder. Finally, the determined landmarks were used for standardized analysis and visualization of tissue volume, distribution, and symmetry, independent of leg length, slice thickness, and patient position. Excellent test results were observed for landmark detection (z-deviation = 4.5 ± 3.1 mm) and segmentation (Dice score: SCT = 0.989 ± 0.004, SFT = 0.994 ± 0.002). The proposed DL pipeline allows for standardized analysis of tissue volume and distribution and may assist in diagnosis of lipedema and lymphedema or monitoring of conservative and surgical treatments. • Efficient use of volume information that MRI inherently provides can be extracted automatically by deep learning and enables in-depth assessment of tissue volumes in lipedema and lymphedema. • The deep learning pipeline consisting of body part regression, keypoint detection, and quality-assured tissue segmentation provides detailed information about the volume, distribution, and asymmetry of lower extremity tissues, independent of leg length, slice thickness, and patient position.


Direct percutaneous jejunostomy--an underutilized interventional technique?
Our aim in this study was to report our single-center experience with direct percutaneous jejunostomy over a 4-year period with regard to technical success rate, immediate and late complications, and patient tolerance of the procedure. Institutional records of 22 consecutive patients who underwent radiological insertion of a percutaneous jejunostomy for a variety of indications were reviewed. The proximal jejunum was punctured under either fluoroscopic or ultrasonic guidance, and following placement of retention sutures, a 10- to 12-Fr catheter inserted. There was a 100% technical success rate in placement involving a total of seven operators. The indications for placement were prior gastric resection, newly diagnosed resectable esophageal or gastric carcinoma, unresectable gastric carcinoma with outlet obstruction, and palliative drainage of bowel obstruction. Mean duration of follow-up was 100 days, and catheter placement 57.7 days. There were six minor early complications, consisting of loss of two retention anchors requiring repuncture, three cases of localized excessive postprocedural pain, and one failed relief of symptoms of small bowel obstruction. Four tubes developed late complications (two blocked, one catheter cracked, and one inadvertently pulled out). Three of the four were successfully replaced through the existing tracts. One patient subsequently developed a minor skin infection, while another developed late pericatheter leakage from ascites. We conclude that direct percutaneous jejunostomy is a valuable treatment modality applicable to a number of clinical scenarios, with a high technical success rate and low serious complication rate.


Effect of a new type of head and neck fixation and traction device in the surgical treatment of patients with irreducible atlantoaxial dislocation.
In order to improve the clinical medical technology, enhance the clinical effect and improve the disease detection rate, the clinical incidence rate of atlantoaxial dislocation and vertebral body malformation that are difficult to summarize is increasing year by year. A total of 80 patients with atlantoaxial dislocation deformity treated in our hospital from January 2017 to May 2021 are selected for this study. According to the number table method, 80 patients are randomly divided into the auxiliary group and the traditional group, with 40 cases in each group. The traditional group is treated with posterior atlantoaxial pedicle screw system internal fixation and intervertebral fusion, and the auxiliary implementation and application of a new head and neck fixation and traction device through nasal cannula and oral release decompression fixation for posterior fusion. The patients in the two groups are compared changes and differences in efficacy, spinal cord function index, pain score, surgery, and quality of life. Compared with the traditional group, the total clinical effective rate, cervical spine extension and flexion range of motion, physical function, physical function, psychological function, and social function in the auxiliary group are significantly improved. The operation time, intraoperative blood loss, and VAS score are significantly reduced (P < 0.05). The new head and neck fixation traction device can improve the surgical efficacy and quality of life of patients with irreversible atlantoaxial dislocation, enhance spinal cord function, reduce pain symptoms and surgical risks, and is worthy of clinical application.


