Decomposing decomposition: isolating direct effects of temperature from other drivers of detrital processing.
Understanding the observed temperature dependence of decomposition (i.e., its "apparent" activation energy) requires separation of direct effects of temperature on consumer metabolism (i.e., the "inherent" activation energy) from those driven by indirect seasonal patterns in phenology and biomass, and by longer-term, climate-driven shifts in acclimation, adaptation, and community assembly. Such parsing is important because studies that relate temperature to decomposition usually involve multi-season data and/or spatial proxies for long-term shifts, and so incorporate these indirect factors. The various effects of such factors can obscure the inherent temperature dependence of detrital processing. Separating the inherent temperature dependence of decomposition from other drivers is important for accurate prediction of the contribution of detritus-sourced greenhouse gases to climate warming and requires novel approaches to data collection and analysis. Here, we present breakdown rates of red maple litter incubated in coarse- and fine-mesh litterbags (the latter excluding macroinvertebrates) for serial approximately one-month increments over one year in nine streams along a natural temperature gradient (mean annual: 12.8°-16.4°C) from north Georgia to central Alabama, USA. We analyzed these data using distance-based redundancy analysis and generalized additive mixed models to parse the dependence of decomposition rates on temperature, seasonality, and shredding macroinvertebrate biomass. Microbial decomposition in fine-mesh bags was significantly influenced by both temperature and seasonality. Accounting for seasonality corrected the temperature dependence of decomposition rate from 0.25 to 0.08 eV. Shredder assemblage structure in coarse-mesh bags was related to temperature across both sites and seasons, shifting from "cold" stonefly-dominated communities to "warm" communities dominated by snails or crayfish. Shredder biomass was not a significant predictor of either coarse-mesh or macroinvertebrate-mediated (i.e., coarse- minus fine-mesh) breakdown rates, which were also jointly influenced by temperature and seasonality. Unlike fine-mesh bags, however, temperature dependence of litter breakdown did not differ between models with and without seasonality for either coarse-mesh (0.36 eV) or macroinvertebrate-mediated (0.13 eV) rates. We conclude that indirect (non-thermal) seasonal and site-level effects play a variable and potentially strong role in shaping the apparent temperature dependence of detrital breakdown. Such effects should be incorporated into studies designed to estimate inherent temperature dependence of slow ecological processes.


Long-term culture of hematopoietic stem cells - validating the stromal component of the CAFC assay.
The stroma-based long-term culture is the assay of choice when a functional detection of primitive hematopoietic cells in vitro is sought. However, different stromal cell lines varying in supporting capacity have been raised and applied in different laboratories, resulting in a wide range in published frequencies of LTCIC alternative CAFC. In order to identify the most suitable stromal source in terms of supportive capacity, reproducibility, and ease of handling, we have compared some of the most commonly employed murine cell lines to human bone marrow stroma in secondary long-term culture set-ups. Seeking an approximation to the supportive capacity of human BM stroma we found the FBMD-1 cell line supplemented with G-CSF and IL-3 superior to FBMD-1 cells alone, and to M2-10B4 and Sl/Sl cells. Moreover, in co-cultures of CD34(+) cells and the FBMD-1 line, we found week 5 CAFC content highly reproducible (50.5 +/- 6.66 - 54.6 +/- 7.07/10(4) plated cells, p value > 0.95) and the assay was suitable for inter-individual comparison in a clinical setting. In fact, the week 5 CAFC results were even more reproducible than those of the CFU assays (CV 0.03 for the CAFC assay versus 0.13-0.33 for the CFU assays). On the other hand, when extending the culture period to 8 weeks, the cobblestone area formation was best maintained by human BM stroma and the high reproducibility in CAFC enumeration in cultures supported by the FBMD-1 was lost. Among the stromal cell sources tested, the FBMD-1 line was found to be superior in terms of ease of handling and week 5 CAFC reproducibility. However, this robustness could not be extended to week 8 CAFC.


Closed-loop helium circulation system for actuation of a continuously operating heart catheter pump.
Currently available, pneumatic-based medical devices are operated using closed-loop pulsatile or open continuous systems. Medical devices utilizing gases with a low atomic number in a continuous closed loop stream have not been documented to date. This work presents the construction of a portable helium circulation addressing the need for actuating a novel, pneumatically operated catheter pump. The design of its control system puts emphasis on the performance, safety and low running cost of the catheter pump. Static and dynamic characteristics of individual elements in the circulation are analyzed to ensure a proper operation of the system. The pneumatic circulation maximizes the working range of the drive unit inside the catheter pump while reducing the total size and noise production.Separate flow and pressure controllers position the turbine's working point into the stable region of the pressure creation element. A subsystem for rapid gas evacuation significantly decreases the duration of helium removal after a leak, reaching subatmospheric pressure in the intracorporeal catheter within several milliseconds. The system presented in the study offers an easy control of helium mass flow while ensuring stable behavior of its internal components.


Presence of membranous vesicles in cat seminal plasma: ultrastructural characteristics, protein profile and enzymatic activity.
This study sought to verify the presence of membranous vesicles in cat seminal plasma by means of transmission electron microscopy and to identify protein profile and some of the enzymatic activities associated with these particles. The transmission electron microscopy observations showed the existence of different sized vesicular membranous structures of more or less spherical shape. These vesicles were surrounded by single-, double- or multiple-layered laminar membranes. The vesicle diameters ranged from 16.3 to 387.4 nm, with a mean of 116.5 ± 70.7 nm. Enzyme activity determinations showed the presence of dipeptilpeptidase IV, aminopeptidase, alkaline and acid phosphatase. To our knowledge, this is the first report that identifies and characterizes the membranous vesicles in cat seminal plasma. However, further studies are necessary to identify the exact site of production of these membranous vesicles in the cat male genital tract and to determine their specific roles in the reproductive events of this species.


Vinca alkaloids: anti-vascular effects in a murine tumour.
We have investigated the blood flow modifying effects of the vinca alkaloids, vincristine and vinblastine in the murine carcinoma CaNT. Vinblastine at doses of 7.5 or 10 mg/kg induced profound and chronic reductions in tumour blood flow as measured by 86RbCl extraction. Following the maximum tolerated dose of 10 mg/kg, blood flow was reduced to 10% of pretreatment values after 2 h and remained below 20% of pretreatment values 24 h after drug administration. These findings are consistent with the early induction of necrosis by vinblastine and suggest that vascular-mediated cell death may account for a large part of the 11 day growth delay induced by this drug dose. In contrast to the large reductions in tumour blood flow, in skin, kidney, liver and muscle, blood flow reductions did not, at any time examined, exceed 40%. In all the normal tissues studied, blood flow had fully recovered by 6 h after vinblastine administration. Similar results, albeit less pronounced, have been obtained with vincristine at the maximum tolerated dose of 3 mg/kg. The results clearly show that both vinblastine and vincristine can induce, with some selectivity, a dramatic and prolonged reduction in tumour blood flow and that this may contribute to the anti-tumour effects against the CaNT tumour.


Effect of morbid obesity, gastric banding and gastric bypass on esophageal symptoms, mucosa and function.
Obesity and gastroesophageal reflux disease (GERD) are commonly associated diseases. Bariatric surgery has been shown to have various impacts on esophageal function and GERD. Our aim was to evaluate changes in symptoms, endoscopic findings, bolus passage and esophageal function in patients after primary gastric bypass surgery as compared to patients converted from gastric banding to gastric bypass. Obese patients scheduled for laparoscopic Roux-en-Y gastric bypass (naïve-to-bypass) and patients who previously underwent gastric banding and were considered for conversion from gastric banding to gastric bypass (band-to-bypass) were included. Patients rated esophageal and epigastric symptoms (100 point VAS) and underwent upper endoscopy, impedance-manometry, and modified "timed barium swallow" before/after surgery. Data from 66 naïve-to-bypass patients (51/66, 77 % females, mean age 41.2 ± 11.1 years) and 68 band-to-bypass patients (53/68, 78 % females, mean age 43.8 ± 10.0 years) were available for analysis. Esophageal symptoms, esophagitis, esophageal motility abnormalities and impaired esophageal bolus transit were more common in patients that underwent gastric banding compared to those that underwent gastric bypass. The majority of symptoms, lesions and abnormalities induced by gastric banding were decreased by conversion to gastric bypass. Esophagitis was present in 28/68 (41 %) and 13/47 (28 %) patients in the band-to-bypass group, pre- versus postoperatively, respectively, (p < 0.05). The percentage of swallows with normal bolus transit increased following transformation from gastric band to gastric bypass (57.9 ± 4.1 and 83.6 ± 3.4 %, respectively, p < 0.01). From an esophageal perspective, gastric bypass surgery induces less motility disorders and esophageal symptoms and should be therefore favored over gastric banding in difficult to treat obese patients at risk of repeated bariatric surgery.


Is There a Role for Cellular Therapy in Chronic Lymphocytic Leukemia?
Despite multiple advances in the treatment landscape of chronic lymphocytic leukemia (CLL) during recent years, cellular therapies, such as allogeneic hematopoietic cell transplantation and chimeric antigen-engineered T cells, represent valuable therapeutic options for patients with multiply relapsed or poor-risk disease. This brief overview will summarize current results of cellular therapies in CLL including Richter transformation, suggest an indication algorithm and strategies for performing cellular therapies in these conditions, and discuss the impact of COVID-19 (coronavirus disease 2019) on allogeneic hematopoietic cell transplantation and chimeric antigen-engineered T cells in CLL.


Combinatorial effects of antibiotics and enzymes against dual-species Staphylococcus aureus and Pseudomonas aeruginosa biofilms in the wound-like medium.
Bacterial biofilms are one of the major issues in the treatment of chronic infections such as chronic wounds, where biofilms are typically polymicrobial. The synergy between species can occur during most polymicrobial infections, where antimicrobial resistance enhances as a result. Furthermore, self-produced extracellular polymeric substance (EPS) in biofilms results in a high tolerance to antibiotics that complicates wound healing. Since most antibiotics fail to remove biofilms in chronic infections, new therapeutic modalities may be required. Disruption of EPS is one of the effective approaches for biofilm eradication. Therefore, degradation of EPS using enzymes may result in improved chronic wounds healing. In the current study, we investigated the efficacy of trypsin, β-glucosidase, and DNase I enzymes on the degradation of dual-species biofilms of Pseudomonas aeruginosa and Staphylococcus aureus in a wound-like medium. These species are the two most common bacteria associated with biofilm formation in chronic wounds. Moreover, the reduction of minimum biofilm eradication concentration (MBEC) of meropenem and amikacin was evaluated when combined with enzymes. The minimum effective concentrations of trypsin, β-glucosidase, and DNase I enzymes to degrade biofilms were 1 μg/ml, 8 U/ml, and 150 U/ml, respectively. Combination of 0.15 μg/ml trypsin and 50 U/ml DNase I had a significant effect on S. aureus-P. aeruginosa biofilms which resulted in the dispersal and dissolution of all biofilms. In the presence of the enzymatic mixture, MBECs of antibiotics showed a significant decrease (p < 0.05), at least 2.5 fold. We found that trypsin/DNase I mixture can be used as an anti-biofilm agent against dual-species biofilms of S. aureus-P. aeruginosa.


