[Change in the hexokinase activity of the rat myocardial and skeletal muscle mitochondria and cytoplasm in fasting and on a carbohydrate diet].
Dynamics of the hexokinase activity was stuided in mitochondria and cytoplasm of skeletal muscle and myocardium in rats which were subjected to fasting for three days and then were given a carbohydrate diet. It is established that the hexokinase activity in mitochondria (especially in the miocardium) lowers during fasting to a less extent as compared to cytoplasm and is not restored when feeding on carbohydrates, evidently, due to different quantitative ratio of isoenzymes. It is shown that hexokinase from the myocardium solubilizes more easily that from the skeletal muscles.


Understanding control in adolescent and young adult relationships.
To describe the receipt of controlling behaviors in young women's dating relationships and the association with physical and sexual relationship violence (RV) and to ascertain whether young women experiencing controlling from partners support RV screening and respond honestly. Anonymous audio computer-assisted self-interview. Reproductive health center. A total of 603 women aged 15 to 24 years seeking reproductive care. Self-reported victimization (controlling behaviors and physical and sexual aggression) by a partner in the past year. Sixty-eight percent of participants reported receiving 1 or more episodes of controlling behavior by a partner: 38.1% reported experiencing only controlling behaviors; 11.4% and 10.0% reported receiving controlling behaviors plus physical or sexual victimization, respectively; and 8.6% reported all forms of RV. Adjusted Poisson regression found that age 15 to 18 years (relative risk, 1.40), Hispanic ethnicity (1.29), childhood exposure to domestic violence (1.11), ever pregnant (1.21), older partner (1.28), recent physical (1.89) or sexual (1.93) victimization, and uncomfortable asking for condom use (1.39) were significantly associated with increased episodes of controlling behavior by a partner. Younger women and those who reported being victimized by controlling behaviors were more than twice as likely to object to screening by a health care provider, and those who reported receiving these behaviors were 2.5 times more likely to report that they might not honestly disclose RV. Controlling behaviors are strongly associated with physical and sexual RV. Young women experiencing controlling behaviors are more reticent about screening for RV and may not feel that they can answer honestly.


DoE and Risk-Based DMAIC Principle for Implementation of Enhanced Analytical Quality by Design Approach to Multipurpose-Chromatography Method for Simultaneous Estimation of Multiple Fixed-Dose Combination Products of Aspirin.
Numerous RP-HPLC and HPTLC methods have been reported for estimation of fixed-dose combination (FDC) products of aspirin with anti-hypertensive and anti-lipidemic drugs. Each FDC of aspirin needs separate and dedicated chromatographic conditions for analyses. No chromatographic method has been reported for simultaneous estimation of FDC products of aspirin using a single chromatography condition. A multipurpose HPTLC method was developed for simultaneous estimation of some FDC products of aspirin using an enhanced analytical quality-by-design approach based on a design of experiment (DoE) and risk-based define, measure, analyse, improve and control (DMAIC) principle to save solvent, cost, and time of analysis. The risk-based DMAIC process was carried out with identification of potential method risk parameters and their assessment using risk priority number (RPN) ranking and filtering. The DoE-based DMAIC process was carried out by the implementation of fractional factorial and full factorial design. The mobile phase composition and volume of modifier were found to be critical method risk parameters for resolution of all peaks. The developed method was found to be validated, and assay results of all FDC products of aspirin were found to be in good agreement with their respective labelled claim. The developed method is found to be solvent, cost, and time saving and also fulfilled the analytical requirements of many reported chromatography methods. Hence, the developed method is a multipurpose chromatography for analysis of FDC products of aspirin. DoE and risk-based DMAIC principle to development of the multipurpose-chromatography method. The developed method was applied for the estimation of eight different FDC products of aspirin.


Benchmarking adult mental health organizations.
This paper describes the adult mental health forums that were conducted as part of the National Mental Health Benchmarking Project (NMHBP). Eight adult mental health forums were attended by staff from eight adult mental health services from around the country. The forums provided an avenue for these participants to document their organizations' performances against previously agreed key performance indicators (KPIs), and to compare this performance with that of their peers. The forums also encouraged discussion about appropriate targets. Forum participants found that the inter-organizational range for many of the KPIs was substantial, and they used this to inform practice change within their own organizations. They also found that they could set "alert targets" and "good practice targets" for some KPIs but not others. The discussion that ensued informed participants' understanding of factors that were within the control of their organizations that could be modified to improve service quality. Benchmarking in adult mental health services is not only possible but also likely to be extremely worthwhile as an exercise in improving service quality. For benchmarking to realize its potential, it requires strong national and local leadership, and a spirit of openness on the part of participating organizations.


A subtype of the prototypic karyotype in acute myeloid leukemia t (8; 21) (q22; q22), del 9 (q13; q23).
Two patients with acute myeloid leukemia are described in whom G- and C-banding analysis of bone marrow cells revealed, besides the translocation t(8;21), an additional structural anomaly characterized by the deletion of bands q13 to q23 of one chromosome no. 9. Findings in the literature support the proposal that this constellation represents a hitherto unreported subtype of the prototypic karyotype in AML.


Prognostic Potential of the Baseline Pan-Immune-Inflammation Value and Neutrophil/Lymphocyte Ratio in Stage I to III Melanoma Patients.
Prognostic biomarkers derived from complete blood count (CBC) have received marked interest as an indirect measure of the inflammatory pressure in cancers such as metastatic melanoma. Here, we evaluated the novel pan-immune-inflammation value (PIV) and the frequently assessed neutrophil/lymphocyte ratio (NLR) in a large cohort of patients with cutaneous melanoma (CM) without distant metastases (stages I to III). PIV and NLR were calculated at CM diagnosis. Healthy controls were also included. We used the Kaplan-Meier method to estimate crude survival probabilities and used Cox proportional hazards regression for multiple adjustment of hazard ratios. We observed that higher PIV (HR: 1.72, 95% CI 1.14 to 2.58 and HR: 1.696, 95% CI 1.029 to 2.795, respectively) and NLR (HR: 1.70, 95% CI 1.10 to 2.62) values were associated with CM relapse and CM-specific death in the crude analysis. However, when adjusting for potential confounders, in particular age and tumor thickness, the total effect of PIV and NLR on CM-relapse-free (HR: 1.28, 95% CI 0.83 to 1.98 and HR: 1.26, 95% CI 0.80 to 1.98, respectively) and CM-specific survival (HR: 1.36, 95% CI 0.80 to 2.30 and HR: 1.37, 95% CI 0.80 to 2.33, respectively) was substantially reduced. However, both PIV and NLR were positively correlated with age and tumor thickness, which are important independent predictors for CM relapse and CM-specific death. In conclusion, in stage I to III CM patients PIV as well as NLR appear to be confounded by age and tumor thickness and probably have no potential to further improve the prediction of survival of stage I to III CM patients beyond standard prognostic factors.


Comparison of mometasone furoate 0.1% cream and hydrocortisone 1.0% cream in the treatment of childhood atopic dermatitis.
We conducted a 6-week randomized, blinded study that compared mometasone furoate 0.1% cream, applied once daily, and hydrocortisone 1.0% cream, applied twice daily, in 48 children with moderate to severe atopic dermatitis. Mometasone furoate, a moderate-potency steroid, produced significantly greater improvement than the low-potency hydrocortisone used twice daily. The difference in therapeutic response was particularly evident in patients with involvement of more than 25% of their body surface area. Morning plasma cortisol levels were assayed before treatment, after 1 week of therapy, and at the end of the clinical trial. Plasma cortisol levels were transiently suppressed in one child who was treated with hydrocortisone and in none of the children treated with mometasone.


Positive COVID19-PCR patients as negative controls for COVID19 antibody tests.
COVID-19 serological antibody tests are recently needed for a relatively quick, affordable, and valuable assessment of the immunity toward COVID-19 infection. Furthermore, they can help with evaluating the sufficiency of the vaccination process and its longevity. There are limitations in the current approach of choosing the positive and negative control samples for the validation of those tests. Herein, we are proposing the use of blood samples from positive COVID-19 patients, at the beginning of the disease course, as negative control blood samples for the antibody tests. For more precision, both the negative and the positive control samples can be obtained from the same patients where the accuracy of the test will depend on its ability to detect the seroconversion, from negative to positive antibodies detection, within the same patient. Furthermore, when the validation of the test is accompanied by detecting/sequencing the viral genome in those COVID-19 patients, this can also aid in determining the accuracy of the test in detecting the immune response to specific viral variants. The latter notion is needed for the proper management of the COVID-19 crisis, new vaccines' manufacturing, and evaluating the vaccines' efficiencies. Finally, this approach could be requested/formulated by the regulatory agencies as part of the tests' validation and can be "in-house" obtained by health facilities before its clinical use.


The molecular basis of LST-1 self-renewal activity and its control of stem cell pool size.
PUF RNA-binding proteins have diverse roles in animal development, with a broadly conserved role in stem cells. Two paradigmatic PUF proteins, FBF-1 and FBF-2, promote both self-renewal and differentiation in the C. elegans germline. The LST-1 protein is a pivotal regulator of self-renewal and is oncogenic when mis-expressed. Here, we demonstrate that LST-1 self-renewal activity resides within a predicted disordered region that harbors two KXXL motifs. We find that the KXXL motifs mediate the binding of LST-1 to FBF, and that point mutations of these motifs abrogate LST-1 self-renewal activity. The LST-1-FBF partnership is therefore crucial to stem cell maintenance and is a key element in the FBF regulatory network. A distinct region within LST-1 determines its spatial expression and size of the GSC pool. Most importantly, the molecular understanding of how an IDR-rich protein works in an essential partnership with a conserved stem cell regulator and RNA-binding protein suggests broad new avenues for combinatorial control.


Dyslipidemia in patients with angiographically confirmed coronary artery disease--an opportunity for improvement.
There are few data about lipid profiles in unselected patients with angiographically confirmed coronary artery disease (CAD). The study was undertaken to investigate the demographics, clinical characteristics, angiographic findings, and baseline lipid status of 1,000 consecutive unselected patients with angiographically confirmed CAD. Between April 2001 and July 2002, we obtained informed consent and prospectively collected clinical characteristics, fasting lipid profiles, and angiographic results from 1,000 sequential patients with CAD confirmed by angiography. In these patients with confirmed CAD, 78% had history of hyperlipidemia. Although 62% were receiving lipid-lowering therapy, only 46% had a low-density lipoprotein target of < 100 mg/dl, and only 20% had achieved all four National Cholesterol Education Program-recommended lipid targets. Better strategies to ensure optimal lipid levels are required. One such method using computerized workflow is being evaluated in this population.


