Lipoprotein pattern and plasma lecithin cholesterol acyl transferase activity in children with Alagille syndrome.
Alagille syndrome is frequently associated with hyperlipidemia and xanthoma. The aim of the study was to assess the lipid profile (plasma lipoproteins, apolipoproteins (apo)) and lecithin cholesterol acyl transferase (LCAT) activity, with and without treatment with cholestyramine in Alagille syndrome. Five children (mean age = 6 +/- 4 years) with Alagille syndrome were studied at two different times while receiving no treatment, and while receiving cholestyramine. They were compared with 12 normal controls, who were not different from patients for age and sex. In Alagille syndrome, total serum cholesterol, triglycerides and phospholipids were elevated compared with the controls (P < 0.008). VLDL-cholesterol, LDL-cholesterol, HDL-triglycerides, LDL-triglycerides and VLDL-phospholipids were higher, whereas HDL-cholesterol was lower than controls (P < 0.03). Apo B, CIII, E and lipoprotein particles Lp AI were higher (P < 0.001), whereas Lp AI:AII was lower than controls (P < 0.03). Lipoprotein-X was present in the 5 children with Alagille syndrome and explained in part the elevation of plasma cholesterol, phospholipids, and apo CIII. LCAT activity was decreased (P < 0.01) and might cause some abnormalities of HDL with lower cholesterol, higher triglycerides, apo E and apo CIII contents than controls, and abnormalities of VLDL and LDL with higher cholesterol, triglycerides, phospholipids and apo B contents than controls. Some of the risk factors of atherosclerosis were found in Alagille syndrome, namely high levels of plasma cholesterol, LDL cholesterol, apo B, apo B/apo AI. Treatment with cholestyramine resulted in a few modifications to the lipid profile, while lipoprotein-X and the decrease of LCAT activity persisted.


Superior mesenteric artery syndrome in traumatic brain injury: two cases.
One of the many causes of enteral feeding (EF) intolerance after traumatic brain injury (TBI) is superior mesenteric artery syndrome (SMAS). Although it is reported in pediatric brain injury, few cases are noted in adults. To increase awareness of this medically treatable condition, we present two patients who developed SMAS after sustaining severe brain injury. SMAS results from compression of the duodenum by the SMA against the aorta and risk factors include acute weight loss, prolonged recumbency, and spasticity--all frequently encountered in severe TBI. After gastric decompression, symptoms often resolve with weight gain achieved by conservative treatment; including feeding in the left lateral or prone position, hyperalimentation, or extension of a feeding tube beyond the obstruction. SMAS should be considered in the presence of EF intolerance in severe adult TBI because multiple risk factors may be present.


Diversity and prevalence of Bartonella species in small mammals from Slovakia, Central Europe.
Wild-living rodents are important hosts for zoonotic pathogens. Bartonella infections are widespread in rodents; however, in Slovakia, knowledge on the prevalence of these bacteria in small mammals is limited. We investigated the prevalence and diversity of Bartonella species in the spleens of 640 rodents of six species (Apodemus flavicollis, Apodemus sylvaticus, Myodes glareolus, Microtus arvalis, Microtus subterraneus, and Micromys minutus) and in the European mole (Talpa europaea) from three different habitat types in south-western and central Slovakia. Overall, the prevalence of Bartonella spp. in rodents was 64.8%; a rate of 73.8% was found in natural habitat (deciduous forest), 56.0% in suburban forest park and 64.9% in rural habitat. Bartonella spp. were detected in 63.0% of A. flavicollis, 69% of My. glareolus and 61.1% of M. arvalis and in T. europaea. However, Bartonella were not found in the other examined rodents. Molecular analyses of the 16S-23S rRNA intergenic spacer region revealed the presence of four different Bartonella spp. clusters. We identified B. taylorii, B. rochalimae, B. elizabethae, B. grahamii and Bartonella sp. wbs11 in A. flavicollis and My. glareolus. Bartonella genotypes ascribed to B. taylorii and B. rochalimae were found in M. arvalis. B. taylorii was identified in T. europaea. Questing Ixodes ricinus ticks that were collected at the study sites were not infected with Bartonella. This study improves our understanding of the ecoepidemiology of Bartonella spp. in Europe and underlines the necessity for further research on Bartonella-host-vector associations and their consequences on animal and human health in Slovakia.


The impact of maternal obesity and breast milk inflammation on developmental programming of infant growth.
Little is known about how maternal obesity impacts breast milk (BM) composition and how BM composition may impact growth. We sought to determine the role of maternal body mass index (BMI) on BM inflammatory and oxidative stress markers and to delineate the role of these BM markers on infant growth. This was a secondary analysis of 40 mother-infant dyads. We first assessed the association between maternal BMI and BM marker (omega-6:omega-3 polyunsaturated fatty acid ratio (n-6:n-3 PUFA), leptin, interleukin (IL)-8, IL-6, IL-1β and malondialdehyde (MDA)) concentration at one (V1) and four (V4) months postpartum. We then examined the association between BM markers on infant growth trajectory from birth to seven months. Higher maternal BMI was associated with higher BM n-6:n-3 PUFA (V1 β = 0.12, 95% CI 0.01, 0.2; V4 β = 0.13, 95% CI 0.01, 0.3) and leptin (V1 β = 107, 95% CI 29, 184; V4 β = 254, 95% CI 105, 403) concentrations. Infants exposed to high BM n-6:n-3 PUFA had higher BMI z-scores over time (p = 0.01). Higher BM leptin was associated with lower infant percent fat mass at V4 (β = -9, 95% CI -17, -0.6). Infants exposed to high BM IL-8, IL-6, or IL-1β had higher weight z-scores over time (IL-8 p < 0.001; IL-6 p < 0.001; IL-1β p = 0.02). There was no association between BM MDA and maternal BMI or infant growth. Higher maternal BMI is associated with higher BM n-6:n-3 PUFA and leptin concentrations. In addition, higher BM n-6:n-3 PUFA and inflammatory cytokines were associated with accelerated weight gain in infancy.


The effect of ketamine on acute muscular ischaemia reperfusion in rats.
The aim of this study was to investigate any possible protective effect of ketamine in acute muscular ischaemia and reperfusion injury by measuring malondialdehyde using thiobarbituric acid assay in rats. Twelve female Wistar albino rats were anaesthetized with chloral hydrate and randomly assigned into two groups to receive ketamine 1 mg kg(-1) min(-1) or saline infusion. Blood and gastrocnemius muscle samples were obtained 10 min after onset of infusion, before ischaemia. Then, femoral arteries were clamped for 30 min. Blood and muscle samples were obtained at the 30th minute of ischaemia and 10 min after reperfusion. Muscle malondialdehyde concentrations were 27.88 +/- 2.45, 27.62 +/- 3.98 before ischaemia, 32.10 +/- 4.19, 30.77 +/- 2.73 in the 30th minute of ischaemia and 44.34 +/- 2.45, 34.83 +/- 2.78 after reperfusion in saline and ketamine-treated rats, respectively (nmol g(-1), mean +/- SD). The muscle malondialdehyde level after reperfusion was lower in ketamine-treated rats compared to saline group (P < 0.002). Plasma malondialdehyde levels were 3.77 +/- 0.16, 3.78 +/- 0.18 before ischaemia, 3.81 +/- 0.25, 4.00 +/- 0.86 at the 30th minute of ischaemia and 4.00 +/- 0.53, 3.94 +/- 0.95 after reperfusion, respectively, in saline and ketamine-treated rats (micromol L(-1), mean +/- SD). The effect of ketamine on muscular malondialdehyde was not observed in concurrent plasma malondialdehyde levels. Ketamine was found to attenuate acute ischaemia-reperfusion injury in muscle tissue in rats (muscular protective). Ketamine may attenuate lipid peroxidation in muscle tissue in tourniquet-requiring manoeuvres.


Visceral fat assessment in over nourished children by ultrasonography and its relation to anthropometry.
To measure visceral fat (VF) in over nourished children (6-15 y) by ultrasonography (USG) and to find relation between anthropometric measurements (AM) and VF in these children. This case series included 113 children of 6-15 y with Body Mass Index (BMI) >85th centile who attended the nutrition clinic of a tertiary care centre in rural Kerala from January 2009 through June 2010. After recording the base line demographic parameters and anthropometric measurements, VF was assessed by USG. Relation between VF and anthropometric measurements were assessed by correlation. Measurements which showed significant positive correlation were further analyzed by linear regression. The mean total VF was 145.63 (SD = 25.37) mm. Total VF increased with age. Significant positive correlation was found for weight, height, BMI, hip circumference (HC) and waist circumferences (WC). WC showed maximum correlation. The best predictor of VF was WC. The total VF in over nourished children increases with age. Even though the most important predictor of visceral fat is WC, it has a low predictive power.


Abdominal Vascular Evaluation.
The vascular lab (VL) is instrumental in diagnosing vascular diseases such as renal artery stenosis and mesenteric ischemia or following a patient after transjugular intrahepatic portal systemic shunt (TIPS) creation. This article discusses indications, protocol, and diagnostic criteria for abdominal vascular ultrasound. The vascular lab can be used to investigate pathology in the abdomen either as a preliminary screening tool to evaluate for a pathology such as mesenteric artery stenosis in a patient with food fear and weight loss, renal artery stenosis in a patient with refractory hypertension or renal failure, or as a diagnostic tool in follow up after a patient has undergone a transjugular intrahepatic portal systemic shunt (TIPS) for portal hypertension. The technical success of duplex ultrasonography of the abdomen can be compromised by respiratory motion, obesity, and intestinal gas. Therefore, duplex scanning is performed in the fasting state particularly in elective outpatient cases. In emergent cases when pathology such as acute mesenteric ischemia is suspected evaluation with CT angiography may be best.


Roentgen examination of groin and hip pain in the athlete.
Stress fractures and reactions of the pubic ramus, pubic symphsitis, gracilis syndrome, pelvic avulsion injuries, femoral stress fractures, degenerative osteoarthritis, discogenic pain, and spondylolysis are among the multiple conditions causing groin pain in the athlete. These conditions occasionally have uncertain etiologies and are contributed to by poor training techniques and ill-repaired running shoes, combined with minor congenital anomalies that may have been silent prior to the demands of athletic competition. Roentgen documentation of the specific injury enables early appropriate treatment and minimal "down time".


