Genetic dissection of TLR9 reveals complex regulatory and cryptic proinflammatory roles in mouse lupus.
In lupus, Toll-like receptor 7 (TLR7) and TLR9 mediate loss of tolerance to RNA and DNA, respectively. Yet, TLR7 promotes disease, while TLR9 protects from disease, implying differences in signaling. To dissect this 'TLR paradox', we generated two TLR9 point mutants (lacking either ligand (TLR9K51E) or MyD88 (TLR9P915H) binding) in lupus-prone MRL/lpr mice. Ameliorated disease of Tlr9K51E mice compared to Tlr9-/- controls revealed a TLR9 'scaffold' protective function that is ligand and MyD88 independent. Unexpectedly, Tlr9P915H mice were more protected than both Tlr9K51E and Tlr9WT mice, suggesting that TLR9 also possesses ligand-dependent, but MyD88-independent, regulatory signaling and MyD88-mediated proinflammatory signaling. Triple-mixed bone marrow chimeras showed that TLR9-MyD88-independent regulatory roles were B cell intrinsic and restrained differentiation into pathogenic age-associated B cells and plasmablasts. These studies reveal MyD88-independent regulatory roles of TLR9, shedding light on the biology of endosomal TLRs.


[Treatment of not-with cystic fibrosis associated forms bronchiectasis (non-CF bronchiectasis)].
Bronchiectasis has become more rarely because of the development of antibiotic therapy and vaccination. At present the great majority of bronchiectasis is more likely caused by congenital disorders than by infective reasons. Therapeutic strategies based on the experiences from cystic fibrosis and chronic obstructive pulmonary disease are not always conferrable to patients suffering from bronchiectasis. There are not enough controlled studies to give evidence-based recommendations in the treatment of bronchiectasis, which are not associated with cystic fibrosis. Goals in the treatment are improvement of the mucociliar clearance, the therapy of infections and treatment of inflammation. Currently several agents are under examination. To improve the prognosis and therapy options it would be reasonable to build up a national register for patients with bronchiectasis.


[Effect of multiple-micronutrient supplementation on learning and memorizing ability of young rats and the ultra-structure in CA3 region of hippocampus of rat's brain].
To study the effects of multiple-micronutrient on the learning and memory ability of young rats using shuttle-box, as well as to observe the ultra-structure and the synaptophysin (SYN) immunoreactive expression in the region of hippocampal CA3. Forty 5-week-old male Sprague-Dawley rats were randomized divided into control group and 3 test groups by body weight. Rats were injected intraperitoneally with multiple-micronutrient [0 g/(kg x d), 0.74 g/(kg x d), 1.48 g/(kg x d) and 2.22 g/(kg x d)] once per day for 30 days. Active avoidance behayior of learning and memory performance in different groups were measured by shuttle-box. The immune expression of Syn in the region of hippoeampal CA3 were tested with immunohistochemical method. Moreover, ultrastructural pathologic features of the CA3 region of hippocampus were investigated by transmission electron microscope. The shuttle-box test showed that the time of escape reaction of high-dose group (13.15 +/- 8.106, 9.50 +/- 5.063) was longer (P < 0.05) than that of control group. The results revealed a significant increase in the number of synapses, the thickness of postsynaptic density, synaptic curvature and the absorbency of positive product of Syn immunoreaction in the region of hippocampal CA3 in high-dose group compared with control group, which were significant difference (P < 0.05). Our study suggests that synaptic plasticity might be the probable mechanism on improving the learning and memory ability by multiple-micronutrient in young rats.


The synthesis of yeast pyruvate decarboxylase is regulated by large variations in the messenger RNA level.
The yeast PDC1 gene coding for the fermentative enzyme pyruvate decarboxylase was isolated. This DNA sequence was used to identify the corresponding messenger RNA by hybridization. It could be shown that the synthesis of pyruvate decarboxylase is efficiently regulated by variations in the amount of PDC1 mRNA. Very low levels of PDC1 mRNA were found in cells growing in a medium containing ethanol. Glucose addition to these cells leads to a rapid accumulation of PDC1 mRNA. The PDC1 mRNA levels found in different mutants and in cells growing in media containing carbon sources other than glucose or ethanol suggest that the amount of PDC1 mRNA in yeast cells is affected by a number of different factors.


Increasing Prevalence of Frailty and Its Association with Readmission and Mortality Among Hospitalized Patients with IBD.
Although age is often used as a clinical risk stratification tool, recent data have suggested that adverse outcomes are driven by frailty rather than chronological age. In this nationwide cohort study, we assessed the prevalence of frailty, and factors associated with 30-day readmission and mortality among hospitalized IBD patients. Using the Nationwide Readmission Database, we examined all patients with IBD hospitalized from 2010 to 2014. Based on index admission, we defined IBD and frailty using previously validated ICD codes. We used univariable and multivariable regression to assess risk factors associated with all-cause 30-day readmission and 30-day readmission mortality. From 2010 to 2014, 1,405,529 IBD index admissions were identified, with 152,974 (10.9%) categorized as frail. Over this time period, the prevalence of frailty increased each year from 10.20% (27,594) in 2010 to 11.45% (33,507) in 2014. On multivariable analysis, frailty was an independent predictor of readmission (aRR 1.16, 95% CI: 1.14-1.17), as well as readmission mortality (aRR 1.12, 95% CI 1.02-1.23) after adjusting for relevant clinical factors. Frailty also remained associated with readmission after stratification by IBD subtype, admission characteristics (surgical vs. non-surgical), age (patients ≥ 60 years old), and when excluding malnutrition, weight loss, and fecal incontinence as frailty indicators. Conversely, we found older age to be associated with a lower risk of readmission. Frailty, independent of age, comorbidities, and severity of admission, is associated with a higher risk of readmission and mortality among IBD patients, and is increasing in prevalence. Given frailty is a potentially modifiable risk factor, future studies prospectively assessing frailty within the IBD patient population are needed.


The effect of Thymus vulgaris and Thymbra spicata essential oils and/or extracts in pectin edible coating on the preservation of sliced bolognas.
The aim of this research was to determine the effect of pectin coating made with essential oils and/or extracts of Thymus vulgaris (thyme) and Thymbra spicata (thymbra) on the preservation of aerobically packaged sliced bolognas during cold storage. The treatment made with essential oils resulted in a reduction of 1.73 log CFU/g of Salmonella typhimurium ATCC 14028. Also, pectin coating made with essential oil-treated sliced bolognas had the lowest total mesophilic bacteria (6.27 log CFU/g), and total lactic acid bacteria (1.72 CFU/g), in comparison to non-treated bolognas, with 7.65 log CFU/g for total mesophilic bacteria and 4.99 log CFU/g for lactic acid bacteria. Application of an emulsion significantly (P < 0.05) affected L*(lightness), a*(redness), and b*(yellowness) values. The essential oil treatment had the highest TBARS values at the end of the storage period. The pH was not affected by the treatment (P > 0.05), but storage had a significant (P < 0.05) effect on the pH values.


Early complications and reoperation rates are similar amongst open reduction internal fixation, intramedullary nail, and distal femoral replacement for periprosthetic distal femur fractures: a systematic review and meta-analysis.
Our purpose was to perform a systematic review and meta-analysis to evaluate complication and revision rates for periprosthetic distal femur fractures (PPDFF) treated with: (1) ORIF using periarticular locking plates (ORIF), (2) retrograde intramedullary nail (IMN), and (3) distal femoral replacement (DFR). Systematic review of the literature was performed to identify eligible studies (N = 52). Identified treatment groups were: ORIF (N = 1205 cases), IMN (N = 272 cases), and DFR (N = 353 cases). Median follow-up was 30 months (range 6-96 months). Primary outcomes were: (1) major complication rates and (2) reoperation rates over the follow-up period. Secondary outcomes were incidence of deep infection, periprosthetic fracture, mortality over the follow-up period, 1-year mortality, non-union, malunion, delayed union, and hardware failure. Data for primary and secondary outcomes were pooled and unadjusted analysis was performed. Meta-analysis was performed on subset of individual studies comparing at least two of three treatment groups (N = 14 studies). Odds-ratios and their respective standard errors were determined for each treatment group combination. Maximum likelihood random effects meta-analysis was conducted for primary outcomes. From the systematic review, major complication rates (p = 0.55) and reoperation rates (p = 0.20) were not significantly different between the three treatment groups. DFR group had a higher incidence of deep infection relative to IMN and ORIF groups (p = 0.03). Malunion rates were higher in IMN versus ORIF (p = 0.02). For the meta-analysis, odds of major complications were not significantly different between IMN versus DFR (OR 1.39 [0.23-8.52]), IMN versus ORIF (OR 0.86 [0.48-1.53]), or the ORIF versus DFR (OR 0.91 [0.52-1.59]). Additionally, odds of a reoperation were not significantly different between IMN versus DFR (OR 0.59 [0.08-4.11]), IMN versus ORIF (OR 1.26 [0.66-2.40]), or ORIF versus DFR (OR 0.91 [0.51-1.55]). There was no difference in major complications or reoperations between the three treatment groups. Deep infection rates were higher in DFR relative to internal fixation, malunion rates were higher in IMN versus ORIF, and periprosthetic fracture rates were higher in DFR and IMN versus ORIF.


Comparison of the in vitro characteristics of von Willebrand factor in British and commercial factor VIII concentrates.
Qualitative/quantitative analysis of von Willebrand factor antigen (vWf:Ag) in either heat or solvent/detergent treated factor VIII concentrates, used for haemophilia replacement therapy, was undertaken to assess their suitability for the treatment of vWD. For the first time immunoaffinity purified vWf:Ag (Monoclate by-product) was also evaluated by in vitro assessment. Potencies of vWf:Ag varied considerably but were consistently higher (28.9-420.5 iu/ml) than factor VIII:C (one-stage) activity (8.13-42.44 iu/ml). The functional activity of vWf was assessed by either Ristocetin Cofactor (vWf:RCo) or collagen binding methods (vWf:CBA) with typical vWf:RCo/vWf:Ag ratios ranging from 0.08 to 0.94. Multimeric analysis confirmed that in vitro biological activity was dependent on the presence of the high molecular weight forms of vWf:Ag. A significant correlation (r = 0.95) between vWf:RCo activity and collagen binding was observed in all of the concentrates with the exception of the immunopurified product. The data suggest that either NHS 8Y (mean vWfRCo/vWf:Ag = 0.94), Haemate P (mean vWf:RCo/vWf:Ag = 0.69) and high purity Octapharma V.I (vWf:RCo/vWf:Ag = 0.82) which contain medium/high MW vWf:Ag multimers are likely to be most cost-effective in the treatment of symptomatic severe vWD patients than other currently available concentrates.