[Fear of progression in partners of chronically ill patients].
Fear of progression (FoP) is one of the most prevalent symptoms in patients with chronic diseases. Little is known about FoP in partners of chronically ill patients. Therefore, this study assessed FoP in 332 partners of lung, colon cancer, migraine and rheumatism patients. Objectives were to ascertain the influence of individual, dyadic and disease related factors on FoP. 49% of partners were experiencing high levels of FoP varied according to the nature of the disease (highest FoP in spouses of lung cancer patients, lowest in partners of migraine patients). As significant predictors emerged more medical consultations of the patient, high avoidance symptoms, and own dyadic coping nor dyadic coping of the patient. FoP seems to impact the psychological functioning of the partner as well. Therefore, investigating FoP in partners of chronically ill patients is a promising approach to extending a program of care for patients to their partners.


Novel functions of the root barrier to radial oxygen loss - radial diffusion resistance to H2 and water vapour.
The root barrier to radial O2 loss (ROL) is a trait enabling waterlogging tolerance of plants. The ROL barrier restricts O2 diffusion to the anoxic soil so that O2 is retained inside root tissues. We hypothesised that the ROL barrier can also restrict radial diffusion of other gases (H2 and water vapour) in rice roots with a barrier to ROL. We used O2 and H2 microsensors to measure ROL and permeability of rice roots, and gravimetric measurements to assess the influence of the ROL barrier on radial water loss (RWL). The ROL barrier greatly restricted radial diffusion of O2 as well as H2 . At 60 kPa pO2 , we found no radial diffusion of O2 across the barrier, and for H2 the barrier reduced radial diffusion by 73%. Similarly, RWL was reduced by 93% in roots with a ROL barrier. Our study showed that the root barrier to ROL not only completely blocks radial O2 diffusion under steep concentration gradients but is also a diffusive barrier to H2 and to water vapour. The strong correlation between ROL and RWL presents a case in which simple measurements of RWL can be used to predict ROL in screening studies with a focus on waterlogging tolerance.


Diagnostic accuracy of random urinary protein-to-creatinine ratio for proteinuria in patients with suspected pre-eclampsia.
To evaluate the correlation between urine protein/creatinine ratio (UPCR) and proteinuria in a 24-h urine collection and to calculate the predicative accuracy of different cutoffs of UPCR for the diagnosis of proteinuria. A retrospective cohort study including women who admitted for the evaluation for suspected preeclampsia (PET) beyond 20 weeks of gestation in a single tertiary center. Both UPCR test and quantification of proteinuria using 24-h urine collection were obtained during their index hospitalization no more than 48 h apart. Women with pre-existing diabetes mellitus, known renal disease or proteinuria prior to pregnancy or chronic hypertension were excluded. Predictive accuracy of UPCR for several cutoffs of proteinuria was evaluated. Multivariate logistic regression analysis was used to assess diagnostic accuracy of UPCR in sub-populations according to obstetrical characteristics. Overall 463 patients were included. Of them 316 (68.3%) have 24-h urine protein collection of ≥ 300 mg/day. Mean gestational age at evaluation was 34.0 ± 3.4 weeks. Median (and interquartile range) time interval between UPCR and 24-h urine collection was 1.8 (1.6-1.9) days. Sensitivity and specificity of UPCR of 0.3 for predicting proteinuria ≥ 300 mg/day were 90.1% and 63.3%, respectively. The corresponding values for difference proteinuria cutoffs: ≥ 1000 mg/day and 5000 mg/day were 98.4, 100% and 29.1, 36.0%, respectively. The optimal UPCR thresholds for 24-h urine protein collection of ≥ 300 mg/day, ≥ 1000 mg/day and 5000 mg/day were 0.31, 0.70 and 2.49, respectively. The predictive accuracy of UPCR > 0.30 in predicting proteinuria was unaffected by demographic and obstetrical characteristics as maternal age, pre-pregnancy BMI, gestational age at examination, creatinine levels or by multiple gestation [adjusted OR 18.27 (95% CI 9.97-33.47)]. UPCR was strongly correlated with various cutoffs of proteinuria obtained by 24-h urine collection. UPCR cutoff varied depending on the specific measured outcome. This correlation was not affected by gestational age at examination.


Transformation of phosphorus by MgCl2 and CaCl2 during sewage sludge incineration.
Phosphorus (P) recovery from sewage sludge (SS) have been regarded as an effective method of P recycling. The effects of incineration temperature, incineration time, and chlorine additives on the distribution of P speciation during sludge incineration were studied. Moreover, the reactions between model compounds AlPO4 and additives (MgCl2 and CaCl2) were investigated by thermogravimetric differential thermal analysis and X-ray diffraction measurements. The results demonstrated that the increase in temperature and time stimulated the volatilization of non-apatite inorganic phosphorus (NAIP) instead of apatite phosphorus (AP). MgCl2 and CaCl2 can greatly promote the conversion of NAIP to AP. Additionally, AlPO4 reacted with MgCl2 are incinerated at 500-600 °C to form Mg3(PO4)2, which is mainly due to the reaction of the intermediate product MgO and AlPO4. Reactions between AlPO4 and CaCl2 occurred at 700-750 °C and produced Ca2PO4Cl, which can be directly used with high bioavailability. These findings suggested that chlorine additives in the SS incineration process can obtain phosphorus-containing minerals with higher bioavailability to realize the resource utilization of P in sludge.


Amplicon-Based Next-Generation Sequencing for Detection of Fungi in Formalin-Fixed, Paraffin-Embedded Tissues: Correlation with Histopathology and Clinical Applications.
Invasive fungal infections are increasing in prevalence because of an expanding population of immunocompromised individuals. To reduce morbidity and mortality, it is critical to accurately identify fungal pathogens to guide treatment. Current methods rely on histopathology, fungal culture, and serology, which are often insufficient for diagnosis. Herein, we describe the use of a laboratory-developed internal transcribed spacer-targeted amplicon-based next-generation sequencing (NGS) assay for the identification of fungal etiology in fungal stain-positive formalin-fixed, paraffin-embedded tissues by using Illumina MiSeq. A total of 44 specimens from 35 patients were included in this study, with varying degrees of fungal burden from multiple anatomic sites. NGS identified 20 unique species across the 54 total organisms detected, including 40 molds, 10 yeasts, and 4 dimorphic fungi. The histopathologic morphology and the organisms suspected by surgical pathologist were compared with the organisms identified by NGS, with 100% (44/44) and 93.2% (41/44) concordance, respectively. In contrast, fungal culture only provided an identification in 27.3% (12/44) of specimens. We demonstrated that NGS is a powerful method for accurate and unbiased fungal identification in formalin-fixed, paraffin-embedded tissues. A retrospective evaluation of the clinical utility of the NGS results also suggests this technology can potentially improve both the speed and the accuracy of diagnosis for invasive fungal infections.


The effect of vagal nerve stimulation on hippocampal-thalamic functional connectivity in epilepsy patients.
Vagal nerve stimulation (VNS) is widely used as an auxiliary treatment for patients with intractable epilepsy. Up to now, the therapeutic mechanisms remain elusive, and no surgical prediction criteria has been proposed. In this study, the resting-state functional magnetic resonance imaging (rs-fMRI) was chosen to explore aberrant intrinsic brain activity and functional connections in 14 epilepsy patients with VNS stimulators between March 2019 and April 2019. Seven patients who ≥ 50 % seizure reduction was defined as responders, and seven non-responders. All patients had got rs-fMRI scan before and after operation. The hippocampal - thalamic connections (hippocampal and thalamus as regions of interest) were detected to evaluate the diversity in all 14 patients and seven responders with stimulation at 0, 0.5, 1.0, and 1.5 mA. The hippocampal-thalamic connections before operation were also examined between responders and non-responders. The preoperative left hippocampal - left thalamic connections and left hippocampal - right thalamic connections in responders were lower than those in non-responders (p < 0.05). While, there was no significant difference in hippocampal - thalamic connections in all epilepsy patients or responders with different current intensities (p > 0.05). VNS may be more suitable for patients with lower left hippocampal - left thalamic connections and/or left hippocampal - right thalamic connections. The current intensity ≤ 1.5 mA and stimulation time ≤ 3 months may not cause significant changes in hippocampal-thalamic functional connectivity.


Generation of monoclonal antibodies to the zinc finger domain of the eukaryotic transcription factor Sp1.
Using a synthetic peptide that encompasses the zinc finger domain of the eukaryotic transcription factor Sp1, we produced a number of monoclonal antibodies that specifically reacted with the target antigen. Analysis by competitive inhibition assay of five of the monoclonal antibodies revealed that they all recognized a dominant epitope in the synthetic peptide and reacted strongly to recombinantly synthesized beta-galactosidase-Sp1 fusion polypeptide. To determine cellular distribution of Sp1-like molecules, cytoplasmic and nuclear proteins from human lung fibroblasts (HFL-1) and a human rhabdomyosarcoma cell line (A204) were immunoblotted and reacted with our antibodies. In addition to the well characterized 95 Kd and 105 Kd proteins, considered to be the authentic Sp1 polypeptide, a number of other cellular proteins reacted with these antibodies. Immunofluorescence staining of the cells with mAb to the zinc finger of Sp1 also revealed cell-specific differences in intracellular distribution of Sp1-like molecules. Both cytoplasmic and nuclear staining was readily observed in the rhabdomyosarcoma cells. In contrast, while some HFL-1 cells exhibited staining of only cytoplasm, both cytoplasmic and nuclear immunofluorescence was seen in others.


Pelvic rhabdomyosarcoma: a review of the RPMI experience.
Between 1959 and 1983, 16 patients with pelvic rhabdomyosarcoma were treated at Roswell Park Memorial Institute (RPMI). A multidisciplinary approach was utilized consisting of surgery, radiotherapy (XRT), and combined chemotherapy which resulted in prolonged survivals of thirteen to one hundred forty-four months in 10 patients. This improved survival was observed despite the fact that 63 per cent of the patients (10/16) presented with advanced stages of the disease. Herein we present a retrospective study of these 16 patients.