Expanding the Role of Women in Vector Control: Case Studies From Madagascar, Rwanda, and Zambia.
Historically, vector control, including entomological monitoring, has been a field dominated by men. Each year, the U.S. President's Malaria Initiative (PMI) VectorLink project hires 50,000 to 70,000 seasonal workers across the countries in which it works to implement vector control activities, creating an economic opportunity for both men and women. Remaining barriers to women's employment in vector control include social and cultural norms regarding acceptability of formal employment for women, perceptions that women are not fit to serve as spray operators, and a historical context of male-dominated fields such as entomology. We use PMI VectorLink project data from Madagascar, Rwanda, and Zambia for 2019-2021 and key informant interviews with project staff in these countries to examine levels of female employment, effectiveness and efficiency of female versus male malaria spray operators, and strategies to expand the role of women in vector control. The percentage of female seasonal employees ranges from 25% in Madagascar to 32% in Rwanda and 45% in Zambia. The percentage of women in leadership positions ranges from 32% in Madagascar and Rwanda to 38% in Zambia. Men and women are equally effective and efficient as spray operators. Best practices for recruiting and retaining women in vector control include engaging community leaders in recruitment, implementing affirmative action hiring policies, mentoring women to progress to leadership positions, and ensuring equitable, safe, and attractive workplaces. As vector control programs transition away from donor funding and are increasingly government led, sustaining gains in female empowerment is critical. Country programs should work closely with national, regional, district, and local leaders to demonstrate the importance of hiring women in vector control-including leadership positions-and the impact on female economic empowerment, community well-being, and success of vector control programs.


Dioxin-like compounds formation mediated by Fe3+-montmorillonite: The substituent effects of halophenols.
Toxic dioxin or/and dioxin-like compounds could be naturally formed from the reaction of halophenols on Fe3+-montmorillonite minerals under ambient conditions. Given that the toxicities and productions of dioxin or/and dioxin-like compounds are largely determined by the number, species, and position of the carried halogen atoms, it is necessary to explore the substituent effects on the reaction of halophenols with Fe3+-montmorillonite. Herein, Fe3+-montmorillonite catalyzed polymerizations of six halophenols were examined in a wide range of relative humidity (10%∼80%) using combinations of mass spectrometry identifications and density functional theory calculations. Results show that both the position and species of the substituents substantially impact the reaction rate, product species, and transformation pathways. In general, regardless of humidity ortho-substituted chlorophenols are more reactive than meta-substituted chlorophenols, which is also supported by the density functional theory calculations indicating that the ortho positions are more likely to be attacked. Regarding substituent species, bromophenols are slightly more reactive and also more easily affected by humidities than chlorophenols, which is due to the weaker electron absorbing ability of the bromine atom than the chlorine atom. Hydroxylated polyhalogenated diphenyl ethers are more frequently detected polymerization products, although hydroxylated polyhalogenated biphenyls are greater quantity of products. Overall, this study provides useful information for understanding the natural formation of dioxin or/and dioxin-like compounds mediated by clay minerals and underlying reaction mechanisms.


Early anatomical changes and association with photodynamic therapy induced acute exudative maculopathy in patients with macular diseases.
The purpose of this study was to investigate the occurrence rate and predictors of photodynamic therapy (PDT) induced acute exudative maculopathy (PAEM). This retrospective study included 39 eyes of 39 patients (32 males and 7 females), who were treated with initial PDT. PAEM was defined as an increase in central retinal thickness (CRT) of 15% or more measured by OCT on day 3 after PDT compared with baseline. Sixteen of 39 eyes (41%) were classified in the PAEM+ group. CRT and central choroidal thickness (CCT) were significantly increased at 3 days in the PAEM+ group and significantly decreased at 1 month after PDT in the PAEM- group. In a multiple comparison, neovascular age-related macular degeneration (nAMD) had a significantly higher incidence of PAEM compared to polypoidal choroidal vasculopathy (PCV) and central serous chorioretinopathy (CSC). The incidence of PAEM was lower in PCV and CSC, and higher in nAMD. BCVA at 1 month was significantly worse in the PAEM group, which may be related to visual prognosis after PDT. Since both CRT and CCT decrease at 1 month, the detection of PAEM needs to be assessed a few days after PDT.


Treatment of skin and soft tissue infections with imipenem/cilastatin.
Ninety-eight adult patients with skin and soft tissue infections caused by a variety of bacterial pathogens were treated with imipenem/cilastatin (71), cefazolin (21), or moxalactam (six) at three medical centers. Favorable clinical responses were observed in 87 of the 90 evaluable cases (97 percent). Most etiologic pathogens were eradicated during treatment including five of seven which demonstrated in vitro resistance to the therapeutic agent. Strains that persisted during treatment were not associated with therapeutic failure except in one cefazolin-treated patient who was infected with Bacteroides fragilis. All three drugs were well tolerated and no specific patterns of adverse reactions were observed.


Defense of winter-dormant Alaska paper birch against snowshoe hares.
Mature growth-phase internodes of Alaska paper birch (Betula resinifera) are preferred by the snowshoe hare (Lepus americanus) over juvenile growth-phase internodes due to the low food value of the latter. While the mature over juvenile preferencec cannot be explained by the levels of inorganic nutrients or gross chemical fractions (resins or phenols), it can be explained by the striking differences in secondary metabolites of the two growth phases. The principle compound which renders the juvenile phase internodes unpalatable is papyriferic acid, a triterpene which is a demonstrated feeding deterrent to snowshoe hares and which is present in juvenile internodes at concentrations 25 times greater than those in mature internodes.


Intraoperative blood loss and haemoglobin drop in patients with developmental dysplasia of the hip in Jordan undergoing total hip arthroplasty.
Developmental dysplasia of the hip is still a prevailing secondary cause of early hip osteoarthritis in Jordan. Dysplastic coxarthrosis can result in significant and disabling hip pain with impaired patient's functionality. Due to this significant morbidity, patients ultimately need total hip arthroplasty, which offers the best functional outcome. Significant anatomical aberrances do exist in such hips as a result of old dysplasia; such pathoanatomical changes can complicate an already difficult surgery and lead to significant intraoperative blood loss and haemoglobin drop postoperatively. So, the aim of this research was to investigate on the intraoperative blood loos, and postoperative haemoglobin drop in these patients. A cross-sectional study design was adopted, and 162 patients with advanced hip osteoarthrosis secondary to developmental dysplasia of the hip (DDH) were studied. We studied predictors of hemoglobin drop and blood loss and linked some variables to this outcome variable using different statistical tests. Our results showed a positive correlation between blood loss and BMI (r = 0.27, p = 0.73), haemoglobin drop and duration of surgery (r = 0.14, p = 0.07), length of hospital stay and duration of surgery (r = 0.25, p = 0.001). No significant differences between outcome measures (blood loss, haemoglobin drop, and duration of surgery) between males and females (p = 0.38, 0.93, 0.77 respectively). However, there was a statistically significant differences in haemoglobin drop among patients underwent general versus spinal anaesthesia (p = 0.03). additionally, there was a statistically significant association in length of hospital stay among smokers (p = 0.03), and patients who didn't prescribed anxiolytic preoperatively (p = 0.008). Haemoglobin drop and blood loss in patients with dysplastic coxarthrosis were linked to increased preoperative BMI. Use of preoperative anxiolytics, and being non-smoker decreased the length of hospital stays. General anaesthesia was associated with more haemoglobin drop as well.


Oxytocin weakens self-other distinction in males during empathic responses to sadness: an event-related potentials study.
By making use of event-related potential (ERP) technology, a randomized, double-blind, between-subject design study was performed in order to investigate whether OXT can weaken men's self-other distinction during empathic responses to sad expressions. In the two experimental tasks, 39 male subjects were asked to either evaluate the emotional state shown in a facial stimulus (other-task) or to evaluate their own emotional responses (self-task). The results revealed that OXT reduced the differences in P2 (150-200 ms) amplitudes between sad and neutral expressions in the self-task but enhanced P2 to sad expressions in the other-task, indicating OXT's role in integrating the self with others instead of separating them. In addition, OXT also reduced the LPC (400-600 ms) amplitudes between sad-neutral expressions in the self-task, implying that OXT's weakening effects on the self-other distinction could occur at both the early and late cognitive control stages of the empathic response.


Hypovascular renal tumors: an aggressive diagnostic approach required.
The value of a fine needle aspiration biopsy for confirmation of malignancy is demonstrated in 3 cases of angiographically hypovascular renal tumors. In 2 cases ultrasound examination suggested solid lesions but in 1 case it was predominantly sonolucent. Reliable documentation in the literature indicates that the risk of spreading tumor cells and, hence, of decreasing the survival rate is negligible.


Islets of Langerhans phenotype alterations induced by fatty diet and physical activity levels in Wistar rats.
Physical inactivity (PIn) and a fatty diet (FD) are closely linked to development of metabolic syndrome (MetS), overloading the endocrine pancreas seeking energy homeostasis. However, the relative contribution of FD and PIn to the pancreatic overload is unknown. The aim of this study was to verify the isolated and conjugated influence of FD and PIn in the islets of Langer hans (islets) structure and function related to overload in Wistar rats. Male Wistar rats were divided into four groups (n = 10/group): active groups, fed with fat (AFD) or standard (ASD) diet; and physically inactive groups, fed with fat (SFD) or standard (SSD) diet for 21 wk. Glucose tolerance (GT) and insulin sensitivity (IS) were assessed before sacrifice. Retroperitoneal adipose tissue and pancreas were weighted (PW), and pancreas samples processed for histologic analyses. Only the FD-fed animals presented MS. Compared with standard diet, FD impaired GT and IS, decreased PW, and enlarged islets dimensions, with islets cellular death, inflammatory response, and enhanced collagen content, which were attenuated in AFD. Independent of the diet, PIn groups presented higher amounts of islets connective tissue, but without influence on inflammatory reaction and cellular death. The GT impairment was higher in the FD-fed groups, whereas the decreased IS was more pronounced in the PIn groups. FD induced MS with detrimental effects on pancreas overload, inducing islets morphologic and functional maladaptation, which were attenuated in active animals. Physical activity was not able to prevent FD-induced MS. FD showed a negative influence on GT, whereas PIn mainly affected IS.


Stage I uterine carcinosarcoma: Matched cohort analyses for lymphadenectomy, chemotherapy, and brachytherapy.
To determine if lymphadenectomy, chemotherapy and radiotherapy are associated with survival benefit among women with stage I uterine carcinosarcoma. Women with stage I uterine carcinosarcoma (n=5614) were identified from the 1998-2013 National Cancer Data Base. Kaplan-Meier survival estimates and Cox proportional-hazards regression models were used to evaluate predictors of overall survival. Effects of these predictors were also estimated using propensity score matched analyses for lymphadenectomy, adjuvant chemotherapy, and radiotherapy. 42.0% (2360/5614) of women in the cohort received no adjuvant radiation or chemotherapy. Black race and positive surgical margin status were associated with decreased survival by multivariable Cox regression. Among women with pathologically node-negative disease, the hazard of death increased 5% (4-7%) per each one centimeter increase in tumor size (P=1.9×10-10). From matched cohort analyses, omitting lymphadenectomy was associated with decreased median (interquartile range) survival: 45.2 (36.4-57.6) versus 73.9 (63.8-91.6) months, hazard ratio (HR) (95% CI) 1.38 (1.20-1.59), P=9.4×10-6. Hazard of death decreased by 3% (1-5%) for each five lymph nodes removed (P=0.01). Multiagent chemotherapy and vaginal brachytherapy were associated with decreased hazard of death (HR (95% CI) 0.62 (0.54-0.73), P=1.1×10-9 and HR (95% CI) 0.83 (0.70-0.97), P=0.02, respectively). Highest five-year survival was observed after brachytherapy and multiagent chemotherapy (74.1% (68.3-80.3%), P<2.0×10-16). Lymphadenectomy to at least 15-20 removed nodes is associated with increased survival of women with node-negative uterine carcinosarcoma. Adjuvant "cuff and chemo" with vaginal brachytherapy and multiagent chemotherapy is associated with increased survival.