Allergic respiratory disease.
Allergic rhinitis and extrinsic allergic alveolitis are the most common allergic disorders of the bovine respiratory system. Environmental and management factors play significant roles in the pathogenesis of these disorders. When compared to infectious or toxic respiratory disease, allergic respiratory disease is relatively rare and of far less economic importance in North American cattle; however, the environmental and management conditions conducive to these diseases exist in many regions. Therefore, familiarity with the clinical and epidemiologic features of these unique diseases will aid the veterinarian in establishing an accurate diagnosis. Signs of respiratory dysfunction are common to anaphylactic and anaphylactoid reactions. Early recognition of these adverse reactions will provide the practitioner with the greatest chance of successful treatment.


TIM4 expression by dendritic cells mediates uptake of tumor-associated antigens and anti-tumor responses.
Acquisition of cell-associated tumor antigens by type 1 dendritic cells (cDC1) is essential to induce and sustain tumor specific CD8+ T cells via cross-presentation. Here we show that capture and engulfment of cell associated antigens by tissue resident lung cDC1 is inhibited during progression of mouse lung tumors. Mechanistically, loss of phagocytosis is linked to tumor-mediated downregulation of the phosphatidylserine receptor TIM4, that is highly expressed in normal lung resident cDC1. TIM4 receptor blockade and conditional cDC1 deletion impair activation of tumor specific CD8+ T cells and promote tumor progression. In human lung adenocarcinomas, TIM4 transcripts increase the prognostic value of a cDC1 signature and predict responses to PD-1 treatment. Thus, TIM4 on lung resident cDC1 contributes to immune surveillance and its expression is suppressed in advanced tumors.


Survey data on the knowledge, attitudes and practices of Nigerians towards the prevention and spread of COVID-19 during the lockdown period in Nigeria.
There had been an urgent call for the collection of standardized data describing clinical presentations, severity, outcomes, and epidemiology of COVID-19 by the World Health Organization (WHO). These data were expected to compliment the national pandemic data collated from countries by the World Health Organization (WHO). Nigeria, among other countries, is not an exception. This survey collected data on the respondent's knowledge on COVID-19, their attitude and practices towards the control of the spread of COVID-19 amongst Nigerians. The data were collected through an online survey. There were 1320 respondents from Nigeria that answered the survey questions. The survey was conducted between March 31 and April 28, 2020 which were within the lockdown period in the country. These data could serve as auxiliary information and/or research data for other researchers in Nigeria. It could also serve as guide or reference data to other researchers outside Nigeria who may be interested in carrying out similar research in another country.


Management and Surgical Options for Articular Defects in the Shoulder.
Isolated, full-thickness chondral lesions of the glenohumeral joint are a significant pathology encountered by laborers, athletes, and the elderly. A thorough history should be obtained in any patient presenting to the office with shoulder pain and concern for the etiology being an articular cartilage defect. The first-line imaging should include plain radiographs of the glenohumeral joint; MRI and CT can be ordered as necessary to provide greater detail. Typically, the initial treatment of glenohumeral chondral disease is nonsurgical; however, many surgical treatment options have been refined to provide pain relief, create reparative tissue, or restore the articular surface.


Training and assessment of psychomotor skills for performing laparoscopic surgery using BEST-IRIS virtual reality training simulator.
In this article, we present the results of a pilot study that examined the performance of people training on a Virtual Reality based BEST-IRIS Laparoscopic Surgery Training Simulator. The performance of experienced surgeons was examined and compared to the performance of residents. The purpose of this study is to validate the BEST-IRIS training simulator. It appeared to be a useful training and assessment tool.


Well-leg compartment syndrome after robot assisted laparoscopic surgery for rectal cancer: A case report.
Lower limb compartment syndrome caused by improper positioning during surgery is called well-leg compartment syndrome. Although well-leg compartment syndrome has been reported in urological and gynecological patients, there have been no reports of well-leg compartment syndrome in patients who have undergone robot-assisted surgery for rectal cancer. A 51-year-old man was diagnosed with lower limb compartment syndrome by an orthopedic surgeon due to pain in both of his lower legs immediately following robot-assisted surgery for rectal cancer. Due to this, we started placing the patient in the supine position during these surgeries, and repositioned the patient to the lithotomy position following intestinal tract cleansing after rectal movement in the latter half of the surgery. This avoided the long-term effects of being in the lithotomy position. We compared the operation time and complications before and after the above measures were changed, in 40 cases of robot-assisted anterior rectal resection for rectal cancer performed at our hospital from 2019 to 2022. We found no extension of operation time and no occurrence of lower limb compartment syndrome. There have been several reports describing the risk reduction of WLCS using intraoperative postural changes. An intraoperative postural change from a natural supine position without pressure which we reported is considered to be a simple preventive method for WLCS. Changing the patient from the supine position to the lithotomy position during surgery may be a clinically acceptable countermeasure to prevent lower limb compartment syndrome.


[Organ manifestations, immunologic findings and roentgen morphologic changes in the bones of the hand in progressive scleroderma].
In 60 patients with progressive sclerodermia apart from investigations of clinical and paraclinical parameters detailed evaluations of the X-ray-morphological findings at the skeleton of the hand were performed. Possible connections between the proof of pathological immunophenomena, the frequency of visceral manifestations at other organs, the duration of the disease and pathological X-ray-morphological changes at the skeleton of the hand are discussed and own conclusions are drawn.


The value of CT, MRI, and PET-CT in detecting retropharyngeal lymph node metastasis of head and neck squamous cell carcinoma.
The diagnostic accuracies of the imaging studies should be clearly acknowledged in managing head and neck cancer patients; however, the accuracies of preoperative imaging studies in detecting retropharyngeal lymph node (RPLN) metastasis are still not clarified. This study was to evaluate diagnostic accuracies of computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography-computed tomography (PET-CT) in detecting RPLN metastasis of head and neck squamous cell carcinomas. For 123 patients who had performed RPLN dissection during the surgery of their squamous cell carcinoma of the head and neck, preoperative CT, MRI, and/or PET-CT were reviewed for RPLN metastasis in a blinded fashion by one experienced radiologist. Sensitivity, specificity, positive predictive value, negative predictive value, and overall accuracy of each imaging modality were assessed, by comparing with the histopathologic findings of the resected RPLNs that served as the standard of reference. RPLNs were pathologically positive for metastasis in 43 of the 123 patients (35%). Sensitivity, specificity, positive predictive value, negative predictive value, and overall accuracy in detecting metastasis to RPLN were 65, 94, 85, 83, and 84% for CT; 74, 94, 87, 87 and 87% for MRI; 83, 93, 89, 89 and 89% for PET-CT, respectively. When all the three imaging modalities were considered together (n = 74), they offered sensitivity of 90%, specificity of 91%, positive predictive value of 87%, negative predictive value of 93%, and accuracy of 91%. The preoperative imaging studies offered relatively high specificity rates, but rather low sensitivity rates. The three imaging modalities altogether increased diagnostic accuracies, which highlights the potential of the three studies when used altogether can minimize missed diagnoses of RPLN metastasis.


The SOCS-1 -1478CA/del functional polymorphism (rs33989964) is associated with gastric cancer but is unrelated to overall survival.
In vitro studies have shown that the functional - 1478CA > del polymorphism (rs33989964) of the suppressor of cytokine signaling (SOCS)-1 gene is associated with an altered trascriptional activity. Here, we sought to examine the potential association of this polymorphism with the risk of gastric cancer (GC) and to analyze its prognostic impact on overall survival (OS). The study cohort consisted of 74 Turkish patients with GC and 52 healthy controls. Genotyping of the SOCS-1 -1478CA > del polymorphism was carried out using restriction fragment length polymorphism analysis. After allowance of age and sex, multivariable logistic regression analysis revealed that the carriage of the del allele of the SOCS-1 -1478CA > del polymorphism was independently associated with an increased risk of GC (odds ratio = 6.78, 95% confidence interval = 3.24-10.99, P < 0.001). Kaplan-Meier analysis revealed no significant differences in OS for patients harboring at least one del allele of rs33989964 compared with CA/CA homozygotes (log-rank test, P = 0.17). While the SOCS-1 -1478CA > del polymorphism is significantly associated with the risk of GC in the Turkish population, it does not affect OS.


ERp29 regulates response to doxorubicin by a PERK-mediated mechanism.
ERp29 is an endoplasmic reticulum (ER) luminal protein with a putative secretion factor/escort chaperone function. Accumulated evidence has implicated ERp29 in the thyroglobulin secretion, polyoma virus transport and recently in carcinogenesis. ERp29 levels were elevated in the tumors of various origins and under the conditions of genotoxic stress, such as ionizing radiation. Here we report the induction of ERp29 during the treatment of cells with doxorubicin, a commonly used antineoplastic agent. Experiments in the p53 -/- cells and p53 knockout mouse revealed that doxorubicin effect on ERp29 is p53 dependent. The increase of ERp29 level appears to activate a negative feedback loop where the elevated amounts of ERp29 augment cell viability as shown by a clonogenic cell survival assay. To elucidate the mechanisms behind the doxorubicin effects we have studied the impact of ERp29 on the interaction with the ER stress-activated eukaryotic translation initiation factor 2-alpha kinase 3 (PERK) that was shown to facilitate tumor cells' resistance to drug toxicity. Co-immunoprecipitation demonstrated physical interaction of ERp29 with PERK and moreover, overexpression of ERp29 enhanced endogenous levels of PERK. Our results identify ERp29 as a novel regulator of PERK and provide evidence for the role of ER resident factors in the regulation of chemotherapeutic efficacy. These findings show that PERK may represent a nodal point between ER stress and chemotherapeutic response.


Secondhand smoke exposure from the indoor and outdoor shisha centers located at the perimeter of educational institutions in Malaysia: a cross-sectional study.
Shisha is a centuries-old traditional smoking habit rapidly gaining popularity among the students and young adults in Malaysia. The present study evaluated secondhand smoke exposure (SHS) and characteristics of 25 indoor and 25 outdoor shisha centers (SC) operating around the educational institutes such as universities in Petaling Jaya, Malaysia. We observed a significantly higher particulate matter (PM)2.5 concentration in indoor than outdoor SC (3595.28 μg/m3 and 65.12 μg/m3, p < 0.001, respectively). SCs are offering different flavors to attract clients and exposing students and young professionals to a significantly high concentration of SHS. Such exposures may pose a serious health risk. Therefore, policymakers need to strengthen tobacco guidelines and eliminate loopholes in the sale of shisha by enforcing comprehensive and strict smoke-free laws.


