Dissected Leaf 1 encodes an MYB transcription factor that controls leaf morphology in potato.
The transcription factor StDL1 regulates dissected leaf formation in potato and the genotype frequency of recessive Stdl1/Stdl1, which results in non-dissected leaves, has increased in cultivated potatoes. Leaf morphology is a key trait of plants, influencing plant architecture, photosynthetic efficiency and yield. Potato (Solanum tuberosum L.), the third most important food crop worldwide, has a diverse leaf morphology. However, despite the recent identification of several genes regulating leaf formation in other plants, few genes involved in potato leaf development have been reported. In this study, we identified an R2R3 MYB transcription factor, Dissected Leaf 1 (StDL1), regulating dissected leaf formation in potato. A naturally occurring allele of this gene, Stdl1, confers non-dissected leaves in young seedlings. Knockout of StDL1 in a diploid potato changes the leaf morphology from dissected to non-dissected. Experiments in N. benthamiana and yeast show that StDL1 is a transcriptional activator. Notably, by calculating the genotype frequency of the Stdl1/Stdl1 in 373-potato accessions, we found that it increases significantly in cultivated potatoes. This work reveals the genetic basis of dissected leaf formation in potato and provides insights into plant leaf morphology.


Molecular interactions of a model bile salt and porcine bile with (1,3:1,4)-β-glucans and arabinoxylans probed by (13)C NMR and SAXS.
Two main classes of interaction between soluble dietary fibres (SDFs), such as (1,3:1,4)-β-D-glucan (βG) and arabinoxylan (AX) and bile salt (BS) or diluted porcine bile, were identified by (13)C NMR and small angle X-ray scattering (SAXS). Small chemical shift differences of BS NMR resonances were consistent with effective local concentration or dilution of BS micelles mostly by βG, suggesting dynamic interactions; whilst the reduced line widths/intensities observed were mostly caused by wheat AX and the highest molecular size and concentrations of βG. SAXS showed evidence of changes in βG but not AX in the presence of BS micelles, at >13 nm length scale consistent with molecular level interactions. Thus intermolecular interactions between SDF and BS depend on both SDF source and its molecular weight and may occur alone or in combination.


Moss Phylogeny Reconstruction Using Nucleotide Pangenome of Complete Mitogenome Sequences.
Stability of composition and sequence of genes was shown earlier in 13 mitochondrial genomes of mosses (Rensing, S. A., et al. (2008) Science, 319, 64-69). It is of interest to study the evolution of mitochondrial genomes not only at the gene level, but also on the level of nucleotide sequences. To do this, we have constructed a "nucleotide pangenome" for mitochondrial genomes of 24 moss species. The nucleotide pangenome is a set of aligned nucleotide sequences of orthologous genome fragments covering the totality of all genomes. The nucleotide pangenome was constructed using specially developed new software, NPG-explorer (NPGe). The stable part of the mitochondrial genome (232 stable blocks) is shown to be, on average, 45% of its length. In the joint alignment of stable blocks, 82% of positions are conserved. The phylogenetic tree constructed with the NPGe program is in good correlation with other phylogenetic reconstructions. With the NPGe program, 30 blocks have been identified with repeats no shorter than 50 bp. The maximal length of a block with repeats is 140 bp. Duplications in the mitochondrial genomes of mosses are rare. On average, the genome contains about 500 bp in large duplications. The total length of insertions and deletions was determined in each genome. The losses and gains of DNA regions are rather active in mitochondrial genomes of mosses, and such rearrangements presumably can be used as additional markers in the reconstruction of phylogeny.


Kikuchi-Fujimoto disease is mediated by an aberrant type I interferon response.
Kikuchi-Fujimoto disease (KFD) is a reactive lymphadenitis of unclear etiology. To understand the pathogenesis of KFD, we performed targeted RNA sequencing of a well-characterized cohort of 15 KFD specimens with 9 non-KFD lymphadenitis controls. Two thousand and three autoimmunity-related genes were evaluated from archived formalin-fixed paraffin-embedded lymph node tissue and analyzed by a bioinformatics approach. Differential expression analysis of KFD cases compared to controls revealed 44 significantly upregulated genes in KFD. Sixty-eight percent of these genes were associated with the type I interferon (IFN) response pathway. Key component of the pathway including nucleic acid sensors, IFN regulatory factors, IFN-induced antiviral proteins, IFN transcription factors, IFN-stimulated genes, and IFN-induced cytokines were significantly upregulated. Unbiased gene expression pathway analysis revealed enrichment of IFN signaling and antiviral pathways in KFD. Protein-protein interaction analysis and a molecular complex detection algorithm identified a densely interacting 15-gene module of type I IFN pathway genes. Apoptosis regulator IFI6 was identified as a key seed gene. Transcription factor target analysis identified enrichment of IFN-response elements and IFN-response factors. T-cell-associated genes were upregulated while myeloid and B-cell-associated genes were downregulated in KFD. CD123+ plasmacytoid dendritic cells (PDCs) and activated T cells were noted in KFD. In conclusion, KFD is mediated by an aberrant type I interferon response that is likely driven by PDCs and T cells.