In Silico Prediction of Selected Bioactive Compounds Present in Alpinia elegans (C.Presl) K.Schum Seed Oil as Potential Drug Candidates Against Human Cancer Cell Lines.
Alpinia elegans (Zingiberaceae) is a Philippine endemic plant reported to have various folkloric uses. The seed oil of A. elegans has been shown to contain a majority of the following bioactive compounds: D-limonene, α-pinene, and caryophyllene oxide. The study sought to determine if the bioactive compounds found in A. elegans seed oil would be a good natural, inexpensive, and less-detrimental alternative for cancer treatment. The study utilized in silico (Way2Drug predictive services, SwissADME, AutoDock 4) experiment to examine the aforementioned compounds as viable therapeutic candidates against human cancer cell lines. Results determined that the compounds D-limonene, α-pinene, and caryophyllene oxide were most potent against thyroid gland carcinoma (8505C) cells, brain glaucoma (Hs 683) cells, and promyeloblast leukemia (HL-60) cells, respectively. Additionally, D-limonene was the only compound to show arrhythmia as an adverse effect. Predictions showed that the compounds could inhibit cellular growth factors and serine/threonine-protein kinase activity. The compounds generated a bioavailability score of 0.55 and exhibited blood-brain barrier (BBB) penetration. D-limonene, α-pinene, and caryophyllene oxide had binding energy of -4.59, -5.43, and -6.92, respectively. The binding energy indicated that the ligands could securely dock to the receptors, thus suggesting that interaction between the ligands and receptors was stable. Results have shown that the compounds are promising candidates against human cancer cell lines by inhibiting cell proliferation and inducing apoptosis.


A critical review of permeabilized cell systems for studying mammalian DNA repair.
Permeabilized cell systems have proven valuable for studies of the enzymology of mammalian DNA repair and this review will summarize and contrast the different systems used to this end. Results from permeable cell studies will be reviewed which pertain to 3 questions of DNA repair: the role(s) of ATP, DNA polymerase enzymology, and the isolation of repair factors by in vitro correction of repair-defective cells.


VirPreNet: a weighted ensemble convolutional neural network for the virulence prediction of influenza A virus using all eight segments.
Influenza viruses are persistently threatening public health, causing annual epidemics and sporadic pandemics. The evolution of influenza viruses remains to be the main obstacle in the effectiveness of antiviral treatments due to rapid mutations. Previous work has been investigated to reveal the determinants of virulence of the influenza A virus. To further facilitate flu surveillance, explicit detection of influenza virulence is crucial to protect public health from potential future pandemics. In this article, we propose a weighted ensemble convolutional neural network (CNN) for the virulence prediction of influenza A viruses named VirPreNet that uses all eight segments. Firstly, mouse lethal dose 50 is exerted to label the virulence of infections into two classes, namely avirulent and virulent. A numerical representation of amino acids named ProtVec is applied to the eight-segments in a distributed manner to encode the biological sequences. After splittings and embeddings of influenza strains, the ensemble CNN is constructed as the base model on the influenza dataset of each segment, which serves as the VirPreNet's main part. Followed by a linear layer, the initial predictive outcomes are integrated and assigned with different weights for the final prediction. The experimental results on the collected influenza dataset indicate that VirPreNet achieves state-of-the-art performance combining ProtVec with our proposed architecture. It outperforms baseline methods on the independent testing data. Moreover, our proposed model reveals the importance of PB2 and HA segments on the virulence prediction. We believe that our model may provide new insights into the investigation of influenza virulence. Codes and data to generate the VirPreNet are publicly available at https://github.com/Rayin-saber/VirPreNet. Supplementary data are available at Bioinformatics online.


Development of a novel and synthetic HematoMiR technology that broadly modulates quiescence of stem cells and enhances HSC expansion.
Hematopoietic stem cell (HSCs) transplantation is the primary therapeutic modality used to treat hematopoietic disorders. It centers on the capability of a small quantity of HSCs to repopulate whole blood lineages. Along with limited availability of suitable donors, the need for sufficient number of donor HSCs is still challenging in clinical relevance. This has been addressed by ex vivo HSC expansion albeit with partial success, and thus development of an alternative strategy that could improve HSC expansion is required. To that end, we aimed to build HematoMiR, an oligo-based technology that broadly targets HSC quiescence factors. Here, we show that HematoMiRs and their combinations targeting over 50 factors involved in HSC quiescence could induce robust ex vivo murine and human HSC expansion. In particular, HematoMiR-5 treatment enhanced cell cycle through down-regulation of negative cell cycle regulators in HSCs. HematoMiR-5 treated HSPCs had reduced DNA damage during the course of ex vivo expansion. Moreover, HematoMiR-5 treatment led to sustained HSC self-renewal ability and a low apoptosis rate. In addition, HematoMiR-5 expanded HSCs demonstrated successful engraftment and repopulation capacity in the recipient animals. Furthermore, combinatorial treatments of HematoMiR-2 and 5 allowed vigorous ex vivo HSC expansion. These findings demonstrate that novel and synthetic HematoMiR technology is feasible for HSC ex vivo expansion through the sequence-dependent modulation of numerous HSC quiescence modulators.


Synergistic effect of a granulocyte-macrophage colony-stimulating factor-transduced tumor vaccine and systemic interleukin-2 in the treatment of murine colorectal cancer hepatic metastases.
Granulocyte-macrophage colony-stimulating factor-transduced tumor cell vaccines are less effective against cancer as the interval between metastasis and the initial vaccination increases. Hepatic metastases were generated in BALB/c mice by using a syngeneic colorectal cancer line (CT26) with a splenic injection model. Irradiated CT26 cells transduced to secrete granulocyte-macrophage colony-stimulating factor were used as vaccine. Treatment groups received vaccine, systemic interleukin (IL-2), or both. Livers were examined for gross metastases 21 days after tumor challenge. Splenocytes were analyzed for in vitro activity against CT26 by using an enzyme-linked immunospot assay and a cytotoxic T lymphocyte assay. Eighty-eight percent of mice treated with vaccines and IL-2 were tumor free on day 21 (P </=.001 vs. control). Treatment with vaccines or IL-2 alone did not result in a significant treatment effect. Splenocytes from mice treated with both vaccines and IL-2 showed greater CT26 lysis than splenocytes from mice treated with vaccines alone at effector:target ratios of 100, 30, and 10 (P <.05 for all). More splenocytes from these mice released interferon-gamma in response to stimulation with the CT26 tumor antigen AH1 compared with mice treated with vaccines alone (P =.05). Systemic IL-2 augments tumor vaccine efficacy in the treatment of microscopic murine colorectal hepatic metastases.


A functional neuroanatomical investigation of the role of the medial preoptic area in neural circuits regulating maternal behavior.
The medial preoptic area (MPOA) is essential for normal maternal behavior in the rat. Hormone stimulation of the MPOA facilitates the behavior and lesions of the MPOA and the adjoining ventral part of the bed nucleus of the stria terminalis (vBST) disrupt the behavior. The MPOA/vBST also show increases in Fos protein expression during maternal behavior. The present study examines the larger neural circuitry within which the MPOA/vBST might operate to influence maternal behavior. Combining Fos immunocytochemistry with unilateral excitotoxic amino acid lesions or lateral knife cuts of the MPOA/vBST, we sought to identify brain regions which might be under the influence of Fos expressing neurons in the MPOA/vBST. Two brain regions, the shell of the nucleus accumbens (NAs), and the intermediate part of the lateral septum (LSi) were identified. Both the NAs and LSi exhibited elevated Fos expression during maternal behavior, while unilateral MPOA/vBST damage resulted in an ipsilateral reduction of maternal behavior-induced Fos expression in each area, suggesting that MPOA/vBST neurons modulate Fos expression and associated neural activity in both of these structures during maternal behavior. Importantly, these unilateral preoptic lesions also depressed maternal behavior-induced Fos expression in the ipsilateral MPOA and vBST. The effects of these lesions on Fos expression in the periaqueductal gray (PAG) and other brain regions are also presented.


The neuroinflammatory marker sTNFR2 relates to worse cognition and tau in women across the Alzheimer's disease spectrum.
Despite women showing greater Alzheimer's disease (AD) prevalence, tau burden, and immune/neuroinflammatory response, whether neuroinflammation impacts cognition differently in women versus men and the biological basis of this impact remain unknown. We examined sex differences in how cerebrospinal fluid (CSF) neuroinflammation relates to cognition across the aging-mild cognitive impairment (MCI)-AD continuum and the mediating role of phosphorylated tau (p-tau) versus other AD biomarkers. Participants included 284 individuals from the Alzheimer's Disease Neuroimaging Initiative study. CSF neuroinflammatory markers included interleukin-6, tumor necrosis factor α, soluble tumor necrosis factor receptor 2 (sTNFR2), and chitinase-3-like protein 1. AD biomarkers were CSF p-tau181 and amyloid beta1-42 levels and magnetic resonance imaging measures of hippocampal and white matter hyperintensity volumes. We found a sex-by-sTNFR2 interaction on Mini-Mental State Examination and Clinical Dementia Rating-Sum of Boxes. Higher levels of sTNFR2 related to poorer cognition in women only. Among biomarkers, only p-tau181 eliminated the female-specific relationships between neuroinflammation and cognition. Women may be more susceptible than men to the adverse effects of sTNFR2 on cognition with a potential etiological link with tau to these effects.


Identification of a functional 3',5'-cyclic adenosine monophosphate response element within the second promoter of the mouse somatostatin receptor type 2 gene.
Important physiological actions of somatostatin are mediated by the somatostatin receptor type 2. Its transcription is regulated by three tissue specific, alternative promoters. It is known that the mRNA of the somatostatin receptor type 2 gene is induced by cAMP, but little is known about the mechanisms underlying this regulation. We have identified and characterized a cAMP responsive element located at nucleotide -162 on the second promoter of the gene consisting of the classical palindromic octameric sequence 5'-TGACGTCA-3'. Using transient expression of reporter gene deletion constructs in NGC108-15 cells the necessity of the intact element for forskolin-induced reporter gene activity was demonstrated. The first and the third promoter are not responsive to forskolin, nor did any promoter respond to the phorbol ester PMA. Electrophoretic mobility shift assays in combination with competition experiments suggest the interaction of the promoter element with the cAMP responsive element binding protein.