Risk stratification of patients with syncope.
To develop and validate a risk classification system for patients presenting to emergency departments with syncope. Two prospective studies were carried out at a large urban teaching hospital ED. One cohort of 252 patients with syncope who reported to the ED was used to develop the risk classification system; a second cohort of 374 patients with syncope was used to validate the system. Data from the patient's history, physical examination and ED ECG were used to identify predictors of arrhythmias or mortality within the first year. Arrhythmias were detected by cardiac monitoring or electrophysiologic studies. Logistic regression and Cox proportional hazards models were used to identify the important risk factors for the classification system. Performance of the system was measured by comparing the proportion of patients with arrhythmias or death at various levels of the risk and receiver operating characteristic curves. Multivariate predictors of arrhythmia or 1-year mortality were an abnormal ED ECG (odds ratio [OR], 3.2; 95% confidence interval [CI], 1.6 to 6.4); history of ventricular arrhythmia (OR, 4.8; 95% CI, 1.7 to 13.9); history of congestive heart failure (OR, 3.2; 95% Cl, 1.3 to 8.1). Arrhythmias or death within 1 year occurred in 7.3% (derivation cohort) to 4.4% (validation cohort) of patients without any risk factors and in 80.4% (derivation) to 57.6% (validation) of patients with three or four risk factors. Historical and ECG factors available at the time of presentation can be used to stratify risk of arrhythmias or mortality within 1 year in ED patients presenting with syncope.


Effects of azaprophen, scopolamine and trihexyphenidyl on schedule-controlled behavior, before and after chronic physostigmine.
The effects of the muscarinic acetylcholine receptor antagonists, azaprophen (0.3-10.0 mg/kg), scopolamine (0.01-3.0 mg/kg) and trihexyphenidyl (0.3-10.0 mg/kg) were examined in rats using a VI 18 s schedule of food reinforcement, before and after chronic physostigmine administration. All three compounds produced dose-dependent decreases [corrected] in the rate of responding. Scopolamine was more potent than trihexyphenidyl which was equipotent to azaprophen. All three compounds antagonized the response rate-decreasing effects of physostigmine in a dose-dependent fashion. Following 43 consecutive daily administrations of physostigmine (0.4 mg/kg), partial tolerance developed to its response rate-decreasing effects. When the three antagonists were again examined (alone and in combination with physostigmine), their effects were generally unchanged. These results further characterize the behavioral effects of azaprophen, scopolamine and trihexyphenidyl. These results also suggest that tolerance to physostigmine's effects can be mediated through behavioral rather than pharmacological mechanisms.


A multifunctional monolithic interfacial sensor based on gold nanoparticle.
The spatial and temporal uneven distribution of complex biochemical reactions creates the diversity of biological systems. And the microenvironment confers fine regulation of these reactions, a stunning example of which is liquid-liquid phase separation (LLPS). LLPS can form a separate compartment without the physical separation formed by conventional membrane structures, and the reactions within the interface have specific reaction dynamics. Inspired by this, we report an interfacial sensor based on gold nanoparticles showing that interfacial factors have similar properties operating in natural biological environments and sensors. It repels molecules outside the interface and adjusts the DNA conformation within the interface to produce unique dynamics. The sensor adopts a modular design, allowing functional modules assembled on a single nanoparticle to avoid complex designs. We demonstrate the functionality of logical operations, using apurinic/apyrimidinic endonuclease 1 and micro RNA as inputs, showing that the sensor has the ability and potential to become a multifunctional platform with clear interface nature.


A dual cardiomyocyte reporter model derived from human pluripotent stem cells.
Cardiovascular diseases (CVD) remain the leading cause of death in the USA. Cardiomyocytes (CMs) derived from human pluripotent stem cells (hPSCs) provide a valuable cell source for regenerative therapy, disease modeling, and drug screening. Here, we established a hPSC line integrated with a mCherry fluorescent protein driven by the alpha myosin heavy chain (aMHC) promoter, which could be used to purify CMs based on the aMHC promoter activity in these cells. Combined with a fluorescent voltage indicator, ASAP2f, we achieved a dual reporter CM platform, which enables purification and characterization of CM subtypes and holds great potential for disease modeling and drug discovery of CVD.


Proximal first metatarsal opening wedge osteotomy: geometric analysis on saw bone models.
For hallux valgus correction, distal first metatarsal osteotomy is generally used for minor to moderate deformities, diaphyseal osteotomy for moderate deformities and basal osteotomy or arthrodesis for severe deformities. With the advent of locking plates, there has been renewed interest in opening wedge basal osteotomy. We undertook this study in order to understand the power and limitations of this osteotomy. Proximal opening wedge osteotomies were performed on saw bone models in four orientations, with three different wedge sizes: (1) perpendicular to the ground (PG); (2) perpendicular to the shaft (PS); (3) perpendicular to shaft with 30° declination (DEC); (4) 30° oblique (OB). Pre- and post-osteotomy measurements were made of axial and plantar translation and inter-metatarsal angle. Plantar translation and intermetatarsal angle correction increased with increasing wedge size. The DEC osteotomy produced the greatest increase in length of metatarsal shaft, while the PS osteotomy gave the least. The most plantar translation was achieved with the DEC osteotomy. Overall, the PS osteotomy gave the largest correction of the intermetatarsal angle. Although there are several published clinical case series of the proximal opening wedge osteotomy, this is the first study to fully evaluate its geometry.


Tales from the frontlines: An alarming rise in hospitalizations related to opioid use disorder in the era of COVID-19.
The coronavirus disease 2019 (COVID-19) pandemic has had harmful effects on the opioid epidemic. While a negative effect was predicted, we report on this reality in the hospital setting. We have seen a sharp rise in hospitalized patients with opioid use disorder (OUD). Our data should encourage ongoing efforts to reduce barriers in accessing medications for treatment, harm reduction interventions and additional education for trainees, primary care providers, and hospitalists alike. In the current climate, these interventions are critical to save the lives of patients with OUD.


Change in prescribing patterns of general practitioners in Italy before and after the Reform Drug Act. A case study of changes in the city of Turin.
As of 1 January 1994, the introduction of a new classification of the drugs to be reimbursed by the National Health Service was approved by the Italian parliament in order to limit expenditure on pharmaceutical agents. This has set off a 'cultural revolution', unprecedented in Italy. The criteria that inspired the expert group charged with attributing drugs to different classes (Class A: essential, free of charge drugs; Class B: drugs to be paid for 50% by the patient; Class C: drugs to be paid entirely by the patient) were principally scientific rather than merely economic or administrative. Expectedly, the creation of Class C (drugs not reimbursed by the National Health Service on account of their insufficiently proven clinical effectiveness, or their unfavourable cost/benefit ratio with respect to therapeutically equivalent agents) has provoked remarkable changes in general practitioners' prescription options, particularly given the fact that many of these drugs were among the most prescribed in Italy. A database including the prescriptions of about 940 general practitioners, dispensed through the 280 community pharmacies of the city of Turin, has been analysed for a comparative sample of time periods in 1993 and 1994, in order to quantify the changes that occurred and to qualify them with respect to more relevant therapeutic groups and sentinel drugs.


The evolution of atomistic structure and mechanical property of coke in the gasification process with CO2 and H2O at different temperatures: A ReaxFF molecular dynamics study.
An atomistic coke carbon model was constructed to simulate the structural evolution in the gasification and stretching process. The coke model was placed in a box with different CO2/H2O content to investigate the evolution of the atomistic structure of coke during the gasification. It was found that different atmospheric concentrations had different effects on the structure and reaction sites of the coke model. The CO2 molecules tended to dissolve on the surface of coke and disrupt its surface structure, while H2O molecules were more likely to enter the coke model to disrupt the internal structure. For tensile simulation, it was found that CO2 and H2O had different effects on the tensile resistance of the coke model. Controlling the composition content of the reaction gas can effectively influence the tensile strength of the coke model. By revealing the behavior of coke model at the micro scale, it provides a theoretical basis for the industrial coke application process. Large-scale Atomic/Molecular Massively Parallel Simulator (LAMMPS) was used to conduct the molecular dynamics using the reactive force field (ReaxFF). The atomistic model of coke carbon was constructed using the well-known annealing and quenching method, and its composition is determined according to the element analysis of industrial coke. The structural evolution in the gasification with CO2/H2O and the stretching process were analyzed in detail. Molecular dynamics simulations with reactive force field (ReaxFF-MD) were used to simulate the coke dissolution reaction under CO2/H2O atmosphere and the coke stretching process. The atmosphere ratio was modified to investigate the changes in coke structure under different atmosphere conditions. The Packmol software was used to place gas and coke models into the same box. During the reaction process, the Ovito software was used to perform corresponding visualization analysis on the changes in the atomic structure of coke.


Emergency nurses' experiences of the implementation of early goal directed fluid resuscitation therapy in the management of sepsis: a qualitative study.
Severe sepsis can lead to organ failure and death if immediate treatment, such as intravenous fluids and antibiotics, are not commenced within the first hour. Time - critical initiation of intravenous fluids which in other words is early goal directed fluid resuscitation has not always been given its clinical priority. This qualitative study aimed at exploring the experiences of emergency nurses initiating early goal directed fluid resuscitation in patients with sepsis. Using an exploratory approach, face - to - face semi - structured interviews were conducted with ten registered nurses working in emergency departments across New South Wales, Australia. Thematic analysis was used for data analysis. Participants described various factors that inhibited the timely initiation of early goal directed fluid resuscitation, some clinical practice challenges, and strategies to improve nursing practice. Most participants, particularly those practicing as Clinical Initiatives Nurses suggested the incorporation of nurse initiated early goal directed fluid resuscitation for patients with sepsis as part of their scope of practice. Our findings identified several barriers that inhibit effective nurse - initiated early goal directed fluid resuscitation. It is anticipated that these findings will provide validation for the re-evaluation of the existing protocols and practice guidelines to increase the scope of practice of emergency nurses initiating early goal directed fluid resuscitation.