Simultaneous Removal of Microcystis aeruginosa and 2,4,6-Trichlorophenol by UV/Persulfate Process.
UV/persulfate (UV/PS) could effectively degrade algal cells and micro-organic pollutants. This process was firstly applied to remove Microcystis aeruginosa (M. aeruginosa) and 2,4,6-trichlorophenol (TCP) simultaneously in bench scale. Algal cells can be efficiently removed after 120 min reaction accompanied with far quicker removal of the coexisted TCP, which could be totally removed within 5 min in the UV/PS process. Both SO 4 • - and HO• were responsible for algal cells and TCP degradation, while SO 4 • - and HO• separately dominated TCP degradation and algal cells removal. Apart from the role of radicals ( SO 4 • - and HO•) for algal cells and TCP degradation, UV also played a role to some extent. Increased PS dose (0-4.5 mM) or UV intensity (2.71-7.82 mW/cm2) could enhance the performance of the UV/PS process in both TCP and algae removal. Although some intracellular organic matters can be released to the outside of algal cells due to the cell lysis, they can be further degraded by UV/PS process, which was inhibited by the presence of TCP. This study suggested the good potential of the UV/PS process in the simultaneous removal of algal cells and micro-organic pollutants.


Treatment of malignant metastatic pancreatic insulinoma with streptozotocin. Review of 21 cases described in detail in the literature and report of complete remission of a new case.
The possibilities of treating different types of pancreatic islet cell cancer with the active drug streptozotocin have been studied in reports of 21 patients published during the last 8 years. The unusual features of the symptomatology, dosage and injection methods, side-effects after different infusion schedules and complications of streptozotocin therapy, are compared. A new case with pancreatic carcinoma and liver metastases was treated with a total dose of 14 g streptozotocin, divided into 7 injections with an increasing interval between them. This patient underwent a marked amelioration of the disease, without serious side-effects of the streptozotocin treatment. She has been apparently well for the 22 months which have now elapsed since the beginning of treatment. This seems to be one of the longest remission periods yet published in the insulinoma literature.


Preparation of sera for typing of adenovirus infections by immunofluorescence.
The conditions for preparation of adenovirus antisera with group, subgroup and type-specific reactivity to be used in the immunofluorescence technique have been evaluated. Group-specific antibodies were prepared by passing an antiserum against virions or hexons of one serotype through an immunosorbent column containing soluble viral components of an adenovirus type belonging to a different subgroup. The group-specific antibodies were recovered from the solid phase by elution at pH 2.8. Reagents specific for subgroup I and II were obtained by passing anti-dodecon sera through an immunosorbent column containing soluble viral components from heterologous subgroups. In this case antibodies not attaching to the absorbent were recovered. Sera against fibers of subgroup III members could be used as subgroupspecific sera without absorption. Type-specific antibodies were prepared by removal of antibodies of other specificities by passing anti-virion or anti-hexon sera through immunosorbent columns containing soluble viral components of an adenovirus type belonging to the same subgroup. Reagents specific for seven adenovirus types representing Rosen's three subgroups were prepared according to the outlined procedures.


Exposure to ethephon compromises endometrial decidualization in mice during early pregnancy via GPR120.
Exposure to ethephon (ETH), a plant growth regulator commonly used for several purposes, can potentially decrease sperm numbers and viability. Occasional findings regarding ETH effects on female reproduction during early pregnancy have also been reported. During early pregnancy, endometrial decidualization is a critical event for embryo implantation and pregnancy maintenance. Thus, we aimed to explore the effect and mechanism of ETH on endometrial decidualization both in vivo and in vitro. Mice were gavaged with 0 and 285 mg/kg b.w. ETH from gestational days (GD)1 until sacrifice, whereas pseudopregnant mice from pseudopregnant day 1 (PPD-1) until PPD-8. Primary mouse endometrial stromal cells (mESCs) received 640 ug/ml ETH and added E2 and P4 to induce decidualization. Results indicated female albino CD1 mice exposed to high dose of ETH (285 mg/kg b.w.) by oral gavage, the number of embryo implantation sites on GD6 and GD8 were significantly decreased, the levels of serum E2 and P4 on GD8 were significantly decreased. Compared with the control group, the decidualization response artificially induced by corn oil in pseudopregnant mice and by E2 and P4 in primary mouse endometrial stromal cells (mESCs) was weakened in the high dose of ETH treated group. The high dose, 285 mg/kg b.w ETH treated group altered the expression of endometrial decidual markers on GD6 and GD8. The triglyceride and fatty acid metabolism-related genes were significantly increased after female albino CD1 mice exposed to high does, 285 mg/kg b.w ETH on GD6 and GD8. GPR120 was substantially reduced after ETH treatment. When overexpression of GPR120, the compromised decidualization induced by ETH treatment was rescued. Furthermore, molecular docking presented Thr234 and His251 of GPR120 as preferred binding sites for ETH. Mutation of these two sites rescued the compromised decidualization induced by ETH. In conclusion, we demonstrated that ETH exposure could impair decidualization during early pregnancy. GPR120 expression and binding between GPR120 and ETH are crucial for impaired decidualization mediated via ETH.