Faces do not guide attention in an object-based facilitation manner.
Numerous studies on face processing have revealed their special ability to affect attention, but relatively little research has been done on how faces guide spatial attention allocation. To enrich this field, this study resorted to the object-based attention (OBA) effect in a modified double-rectangle paradigm where the rectangles were replaced with human faces and mosaic patterns (non-face objects). Experiment 1 replicated the typical OBA effect in the non-face objects, but this effect was absent in Asian and Caucasian faces. Experiment 2 removed the eye region from Asian faces, but still found no object-based facilitation in the faces without eyes. In Experiment 3, the OBA effect was also observed for faces when the faces disappear a short period before the responses. Overall, these results revealed that when two faces are presented together, they do not exert object-based facilitation regardless of their facial features such as race and the presence of eyes. We argue that the lack of a typical OBA effect is due to the filtering cost induced by the entire face content. This cost slows down the response when attention shifts within a face and results in the absence of object-based facilitation.


Parotid gland lesions: diagnosis of malignancy with MRI and flow cytometric DNA analysis and cytology in fine-needle aspiration biopsy.
The purpose of this study was to assess the capability of magnetic resonance imaging (MRI) and cytology and flow cytometric (FCM) deoxyribonucleic acid (DNA) analysis in fine-needle aspiration biopsy (FNAB)-derived materials for diagnosing malignancy of the parotid lesions and the efficacy of FCM analysis in FNAB. Magnetic resonance imaging findings and FCM results (ploidy and S + G2 + M phases [S + G2M] fraction) and cytology in FNAB-derived materials in 26 patients with 26 parotid lesions (12 benign lesions, 14 malignancies) were assessed for predicting malignancy. Flow cytometric results in aspirates were compared with those in surgically resected tissues. When a single predictor was used, cytology (92% accuracy) was most accurate for malignancy, followed by ill-defined margin (88% accuracy) and aneuploidy (88% accuracy). The combination of FCM and cytology raised the rate of sufficient materials from 92% to 100% and accuracy from 92% to 96% compared with cytology alone. The same highest accuracy (96%) was obtained with the combination of the ill-defined margin or other findings such as cytology, aneuploidy, or a high (S + G2M) fraction (6% <). Deoxyribonucleic acid ploidy in the FNAB showed full agreement with that in the surgical specimens. Receiver operating characteristic curves showed that the diagnosis of malignancy with (S + G2M) fraction in FNAB was superior to that in surgical specimens, but no significant difference was noted. A combination of MRI findings, cytology, and FCM results is optimal for diagnosing malignancies of the parotid lesions, and FNAB may replace the surgical specimens in FCM analysis.


Midlife concerns of women: implications of the menopause.
Midlife has received recent attention but is still difficult to define. Women's developmental phases are most appropriately understood as different from men's, with a complex integration of biological context, family development and roles, and individual development. Menopause has been considered a determining event, and a variety of symptoms have been attributed to menopausal changes. Emerging data indicate that menopause does not appear to be responsible for most of the symptoms. Midlife stresses are the result of a combination of personal, family, social, and biological variables, with postmenopausal development an important phase.


Association between Decreased Social Participation and Depressive Symptom Onset among Community-Dwelling Older Adults: A Longitudinal Study during the COVID-19 Pandemic.
The coronavirus disease (COVID-19) pandemic has imposed restrictions on people's social behavior. However, there is limited evidence regarding the relationship between changes in social participation and depressive symptom onset among older adults during the pandemic. We examined the association between changes in social participation and the onset of depressive symptoms among community-dwelling older adults during the COVID-19 pandemic. This was a longitudinal study. Communities in Minokamo City, a semi-urban area in Japan. We recruited community-dwelling older adults aged ≥ 65 years using random sampling. Participants completed a questionnaire survey at baseline (March 2020) and follow-up (October 2020). Depressive symptoms were assessed using the Two-Question Screen. Based on their social participation status in March and October 2020, participants were classified into four groups: "continued participation," "decreased participation," "increased participation," and "consistent non-participation." A total of 597 older adults without depressive symptoms at baseline were analyzed (mean age = 79.8 years; 50.4% females). Depressive symptoms occurred in 20.1% of the participants during the observation period. Multivariable Poisson regression analysis showed that decreased social participation was significantly associated with the onset of the depressive symptoms, compared to continued participation, after adjusting for all covariates (incidence rate ratio = 1.59, 95% confidence interval = 1.01-2.50, p = 0.045). Older adults with decreased social participation during the COVID-19 pandemic demonstrated a high risk of developing depressive symptoms. We recommend that resuming community activities and promoting the participation of older adults, with sufficient consideration for infection prevention, are needed to maintain mental health among older adults.


Risk of recurrence in children operated for thyroglossal duct cysts: A systematic review.
To determine the rate of recurrence following surgical treatment of thyroglossal duct cysts (TDGCs) in children. A search of electronic databases (Pubmed and MEDLINE) was performed in order to identify studies concerning surgical treatment of TGDCs in children published between 1980 and 2012. The following terms were used: "thyroglossal duct cysts", "recurrent", "recurrence", "children", "pediatric". Sixteen articles were selected with the majority published during the last decade. The total number of included subjects was 1233. The mean (95% confidence interval (CI)) rate of recurrences was 10.7% (9.1%-12.6%). Eleven studies involving 751 subjects reported the frequency of recurrences separately for primary cases. The mean (95% CI) rate of recurrences was 10.8% (8.7%-13.3%). Five studies reported separately results of surgery for secondary cases. The mean (95% CI) rate of recurrences was 20.0% (12.2%-30.8%). Eight of the sixteen studies reported data on risk factors for recurrence. The use of the Sistrunk technique is a protective factor, whereas children who experienced repeated episodes of infection prior to surgery are exposed to a higher risk of recurrence. Recurrences after surgery for TDGCs remain a clinically relevant issue. One of ten operated children experiences a recurrence. Available data support the use of the Sistrunk technique but further studies aimed at improving the clinical management of TDGCs are required.


Insights into an analytical simulation of a natural convection flow controlled by Arrhenius kinetics in a micro-channel.
The focus of this paper is the investigation of an Arrhenius-driven chemical reaction in an upstanding micro-channel over an imposed transverse magnetic field with fully developed constant free convection flow. Subject to suitable boundary conditions, the temperature and velocity equations are resolved in non-dimensional form employing the homotopy perturbation method (HPM). the fundamental flow behaviors of temperature, velocity, and volumetric flow are explored as a consequence of regulating characteristics such as fluid-wall interaction parameter, rarefaction parameter, chemical reaction parameters, wall-ambient temperature difference ratio, and Hartman number. The findings are carefully investigated and graphically represented in several mesh grid graphs. It was established that increasing the values of the rarefaction parameters and chemical reaction results in an upsurge in the fluid velocity and volume flow rate, respectively, whereas increasing the Hartman number results in observable flow retardation. Additionally, when the chemical reactant parameter is ignored, the numerical comparison is in excellent agreement with the previously published results.


Are results of bariatric surgery different in the Middle East? Early experience of an international bariatric surgery program and an ACS NSQIP outcomes comparison.
Bariatric operations performed at the Bariatric and Metabolic Institute Abu Dhabi are submitted randomly from the entire surgery volume at Sheikh Khalifa Medical City to the American College of Surgeons (ACS) NSQIP. Our aim is to report our early experience and compare our bariatric surgery outcomes with ACS NSQIP hospitals of similar size. We queried the ACS NSQIP database for bariatric surgery codes between August 2009 and August 2012 for hospitals with >500 beds. Statistical analysis was performed (p < 0.05). We performed 275 bariatric operations compared with a total of 29,715 at other NSQIP hospitals. The ACS NSQIP bariatric surgery cohort at the Bariatric and Metabolic Institute Abu Dhabi represents 275 of 312 (89.3%) of our entire bariatric surgery volume. Our patients were statistically significantly younger (mean age 36 vs 44.8 years), healthier (American Society of Anesthesiologists scores 1 to 2 in 78.6% vs 35.7%), and heavier (body mass index 47.4 vs 45.5). In addition, we had fewer diabetic (18.5% vs 27.3%) and hypertensive (21.1% vs 52.2%) patients. We performed more Roux-en-Y gastric bypass (69.8% vs 54.5%) and sleeve gastrectomy (24.8% vs 17.2%) and fewer laparoscopic adjustable gastric banding (0.8% vs 22.7%). Outcomes were similar with regard to rates of reoperation, wounds, urinary tract infection, bleeding, thromboembolic, respiratory, and overall complications. We had lower septic, cardiac, and renal failure complications; lower mortality, and longer hospital stay by 0.4 days. We achieved 94.9% 30-day follow-up compared with 90.7% at other ACS NSQIP hospitals. This is the first report comparing outcomes of an international bariatric surgery program (Bariatric and Metabolic Institute Abu Dhabi) with ACS NSQIP bariatric surgery programs. Our outcomes are equivalent to ACS NSQIP bariatric surgery programs.


Melatonin biosynthesis restored by CpG oligodeoxynucleotides attenuates allergic airway inflammation via regulating NLRP3 inflammasome.
Both CpG oligodeoxynucleotide (CpG-ODN) and melatonin have been reported to induce Th1 response and contribute to allergic asthma resistance. Here, we aimed to reveal how they confer such effect as well as whether they crosstalk with each other. Six-week-old Female C57BL/6 mice were challenged by OVA to induce allergic airway inflammation, and were treated with CpG-ODN, CpG-ODN plus Luzindole or melatonin respectively. Bronchoalveolar lavage fluid (BALF) cellularity was classified and counted by Wright's-Giemsa staining. HE and PAS staining were used to analyze airway inflammation. The levels of IL-4, IL-5, IL-13,GM-CSF and IFN-γ, as well as IL-1β and IL-18 were analyzed by ELISA. Protein expressions of ASMT, AANAT, NLRP3, IL-1β and caspase-1 in lung tissue were detected by Western blotting, expression of ASMT and AANAT were further observed by immunohistochemistry. We found that CpG-ODN considerably suppressed OVA-induced airway leukocytes infiltration, goblet cell hyperplasia and Th2 cytokines production. Furthermore, the resolution effect of CpG-ODN on OVA-induced allergic airway inflammation occurred in parallel with decreased-activation of NLRP3 inflammasome and increased biosynthesis of melatonin. Blocking the effect of endogenous melatonin by Luzindole abolished the suppressive effect of CpG-ODN on OVA-induced airway inflammation and activation of NLRP3 inflammasome, suggesting such effect was mediated by endogenous melatonin. Moreover, exogenous melatonin pronouncedly ameliorated airway inflammation and decreased the activation of NLRP3 inflammasome. These results proven that CpG-ODN protects against allergic airway inflammation via suppressing the activation of NLRP3 inflammasome, and such effect may be resulted from the restored-production of melatonin.