Modeling and simulation of intravenous levetiracetam pharmacokinetic profiles in children to evaluate dose adaptation rules.
To develop a pharmacokinetic model for intravenous levetiracetam in children, based on adult intravenous data and pediatric oral data. Data from two adult Phase-I studies in which levetiracetam was given intravenously were utilized to develop the adult population pharmacokinetic two-compartment intravenous model. After model qualification, combination with an existing pediatric one-compartment oral population pharmacokinetic model enabled simulation of twice-daily intravenous infusions of levetiracetam in children. Median and 90% confidence intervals for C(trough), C(max) (end of infusion) and AUC(tau) were simulated for 2000 children and compared to the values observed in adults. The population pharmacokinetic two-compartment model successfully described intravenous levetiracetam pharmacokinetics in healthy adults. After combination with the oral pediatric population model, steady-state concentrations at the end of 15-, 30- and 60 min b.i.d. levetiracetam intravenous infusions in children were predicted to be 29-41, 17-24 and 6-13% higher than those observed after oral dosing of 30 mg/kg b.i.d. Concentrations returned to the range of oral exposures within 1h after the infusion peak. The combined model predicted that steady-state peak plasma concentrations and AUC(tau) in children receiving 30 mg/kg twice daily as 15 min intravenous infusions were within the range of predicted and observed C(max,ss) and AUC(tau )values of adults receiving 15 min intravenous infusions of 1500 mg levetiracetam. The simulations suggest that levetiracetam may be administered intravenously in children as 15 min infusions.


Cell sheet technology for tissue engineering: the self-assembly approach using adipose-derived stromal cells.
In the past years, adipose tissue has spurred a wide interest, not only as a source of adult multipotent stem cells but also as a highly eligible tissue for reconstructive surgery procedures. Tissue engineering is one field of regenerative medicine progressing at great strides in part due to its important use of adipose-derived stem/stromal cells (ASCs). The development of diversified technologies combining ASCs with various biomaterials has lead to the reconstruction of numerous types of tissue-engineered substitutes such as bone, cartilage, and adipose tissues from rodent, porcine, or human ASCs. We have recently achieved the reconstruction of connective and adipose tissues composed entirely of cultured human ASCs and their secreted endogenous extracellular matrix components by a methodology known as the self-assembly approach of tissue engineering. The latter is based on the stimulation of ASCs to secrete and assemble matrix components in culture, leading to the production of cell sheets that can be manipulated and further assembled into thicker multilayer tissues. In this chapter, protocols to generate both reconstructed connective and adipocyte-containing tissues using the self-assembly approach are described in detail. The methods include amplification and cell banking of human ASCs, as well as culture protocols for the production of individual stromal and adipose sheets, which are the building blocks for the reconstruction of multilayered human connective and adipose tissues, respectively.


[Sleep in children: physiology and update of a literature review].
Sleep is an active and cyclic physiological process that has a critical impact on health. Its functions are numerous: growth, development, learning, memory, synaptic efficiency, regulation of behavior, emotion, immune strengthening and cleaning time of neurotoxic substances. During the first years of life, there are a number of important changes in development, which lead to the expected pattern of sleep and wakefulness in adults. The sleep occupies a third of the adult's life. However, sleeping during the first months of life takes up more than 50% of time. This review of the topic will describe normal sleep patterns in childhood.


Solid Pseudopapillary Neoplasms of the Pancreas: a Single-Center Experience and Review of the Literature.
Pancreatic solid pseudopapillary neoplasms (SPNs) are rare borderline tumours mainly affecting young female patients. The number of patients diagnosed with SPNs has increased significantly in the last decades owing to the increased use of cross-sectional imaging investigating different abdominal symptoms, whilst a significant proportion are incidentally discovered during the process of evaluating other pathologies. We herein present our institutional experience of patients with SPN who underwent curative resection focusing on clinical, pathological features, and the long-term outcomes. All patients undergoing pancreatectomy in our institution for SPN from January 2010 until December 2018 were included. Clinical, perioperative, histological, and long-term outcomes were collected and analysed. During the inclusion period, a total of 19 patients had a pathological diagnosis of SPNs after surgical resection. Sixteen of them were female (84%), while the median patient age was 30 (range 16-66) years. Nine patients (47%) underwent distal pancreatectomy and splenectomy, 2 (11%) underwent spleen preserving distal pancreatectomy, 6 (32%) underwent pancreatoduodenectomy, one (5%) underwent total pancreatectomy, and one (5%) central pancreatectomy. Seventeen patients underwent R0 resection. During a median follow-up of 23 months, no tumour recurrence or death was recorded. In our experience, SPNs are rare tumours with low malignant potentials. Surgical resection remains the gold standard treatment and is associated with good prognosis.


The influence of acclimatization on stress hormone concentration in serum during heat stress.
This study was aimed to examine the influence of acclimatization on the change of concentration of stress hormones in men's serum exposed to heat stress during physical training. The study included a total of 40 men, aged 19-21 years, divided randomly into four groups: CTRL group: control, exposed to the Exercise Tolerance Testing in comfortable conditions; O group: exposed to Exercise Tolerance Testing in a warm environment; P group: exposed to passive acclimation to heat for 10 days, followed by Exercise Tolerance Testing in a warm environment; A group: exposed to active acclimation to heat for 10 days, followed by Exercise Tolerance Testing in a warm environment. All participants were tested for thermoregulation and acclimatization, skin and tympanic temperature, heart rate (HR), hormonal status and sweating. The mean skin temperature was the lowest in the control group of subjects exposed to physical exertion under comfortable conditions, and at each point of measurement it was statistically significantly different from that of the other study groups (p < 0.001). Sweating intensity was statistically significantly the lowest in the CTRL group (0.32 ± 0.04 l/m2/h; p < 0.001), compared to all other groups. Cortisol was significantly altered in O group (632.2 ± 92.3; 467.2 ± 89.7), testosterone levels were significantly altered in P (19.2 ± 9.3; 16.4 ± 7.3) and in A groups (22.1 ± 12.4; 14.9 ± 9.9), while prolactin was changed in O (392.1 ± 51.3; 181.4 ± 42.3), P (595.1 ± 191.1; 191.2 ± 52.5), and A group (407.4 ± 189.3; 173.4 ± 43.9) after the experimental period. The impact of acclimatization on hormonal indicators emphasizes its importance in the response of the endocrine system of soldiers to perform military activities in warm climates.


Root distribution with the use of drip irrigation on layered soils at greenhouses crops.
Greenhouse cultivation has proven to be an efficient solution to extra-early horticultural production, allowing the cycle of vegetable production to be closed throughout the year. This efficient solution depends on many factors, perhaps the main one being the localized irrigation system. On the other hand, the availability of water for irrigation will be one of the most limiting factors for the development of this agricultural practice. The permanent search for improving irrigation efficiency must be considered as one of the great challenges of sustainable agriculture and in the interest of environmental conservation. In this study, the distribution of the roots of the two main horticultural crops, tomato (Solanum lycopersicum L.) and peppers (Capsicum annuum L.), has been analyzed with the localized irrigation system. In addition, they have been studied for layered soils, which represent an advance in terms of resources, since they are artificial soils, where the natural soil does not allow a horticultural crop. It has been found for these stratified soils, that in pepper crop 90% of the root density is in the soil layer 0 to 9 cm. However, for tomato crops 90% of the root density is in the soil layer from 0 to 11 or 15.5 cm according to the type of soil, in other words filling almost all the added soil. The results obtained in this research allow the Hydrus 3D model for stratified soils to be calibrated. This work allows opening new perspectives in the efficient management of adding soils for new greenhouse construction and for localized irrigation of horticultural crops in general, tomato, and peppers in particular.


The emerging mechanisms of isoform-specific PI3K signalling.
Phosphoinositide 3-kinases (PI3Ks) function early in intracellular signal transduction pathways and affect many biological functions. A further level of complexity derives from the existence of eight PI3K isoforms, which are divided into class I, class II and class III PI3Ks. PI3K signalling has been implicated in metabolic control, immunity, angiogenesis and cardiovascular homeostasis, and is one of the most frequently deregulated pathways in cancer. PI3K inhibitors have recently entered clinical trials in oncology. A better understanding of how the different PI3K isoforms are regulated and control signalling could uncover their roles in pathology and reveal in which disease contexts their blockade could be most beneficial.


Effect of probenecid on the transport of methyl mercury in erythrocytes by the organic anion transport system.
The uptake of methyl mercury (MeHg) by isolated erythrocytes from rats was studied at 5 degrees and 20 degrees C. The Na+ ion was used to examine exerted effects of probenecid on the uptake of MeHg through the organic anion transport system. Different extracellular pH levels were used to examine effects on the uptake of MeHg and on probenecid induced effects on the uptake of MeHg through the organic anion transport system; the effects of three anisotonic conditions were also determined. The results showed: (1) probenecid might partially change the role of Na+ ion from inhibition to stimulation for the uptake of MeHg; (2) the organic anion transport system for the uptake of MeHg was pH-dependent within the physiological range of extracellular pH; (3) the organic transport system for the uptake of MeHg was independent of deformation of the erythrocyte membrane.


Treatments, Perceived Stigma, and Employment Outcomes among Substance Abusers in China.
Employment is a vital component of a substance abuser's recovery, but little is known about how stigma affects employment for substance abusers receiving treatment. The current study investigates the effects of stigma and treatment on employment in the Chinese context. Using a sample of substance abusers (N = 3.978), multiple logistics regressions with moderation effects were employed. The findings show that treatments positively reduce confirmative experiences of anticipated stigma, and promote employment only when respondents do not perceive stigma. The findings highlight the impact of perceived stigma on limiting substance abusers' chances of being employed, implying that eliminating stigma is the foundation for recovery. Possible strategies that can be explored for reducing stigma are discussed.