Ultrasensitive determination of 1,4-dihydroxybenzene based on fluorescence resonance energy quenching of luminescent quantum dots modified on surface of silica nanoparticles.
An ultrasensitive solid-phase fluorescence resonance energy quenching (FREQ) method for determination of 1,4-dihydroxybenzene (DHB) using mercaptosuccinic acid (MSA)-capped CdTe quantum dots (QDs) immobilized on silica nanoparticles (NPs) as donors was developed. In the method, silica NPs were first modified with 3-aminopropyltriethoxysilane (APTS). Then, MSA-capped CdTe QDs were immobilized on the surface of the APTS-modified silica NPs. Finally, DHB in the solution was attached to the empty sites on the surface of silica NPs with QDs through electrostatic interaction. The fluorescence emission of the QDs was quenched by the proximal DHB molecules on the silica NPs. The quenching efficiency of the solid-phase FREQ method was 200-times higher than that of the solution-phase FREQ method. Using the ultrasensitive solid-phase FREQ method, DHB as low as 2.4×10(-12) mol/L could be detected. The method was applied to quantify trace DHB in water samples.


Hydrodynamic cavitation: A feasible approach to intensify the emulsion cross-linking process for chitosan nanoparticle synthesis.
Chitosan nanoparticles (NPs) exhibit great potential in drug-controlled release systems. A controlled hydrodynamic cavitation (HC) technique was developed to intensify the emulsion crosslinking process for the synthesis of chitosan NPs. Experiments were performed using a circular venturi and under varying operating conditions, i.e., types of oil, addition mode of glutaraldehyde (Glu) solution, inlet pressure (Pin), and rheological properties of chitosan solution. Palm oil was more appropriate for use as the oil phase for the HC-intensified process than the other oil types. The addition mode of water-in-oil (W/O) emulsion containing Glu (with Span 80) was more favorable than the other modes for obtaining a narrow distribution of chitosan NPs. The minimum size of NPs with polydispersity index of 0.342 was 286.5 nm, and the maximum production yield (Py) could reach 47.26%. A positive correlation was found between the size of NPs and the droplet size of W/O emulsion containing chitosan at increasing Pin. Particle size, size distribution, and the formation of NPs were greatly dependent on the rheological properties of the chitosan solution. Fourier transform infrared spectroscopy (FTIR) analysis indicated that the molecular structure of palm oil was unaffected by HC-induced effects. Compared with ultrasonic horn, stirring-based, and conventional drop-by-drop processes, the application of HC to intensify the emulsion crosslinking process allowed the preparation of a finer and a narrower distribution of chitosan NPs in a more energy-efficient manner. The novel route developed in this work is a viable option for chitosan NP synthesis.