Perioperative, functional, and oncologic outcomes of minimally-invasive surgery for highly complex renal tumors (RENAL or PADUA score ≥ 10): an evidence-based analysis.
The primary objective of the current study is to undertake a comparative analysis of the effectiveness and safety of minimally-invasive partial nephrectomy (MIPN; including laparoscopic and robotic approaches) and open partial nephrectomy (OPN) for the treatment of highly complex renal tumors (defined as PADUA or RENAL score ≥ 10). A comprehensive search was conducted in four electronic databases (PubMed, Web of Science, Embase, and Cochrane Library) to identify relevant studies published in the English language up to April 2023. The current study employed Review Manager 5.4 and encompassed controlled trials of both MIPN and OPN for the treatment of highly complex renal tumors. This study comprised a total of eight comparative trials involving 1161 patients. MIPN demonstrated a significant reduction in length of hospital stay (weighted mean difference [WMD] - 2.08 days, 95% confidence interval [CI] - 2.48, - 1.68; p < 0.00001), blood loss (WMD - 39.86 mL, 95% CI - 75.32, - 4.39; p = 0.03), transfusion rates (odds ratio [OR] 0.30, 95% CI 0.13, 0.71; p = 0.006), and overall complications (OR 0.46, 95% CI 0.31, 0.70; p = 0.0003). However, there were no significant differences between MIPN and OPN in terms of operative time, warm ischemia time, conversion to radical nephrectomy rates, renal functional and oncologic outcomes. This study reveals that MIPN presents several benefits in comparison to OPN, including decreased length of hospital stay, blood loss, transfusion rates, and complications, while still offering renal functional and oncological outcomes that are comparable to those of OPN in patients with highly complex renal tumors.


Effects of exercise and cold-water exposure on microvascular muscle perfusion.
Microvascular blood flow (MBF) and its intramuscular regulation are of importance for physiological responsiveness and adaptation. The quantifiable in-vivo monitoring of MBF after cycling or systemic cold-water exposure may reveal new insights into capillary regulatory mechanisms. This study aimed to assess the role of exercise and cold therapy on MBF by using contrast-enhanced ultrasound (CEUS). Twenty healthy athletes were recruited and randomly assigned to an intervention (IG) or a control group (CG). MBF was quantified in superficial (rectus femoris, RF) and deep muscle layers (vastus intermedius, VI). Representative perfusion parameters (peak enhancement (PE) and wash-in area under the curve (WiAUC)) were measured after a standardized measurement protocol for both groups at resting conditions (t0) and after cycling (20 min., 70% Watt max, t1) for both groups, after cold-water immersion exposure for IG (15 min., 12°C) or after precisely 15 minutes of rest for CG (t2) and for both groups after 60 minutes of follow-up (t3). At t1, MBF in VI increased significantly compared to resting conditions in both groups in VI (p= 0.02). After the cold-water exposure (t2), there were no statistically significant changes in perfusion parameters as well as after 60 minutes of follow-up (t3) (p = 0.14). Cycling leads to an upregulation of MBF. However, cold exposure does not change the MBF. The implementation of CEUS during different physiological demands may provide deeper insight into intramuscular perfusion regulation and regenerative processes.


Immunohistochemistry indicates that persistent inflammation determines failure of tail, limb and finger regeneration in the Lizard Podarcis muralis.
The presence of white blood inflammatory cells in injured tissues and their effect on the process of organ regeneration in lizards has been assessed on tail, limb and digits. The present immunohistochemical survey analyzes the occurrence of CD68-labeled cells in lizard organs uncapable of regenerating tissues that exhibit strong inflammatory activity. This marker mainly identifies macrophages and mast cells present in large number within tissues of injured limbs and digits. Also a high inflammation is associated with amputated tails that do not regenerate, derived from cauterization or infection of tissues of the tail stump. In the healing limbs and fingers at 12-20 days post-amputation, numerous CD68-labeled cells, most likely macrophages, are seen among superficial connective tissues and injured muscles and bones. These cells likely stimulate and give rise to scarring tissues and no regeneration of limb and fingers occurs. In the cauterized or in the infected tail stump a strong accumulation of CD68-positive mast cells and macrophages is observed, where they likely evoke epidermal coagulation, formation of scarring connective tissue, and loss of regeneration. The present observations provide further cytological evidence that support the notion that a strong and lasting inflammatory condition impedes organ regeneration in specifically lizards and, more generally other vertebrates as well.


[Large rapidly growing retroperitoneal lipoma following Wertheim's operation].
Report on a rapidly growing large retroperitonally placed tumor which after fifteen months was extirpated by applying a Wertheim-radical operation and following ray-therapy. The tumor weighed 6 kg and turned out to be a good-natured lipom.


Interaction between biphenols and anions: selective receptor for dihydrogenphosphate.
Biphenol was shown to bind dihydrogenphosphate (H2PO4-) selectively over various other anions (MeCO2-, Cl-, Br-, I-, NO3-, HSO4-). The highly selectivity of biphenol toward dihydrogenphosphate is explained in terms of the basicity and shape of the guest anion.


A new synthesis of isoaurones: cytotoxic activity of compounds related to the alleged structure of isoaurostatin.
A new synthesis of isoaurones related to the alleged structure of isoaurostatin, via Heck intramolecular cyclization of cinnamic esters of 2-iodophenols, is reported. The cytotoxic activity of these isoaurones is lower than that of the structurally very similar 4-arylcoumarins.