High prevalence of non-dipping patterns among Black Africans with uncontrolled hypertension: a secondary analysis of the CREOLE trial.
Dipping of blood pressure (BP) at night is a normal physiological phenomenon. However, a non-dipping pattern is associated with hypertension mediated organ damage, secondary forms of hypertension and poorer long-term outcome. Identifying a non-dipping pattern may be useful in assessing risk, aiding the decision to investigate for secondary causes, initiating treatment, assisting decisions on choice and timing of antihypertensive therapy, and intensifying salt restriction. To estimate the prevalence and factors associated with non-dipping pattern and determine the effect of 6 months of three antihypertensive regimens on the dipping pattern among Black African hypertensive patients. This was a secondary analysis of the CREOLE Study which was a randomized, single blind, three-group trial conducted in 10 sites in 6 Sub-Saharan African countries. The participants were 721 Black African patients, aged between 30 and 79 years, with uncontrolled hypertension and a baseline 24-h ambulatory blood pressure monitoring (ABPM). Dipping was calculated from the average day and average night systolic blood pressure measures. The prevalence of non-dipping pattern was 78% (564 of 721). Factors that were independently associated with non-dipping were: serum sodium > 140 mmol/l (OR = 1.72, 95% CI 1.17-2.51, p-value 0.005), a higher office systolic BP (OR = 1.03, 95% CI 1.01-1.05, p-value 0.003) and a lower office diastolic BP (OR = 0.97, 95% CI 0.95-0.99, p-value 0.03). Treatment allocation did not change dipping status at 6 months (McNemar's Chi2 0.71, p-value 0.40). There was a high prevalence of non-dipping among Black Africans with uncontrolled hypertension. ABPM should be considered more routinely in Black Africans with uncontrolled hypertension, if resources permit, to help personalise therapy. Further research is needed to understand the mechanisms and causes of non-dipping pattern and if targeting night-time BP improves clinical outcomes. Trial registration ClinicalTrials.gov (NCT02742467).


Differential effects of iron and inflammation on ferritin synthesis on free and membrane-bound polyribosomes of rat liver.
We have examined the distribution of ferritin mRNA to free and endoplasmic reticulum (ER)-bound liver polyribosomes during inflammation and iron treatment of rats. Postnuclear tissue supernatants were fractionated on a discontinuous sucrose gradient developed to separate free and bound polyribosomes. Total RNA recovered averaged 3.2 mg/g tissue, 40% of which was with ER and 30% with the free polyribosomes, about 25% being with the postribosomal/RNP fraction. Slot-blot hybridization of equal portions of RNA revealed that 12 h after injection of turpentine to induce inflammation, ferritin mRNA was concentrated on the ER-bound polyribosomes, while it was concentrated on the free polyribosomes 2 h after injection of ferric ammonium citrate. Differences were highly significant, based on multiple determinations and densitometry. Profiles of ferritin mRNA distribution on linear sucrose gradients corroborated the differential findings. Concentrations of total ferritin mRNA per gram liver doubled with iron treatment but were not significantly different 12 h after turpentine treatment. At the same time point after turpentine, ferritin protein synthesis was increased twofold, as measured by the 1 h incorporation of [14C]leucine. We conclude that a significant portion of ferritin mRNA always associates with the ER-bound polyribosomes, and that inflammation and iron differentially alter the polysomal distribution of ferritin mRNA, suggesting that two different kinds of mRNA may be involved.


XIAP gene therapy effects on retinal ganglion cell structure and function in a mouse model of glaucoma.
Glaucoma is a prevalent neurodegenerative disease that is characterized by progressive visual field loss. It is the leading cause of irreversible blindness in the world. The main risk factor for glaucoma is elevated intraocular pressure that results in the damage and death of retinal ganglion cells (RGCs) and their axons. The death of RGCs has been shown to be apoptotic. We tested the hypothesis that blocking the activation of apoptosis may be an effective strategy to prevent RGC death and preserve functional vision in glaucoma. In the magnetic microbead mouse model of induced ocular hypertension, inhibition of RGC apoptosis was targeted through viral-mediated ocular delivery of the X-linked inhibitor of apoptosis (XIAP) gene, a potent caspase inhibitor. Pattern electroretinograms revealed that XIAP therapy resulted in significant protection of both somal and axonal RGC function in glaucomatous eyes. Histology confirmed that the treated optic nerves showed preservation of axon counts and reduced glial cell infiltration. These results show that XIAP is able to provide both functional and structural protection of RGCs in the microbead model of glaucoma and provide important proof-of-principle for XIAP's efficacy as a neuroprotective treatment for glaucoma.


Corrigendum to "Ferulic Acid Induces Th1 Responses by Modulating the Function of Dendritic Cells and Ameliorates Th2-Mediated Allergic Airway Inflammation in Mice".
[This corrects the article DOI: 10.1155/2015/678487.].


The effect of a stem on the tibial component of knee arthroplasty. A roentgen stereophotogrammetric study of uncemented tibial components in the Freeman-Samuelson knee arthroplasty.
We studied the effect of a metal tray with an intramedullary stem on the micromotion of the tibial component in total knee arthroplasty. Of 32 uncemented Freeman-Samuelson knee arthroplasties performed in London and Gothenburg, nine had a metal backing and stem added to the tibial component. Micromotion of the tibial components, expressed as migration and inducible displacement, was analysed using roentgen stereophotogrammetric analysis up to two years follow-up. The addition of a metal back and a 110 mm stem to the standard polyethylene component significantly reduced both migration over two years and inducible displacement.


Differentiating passive from transporter-mediated uptake by PepT1: a comparison and evaluation of four methods.
To quantify transmembrane transport of dipeptides by PepT1, passive uptake (non-PepT1 mediated) must be subtracted from total (measured) uptake. Three methods have been described to estimate passive uptake: perform experiments at cold temperatures, inhibit target dipeptide uptake with a greater concentration of a second dipeptide, or use modified Michaelis-Menten kinetics. We hypothesized that performing uptake experiments at pH 8.0 would estimate passive uptake accurately, because PepT1 requires a proton gradient. Our aim was to determine the most accurate method to estimate passive uptake. Caco-2 cells were incubated with various concentrations of glycyl-sarcosine (gly-sar) at pH 6.0 and at 37°C to measure total uptake. Passive uptake was estimated: (1) by incubating Caco-2 cells with varying concentrations of gly-sar at 4°C, (2) in the presence of 50 mM glycyl-leucine, (3) in solution at pH 8.0, or (4) using modified Michaelis-Menten kinetics. PepT1-mediated uptake was calculated by subtracting passive uptake from total uptake. K(m), V(max), and % gly-sar transported by PepT1 were calculated and compared. K(m), V(max), and % gly-sar transported by PepT1 varied from 0.7 to 2.4 mM, 8.4 to 21.0 nmol/mg protein/10 min, and 69% to 87%, respectively. Uptakes calculated with cold, 50 mM gly-leu and using modified Michaelis-Menten kinetics were similar but differed significantly from uptake at pH 8.0 (P < 0.001). Estimating passive uptake at pH 8.0 does not appear to be accurate. Measuring uptake at cold temperatures or in the presence of a greater concentration of a second dipeptide, and confirming results with modified Michaelis-Menten kinetics is recommended.


Graded pitch profile for the helicoidal broadband reflector and left-handed circularly polarizing cuticle of the scarab beetle Chrysina chrysargyrea.
The cuticle of the beetle Chrysina chrysargyrea reflects left-handed polarized light in the broad spectral range from 340 to 1000 nm. Interference oscillations in the experimental Mueller-matrix spectroscopic ellipsometry data reveal that transparent materials comprise the cuticle. A spectral analysis of the interference oscillations makes evident that the pitch profile across the cuticle is graded. The graded pitch and effective refractive indices are determined through non-linear regression analysis of the experimental Mueller matrix by using a cuticle model based on twisted biaxial dielectric slices. Non-uniformity in cuticle thickness as well as in pitch profile near the cuticle surface account for depolarizance of the Mueller matrix. Transmission electron microscopy supports the reliability of the results.


The embryotoxic and osteolathyrogenic effects of semicarbazide.
The osteolathyrogenic agent semicarbazide was assayed for its toxicity and teratogenicity using early embryos of the frog Xenopus laevis. The 96-h LC50 is 1504.20 mg/l while the 96-h EC50 is 76.28 mg/l. Embryo length is altered prior to the onset of other effects indicated by a reduction in stage of development. The major malformation is associated with the notochord where the notochordal sheath is reduced owing to the disruption in the maturation and/or deposition of the connective tissue fibers.


Central neurocytoma: its differentiation from intraventricular oligodendroglioma.
Two patients with intraventricular tumours are presented. Both had similar features on light microscopic examination. On the basis of the specific immunohistochemical staining patterns and the ultrastructural findings, one was diagnosed as a central neurocytoma while the other was diagnosed as an intraventricular oligodendroglioma. The possibility of central neurocytoma should be considered in all young patients including children presenting with an intraventricular lesion. Definitive diagnosis requires electron microscopic and immunohistochemical studies.


Alpha-chain disease. A case report with autopsy findings.
A 19-year-old Coloured man with alpha-chain disease died after perforation of a lymphoma in the duodenojejunal region. At autopsy he was found to have a dense plasma cell infiltration of the lamina propria of the entire small bowel, causing thickening of that organ, and a malignant lymphoma in the duodenojejunal region which had spread to regional mesenteric nodes and to the liver only.


Same-Day Initiation of Oral Pre-Exposure Prophylaxis is High Among Adolescent Men Who Have Sex With Men and Transgender Women in Brazil.
This study analyzed the sociodemographic and behavioral characteristics of adolescent men who have sex with men (aMSM) and transgender women (aTGW) initiating oral pre-exposure prophylaxis (PrEP) in human immunodeficiency virus (HIV) prevention clinics. PrEP1519 is a prospective, multicenter, open-label PrEP demonstration cohort study of aMSM and aTGW aged 15-19 years living in three large Brazilian capital cities. For this analysis, we included adolescents who enrolled in PrEP1519 from February 2019 to August 2021. Adolescents who visited PrEP clinics were classified into four groups based on PrEP eligibility and on their decision to use PrEP: (1) ineligible for same-day PrEP initiation; (2) eligible for same-day PrEP initiation, initiated PrEP at first visit; (3) eligible for PrEP initiation, initiated PrEP after the first visit; and (4) eligible for same-day PrEP initiation but declined. The groups that were eligible for same-day PrEP initiation were compared using the Chi-square and Fisher's exact tests. Of the 1,254 adolescents enrolled in the PrEP1519 study, 61 (4.9%) were considered ineligible for same-day PrEP initiation. Of the 1,193 eligible for same-day PrEP initiation, 1,113 (93.3%) initiated PrEP [1,054 initiated PrEP in the first visit (88.3%) and 59 in subsequent visits (4.9%)] and 80 (6.7%) did not. Despite 90% of the PrEP decliners reporting a low risk of HIV infection, most reported condomless anal sex in the past six months (70%). Same-day PrEP initiation among aMSM and aTGW was high, highlighting that this strategy was important to promote PrEP initiation among adolescents with increased vulnerability to HIV in Brazil.