Enhancing the robustness of ocean sound speed profile representation via interpretable deep matrix decomposition.
Developing an effective and robust representation model for ocean sound speed profiles (SSPs) is crucial for numerous ocean acoustic applications. However, the performance of existing sound speed profile (SSP) representation methods, such as empirical orthogonal function and K-singular value decomposition, heavily relies on the number of selected basis functions. This could lead to overfitting of noise, as these methods are unable to distinguish between signals and noise during the basis function learning process. To overcome these limitations and effectively learn a large number of basis functions with strong representation power from potentially noisy SSP data, we propose a novel algorithm called deep matrix decomposition (deep MD). This algorithm utilizes untrained deep neural networks as priors to reject noise within the interpretable matrix decomposition framework. To achieve optimal performance with deep MD, we propose a stopping strategy based on the rank estimate to determine the termination epoch. Experimental results using real-life datasets demonstrate that deep MD is robust against various types of noise and outperforms traditional SSP representation methods in terms of SSP reconstruction and characterizing the transmission loss in underwater acoustics.


Residential road traffic noise exposure and colorectal cancer survival - A Danish cohort study.
Residential traffic noise exposure may entail sleep disruption and compromised circadian functioning; two factors which have been associated with a poor colorectal cancer (CRC) prognosis. Hence, the aim of the present study was to investigate the association between residential road traffic noise and CRC survival. Road traffic noise was calculated for all residential addresses from 1987 to February 2012 for incident CRC cases (n = 1,234) in a cohort of 57,053 Danes. We used Cox Proportional Hazard Models to investigate the association between residential road traffic noise at different time-windows, and overall and CRC-specific mortality. Furthermore, we investigated interaction with sex, age, prognostic factors, and comorbidity. Mortality Rate Ratios (MRR) were calculated in unadjusted models, and adjusted for railway noise, lifestyle factors, and socioeconomic variables. During a median follow-up of 4 years, 594 patients died; 447 from CRC. We found no association between road traffic noise exposure and overall (MRR 1.00 (0.88-1.13) per 10 dB) or CRC-specific mortality (MRR 0.98 (0.85-1.13) per 10 dB) over the entire follow-up period, or 1 year preceding death. Results did not differ when examining colon and rectal cancer separately. Interaction analyses suggested that patients with less clinically advanced disease could be more susceptible to harmful effects of traffic noise. The present study suggests no overall association between residential road traffic noise and concurrent mortality in CRC patients. As it is the first study of its kind, with relatively limited power, further studies are warranted.


Statistical analysis of shoreline change reveals erosion and baseline are increasing off the northern Tamil Nadu Coasts of India.
Many tourists have been recently attracted towards the coasts around the world, especially to the large urban centres and economically significant areas. In the last four decades, there is a significant increase in the key coastal developments and tourist's attractions like major ports, minor ports, fishing harbours, desalination plants, shore protection structures, and many more along the southeast coasts of India, in particular, northern Tami Nadu coastal stretches. The shoreline change study of these regions were carried out using the geospatial technologies (satellite remote sensing and geographical information system) to examine potential modifications occurred during the last 32 years between March 1990 and May 2022. This study used Landsat satellite images of spatial resolution 30 m to track the shoreline changes which was extracted using the Digital Image Processing software and techniques. In addition, the United States Geological Survey (USGS) developed Digital Shoreline Analysis System (DSAS) v5.2 software, an add-on tool to ArcGIS used for the statistical analysis to compute the shoreline rate of change. The linear regression rate (LRR) and end point rate (EPR) statistics were used to identify the eroding, accreting, and stable shoreline between Kattupalli coast and Kalpakkam coast of the northern Tamil Nadu coasts. This shoreline study of 106 km was carried out by dividing it into six zones (zone 1 to zone 6), and the DSAS analysis conveys that the shoreline of zone 1 (Kattupalli) and zone 2 (Ennore) shows erosion compared to other four zones. In locations where the coast is vulnerable, national mitigation measures must be implemented.