The effect of Nd:YAG iridotomy on intraocular pressure in hypertensive eyes with shallow anterior chambers.
Eighty one eyes of 48 patients with raised IOP and shallow anterior chambers underwent Nd:YAG iridotomy to prevent further angle closure glaucoma and to remove any pupil block that might be contributing to the raised IOP. These eyes were followed for 18-34 months to assess the effect on IOP control. Seventy three eyes of 43 patients were asymptomatic. In eyes with no PAS none responded with drop in IOP but in eyes with well established PAS 69% showed a drop in IOP. By comparison eight eyes of five patients had a history of episodes of subacute angle closure glaucoma. All had PAS present pre-operatively. Iridotomy reduced IOP in 87.5% of the eyes in this group and rendered 100% symptom free. Permanent posterior synechiae between lens and iris were an invariable complication in those eyes that required long-term miotic treatment for IOP control following iridotomy. In asymptomatic eyes with chronic pressure elevation and narrow angles laser iridotomy is unlikely significantly to reduce the IOP. We recommend that in such eyes iridotomy should be reserved for those eyes with established closure of the angle by PAS in which IOP control can be achieved without the use of miotics.


Differential antidepressant-like response to lithium treatment between mouse strains: effects of sex, maternal care, and mixed genetic background.
Lithium is a mood stabilizer with both antidepressant and antimanic properties, however its mechanism of action is unclear. Identifying the genetic factors that influence lithium's therapeutic actions will be an important step to assist in identifying such mechanisms. We previously reported that lithium treatment of male mice has antidepressant-like effects in the C57BL/6J strain but that such effects were absent in the BALB/cJ strain. This study aimed to assess the roles of both genetic and non-genetic factors such as sex and non-shared environmental conditions that may mediate differential behavioral responses to lithium. Mice were treated with lithium for 10 days and then tested in the forced swim test followed by lithium discontinuation and retesting to assess effects of lithium withdrawal. We also assessed effects of sex and cross-fostering on lithium response between the C57BL/6J and BALB/cJ strains, and antidepressant-like effects of lithium in the hybrid CB6F1/J strain that is derived from C57BL/6J and BALB/cJ parental strains. Neither sex nor maternal care significantly influenced the differential antidepressant-like response to lithium. Withdrawal from lithium treatment reversed antidepressant-like effects in the C57BL/6J strain but had no effects in BALB/cJ mice. Lithium treatment did not result in antidepressant-like effects in the CB6F1/J strain. Genetic factors are likely primarily responsible for differential antidepressant-like effects of lithium in the C57BL/6J and BALB/cJ strains. Future studies identifying such genetic factors may help to elucidate the neurobiological mechanisms of lithium's therapeutic actions.


Hormonal and cardiac response of autistic children to changes in environmental stimulation.
A study was made of physiological responses of autistic children to variations in environmental load in order to examine the under- versus over-arousal dichotomy. More specifically, measures of urinary mucoprotein excretion and mean heart rate and three measures of heart rate variability were compared with matched controls in conditions of normal, high, and low total environmental load. The results suggest that, although behaviorally unresponsive, the autistic children responded physiologically, were generally in a lower state of arousal than the control group, and were labile in response to changes in stimulation.


A geographical origin assessment of Italian hazelnuts: Gas chromatography-ion mobility spectrometry coupled with multivariate statistical analysis and data fusion approach.
Hazelnut is a commodity that has gained interest in the food science community concerning its authenticity. The quality of the Italian hazelnuts is guaranteed by Protected Designation of Origin and Protected Geographical Indication certificates. However, due to their modest availability and the high price, fraudulent producers/suppliers blend, or even substitute, Italian hazelnuts with others from different countries, having a lower price, and often a lower quality. To contrast or prevent these illegal activities, the present work investigated the application of the Gas Chromatography-Ion mobility spectrometry (GC-IMS) technique on the hazelnut chain (fresh, roasted, and paste of hazelnuts). The raw data obtained were handled and elaborated using two different ways, software for statistical analysis, and a programming language. In both cases, Principal Component Analysis and Partial Least Squares-Discriminant Analysis models were exploited, to study how the Volatile Organic Profiles of Italian, Turkish, Georgian, and Azerbaijani products differ. A prediction set was extrapolated from the training set, for a preliminary models' evaluation, then an external validation set, containing blended samples, was analysed. Both approaches highlighted an interesting class separation and good model parameters (accuracy, precision, sensitivity, specificity, F1-score). Moreover, a data fusion approach with a complementary methodology, sensory analysis, was achieved, to estimate the performance enhancement of the statistical models, considering more discriminant variables and integrating at the same time further information correlated to quality aspects. GC-IMS could be a key player as a rapid, direct, cost-effective strategy to face authenticity issues regarding the hazelnut chain.


Treatment and outcome in 12 cases of olfactory neuroblastoma at Mexico´s National Cancer Institute: A retrospective clinical analysis and literature review.
Olfactory neuroblastoma (ONB) is a malignant neoplasm that arises from the upper nasal vault. We present a retrospective case series and clinical analysis of 12 ONB cases. Patients with ONB treated at Mexico´s National Cancer Institute between 2011 and 2018. The Kadish proportion of B, C, and D stage was 16%, 58%, or 25%, respectively. Hyams Grade 1, 2, or 3 was 25%, 50%, and 25%, respectively. The most common surgical approach was the craniofacial in 5 cases (42%), followed by the transfacial in 4 cases (33%), and the endonasal endoscopic approach in 3 cases (25%). Gross total resection was achieved in 8 patients (67%). Five patients (42%) underwent a second operation due to recurrent/progressive disease. The surgical complication rate was 8.3%. Progression-free survival was 41 months and the mean overall survival was 63.6 months. Surgical resection followed by radiotherapy, and chemotherapy for metastatic and recurrent disease provides the best outcome in terms of survival and recurrence. To the best of our knowledge, this is the first series of cases reported in Mexico.