Comparative Study on the Antioxidant Activity of Monascus Yellow Pigments From Two Different Types of Hongqu-Functional Qu and Coloring Qu.
This study is the first to investigate the difference in the composition of Monascus azaphilone pigments (MonAzPs) between functional Qu (FQ) and coloring Qu (CQ) and analyze their relationships with antioxidant activity. The composition of key active components and antioxidant activity of the ethanol extracts of FQ and CQ were analyzed by Uv-vis, HPLC, and chemical antioxidant tests. The composition of MonAzPs of the ethanol extracts was further analyzed by HPLC-MS. Seven Monascus yellow pigments (MYPs) with high abundance were successfully purified for the antioxidation evaluation in vitro and in the cell. Correlation analysis between the metabolites and the antioxidant activity of Hongqu indicated that MonAzPs might play an essential role in the antioxidant activity (r > 0.80). By contrast, the monacolin K (MK), polysaccharide, ergosterol, and γ-aminobutyric acid (GABA) were not significantly correlated with the antioxidant activity. Orthogonal partial least squares discriminant analysis (OPLS-DA) based on the composition of MonAzPs revealed that the abundance of MYPs is significantly different between FQ and CQ (P < 0.05 and VIP > 1.0). Seven MYPs (monasfluore A, monaphilone B, monascuspilion, monascin, monaphilone A, ankaflavin, and new yellow pigment) with high abundance were successfully purified for the antioxidation evaluation. Chemical antioxidant tests revealed that the antioxidant activities of monaphilone A, ankaflavin, and new yellow pigment only from CQ were significantly more potent than monasfluore A and monascuspilion only separated from FQ. The cellular antioxidant assay (CAA) showed that the new yellow pigment had the best antioxidant activity (quercetin equivalent 7.23 μM), followed by monasfluore A and monaphilone B, all of which were significantly better than monascin and ankaflavin, the two most frequently reported MYPs. Research on the structure-activity relationship demonstrated that alterations of the hydroxyl that occurred on C-3' or C-11 obviously affected the antioxidant activities of MYPs. Our findings provide evidence that MYPs may be the key active components for CQ to have a more potent antioxidant capacity than FQ. The alterations of the hydroxyl that occurred on C-3' or C-11 obviously affected the antioxidant activities of MYPs.


What determines treatment satisfaction of patients with type 2 diabetes on insulin therapy? An observational study in eight European countries.
Patients with type 2 diabetes (T2DM) on insulin therapy are less satisfied with their diabetes treatment than those on oral hypoglycaemic therapies or lifestyle advice only. Determinants of satisfaction in patients with T2DM on insulin therapy are not clearly known. The aim of this study was to determine the association of treatment satisfaction with demographic and clinical characteristics of patients with T2DM. For this study we used data from the GUIDANCE (Guideline Adherence to Enhance Care) study, a cross-sectional study among 7597 patients with T2DM patients from Belgium, France, Germany, Ireland, Italy, Sweden, the Netherlands and the UK. The majority of patients were recruited from primary care. Treatment satisfaction was assessed by the Diabetes Treatment Satisfaction Questionnaire (DTSQ, score 0-36; higher scores reflecting higher satisfaction). To determine which patient characteristics and laboratory values were independently associated with treatment satisfaction, a linear mixed model analysis was used. In total, 1984 patients on insulin were analysed; the number of included patients per country ranged from 166 (the Netherlands) to 384 (Italy). The mean DTSQ score was 28.50±7.52 and ranged from 25.93±6.57 (France) to 30.11±5.09 (the Netherlands). Higher DTSQ scores were associated with having received diabetes education (β 1.64, 95% CI 0.95 to 2.32), presence of macrovascular complications (β 0.76, 95% CI 0.21 to 1.31) and better health status (β 0.08 for every one unit increase on a 0-100 scale, 95% CI 0.07 to 0.10). Lower DTSQ scores were associated with more frequently perceived hyperglycaemia (β -0.32 for every 1 unit increase on a seven-point Likert scale, 95% CI -0.50 to -0.13), and higher glycated haemoglobin (β -0.52 for every percentage increase, 95% CI -0.75 to -0.29). A number of factors including diabetes education, perceived and actual hyperglycaemia and macrovascular complications are associated with treatment satisfaction. Self-management education programmes should incorporate these factors for ongoing support in patients with T2DM.


Effects and synergy of feed ingredients on canine neoplastic cell proliferation.
Adjunctive use of nutraceuticals in human cancer has shown promise, but little work has been done in canine neoplasia. Previous human research has shown that polyphenols and carotenoids can target multiple pathways in vitro and in vivo. These compounds could synergize or antagonize with currently used chemotherapies, either increasing or decreasing the effectiveness of these drugs. Considering the routine and well controlled feeding practices of most dogs, the use of nutraceuticals incorporated into pet food is attractive, pending proof that the extracts are able to improve remission rates. The aim of this study was to examine five feed ingredients for antiproliferative effects, as well as the interaction with toceranib phosphate and doxorubicin hydrochloride, when treating canine neoplastic cell lines in vitro. Screening using MTT proliferation assays showed that green tea, turmeric, and rosemary extracts were the most effective. Turmeric extract (TE) was the most potent and exhibited synergy with a rosemary extract (RE) at concentrations from 1 to 25 μg mL(-1). This combination had an additive or synergistic effect with chemotherapeutic agents at selected concentrations within each cell line. No significant effects on cell viability were observed when the combination therapy was used with normal primary cells. The use of turmeric and rosemary extracts in combination may be worthwhile to investigate in the pre-clinical and clinical neoplastic considering there are no negative effects on traditional chemotherapy treatment. Further studies into the pharmacokinetics and mechanisms of action of these extracts should be investigated.


Traditional healers working with primary care and mental health for early intervention in psychosis in young persons: protocol for the feasibility cluster randomised controlled trial.
In low/middle-income countries (LMICs), more than half of patients with first-episode psychosis initially seek treatment from traditional and religious healers as their first care. This contributes to an excessively long duration of untreated psychosis (DUP). There is a need for culturally appropriate interventions to involve traditional and spiritual healers to work collaboratively with primary care practitioners and psychiatrists through task-shifting for early detection, referral and treatment of first episode of psychosis. To prevent the consequences of long DUP in adolescents in LMICs, we aim to develop and pilot test a culturally appropriate and context-bespoke intervention. Traditional HEalers working with primary care and mental Health for early interventiOn in Psychosis in young pErsons (THE HOPE) will be developed using ethnographic and qualitative methods with traditional healers and caregivers. We will conduct a randomised controlled cluster feasibility trial with a nested qualitative study to assess study recruitment and acceptability of the intervention. Ninety-three union councils in district Peshawar, Pakistan will be randomised and allocated using a 1:1 ratio to either intervention arm (THE HOPE) or enhanced treatment as usual and stratified by urban/rural setting. Data on feasibility outcomes will be collected at baseline and follow-up. Patients, carers, clinicians and policymakers will be interviewed to ascertain their views about the intervention. The decision to proceed to the phase III trial will be based on prespecified stop-go criteria. Ethical approval has been obtained from Keele University Ethical Review Panel (ref: MH210177), Khyber Medical University Ethical Review Board (ref: DIR/KMU-EB/IG/001005) and National Bioethics Committee Pakistan (ref no. 4-87/NBC-840/22/621). The results of THE HOPE feasibility trial will be reported in peer-reviewed journals and academic conferences and disseminated to local stakeholders and policymakers. ISRCTN75347421.


The Association between Personality Factors and Metabolic Parameters among Patients with Non-Alcoholic-Fatty Liver Disease and Type 2 Diabetes Mellitus-A Cross-Sectional Study.
The increasing prevalence of type 2 diabetes mellitus (T2DM) and non-alcoholic fatty liver disease (NAFLD) states a serious problem for public health. The introduction of effective methods of treatment and prevention is crucial to avoid complications of these diseases. Among them, we can specify psychological factors that affect everyday life and determine the patient's attitude towards therapy, and what follows, their compliance in treatment. The literature indicates these connections in various ways; in our study, we extend this view to include a broader perspective of human personality. We decided to investigate the associations between personality factors and metabolic parameters in patients with NAFLD and T2DM in order to better understand the patient's approach to the treatment of a chronic disease, such as those mentioned, and to establish the basis for further research implementing psychological interventions in the treatment of NAFLD and T2DM. One hundred participants with NAFLD and T2DM underwent blood tests and anthropometric measures. Each of them was asked to complete five questionnaires evaluating their personality properties. We revealed that a rise in body mass index is related to a fall in the emotional intelligence factor of utilizing emotions, and a rise in emotional perception. The decrease in task-oriented coping style and a rise in emotion-oriented coping style are associated with a waist-hip ratio increase. The increase in fasting plasma glucose is predicted by a decrease in task-oriented coping style score. A fall in social diversion coping style score is associated with a high-density lipoprotein increase; in turn, a triglycerides increase is connected with a decline in rhythmicity score. The personality factors are in relationship in the management of NAFLD and T2DM. They affect a patient's approach to treatment, which is very important, because we know lifestyle and dietary interventions are an important part of the treatment of these diseases. The compliance manifests by lifestyle modifications, taking medications regularly, measuring blood glucose, and inspection visits in outpatients' clinics are a large part of a diabetic's life. Future studies introducing psychological intervention to improve, e.g., coping styles or rhythmicity are needed to implement new methods of patient management.


Is there any relationship between mean platelet volume and varicocele?
Mean platelet volume (MPV) is a parameter that is obtained from an automatic haemogram device during routine blood count and measures platelet reactivity. Increased platelet volume has been considered to be a risk factor for vascular diseases. The aim of this study was to evaluate the relationship between the presence of varicocele and the MPV, platelet count (PLT) and platelet distribution width (PDW) values. We included 264 patients with a diagnosis of varicocele in Group 1, and 220 patients with no varicocele in Group 2. The varicocele diagnosis was performed both with physical examination findings and colour Doppler ultrasonography (CDU). Mean platelet volume values were statistically significantly high (P < 0.001) whereas PLT and PDW values were statistically significantly low (P = 0.011), (P = 0.008) in the varicocele group compared with the control group respectively. However, no significant correlation was found between MPV and PDW in patients diagnosed with varicocele and the varicocele grade on examination and spermatic vein diameter on CDU. Mean platelet volume, which is used widely to measure the size of platelets and indicates platelet reactivity, can provide guidance in the investigation of varicocele pathophysiology and the relevant vascular pathologies.