Nadroparin carries a potentially high risk of inducing cutaneous delayed-type hypersensitivity responses.
Heparins are widely used for the prophylaxis/treatment of thromboembolic events. As adverse effects, heparin-induced skin lesions occur frequently (in 7.5-39% of patients). Skin lesions may be the only clinical manifestation of life-threatening immune-mediated heparin-induced thrombocytopenia, but are commonly caused by a delayed-type hypersensitivity response [heparin-induced delayed-type hypersensitivity (HIHS)]. Risk factors have not been prospectively identified. To identify possible risk factors for heparin-induced skin lesions from three independent clinical trials in a combined analysis. A pooled analysis from prospective studies was performed, and possible risk factors were included in a multiple logistic regression analysis. Obesity (body mass index of > 25), prolonged anticoagulant therapy, prior heparin exposure and younger age (< 55 years) were confirmed as independent risk factors for HIHS. The choice of anticoagulant preparation had the greatest influence. On comparison of dalteparin, enoxaparin, fondaparinux, unfractionated heparin, and nadroparin, the latter was associated with the highest risk of eliciting HIHS (odds ratio of 30.2, 95%CI: 11.7-77.9). The high risk associated with nadroparin has been validated in controlled trials, and this emphasizes the singularity of each heparin preparation in terms of allergenicity and that individualized anticoagulation is required.


Primary systemic amyloidosis associated with multiple myeloma: a case report and review of the literature.
Amyloidosis is a broad and complex class of diseases that comprises several etiologies, many manifestations, and a diversity of outcomes. We discuss a patient with primary systemic amyloidosis associated with multiple myeloma that illustrates many of the typical and atypical features of the disease process. Despite more in-depth assessment and accurate classification, survival for patients with primary systemic disease remains poor.


Electron localization in rod-shaped triicosahedral gold nanocluster.
Atomically precise gold nanocluster based on linear assembly of repeating icosahedrons (clusters of clusters) is a unique type of linear nanostructure, which exhibits strong near-infrared absorption as their free electrons are confined in a one-dimensional quantum box. Little is known about the carrier dynamics in these nanoclusters, which limit their energy-related applications. Here, we reported the observation of exciton localization in triicosahedral Au37 nanoclusters (0.5 nm in diameter and 1.6 nm in length) by measuring femtosecond and nanosecond carrier dynamics. Upon photoexcitation to S1 electronic state, electrons in Au37 undergo ∼100-ps localization from the two vertexes of three icosahedrons to one vertex, forming a long-lived S1* state. Such phenomenon is not observed in Au25 (dimer) and Au13 (monomer) consisting of two and one icosahedrons, respectively. We have further observed temperature dependence on the localization process, which proves it is thermally driven. Two excited-state vibration modes with frequencies of 20 and 70 cm-1 observed in the kinetic traces are assigned to the axial and radial breathing modes, respectively. The electron localization is ascribed to the structural distortion of Au37 in the excited state induced by the strong coherent vibrations. The observed electron localization phenomenon provides unique physical insight into one-dimensional gold nanoclusters and other nanostructures, which will advance their applications in solar-energy storage and conversion.


Efficiency and persistence of licking in rats.
Thirsty rats tested in 60-min sessions licked an empty spout for access to a water spout. We raised the behavioral price of the water lick by requiring more licks at the empty spout per lick at the water spout. At relatively high prices the rats made relatively few water licks but licked more efficiently, getting more water per lick. Controls showed that the rise in efficiency with price was not attributable to two variables previously confounded with price: the total number of water licks, and the temporal pattern of access. At a higher price the rats also licked more persistently, making more extra water licks before the shutter could occlude the spout. However, yoked controls showed that the greater persistence resulted not from price, but from the relatively stringent pattern of access that accompanied the higher price. Extra water licks diminished as the session progressed, apparently from satiety, not fatigue. The results have implications for behavioral ecology, behavioral economics, motivation, and the methodology of reward.