Relations between tensile impact properties and microstructure of compact bone.
Standardized human and beef femoral compact bone specimens were tested in tensile impact and the dynamic mechanical properties were determined. The microstructure of 45 beef and 47 human bone specimens were examined histologically to determine if there is a structural basis to account for strength differences in the bone samples. Strong negative correlations were obtained between the maximum stress and the percentage area of secondary osteons in each specimen. For human bone samples, the energy absorption capacity and the modulus of elasticity were also found to have strong negative correlations with the percentage area of secondary osteons present in each specimen. Linear regression equations were obtained describing the impact strength properties in terms of the percentage areas of secondary osteons and cavities in the samples. Fracture surfaces of the tested bone specimens were examined in a scanning electron microscope. Most surfaces exhibited a fairly rough texture indicating a quasi-cleavage type of failure. Fractographic analysis of bone fracture surface was helpful in understanding the micromechanics of bone fracture.


Outcomes and prognosis of adjustment disorder in adults: A systematic review.
Adjustment disorder (AD) is one of the most commonly diagnosed mental health disorders and is generally conceptualized to be mild and short-lived. Despite the frequent use of AD in clinical settings, little is known about the prognosis of this condition. Our goal was to systematically review research on a range of AD outcomes in order to provide a broad characterization of AD prognosis. We conducted searches in MEDLINE, EMBASE, and PsycINFO. We included 31 cohort or randomized controlled trials with a total of 1,385,358 participants. Many patients maintained an AD diagnosis or were diagnosed with another mental health disorder months to years after initial diagnosis. Patients with AD tended to show symptom improvement at higher rates and to utilize less treatment than did patients with other disorders. AD-diagnosed groups experienced subsequent development of numerous physical conditions, such as infection, cancers, Parkinson's disease, and cardiovascular events, at higher rates than did control groups. Results were mixed regarding suicidality and occupational impairment. We rated most studies as having a moderate risk of bias. Based on limited findings, AD appears to progress as a milder disorder than do other disorders, but it not uncommonly transitions to more severe mental health states and may predict the development of future health issues, both mental and physical. Future prospective research that conforms to prognosis study guidelines is needed to better understand the course of this common disorder.


Cooperative binding of DNA and CBFbeta to the Runt domain of the CBFalpha studied via MD simulations.
The Runt domain (RD) is the DNA-binding region of the Runx genes. A related protein, known as core binding factor beta (CBFbeta) also binds to the RD to enhance RD-DNA interaction by 6- to 10-fold. Here, we report results from molecular dynamics (MD) simulations of RD alone, as a dimer in complexes with DNA and CBFbeta and in a ternary complex with DNA and CBFbeta. Consistent with the experimental findings, in the presence of CBFbeta the estimated free energy of binding of RD to the DNA is more favorable, which is shown to be due to more favorable intermolecular interactions and desolvation contributions. Also contributing to the enhanced binding are favorable intramolecular interactions between the 'wing' residues (RD residues 139-145) and the 'wing1' residues (RD residues 104-116). The simulation studies also indicate that the RD-CBFbeta binding is more favorable in the presence of DNA due to a more favorable RD-CBFbeta interaction energy. In addition, it is predicted that long-range interactions involving ionic residues contribute to binding cooperativity. Results from the MD calculations are used to interpret a variety of experimental mutagenesis data. A novel role for RD Glu116 to the RD-CBFbeta interaction is predicted.


Nine out of 10 sunbeds in England emit ultraviolet radiation levels that exceed current safety limits.
Exposure to ultraviolet (UV) radiation from sunlight is recognized as the principal cause of skin cancer. Moreover, sunbeds have been classified as carcinogenic by the International Agency for Research on Cancer. Despite this, there is a shortage of objective data on UV exposure levels in sunbeds in England. We set out to measure UV emission levels in sunbeds at sites around England, and to compare these levels with both current standards and natural sunlight. Between October 2010 and February 2011, UV spectra were measured on site from a total of 402 artificial tanning units in England. Measurement instrumentation was calibrated, traceable to the National Physical Laboratory. Compliance with the relevant British and European standard was determined, and a skin-cancer weighting factor was used to compare the carcinogenic potential of sunbeds with that of sunlight. For compliance with the European standard, erythemal-effective irradiance should not exceed 0·3 W m(-2). The values that we measured ranged between 0·10 and 1·32 W m(-2) with a mean of 0·56 ± 0·21 W m(-2) . Only 10% of sunbeds surveyed were within the recommended limit. Application of the skin-cancer weighting factor produced values that varied from 0·17 to 2·52 W m(-2) with a mean of 0·99 ± 0·41 W m(-2). The comparable value for Mediterranean noon day sun was 0·43 W m . Nine out of 10 sunbeds surveyed throughout England emitted levels of UV radiation that exceed the maximum levels contained within the European standard. Moreover, the skin cancer risk for comparable times of exposure was up to six times higher than that for Mediterranean sunlight. This situation is unacceptable and stricter control measures must be put in place.