Nicotine and some related compounds: effects on schedule-controlled behaviour and discriminative properties in rats.
Behavioural effects of d- and l-nicotine, d- and l-nornicotine and l-cotinine were studied in two paradigms. In experiment 1, rats responded under a multiple fixed-interval (FI) 5 min, fixed-ratio (FR) 20 schedule of food presentation. Aside from differences in potency and time course, l-nicotine and the stereoisomers of nornicotine produced qualitatively similar effects on rates of responding. With increasing doses of drugs, FI response rates first increased and then decreased, while FR response rates only decreased. In contrast, d-nicotine did not significantly increase FI response rates at lower doses, and only decreased FI and FR response rates at higher doses. At doses up to 100 mg/kg, cotinine produced only dose-dependent increases in FI response rates and had no effect on FR response rates. Rate-increasing effects of cotinine were not blocked by mecamylamine. In experiment 2, rats were trained to discriminate between l-nicotine (0.1 mg/kg SC) and saline (0.1 ml/kg SC) in a two-bar, operant conditioning procedure under a tandem variable-interval (VI) 1 min, FR 10 schedule of food presentation. Full generalization was obtained to d-nicotine and to l- and d-nornicotine. Generalization to cotinine occurred only with large doses that contained significant amounts of nicotine present as an impurity. There was no generalization to non-nicotinic drugs (morphine and clenbuterol), even at doses that reduced response rates.(ABSTRACT TRUNCATED AT 250 WORDS)


Ultrashort gonadotropin-releasing hormone agonist (GnRH-a) protocol in comparison with the long-acting GnRH-a protocol and menotropin alone.
To compare the in vitro fertilization and embryo transfer (IVF-ET) outcome of a 3-day gonadotropin-releasing hormone agonist (GnRH-a) administration: ultrashort protocol with the outcome of long-acting GnRH-a cycles or human menopausal gonadotropin (hMG) alone. Ninety-two cycles of the ultrashort protocol were matched with 92 cycles with long GnRH-a and with 92 hMG cycles. The IVF-ET program. Amount and duration of hMG treatment, hormonal profile on the day of human chorionic gonadotropin administration, cancellation rate, number of oocytes retrieved, and fertilization and pregnancy rates (PRs) were examined and compared among the three groups. The ultrashort group needed a higher number of hMG ampules than the hMG group but significantly less than in the long GnRH-a regimen. The number of oocytes in the ultrashort protocol was the same as in the long GnRH-a, but the number of embryos per retrieval was significantly lower than with the long GnRH-a protocol and similar to that found in the hMG group. The ultrashort protocol yielded 10% PR per cycle and 17% per replacement, significantly lower than with the long GnRH-a protocol, 26% and 36%, respectively, but also lower than in the hMG one, namely 13% and 28%. The ultrashort protocol, although being convenient and having some advantages found in the long GnRH-a protocol, is inferior in its outcome compared with the two other protocols.


Right atrial thrombus formation after transvenous catheter ablation of the atrioventricular node.
The formation of a right atrial mass was detected in a patient by two-dimensional echocardiography 3 weeks after successful transvenous electrical ablation of the atrioventricular node had been performed. The mass was attached to the atrial septum at the site where the electrode catheter used for the ablation had supposedly been located and it exhibited no mobility. It was interpreted as a right atrial thrombus induced by the ablation procedure. Although no pulmonary embolic events have been observed during a 7 month follow-up period, right atrial thromboembolism must be considered a potentially dangerous complication of transvenous catheter ablation to control cardiac arrhythmias.


Percutaneous approaches to mitral valve regurgitation.
Mitral regurgitation is a common problem associated with significant morbidity and mortality. Mitral valve surgery has been the treatment of choice for symptomatic patients with severe mitral regurgitation or asymptomatic patients with high-risk clinical features. However, a significant number of patients remain untreated related mainly due to a projected high surgical risk. Therefore, alternative percutaneous treatments including indirect annuloplasty, which takes advantage of the coronary sinus, and direct annuloplasty have recently been explored. Most recently, promising results of the first randomized trial comparing conventional mitral valve surgery to percutaneous therapy with a clip creating a double orifice much like the surgical Alfieri approach have been presented. Finally, percutaneous mitral valve replacement in an animal model has been pursued. This review serves to familiarize the reader with some anatomical concepts and devices for percutaneous mitral repair.


Extremely low frequency magnetic field measurements in buildings with transformer stations in Switzerland.
The aim of this study was to evaluate an exposure assessment method that classifies apartments in three exposure categories of extremely low frequency magnetic fields (ELF-MF) based on the location of the apartment relative to the transformer room. We completed measurements in 39 apartments in 18 buildings. In each room of the apartments ELF-MF was concurrently measured with 5 to 6 EMDEX II meters for 10 min. Measured arithmetic mean ELF-MF was 0.59 μT in 8 apartments that were fully adjacent to a transformer room, either directly above the transformer or touching the transformer room wall-to-wall. In apartments that only partly touched the transformer room at corners or edges, average ELF-MF level was 0.14 μT. Average exposure in the remaining apartments was 0.10 μT. Kappa coefficient for exposure classification was 0.64 (95%-CI: 0.45-0.82) if only fully adjacent apartments were considered as highly exposed (>0.4 μT). We found a distinct ELF-MF exposure gradient in buildings with transformer. Exposure classification based on the location of the apartment relative to the transformer room appears feasible. Such an approach considerably reduces effort for exposure assessment and may be used to eliminate selection bias in future epidemiologic studies.


Splenectomy reduces infarct volume and neuroinflammation in male but not female mice in experimental stroke.
The peripheral immune response contributes to neurodegeneration after stroke yet little is known about how this process differs between males and females. The current study demonstrates that splenectomy prior to experimental stroke eliminates sex differences in infarct volume and activated brain monocytes/microglia. In the periphery of both sexes, activated T cells correlate directly with stroke outcome while monocytes are reduced by splenectomy only in males. This study provides new information about the sex specific mechanisms of the peripheral immune response in neurodegeneration after stroke and demonstrates the need for representation of both sexes in basic and clinical stroke research.


Assessment of probiotic adhesion and inhibitory effect on Escherichia coli and Salmonella adhesion.
In this study, we screened bacterial strains to identify specific probiotics to treat pig diarrhea caused by Escherichia coli or Salmonella. The potential probiotics were assayed for their survival in gastrointestinal solution, their antimicrobial activity, cell-surface properties, adhesion to Caco-2 cells, and inhibition of pathogen adhesion. Nine out of the 20 strains tested showed high tolerance of a simulated gastrointestinal environment and six strains exerted antagonistic effects against enterohemorrhagic E. coli (EHEC) O157:H7 and Salmonella Typhimurium MQ. Lactobacillus johnsonii pDX1e exhibited a higher potent antibacterial activity. Four strains (pDX1a, pDX1e, pDX3a, and pDX5a) displayed auto-aggregation, hydrophobicity, and adhesion to Caco-2 cells similar to those of the reference strain Lacticaseibacillus rhamnosus GG (LGG). Enterococcus durans pDX5a showed the highest adhesion capacity (13.86%), followed by the reference strain LGG (11.20%). All the tested strains competitively suppressed the attachment of pathogens to Caco-2 cells (by 30.73-55.18%); L. johnsonii pDX1e and Ent. durans pDX5a significantly inhibited the adhesion of pathogens by substitution and exclusion, respectively. Therefore, pDX1e and pDX5a were selected as probiotic strains for further investigation and application.


Radiographic laxity of the trapeziometacarpal joint is correlated with generalized joint hypermobility.
Increased joint laxity has been associated with the risk of ligament injury and development of osteoarthritis in large joints such as the knee, but this has not been investigated in depth in the hand. We hypothesized that generalized joint laxity would correlate with radiographic measures of trapeziometacarpal (TM) joint subluxation, as measured in carpometacarpal stress view radiographs. We recruited volunteer subjects of all ages and examined them for generalized laxity using the Beighton-Horan index. A total of 163 subjects, 81 men and 82 women, with an average age of 48 years (range, 20-83 y), were examined. Each subject underwent a stress view radiograph of both TM joints using a previously described technique. Different examiners independently measured radial subluxation of the thumb metacarpal over the trapezium and the articular width of the thumb metacarpal and averaged them. The ratio of the radial subluxation to the articular width was calculated as a measure of radiographic TM laxity. The average Beighton score was 2 (range, 0-9). A total of 40 subjects had Beighton scores greater than 4. The mean stress view ratio was 0.31 (range, 0.06-0.58). When we calculated the Pearson correlation coefficient to assess the relationship between the stress view ratio and the Beighton score, a statistically significant correlation was demonstrated. In normal volunteers generalized joint laxity is positively correlated with increased mobility of the TM joint, as demonstrated on carpometacarpal stress view radiographs. Diagnostic I.


Ovulation induction with subcutaneous pulsatile gonadotropin-releasing hormone: singleton pregnancies in patients with previous multiple pregnancies after gonadotropin therapy.
Three patients with hypothalamic amenorrhea who had previously had multiple pregnancies following gonadotropin therapy were treated with subcutaneous pulsatile gonadotropin-releasing hormone (GnRH), administered by a portable pump. After treatment with lower doses in some cases, pulses of 5 to 10 micrograms were given at 90-minute intervals, resulting in ovulation on six occasions. Ovarian steroid profiles closely resembled those of normal ovulatory cycles, and spontaneous ovulation of a single ovarian follicle was consistently demonstrated by ultrasound. Singleton pregnancy was confirmed in each patient. The results imply normal operation of the ovarian-pituitary feedback loop and suggest that subcutaneous pulsatile GnRH therapy is a safe and effective means of ovulation induction in clomiphene-resistant cases of hypothalamic amenorrhea and may possibly become the preferred method of treatment.


Apremilast with Add-On Calcipotriene/Betamethasone Dipropionate for Treating Moderate to Severe Plaque Psoriasis.
About 20% of patients taking apremilast alone obtain PASI 75 by week 8. This single-center, pilot study aimed to determine whether add-on topical therapy with calcipotriene/betamethasone dipropionate (C/BD) could improve responses of partial apremilast responders by week 12. Adults (≥18 years of age) with moderate to severe plaque psoriasis (baseline PGA ≥3, BSA affected ≥10%, PASI ≥12) took oral apremilast (30 mg twice daily) for 8 weeks. Patients who achieved between PASI 25–74 at week 8 used add-on, daily topical C/BD (.005%/.064%) foam up to week 12; those with <PASI 25 at week 8 were discontinued. Of 50 patients enrolled, 26 achieved PASI 25−74 and 8 PASI 75 at week 8. At week 12, 29 achieved PASI 75, and 24 at week 16. Of the week-8 partial responders, 21/26 achieved PASI 75 at week 12 on combination therapy and 15 maintained PASI 75 through week 16 on apremilast alone (4 did not maintain; 2 lost to follow up). In partial responders, mean PGA and BSA affected improved by 30% and 33% on apremilast, respectively, and by 67% and 86% at week 12 on the combination therapy, respectively. The most commonly reported adverse events (AEs; >5% occurrence) were headache (14%), diarrhea (10%), and nausea (8%); majority were mild. No related serious AEs occurred. We show that most week-8 partial apremilast responders can achieve PASI 75 at week 12 with combination C/BD topical therapy, and maintain PASI 75 through week 16 with apremilast monotherapy. J Drugs Dermatol. 2020;19(12): doi:10.36849/JDD.2020.5435.