Overexpressing STAMP2 attenuates diabetic renal injuries via upregulating autophagy in diabetic rats.
Diabetic nephropathy (DN) is one of the most serious and major renal complications of diabetes. Previously, Six-transmembrane Protein of Prostate 2 (STAMP2) was reported to contribute to nutritional stress. The purpose of this study is to investigate whether overexpression of STAMP2 attenuates diabetic renal injuries in DN rats. We induced the DN rat model by high-fat diet and low-dose streptozotocin and evaluated the metabolite and urine albumin/creatinine. Recombinant adeno-associated virus vectors were injected for overexpression of STAMP2. Pathophysiologic and ultrastructure features of DN by histochemical stain and transmission electron microscope, autophagy-related proteins and signaling pathway by western blotting were assessed. We found the expression of STAMP2 was decreased and autophagy was blunted in DN rat kidneys. Overexpressing STAMP2 significantly ameliorated metabolic disturbance, insulin resistance, and specifically restoring diabetic renal injury. Furthermore, overexpressing STAMP2 improved the autophagy deficiency in DN rats, as revealed by changes in the expressions of Beclin1, p62, and LC3. Furthermore, STAMP2 overexpressing promoted autophagy by inhibiting the mTOR and activating the AMPK/SIRT1 signaling pathway. Our results suggested that STAMP2 overexpression attenuated renal injuries via upregulating autophagy in DN rats. STAMP2 overexpressing promoted autophagy may been involved with inhibition of the mTOR/ULK1 and activation of the AMPK/SIRT1 signaling pathway.


Sustained reduction in discharge opioid volumes through provider education: Results of 1168 cancer surgery patients over 2 years.
An opioid reduction education program to decrease discharge opioid prescriptions was initiated in our Department of Surgical Oncology. The study's aim was to measure the results and sustainability of these interventions 1 year later. This prospective quality improvement project identified patients undergoing resection in five index tumor sites (peritoneal surface, sarcoma, stomach, pancreas, liver) at a high-volume cancer center. Patients were grouped into pre-education (PRE: July 2017-July 2018) and posteducation (POST: September 2018-July 2019) periods, before and after departmental education talks and videos in August 2018. Opioids were converted to oral morphine equivalents (OME) to compare the groups. Of 1168 evaluable patients (PRE 646, 55%; POST 522, 45%), the median last-24-h inpatient OME was 15 mg in PRE patients and 10 mg in POST patients (p < .001). Median discharge OME decreased from 200 mg in PRE to 100 mg in POST patients (p < .001). The frequency of patients with zero discharge opioids increased from 11% to 19% (p < .001). This discharge OME reduction amounted to 52,200 mg OME saved, or the equivalent of 6960 5-mg oxycodone pills not disseminated. A perioperative opioid reduction education program targeted to providers halved discharge OME, with sustained reductions 1 year later.


A Randomized Trial of Alerting to Hypocholesterolemia Results of the Low Indexes of Metabolism Intervention Trial-C (LIMIT-C).
The benefit of alerting clinical staff to drug-induced hypocholesterolemia in patients aged 75 years and older remains uncertain. The study included 1791 patients with serum cholesterol <160 mg/dL and on cholesterol-lowering drugs who were assigned to have an e-mail alert sent to their physician, and 1804 patients who were assigned to receive usual clinical care (control group). The primary outcome of the trial was annual death rate. Secondary outcomes included cholesterol-lowering drug dose reduction and emergency department (ED) visits. At 1 year, 58 patients (3.2%) in the intervention group and 61 (3.4%) in the control group had died [relative risk 0.94, 95% confidence interval (CI) 0.66-1.34; P = .74]. Quarter-averaged cholesterol-lowering drug defined daily doses were reduced by -13.5 ± 47.0 (-17% ± 60%) in the intervention group and by -5.1 ± 42.2 (-6%±54%) in the control group (difference -8.5 ± 1.5, 95% CI -5.5 to -11.4; P < .0001). Annual ED visit rates per 1000 patients were 291 in the intervention group and 336 in the control group (45 fewer visits per 1000 patients in the intervention group, 95% CI -1 to -89; P = .04). In this trial, alerting clinical staff to hypocholesterolemia in patients aged 75 years and older being treated with cholesterol-lowering drugs was associated with mildly reduced cholesterol-lowering drugs doses and marginally reduced ED visit rates. This e-mail alert intervention was not associated with a significant difference in 1-year survival rate compared with usual clinical care.