Metabolomics unravels subtype-specific characteristics related to neoadjuvant therapy response in breast cancer patients.
Breast cancer is the most diagnosed tumor and the leading cause of cancer death in women worldwide. Metabolomics allows the quantification of the entire set of metabolites in blood samples, making it possible to study differential metabolomics patterns related to neoadjuvant treatment in the breast cancer neoadjuvant setting. Characterizing metabolic differences in breast cancer blood samples according to their response to neoadjuvant treatment. One hundred and three plasma samples of breast cancer patients, before receiving neoadjuvant treatment, were analyzed through UPLC-MS/MS metabolomics. Then, metabolomics data were analyzed using probabilistic graphical models and biostatistics methods. Metabolomics data allowed the identification of differences between groups according to response to neoadjuvant treatment. These differences were specific to each breast cancer subtype. Patients with HER2+ tumors showed differences in metabolites related to amino acids and carbohydrates pathways between the two pathological response groups. However, patients with triple-negative tumors showed differences in metabolites related to the long-chain fatty acids pathway. Patients with Luminal B tumors showed differences in metabolites related to acylcarnitine pathways. It is possible to identify differential metabolomics patterns between complete and partial responses to neoadjuvant therapy, being this metabolomic profile specific for each breast cancer subtype.


E-Jet 3D-Printed Scaffolds as Sustained Multi-Drug Delivery Vehicles in Breast Cancer Therapy.
Combination chemotherapy is gradually receiving more attention because of its potential synergistic effect and reduced drug doses in clinical application. However, how to precisely control drug release dose and time using vehicles remains a challenge. This work developed an efficient drug delivery system to combat breast cancer, which can enhance drug effects despite reducing its concentration. Controlled-release poly-lactic-co-glycolic acid (PLGA) scaffolds were fabricated by E-jet 3D printing to deliver doxorubicin (DOX) and cisplatin (CDDP) simultaneously. This drug delivery system allowed the use of a reduced drug dosage resulting in a better effect on the human breast cancer cell apoptosis and inhibiting tumor growth, compared with the effect of each drug and the two drugs administrated without PLGA scaffolds. Our study suggested that DOX-CDDP-PLGA scaffolds could efficiently destroy MDA-MB-231 cells and restrain tumor growth. The 3D printed PLGA scaffolds with their time-programmed drug release might be useful as a new multi-drug delivery vehicle in cancer therapy, which has a potential advantage in a long term tumor cure and prevention of tumor recurrence.


Ideologies and intervention strategies in an urban sample of drug-abuse agencies.
The study assessed the usefulness of a "levels of analysis" criterion for distinguishing ideological orientations in an urban sample of agencies working with drug-abuse clients: 39 directors reported on their programs' goals, and on their personal philosophies about the causes of drug-abuse problems. The authors used Frank and Atkins' procedures to classify goals and philosophies based on individual, family/group, or social systems levels of analysis. As predicted, agency goals better accounted for program and organizational differences than directors' philosophies: Agencies with social systems level goals characteristically combined advocacy strategies with community networking and outreach activities. However, an unexpected finding was that agencies with individual level goals were most likely to work with poor and minority clients. The discussion emphasizes the importance of an ideological/organizational/community context for evaluating intervention strategies in community-based agencies.


Results of blood cultures for detection of mycobacteria in AIDS patients.
Since the advent of the acquired immunodeficiency syndrome (AIDS) numerous M. avium intracellulare disseminated infections have been recognised. Blood culture is a convenient method for diagnosing these infections. At Pitié-Salpêtrière hospital AIDS patients with persistent unexplained fever each had three blood cultures. The blood samples, taken on 3 consecutive days without taking in account fever peaks, were collected in the Isolator-10 lysis-centrifugation system and inoculated onto Löwenstein-Jensen medium with and without 0.25% sodium pyruvate. From February 1986-September 1987, 564 samples taken from 165 patients were cultivated for the detection of mycobacteria. Sixty one (10.8%) taken from 19 patients (11.5%) were positive. M. avium intracellulare was the most frequently isolated mycobacterial species. In 10 patients, the positive blood culture was the only or the first positive culture for mycobacteria.


A 90-Day Prognostic Model Based on the Early Brain Injury Indicators after Aneurysmal Subarachnoid Hemorrhage: the TAPS Score.
This study aimed to establish a new scoring model based on the early brain injury (EBI) indicators to predict the 90-day functional outcomes in patients with aneurysmal subarachnoid hemorrhage (aSAH). We retrospectively enrolled 825 patients and prospectively enrolled 108 patients with aSAH who underwent surgical clipping or endovascular coiling (derivation cohort = 640; validation cohort = 185; prospective cohort = 108) in our institute. We established a logistic regression model based on independent risk factors associated with 90-day unfavorable outcomes. The discrimination of the prognostic model was assessed by the area under the curve in a receiver operating characteristic curve analysis. The Hosmer-Lemeshow goodness-of-fit test and a calibration plot were used to evaluate the calibration of the prediction model. The developed scoring model named "TAPS" (total score, 0-7 points) included the following admission variables: age > 55 years old, WFNS grade of 4-5, mFS grade of 3-4, Graeb score of 5-12, white blood cell count > 11.28 × 109/L, and surgical clipping. The model showed good discrimination with the area under the curve in the derivation, validation, and prospective cohorts which were 0.816 (p < 0.001, 95%CI = 0.77-0.86), 0.810 (p < 0.001, 95%CI = 0.73-0.90), and 0.803 (p < 0.001, 95%CI = 0.70-0.91), respectively. The model also demonstrated good calibration (Hosmer-Lemeshow goodness-of-fit test: X2 = 1.75, df = 8, p = 0.988). Compared with other predictive models, TAPS is an easy handle tool for predicting the 90-day unfavorable outcomes of aSAH patients, which can help clinicians better understand the concept of EBI and quickly identify those patients at risk of poor prognosis, providing more positive treatment strategies. Trial registration: NCT04785976. Registered 5 March 2021-retrospectively registered, http://www.clinicaltrials.gov .