Generating high-valent iron-oxo ≡FeIV=O complexes by calcium sulfite activation in neutral microenvironments for enhanced degradation of CIP.
Although alkaline sulfite activation of ferrate (Fe(VI)) has advantages of fast response and high activity for degradation of organic contaminants, the specific production pathways of active species and the pH conditions still hinder its widespread application. Based on this, our study constructed a novel advanced oxidation process of calcium sulfite (CaSO3) could activated Fe(VI) continuously by Ca2+ buffering and investigated the mechanism under different pH values and CaSO3 dosages with ciprofloxacin as a target organic pollutant. The results showed that Ca2+ stabilized the process at a neutral/weakly alkaline microenvironment of pH 7-8, which could alleviate the hydrolysis of ≡FeIV=O by protons and iron hydroxyl groups. Besides, the removal of pollutants occurred efficiently when sulfate (SO32-) was excessive and had a 3:1 ratio of SO32- to Fe(VI), achieving more than 99% removal of electron-rich phenolic organic pollutants within 2 min. By adding different radical scavengers and combining electrochemical analysis methods and electron paramagnetic resonance spectroscopy techniques to revealed that the main active species in Fe(VI)/CaSO3 process were ≡FeIV=O/≡FeV=O. Furthermore, the reactivity of various sulfate species (such as SO32-, SO3•-, SO4•-, SO5•-) with Fe(VI) was calculated using density functional theory (DFT), and it was found that Fe(VI)-SO32- reaction has a much lower energy barrier (-36.08 kcal/mol), indicating that SO32- can readily activate Fe(VI) and generate ≡FeIV=O to attack the atoms with high Fukui index (f -) in organic pollutants. The above results confirm the feasibility of Fe(VI)/CaSO3 process. Thus, this study can theoretically and practically prove that the main active species is ≡FeIV=O, rather than SO4•- or •OH in Fe(VI)/CaSO3 process.


Survival curve and factors related to drainage during the first 24 h after total knee arthroplasty.
Routine use of drains in total knee arthroplasty (TKA) is controversial. The aim of this study is to define the hourly risk of bleeding in the first 24 h following TKA using a survival study, to detect factors that might modify this risk, and establish a predictive model. In a retrospective study including 112 knees, patients with a coagulation disorder, platelet disease, or anticoagulation treatment were excluded. The risk factors studied included anesthesia score of the American society of anesthesiologists (ASA), proteinemia, total volume of fluid drained, and the use of low molecular weight heparin. The Kaplan-Meier test, Mantel-Haenszel test, and Cox regression analysis were used for the statistical calculations. The results indicate that the drains used in TKA can be removed within the first 18 h with a high degree of safety and low risk of persistent bleeding. The evolution of postoperative bleeding was independent of the factors studied.


Long-term colorectal cancer incidence and mortality after adenoma removal in women and men.
Women and men with colorectal adenomas are at increased risk of colorectal cancer and colonoscopic surveillance is recommended. However, the long-term cancer risk remains unknown. To investigate colorectal cancer incidence and mortality after adenoma removal in women and men METHODS: We identified all individuals who had adenomas removed in Norway from 1993 to 2007, with follow-up through 2018. We calculated standardized incidence ratios (SIR) and incidence-based mortality ratios (SMR) with 95% confidence intervals (CI) for colorectal cancer in women and men using the female and male population for comparison. We defined high-risk adenomas as ≥2 adenomas, villous component, or high-grade dysplasia. The cohort comprised 40 293 individuals. During median follow-up of 13.0 years, 1079 women (5.5%) and 866 men (4.2%) developed colorectal cancer; 328 women (1.7%) and 275 men (1.3%) died of colorectal cancer. Colorectal cancer incidence was more increased in women (SIR 1.64, 95% CI 1.54-1.74) than in men (SIR 1.12, 95% CI 1.05-1.19). Colorectal cancer mortality was increased in women (SMR 1.13, 95% CI 1.02-1.26) and reduced in men (SMR 0.79, 95% CI 0.71-0.89). Women with high-risk adenomas had an increased risk of colorectal cancer death (SMR 1.37, 95% CI 1.19-1.57); women with low-risk adenomas (SMR 0.90, 95% CI 0.76-1.07) and men with high-risk adenomas had a similar risk (SMR 0.89, 95% CI 0.76-1.04), while men with low-risk adenomas had reduced risk (SMR 0.70, 95% CI 0.59-0.84). After adenoma removal, women had an increased risk of colorectal cancer death, while men had reduced risk, compared to the general female and male populations. Sex-specific surveillance recommendations after adenoma removal should be considered.


Predictive model with analysis of the initial spread of COVID-19 in India.
The Coronavirus Disease 2019 (COVID-19) has currently ravaged through the world, resulting in over thirteen million confirmed cases and over five hundred thousand deaths, a complete change in daily life as we know it, worldwide lockdowns, travel restrictions, as well as heightened hygiene measures and physical distancing. Being able to analyse and predict the spread of this epidemic-causing disease is hence of utmost importance now, especially as it would help in the reasoning behind important decisions drastically affecting countries and their people, as well as in ensuring efficient resource and utility management. However, the needs of the people and specific conditions of the spread are varying widely from country to country. Hence, this article has two fold objectives: (i) conduct an in-depth statistical analysis of COVID-19 affected patients in India, (ii) propose a mathematical model for the prediction of spread of COVID-19 cases in India. There has been limited research in modeling and predicting the spread of COVID-19 in India, owing both to the ongoing nature of the pandemic and limited availability of data. Currently famous SIR and non-SIR based Gauss-error-function and Monte Carlo simulation models do not perform well in the context of COVID-19 spread in India. We propose a 'change-factor' or 'rate-of-change' based mathematical model to predict the spread of the pandemic in India, with data drawn from hundreds of sources. Average age of affected patients was found to be 38.54 years, with 66.76% males, and 33.24% females. Most patients were in the age range of 18-40 years. Optimal parameter values of the prediction model are identified (α = 1.35, N = 3 and T = 10) by extensive experiments. Over the entire course of time since the outbreak started in India, the model has been 90.36% accurate in predicting the total number of cases the next day, correctly predicting the range in 150 out of the 166 days looked at. The proposed system showed an accuracy of 90.36% for prediction since the first COVID-19 case in India, and 96.67% accuracy over the month of April. Predicted number of cases for the next day is found to be a function of the numbers over the last 3 days, but with an 'increase' factor influenced by the last 10 days. It is noticed that males are affected more than females. It is also noticed that in India, the number of people in each age bucket is steadily decreasing, with the largest number of adults infected being the youngest ones-a departure from the world trend. The model is self-correcting as it improves its predictions every day, by incorporating the previous day's data into the trend-line for the following days. This model can thus be used dynamically not only to predict the spread of COVID-19 in India, but also to check the effect of various government measures in a short span of time after they are implemented.


Focal deformity of the cranial nerves observed on multislice motion-sensitized driven equilibrium (MSDE) in patients with neurovascular compression.
Our purpose is to demonstrate the deformity of the cranial nerves by arterial compression using a novel technique, multislice motion-sensitized driven equilibrium (MSDE). Subjects were 10 patients with neurovascular compression (5 patients with trigeminal neuralgia and 5 patients with hemifacial spasm). We observed the existence and extent of deformity of nerves by MSDE. Afterward, we compared operative findings with preoperative imaging findings and evaluated the validity of the latter. All compressing, blood vessels could be correctly identified through preoperative evaluation. Of all patients, 7 showed deformity of the cranial nerves, which was consistent with operative findings except in one case. In postoperative evaluation, patients' neurological symptoms improved and the deformity disappeared. Three patients did not show deformity on preoperative MSDE images. In these patients, neural compression was also not observed during the operation. The deformity of cranial nerves in patients with neurovascular compression was clearly shown using MSDE.


Development of the Behavioral Assessment and Research System (BARS) to detect and characterize neurotoxicity in humans.
The Behavioral Assessment and Research System (BARS) is a computer-based testing system designed to assess neurobehavioral function in humans. It was developed to provide a series or battery of neurobehavioral tests optimized for the detection of neurotoxicity in non-mainstream human populations, specifically people with limited education or literacy. Key to meeting this goal were simply-stated instructions divided into an elemental series of steps, a 9BUTTON response unit to replace the computer keyboard for responding, and spoken instructions. Modifications all underwent serial testing in target populations to successively hone the changes to be more effective. A similar process was followed when developing adjustable parameters, test reliability assessments, and when implementing these tests with populations from different cultural groups and children. The principles and experiences that guided the development of BARS should inform the development of future testing systems to ensure that the new tests can be used with non-mainstream populations, which may be increasingly subject to neurotoxic exposures.


Fatigue and serum testosterone in obstructive sleep apnea patients.
Obstructive sleep apnea (OSA)-related fatigue is a common understudied symptom. Fatigue is associated with low serum testosterone level in non-OSA patients. No data are available about this association in OSA patients. To investigate in adult obese males affected by OSA, the relationship between fatigue and serum testosterone in order to identify predictors for OSA-related fatigue. Fifteen OSA patients and 15 control subjects participated. The parameters analyzed were serum testosterone morning concentration, polysomnography parameters, daytime sleepiness (Epworth Sleepiness Scale) and fatigue (Multidimensional Fatigue Inventory). Regression test was applied in order to show predictors of fatigue. Kruskal-Wallis test followed by post-hoc analysis was performed to test for differences between controls and OSA subgroups for testosterone, fatigue components and sleepiness. Mean testosterone level was 3.55 ± 0.7 ng/mL in the OSA group, significantly lower than in controls (4.26 ± 1.1 ng/mL, P = 0.049). An inverse correlation was found between testosterone and fatigue scores (P < 0.01). Furthermore, a statistically significant difference was found between the control group and the severe OSA subgroup for general fatigue, physical fatigue, reduced activity and mental fatigue. However, no significant differences were found between controls and mild OSA. Among all variables, testosterone was the only independent significant predictor of physical fatigue (t = -2.56, P = 0.033, R = 0.978, R(2) = 0.958) and reduced activity (t = -4.41, P = 0.002, R = 0.966, R(2) = 0.934) in the OSA patients. OSA-related fatigue was strongly associated with serum testosterone, together with OSA severity.