Ferritin as an important player in neurodegeneration.
Oxidative stress is considered one of the pathways leading to neuronal death in neurodegenerative disease. Many published studies aimed to assess the possible role of iron in this process but no consensus has been reached. On the other hand little is known about the role played by the main iron storage protein - ferritin. In this review we discuss the data obtained using several methods - Mössbauer spectroscopy, electron microscopy and ELISA - from human brain tissue both in controls and in four neurodegenerative disorders - Parkinson's (PD) and Alzheimer's disease, progressive supranuclear palsy and neuroferritinopathy. Iron may only cause oxidative stress injury when it is available as labile iron for Fenton reaction. This may be related to the decreased ability of ferritin to retain iron within the iron core of ferritin. This happens in PD and in neuroferritinopathy. In PD there is a decrease in the concentration of L ferritin, while in neuroferritinopathy there is a genetically induced mutation in L ferritin causing its loss of function. We discuss the importance of the ratio H/L ferritin and its changes in neurodegeneration.


C-terminal modification of monoclonal antibody drugs: amidated species as a general product-related substance.
Twelve therapeutic mAbs, comprising 10 IgG1s and 2 IgG4s, were analyzed by a peptide mapping technique to detect and quantify C-terminal modifications. C-terminal amidated structures were found in 8 out of the 12 mAbs. An in vitro study using a commercially available peptidylglycine alpha-amidating monooxygenase (PAM) revealed that both IgG1 and IgG4 can be substrates for PAM. This study showed that C-terminal amidation is a general C-terminal modification on the heavy chains of therapeutic mAbs and that C-terminal amidation of mAbs can be catalyzed by a certain PAM(s) in the Chinese hamster ovary (CHO) cells that are widely used for manufacturing therapeutic mAbs.


Virtual screening and in vitro assay of potential drug like inhibitors from spices against glutathione-S-transferase of filarial nematodes.
Glutathione-S-transferase(s) (GST) enzyme from Brugia malayi has been exploited as a target in lymphatic filariasis therapeutics. An active GST is a homodimer of a 208 residue long monomer consisting of two domains, a smaller α/β domain and a larger α domain. The components of the glutathione (GSH) system, mainly GST enzymes, are critical antioxidant and detoxification system responsible for the long-term existence of filarial worms in mammalian host; hence they are major chemotherapeutic targets in filarial species. In the present study, 58 phytochemicals from 10 plants, predicted and reported to have potential nematicidal activity and ADMET satisfaction, have been docked to GST enzyme of B. malayi to assess their binding affinity and consequently their inhibitory activity. A comparative study has been made with commonly employed chemotherapeutic GST inhibitors such as cibacron-blue, butylated hydroxyanisole, hexyl glutathione and ethacrynic acid. In vitro effects of potential drug like compound from in silico results have been done for validation of docking studies. In vitro assay revealed efficacy in GST inhibition in the following compounds: linalool (97.50%), alpha-pinene (90.00%), strychnine (87.49%), vanillin (84.99%), piperine (79.99%), isoeugenol (62.49%), curcumin (57.49%), beta-caryophyllene (39.50%), cinnamic acid (27.49%), capsaicin (19.99%), citronellol (19.99%) and geraniol (17.49%). An online database ( www.spicebioinfo.res.in/gstleadbase ) has been developed, which will serve as a useful repository of information on GST inhibitors for future development of drugs against filarial nematodes. These findings thus suggest that the above phytochemicals could be potentially developed as lead molecules for targeting GST of lymphatic filarial parasites.


Vocal tract configurations in male alto register functions.
Professional male altos (countertenors) mostly use a register function, which is considered to be derived from falsetto. However, the sound produced differs in professional altos compared with the modal register or falsetto of untrained voices. The aim of this study was to analyze differences of the vocal tract shapes in male alto register functions. Dynamic real-time magnetic resonance imaging of eight frames per second was used to analyze the vocal tract profile in seven professional male altos who sang on the vowel /a/, an ascending and descending scale from G3 (196 Hz) to E4 (330 Hz). The scale included their register transition from modal register to stage (counter) falsetto and naïve falsetto. Register transitions from modal register to stage falsetto were associated with increased lip opening, jaw retraction, elevation and back positioning of the tongue, pharynx narrowing, uvula elevation, drop of larynx height, and tilting of the larynx. Differences between stage and naïve falsetto were found mostly with regard to lip opening and pharynx width. The differences between the vocal tract configurations might have an impact on the acoustic characteristics observed in professional male alto register functions.


A review of spinal cord perfusion pressure guided interventions in traumatic spinal cord injury.
To evaluate the causality between interventions on spinal cord perfusion pressure and neurological outcome in traumatic spinal cord injury. A systematic review was conducted in concordance with PRISMA guidelines. The literature was found in the EMBASE, PUBMED, SCOPUS, and WEB OF SCIENCE. Eligible studies included those that reported measurements and interventions on the spinal cord perfusion pressure in either animals or patients suffering from spinal cord injury. Only studies that reported a clinical or relevant clinical outcome measure (i.e., neurophysiology) were included. The search yielded 795 unique records, and six studies were included after careful review. These studies suggested a positive correlation between spinal cord perfusion pressure and neurological outcome, but conclusions on causality could not be made. In spite of growing indications that neurological outcomes are related to the spinal cord perfusion pressure in traumatic spinal cord injuries, a solid conclusion cannot be made due to the limited literature available. Additional well-designed studies are needed to address this issue.


Evaluation of glucose controllers in virtual environment: methodology and sample application.
Adaptive systems to deliver medical treatment in humans are safety-critical systems and require particular care in both the testing and the evaluation phase, which are time-consuming, costly, and confounded by ethical issues. The objective of the present work is to develop a methodology to test glucose controllers of an artificial pancreas in a simulated (virtual) environment. A virtual environment comprising a model of the carbohydrate metabolism and models of the insulin pump and the glucose sensor is employed to simulate individual glucose excursions in subjects with type 1 diabetes. The performance of the control algorithm within the virtual environment is evaluated by considering treatment and operational scenarios. The developed methodology includes two dimensions: testing in relation to specific life style conditions, i.e. fasting, post-prandial, and life style (metabolic) disturbances; and testing in relation to various operating conditions, i.e. expected operating conditions, adverse operating conditions, and system failure. We define safety and efficacy criteria and describe the measures to be taken prior to clinical testing. The use of the methodology is exemplified by tuning and evaluating a model predictive glucose controller being developed for a wearable artificial pancreas focused on fasting conditions. Our methodology to test glucose controllers in a virtual environment is instrumental in anticipating the results of real clinical tests for different physiological conditions and for different operating conditions. The thorough testing in the virtual environment reduces costs and speeds up the development process.


Valve-sparing aortic root replacement in a patient with retroaortic course of the left circumflex artery.
Anomalous origin of the left circumflex artery (LCA) arising from the right coronary sinus was observed in a 45-year-old man with aortic root aneurysm. Valve-sparing aortic root replacement (VSARR) was decided despite the subannular course of the LCA. A modified Tirone David procedure was performed with specific consideration for distribution of the proximal suture line due to the periaortic and subannular course of the LCA. Due to the risk of LCA injury, a coronary artery bypass grafting was performed using the left internal thoracic artery to secure the perfusion of the LCA. The challenging association of aortic root aneurysm and anomalous origin and course of the LCA was managed successfully during VSARR.


Post-traumatic combined flexion of the thumb, index and middle finger after intrinsic muscles reconstruction of the hand: a case report.
We report a case in which simultaneous flexion of the thumb, index and middle finger occurred 6 months after the surgical reconstruction of the adductor (AM) and first dorsal interosseous (IO) muscles. An anomalous connection in the form of tendon slip associated to fibrous adhesions between the flexor pollicis longus (FPL) tendon, flexor digitorum profundus indicis (FDPI) and middle finger (FDPM) tendons were found. Either ultrasound (US) examination or magnetic resonance imaging (MRI) were unable to detect the site of adhesion. Excision of the slip and radical tenosynoviectomy led to early functional recovery.


ILP-based maximum likelihood genome scaffolding.
Interest in de novo genome assembly has been renewed in the past decade due to rapid advances in high-throughput sequencing (HTS) technologies which generate relatively short reads resulting in highly fragmented assemblies consisting of contigs. Additional long-range linkage information is typically used to orient, order, and link contigs into larger structures referred to as scaffolds. Due to library preparation artifacts and erroneous mapping of reads originating from repeats, scaffolding remains a challenging problem. In this paper, we provide a scalable scaffolding algorithm (SILP2) employing a maximum likelihood model capturing read mapping uncertainty and/or non-uniformity of contig coverage which is solved using integer linear programming. A Non-Serial Dynamic Programming (NSDP) paradigm is applied to render our algorithm useful in the processing of larger mammalian genomes. To compare scaffolding tools, we employ novel quantitative metrics in addition to the extant metrics in the field. We have also expanded the set of experiments to include scaffolding of low-complexity metagenomic samples. SILP2 achieves better scalability throughg a more efficient NSDP algorithm than previous release of SILP. The results show that SILP2 compares favorably to previous methods OPERA and MIP in both scalability and accuracy for scaffolding single genomes of up to human size, and significantly outperforms them on scaffolding low-complexity metagenomic samples. Equipped with NSDP, SILP2 is able to scaffold large mammalian genomes, resulting in the longest and most accurate scaffolds. The ILP formulation for the maximum likelihood model is shown to be flexible enough to handle metagenomic samples.


Patient-reported outcomes in autosomal inherited bleeding disorders: A systematic literature review.
Currently, it is unknown which patient-reported outcomes are important for patients with autosomal inherited bleeding disorders. Therefore, the purpose of this study is to systematically review the available literature assessing patient-reported outcomes and their measurement methods in autosomal inherited bleeding disorders. The Embase, Medline ALL, Web of Science Core Collection, Cochrane Central Register of Controlled Trails and Google Scholar databases were searched from inception until 14 August 2020. Studies on patient-reported outcomes in patients with von Willebrand disease, inherited platelet function disorders and coagulation factor deficiencies were included. Twenty-one articles met the inclusion criteria. Three studies were assessed as having poor quality, and therefore a high risk of bias. Nineteen studies had fair quality rating. Different measurements methods were used, ranging from predefined to self-developed questionnaires. The majority of included studies focused on von Willebrand disease. Patients with von Willebrand disease reported lower health-related quality of life compared to the general population. Overall, this trend was especially visible in the following domains: vitality, physical and social functioning and pain. Women with inherited bleeding disorders scored lower on health-related quality of life compared to men, especially women with heavy menstrual bleeding. Patients with joint bleeds or heavy menstrual bleeding reported an increased level of pain. Patients with autosomal inherited bleeding disorders report lower health related quality of life, especially those with joint bleeds or heavy menstrual bleeding. Numerous measurement methods are used in patients with autosomal inherited bleeding disorders, highlighting the need for studies using established, standardized measurement methods.