Designing cost-effective biopharmaceutical facilities using mixed-integer optimization.
Chromatography operations are identified as critical steps in a monoclonal antibody (mAb) purification process and can represent a significant proportion of the purification material costs. This becomes even more critical with increasing product titers that result in higher mass loads onto chromatography columns, potentially causing capacity bottlenecks. In this work, a mixed-integer nonlinear programming (MINLP) model was created and applied to an industrially relevant case study to optimize the design of a facility by determining the most cost-effective chromatography equipment sizing strategies for the production of mAbs. Furthermore, the model was extended to evaluate the ability of a fixed facility to cope with higher product titers up to 15 g/L. Examination of the characteristics of the optimal chromatography sizing strategies across different titer values enabled the identification of the maximum titer that the facility could handle using a sequence of single column chromatography steps as well as multi-column steps. The critical titer levels for different ratios of upstream to dowstream trains where multiple parallel columns per step resulted in the removal of facility bottlenecks were identified. Different facility configurations in terms of number of upstream trains were considered and the trade-off between their cost and ability to handle higher titers was analyzed. The case study insights demonstrate that the proposed modeling approach, combining MINLP models with visualization tools, is a valuable decision-support tool for the design of cost-effective facility configurations and to aid facility fit decisions. 2013.


Learning in patient-based education sessions: a prospective evaluation.
The educational impact of on-call scheduling for physicians in training is not well understood. The benefit of patient-based educational sessions during postcall periods may be enhanced by the greater patient familiarity associated with long on-call shifts, or it may be attenuated by fatigue. The objective was to evaluate the impact of in-house call on cognitive attention, learning, and recall of critical care medicine trainees, before and after a reduction in call period. A prospective before and after survey during 8 wks in 2004. Two critical care units at the Hospital for Sick Children, Toronto. Trainees in a university-affiliated critical care medicine program at the Hospital for Sick Children. Duty hour reduction from 26.5-hr to 18-hr on-call shifts. Likert scales were completed after morning educational seminars self-reporting alertness, concentration, how well discussions were followed, and the acquisition of new or practice changing knowledge. Respondents were classified according to how recently they had been on call. Eleven trainees completed 231 questionnaires (80% response rate). Fellows with more recent on-call periods had reduced concentration (p = .002), alertness (p < .0001), and recall of the previous session (p = .009) and followed discussions less well (p = .019). Eighteen-hour shifts were associated with increased postcall alertness (p = .002), concentration (p = .03), and assimilation of discussions (p = .045). However, neither the duration of call nor the length of time since being on call was associated with differences in the acquisition of new theoretical or practice-changing knowledge. Reduced mental attention after being on call is more pronounced after longer shifts. Learning was not affected by shift duration or by how recently trainees were on call. Increased patient familiarity does not augment learning in patient-based medical education.


Diagnosis of arrhythmogenic right ventricular cardiomyopathy by fourier analysis of gated blood pool single-photon emission tomography.
To evaluate the diagnostic performance of Fourier phase analysis of gated blood pool single-photon emission computed tomography (GBP SPECT) in arrhythmogenic right ventricular (RV) cardiomyopathy, 18 patients with confirmed arrhythmogenic RV cardiomyopathy underwent GBP SPECT and x-ray cineangiography. Results were compared with data obtained with GBP SPECT in 10 control subjects. This 3-dimensional method demonstrated good correlation with cineangiography for measurements of RV enlargement and extent of the disease; RV and left ventricular segments were analyzed with the same accuracy. Tomographic abnormalities were significant decreased RV ejection fraction, RV dilatation, nonsynchronized contraction of the ventricles, increased RV contraction dispersion, presence of segmental RV wall motion disorders and/or phase delays, and occasionally regional left ventricular abnormalities. RV-delayed phase areas were always present in our population. A scoring system with RV criteria was proposed to diagnose RV disease. Because Fourier analysis of GBP SPECT provides ventricular morphologic information for the right ventricle with the same accuracy as for the left ventricle, it may replace planar radionuclide studies. Therefore, this method is helpful in patients with a strong clinical suspicion of arrhythmogenic RV cardiomyopathy, and should be used as a screening method before right ventriculography.