Towards a rational design of an asymptomatic clinical herpes vaccine: the old, the new, and the unknown.
The best hope of controlling the herpes simplex virus type 1 and type 2 (HSV-1 and HSV-2) pandemic is the development of an effective vaccine. However, in spite of several clinical trials, starting as early as 1920s, no vaccine has been proven sufficiently safe and efficient to warrant commercial development. In recent years, great strides in cellular and molecular immunology have stimulated creative efforts in controlling herpes infection and disease. However, before moving towards new vaccine strategy, it is necessary to answer two fundamental questions: (i) why past herpes vaccines have failed? (ii) Why the majority of HSV seropositive individuals (i.e., asymptomatic individuals) are naturally "protected" exhibiting few or no recurrent clinical disease, while other HSV seropositive individuals (i.e., symptomatic individuals) have frequent ocular, orofacial, and/or genital herpes clinical episodes? We recently discovered several discrete sets of HSV-1 symptomatic and asymptomatic epitopes recognized by CD4(+) and CD8(+) T cells from seropositive symptomatic versus asymptomatic individuals. These asymptomatic epitopes will provide a solid foundation for the development of novel herpes epitope-based vaccine strategy. Here we provide a brief overview of past clinical vaccine trials, outline current progress towards developing a new generation "asymptomatic" clinical herpes vaccines, and discuss future mucosal "asymptomatic" prime-boost vaccines that could optimize local protective immunity.


Assessing competence needs for doctors in the emergency department duty rosters: an observational study.
The purpose of our investigation is to analyze if emergency epidemiology is randomly variable or predictable. If emergency admissions show a predictable pattern, we can use it for multiple planning purposes, especially defining competence needs for duty roster personnel. An observational study of consecutive emergency admissions at Haukeland University Hospital in Bergen over six years. We extracted the discharge diagnoses from our electronic patient record and sorted the patients by diagnoses and frequency. Data were loaded into a Jupyter notebook and presented in form of frequency diagrams. The study population, 213,801 patients, comprises all emergency admissions in need of secondary emergency care from the relevant specialities in the catchment area of our hospital in the western health region of Norway. Patients in need of tertiary care from the whole region are also included. Our analysis shows an annually reproducible distribution pattern regarding type and number of patients. The pattern adhere to an exponential curve that is stable from year to year. An exponential distribution pattern also applies when we sort patients according to the capital letters groups in the ICD 10 system. The same applies if patients are sorted adhering to primarily surgical or medical diagnoses. Analysis of the emergency epidemiology of all admitted emergency patients in a defined geographical area gives a solid basis for defining competence needs for duty roster work.


A modified induced membrane 2-stage technique using a thoracodorsal artery perforator free flap followed by vascularized or non-vascularized free fibular transfer for the treatment of complex bone infection with concomitant severe soft tissue lesion-A case series of 9 cases.
Treatment of post-traumatic complex bone infection is very challenging. The two principal bone reconstruction approaches are the single-stage vascularized bone graft technique and the two-stage induced membrane technique (IMT). Here we introduce a modified 2-stage induced membrane technique (MIMT) for complex long bone infection with a major bone defect and a concomitant severe soft tissue lesion. The 2-stage procedure consists of bone debridement, placement of a PMMA spacer and soft tissue reconstruction with a thoracodorsal artery perforator free flap ("Tdap") at stage 1. At stage 2, the thoracodorsal artery perforator flap is elevated and a fibular strut graft (either vascularized of non-vascularized) is placed for bone reconstruction. We retrospectively analyzed the extents of lower extremity, long bone, post-traumatic bone infection treated via MIMT from 2008 to 2020. There were nine such cases (eight males) of mean age 59.8 (range 31 to 79) years. The osteomyelitis durations ranged from 3 to 360 months (mean 53 months). The cortical bone defect sizes was ranged from 9 to 14 cm (mean10.7 cm). All skin resurfacing employed Tdap. Vascularized fibular grafts were placed in six patients and non-vascularized grafts were placed in three. The fibular graft size ranged from 12.5 to 19 cm (mean 16.2 cm). Non-vascularized iliac bone grafts served as the fibula docking sites. Unfortunately, all patients suffered complications before bone union was achieved. One case of plate stress fracture and one case of screw fracture required plate and screw change. In three cases of cellulitis, one resolved by use of intravenous antibiotics, others required plate and screw removal. Wound disruption required re-suture and distal skin flap partial necrosis was covered by perforator-based island flap. One case of fibular stress fracture needed cast for 4 weeks. A peroneal nerve palsy patient recovered spontaneously. Bone union was achieved after 6 months in five patients and after 8 months in three (mean 6.9 months). All patients were able to walk unaided. The follow-up period ranged from 2 to 14 years (mean 6.2 years). MIMT saves the limbs in cases with difficult post-traumatic bone infection. It is valid treatment option for complex bone infections with severe soft tissue lesions. However, even with this technique potential complication must be considered.


Changes in depressive symptoms and cognitive impairment in older long-stay nursing home residents in the USA: a latent transition analysis.
To longitudinally examine the latent statuses of depressive symptoms and their association with cognitive impairment in older U.S. nursing home (NH) residents. Using Minimum Data Set 3.0, newly-admitted, long-stay, older NH residents with depression in 2014 were identified (n = 88,532). Depressive symptoms (Patient Health Questionnaire-9) and cognitive impairment (Brief Interview of Mental Status) were measured at admission and 90 days. Latent transition analysis was used to examine the prevalence of and the transition between latent statuses of depressive symptoms from admission to 90 days, and the association of cognitive impairment with the statuses at admission. Four latent statuses of depressive symptoms were identified: 'Multiple Symptoms' (prevalence at admission: 17.3%; 90 days: 13.6%), 'Depressed mood' (20.0%; 19.5%), 'Fatigue' (27.4%; 25.7%), and 'Minimal Symptoms' (35.3%; 41.2%). Most residents remained in the same status from admission to 90 days. Compared to residents who were cognitively intact, those with moderate impairment were more likely to be in 'Multiple Symptoms' and 'Fatigue' statuses; those with severe impairment had lower odds of belonging to 'Multiple Symptoms', 'Depressed Mood', and 'Fatigue' statuses. By addressing the longitudinal changes in the heterogeneous depressive symptoms and the role of cognitive impairment, findings have implications for depression management in older NH residents.


The life cycle energetics of Rhopaea verreauxi (Coleoptera: Scarabaeidae).
Life cycle energy budgets were constructed for the scarabaeid Rhopaea verreauxi. The acquisition and utilization of energy was most efficient in the early phases of the first larval instar; the cumulative conversion efficiencies (A c /C c , P c /C c andd P c /A c ) declining throughout the life cycle. The third larval instar dominated the energy budget. Production in this stage was mainly the accumulation of lipids. In terms of energetics, the reproductive effort of a female R. verreauxi was particularly high. The amount of production eliminated as exuviae was similar to that in other holometabolous insects and a negligible fraction of consumption and assimilation. The life cycle A c /C c of 31% for R. verreauxi was typical of nonspecialist herbivores and the life cycle P c /A c of 20% typical of relatively long-lived ectotherms.It was noted that the production of methane could represent a possible loss of up to 6% of the gross energy intake. Despite this, despite the use of constant temperatures and despite the fact that R was not 'corrected', the cummulative energy budgets constructed were considered to be reasonably accurate representations of the dimensional changes that occur in the energy budget of an individual R. verreauxi.


The use of HaloTag-based technology in flow and laser scanning cytometry analysis of live and fixed cells.
Combining the technologies of protein tag labeling and optical microscopy allows sensitive analysis of protein function in cells. Here, we describe development of applications using protein tag technology (HaloTag (HT)-based) for flow and laser scanning cytometry (LSC). Cell lines, expressing recombinant surface β1-integrin-HT and HT-p65 fusion protein, and a CD4 T cell line (Jurkat) infected with human immunodeficiency virus type 1 (HIV-1) reporter virus expressing the unfused HT (HIV-1Lai-Halo), were stained with different HT ligands and successfully detected by flow cytometers equipped with 488 and 561 nm lasers as well as a laser scanning cytometer (equipped with 488 and 405 nm lasers) alone or combined with cell cycle and viability markers. Use of HT technology for cytometric applications has advantages over its use in microscopy as it allows for the statistical measurement of protein expression levels in individual cells within a heterogeneous cell population in combination with cell cycle analysis. Another advantage is the ability of the HaloTag to withstand long fixation and high concentration of fixative, which can be useful in research of infectious agents like HIV and/or mycobacteria.


Tumor promoter 12-O-tetradecanoylphorbol-13-acetate is not a prostaglandin E-type agonist.
The tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA), proposed to fit a prostaglandin type receptor, does not compete with [3H] prostaglandin E1 (PGE1) for the established PGE1 receptor of fat cells.


Oral ferroportin inhibitor VIT-2763: First-in-human, phase 1 study in healthy volunteers.
Restriction of iron availability by ferroportin inhibition is a novel approach to treating non-transfusion-dependent thalassemia (β-thalassemia intermedia). This first-in-human, Phase I study (https://www.clinicaltrialsregister.eu; EudraCT no. 2017-003395-31) assessed the safety, tolerability, pharmacokinetics and pharmacodynamics of single- and multiple-ascending doses (SAD and MAD) of the oral ferroportin inhibitor, VIT-2763, in healthy volunteers. Participants received VIT-2763 5/15/60/120/240 mg or placebo in the SAD phase and VIT-2763 60/120 mg once daily, VIT-2763 60/120 mg twice daily, or placebo for 7 days in the MAD phase. Seventy-two participants completed treatment. VIT-2763 was well tolerated and demonstrated a similar safety profile to the placebo. There were no serious or severe adverse events, or discontinuations due to adverse events. VIT-2763 absorption was relatively fast, with detectable levels 15 to 30 minutes post-dose. Following multiple dosing there was no apparent change in absorption and accumulation was minimal. Mean elimination half-life was 1.9 to 5.3 hours following single dosing, and 2.1 to 3.8 hours on Day 1 and 2.6 to 5.3 hours on Day 7, following repeated dosing. There was a temporary decrease in mean serum iron levels with VIT-2763 single doses ≥60 mg and all multiple doses; mean calculated transferrin saturation (only assessed following multiple dosing) also temporarily decreased. A shift in mean serum hepcidin peaks followed administration of all iron-lowering doses of VIT-2763. This effect was less pronounced after 7 days of multiple dosing (aside from with 120 mg once daily). These results support the initiation of clinical studies in patients with non-transfusion-dependent thalassemia and documented iron overload due to ineffective erythropoiesis.