The epidemiology of invasive group A streptococcal disease in Victoria, 2007-2017: an analysis of linked datasets.
To describe the incidence and severity of invasive group A streptococcal disease (iGAS) in Victoria, Australia. Retrospective analysis of iGAS cases identified in linked datasets, 2007-2017: laboratory data from the Victorian Hospital Pathogen Surveillance Scheme; hospitalisation data from the Victorian Admitted Episodes Dataset; and deaths reported by the Australian Coordinating Registry. There were 1,369 confirmed and 610 probable cases of iGAS identified from 2007 to 2017 in Victoria, Australia. The median annual incidence was 3.1 (range 2.4-5.2) per 100,000 population. The incidence was highest in 2017, with 5.2 (95%CI: 4.6-5.8) cases per 100,000 population. The median length of stay in hospital was 10 days, with 33.1% (578/1,744) of cases admitted to the intensive care unit, of whom 49.5% (286/578) were mechanically ventilated. The case fatality rate was 5.6% (110/1,979), reaching 13.5% (51/378) among those aged 75 years or older. There was an increased incidence of iGAS in 2017 in Victoria, with substantial healthcare utilisation and a high case fatality rate among older Victorians. These data support mandatory notification of iGAS, which will enable better characterisation of the disease, rapid identification of changes in epidemiology and targeted public health responses.


Regulation of outside-in signaling in platelets by integrin-associated protein kinase C beta.
Studies with inhibitors have implicated protein kinase C (PKC) in the adhesive functions of integrin alpha(IIb)beta(3) in platelets, but the responsible PKC isoforms and mechanisms are unknown. Alpha(IIb)beta(3) interacts directly with tyrosine kinases c-Src and Syk. Therefore, we asked whether alpha(IIb)beta(3) might also interact with PKC. Of the several PKC isoforms expressed in platelets, only PKC beta co-immunoprecipitated with alpha(IIb)beta(3) in response to the interaction of platelets with soluble or immobilized fibrinogen. PKC beta recruitment to alpha(IIb)beta(3) was accompanied by a 9-fold increase in PKC activity in alpha(IIb)beta(3) immunoprecipitates. RACK1, an intracellular adapter for activated PKC beta, also co-immunoprecipitated with alpha(IIb)beta(3), but in this case, the interaction was constitutive. Broad spectrum PKC inhibitors blocked both PKC beta recruitment to alpha(IIb)beta(3) and the spread of platelets on fibrinogen. Similarly, mouse platelets that are genetically deficient in PKC beta spread poorly on fibrinogen, despite normal agonist-induced fibrinogen binding. In a Chinese hamster ovary cell model system, adhesion to fibrinogen caused green fluorescent protein-PKC beta I to associate with alpha(IIb)beta(3) and to co-localize with it at lamellipodial edges. These responses, as well as Chinese hamster ovary cell migration on fibrinogen, were blocked by the deletion of the beta(3) cytoplasmic tail or by co-expression of a RACK1 mutant incapable of binding to beta(3). These studies demonstrate that the interaction of alpha(IIb)beta(3) with activated PKC beta is regulated by integrin occupancy and can be mediated by RACK1 and that the interaction is required for platelet spreading triggered through alpha(IIb)beta(3). Furthermore, the studies extend the concept of alpha(IIb)beta(3) as a scaffold for multiple protein kinases that regulate the platelet actin cytoskeleton.


Transport changes associated with growth control and malignant transformation.
We can distinguish two classes of membrane transport changes in cultured cells: (a) growth-rate contingent changes are those which occur in coordination with the onset of density-dependent inhibition of growth; (b) transformation-specific changes are those which occur when cells become transformed, and which can be detected even when normal and transformed cells are growing at the same rate. Growth-rate contingent changes include the density-dependent changes in phosphate, nucleoside, glucose, amino acid, and potassium transport. Only one transformation-specific transport change has been found in Rous-transformed chicken embryo fibroblasts: an increased rate of hexose transport. The variation in potassium transport are associated with variations in the number of ouabain binding sites in the membrane. The molecular basis for changes in the rate of hexose transport is unknown, although gross changes in membrane bilayer composition and "fluidity" seem not to be involved. In analyzing the regulation of hexose transport activity, we find that decreased cAMP may play a role in the transformation-specific increase in hexose transport, but that fibrinolytic activity is not necessary.


Competition for antigen presentation in living cells involves exchange of peptides bound by class II MHC molecules.
T cells recognize foreign proteins as peptides bound to self molecules encoded by the major histocompatibility complex (MHC). The kinetics of interaction between purified class II MHC molecules and peptides is unusual, in that the rate of association is very slow, but once formed, the complexes are extremely stable. This raises the question of how the antigen-presenting cell provides a sufficient number of free MHC binding sites to ensure T cell immunity. We present results suggesting that an exchange of peptide in MHC binding sites may take place under physiological conditions.


Examining organisational responses to performance-based financial incentive systems: a case study using NHS staff influenza vaccination rates from 2012/2013 to 2019/2020.
Financial incentives are often applied to motivate desirable performance across organisations in healthcare systems. In the 2016/2017 financial year, the National Health Service (NHS) in England set a national performance-based incentive to increase uptake of the influenza vaccination among frontline staff. Since then, the threshold levels needed for hospital trusts to achieve the incentive (ie, the targets) have ranged from 70% to 80%. The present study examines the impact of this financial incentive across eight vaccination seasons. A retrospective observational study examining routinely recorded rates of influenza vaccination among staff in all acute NHS hospital trusts across eight vaccination seasons (2012/2013-2019/2020). The number of trusts included varied per year, from 127 to 137, due to organisational changes. McCrary's density test is conducted to determine if the number of hospital trusts narrowly achieving the target by the end of each season is higher than would be expected in the absence of any responsiveness to the target. We refer to this bunching above the target threshold as a 'threshold effect'. In the years before a national incentive was set, 9%-31% of NHS Trusts reported achieving the target, compared with 43%-74% in the 4 years after. Threshold effects did not emerge before the national incentive for payment was set; however, since then, threshold effects have appeared every year. Some trusts report narrowly achieving the target each year, both as the target rises and falls. Threshold effects were not apparent at targets for partial payments. We provide compelling evidence that performance-based financial incentives produced threshold effects. Policymakers who set such incentives are encouraged to track threshold effects since they contain information on how organisations are responding to an incentive, what enquiries they may wish to make, how the incentive may be improved and what unintended effects it may be having.


Cross-cultural adaptation and validation of the RhinAsthma Patient Perspective (RAPP) in Spanish.
the RhinAsthma Patient Perspective (RAPP) is the only available tool to assess HRQoL in daily practice. The aim of this study is to cross-culturally validate the RAPP in Spanish. The RAPP was translated into Spanish. Adult patients receiving usual care for asthma and allergic rhinitis (AR) were recruited consecutively and assessed twice with a four-week interval between visits to test the psychometric properties of the questionnaire. 149 patients (62.8% female) with a mean age of 37.7 years completed the study. Exploratory and confirmatory factor analysis confirmed the uni-dimensional structure of the questionnaire. Internal consistency (0.73 at visit 1; 0.87 at visit 2), convergent and discriminant validity (p<.05 at both visits) were satisfactory. Reliability was confirmed by an ICC of 0.69 and a CCC of 0.74. Responsiveness was supported by a significant association with VAS (r=0.28, p<0.003) and ACT (r=-0.35, p<0.01). The minimal clinical difference (MID) value in the analyzed population was 2. The Spanish version of RAPP was demonstrated to have satisfactory psychometric properties and is a valid, reliable and responsive tool for the assessment of asthma and AR HRQoL in clinical practice.


A wheat resistosome defines common principles of immune receptor channels.
Plant intracellular nucleotide-binding leucine-rich repeat receptors (NLRs) detect pathogen effectors to trigger immune responses1. Indirect recognition of a pathogen effector by the dicotyledonous Arabidopsis thaliana coiled-coil domain containing NLR (CNL) ZAR1 induces the formation of a large hetero-oligomeric protein complex, termed the ZAR1 resistosome, which functions as a calcium channel required for ZAR1-mediated immunity2-4. Whether the resistosome and channel activities are conserved among plant CNLs remains unknown. Here we report the cryo-electron microscopy structure of the wheat CNL Sr355 in complex with the effector AvrSr356 of the wheat stem rust pathogen. Direct effector binding to the leucine-rich repeats of Sr35 results in the formation of a pentameric Sr35-AvrSr35 complex, which we term the Sr35 resistosome. Wheat Sr35 and Arabidopsis ZAR1 resistosomes bear striking structural similarities, including an arginine cluster in the leucine-rich repeats domain not previously recognized as conserved, which co-occurs and forms intramolecular interactions with the 'EDVID' motif in the coiled-coil domain. Electrophysiological measurements show that the Sr35 resistosome exhibits non-selective cation channel activity. These structural insights allowed us to generate new variants of closely related wheat and barley orphan NLRs that recognize AvrSr35. Our data support the evolutionary conservation of CNL resistosomes in plants and demonstrate proof of principle for structure-based engineering of NLRs for crop improvement.


Association between dietary diversity and cognitive impairment among the oldest-old: Findings from a nationwide cohort study.
Dietary diversity is widely recommended in national and international guidelines; however, whether the beneficial effects on cognitive function still apply in the oldest-old (80+) has rarely been studied. This study aimed to evaluate the associations of dietary diversity with cognitive function among the oldest-old in a large prospective cohort in China. We conducted a long-term prospective analysis on 11,970 participants aged 80+ (6581 octogenarians, 3730 nonagenarians, and 1659 centenarians). We constructed the baseline dietary diversity score (DDS) based on eight food items of a food frequency questionnaire. Mini-mental state examination (MMSE) was used to classify the participants as having cognitive impairment or not and was also used as a continuous metric. Non-linear associations of DDS with cognitive impairment was evaluated by cox models with penalized splines. We used mixed-effect models for longitudinal data with repeated measurements of MMSE (for up to seven time during the follow-up between 1998 and 2014). We documented 4778 cognitive impairment during 46,738 person-years of follow-up. Each one unit increase in DDS was associated with a 4% lower risk of cognitive impairment (adjusted hazard ratio (HR): 0.96; 95% confidential interval (CI): 0.94-0.98). Compared to participants with DDS of 0 score, those with a DDS of 1-2, 3-4, and higher than 5 scores had a lower cognitive impairment risk, the HRs were 0.86 (0.79-0.95), 0.82 (0.74-0.91), and 0.72 (0.64-0.82) respectively, and a significant trend emerged (p < 0.001). Compared with DDS of zero score, a DDS of 1-2,3-4, ≥5 was related to slower MMSE decline (β = 0.128, 0.162, 0.301, respectively, p < 0.01). Even after the age of 80, dietary diversity may offer a simple and straightforward mean of identifying and screening individuals at high risk for cognitive impairment. Recommendation of dietary diversity may be advocated to attenuate cognitive decline and decrease the risk of cognitive impairment in the oldest-old, especially in a low income or middle-income countries.


tert-butyl hydroperoxide, an organic peroxide, causes temporary delay in hair growth in a neonatal rat model.
tert-butyl hydroperoxide (tBHP), an organic peroxide, has been shown to cause irreversible damage to keratinocytes in vitro with prolonged administration at high concentrations, and reversible damage with short-term administration at low concentrations. To investigate the effects of tBHP on keratinocytes in vivo, we analysed hair growth in tBHP-treated neonatal rats. Sprague-Dawley and Long-Evans rat pups were injected subcutaneously with tBHP or vehicle once daily for 6 days, and hair growth was monitored. The tBHP-treated rats had a significant delay in hair growth. However, this delay reversed within days, and the hair coats, including hair pigmentation, of tBHP-treated and sham-treated rats were indistinguishable 2 weeks later. Histological analysis and BrdU labelling of S phase cells confirmed the delay in hair-follicle growth and its reversal in tBHP-treated rats. Our results indicated that the changes incurred in hair follicles by short-term use of high-dose oxidants in vivo are temporary and reversible.