Guard cell- and phloem idioblast-specific expression of thioglucoside glucohydrolase 1 (myrosinase) in Arabidopsis.
Thioglucoside glucohydrolase 1 (TGG1) is one of two known functional myrosinase enzymes in Arabidopsis. The enzyme catalyzes the hydrolysis of glucosinolates into compounds that are toxic to various microbes and herbivores. Transgenic Arabidopsis plants carrying beta-glucuronidase and green fluorescent protein reporter genes fused to 0.5 or 2.5 kb of the TGG1 promoter region were used to study spatial promoter activity. Promoter activity was found to be highly specific and restricted to guard cells and distinct cells of the phloem. No promoter activity was detected in the root or seed. All guard cells show promoter activity. Positive phloem cells are distributed in a discontinuous pattern and occur more frequent in young tissues. Immunocytochemical localization of myrosinase in transverse and longitudinal sections of embedded material show that the TGG1 promoter activity reflects the position of the myrosinase enzyme. In the flower stalk, the myrosinase-containing phloem cells are located between phloem sieve elements and glucosinolate-rich S cells. Our results suggest a cellular separation of myrosinase enzyme and glucosinolate substrate, and that myrosinase is contained in distinct cells. We discuss the potential advantages of locating defense and communication systems to only a few specific cell types.


The fate of arsenic adsorbed on iron oxides in the presence of arsenite-oxidizing bacteria.
Arsenic (As) is a redox-active metalloid whose toxicity and mobility in soil depend on its oxidation state. Arsenite [As(III)] can be oxidized by microbes and adsorbed by minerals in the soil. However, the combined effects of these abiotic and biotic processes are not well understood. In this study, the fate of arsenic in the presence of an isolated As(III)-oxidizing bacterium (Pseudomonas sp. HN-1, 10(9) colony-forming units (CFUs)·ml(-1)) and three iron oxides (goethite, hematite, and magnetite at 1.6 g L(-1)) was determined using batch experiments. The total As adsorption by iron oxides was lower with bacteria present and was higher with iron oxides alone. The total As adsorption decreased by 78.6%, 36.0% and 79.7% for goethite, hematite and magnetite, respectively, due to the presence of bacteria. As(III) adsorbed on iron oxides could also be oxidized by Pseudomonas sp. HN-1, but the oxidation rate (1.3 μmol h(-1)) was much slower than the rate in the aqueous phase (96.2 μmol h(-1)). Therefore, the results of other studies with minerals only might overestimate the adsorptive capacity of solids in natural systems; the presence of minerals might hinder As(III) oxidation by microbes. Under aerobic conditions, in the presence of iron oxides and As(III)-oxidizing bacteria, arsenic is adsorbed onto iron oxides within the adsorption capacity, and As(V) is the primary form in the solid and aqueous phases.


Advanced tools in marine natural drug discovery.
Marine natural products (MNPs) remain promising drug sources with several marine-derived drugs having been successfully approved. Nevertheless, it is never a smooth sailing to seek bioactive compounds from marine environments, during which many challenges are need to be faced to, for example, discovering unique marine resources, reviving unculturable organisms outside the marine environment, distinguishing novel compounds from the known ones, and disclosing the function of MNPs and optimizing their pharmacological use. Herein we review some advanced techniques and methodologies that can be employed to deal with above challenges with the intent of inspiring the forthcoming efforts in MNPs discovery pipelines.


[The work of child protection groups in Austria].
To document the number of child protection groups (CPG) in children's hospitals and paediatric surgeries in Austria. Further, to document detection frequency of abuse syndromes per inpatients per year and structural differences between departments with and without CPGs. Self-compiled questionnaire was distributed to all pediatric (43) and all pediatric surgery units (7). 68% of children's hospitals and 100% of paediatric surgical units had a CPG. Average detection frequency was reported to be 0.8 +/- 0.67% (range, 0-3.5). Distribution of CPG diagnoses is comparable, only sexual abuse was reported more frequently than reported internationally. Departments with CPG have more beds, more personnel, especially more psychosocial workers, and higher detection frequency. Frequency of CPGs is comparable to U.S. and Swiss data. Detection rates are low normal, but in departments without CPG, far below international standards.


Effect of Increased Intensity of Physiotherapy on Patient Outcomes After Stroke: An Economic Literature Review and Cost-Effectiveness Analysis.
Functional improvements have been seen in stroke patients who have received an increased intensity of physiotherapy. This requires additional costs in the form of increased physiotherapist time. The objective of this economic analysis is to determine the cost-effectiveness of increasing the intensity of physiotherapy (duration and/or frequency) during inpatient rehabilitation after stroke, from the perspective of the Ontario Ministry of Health and Long-term Care. The inputs for our economic evaluation were extracted from articles published in peer-reviewed journals and from reports from government sources or the Canadian Stroke Network. Where published data were not available, we sought expert opinion and used inputs based on the experts' estimates. The primary outcome we considered was cost per quality-adjusted life-year (QALY). We also evaluated functional strength training because of its similarities to physiotherapy. We used a 2-state Markov model to evaluate the cost-effectiveness of functional strength training and increased physiotherapy intensity for stroke inpatient rehabilitation. The model had a lifetime timeframe with a 5% annual discount rate. We then used sensitivity analyses to evaluate uncertainty in the model inputs. We found that functional strength training and higher-intensity physiotherapy resulted in lower costs and improved outcomes over a lifetime. However, our sensitivity analyses revealed high levels of uncertainty in the model inputs, and therefore in the results. There is a high level of uncertainty in this analysis due to the uncertainty in model inputs, with some of the major inputs based on expert panel consensus or expert opinion. In addition, the utility outcomes were based on a clinical study conducted in the United Kingdom (i.e., 1 study only, and not in an Ontario or Canadian setting). Functional strength training and higher-intensity physiotherapy may result in lower costs and improved health outcomes. However, these results should be interpreted with caution.