Early effects of acute gamma-radiation on vascular arterial tone.
1. To determine the acute effects of irradiation on the functionality of vessel, rat aortic rings were mounted in an organ bath for isometric tension measurements and irradiated (60Co, 1 Gy min(-1), 15 min). 2. Irradiation, which is without effect on non-contracted or endothelium-denuded vessels, led to an immediate and reversible increase in vascular tone on (-)-phenylephrine (1 microM)-precontracted aortic rings. The tension reached a plateau about 5 min after the beginning of irradiation. 3. The maximal radiation-induced contraction occurred on aortic rings relaxed by acetylcholine (ACh) (1 microM). In this condition, the addition of catalase (1000 u ml(-1)), which reduces hydrogen peroxide, and DMSO (0.1% v/v), which scavenges hydroxyl radical, had no influence on tension level while superoxide dismutase (SOD) (100 u ml(-1)), a superoxide anion scavenger, reduced the observed contraction. A similar result was obtained in the presence of indomethacin (10 microM), a cyclo-oxygenase blocker. 4. Pretreatment of rings with the nitric oxide synthase inhibitor, N(omega)-nitro-L-arginine methyl ester (L-NAME) (10-100 microM) inhibited the radiation-induced contraction. 5. This effect was dose rate-dependent and even occurred for a very low dose rate (0.06 Gy min(-1)). 6. The present results indicate that gamma-radiation induces an instantaneous vascular tone increase that is endothelium and dose rate-dependent. This effect is (i) maximal when nitric oxide (NO) is produced, (ii) greatly reduced by SOD and (iii) inhibited by L-NAME, suggesting a major involvement of complexes between NO and superoxide anion.


Transition from stable to unstable growth by an inertial force.
We introduce a simple growth model where the growth of the interface is affected by an inertial force and a white noise. The magnitude of the inertial force is controlled by a constant p between 0 and 1. An inertial force increases continuously from 0, as p does from 0 to 1. In our model, the interface starts growing from a flat state. When p<p(c), the interface width in our model increases continuously from 0 as time elapses, but it saturates to a constant value in the long time limit. The saturated values of the interface width are the same for different values of p if p<p(c). When p>p(c), however, the interface width increases continuously without saturation as time elapses. We explain via simple calculation how this interesting phenomenon occurs in our model. We find p(c)=0.5 from the calculation. This critical value is in excellent agreement with the critical value p(c)=0.50(1) found from the simulations of our model.


Descriptive Characterization of High-Frequency Distortion Product Otoacoustic Emission Source Components in Children.
Distortion product otoacoustic emissions (DPOAEs) provide an objective assessment of cochlear function and are used for serial ototoxicity monitoring in pediatric cancer patients. DPOAEs are modeled as having distortion (near f2) and reflection (near 2f1-f2) component sources, and developmental changes are observed in these components' relative strengths in infants compared with adults. However, little is known about source component strengths in childhood or at extended high frequencies (EHFs; > 8 kHz). Thus, the purpose of this study was to describe the effects of age and stimulus frequency on DPOAE components in children. DPOAEs were collected with varied frequency ratios (f2/f1 = 1.1-1.25) for a wide range of frequencies (2-16 kHz) in 39 younger (3-6 years) and 41 older (10-12 years) children with constant levels (L1/L2) of 65/50 dB SPL. A depth-compensated simulator sound pressure level method of calibration was employed. A time waveform representation of the results across various ratios was created to estimate peak pressures and latencies of each DPOAE component. Estimated peak pressures of DPOAE components revealed the greatest differences in DPOAE sources between children occurring at the highest frequencies tested, where the peak pressure of both components was largest for younger compared with older children. Latency differences between the children were only noted at higher frequencies for the distortion component. These results suggest that DPOAE levels decrease with age and reflection emissions are vulnerable to cochlear change. This work guides optimization of protocols for pediatric ototoxicity monitoring, whereby including EHF otoacoustic emissions is clearly warranted and choosing to isolate DPOAE sources may prove beneficial. https://doi.org/10.23641/asha.23669214.


Preservation in Young Patients of Pulp Vitality and Anatomical-Functional Restoration of the Lost Structure.
Often, young patients (≤30 years old) present with carious lesions that progress acutely, compromising a large amount of tooth structure. In these cases, a treatment to prevent the occurrence of pulp exposure and promote remineralization of caries-affected dentin is necessary to maintain healthy dental structure and allow more conservative interventions. The approach will be different when pulp exposure occurs: The therapeutic treatments will be focused on reparative dentin formation and prevention of microorganisms penetrating the pulp organ. Due to the different possible treatments that can be performed to avoid pulp necrosis and the various materials that can be used for this purpose, professionals may have some difficulties understanding all the indications for conservative pulp treatments. The objective of this article is to describe and discuss a successful pulp capping and stepwise excavation associated with restorative treatment for deep caries lesions of anterior upper teeth.


Transient osteoporosis: Not just the hip to worry about.
Transient osteoporosis (TO) is a clinical syndrome characterized by joint pain and the presence of bone marrow edema on magnetic resonance imaging (MRI), both of which spontaneously resolve over time. Transient osteoporosis most commonly affects the hip, but also may involve other lower extremity sites. TO likely represents a disorder that may be monoarticular or "migratory" with involvement of two or more lower extremity sites sequentially affected over a number of months. We report on two cases of transient osteoporosis, one involving the knee and one involving the hip, demonstrating the utility of serial bone mineral density measurements at both sites. Additionally, we are able to report on the microarchitectural changes seen at the distal femur on ultra-high resolution (7 T) MRI. Case #1 describes a recurrence of transient osteoporosis of the hip three years after a similar presentation at the contralateral hip and highlights the findings of rapidly changing bone mineral density in this clinical syndrome. In contrast to the spine, hip and forearm, peripheral bone density measurements at the knee are rarely reported and to our knowledge Case #2 represents the first report of transient osteoporosis of the knee demonstrating bone density findings similar to that seen in the hip. We postulate that transient osteoporosis of the knee is part of a clinical spectrum most commonly seen in the hip and one that is marked by lower extremity joint pain, bone marrow edema on MRI and transient decreases in bone mineral density all of which spontaneously resolve without sequelae.


Extensive bullous lichen sclerosus et atrophicus.
Lichen sclerosus et atrophicus is a chronic disease of unknown etiology characterized by atrophic and sclerotic plaques in both genital and extragenital regions. Extensive bullous lichen sclerosus et atrophicus (BLSA) is a severe variant of the disease with no widely accepted treatment. We present a 63-year-old woman with extensive extragenital, ivory-colored, atrophic plaques on her trunk and extremities and disseminated hemorrhagic bullae. The patient was unsuccessfully treated with standard topical corticosteroid therapy, doxycycline and chloroquine. According to the literature, there is little evidence of the efficacy of doxycycline and hydroxychloroquine in the treatment of BLSA. We report a rare case of extensive BLSA that is unresponsive to these drugs.


A new bent-toed gecko (Squamata: Gekkonidae: Cyrtodactylus) from the Western Himalayas, Himachal Pradesh, India.
We describe a new species of the gekkonid genus Cyrtodactylus based on a series of six specimens from the Chamba Valley in the Western Himalayas, Himachal Pradesh state, India. Cyrtodactylus chamba sp. nov. is a member of the subgenus Siwaligekko and can be diagnosed from congeners in the Western Himalayas by a combination of its small size (snout to vent length up to 63 mm), a continuous series of five precloacal pores on males, 13-15 rows of dorsal tubercles, 33-43 scales across the belly, no regular series of enlarged subcaudals, and a dorsal colour pattern of 5-7 irregular, broad, dark bands with much narrower, light interspaces. The new species is 14% divergent in ND2 sequence from the most similar sampled congener, Cyrtodactylus (Siwaligekko) himalayanus from Jammu and Kashmir, and is 0.5-1.1% divergent in nuclear sequence data from sampled Siwaligekko species. Many more undiscovered Cyrtodactylus species probably exist across the Himalayas at elevations below ~2000 m; basic field surveys for reptiles and other poorly known groups and examination of existing material should be a priority if we are to appreciate the true diversity of this spectacular mountainous landscape.


c-abl and YWHAZ gene expression in gastric cancer.
This study aims to determine the gene expression for c-abl and YWHAZ in gastric cancer and the differences between the c-abl and YWHAZ gene expression inside the tumor versus healthy tissue (at the resection edges). This prospective study included 34 patients with gastric neoplasia, 21 men and 13 women, aged between 49 and 79 years (65.5 years median). After the surgical procedure, in these cases, we collected two tissue samples: one sample was obtained from inside the tumoral tissue and another sample from the gastric tissue, which was identified as normal apparently, as far as possible from the tumor (resection edge). For determining the c-abl and YWHAZ gene expression, we used the quantitative real-time polymerase chain reaction. Regarding the c-abl gene expression in gastric cancer, c-abl expression was identified as lower inside tumor cells comparing to the normal gastric tissue (resection limit). This difference of gene expression emphasize the role of the c-abl gene in normal tissue growth and the involvement in apoptosis induction when alteration of DNA occurs, as a result to different agents actions as stress, ionizing radiations. The loss of expression or even the down-regulation of the c-abl is a fundamental event that leads to genesis and progression of tumors. No significant differences of the YWHAZ gene expression between the tumoral and normal gastric tissue probes were recorded in our study.


A note on the blood analog for in-vitro testing of heart valve bioprostheses.
Glycerol solution with the viscosity coefficient similar to that of blood is used in evaluating the performance characteristics of prosthetic heart valves in the laboratory. However, physiological saline solution is used as a test fluid in testing tissue heart valves even though the viscosity coefficient does not match that of human blood. It is commonly believed that glycerol is absorbed by the tissue valves and hence the leaflets become stiff, making the test results invalid. However, in our laboratory a comparison of tissue valves exposed to glycerine solution at various times does not indicate any difference in the leaflet opening characteristics. Hence, it is suggested that glycerine solution be used as a test fluid for the evaluation of tissue valves also.