Cesarean delivery and risk of hospitalization for autoimmune disorders before 14 years of age.
It is supposed that cesarean birth is implicated in the development of autoimmunity. We evaluated the association between cesarean delivery and the risk of hospitalization for autoimmune disease in children up to 14 years of age. We performed a longitudinal cohort study of 934,873 children born between 2006 and 2019 in Quebec, Canada. The main exposure measure was cesarean delivery versus vaginal delivery (spontaneous or induced). Outcomes included hospitalization for type 1 diabetes, celiac disease, or other autoimmune disorders before 14 years of age. We used Cox regression models to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association between cesarean delivery and hospitalization for autoimmune disorders, adjusted for patient characteristics. A total of 248,963 children (27%) were delivered by cesarean. Median length of follow-up was 7.4 years. The hospitalization rate for autoimmune disorders was 69.1 per 100,000 person-years for cesarean and 65.9 per 100,000 person-years for vaginal delivery. Cesarean delivery was not associated with autoimmune disorders overall (HR 1.02, 95% CI 0.96-1.10). There was no association with type 1 diabetes (HR 1.00, 95% CI 0.85-1.17), celiac disease (HR 0.86, 95% CI 0.71-1.04), inflammatory bowel disease (HR 1.15, 95% CI 0.88-1.49), or idiopathic thrombocytopenic purpura (HR 1.01, 95% CI 0.82-1.25). Cesarean delivery was not associated with autoimmune disorders at different ages.Conclusion: This study suggests that cesarean delivery is not associated with the risk of hospitalization for autoimmune disorders before 14 years of age. Delivery mode does not seem to mediate the risk of autoimmunity in childhood. What is Known: • Children born by cesarean may be at risk of abnormal immune development. • The association between cesarean delivery and risk of pediatric autoimmune disorders is unclear. What is New: • In this cohort study of over 900,000 children, cesarean delivery was not associated with the risk of hospitalization for a range of autoimmune disorders before 14 years of age. • Cesarean delivery may not be related to the development of autoimmunity.


Recombinant human bone morphogenetic protein 2 combined with an osteoconductive bulking agent for mandibular continuity defects in nonhuman primates.
Recombinant human bone morphogenetic protein 2 (rhBMP-2) is an option for reconstructing mandibular continuity defects. A challenge of this technique is the need to maintain sufficient space to avoid compression of the defect. A compression-resistant matrix (CRM) provides a bulking agent that provides support during the bone formation phase. Thirteen Rhesus Macaque monkeys were used to evaluate different forms of an osteoconductive bulking agent compared with an absorbable collagen alone placed into a critical-sized mandibular defect. A total of 5 groups (26 defects) were evaluated: group A, rhBMP-2/absorbable collagen sponge (ACS) (1.5 mg/mL); group B, rhBMP-2/ACS with ceramic granules (15% hydroxyapatite/85% β-tricalcium phosphate) at 1.5 mg/mL; group C, rhBMP-2 (2.0 mg/mL) with a CRM; group D, rhBMP-2 (0.75 mg/mL) with a CRM; and group E, a CRM alone. Histology and micro computed tomography were used to evaluate and compare new bone formation in the defects. The reconstructed bone was evaluated with regard to the new bone formation, residual voids, and density. Animals treated with the CRM and rhBMP-2 at 2.0 mg/mL (group C) showed significantly higher amounts of new bone formation, bone density, and reduced voids when compared with rhBMP-2 and ACS (1.5 mg/mL) (P < .05). The carrier system CRM combined with rhBMP-2 and a reconstruction plate results in significantly higher bone density and better space maintenance than rhBMP-2 combined with ACS in a nonhuman primate mandibular bone repair model.


Pol III proofreading activity prevents lesion bypass as evidenced by its molecular signature within E.coli cells.
Replication of genomes that contain blocking DNA lesions entails the transient replacement of the replicative DNA polymerase (Pol) by a polymerase specialized in lesion bypass. Here, we isolate and visualize at nucleotide resolution level, replication intermediates formed during lesion bypass of a single N-2-acetylaminofluorene-guanine adduct (G-AAF) in vivo. In a wild-type strain, a ladder of replication intermediates mapping from one to four nucleotides upstream of the lesion site, can be observed. In proofreading-deficient strains (mutD5 or dnaQ49), these replication intermediates disappear, thus assigning the degradation ladder to the polymerase-associated exonuclease activity. Moreover, in mutD5, a new band corresponding to the insertion of a nucleotide opposite to the lesion site is observed, suggesting that the polymerase and exonuclease activities of native Pol III enter a futile insertion-excision cycle that prevents translesion synthesis. The bypass of the G-AAF adduct located within the NarI sequence context requires the induction of the SOS response and involves either Pol V or Pol II in an error-free or a frameshift pathway, respectively. In the frameshift mutation pathway, inactivation of the proofreading activity obviates the need for SOS induction but nonetheless necessitates a functional polB gene, suggesting that, although proofreading-deficient Pol III incorporates a nucleotide opposite G-AAF, further extension still requires Pol II. These data are corroborated using a colony-based bypass assay.


Chaos and illusion.
Pharmacology is the study of the interaction of drugs with living organisms, especially humans. The body is a very complicated system, which suggests that the 'effect' induced by a drug is not a single entity but a change in several variables at the same time, all of which are interrelated in a nonlinear fashion. Research on nonlinear systems in other fields of science--commonly known as chaos theory--may therefore be of use in understanding pharmacology, as explained here by J. M. van Rossum and J. E. G. M. de Bie. They argue that in the study of drug effects, several variables should be measured simultaneously. Many pharmacologists prefer to construct an illusion of reality, studying just one of the essential variables and averaging data in a population of subjects, thus losing the opportunity to understand what a drug really does to a patient.


Lack of efficacy of 2-deoxy-D-glucose in the treatment of experimental herpes genitalis in guinea pigs.
Topical treatment of herpes genitalis in female guinea pigs with 2-deoxy-D-glucose in either agarose gels or miconazole nitrate ointments failed to prevent the development of genital lesions or to reduce the mean titers of recoverable virus in vaginal swabs from infected animals. In contrast, phosphonoacetic acid was therapeutically effective.


Effect of hypoxic exposure on iron absorption in heterozygous hypotransferrinaemic mice.
Heterozygous hypotransferrinaemic mice show serum iron, haemoglobin and reticulocyte levels similar to those of normal (+/+) controls but the plasma apotransferrin level is significantly reduced. Male heterozygous hypotransferrinaemic Balb/cJ mice and control (+/+) littermates were exposed to 1-3 days' hypoxia at 0.5 atmospheres. Controls increased their haemoglobin and iron absorption significantly during the first day of exposure; serum transferrin levels were increased and iron absorption had returned to normal levels by the third day or serum transferrin above normal levels and the elevated iron absorption persisted for longer than in controls. Serum iron levels were lower following hypoxic exposure than in controls. Liver iron loading was significantly enhanced by hypoxia in heterozygotes, but not in controls. These observations demonstrate the importance of the reservoir of plasma apotransferrin in the initial phase of enhanced erythropoiesis, and that the ability to enhance plasma levels of iron-bound transferrin is required in order to increase haemoglobin levels under the hypoxic stress.


Characterization of the complete mitochondrial genome and phylogenetic status of a recently described species of Mountain Dragon, Diploderma vela (Reptilia: Squamata: Agamidae), from the upper Lantsang valley in west China.
The mountain dragon, Diploderma vela, is an endemic and protected valley lizard that inhabits the upper Lantsang Valley in West China. In this study, we sequenced the complete mitochondrial genome of a male individuals of D. vela using next-generation sequencing methodologies. The complete mitogenome is 16,432 bp in length and contains one noncoding control regions, 13 protein-coding, 22 transfer RNA and two ribosomal RNA genes. The mitogenome content and structure of D. vela was consistent with the previously published representatives of the family. A Bayesian phylogenetic analysis using the complete mitochondrial genomes of Agamidae fully resolved D. vela in the Draconinae, a result consistent with previous investigations. This study provides bioinformatic data for better understanding the evolution and the phylogenetic history of the mountain dragon.


Role of lamivudine with transarterial chemoembolization in the survival of patients with hepatocellular carcinoma.
The purpose of the present study was to determine whether lamivudine in combination with transarterial chemoembolization (TACE) could reduce hepatitis B virus (HBV) activation and improve the survival of patients with hepatocellular carcinoma (HCC). From July 2008 to October 2011, a total of 181 consecutive HBV-related HCC patients undergoing TACE were randomized to two groups (92: lamivudine, 89: control). Follow up was every 3 months. Primary and secondary end-points were time to progression (TTP) and overall survival (OS), respectively, both of which were evaluated by the Kaplan Meier technique and summarized by the hazard ratio. The level of HBV-DNA became undetectable in 42 (45.6%) patients in the lamivudine group, compared with 10 (11.2%) in the control group (P < 0.001). The median TTP was 8.2 months in lamivudine group and 4.3 months in control group (P = 0.005), and lamivudine therapy was an independent protective factor related to TTP (P = 0.006). Moreover, 1-, 2-, and 3-year survival rates were 83%, 69%, and 58% in lamivudine group and 60%, 48%, and 48% in control group, respectively (P = 0.002). With multivariate Cox regression model, lamivudine therapy (P = 0.002) and α-fetoprotein (AFP) level (P = 0.003) were two independent predictors for OS. Lamivudine therapy could reduce HBV activation and improve survival of HCC patients treated with TACE. Lamivudine therapy and AFP level are two independent factors affecting OS.