Changing Etiologies and Prognostic Factors in Pediatric Acute Liver Failure.
After the implementation of universal hepatitis A virus vaccination in Argentina, the outcome of pediatric acute liver failure (PALF) remains unknown. We aimed to identify variables associated with the risk of liver transplantation (LT) or death and to determine the causes and short-term outcomes of PALF in Argentina. We retrospectively included 135 patients with PALF listed for LT between 2007 and 2016. Patients with autoimmune hepatitis (AIH), Wilson's disease (WD), or inborn errors of metabolism (IEM) were classified as PALF-chronic liver disease (CLD), and others were classified as "pure" PALF. A logistic regression model was developed to identify factors independently associated with death or need of LT and risk stratification. The most common etiologies were indeterminate (52%), AIH (23%), WD (6%), and IEM (6%). Overall, transplant-free survival was 35%, whereas 50% of the patients underwent LT and 15% died on the waiting list. The 3-month risk of LT or death was significantly higher among patients with pure PALF compared with PALF-CLD (76.5% versus 42.5%; relative risk, 1.8 [1.3-2.5]; P < 0.001), and 3 risk factors were independently associated with worse outcome: international normalized ratio (INR) ≥3.5 (odds ratio [OR], 3.1; 95% confidence interval [CI], 1.3-7.2]), bilirubin ≥17 mg/dL (OR, 4.4; 95% CI, 1.9-10.3]), and pure PALF (OR, 3.8; 95% CI, 1.6-8.9). Patients were identified by the number of risk factors: Patients with 0, 1, or ≥2 risk factors presented a 3-month risk of worse outcome of 17.6%, 36.6%, and 82%, respectively. In conclusion, although lacking external validation, this simple risk-staging model might help stratify patients with different transplant-free survival rates and may contribute to establishing the optimal timing for LT.


Successful laparoscopic management of acute abdominal pain due to spontaneous rupture of subserosal vessels overlying a uterine fibroid: a case report and surgical video.
Acute abdomen comprises several emergencies. Hemoperitoneum associated with uterine fibroids, which can present as acute abdominal pain, is rare and difficult to diagnose. Especially, spontaneous hemorrhage from the rupture of the superficial vessels overlying a uterine fibroid is extremely rare, and its diagnosis and management have not been established. We report a case of a 55-year-old woman who presented at our hospital with acute abdomen. After performing a computed tomography scan, we conducted a laparoscopic examination and diagnosed hemoperitoneum of ambiguous origin. We treated the patient surgically, performing a laparoscopic myomectomy to remove the origin of the hemorrhage. The patient recovered well. We report a case of hemoperitoneum of ambiguous origin that was diagnosed laparoscopically and treated by laparoscopic myomectomy to remove the origin of the hemorrhage. Surgeons should rapidly diagnose and manage acute abdominal pain in women with a history of uterine fibroids to prevent severe morbidity or even mortality. Therefore, laparoscopic surgery is recommended in patients with stable hemodynamics.


Interfacial adsorption of insulin conformational changes and reversibility of adsorption.
The adsorption of human insulin to Teflon particles was studied with respect to conformational changes and the reversibility of adsorption was examined by total internal reflection fluorescence (TIRF). Adsorption isotherms for the adsorption of human insulin indicated high affinity adsorption, even at electrostatic repulsive conditions. The plateau value for adsorption was in accordance with a protein layer consisting primarily of insulin monomers. Conformational changes of the insulin upon adsorption, was investigated by circular dicroism (CD) and fluorescence spectroscopy. The results suggested unfolding of adsorbed insulin, as observed by a decrease in alpha-helix and increase in random coil conformation. The changes in protein structure was not only related to the adsorbed species being monomeric, since CD and fluorescence results were different for adsorbed insulin compared to a monomeric analog of human insulin. Furthermore, the thermal stability in the adsorbed state was changed compared to insulin in solution. On the basis of the TIRF studies with FITC-labelled insulin it was not possible to firmly conclude whether exchange between human insulin in the adsorbed state and in solution takes place, due to the limited time range investigated. However, the desorption mechanism appeared to be different with unlabelled insulin in the bulk solution compared to phosphate buffer.


A Path to Improved Alzheimer's Care: Simulating Long-Term Health Outcomes of Lecanemab in Early Alzheimer's Disease from the CLARITY AD Trial.
Alzheimer's disease (AD), a progressive neurodegenerative disease, is the main cause of dementia and one of the leading causes of death for elderly people in the USA. Lecanemab is a humanized IgG1 monoclonal antibody targeting amyloid protofibrils for the treatment of early AD [i.e., mild cognitive impairment (MCI) or mild AD dementia]. In a recent 18-month phase III trial, using a double-blind, placebo-controlled design, lecanemab treatment led to reduced brain amyloid burden and significant improvements in cognitive and functional abilities in individuals with early AD. An evidence-based patient-level disease simulation model was updated to estimate the long-term health outcomes of lecanemab plus standard of care (SoC) compared to SoC alone in patients with early AD and evidence of brain amyloid burden, using recent phase III trial data and published literature. The disease progression is described by changes in the underlying biomarkers of AD, including measures of amyloid and tau, and their connection to the clinical presentation of the disease assessed through various patient-level scales of cognition and function. Lecanemab treatment was estimated to slow the progression of AD to moderate and severe stages and reduce the time spent in these more advanced states. In individuals with early AD, lecanemab plus SoC was associated with a gain of 0.71 quality-adjusted life-years (QALYs), a 2.95-year delay in mean time to progression to AD dementia, a reduction of 0.11 years in institutional care, and an additional 1.07 years in community care as shown in the base-case study. Improved health outcomes were demonstrated with lecanemab treatment when initiated earlier based on age, disease severity, or tau pathology, resulting in estimated gains in QALYs ranging from 0.77 to 1.09 years, compared to 0.4 years in the mild AD dementia subset, as shown by the model. The study findings demonstrate the potential clinical value of lecanemab for individuals with early AD by slowing down disease progression and prolonging time in earlier stages of disease, which significantly benefits not only patients and caregivers but also society overall. ClinicalTrials.gov identifier, NCT03887455.


Genetic characterization of genogroup I norovirus in outbreaks of gastroenteritis.
In this study, we demonstrate that differences within the P2 domain of norovirus genogroup I (GI) strains can be used to segregate outbreaks which are unrelated, whereas complete conservation within this region allows tracking of strains that are part of a single outbreak and likely to have a common source.


Combination of porphyrins and DNA-alkylation agents: synthesis and tumor cell apoptosis induction.
A series of porphyrin-DNA cross-linking conjugates were synthesized. Their cytotoxicities to tumor cells were tested using MTT assays first. Then, HeLa cell apoptosis induced by these cationic porphyrins under the light was examined by laser confocal microscopy, flow cytometric analysis, and further confirmed by observing the morphological changes and DNA fragmentation mainly.


Workshop 1 (synthesis): relation between industry and other water interests in a catchment context--facilitated stakeholder dialogue.
Workshop 1 considered the nature and identity of water stakeholders and how best to facilitate an open, transparent, democratic process of dialogue leading to agreed strategies to address water problems.


Cophylogenetics and biogeography reveal a coevolved relationship between sloths and their symbiont algae.
Specialized species, like arboreal folivores, often develop beneficial relationships with symbionts to exploit ecologically constrained lifestyles. Although coevolution can drive speciation by specialization of a symbiont to a host, a symbiotic relationship is not indicative of coevolution between host and symbiont. We tested for coevolved relationships between highly specialized two- and three-toed sloths (Choloepus spp. and Bradypus spp., respectively) and their symbiotic algae using cophylogenies and phylogeography. Our phylogeographic analysis showed a biogeographic pattern for the sloth distribution that was not found in the algal phylogeny. We found support for congruence between the sloth and algae phylogenies, implying cospeciation, only in the Bradypus lineage. Algae host-switching occurred from Bradypus spp. to Choloepus spp. Our results support a previously hypothesized symbiotic relationship between sloths and the algae in their fur and indicate that coevolution may have played a role in algae diversification. More broadly, convergent evolution may facilitate host switching between deeply diverged host lineages.


New strategies on the application of artificial intelligence in the field of phytoremediation.
Artificial Intelligence (AI) is expected to play a crucial role in the field of phytoremediation and its effective management in monitoring the growth of the plant in different contaminated soils and their phenotype characteristic such as the biomass of plants. This review focuses on recent applications of various AI techniques and remote sensing approaches in the field of phytoremediation to monitor plant growth with relevant morphological parameters using novel sensors, cameras, and associated modern technologies. Novel sensing and various measurement techniques are highlighted. Input parameters are used to develop futuristic models utilizing AI and statistical approaches. Additionally, a brief discussion has been presented on the use of AI techniques to detect metal hyperaccumulation in all parts of the plant, carbon capture, and sequestration along with its effect on food production to ensure food safety and security. This article highlights the application, limitation, and future perspectives of phytoremediation in monitoring the mobility, bioavailability, seasonal variation, effect of temperature on plant growth, and plant response to the heavy metals in soil by using the AI technique. Suggestions are made for future research in this area to analyze which would help to enhance plant growth and improve food security in long run.


Protecting the exposed skin graft--the Norwich cage.
A simple method of protecting an exposed skin graft is presented. It is cheap, easy to use, and applicable to most sites of the body, even in areas with contours that might otherwise be thought difficult to protect.


MXene/AgNW composite material for selective and efficient removal of radioactive cesium and iodine from water.
Toxic fission products, such as cesium (137Cs) and iodine (129I) are of great concern because of their long half-lives and high solubility in water. The simultaneous removal of Cs and I using a single adsorbent is an area of increasing interest. In this study, MXene/silver nanowire (AgNW) composite was synthesized through physical mixing and employed for simultaneous removal of iodide (I-) and cesium (Cs+) ions from contaminated water. The MXene/AgNW composite demonstrated excellent adsorption capacities of 84.70 and 26.22 mg/g for I- and Cs+, respectively. The experimental data supported the hypothesis of multilayer adsorption of Cs+ owing to the inter-lamellar structures and the presence of heterogeneous adsorption sites in MXene. The interaction between I- and the AgNW involved chemisorption followed by monolayer adsorption. MXene/AgNW composite material exhibited promising results in the presence of competitive ions under extreme pH conditions. Thus, synthesized composite materials holds promising potential as an adsorbent for the remediation of radioactive liquid waste.