Characteristics of Patients Who Are Not Responsive to Alternate Patching for Overcorrected Intermittent Exotropia.
To compare the characteristics of patients with surgically overcorrected intermittent exotropia treated with alternate patching. The medical records of 51 patients who underwent bilateral lateral rectus muscle recession for intermittent exotropia and required alternate patching to correct postoperative overcorrection were retrospectively reviewed. Patients with postoperative esodeviation ≥18 prism diopters (PD) were started on alternate patching on postoperative day 1, whereas those with postoperative esodeviation of 10 to 17 PD were started after 2 weeks. Postoperative esodeviation <10 PD was considered as slight intentional overcorrection after exotropia surgery. Patients not responsive to alternate patching treatment were defined as those with postoperative esodeviation ≥10 PD after 3 months of treatment. Sex, family history, age, refractive error, amblyopia, stereopsis, suppression, type of exotropia, surgical method, preoperative and postoperative angle of deviation, and start time of alternate patching were compared. Among 51 patients, 29 patients responded to alternate patching and 22 patients did not respond. Female sex (p = 0.04), larger preoperative exodeviation at distance (p = 0.04), late onset of postoperative maximal esodeviation (p < 0.01), larger postoperative maximal esodeviation at near (p = 0.02), and late initiation of alternate patching (p = 0.01) were associated with patients in the non-responsive group. Although postoperative angle of deviation was similar for 2 weeks, the angle of postoperative esodeviation was significantly larger in the non-responsive group than in the responsive group, beginning at 1 month postoperatively. Female sex, large preoperative exodeviation, late initiation of alternate patching, and large esodeviation 1-month postoperative predisposed patients to be resistant to alternate patching for postoperative overcorrection.


Conceptualization, operationalization, and content validity of the EQOL-questionnaire measuring quality of life and participation for persons with disabilities.
Measurement of quality of life demands thoroughly developed and validated instruments. The development steps from theory to concepts and from empirical data to items are sparsely described in the literature of questionnaire development. Furthermore, there seems to be a need for an instrument measuring quality of life and participation in a population with diverse disabilities. The aim of this paper was to present and discuss the initial steps in the development of the Electronic Quality of Life questionnaire (EQOL). The development of EQOL included six steps: 1) Establishing conceptual understanding; 2) Development of interview guides which build on the conceptual understanding; 3) Qualitative interviews of 55 participants (10-40 years old) with different types and severities of disabilities; 4) Conceptualization of domains identified in the qualitative data through thematic analysis; 5) Operationalization of the identified domains into items and; 6) Evaluation of content validity of the first version of the EQOL-measure. Content validity was examined by cognitive interviews with participants in the target group as well as by continuous feedback from an advisory board. We identified six domains (function and health, environment (physical and social), social network, wellbeing, occupation, and managing strategies) based on themes derived from the qualitative interviews and on conceptual discussions within the author group. These domains were incorporated in a conceptual model and items were generated to measure the content of each domain. Participants expressed satisfaction with EQOL but most participants felt that there were too many items. In total, 191 items were included in the questionnaire. Participants felt that the EQOL-questionnaire was relevant to their quality of life and participation. We have shown that it is possible to include quality of life and participation for people with various disabilities in one instrument. Although capturing less detail than a condition specific instrument, EQOL includes aspects perceived important for people with disabilities who are not included in general surveys. This is relevant when for example evaluating environmental adaptations and when comparing populations with various disabilities.


Unexpected DNA loss mediated by the DNA binding activity of ribonuclease A.
Ribonuclease A (RNase A) is widely used in molecular biology research both for analytical assays and for nucleic acid preparation. The catalytic mechanism of RNase A is well understood and absolutely precludes activity on DNA; however anecdotal reports of DNA degradation by RNase A are not uncommon. Here we describe a mechanism by which RNase A treatment can lead to apparent DNA degradation. This results from the surprising finding that RNase A remains functional in a phenol:chloroform mixture, to our knowledge the only enzyme that survives this highly denaturing solvent environment. Although RNase A does not cleave the DNA backbone it is capable of binding to DNA, forming stable RNase A-DNA complexes that partition to the interphase or organic phase during phenol:chloroform purification. The unexpected survival of the RNase A DNA-binding activity in phenol means that these complexes are not dissolved and a substantial amount of RNase A-bound DNA is permanently removed from the aqueous phase and lost on phase separation. This effect will impact DNA recovery from multiple procedures and is likely to represent a source of sequence bias in genome-wide studies. Our results also indicate that the results of analytical studies performed using RNase A must be considered with care.


Chloroquine and Hydroxychloroquine Retinal Toxicity Consideration in the Treatment of COVID-19.
The proposed doses of chloroquine (CQ) and hydroxychloroquine (HCQ) for treatment of COVID-19 (1000 mg/day for 10 days, CQ; 800 mg first day then 400 mg/day for 5 days, HCQ) in many guidelines worldwide, are considerably higher than the maximum recommended daily safe doses of both agents (≤2.3 mg/kg/day, CQ; ≤5.0 mg/kg/day, HCQ) for development of retinal toxicity. Irreversible retinal damage can occur if the exposure to the safe doses is >5 years. It is not known whether exposure to high doses over a short period of time can also cause the damage. We recommend that before prescribing CQ or HCQ, history of ocular disease should be obtained to avoid the prescription if appropriate. If either agent is to be used, routine baseline ocular examination is not absolutely necessary. Patients who do not have ocular disease should also be informed about the potential risk of retinal toxicity. Both agents, however, have not yet been proven to be beneficial to COVID-19.


NEK7 promotes gastric cancer progression as a cell proliferation regulator.
Gastric cancer is one of the most common malignant tumors of the digestive system. However, its targeted therapy develops at a slow pace. Thus, exploring the mechanisms of the malignant behavior of gastric cancer cells is crucial to exploit its treatment. Mammalian never-in-mitosis A (NIMA)-related kinases (NEKs) are considered to play a significant role in cancer cell proliferation. However, no study has reported on NIMA family proteins in gastric cancer. Bioinformatics analysis was employed to clarify the expression patterns of NEK1-NEK11 and their effects on prognosis. The effects of NEK7 on immune infiltration and NEK7 related pathways were also analyzed. At the cell level, 5-ethynyl-2-deoxyuridine, cell cycle, and Cell Counting Kit-8 assays were utilized to clarify the effect of NEK7 on gastric cancer cell proliferation. A mouse subcutaneous model revealed the regulating effect of NEK7 on gastric cancer cell proliferation in vivo. Bioinformatics analysis revealed that NEK7 is upregulated in gastric cancer and is related to poor prognosis. NEK7 is also related to T-stage, which is closely associated with cell proliferation. Further analysis showed that NEK7 was correlated with infiltration of multiple immune cells as well as gastric cancer-related pathways. Cell experiments indicated the promoting effect of NEK7 on cell proliferation, while the absence of NEK7 could lead to inhibition of gastric cancer proliferation and G1/S arrest. NEK7 exerts a regulatory effect on cell proliferation and is closely related to tumor immune infiltration.


CIGB-300-Regulated Proteome Reveals Common and Tailored Response Patterns of AML Cells to CK2 Inhibition.
Protein kinase CK2 is a highly pleiotropic and ubiquitously expressed Ser/Thr kinase with instrumental roles in normal and pathological states, including neoplastic phenotype in solid tumor and hematological malignancies. In line with previous reports, CK2 has been suggested as an attractive prognostic marker and molecular target in acute myeloid leukemia (AML), a blood malignant disorder that remains as an unmet medical need. Accordingly, this work investigates the complex landscape of molecular and cellular perturbations supporting the antileukemic effect exerted by CK2 inhibition in AML cells. To identify and functionally characterize the proteomic profile differentially modulated by the CK2 peptide-based inhibitor CIGB-300, we carried out LC-MS/MS and bioinformatic analysis in human cell lines representing two differentiation stages and major AML subtypes. Using this approach, 109 and 129 proteins were identified as significantly modulated in HL-60 and OCI-AML3 cells, respectively. In both proteomic profiles, proteins related to apoptotic cell death, cell cycle progression, and transcriptional/translational processes appeared represented, in agreement with previous results showing the impact of CIGB-300 in AML cell proliferation and viability. Of note, a group of proteins involved in intracellular redox homeostasis was specifically identified in HL-60 cell-regulated proteome, and flow cytometric analysis also confirmed a differential effect of CIGB-300 over reactive oxygen species (ROS) production in AML cells. Thus, oxidative stress might play a relevant role on CIGB-300-induced apoptosis in HL-60 but not in OCI-AML3 cells. Importantly, these findings provide first-hand insights concerning the CIGB-300 antileukemic effect and draw attention to the existence of both common and tailored response patterns triggered by CK2 inhibition in different AML backgrounds, a phenomenon of particular relevance with regard to the pharmacologic blockade of CK2 and personalized medicine.


Folfirinox vs. Gemcitabine + Nab-Paclitaxel as the First-Line Treatment for Pancreatic Cancer: A Systematic Review and Meta-Analysis.
The efficacy and safety of Folfirinox (FFX) or gemcitabine + nab-paclitaxel (GnP) to be used as the first-line drugs for pancreatic cancer (PC) is yet to be established. We conducted an analysis of retrospective studies to assess the efficacy and safety of these two regimens by comparing their survival and safety outcomes in patients with PC. We conducted an extensive review of two electronic databases from inception till February 2023 to include all the relevant studies that compared FFX with GnP published and unpublished work. Retrospective studies were only included. Overall survival (OS) and progression-free survival (PFS) were pooled using hazard ratios (HRs), while objective response rate (ORR) and safety outcomes were pooled using odds ratios (ORs) with 95% confidence interval (CI) using the random effects model. A total of 7,030 patients were identified in a total of 21 articles that were shortlisted. Pooled results concluded that neither FFX nor GnP was associated to increase the OS time (HR: 0.93, 95% CI: 0.83 - 1.04; P = 0.0001); however, FFX was more likely associated with increased PFS when compared to GnP (HR: 0.88, 95% CI: 0.81 - 0.97; P < 0.0001). ORR proved to be non-significant between the two regimens (OR: 0.90, 95% CI: 0.64 - 1.27; P = 0.15). Safety outcomes included neutropenia, anemia, thrombocytopenia and diarrhea. GnP was more associated with diarrhea (OR: 1.96, 95% CI: 1.22 - 3.15; P = 0.001), while FFX was seen to cause anemia (OR: 0.70, 95% CI: 0.51 - 0.98; P = 0.10) in PC patients. Neutropenia and thrombocytopenia were in-significant in the two drug regimens (OR: 1.10, 95% CI: 0.92 - 1.31; P = 0.33 and OR: 0.83, 95% CI: 0.60 - 1.13; P = 0.23, respectively). FFX and GnP showed a significant difference in increasing the PFS, while no difference was observed while measuring OS. Safety outcomes showed that FFX and GnP shared similar safety profiles as FFX was associated with hematological outcomes, while GnP was more associated with non-hematological outcomes.