Changes in biological effectiveness of the neutron beam at Clatterbridge (62 MeV p on Be) measured with cells in vitro.
Chinese hamster V79 cells have been used to assess changes in RBE of the p(62)Be neutron beam at the Clatterbridge Hospital with depth in a phantom and with use of a hydrogenous filter. The cells were exposed at depths of 2 and 12 cm and at a depth of 2 cm with a hydrogenous filter. Two groups of experimenters each conducted two experiments. The ratios of relative biological effectiveness (RBE) at a depth of 12 cm to that at 2 cm were found by the two groups to be 0.99 +/- 0.04 and 0.96 +/- 0.02 (standard errors). The effect of a polythene filter 4.5 cm thick was measured at a depth of 2 cm and the ratio of RBE with and without the filter was found by both groups to be 0.99 +/- 0.02. All the experiments suggest that there may be small effects of beam hardening by depth and filtration but these results are in marked contrast with those obtained using an in vivo system.


Metallothionein-like metal-binding protein in the biomonitor Chaoborus: occurrence and relationship to ambient metal concentrations in lakes.
Larvae of the insect Chaoborus are used to monitor cadmium (Cd) in lakes. We set out to determine if this animal possesses a metallothionein-like protein to which its Cd could be bound and if the concentrations of such a protein are correlated with those of Cd in the insect and in lakewater. To achieve our goals, we collected water and larvae of several Chaoborus species from 10 lakes situated along an environmental Cd gradient. We found that all of the Chaoborus species possess a metallothionein-like protein and that concentrations of the protein and of Cd differed among species. Concentrations of the metallothionein-like protein were directly related to those in Chaoborus and in lakewater. These direct relationships support the use of Chaoborus larvae as a Cd biomonitor.


Analysis and synthesis of the three-dimensional movements of the head, face, and hand of a speaker using cued speech.
In this paper we present efforts for characterizing the three dimensional (3-D) movements of the right hand and the face of a French female speaker during the audiovisual production of cued speech. The 3-D trajectories of 50 hand and 63 facial flesh points during the production of 238 utterances were analyzed. These utterances were carefully designed to cover all possible diphones of the French language. Linear and nonlinear statistical models of the articulations and the postures of the hand and the face have been developed using separate and joint corpora. Automatic recognition of hand and face postures at targets was performed to verify a posteriori that key hand movements and postures imposed by cued speech had been well realized by the subject. Recognition results were further exploited in order to study the phonetic structure of cued speech, notably the phasing relations between hand gestures and sound production. The hand and face gestural scores are studied in reference with the acoustic segmentation. A first implementation of a concatenative audiovisual text-to-cued speech synthesis system is finally described that employs this unique and extensive data on cued speech in action.


Antibiotic therapy for treatment in relapse of intestinal Crohn's disease. A prospective randomized study.
We have undertaken a prospective randomized trial of one month's antimicrobial therapy for patients with symptomatic relapse of Crohn's disease. Criteria for entry included two major symptoms: fever, abdominal pain, diarrhea, weight loss, abdominal mass or complications (excluding perianal disease); and two hematologic abnormalities: hemoglobin, ESR, albumin, C reactive protein, iron, or total iron binding capacity. Patients were monitored for the aforementioned clinical and hematologic (hemoglobin, albumin, CRP) parameters over six weeks and for changes in fecal flora. Randomization was to four groups: metronidazole alone (M), cotrimoxazole alone (C), metronidazole and cotrimoxazole (C plus M), or double placebo (P). Seventy-two patients entered the study (18 = M, 16 = C, 21 = C plus M, 17 = P). After two weeks, improvement was reported as follows: M = 67 percent, C = 17 percent, C plus M = 71 percent, P = 35 percent. In the metronidazole group, two patients required surgery and one had troublesome side effects. In the cotrimoxazole group, two had side effects. In the combined group (C plus M), four had troublesome side effects and two of the placebo group (P) required operation. By four weeks, there was no difference in response among the groups: (M = 44 percent, C = 62 percent, C plus M = 57 percent, P = 41 percent). Antimicrobials had no effect on fecal flora or hematologic parameters. These results indicate that antimicrobials have little therapeutic potential for relapse of intestinal Crohn's disease.


Staphylococcus aureus infection of epidermal keratinocytes promotes expression of innate antimicrobial peptides.
Keratinocytes upregulate expression of endogenous antimicrobial peptides in response to inflammatory stimuli. We show that both viable and heat-inactivated Staphylococcus aureus and lipoteichoic acid differentially alter expression of these peptides upon contact with human keratinocytes. The findings indicate a diversity of staphylococcal factors involved in upregulation of antimicrobial peptide expression in cutaneous epithelia.


The role of rat liver microsomal enzymes in the metabolism of the fungal metabolite fusarin C.
The metabolic activation of fusarin C by a rat liver microsomal monooxygenase resulted in the formation of a water-soluble mutagenic metabolite. However, fusarin C incubated in the presence of a microsomal preparation, but in the absence of an NADPH-generating system, led to the formation of fusarin PM1, a highly water-soluble compound which, like fusarin C, requires metabolic activation to be mutagenic. Enzyme studies using as substrates fusarins A and D, compounds structurally related to fusarin C, together with structural studies of fusarin PM1 indicated that fusarin PM1 was formed by the action of carboxylesterase which hydrolyses the C-20 methyl ester group to a free carboxylic acid.


Task-based characterization of a deep learning image reconstruction and comparison with filtered back-projection and a partial model-based iterative reconstruction in abdominal CT: A phantom study.
We aimed to thoroughly characterize image quality of a novel deep learning image reconstruction (DLIR), and investigate its potential for dose reduction in abdominal CT in comparison with filtered back-projection (FBP) and a partial model-based iterative reconstruction (ASiR-V). We scanned a phantom at three dose levels: regular (7 mGy), low (3 mGy) and ultra-low (1 mGy). Images were reconstructed using DLIR (low, medium and high levels) and ASiR-V (0% = FBP, 50% and 100%). Noise and contrast-dependent spatial resolution were characterized by computing noise power spectra and target transfer functions, respectively. Detectability indexes of simulated acute appendicitis or colonic diverticulitis (low contrast), and calcium-containing urinary stones (high contrast) (|ΔHU| = 50 and 500, respectively) were calculated using the nonprewhitening with eye filter model observer. At all dose levels, increasing DLIR and ASiR-V levels both markedly decreased noise magnitude compared with FBP, with DLIR low and medium maintaining noise texture overall. For both low- and high-contrast spatial resolution, DLIR not only maintained, but even slightly enhanced spatial resolution in comparison with FBP across all dose levels. Conversely, increasing ASiR-V impaired low-contrast spatial resolution compared with FBP. Overall, DLIR outperformed ASiR-V in all simulated clinical scenarios. For both low- and high-contrast diagnostic tasks, increasing DLIR substantially enhanced detectability at any dose and contrast levels for any simulated lesion size. Unlike ASiR-V, DLIR substantially reduces noise while maintaining noise texture and slightly enhancing spatial resolution overall. DLIR outperforms ASiR-V by enabling higher detectability of both low- and high-contrast simulated abdominal lesions across all investigated dose levels.


A randomized, double-blind, placebo-controlled study of the safety and tolerance of regadenoson in subjects with stage 3 or 4 chronic kidney disease.
The safety and tolerability of regadenoson, a pharmacologic stress agent that is excreted primarily by the kidneys, were examined in subjects with chronic kidney disease (CKD). This multicenter, double-blind, randomized, placebo-controlled study involved men and women, ≥18 years of age, with stage 3 or 4 [estimated glomerular filtration rate (eGFR) 30-59 mL/minute/1.73 m(2) and 15-29 mL/minute/1.73 m(2), respectively] CKD and known or suspected coronary artery disease. Subjects were randomized 2:1 to receive one 10-second intravenous injection of regadenoson 0.4 mg or placebo. The primary outcome measure was the frequency of serious adverse events over 24-h post-dose. The study included 432 subjects with stage 3 (regadenoson n = 287; placebo n = 145) and 72 with stage 4 (regadenoson n = 47; placebo n = 25) CKD. No serious adverse events or deaths were reported over 24-h post-dose. The overall adverse event incidence was higher with regadenoson than placebo (62.6% vs 21.2%; P < .0001). Of the most common adverse events (≥5%) reported by subjects receiving regadenoson, headache (24.9% vs 7.1%), dyspnea (19.2% vs 0.6%), chest discomfort (14.7% vs 0.6%), nausea (14.7% vs 1.2%), flushing (12.0% vs 1.8%), and dizziness (9.6% vs 0.6%) occurred significantly more often (P < .0001) with regadenoson than placebo. There were no trends for clinically meaningful changes in eGFR from baseline to 24-h post-dose in subjects with stage 3 or 4 CKD. Regadenoson was not associated with any serious or unexpected adverse events in subjects with stage 3 or 4 CKD.


Frequent Molecular Subtype Switching and Gene Expression Alterations in Lung and Pleural Metastasis From Luminal A-Type Breast Cancer.
Conversion of tumor subtype frequently occurs in the course of metastatic breast cancer but is a poorly understood phenomenon. This study aims to compare molecular subtypes with subsequent lung or pleural metastasis. In a cohort of 57 patients with breast cancer and lung or pleural metastasis (BCLPM), we investigated paired primary and metastatic tissues for differential gene expression of 269 breast cancer genes. The PAM50 classifier was applied to identify intrinsic subtypes, and differential gene expression and cluster analysis were used to further characterize subtypes and tumors with subtype conversion. In primary breast cancer, the most frequent molecular subtype was luminal A (lumA; 49.1%); it was luminal B (lumB) in BCLPM (38.6%). Subtype conversion occurred predominantly in lumA breast cancers compared with other molecular subtypes (57.1% v 27.6%). In lumA cancers, 62 genes were identified with differential expression in metastatic versus primary disease, compared with only 10 differentially expressed genes in lumB, human epidermal growth factor receptor 2 (HER2)-enriched, and basal subtypes combined. Gene expression changes in lumA cancers affected not only the repression of the estrogen receptor pathway and cell cycle-related genes but also the WNT pathway, proteinases (MME, MMP11), and motility-associated cytoskeletal proteins (CK5, CK14, CK17). Subtype-switched lumA cancers were further characterized by cell proliferation and cell cycle checkpoint gene upregulation and dysregulation of the p53 pathway. This involved 83 notable gene expression changes. Our results indicate that gene expression changes and subsequent subtype conversion occur on a large scale in metastatic luminal A-type breast cancer compared with other molecular subtypes. This underlines the significance of molecular changes in metastatic disease, especially in tumors of initially low aggressive potential.