Desymmetrization of Cyclopropenes via the Potassium-Templated Diastereoselective 7- exo- trig Cycloaddition of Tethered Amino Alcohols toward Enantiopure Cyclopropane-Fused Oxazepanones with Antimycobacterial Activity.
A strain-release-driven, cation-templated intramolecular nucleophilic addition of tethered alkoxides to prochiral cyclopropenes is described. Employment of chiral β- and γ-amino alkoxides allowed for highly diastereoselective assembly of a small series of enantiopure cyclopropane-fused oxazepanones. It was shown that the chiral center at C-4 plays a crucial role in controlling desymmetrization of the cyclopropenyl moiety, instigated by a profound potassium-templated effect. The preliminary biological activities of the new cyclopropane-fused medium heterocycles against Gram-positive bacteria, Gram-negative bacteria, mycobacteria, cancer cells, and fungus were evaluated.


Roles of dosage, pharmacokinetics, and cellular sensitivity to damage in the selective toxicity of cyclophosphamide towards B and T cells in development.
Cyclophosphamide (CP) is a known immunomodulating agent. When presented to either late stage chick embryos (e.g. 18 days of incubation (DI] or neonatal chicks. CP induces selective B cell damage resulting in humoral immunosuppression in chickens. The present study was undertaken in order to provide further insights into CP's selective immunotoxic effects. We investigated the influences of age, CP-dose, and drug distribution on CP-induced cytotoxicity in the B and T cell compartments of the developing chick. In this test system, differential immunotoxicity was strongly dosage-dependent; at all ages tested, B cell depletion predominated at low CP dosages (50 and 100 mg/kg) whereas equally extensive lymphocyte toxicity was observed in both thymus and bursa at 200 mg/kg drug levels. Furthermore, while immunotoxicity profiles were similar at the two later developmental timepoints (18 DI and 1 day post-hatch), significantly higher CP dosages were required to induce lymphoid damage at 12 DI. Pharmacokinetic studies with radiolabeled CP revealed that approximately two-fold higher levels of CP and its metabolites are taken up in bursal tissue as compared to the thymus. Experiments concerning the possible inherent differences in susceptibility to CP-induced mitotic inhibition and cell killing mediating selective toxicity towards B cells versus T cells showed that B cell mitosis was inhibited at CP dosages as low as 5 mg/kg. No such inhibition of T cell mitosis was observed at this same low dosage. However, mitosis was completely arrested in both B and T cells at 50 mg/kg CP. Observations of cellularity in immune organs shortly after CP exposure revealed that the bursa is at least ten times more sensitive than the thymus to CP-induced mitotic inhibition and killing of resident lymphocytes. These studies reveal that multiple factors are involved in modulating CP selective immunotoxicity in the developing embryo. These include the dosage level, preferential distribution of the drug to the bursa, and a much greater sensitivity of B cells to CP-mediated mitotic inhibition and cell killing.


Dynamic properties of sensory stimulation evoked responses in mouse cerebellar granule cell layer and molecular layer.
Sensory information coming from climbing fiber and mossy fiber-granule cell pathways, generates motor-related outputs according to internal rules of integration and computation in the cerebellar cortex. However, the dynamic properties of sensory information processing in mouse cerebellar cortex are less understood. Here, we studied the dynamic properties of sensory stimulation-evoked responses in the cerebellar granule cell layer (GCL) and molecular layer (ML) by electrophysiological recordings method. Our data showed that air-puff stimulation (5-10 ms in duration) of the ipsilateral whisker pad evoked single-peak responses in the GCL and ML; whereas a duration of stimulation ≥30 ms in GCL and ≥60 ms in ML, evoked double-peak responses that corresponded with stimulation-on and -off responses via mossy fiber pathway. The highest frequency of stimulation train for evoking GCL responses was 33 Hz. In contrast, the highest frequency of stimulation train for evoking ML responses was 4 Hz. These results indicate that the cerebellar granule cells transfer the high-fidelity sensory information from mossy fibers, which is cut-off by molecular layer interneurons (MLIs). Our results suggest that the MLIs network acts as a low-pass filter during the processing of high-frequency sensory information.


Dental pulp pluripotent-like stem cells (DPPSC), a new stem cell population with chromosomal stability and osteogenic capacity for biomaterials evaluation.
Biomaterials are widely used to regenerate or substitute bone tissue. In order to evaluate their potential use for clinical applications, these need to be tested and evaluated in vitro with cell culture models. Frequently, immortalized osteoblastic cell lines are used in these studies. However, their uncontrolled proliferation rate, phenotypic changes or aberrations in mitotic processes limits their use in long-term investigations. Recently, we described a new pluripotent-like subpopulation of dental pulp stem cells derived from the third molars (DPPSC) that shows genetic stability and shares some pluripotent characteristics with embryonic stem cells. In this study we aim to describe the use of DPPSC to test biomaterials, since we believe that the biomaterial cues will be more critical in order to enhance the differentiation of pluripotent stem cells. The capacity of DPPSC to differentiate into osteogenic lineage was compared with human sarcoma osteogenic cell line (SAOS-2). Collagen and titanium were used to assess the cell behavior in commonly used biomaterials. The analyses were performed by flow cytometry, alkaline phosphatase and mineralization stains, RT-PCR, immunohistochemistry, scanning electron microscopy, Western blot and enzymatic activity. Moreover, the genetic stability was evaluated and compared before and after differentiation by short-comparative genomic hybridization (sCGH). DPPSC showed excellent differentiation into osteogenic lineages expressing bone-related markers similar to SAOS-2. When cells were cultured on biomaterials, DPPSC showed higher initial adhesion levels. Nevertheless, their osteogenic differentiation showed similar trend among both cell types. Interestingly, only DPPSC maintained a normal chromosomal dosage before and after differentiation on 2D monolayer and on biomaterials. Taken together, these results promote the use of DPPSC as a new pluripotent-like cell model to evaluate the biocompatibility and the differentiation capacity of biomaterials used in bone regeneration.


Histochemical changes effected by aldosterone on compensatory renal growth in the rat.
The activity of succinic dehydrogenase, adenosine triphosphatase, alkaline phosphatase and cytochrome oxidase was studied histochemically in the remaining kidney of male albino rats which had been subjected to unilateral nephrectomy and were subsequently treated with aldosterone. A marked increase in the activity of succinic dehydrogenase, adenosine triphosphatase and alkaline phosphatase was noted on the initial postoperative days. The increase noted in succinic dehydrogenase activity is considered particularly important because in the control group succinic dehydrogenase activity remained unchanged throughout the experiment.


The impact of microRNAs on myeloid-derived suppressor cells in cancer.
Inflammation promotes cancer development. To a large extent, this can be attributed to the recruitment of myeloid-derived suppressor cells (MDSCs) to tumors. These cells are known for establishing an immunosuppressive tumor microenvironment by suppressing T cell activities. However, MDSCs also promote metastasis and angiogenesis. Critically, as small non-coding RNAs that regulate gene expression, microRNAs (miRNAs) control MDSC activities. In this review, we discuss how miRNA networks regulate key MDSC signaling pathways, how they shape MDSC development, differentiation and activation, and how this impacts tumor development. By targeting the expression of miRNAs in MDSCs, we can alter their main signaling pathways. In turn, this can compromise their ability to promote multiple hallmarks of cancer. Therefore, this may represent a new powerful strategy for cancer immunotherapy.


Plasma membrane destination of the classical Xenopus laevis progesterone receptor accelerates progesterone-induced oocyte maturation.
Xenopus laevis oocyte maturation is induced by the steroid hormone progesterone through a non-genomic mechanism initiated at the cell membrane. Recently, two Xenopus oocyte progesterone receptors have been cloned; one is the classical progesterone receptor (xPR-1) involved in genomic actions and the other a putative seven-transmembrane-G-protein-couple receptor. Both receptors are postulated to be mediating the steroid-induced maturation process in the frog oocyte. In this study, we tested the hypothesis that the classical progesterone receptor, associated to the oocyte plasma membrane, is participating in the reinitiation of the cell cycle. Addition of a myristoilation and palmytoilation signal at the amino terminus of xPR-1 (mp xPR-1), increased the amount of receptor associated to the oocyte plasma membrane and most importantly, significantly potentiated progesterone-induced oocyte maturation sensitivity. These findings suggest that the classical xPR-1, located at the plasma membrane, is mediating through a non-genomic mechanism, the reinitiation of the meiotic cell cycle in the X. laevis oocyte.


Unified-planning, graded-administration, and centralized-controlling: a management modality for treating acquired immune deficiency syndrome with Chinese medicine in Henan Province of China.
Henan Province in China has a major epidemic of human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS). Chinese medicine (CM) has been used throughout the last decade, and a management modality was developed, which can be described by unified-planning, graded-administration, and centralized-controlling (UGC). The UGC modality has one primary concept (patient-centered medicine from CM theory), four basic foundations (classifying administrative region, characteristics of CM on disease treatment, health resource conditions, and distribution of patients living with HIV), six important relationships (the "three uniformities and three combinations," and the six relationships therein guide the treatment of AIDS with CM), and four key sections (management, operation, records, and evaluation). In this article, the authors introduce the UGC modality, which could be beneficial to developing countries or resource-limited areas for the management of chronic infectious disease.


Therapeutic drug monitoring of beta-lactam antibiotics - Influence of sample stability on the analysis of piperacillin, meropenem, ceftazidime and flucloxacillin by HPLC-UV.
Therapeutic drug monitoring (TDM) is a useful tool to optimize antibiotic therapy. Increasing interest in alternative dosing strategies of beta-lactam antibiotics, e.g. continuous or prolonged infusion, require a feasible analytical method for quantification of these antimicrobial agents. However, pre-analytical issues including sample handling and stability are to be considered to provide valuable analytical results. For the simultaneous determination of piperacillin, meropenem, ceftazidime and flucloxacillin, a high performance liquid chromatography (HPLC) method including protein precipitation was established utilizing ertapenem as internal standard. Long-term stability of stock solutions and plasma samples were monitored. Furthermore, whole blood stability of the analytes in heparinized blood tubes was investigated comparing storage under ambient conditions and 2-8°C. A calibration range of 5-200μg/ml (piperacillin, ceftazidime, flucloxacillin) and 2-200μg/ml (meropenem) was linear with r2>0.999, precision and inaccuracy were <9% and <11%, respectively. The successfully validated HPLC assay was applied to clinical samples and stability investigations. At -80°C, plasma samples were stable for 9 months (piperacillin, meropenem) or 13 months (ceftazidime, flucloxacillin). Concentrations of the four beta-lactam antibiotics in whole blood tubes were found to remain within specifications for 8h when stored at 2-8°C but not at room temperature. The presented method is a rapid and simple option for routine TDM of piperacillin, meropenem, ceftazidime and flucloxacillin. Whereas long-term storage of beta-lactam samples at -80°C is possible for at least 9 months, whole blood tubes are recommended to be kept refrigerated until analysis.