Do Entrepreneurs' Developmental Job Challenges Enhance Venture Performance in Emerging Industries? A Mediated Moderation Model of Entrepreneurial Action Learning and Entrepreneurial Experience.
Drawing on work experience theory and human capital theory, we developed a model of how developmental job challenges (DJC) enhance venture performance. Specifically, we developed and tested a mediated moderation model of DJC linking entrepreneurial action learning (EAL), entrepreneurial experience and venture performance. Based on a sample of Chinese entrepreneurs in emerging industries, we demonstrated that the developmental quality of entrepreneurial tasks had a positive relationship with venture performance and that this relationship was mediated by EAL. Furthermore, we found that entrepreneurs with prior entrepreneurial experience were more likely to engage in EAL behaviors and achieved better venture performance.


Extreme Diversity in the Regulation of Ndt80-Like Transcription Factors in Fungi.
The Saccharomyces cerevisiae Ndt80 protein is the founding member of a class of p53-like transcription factors that is known as the NDT80/PhoG-like DNA-binding family. The number of NDT80-like genes in different fungi is highly variable and their roles, which have been examined in only a few species, include regulation of meiosis, sexual development, biofilm formation, drug resistance, virulence, the response to nutrient stress and programmed cell death. The protein kinase Ime2 regulates the single NDT80 gene present in S. cerevisiae. In this study we used a genetic approach to investigate whether the Aspergillus nidulans Ime2 homolog, ImeB, and/or protein kinases MpkC, PhoA and PhoB regulate the two NDT80-like genes (xprG and ndtA) in A. nidulans. Disruption of imeB, but not mpkC, phoA or phoB, led to increased extracellular protease activity and a defect in mycotoxin production similar to the xprG1 gain-of-function mutation. Quantitative RT-PCR showed that ImeB is a negative regulator of xprG expression and XprG is a negative regulator of xprG and ndtA expression. Thus, in contrast to Ime2, which is a positive regulator of NDT80 in S. cerevisiae, ImeB is a negative regulator as in Neurospora crassa. However, the ability of Ndt80 to autoregulate NDT80 is conserved in A. nidulans though the autoregulatory effect is negative rather than positive. Unlike N. crassa, a null mutation in imeB does not circumvent the requirement for XprG or NdtA. These results show that the regulatory activities of Ime2 and Ndt80-like proteins display an extraordinarily level of evolutionary flexibility.


Matrix Metalloproteinase-9 Relationship With Infarct Growth and Hemorrhagic Transformation in the Era of Thrombectomy.
Objective: To assess the relationship between matrix metalloproteinase 9 (MMP-9), a proteolytic enzyme involved in the breakdown of the blood-brain barrier, and infarct growth and hemorrhagic transformation in acute ischemic stroke (AIS) with large vessel occlusion (LVO) in the era of mechanical thrombectomy (MT) using the kinetics of MMP-9 and sequential magnetic resonance imaging (MRI). Methods: HIBISCUS-STROKE is a cohort study including AIS patients with LVO treated with MT following admission MRI. Patients underwent sequential assessment of MMP-9, follow-up CT at day 1, and MRI at day 6. The CT scan at day 1 classified any hemorrhagic transformation according to the European Co-operative Acute Stroke Study-II (ECASS II) classification. Infarct growth was defined as the difference between final Fluid-Attenuated Inversion Recovery volume and baseline diffusion-weighted imaging volume. Conditional logistic regression analyses were adjusted for main confounding variables including reperfusion status. Results: One hundred and forty-eight patients represent the study population. A high MMP-9 level at 6 h from admission (H6) (p = 0.02), a high glucose level (p = 0.01), a high temperature (p = 0.04), and lack of reperfusion (p = 0.02) were associated with infarct growth. A high MMP-9 level at H6 (p = 0.03), a high glucose level (p = 0.03) and a long delay from symptom onset to groin puncture (p = 0.01) were associated with hemorrhagic transformation. Conclusions: In this MT cohort study, MMP-9 level at H6 predicts infarct growth and hemorrhagic transformation.


[An effect of multi-island flap with shallow branch of gluteus upper artery on repair of sacrum soft tissue defect].
To explore a safe, highly-efficient and rapid approach to the repair of the sacrum soft tissue defect and/or partial exposure of the bone. From February 2003 to April 2006, 6 patients (4 males, 2 femals; aged 28-67 years) with the sacrum soft tissue defect were surgically treated by the multi-island flap with shallow branches of the gluteus upper artery. The soft tissue defects ranged in area from 15 cm x 12 cm to 25 cm x 20 cm, averaged 20 cm x 16 cm. The obtained flaps ranged in area from 18 cm x 15 cm to 30 cm x 25 cm. Of the patients, 5 had a sacral ulcer (Grade III in 3 patients, Grade IV in 2) and 1 had a tumor, with their illness course from 3 weeks to 20 years. All the flaps survived completely in the 6 patients, in whom 5 had an incision healing of the first intention, and the remaining 1 had a healing of the second intention 32 days after the treatment for the minor ischemia and necrosis at the edges of the flap. The follow-up for 2-38 months (average, 19.3 months) revealed that all the flaps grew well with no recurrence of the sacral ulcer. The surgical treatment with the multi-island flap with shallow branches of the gluteus upper artery is a safe, highly-efficient and rapid approach to repair of the sacrum soft tissue defect and/or partial exposure of the bone. This kind of treatment has advantages of simpler procedures, better blood circulation of the flap, fewer complications, and higher success rates.


Implantable cardioverter defibrillator therapy in paediatric practice: a single-centre UK experience with focus on subcutaneous defibrillation.
Sudden cardiac death (SCD) risk can be managed by implantable cardioverter defibrillators (ICD). Defibrillation shocks can be delivered via ICD generator and/or intracardiac or subcutaneous coil configurations. We present our single-centre use of childhood ICDs. Twenty-three patients had ICD implantation, with median age and weight of 12.96 years and 41.35 kg. Indications included eight long QT; four hypertrophic cardiomyopathy; three Brugada syndrome; two idiopathic ventricular fibrillation; two post-congenital heart repair; two family history of SCD with abnormal repolarization; one catecholaminergic polymorphic ventricular tachycardia; and one left ventricle non-compaction. Twelve had out of hospital cardiac arrests prior to implantation. Techniques included 13 conventional ICD implants (pre-pectoral device with endocardial leads), 7 with subcutaneous defibrillation coils (sensing via epicardial or endocardial leads tunnelled to the ICD), and 3 with exclusive subcutaneous ICD (sensing and defibrillation via the same subcutaneous lead). Satisfactory defibrillation efficacy and ventricular arrhythmia sensing was confirmed at implantation. Follow-up ranged from 0.17 to 11.08 years. One child died with the ICD in situ. Ten children received appropriate shocks; five on more than one occasion. Five received inappropriate shocks (for inappropriate recognition of sinus tachycardia or supraventricular tachycardia). Five children underwent six further interventions; all had intracardiac leads. Innovative shock delivery systems can be used in children requiring an ICD. The insertion technique and device used need to accommodate the age and weight of the child, and concomitant need for pacing therapy. We have demonstrated effective defibrillation with shocks delivered via configurations employing subcutaneous coils in children.


Ion-channel genosensor for the detection of specific DNA sequences derived from Plum Pox Virus in plant extracts.
A DNA biosensor for detection of specific oligonucleotides sequences of Plum Pox Virus (PPV) in plant extracts and buffer is proposed. The working principles of a genosensor are based on the ion-channel mechanism. The NH2-ssDNA probe was deposited onto a glassy carbon electrode surface to form an amide bond between the carboxyl group of oxidized electrode surface and amino group from ssDNA probe. The analytical signals generated as a result of hybridization were registered in Osteryoung square wave voltammetry in the presence of [Fe(CN)6]3-/4- as a redox marker. The 22-mer and 42-mer complementary ssDNA sequences derived from PPV and DNA samples from plants infected with PPV were used as targets. Similar detection limits of 2.4 pM (31.0 pg/mL) and 2.3 pM (29.5 pg/mL) in the concentration range 1-8 pM were observed in the presence of the 22-mer ssDNA and 42-mer complementary ssDNA sequences of PPV, respectively. The genosensor was capable of discriminating between samples consisting of extracts from healthy plants and leaf extracts from infected plants in the concentration range 10-50 pg/mL. The detection limit was 12.8 pg/mL. The genosensor displayed good selectivity and sensitivity. The 20-mer partially complementary DNA sequences with four complementary bases and DNA samples from healthy plants used as negative controls generated low signal.


Emodin and baicalein inhibit sodium taurocholate-induced vacuole formation in pancreatic acinar cells.
To investigate the effects of combined use of emodin and baicalein (CEB) at the cellular and organism levels in severe acute pancreatitis (SAP) and explore the underlying mechanism. SAP was induced by retrograde infusion of 5% sodium taurocholate into the pancreatic duct in 48 male SD rats. Pancreatic histopathology score, serum amylase activity, and levels of tumour necrosis factor alpha (TNF-α), interleukin 6 (IL-6), and IL-10 were determined to assess the effects of CEB at 12 h after the surgery. The rat pancreatic acinar cells were isolated from healthy male SD rats using collagenase. The cell viability, cell ultrastructure, intracellular free Ca2+ concentration, and inositol (1,4,5)-trisphosphate receptor (IP3R) expression were investigated to assess the mechanism of CEB. Pancreatic histopathology score (2.07 ± 1.20 vs 6.84 ± 1.13, P < 0.05) and serum amylase activity (2866.2 ± 617.7 vs 5241.3 ± 1410.0, P < 0.05) were significantly decreased in the CEB (three doses) treatment group compared with the SAP group (2.07 ± 1.20 vs 6.84 ± 1.13, P < 0.05). CEB dose-dependently reduced the levels of the pro-inflammatory cytokines IL-6 (466.82 ± 48.55 vs 603.50 ± 75.53, P < 0.05) and TNF-α (108.04 ± 16.10 vs 215.56 ± 74.67, P < 0.05) and increased the level of the anti-inflammatory cytokine IL-10 (200.96 ± 50.76 vs 54.18 ± 6.07, P < 0.05) compared with those in the SAP group. CEB increased cell viability, inhibited cytosolic Ca2+ concentration, and significantly ameliorated intracellular vacuoles and IP3 mRNA expression compared with those in the SAP group (P < 0.05). There was a trend towards decreased IP3R protein in the CEB treatment group; however, it did not reach statistical significance (P > 0.05). These results at the cellular and organism levels reflect a preliminary mechanism of CEB in SAP and indicate that CEB is a suitable approach for SAP treatment.