Cranial coverage involving scalp, bone and dura using free inferior epigastric flap.
Four cases of successful reconstruction of scalp and skull defects are described. The advantages of the free inferior epigastric flap are that it is large enough to cover massive defects of the head and has an excellent vascular pedicle which allows it to be directly sutured to recipient vessels in the neck without interpositional vein grafts.


Clinical and peculiar immunological manifestations of SARS-CoV-2 infection in systemic lupus erythematosus patients.
The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in patients with SLE remains unclear and data on clinical manifestations after infection are lacking. The aim of this multicentre study is to describe the effect of SARS-CoV-2 in SLE patients. SLE patients referring to four Italian centres were monitored between February 2020 and March 2021. All patients with SARS-CoV-2 infection were included. Disease characteristics, treatment, disease activity and SARS-CoV-2-related symptoms were recorded before and after the infection. Fifty-one (6.14%) SLE patients were included among 830 who were regularly followed up. Nine (17.6%) had an asymptomatic infection and 5 (9.8%) out of 42 (82.6%) symptomatic patients developed interstitial pneumonia (no identified risk factor). The presence of SLE major organ involvement (particularly renal involvement) was associated with asymptomatic SARS-CoV-2 infection (P = 0.02). Chronic corticosteroid therapy was found to be associated with asymptomatic infection (P = 0.018). Three SLE flares (5.9%) were developed after SARS-CoV-2 infection: one of them was characterized by MPO-ANCA-positive pauci-immune crescentic necrotizing glomerulonephritis and granulomatous pneumonia. SARS-CoV-2 infection determined autoimmune flares in a small number of patients. Our data seem to confirm that there was not an increased risk of SARS-CoV-2 in SLE. Patients with asymptomatic SARS-CoV-2 infections were those having major SLE organ involvement. This may be explained by the high doses of corticosteroids and immunosuppressive agents used for SLE treatment.


Advances in percutaneous therapy for upper extremity arterial disease.
Upper extremity arteries are affected by occlusive diseases from diverse causes, with atherosclerosis being the most common. Although the overriding principle in managing patients with upper extremity arterial occlusive disease should be cardiovascular risk reduction by noninvasive and pharmacologic means, when target organ ischemia produces symptoms or threatens the patient's well-being, revascularization is necessary. Given their minimally invasive nature and successful outcomes, percutaneous catheter-based therapies are preferred to surgical approaches. The fact that expertise in these techniques resides in not one but several disciplines (vascular surgery, radiology, cardiology, vascular medicine) makes this an area ripe for multidisciplinary collaboration to the benefit of patients.


A Prospective Study of Etiological Agents Among Febrile Patients in Sierra Leone.
Sierra Leone has one of the highest burdens of febrile illnesses in the world. As the incidence of malaria diminishes, a better understanding of the spectrum of etiological agents was important for accurate diagnosis and empirical treatment of febrile illness. Blood, nasopharyngeal, and fecal specimens were collected from febrile patients for serological, molecular detection, and microbiologic culture to identify potential pathogens. For this prospective study, 142 febrile patients were enrolled. The prevalence of malaria was higher in children aged 5-15 years old (P = 0.185) and adults (P = 0.018). Acute respiratory infection (ARI) presented more commonly in the under 5 years old group (P = 0.009). For diarrhea, all children groups (P = 0.024) were predominant. A total of 22.5% of the febrile patients had malaria infection, 19.7% had typhoid infection, and 2.8% were coinfected with malaria and typhoid. ARI was the most common causes of fever, accounting for 31.7% of patients, influenza A virus, Mycoplasma pneumoniae, and five other respiratory pathogens were found. Diarrhea accounted for 16.2%, and seven kinds of diarrhea bacteria were isolated. Hepatitis B accounted for 8.5%, including five cases of spontaneous bacterial peritonitis, and ascites smear staining were both Gram-negative bacteria. Tuberculous encephalitis, parasitic diseases (ascaris and filariasis), and skin infection caused by Staphylococcus aureus accounted for 0.7%, 2.1%, and 0.7%, respectively. Evidence of a wide spectrum of febrile etiological agents other than malaria was identified. The spread of malaria rapid diagnostic tests (RDTs) out of hospital and establishment of a national standard for Widal test will reduce the misdiagnosis of febrile diseases. Antibiotics against Gram-negative bacteria are helpful for empirical treatment.