Aneurysmal bone cyst: results of an off label treatment with Denosumab.
The treatment of aneurysmal bone cysts (ABCs) has evolved and less invasive methods have been tried. Denosumab is a monoclonal antibody which inhibits osteoclasts. It has been shown to be effective in giant cell tumour of bone (GCT) of bone and hence promises some effect also in ABC. We report on 6 patients treated with Denosumab and compare our results to the cases already published. Data of 6 patients with ABCs and patients whose treatment included Denosumab were retrospectively analyzed. Denosumab was used at a dose of 120 mg on days 1, 8, 15 and 29, and every 4 weeks thereafter. In some of these patients the dose was reduced at the end of the treatment. Clinical and radiological responses were evaluated. In 4 female and 2 male patients with a mean age of 17 years (range: 6-30 years) the lesions were located in the sacrum (2), in distal radius, distal femur, talus and pelvis. One of the sacral lesions healed after 12 months and has stayed stable for 3 years since. The second patient received 2 years of therapy with recalcification, but recurred 1 year later and is under renewed therapy. The pelvic lesion improved but recurred. This patient has a 13-years history of intermittent therapy including surgery, two pregnancies and remains in a stable situation. The lesion of the talus did not improve with Denosumab after surgery and was complicated by destruction of the ankle joint with osteoarthritis. Recurrent lesions of the distal femur and the distal radius, previously treated by curettage and bone grafting healed under Denosumab and have remained stable for 2 and 3 years, respectively. One case of severe hypercalcemia was observed in a 7-year old child 6 months after discontinuation of Denosumab. Denosumab provides a treatment option for ABCs in anatomically critical locations. Adjuvant application might reduce the rate of local recurrence. In young patients, severe rebound hypercalcemia months after discontinuation of Denosumab may occur.


A kinetic analysis of solid waste composting at optimal conditions.
Six municipal solid waste (MSW) and yard waste components (food waste, mixed paper, yard waste, leaves, branches, grass clippings) were aerobically decomposed to measure the extent of decomposition under near optimal conditions. Decomposition was characterized by at least two principal stages, for most components, as was indicated by the carbon dioxide production rates. An aerobic biodegradation conceptual model is presented here based on the principle that solids hydrolysis is the rate-limiting step during solid waste composting. The mineralizable solid carbon of each solid waste component was assumed to comprise the readily, the moderately and the slowly (or refractory) hydrolysable carbons, each hydrolyzing at different rates to aqueous (water soluble) carbon. Aqueous carbon mineralizes to CO2 at rapid rates that are not rate-limiting to the process. Solids hydrolysis rate constants were calculated after fitting the experimentally determined carbon dioxide production rate data to model results. Hydrolysis rates for the readily hydrolysable carbon in all components ranged from approximately 0.06 to 0.1 d(-1); hydrolysis rates for the moderately hydrolysable carbon ranged from 0.005 to 0.06 d(-1). Leaves, branches and grass clippings did not have a readily hydrolysable carbon fraction, whilst the leaves and branches had the largest slowly hydrolysable carbon fractions (70%, 82%, respectively, of the total solid organic carbon). Grass and yard waste did not contain slowly hydrolysable carbon fractions. Food waste had the largest readily hydrolysable carbon fraction and produced the highest amount of CO2 among all substrates. Moderately hydrolysable solid carbon fractions ranged from 16% to 90% of the total solid organic carbon for all substrates used.


Endoscopic Orientation of Juxta-Pituitary Carotid in Transsphenoidal Approaches: Critical Considerations for Clinical Applications.
Accidental injury of the internal carotid artery (ICA) remains one of the most challenging complications reported in the endoscopic endonasal transsphenoidal approaches (EETA) particularly, in sphenoid sinuses with ill-defined carotid bony landmarks. The purpose of this study was to describe an anatomical model for the endoscopic orientation of juxta-pituitary segment of ICA in relation to the lateral optico-carotid recess (OCR) as a nearby bony landmark. Cadaveric dissection was conducted progressively in twenty fresh adult cadavers simulating the EETA. After reducing posterior and lateral walls of sphenoid sinuses, various measurements were taken from both lateral OCRs to "contact points" of the juxta-pituitary segment of ICA and lateral margins of the pituitary gland. Current results have enabled us to divide the region between lateral OCRs into three compartments. Two lateral parasellar compartments contain juxta-pituitary segments of ICA showing a mean width of 8 mm; with a narrow range of 7-10 mm; and a central inter-carotid sellar compartment represents the safe region for bone drilling showing widely variable widths ranging between 9 to 20 mm. In all specimens; variation in the width of the inter-carotid compartment correlated with the distance between both lateral OCRs. This study improves surgeons' awareness of the ICA course variations in the EETA through sphenoid sinuses with ill-defined bony landmarks. An appreciation of the measurements gathered from this study can help in operative training, and can also provide a base for future studies to confirm ICA courses associated with higher risk of injury.


Short and long-term outcomes after pediatric redo fundoplication.
Redo fundoplication (RF) is the most common surgical treatment for recurrent gastroesophageal reflux disease (GERD) in children, but outcomes after RF are rarely reported. The aim of this study was to assess short- and long-term outcomes after RF in childhood. The study is a follow-up study of patients undergoing RF from 2002 to 2020 at a teriary care center. Patients/parents were sent questionnaires recording symptoms of recurrent GERD, troublesome side-effects and satisfaction. Retrospective chart review was also performed. 24/28 (86%) patients were included median 9 (1.6 months-17.7 years) years after RF. 16 (67%) had neurologic impairment. Indications for RF was recurrence of GERD (n = 18), discomfort or dysphagia from a herniated wrap (n = 5) and dysphagia from a slipped fundoplication (n = 1). Median operating time was 128 (95-250) min. Six (25%) patients experienced early major complications, of which two were gastrostomy related. Five (21%) patients experienced recurrence after RF. Three of these were symptom free at follow-up with medical treatment or re-RF. The most common symptom at follow-up was stomach pain (37%) and excessive flatulence (38%). 18/22 (95%) patients/parents would choose RF again, and 21/22 would recommend RF to someone in a similar situation. RF is successful in treating recurrent GERD after primary fundoplication, and patient/parental satisfaction is high.


Improvement of clinical fracture healing - What can be learned from mechano-biological research?
The most significant predictors of reoperation following operative management of fractures are the presence of a third degree open fracture, remaining fracture gaps and a transverse fracture. However clinical studies provide no information regarding the involvement of various soft tissues or how the mechanical environment affects revascularisation and bone healing. Here the results of experimental and numerical mechano-biological studies on fracture healing are summarized to provide guidance toward clinical treatment of fractures. In experimental studies, isolated muscle crush appeared to only temporarily impair fracture healing, with no significant effect to the final bone healing, whereas a more severe muscle trauma significantly reduced callus formation and biomechanical properties of the healed bones. An intraoperative trauma can furthermore impede vascularization. Surgical removal of the haematoma or periosteum disturbs fracture healing. While reaming for intramedullary nailing reduced blood flow in the bone during the early phase of bone healing, it did not affect the stiffness or strength of the final bone healing. The optimal conditions for rapid vascularization and bone healing result from fracture fixation that minimizes shearing movements in the healing zone while allowing moderate compressive movements. Bone healing is increasingly delayed with increasing fracture gap size and critical-size defects do not heal sufficiently independent of the mechanical environment. The stiffness of fracture fixation systems like nails and external fixators applied in clinical treatments frequently display a too low stiffness, whereas plate systems often cause a too stiff fixation that suppresses bone healing.


Giardiasis in Canterbury: the first nine months reported cases.
To obtain epidemiological information about giardiasis in Canterbury. From October 1990 general practitioners were requested to report laboratory confirmed cases. The first 100 cases were sent a questionnaire and also asked to provide the details of two persons to be controls. In the first nine months 109 cases were reported. Eighty four cases completed questionnaires and 51 were matched with controls. The overall reported attack rate was 4.0 per 10,000 population per year. The rate was highest for preschool children and young adults and in rural areas. There was a significant risk associated with having contact with sewage or travelling overseas and a marginal risk for drinking water outside Christchurch. The results indicated that giardiasis was relatively common in Canterbury and confirmed that the major mechanisms of infection were probably the same as those previously identified overseas, namely person to person spread via faecal-oral transmission and the drinking of inadequately filtered water.


Clinical and cardiovascular effects of alpha methyldopa in combination with decarboxylase inhibitors.
The peripheral decarboxylase inhibitor carbidopa, given (100 mg/day) for 6 wk in a double-blind trial, lowered supine diastolic pressure of 10 patients with essential hypertension treated with alpha methyldopa by a small (6 mm Hg) but significant (p less than 0.05) amount. Large doses of benserazide (1.5 gm) did not modify the hypotensive effect of 1.0 gm of alpha methyldopa in untreated hypertension but significantly reduced the central nervous side effects of sedation and dry mouth. These studies indicate that extensive peripheral decarboxylation is not necessary for alpha methyldopa to lower blood pressure and would be compatible with the central nervous site of hypotensive action of this drug.


Salicylaldehyde derivatives from a marine-derived fungus Eurotium sp. SCSIO F452.
Two pairs of new salicylaldehyde derivative enantiomers, salicylaldehydiums A and B (1 and 2), along with five known analogues were isolated and identified from a marine-derived fungus Eurotium sp. SCSIO F452. Their structures and absolute configuration were determined by extensive spectroscopic analysis and electronic circular dichroism (ECD) calculations. All the new optical pure enantiomers [(+)-1, (-)-1, (+)-2, (-)-2] were evaluated for their cytotoxic and antioxidative activities. Compound (-)-1 exhibited weak cytotoxic activity.


Extra digital glomus tumor causing scapulothoracic impingement: A case report.
Glomus tumor is a painful benign neoplasm which arises from the glomus body. The glomus body is neuromyoarterial receptor responsible for regulating the peripheral skin blood flow and local temperature. The classical clinical symptoms of the glomus tumor are acute local pain, pin point tenderness and hypersensitivity to cold. The commonest location of the glomus tumor is the subungual region of the distal phalanx of the fingers and toes. We hereby describe a very rare case of extradigital glomus tumor in the interspace between the scapula and the posterior chest wall causing paroxysmal severe pain on the movement of the right shoulder. Being deep in location, the tumor was not clinically palpable or identifiable. The lesion was eventually located on MRI. Surgical resection of the tumor led to complete resolution of patient's symptoms.