A Nuclear RNA Degradation Pathway Helps Silence Polycomb/H3K27me3-Marked Loci in Caenorhabditis elegans.
In fission yeast and plants, RNA-processing pathways contribute to heterochromatin silencing, complementing well-characterized pathways of transcriptional repression. However, it was unclear whether this additional level of regulation occurs in metazoans. In a genetic screen, we uncovered a pathway of silencing in Caenorhabditis elegans somatic cells, whereby the highly conserved, RNA-binding complex LSM2-8 contributes to the repression of heterochromatic reporters and endogenous genes bearing the Polycomb mark H3K27me3. Importantly, the LSM2-8 complex works cooperatively with a 5'-3' exoribonuclease, XRN-2, and disruption of the pathway leads to selective mRNA stabilization. LSM2-8 complex-mediated RNA degradation does not target nor depend on H3K9me2/me3, unlike previously described pathways of heterochromatic RNA degradation. Up-regulation of lsm-8-sensitive loci coincides with a localized drop in H3K27me3 levels in the lsm-8 mutant. Put into the context of epigenetic control of gene expression, it appears that targeted RNA degradation helps repress a subset of H3K27me3-marked genes, revealing an unappreciated layer of regulation for facultative heterochromatin in animals.


Histologic response to intradermal Zyderm and Zyplast (glutaraldehyde cross-linked) collagen in humans.
Biopsies were periodically taken over 6 months from sites injected intradermally with purified bovine collagen, Zyderm collagen implant, and a similar collagen, cross-linked with glutaraldehyde, Zyplast implant. The ultimate fate of the implants differed. Zyderm collagen was dispersed among host collagen fibers and gradually lost the appearance of a cohesive implant. By 90 days, the injected material could not be detected and was presumably resorbed, without becoming colonized by host fibroblasts. In contrast, the cross-linked implant remained as distinct foci for 3 to 6 months accompanied by massing of fibroblasts around the periphery. These fibroblasts subsequently invaded the implant and provoked an inflammatory reaction which replaced the implant by new host collagen. The fine collagen bundles in parallel arrays along with many small blood vessels were deposited in the site formerly occupied by the implant. These findings indicate that Zyplast collagen might provide longer-lasting correction of soft tissue defects.


Characteristics of ethacrynic acid highly sensitive Mg2+-ATPase in microsomal fractions of the rat brain: functional molecular size, inhibition by SITS and stimulation by Cl-.
Studies were performed to characterize ethacrynic acid (EA) highly sensitive Mg2+-ATPase isolated from microsomal fractions of the rat brain. The functional molecular sizes of the EA highly sensitive and EA less sensitive Mg2+-ATPases, estimated by a radiation inactivation method, were 480 and 80 kDa, respectively. An anion transport inhibitor, 4-acetamido-4'-isothiocyanostilbene-2,2'-disulfonic acid (SITS) inhibited the EA highly sensitive Mg2+-ATPase activity. The type of inhibition was uncompetitive with respect to ATP, and the inhibition was suppressed by anions such as Cl-, Br- and I-. Chloride ions stimulated enzyme activity with an increase in Vmax, but not in Km, for ATP. Anions tested also increased the enzyme activity in the following order of decreasing potency: Cl- greater than Br- greater than CH3COO- = I- greater than SO4(2-) = HCO3- greater than SO3(2-). These results suggest that EA highly sensitive Mg2+-ATPase is a relatively large molecule with anion-sensitive sites that affect the ATP hydrolyzing activity and the SITS binding capacity through anions, with Cl- being the most potent.


[Survey on HIV/AIDS-related knowledge and behavior of high risk population in Taiyuan City].
To understand the status of HIV/AIDS-related knowledge and behavior of high risk population in Taiyuan City, and to explore the correlation between the two factors. The questionnaires were designed according to the questionnaire for monitoring the behavior of HIV/AIDS-related high risk population in China, the basic knowledge, high-risk behavior and so on were included in the questionnaires. A random cluster sampling and stratified sampling method was used to interview with commercial sex workers, drug users and MSM (men who have sex with men) in Taiyuan City. EpiData 3.02 and SPSS 13.0 were used for data analysis. In the total of 531 respondents recruited in this study, 186 were commercial sex workers, 238 were drug users and 107 were MSM. The awareness of HIV/AIDS-related knowledge in sex workers was 61.9%, in drug users was 77.2% and in MSM was 90.4%. The condom user in sex workers at the last sexual activity was 74.9%, and in MSM was 58.9%. Sharing needle with others in intravenous drug users during the month before entering into the drug addiction treatment center was 57.9%. Except of sex workers in the top grade entertainment places, there was no statistically significant correlation between knowledge and behavior in these three high risk groups (r(s) = 0.789, P < 0.01). The awareness of HIV/AIDS-related knowledge and the frequency of using condom among these three high risk groups are relatively low. Health education as well as behavioral intervention should be emphasized.


The inhibitory effect of somatostatin on growth hormone, insulin and glucagon secretion in diabetes mellitus.
The inhibitory effect of somatostatin on insulin, glucagon and growth hormone secretion was studied in 5 patients with diabetes mellitus. In three maturity onset diabetics, somatostatin infusion abolished the insulin rise induced by breakfast and oral glucose, and in 2 of them, inhibited the basal insulin secretion by 50% seen during control studies. Concomitantly, there was a marked and prompt reduction of glucagon levels (50%) with a sustained effect. The plasma glucose levels were either unchanged or slightly increased. Following the somatostatin infusion, there was a prompt rebound increase in both insulin and glucagon levels with a relatively stable plasma glucose concentration. In contrast, a drastic reduction of plasma glucose in face of a relatively small fall in plasma glucagon in response to somatostatin infusion was observed in 2 insulin-dependent diabetics. In all patients, the episodic release of growth hormone seen during the control day was abolished during somatostatin infusion.


Msa1 and Msa2 Modulate G1-Specific Transcription to Promote G1 Arrest and the Transition to Quiescence in Budding Yeast.
Yeast that naturally exhaust their glucose source can enter a quiescent state that is characterized by reduced cell size, and high cell density, stress tolerance and longevity. The transition to quiescence involves highly asymmetric cell divisions, dramatic reprogramming of transcription and global changes in chromatin structure and chromosome topology. Cells enter quiescence from G1 and we find that there is a positive correlation between the length of G1 and the yield of quiescent cells. The Swi4 and Swi6 transcription factors, which form the SBF transcription complex and promote the G1 to S transition in cycling cells, are also critical for the transition to quiescence. Swi6 forms a second complex with Mbp1 (MBF), which is not required for quiescence. These are the functional analogues of the E2F complexes of higher eukaryotes. Loss of the RB analogue, Whi5, and the related protein Srl3/Whi7, delays G1 arrest, but it also delays recovery from quiescence. Two MBF- and SBF-Associated proteins have been identified that have little effect on SBF or MBF activity in cycling cells. We show that these two related proteins, Msa1 and Msa2, are specifically required for the transition to quiescence. Like the E2F complexes that are quiescence-specific, Msa1 and Msa2 are required to repress the transcription of many SBF target genes, including SWI4, the CLN2 cyclin and histones, specifically after glucose is exhausted from the media. They also activate transcription of many MBF target genes. msa1msa2 cells fail to G1 arrest and rapidly lose viability upon glucose exhaustion. msa1msa2 mutants that survive this transition are very large, but they attain the same thermo-tolerance and longevity of wild type quiescent cells. This indicates that Msa1 and Msa2 are required for successful transition to quiescence, but not for the maintenance of that state.


Message Delivery for the Treatment of Posttraumatic Stress Disorder: Longitudinal Observational Study of Symptom Trajectories.
Individuals with posttraumatic stress disorder (PTSD) face symptoms that can hinder access to treatment, such as avoidance and guilt. Telemedicine offers a technological solution to increase access to mental health care and overcome barriers to treatment. Although an increasing body of literature focused on synchronous telehealth (eg, live video), no studies have examined the delivery of PTSD treatment via two-way multimedia messages (ie, texting or messaging). The aim of this study was to conduct a longitudinal observation of treatment for PTSD delivered using two-way asynchronous messaging. We also sought to identify individual and treatment characteristics that could predict the observed outcome differences. Outpatients diagnosed with PTSD (N=475) received interventions from licensed therapists, which were delivered via messaging once or more than once per day, 5 days a week for 12 weeks. PTSD symptoms were assessed every 3 weeks using the PTSD Checklist for Diagnostic and Statistical Manual of Mental Disorders-5. Trajectories of PTSD symptoms were identified using growth mixture modeling (GMM). Using logistic regression, the demographic, treatment, and messaging characteristics of patient groups that improved were compared with the characteristics of patient groups that did not improve. The GMM identified 4 trajectories of PTSD symptoms: moderate improvement (197/475, 41.4%), high symptoms (197/475, 41.4%), chronic symptoms (61/475, 12.9%), and acute improvement (20/475, 4.3%). Patients with a clinically significant reduction in PTSD symptoms (231/475, 48.6%) were more likely to communicate via video (odds ratio [OR] 1.01, 95% CI 1.01-1.05; P=.03), have a higher working alliance with their therapist (OR 1.03, 95% CI 1.01-1.05; P=.02), and be at their first treatment experience (OR 2.03, 95% CI 1.18-3.54; P=.01). Treatment adherence was associated with greater therapeutic alliance (OR 1.07, 95% CI 1.03-1.10; P<.001), education (OR 2.13, 95% CI 1.13-4.03; P=.02), and more patient-generated messages per week (OR 1.08, 95% CI 1.04-1.13; P<.001). Multimedia message delivery for PTSD treatment showed symptom-reduction rates similar to traditional forms of treatment delivery, suggesting further study of messaging as a treatment medium. Most patients completed an 8-week course, reflecting the acceptability of messaging interventions. Delivering treatment via two-way messaging offers increased opportunities for widespread access to mental health care.


Colostrum and milk as risk factors for infection with Mycobacterium avium subspecies paratuberculosis in dairy cattle.
Mycobacterium avium ssp. paratuberculosis (MAP) infections cause major losses to the dairy industry. Transmission of MAP occurs primarily via feces and in utero, but MAP can also be excreted in colostrum and milk. The objective of this study was to determine whether colostrum and milk fed to calves are important risk factors for infection with MAP. A questionnaire was sent to 1,050 farms participating in the Danish control program on paratuberculosis in early 2007. Details on practices regarding colostrum and milk feeding between 1999 and 2006 were obtained from 808 (77%) herds. Nine vaccinated herds were excluded. Information on MAP antibody-ELISA results, date of birth, and herd of birth of 93,994 animals was obtained from the Danish Cattle Database. A 2-level logistic regression model was fitted with a dichotomized ELISA response, with outcome, age, source of colostrum, and milk as fixed effects, and herd as a random effect. Animals fed colostrum from multiple cows had an odds ratio of 1.24 of being ELISA positive compared with animals fed colostrum from their own dam only. Calves suckling with foster cows had an odds ratio of 2.01 of being ELISA positive compared with calves fed milk replacer. Feeding bulk tank milk and pooled milk from cows with high somatic cell counts did not increase the risk of being ELISA positive. Overall, the results of the study suggested that source of milk was not of great importance for the transmission of MAP, but colostrum should be fed only from the dam of that calf.