Detection of EBV in nasopharyngeal carcinoma by quantum dot fluorescent in situ hybridization.
Nasopharyngeal carcinoma (NPC) is a common cancer in Southeast Asia and is frequently associated with Epstein-Barr virus (EBV) infection. The primary aim of this study was to improve the method of EBV detection by exploring quantum dots in FISH detection, and compare QD-based FISH with conventional ISH. Biopsy specimens were retrospectively retrieved from 35 NPC patients as paraffin-embedded tissue blocks. QD-FISH was developed to detect the presence of EBV encoded small RNA (EBER) using biotin-labeled EBER oligonucleotide probe indirectly labeled with streptavidin-conjugated quantum dots. Conventional ISH was also performed using a commercial kit to assess concordance between the two methods. All the 35 NPC cases were nonkeratinizing carcinoma (7 differentiated and 28 undifferentiated subtypes). EBER-positive signals were detected in 91.43% (32/35) and 80% (28/35) cases by QD-FISH and ISH, respectively. There was no significant difference in the number of EBER-positive cases by the two methods. A moderate concordance was found between QD-FISH and ISH for EBER status (κ=0.55). Four EBER-negative cases by ISH showed EBER-positive signals when detected by QD-FISH. EBV is closely associated with NPC in Chinese patients. QD-FISH is a novel effective method for EBER detection, and has a moderate concordance with conventional ISH.


Jiedu Tongluo Baoshen formula enhances podocyte autophagy and reduces proteinuria in diabetic kidney disease by inhibiting PI3K/Akt/mTOR signaling pathway.
Traditional Chinese medicine (TCM) has been applied to diabetic kidney disease (DKD). A large number of animal trials each year focus on TCM for DKD, but the evidence for these preclinical studies is not clear. The aim of this study was to study the therapeutic effect of Jiedu Tongluo Baoshen formula (JTBF) on DKD proteinuria and renal protection. At the same time, it is verified that JTBF can reduce podocyte injury by enhancing autophagy function, and then achieve the effect of proteinuria. We use high performance liquid chromatography to detect and analyze the fingerprint of JTBF to find the chemical composition. Subsequently, we constructed a DKD rat model induced by high-fat diet and streptozocin (HFD + STZ). Urine and blood biochemical automatic analyzer were used to detect 24-h urine protein quantification (24 h-UP) and renal function. The renal pathological changes were observed by H&E and transmission electron microscopy (TEM), and the levels of autophagy-related proteins and mRNA in podocytes were detected by immunohistochemistry, RT-qPCR and Western Blot. The chemical composition of JTBF was screened from traditional Chinese medicine systems pharmacol (TCMSP) and PubChem databases, and the potential targets and associated pathways of JTBF were predicted using kyoto encyclopedia of genes and genomes (KEGG) and protein-protein interaction (PPI) network analysis in network pharmacology, and confirmed in animal experiments and histopathological methods. We discovered 77 active ingredients of JTBF. Through animal experiments, it was found that JTBF reduced 24 h-UP and promoted the expression of podocin, nephrin, and WT-1 in podocytes, thereby reducing podocyte damage. At the same time, JTBF activates the expression of podocyte autophagy-related proteins (beclin-1, LC3 and P62). Subsequently, through network pharmacology predictions, 208 compounds were obtained from JTBF, and phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) was a potential signal pathway. JTBF was obtained in DKD rat kidney tissue to inhibit the expression of PI3K, Akt and mTOR related proteins. JTBF enhance podocyte autophagy to reduce podocyte damage, thereby effectively treating DKD proteinuria and protecting kidney function.


Effects of subanesthetic concentrations of nitrous oxide on cold-pressor pain in humans.
Nitrous oxide (N2O) has analgesic properties as determined in both animal and human research. In the present study, we sought to determine whether N2O given in subanesthetic concentrations would reduce cold pressor (CP)-induced pain. A crossover, double-blind study was conducted in 10 healthy volunteers. Each subject participated in four separate sessions, and in each session the effects of one of four concentrations of N2O in oxygen (0, 20, 30, and 40%) were assessed. The duration of inhalation was 40 min, and within each session, subjects immersed their nondominant arm in water (2-3 degrees C) twice for 3 min (at 10 and 30 min intrainhalation). Pain intensity, the degree to which the pain was bothersome (measured on a verbal scale of 0-10, 0 = "not at all" and 10 = "extremely" painful/bothersome), and pain quality [measured by the short-form McGill Pain Questionnaire (SF-MPQ)] were assessed during the forearm immersion. Mood effects were measured with the use of visual analogue scales (VAS) in the presence and absence of pain. Self-reported pain intensity and bothersomeness, SF-MPQ ratings of "sharp pain" and "throbbing pain," and VAS rating of "unpleasant bodily sensations" were significantly reduced by N2O (p < 0.05) in a concentration-dependent manner. Nitrous oxide had a number of effects on mood (e.g., increased VAS ratings of "stimulated," "high," "coasting," "carefree," and "having pleasant bodily sensations"). The cold-water immersion also influenced mood, but had little impact on modulating N2O effects.(ABSTRACT TRUNCATED AT 250 WORDS)


Protecting the infant-parent relationship: special emphasis on perinatal mood and anxiety disorder screening and treatment in neonatal intensive care unit parents.
Perinatal mood and anxiety disorders (PMADs) are common, particularly among parents of infants requiring admission to the neonatal intensive care unit (NICU), yet remain underdiagnosed and undertreated. Undertreated parental mental health disorders can interfere with healthy infant development, compounding abnormal neurodevelopment and psychosocial development that preterm or ill newborns may already face. Interdisciplinary efforts to increase PMAD awareness, screening, and referral uptake may improve family-infant health and developmental outcomes in high-risk infants requiring NICU admission. Therefore, special emphasis on PMAD screening and treatment in NICU parents aligns with the American Academy of Pediatrics mission and should be a focus in neonatal care and included in education, quality improvement, and outcome-based research initiatives.


A microfluidic platform for the controlled synthesis of architecturally complex liquid crystalline nanoparticles.
Soft-matter nanoparticles are of great interest for their applications in biotechnology, therapeutic delivery, and in vivo imaging. Underpinning this is their biocompatibility, potential for selective targeting, attractive pharmacokinetic properties, and amenability to downstream functionalisation. Morphological diversity inherent to soft-matter particles can give rise to enhanced functionality. However, this diversity remains untapped in clinical and industrial settings, and only the simplest of particle architectures [spherical lipid vesicles and lipid/polymer nanoparticles (LNPs)] have been routinely exploited. This is partially due to a lack of appropriate methods for their synthesis. To address this, we have designed a scalable microfluidic hydrodynamic focusing (MHF) technology for the controllable, rapid, and continuous production of lyotropic liquid crystalline (LLC) nanoparticles (both cubosomes and hexosomes), colloidal dispersions of higher-order lipid assemblies with intricate internal structures of 3-D and 2-D symmetry. These particles have been proposed as the next generation of soft-matter nano-carriers, with unique fusogenic and physical properties. Crucially, unlike alternative approaches, our microfluidic method gives control over LLC size, a feature we go on to exploit in a fusogenic study with model cell membranes, where a dependency of fusion on particle diameter is evident. We believe our platform has the potential to serve as a tool for future studies involving non-lamellar soft nanoparticles, and anticipate it allowing for the rapid prototyping of LLC particles of diverse functionality, paving the way toward their eventual wide uptake at an industrial level.


Nicotine, IFN-γ and retinoic acid mediated induction of MUC4 in pancreatic cancer requires E2F1 and STAT-1 transcription factors and utilize different signaling cascades.
The membrane-bound mucins are thought to play an important biological role in cell-cell and cell-matrix interactions, in cell signaling and in modulating biological properties of cancer cell. MUC4, a transmembrane mucin is overexpressed in pancreatic tumors, while remaining undetectable in the normal pancreas, thus indicating a potential role in pancreatic cancer pathogenesis. The molecular mechanisms involved in the regulation of MUC4 gene are not yet fully understood. Smoking is strongly correlated with pancreatic cancer and in the present study; we elucidate the molecular mechanisms by which nicotine as well as agents like retinoic acid (RA) and interferon-γ (IFN-γ) induce the expression of MUC4 in pancreatic cancer cell lines CD18, CAPAN2, AsPC1 and BxPC3. Chromatin immunoprecipitation assays and real-time PCR showed that transcription factors E2F1 and STAT1 can positively regulate MUC4 expression at the transcriptional level. IFN-γ and RA could collaborate with nicotine in elevating the expression of MUC4, utilizing E2F1 and STAT1 transcription factors. Depletion of STAT1 or E2F1 abrogated the induction of MUC4; nicotine-mediated induction of MUC4 appeared to require α7-nicotinic acetylcholine receptor subunit. Further, Src and ERK family kinases also mediated the induction of MUC4, since inhibiting these signaling molecules prevented the induction of MUC4. MUC4 was also found to be necessary for the nicotine-mediated invasion of pancreatic cancer cells, suggesting that induction of MUC4 by nicotine and other agents might contribute to the genesis and progression of pancreatic cancer. Our studies show that agents that can promote the growth and invasion of pancreatic cancer cells induce the MUC4 gene through multiple pathways and this induction requires the transcriptional activity of E2F1 and STAT1. Further, the Src as well as ERK signaling pathways appear to be involved in the induction of this gene. It appears that targeting these signaling pathways might inhibit the expression of MUC4 and prevent the proliferation and invasion of pancreatic cancer cells.


Circumventing intratumoral heterogeneity to identify potential therapeutic targets in hepatocellular carcinoma.
Identifying target genetic mutations in hepatocellular carcinoma (HCC) for therapy is made challenging by intratumoral heterogeneity. Circulating cell-free DNAs (cfDNA) may contain a more complete mutational spectrum compared to a single tumor sample. This study aimed to identify the most efficient strategy to identify all the mutations within heterogeneous HCCs. Whole exome sequencing (WES) and targeted deep sequencing (TDS) were carried out in 32 multi-regional tumor samples from five patients. Matched preoperative cfDNAs were sequenced accordingly. Intratumoral heterogeneity was measured using the average percentage of non-ubiquitous mutations (present in parts of tumor regions). Profiling efficiencies of single tumor specimen and cfDNA were compared. The strategy with the highest performance was used to screen for actionable mutations. Variable levels of heterogeneity with branched and parallel evolution patterns were observed. The heterogeneity decreased at higher sequencing depth of TDS compared to measurements by WES (28.1% vs. 34.9%, p<0.01) but remained unchanged when additional samples were analyzed. TDS of single tumor specimen identified an average of 70% of the total mutations from multi-regional tissues. Although genome profiling efficiency of cfDNA increased with sequencing depth, an average of 47.2% total mutations were identified using TDS, suggesting that tissue samples outperformed it. TDS of single tumor specimen in 66 patients and cfDNAs in four unresectable HCCs showed that 38.6% (26/66 and 1/4) of patients carried mutations that were potential therapeutic targets. TDS of single tumor specimen could identify actionable mutations targets for therapy in HCC. cfDNA may serve as secondary alternative in profiling HCC genome. Targeted deep sequencing of single tumor specimen is a more efficient method to identify mutations in hepatocellular carcinoma made from mixed subtypes compared to circulating cell-free DNA in blood. cfDNA may serve as secondary alternative in profiling HCC genome. Identifying mutations may help clinicians choose targeted therapy for better individual treatments.