Impaired cytosolic NADH shuttling and elevated UCP3 contribute to inefficient citric acid cycle flux support of postischemic cardiac work in diabetic hearts.
Diabetic hearts are subject to more extensive ischemia/reperfusion (ISC/REP) damage. This study examined the efficiency of citric acid cycle (CAC) flux and the transfer of cytosolic reducing equivalents into the mitochondria for oxidative support of cardiac work following ISC/REP in hearts of c57bl/6 (NORM) and type 2 diabetic, db/db mouse hearts. Flux through the CAC and malate-aspartate shuttle (MA) were monitored via dynamic (13)C NMR of isolated hearts perfused with (13)C palmitate+glucose. MA flux was lower in db/db than NORM. Oxoglutarate malate carrier (OMC) was elevated in the db/db heart, suggesting a compensatory response to low NADHc. Baseline CAC flux per unit work (rate-pressure-product, RPP) was similar between NORM and db/db, but ISC/REP reduced the efficiency of CAC flux/RPP by 20% in db/db. ISC/REP also increased UCP3 transcription, indicating potential for greater uncoupling. Therefore, ISC/REP induces inefficient carbon utilization through the CAC in hearts of diabetic mice due to the combined inefficiencies in NADHc transfer per OMC content and increased uncoupling via UCP3. Ischemia and reperfusion exacerbated pre-existing mitochondrial defects and metabolic limitations in the cytosol of diabetic hearts. These limitations and defects render diabetic hearts more susceptible to inefficient carbon fuel utilization for oxidative energy metabolism.


Evaluation of pectus excavatum with repeated CT scans.
The use of a single CT scan to evaluate the severity of pectus excavatum has been popular since its inception. However, there is no objective data to address the evolution of the deformity. Using repeated CT scans taken an average of 1 year and 3 months apart, eight children with pectus excavatum were prospectively followed. The initial pectus indices ranged from 3.6 to 6.8 (mean 5.4 +/- 1.3) and the follow-up indices, from 3.5 to 6.7 (mean 5.3 +/- 1.0). No progress of pectus excavatum was found during the study period. Our routine five axial chest CT sections also helped to specify a pectus index based on the central section taken through the deepest part of the deformity, and provided useful information for further conservative or surgical management.


Fractional CO2 Laser for Transcutaneous Drug Delivery of Onabotulinum Toxin in Palmar Hyperhidrosis.
Palmar hyperhidrosis is a common disorder of excessive sweating due to over-stimulation of cholinergic receptors on eccrine glands. To compare the efficacy of laser-assisted drug delivery of onabotulinum toxin A (BoNTA) and intradermal BoNTA injections in the management of palmar hyperhidrosis. This intrapatient comparative study was conducted on 30 adult patients with idiopathic palmar hyperhidrosis. The palms of the patients were divided into 2 groups. Group 1 was treated with intradermal injections of 50 units of BoNTA, whereas Group 2 was subjected to laser-assisted transcutaneous BoNTA delivery using fractional CO2 laser at different doses (25, 50, and 75 units). Each treatment modality was evaluated using the iodine starch test, hyperhidrosis disease severity scale, and gravimetric scoring. Delivery of 75 units of BoNTA to the dermis on the right-sided palms assisted by fractional CO2 laser was clinically equivalent to 50 units of injection on the left side. Pain intensity was significantly higher on the injected side than on the other side. Laser-assisted drug delivery of botulinum toxin can be considered an effective and safe alternative for treatment of palmar hyperhidrosis with minimal side effects and complications.


miR-92a Suppresses Mushroom Body-Dependent Memory Consolidation in Drosophila.
MicroRNAs (miRNAs) fine tune gene expression to regulate many aspects of nervous system physiology. Here, we show that miR-92a suppresses memory consolidation that occurs in the αβ and γ mushroom body neurons (MBns) of Drosophila, making miR-92a a memory suppressor miRNA. Bioinformatics analyses suggested that mRNAs encoding kinesin heavy chain 73 (KHC73), a protein that belongs to Kinesin-3 family of anterograde motor proteins, may be a functional target of miR-92a. Behavioral studies that employed expression of khc73 with and without its 3' untranslated region (UTR) containing miR-92a target sites, luciferase assays in HEK cells with reporters containing wild-type and mutant target sequences in the khc73 3'UTR, and immunohistochemistry experiments involving KHC73 expression with and without the wild-type khc73 3'UTR, all point to the conclusion that khc73 is a major target of miR-92a in its functional role as a miRNA memory suppressor gene.


Hypothesis-driven weight of evidence framework for evaluating data within the US EPA's Endocrine Disruptor Screening Program.
"Weight of Evidence" (WoE) approaches are often used to critically examine, prioritize, and integrate results from different types of studies to reach general conclusions. For assessing hormonally active agents, WoE evaluations are necessary to assess screening assays that identify potential interactions with components of the endocrine system, long-term reproductive and developmental toxicity tests that define adverse effects, mode of action studies aimed at identifying toxicological pathways underlying adverse effects, and toxicity, exposure and pharmacokinetic data to characterize potential risks. We describe a hypothesis-driven WoE approach for hormonally active agents and illustrate the approach by constructing hypotheses for testing the premise that a substance interacts as an agonist or antagonist with components of estrogen, androgen, or thyroid pathways or with components of the aromatase or steroidogenic enzyme systems for evaluating data within the US EPA's Endocrine Disruptor Screening Program. Published recommendations are used to evaluate data validity for testing each hypothesis and quantitative weightings are proposed to reflect two data parameters. Relevance weightings should be derived for each endpoint to reflect the degree to which it probes each specific hypothesis. Response weightings should be derived based on assay results from the test substance compared to the range of responses produced in the assay by the appropriate prototype hormone and positive and negative controls. Overall WoE scores should be derived based on response and relevance weightings and a WoE narrative developed to clearly describe the final determinations.


Occurrence of significant long PR intervals in patients implanted for sinus node dysfunction and monitored with SafeR™: The PRECISE study.
Long PR intervals may increase cardiovascular complications, including atrial fibrillation. In pacemakers, the SafeR™ mode monitors PR intervals, switching from AAI to DDD when criteria for atrioventricular block are met. The PRECISE study evaluated the incidence and predictors of long PR intervals and their association with incident atrial fibrillation after 1 year in patients implanted for sinus node dysfunction and free from significant conduction disorders at baseline. This French, prospective, multicentre, observational trial enrolled patients implanted with a REPLY™ dual-chamber pacemaker. Pacemaker memory recorded long PR intervals (defined as first-degree atrioventricular block mode switches occurring after six consecutive PR/AR intervals≥350/450ms) and atrial fibrillation incidence (fallback mode switch>1minute/day). Predictors were identified from baseline variables (age, sex, AR and PR intervals, atrial rhythm disorder and medication) using logistic regression. Of 291 patients with sinus node dysfunction enrolled, 214 were free from significant conduction disorders at baseline (mean age 79±8 years; 44% men; PR/AR intervals<350/450ms). After 1 year, long PR intervals had occurred in 116 patients (54%) and atrial fibrillation in 63 patients (30%). Amiodarone was the only independent predictor of long PR interval occurrence (odds ratio 2.50, 95% confidence interval 1.20-5.21; P=0.014). There was a strong trend towards an association between long PR interval and atrial fibrillation incidence (odds ratio 1.86, 95% confidence interval 0.97-3.61; P=0.051). Half of the patients with pure sinus node dysfunction developed long PR intervals in the year following pacemaker implantation. Amiodarone was the only independent predictor of long PR intervals. There was a strong trend towards an association between long PR intervals and incident atrial fibrillation.


Macrophage migration inhibitory factor (MIF) -173 polymorphism is associated with clinical erythema nodosum in Löfgren's syndrome.
Macrophage migration inhibitory factor (MIF) has been shown to be a key regulator in innate and adaptive immune responses. A single nucleotide polymorphism in the 5' region of the MIF gene, MIF -173∗G/C, is associated with increased MIF protein production, in vivo and in vitro. Associations have been shown between the minor MIF -173C allele and sarcoidosis patients with erythema nodosum (EN). Löfgren's syndrome is an acute and usually self-remitting phenotype of sarcoidosis. It is defined as having an acute onset with bilateral hilar lymphadenopathy (BHL), fever, erythema nodosum (EN) and/or arthritis. The aim of this study was to investigate whether MIF -173G/C associates with the susceptibility to and the clinical manifestations, i.e. arthritis or EN, of Löfgren's syndrome. A total of 171 patients with Löfgren's syndrome and 313 controls were genotyped for a single nucleotide polymorphism at position -173 of the MIF gene (SNP rs755622), using a PCR and a restriction enzyme technique. There were no significant differences found in the MIF -173C allele frequencies between patients with Löfgren's syndrome and controls. In patients with Löfgren's syndrome with only EN, a significantly increased frequency of the C minor allele was observed compared to patients with arthritis only (p=0.0095; OR 3.08, CI: 1.28-7.39). Patients with only EN compared to patients with EN and arthritis showed a significantly increased frequency of the minor C allele (p=0.044; OR 1.97, CI: 1.01-3.85). But patients with only arthritis compared to patients with EN and arthritis did not show a significant difference in C allele frequency (p=0.270; OR 0.64, CI: 0.29-1.42). The MIF -173C allele is associated with erythema nodosum in Löfgren's syndrome, but not with susceptibility to sarcoidosis. This indicates a role for MIF after antigen presenting to the T cell has taken place and the sarcoid inflammatory response has begun.


Rational Design of PLGA Nanoparticle Vaccine Delivery Systems To Improve Immune Responses.
Nanoparticle-based vaccine delivery systems have been extensively used to promote and induce immune responses to protein antigens. The properties of the nanoparticles, such as size, surface charge, and antigen loading mode, have been proved to significantly influence the adjuvant effect and immunoreactivity of nanoparticle-based vaccine delivery systems. The purpose of the study was to investigate how the surface charge and antigen loading mode of nanoparticles impact the immune responses. In this study, three ovalbumin (OVA)-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles with different surface charges and antigen loading modes were developed. The three nanoparticles were designed as antigen encapsulated with negatively charged (Angelica sinensis polysaccharide (ASP)-PLGA/OVA), antigen encapsulated with polyethylenimine (PEI)-coated (ASP-PLGA/OVA-PEI), and antigen adsorbed on PEI-coated (ASP-PLGA-PEI-OVA) nanoparticles. The Angelica sinensis polysaccharide (ASP) was used as the immunopotentiator and encapsulated into three nanoparticles. The results demonstrated that both PEI-coated (positively charged) nanoparticles promoted the antigen escape from the endosome, which led to the cytoplasmic antigen delivery to generate cross presentation, compared to negatively charged nanoparticles. In addition, PEI-coated nanoparticles activated the DCs in lymph nodes 5 days after the primary vaccination. In vivo experiments demonstrated that both antigen-encapsulated nanoparticles induced more potent and long-term antigen-specific antibody responses, compared to that of antigen-adsorbed nanoparticles. Thus, the PEI-coated and antigen-encapsulated nanoparticles (ASP-PLGA/OVA-PEI) as a vaccine adjuvant delivery system have the potential to induce strong and long-term humoral and cellular immune responses.