Sirtuin 1 overexpression contributes to the expansion of follicular helper T cells in Systemic lupus erythematosus and serves as an easy-to-intervene therapeutic target.
SIRT1, an NAD+-dependent deacetylase, is up-regulated in CD4+ T cells from SLE patients and MRL/lpr lupus-like mice. This study aimed to explore the role of SIRT1 in Tfh cell expansion and its potential value as a therapeutic target for SLE. Frequencies of CD4+CXCR5+PD-1+ Tfh cells in peripheral blood from SLE patients and their expression of SIRT1 and BCL-6 were determined with flow cytometry. Naïve CD4+ T cells were transfected with SIRT1-expressing lentivirus and small interfering RNA (siRNA) targeting SIRT1, respectively, and then cultured in a Tfh-polarizing condition to study the impact of SIRT1 on Tfh cell differentiation. This impact was also evaluated in both CD4+ T cells and naïve CD4+ T cells by treatment with SIRT1 inhibitors (EX527 and nicotinamide) in vitro. MRL/lpr mice and pristane-induced lupus mice were treated with continuous daily intake of nicotinamide, and their lupus phenotypes including skin rash, arthritis, proteinuria and serum anti-dsDNA autoantibodies were compared with controls. Expression of SIRT1 was elevated in Tfh cells from SLE patients and positively correlated with Tfh cell frequencies. SIRT1 expression gradually increased during Tfh cell differentiation. Overexpression of SIRT1 by lentiviral vectors significantly promoted Tfh cell differentiation/proliferation. Reciprocally, suppressing expression of SIRT1 by siRNA and inhibiting SIRT1 activity by EX-527 or nicotinamide hindered Tfh cell expansion. Continuous daily intake of nicotinamide alleviated lupus-like phenotypes and decreased serum CXCL13 in the two mouse models. SIRT1 overexpression contributes to the expansion of Tfh cells in SLE and may serve as a potential target for treatment.


Differential effects of methamphetamine and haloperidol on the control of an internal clock.
Humans and animals process temporal information as if they were using an internal stopwatch that can be stopped and reset, and whose speed is adjustable. Previous data suggest that dopaminergic drugs affect the speed of this internal stopwatch. Using a paradigm in which rats have to filter out the gaps that (sometimes) interrupted timing, the authors found that methamphetamine and haloperidol also affect the stop and reset mechanism of the internal clock, possibly by modulating attentional components that are dependent on the content and salience of the timed events. This is the first report of both clock and attentional effects of dopaminergic drugs on interval timing in the same experimental setting.


Effect of low oxygen tension on tissue-engineered cartilage construct development in the concentric cylinder bioreactor.
Cartilage is exposed to low oxygen tension in vivo, suggesting culture in a low-oxygen environment as a strategy to enhance matrix deposition in tissue-engineered cartilage in vitro. To assess the effects of oxygen tension on cartilage matrix accumulation, porous polylactic acid constructs were dynamically seeded in a concentric cylinder bioreactor with bovine chondrocytes and cultured for 3 weeks at either 20 or 5% oxygen tension. Robust chondrocyte proliferation and matrix deposition were achieved. After 22 days in culture, constructs from bioreactors operated at either 20 or 5% oxygen saturation had similar chondrocyte densities and collagen content. During the first 12 days of culture, the matrix glycosaminoglycan (GAG) deposition rate was 19.5 x 10(-9) mg/cell per day at 5% oxygen tension and 65% greater than the matrix GAG deposition rate at 20% oxygen tension. After 22 days of bioreactor culture, constructs at 5% oxygen contained 4.5 +/- 0.3 mg of GAG per construct, nearly double the 2.5 +/- 0.2 mg of GAG per construct at 20% oxygen tension. These data demonstrate that culture in bioreactors at low oxygen tension favors the production and retention of GAG within cartilage matrix without adversely affecting chondrocyte proliferation or collagen deposition. Bioreactor studies such as these can identify conditions that enhance matrix accumulation and construct development for cartilage tissue engineering.


Development and Student Evaluation of an Anatomically Correct High-Fidelity Calf Leg Model.
Obstetrical chain placement requires location of specific landmarks and a certain dexterity that must be practiced. Use of low-fidelity models may not always provide students with a realistic experience. In this study we developed an anatomically correct high-fidelity calf leg model that would serve as a better teaching model for pre-clinical veterinary students than a pre-existing low-fidelity polyvinyl chloride (PVC) model. One hundred and twenty pre-clinical veterinary students were instructed how to use obstetrical chains with a low-fidelity PVC model and the anatomically correct high-fidelity calf leg model. After a 45-minute lab, students were surveyed on their experience with both models. Overall students felt the anatomically correct high-fidelity calf leg model increased accuracy in chain placement and provided more accurate landmarks, a more realistic model, and more real-life scenario training.


The "worth" of the worth four dot test.
Worth's four dot test was first described one hundred years ago. Despite many technological advances in equipment and techniques during the last century, this simple test is still used routinely by many strabismus specialists. It is an invaluable test when used in the evaluation of longstanding and acquired strabismus in adults and in the management of complex diplopia. Techniques using the test include selecting an optimal prism, assessing the effect of a prescribed prism or compensatory head posture on the range of binocular single vision, identifying non-organic responses, diffe1rentiating monocular from binocular diplopia, especially when they co-exist, and blurred from double vision in older patients with divergence paresis. It also can be used with prisms preoperatively to determine the risks of postoperative diplopia and give clues to the presence of torsion or a visual field defect.


[Anti-angiogenic therapy of a renal angiomyolipoma in a seriously disabled patient suffering from multiple sclerosis].
Angiomyolipoma, although rare, belong together with oncocytomas to the most common benign renal neoplasms. Although angiomyolipoma is usually a non-invasive tumor that does not metastasize, chirurgical intervention, especially in case of large or enlarging tumors, is recommended due to their capacity to cause haemorrhage and other significant clinical complications. We report the case of a renal angiomyolipoma in a female patient seriously disabled by multiple sclerosis with reduced physical and nutritional condition. The woman already underwent a nephrectomy 20 years ago due to an angiomyolipoma of the opposite kidney. The patient received oral gefitinib at a dose of 500 mg/day for 28 days. By a four-weekly course of EGFR-inhibitor gefitinib (Iressa), we achieved a control of the angiomyolipoma and were able to prevent nephrectomy. The use of EGFR inhibitors, whose anti-proliferative activity in renal cell tumors derives not only from direct inhibition of cell proliferation, but also from the inhibition of angiogenesis, requires further investigation.


Repeated Incremental Workbouts Separated by 1 Hour Increase the Electromyographic Fatigue Threshold.
Bremer, N, Peoples, G, Hasler, B, Litzenburg, R, Johnson, A, and Malek, MH. Repeated incremental workbouts separated by 1 hour increase the electromyographic fatigue threshold. J Strength Cond Res 35(5): 1397-1402, 2021-Studies examining the influence of priming, for continuous exercise, have mainly focused on improved exercise capacity related to oxygen uptake kinetics rather than on neuromuscular fatigue of the muscle. The purpose of this study, therefore, was to determine whether or not the electromyographic fatigue threshold (EMGFT) could be modulated by having subjects perform 2 incremental tests separated by 1 hour. We hypothesized that the EMGFT determined from the second incremental test would be higher than the EMGFT determined from the first incremental test. Nine healthy college-aged men (mean ± SEM: age: 23.8 ± 0.6 years; body mass: 79.5 ± 3.3 kg; height: 1.78 ± 0.02 m) were recruited from the university population. Each subject visited the laboratory on 1 occasion and performed 2 incremental single-leg knee-extensor ergometry to voluntary fatigue separated by 1 hour. The EMGFT was determined for each trial and statistically compared using paired-samples t-test. The results indicated significant mean differences between the EMGFT for the 2 trials (trial 1: 27 ± 1 W vs. trial 2: 34 ± 2 W; p = 0.001), whereas there were no significant mean differences for maximal power output (trial 1: 53 ± 2 W vs. trial 2: 57 ± 2; p = 0.09). These findings suggest that postactivation potentiation may, in part, explain the differences in EMGFT because the exercise mode used in the current study minimizes the cardiorespiratory responses to exercise.


Root Resection and Hemisection Revisited. Part II: A Retrospective Analysis of 195 Treated Patients with Up to 40 Years of Follow-up.
Root resection and hemisection is a well-documented treatment option for extending the life span of furcated molars. The aim of the present study was to retrospectively evaluate the long-term results of root resection and hemisection of 195 patients with up to 40 years of follow-up. Records of 195 patients who had undergone root resection or hemisection were reviewed. A minimum follow-up of 5 years was needed. A molar was recorded as a survival if it was still present and functional without any signs of discomfort, pain, or pathology from restorative, endodontic, and periodontal points of view. Ninety-eight patients were excluded for not accomplishing the minimum 5-year observation period. Of the 97 remaining patients, 5 teeth were lost during the first 5 years of treatment and 92 teeth survived the follow-up period, ranging from 5 to 40 years. The overall survival rate was 94.8%. When up to 40 years of follow-up data were analyzed, it was found that high survival rates can be obtained with root resection and hemisection. The results are satisfying when a proper case selection, endodontic treatment, restorative design, and good maintenance program are given. This treatment option should always be considered before every extraction and implant placement.


The identification of mouse sperm-surface-associated proteins and characterization of their ability to act as decapacitation factors.
Mammalian spermatozoa must undergo capacitation before acquiring the ability to fertilize the oocyte. This process is believed to be initiated following the release of surface-associated decapacitation factors that are elaborated by both the epididymis and the male accessory organs. Herein, we report the identification of a number of proteins that are actively released from the surface of mouse spermatozoa during capacitation in vitro. As anticipated, the addition of these factors back to suspensions of mouse spermatozoa was shown to suppress several correlates of the capacitation process. Specifically, they induced a significant, dose-dependent inhibition of the ability of spermatozoa to undergo a progesterone-induced acrosome reaction and to bind to the zona pellucida in vitro. Inhibition of these functions was associated with the suppression of tyrosine phosphorylation in the sperm plasma membrane but had no effect on the phosphorylation of internal proteins in either the sperm head or tail. This inhibitory activity was attributed to a subset of the isolated proteins compromising at least four putative decapacitation factors. These proteins were identified via tandem-mass spectrometry amino acid sequence analysis as plasma membrane fatty acid binding protein, cysteine-rich secretory protein 1 (CRISP1), phosphatidylethanolamine binding protein 1 (PBP), and an unnamed protein product that we have termed decapacitation factor 10 (DF10). Of these proteins, PBP was identified as a primary candidate for a decapacitation factor.