Xanthone-enriched fraction of Garcinia mangostana and α-mangostin improve the spatial learning and memory of chronic cerebral hypoperfusion rats.
Xanthones isolated from the pericarp of Garcinia mangostana has been reported to exhibit neuroprotective effect. In this study, the effect of xanthone-enriched fraction of Garcinia mangostana (XEFGM) and α-mangostin (α-MG) were investigated on cognitive functions of the chronic cerebral hypoperfusion (CCH) rats. HPLC analysis revealed that XEFGM contained 55.84% of α-MG. Acute oral administration of XEFGM (25, 50 and 100 mg/kg) and α-MG (25 and 50 mg/kg) before locomotor activity and Morris water maze (MWM) tests showed no significant difference between the groups for locomotor activity. However, α-MG (50 mg/kg) and XEFGM (100 mg/kg) reversed the cognitive impairment induced by CCH in MWM test. α-MG (50 mg/kg) was further tested upon sub-acute 14-day treatment in CCH rats. Cognitive improvement was shown in MWM test but not in long-term potentiation (LTP). BDNF but not CaMKII was found to be down-regulated in CCH rats; however, both parameters were not affected by α-MG. In conclusion, α-MG ameliorated learning and memory deficits in both acute and sub-acute treatments in CCH rats by improving the spatial learning but not hippocampal LTP. Hence, α-MG may be a promising lead compound for CCH-associated neurodegenerative diseases, including vascular dementia and Alzheimer's disease.


Rich but not poor conditions determine sex-specific differences in growth rate of juvenile dioecious plants.
Causes of secondary sexual dimorphism (SSD) in dioecious plants are very poorly understood, especially in woody plants. SSD is shown mainly in mature plants, but little is known about whether secondary sexual dimorphism can occur in juveniles. It is also assumed that stress conditions intensify differences between the sexes due to the uneven reproductive effort. Therefore, the following research hypotheses were tested: (1) secondary sexual dimorphism will be visible in juveniles; (2) unfavourable soil conditions are the cause of more pronounced differences between the sexes. Rooted shoots of the common yew (Taxus baccata L.) and common juniper (Juniperus communis L.), previously harvested from parental individuals of known sex were used in the study. During two growing seasons vegetation periods and four times a year, comprehensive morphological features of whole plants were measured. Some SSD traits were visible in the analysed juveniles. Contrary to expectations, differences were more pronounced in the fertilized treatment. Both species reacted to fertilization in different ways. Female yew had a clearly higher total plant mass, root mass, and mean root area when fertilized, whereas male juniper had a higher root mass when fertilized. Differences between the sexes independent of the fertilization treatment were seen, which can be interpreted as sexual adaptations to a continued reproduction. Female yews and male junipers made better use of fertile habitats. Our study showed that SSD may be innate, and sexual compensatory mechanisms could generate uneven growth and development of both sexes. Because the SSD pattern was rather different in both species, it was confirmed that SSD is connected with the specific life histories of specific species rather than a universal strategy of dioecious species.


The neural rejuvenation hypothesis of cocaine addiction.
A leading hypothesis guiding current molecular and cellular research into drug addiction conceptualizes key aspects of addiction as a form of memory in which common neuroplasticity mechanisms that mediate normal learning and memory processes are 'hijacked' by exposure to drugs of abuse to produce pathologic addiction-related memories. Such addiction-related memories are particularly robust and long-lasting and once formed are less amenable to updating. Here we propose a neural rejuvenation hypothesis of cocaine addiction. According to this hypothesis, repeated exposure to drugs of abuse induces some plasticity mechanisms normally associated with brain development within the reward circuitry that mediate the highly efficient and unusually stable memory abnormalities that characterize addiction.


Erratum regarding missing Declaration of Competing Interest statements in previously published articles.
[This corrects the article DOI: 10.1016/j.jor.2020.06.011.][This corrects the article DOI: 10.1016/j.jor.2019.08.023.][This corrects the article DOI: 10.1016/j.jor.2020.03.020.][This corrects the article DOI: 10.1016/j.jor.2019.09.012.][This corrects the article DOI: 10.1016/j.jor.2018.08.010.][This corrects the article DOI: 10.1016/j.jor.2019.05.012.][This corrects the article DOI: 10.1016/j.jor.2019.12.006.][This corrects the article DOI: 10.1016/j.jor.2018.08.004.][This corrects the article DOI: 10.1016/j.jor.2019.04.012.][This corrects the article DOI: 10.1016/j.jor.2018.01.003.][This corrects the article DOI: 10.1016/j.jor.2018.01.021.][This corrects the article DOI: 10.1016/j.jor.2019.10.019.][This corrects the article DOI: 10.1016/j.jor.2019.02.012.][This corrects the article DOI: 10.1016/j.jor.2019.08.028.][This corrects the article DOI: 10.1016/j.jor.2018.02.004.].


Quercetin-mediated SIRT1 activation attenuates collagen-induced mice arthritis.
Herba taxilli (HT, Sangjisheng in Chinese), which is composed of the dried stems and leaves of Taxillus chinensis (DC.) Danser, has been commonly used to treat inflammation and arthritis in traditional Chinese medicine (TCM). Quercetin (Que) is a major active flavonoid component isolated from HT and is one of the quality control indexes of HT. In the clinical practice of TCM, formulas containing HT are commonly used to treat rheumatoid arthritis (RA). Recent studies have shown that Que exerts antiarthritic effects. However, the mechanism by which Que treatment affects RA is not fully understood. This study aimed to explore the antiarthritic activity of Que in a collagen-induced arthritis (CIA) mouse model and investigate the underlying mechanisms. The antiarthritic activity of Que was evaluated in a CIA mouse model by determining the paw clinical arthritis scores and left ankle thicknesses and by conducting micro-PET imaging and histopathological analysis of ankle joint tissues. The proinflammatory cytokine (IL-6, TNF-α, IL-1β, IL-8, IL-13, IL-17) levels in the serum and ankle joint tissues were measured by ELISA. Mitochondrial oxidative stress was assessed by biochemical methods. Mitochondrial biogenesis was analysed by RT-qPCR. The protein levels of silent information regulator 1 (SIRT1), peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), nuclear respiratory factor 1 (NRF1), mitochondrial transcription factor A (TFAM), high-mobility group box 1 (HMGB1), Toll-like receptor 4 (TLR4), p38, phospho-p38, extracellular signal-regulated kinases (ERK)-1/2, phospho-ERK1/2, p65, and phospho-p65 in ankle joint tissues were detected by Western blot analysis. A total of 30 RA patients were recruited to investigate the relationship between the disease activity score (DAS28) and the SIRT1, PGC-1α, NRF1, and HMGB1 plasma levels. Que treatment decreased the clinical score and left ankle thickness of CIA mice, attenuated the synovial inflammation and hyperplasia and bone/cartilage destruction in ankle joints, and decreased the secretion of IL-6, TNF-α, IL-1β, IL-8, IL-13, and IL-17. Mechanistically, Que treatment improved impaired mitochondrial biogenesis and mitochondrial function by regulating the SIRT1/PGC-1α/NRF1/TFAM pathway and inhibited inflammation via the HMGB1/TLR4/p38/ERK1/2/NF-κB p65 pathway. Notably, epidemiological data revealed correlations between abnormal circulating levels of SIRT1, PGC-1α, NRF1, HMGB1 and RA disease activity in patients. Our data suggested a potential role of Que as a dietary therapeutic drug for RA treatment that may act through SIRT1 to target mitochondrial biogenesis. Additionally, the role of impaired mitochondrial biogenesis in RA was evaluated.


Subtypes of protein kinase C in rat cerebral microvessels.
Protein kinase C in rat cerebral microvessels was characterized. By hydroxyapatite column chromatography, protein kinase C in the soluble fraction was resolved into two major peaks corresponding to type II and III enzymes, in the proportion of 57% and 38%, respectively. Since each subtype is considered to have a distinct role, the high proportion of type II enzyme found in this study suggests that this type may be involved in specific functions of the cerebral microvessels.


Estimating the date of confinement: ultrasonographic biometry versus certain menstrual dates.
Our purpose was to evaluate the clinical implications of current pregnancy dating policies in a population where routine ultrasonography is performed in the first half of pregnancy. A total of 34,249 computer files of singleton pregnancies that had both "certain" menstrual dates and ultrasonographic biometry were retrieved from the East Midlands Obstetric Database. The estimated dates of delivery were calculated by five different methods: menstrual dates alone, ultrasonography alone, or a combination of both with menstrual dates used if the discrepancy with the ultrasonography dates was within 7, 10, or 14 days, respectively. The accuracy of each method in predicting the actual date of delivery was calculated. Differences among methods were evaluated with nonparametric tests. Compared with use of certain menstrual dates, ultrasonographic dating led to a 70% reduction in the number of pregnancies considered postterm. Delivery occurred within +/- 7 days of the estimated date of confinement in 49.5% cases when menstrual dates alone were used and in 55.2% if ultrasonography alone was used; for +/- 10 days, the corresponding figures were 64.1% and 70.3%. Scan dating alone was significantly better in predicting the actual date of delivery than any of the dating policies taking menstrual dates alone or in combination with ultrasonography. Even if menstrual dates are considered "certain," there is no advantage in taking them into consideration for calculating the expected date of delivery if a dating ultrasonography result is available. Dating by ultrasonographic biometry in the first half of pregnancy results in a more accurate prediction of the delivery date than using menstrual data alone or in combination with ultrasonography.


TGF-β1 serum concentration as a complementary diagnostic biomarker of lung cancer: establishment of a cut-point value.
Lung cancer is a malignant disease with increasing mortality rates. Cytokines play a role in normal cell growth regulation and differentiation and are also implicated in malignant disease. Among these cytokines, Transforming Growth Factor β type 1 (TGF-β1) acts as a tumor promoter in malignant cells. Several clinical studies have found high levels of TGF-β1 in various cancer types. The aim of this study was to establish a TGF-β1 cut-off point as a complementary diagnostic tool in lung cancer detection. Therefore, 72 clinically well-characterized individuals were studied, 41 lung cancer patients and 31 healthy subjects. Serum TGF-β1 concentration was measured by an enzyme-linked immunosorbent assay (ELISA). We compared statistically the serum TGF-β1 concentration between both groups with analysis of variance, linear regression and receiver operating curve analysis. We observed that lung cancer patients produced higher TGF-β1 levels than healthy individuals (37,225±9,436 vs. 28,416±9,324 pg/ml, P<0.001). The cut-point diagnostic value was 30,500 pg/ml with 80.5% sensitivity, 64.5% specificity and odds ratio: 7.5, 95% CI: 2.6-21.8. We found significantly higher TGF-β1 levels in lung cancer patients than in healthy individuals. We propose the measurement of serum TGF-β1 levels as a complementary diagnostic test in lung cancer detection.