Regulation of glycogen synthetase and phosphorylase phosphatase activities in rat adipose tissue.
Incubation of a rat adipose tissue homogenate causes a time and temperature dependent activation of glycogen synthetase (UDP glucose:glycogen 4-alpha-glucosyltransferase) and simultaneous inactivation of phosphorylase (1,4-alpha-D-glucan: orthophosphate alpha-glucosyltransferase, EC 188.8.131.52). Activation of glycogen synthetase at 15 and 23 degrees C was preceded by a lag period. The duration of the lag period could not be correlated with significant changes in phosphorylase activity. Addition of glucose and methylxanthines caused an increase in the rates of glycogen synthetase activation and phosphorylase inactivation. The effect on glycogen synthetase activation was mainly on the linear phase. Addition of AMP inhibited phosphorylase inactivation and accelerated glycogen synthetase activation. Addition of muscle phosphorylase alpha caused a prolongation of the lag period which lasted until phosphorylase alpha activity had decreased to the level originally present in the preparation. It is concluded that in adipose tissue activation of glycogen synthetase is not dependent on prior inactivation of phosphorylase and that other factors should be looked for to explain the lag period preceding glycogen synthetase activation.


When osteotomies should be considered.
Osteotomy at various levels of the facial skeleton is entirely justified in selected aesthetic surgical patients. By the very nature of aesthetic surgery, the morbidity potential associated with such osteotomies must be extremely low. Accordingly, osteotomy at the symphyseal level and the LeFort I level are the most commonly performed procedures in the aesthetic surgical patient. Aesthetic changes required in the vertical plane of space will require osteotomy, because these cannot be reliably and consistently achieved through changes in skeletal surface contour. Lastly, when the extent of change required is greater than what can be naturally achieved with surface augmentation, osteotomy must be considered. This last indication is frequently found in the aesthetic surgical patient presenting with a facial skeletal imbalance that has been previously treated with orthodontics to correct a skeletally based malocclusion. Recent technical advances have markedly reduced the associated morbidity of facial osteotomies and, therefore, have made this treatment option more acceptable to aesthetic surgical patients. Ceramic orthodontic brackets and surgical hooks and lingual orthodontic appliances have made presurgical orthodontic preparation more aesthetic and socially acceptable for LeFort I osteotomy patients. The use of rigid fixation, obviating the need for any postoperative intermaxillary fixation, has also made this treatment approach more appealing to aesthetic patients. Lastly, the efficacy of nonresorbable bone substitutes--in particular, porous, block hydroxyapatite--has, to a significant extent, obviated the need for harvesting autogenous bone grafts, further reducing surgical morbidity.


Free tendon grafts in elder patients, a case report of repair of flexor pollicis longus tendon with a free palmaris longus graft in an 89-year-old woman.
Flexor tendon rupture is a potential complication after volar plating of distal radius fracture. Palliative procedures such as tenodesis and arthrodesis are usually employed in elder patients with imperfect results. We report a case of delayed flexor pollicis longus rupture seven years after volar plating of a distal radius fracture occurring in an 89-year-old woman. The repair with a free tendon graft of palmaris longus was successful in terms of strength and range of motion. Free tendon grafts should not be limited to younger patients and could be used in elder patients after careful selection.