Using Direct Oral Anticoagulants in Patients with Atrial Fibrillation: Assessment, Monitoring and Treatment Reversal.
It is essential to prevent thromboembolic events in atrial fibrillation. The risks of thromboembolic and haemorrhagic events must be carefully assessed and weighed against one another, both in routine situations and in relation to invasive procedures. Vitamin K antagonists, until recently the first-line treatment for prophylaxis against thromboembolic events in patients with atrial fibrillation, have various drawbacks. Direct-acting oral anticoagulants overcome these limitations and are efficacious and safe. The recent developments of tests to monitor anticoagulant levels, and of target-specific reversal agents for these newer drugs, has facilitated their use in several situations, including emergencies. For these reasons, the European Society of Cardiology and other scientific societies now recommend direct-acting oral anticoagulants as first-line treatment for preventing thromboembolic events in atrial fibrillation.


Spatial transcriptomics reveals the distinct organization of mouse prefrontal cortex and neuronal subtypes regulating chronic pain.
The prefrontal cortex (PFC) is a complex brain region that regulates diverse functions ranging from cognition, emotion and executive action to even pain processing. To decode the cellular and circuit organization of such diverse functions, we employed spatially resolved single-cell transcriptome profiling of the adult mouse PFC. Results revealed that PFC has distinct cell-type composition and gene-expression patterns relative to neighboring cortical areas-with neuronal excitability-regulating genes differently expressed. These cellular and molecular features are further segregated within PFC subregions, alluding to the subregion-specificity of several PFC functions. PFC projects to major subcortical targets through combinations of neuronal subtypes, which emerge in a target-intrinsic fashion. Finally, based on these features, we identified distinct cell types and circuits in PFC underlying chronic pain, an escalating healthcare challenge with limited molecular understanding. Collectively, this comprehensive map will facilitate decoding of discrete molecular, cellular and circuit mechanisms underlying specific PFC functions in health and disease.


Pharmacological reactivation of p53 as a strategy to treat cancer.
It has been confirmed through studies using the technique of unbiased sequencing that the TP53 tumour suppressor is the most frequently inactivated gene in cancer. This finding, together with results from earlier studies, provides compelling evidence for the idea that p53 ablation is required for the development and maintenance of tumours. Genetic reconstitution of the function of p53 leads to the suppression of established tumours as shown in mouse models. This strongly supports the notion that p53 reactivation by small molecules could provide an efficient strategy to treat cancer. In this review, we summarize recent advances in the development of small molecules that restore the function of mutant p53 by different mechanisms, including stabilization of its folding by Apr-246, which is currently being tested in a Phase II clinical trial. We discuss several classes of compounds that reactivate wild-type p53, such as Mdm2 inhibitors, which are currently undergoing clinical testing, MdmX inhibitors and molecules targeting factors upstream of Mdm2/X or p53 itself. Finally, we consider the clinical applications of compounds targeting p53 and the p53 pathway.


Can the identity of a behavior setting be perceived through patterns of joint action? An investigation of place perception.
"Behavior settings" are generated by joint actions of individuals in conjunction with the milieu features (or affordances) that are available. The reported research explores the hypothesis that the identity or meaning of a behavior setting can be perceived by means of the patterns of action collectively generated by the setting's participants. A set of computer animations was created based on detailed observation of activities in everyday settings. Three experiments were conducted to assess whether perceivers could extract "structure from motion" (in this case, collective actions) that was specific to the particular behavior setting displayed by way of the animations. Two experiments assessed whether individuals could accurately perceive the identity of the behavior settings with such displays, and a third experiment indirectly examined this possibility by evaluating whether setting possibilities and constraints were recognized. The results offered some support for the hypothesis, and suggested several refinements in how to conceptualize a typology of behavior settings. An ecological approach to place perception is also discussed.


Analysis of Somatropin by Double-Injection Capillary-Zone Electrophoresis in Polybrene/Chondroitin Sulfate A Double-Coated Capillaries.
Purity determination of somatropin as a recombinant protein is important to ensure its safety and quality. This is carried out by capillary zone electrophoresis in double-injection mode using polybrene/chondroitin sulfate A double-coated capillaries. Modification of the capillary wall eliminates protein-wall interactions which results in improved accuracy and precision of the determinations. In the double-injection mode two somatropin samples are analyzed within a single electrophoretic run. Prior to the second injection, the first injected plug is electrophoresed for a predetermined time period in order to adjust the inter-plug distance. Here, the principle for the separation of somatropin charge variants is described.


Effects of developmental exposure to bisphenol A on spatial navigational learning and memory in rats: A CLARITY-BPA study.
Bisphenol A (BPA) is a ubiquitous industrial chemical used in the production of a wide variety of items. Previous studies suggest BPA exposure may result in neuro-disruptive effects; however, data are inconsistent across animal and human studies. As part of the Consortium Linking Academic and Regulatory Insights on BPA Toxicity (CLARITY-BPA), we sought to determine whether female and male rats developmentally exposed to BPA demonstrated later spatial navigational learning and memory deficits. Pregnant NCTR Sprague-Dawley rats were orally dosed from gestational day 6 to parturition, and offspring were directly orally dosed until weaning (postnatal day 21). Treatment groups included a vehicle control, three BPA doses (2.5μg/kg body weight (bw)/day-[2.5], 25μg/kg bw/day-[25], and 2500μg/kg bw/day-[2500]) and a 0.5μg/kg/day ethinyl estradiol (EE)-reference estrogen dose. At adulthood, 1/sex/litter was tested for seven days in the Barnes maze. The 2500 BPA group sniffed more incorrect holes on day 7 than those in the control, 2.5 BPA, and EE groups. The 2500 BPA females were less likely than control females to locate the escape box in the allotted time (p value=0.04). Although 2.5 BPA females exhibited a prolonged latency, the effect did not reach significance (p value=0.06), whereas 2.5 BPA males showed improved latency compared to control males (p value=0.04), although the significance of this result is uncertain. No differences in serum testosterone concentration were detected in any male or female treatment groups. Current findings suggest developmental exposure of rats to BPA may disrupt aspects of spatial navigational learning and memory.


Parents' Prenatal Mental Health and Emotional, Behavioral and Social Development in Their Children.
This study examines the association between expectant parents' psychological distress and children's development at 36 months old. This is a prospective population study based on the Norwegian Mother and Child Cohort Study, N = 31,663. Logistic regression models were used to assess whether high scores (cutoff ≥ 2.00) on the symptom checklist-5 in parents predicted higher levels (cutoff ≥ 90 percentile) of developmental problems in their children. The risk of emotional and behavioral problems were significantly increased in children when both parents were affected by psychological distress during pregnancy, fully adjusted OR 2.35 (95% CI 1.36, 4.07) and OR 2.65 (96% CI 1.564.48), respectively. The risk was higher when mothers reported high level of psychological distress than when only the fathers did, but the risk of emotional difficulties in children was highest when both parents presented high levels of psychological distress, indicating an additive effect of parental psychological distress.


Age-dependent changes in morphometric and biochemical traits.
This morphometric investigation was based on an anthropological cross-sectional study of five age groups in Israel: (1) newborn infants; (2) 7-year olds; (3) 18-29 years old; (4) 30-60 years old; and (5) 80 years and older. Fluctuating asymmetry (FA) of eight bilateral traits and coefficients of variation (CV) for 21 standard anthropometric traits were investigated in these groups. The results show that the values of FA and CV increase significantly among older people. The frequency of blood groups and enzymatic alleles (13 polymorphic systems), as well as heterozygosities (H), were estimated in two age groups: adults (33-45 yr) and old (80-85 yr) people. Gene frequency distributions conformed with the Hardy-Weinberg equilibrium and were similar in both these populations. Estimates of mean individual H were nonsignificantly lower in the old population.


Systematic evaluation of map quality: human chromosome 22.
Marker positions on nine genetic linkage, radiation hybrid, and integrated maps of human chromosome 22 were compared with their corresponding positions in the completed DNA sequence. The proportion of markers whose map position is <250 kb from their respective sequence positions ranges from 100% to 35%. Several discordant markers were identified, as well as four regions that show common inconsistencies across multiple maps. These shared discordant regions surround duplicated DNA segments and may indicate mapping or assembly errors due to sequence homology. Recombination-rate distributions along the chromosome were also evaluated, with male and female meioses showing significantly different patterns of recombination, including an 8-Mb male recombination desert. The distributions of radiation-induced chromosome breakage for the GB4 and the G3 radiation hybrid panels were also evaluated. Both panels show fluctuations in breakage intensity, with different regions of significantly elevated rates of breakage. These results provide support for the common assumption that radiation-induced breaks are generally randomly distributed. The present studies detail the limitations of these important map resources and should prove useful for clarifying potential problems in the human maps and sequence assemblies, as well as for mapping and sequencing projects in and across other species.


Single-Site Heterogeneous Catalysts: From Synthesis to NMR Signal Enhancement.
Catalysts with well-defined, single, active centers are of great importance and their utilization allows the gap between homo- and heterogeneous catalysis to be bridged and, importantly, the main selectivity problem of heterogeneous catalysis and the main separation challenge of homogeneous catalysis to be overcome. Moreover, the use of single-site catalysts allows the NMR signal to be significantly enhanced through the pairwise addition of two hydrogen atoms from a parahydrogen molecule to an unsaturated substrate. This review covers the fundamentals of the synthesis of single-site catalysts and shows the new aspects of their applications in both modern catalysis and the field of parahydrogen-based hyperpolarization. The different novel aspects of the formation and utilization of single-site catalysts, along with the possibility of NMR signal enhancement observations are described.


[Unmarried women of the war generation: an explorative study of their goals in life and personal satisfaction].
Older never-married women are often confronted with negative stereotypes which find expression in terms like "spinster" or "old maid". Their life-situation, however, has rarely been a subject of empirical studies. In a research project at the University of Münster, started in 1985, some psychological and social aspects of the life-situation of never-married employed women born between 1919 and 1933 (in comparison to married women of the same age not employed) were studied by means of detailed interviews. Parts of the results concerning "life goals" and "life satisfaction" are described. The results relativize the negative stereotypes mentioned above. They indicate that in the retrospective view of their lives the never-married women had many life goals which they could not achieve, but that they do not regret this at present. They rate their life satisfaction as very high and actively pursue present goals and interests. There are only few differences between never-married and married women. The results are discussed with regard to cognitive theories of aging and to the specific historical background of the interviewees.