Process evaluation of the 'Singapore Physical Activity and Nutrition Study'.
The Singapore Physical Activity and Nutrition Study (SPANS) aimed to improve the physical activity (PA) and nutrition behaviours of Singaporean women aged 50 years and over. The SPANS program consisted of PA classes, nutrition workshops, telephone dietary counselling, health booklets, a health calendar and program ambassadors. This study aimed to assess and understand the implementation of the program strategies and gain insight into process evaluation components to inform future programs. The evaluation was guided by a process evaluation framework and collected data via questionnaires (n = 209), program ambassador documentation and exit interviews with program completers (n = 13) and non-completers (n = 12). In total, 295 participants completed the program (response rate = 84 %). Participants reported high levels of satisfaction with the overall program (99.5 %) and program activities (96.7 %), and also rated program ambassadors highly. Participation rates were highest for telephone dietary counselling sessions. The main reason for not attending program activities was having a 'busy schedule' (n = 158). Participants cited a need for improved recreational centre facilities and increased flexibility around program delivery. The process evaluation showed that the program strategies were implemented as planned and were deemed suitable for supporting behaviour change among Singaporean women aged 50 years and over. The program reached and involved the majority of participants throughout the six months. The combination of practical educational resources and supportive program ambassadors were key strategies that facilitated positive PA and dietary behaviours. However, there needs to be some flexibility in the delivery of programs. The findings of this research may inform other programs in the region.


A serum immune factor in detection of an occupational group with increased risk for lung and nose cancer.
Epidemiological studies have demonstrated that workers in the nickel refinery industry have an increased risk for respiratory tract carcinoma. In the present study, serum from 51 workers at a Norwegian nickel refinery have been tested against lung, nasal and breast carcinoma antigens in the humoral leukocyte adherence inhibition test. The breast cancer antigen was used as a non-specific antigen. The frequency of positive response against the lung carcinoma antigen was significantly higher among the refinery workers (21/51) than in the controls (3/17) (P = 0.07). Moreover, among workers employed for 10 years or more, the response was higher than found for workers with shorter employment. Of the nickel workers with nasal dysplasia, 56% (15/27) gave a positive reaction against the lung carcinoma antigen compared to 25% (6/24) of the workers without dysplasia (P = 0.03). The same trends were also found for the nasal carcinoma antigen. The study gives further support for the usefulness of the humoral leukocyte adherence inhibition test in identification of individuals with an increased risk for developing cancer.


Celiac crisis in children in Serbia.
To assess the prevalence and risk factors of celiac crisis (CC) in children with classical celiac disease (CD). This retrospective study comprised 367 children with classical CD diagnosed from 1994 to 2015. The diagnosis of CD was based on the revised ESPGHAN criteria and CC on acute worsening and rapid progression of chronic diarrhea and vomiting followed by severe dehydration, multiple metabolic derangements and a marked decrease of body weight. Celiac crisis was confirmed in six (1.63 %) children, five in the first and one in the second year of life. In three patients CC was precipitated by rotavirus and in one by Salmonella enteritidis infection, while in the remaining two, except for a too long-standing disease and severe malnutrition, no additional causes of CC were found. Celiac crisis in Serbia is still-present in children exclusively below the second year of life as a spontaneous or intestinal infection precipitated complication of previously unrecognized CD.


Broadband bifunctional Luneburg-Fisheye lens based on anisotropic metasurface.
Luneburg lenses and Maxwell fisheye lenses possess distinct properties of focusing, well beyond conventional lenses made of uniform materials. In this paper, a planar broadband bifunctional Luneburg-fisheye lens synthesized by gradient anisotropic metasurface is proposed. The proposed anisotropic metasurface is formed by non-resonant anisotropic cells, so that it can independently realize the equivalent gradient refractive indexes of Luneburg lens and Maxwell fisheye lens along orthogonal directions in a broad band, respectively. To verify the performance of the bifunctional lens, a prototype associated with a feeding log-periodic dipole antenna has been fabricated. Experimental results show that the proposed lens functions well over a wide frequency range with high efficiency and low profile, which coincides well with theoretical predictions and simulated results. It is expected that the proposed design will facilitate the applications of multifunctional metadevices in microwave and optical ranges.


Polytopic dystelephalangy of the fingers.
An 11-year-old girl with dystelephalangy (Kirner deformity) of the right middle, ring, and little, and the left index through little fingers is reported. To the author's best knowledge, such polytopic affection with dystelephalangy has not yet been reported. The parents, one of the siblings and maternal grandfather showed dystelephalangy of the little finger. So, the patient was considered to be a homozygous state of dystelephalangy gene.


Carotid artery repair for radiation-associated atherosclerosis is a safe and durable procedure.
The development of carotid atherosclerosis after neck irradiation is well documented. There has been concern about the safety and durability of carotid artery repair through a radiated field. The objective of this report is to describe the immediate and long-term results of a series of cases collected in a 13-year interval. From 1984 to 1997, 24 patients underwent 26 carotid artery operations. All the patients had undergone prior radiation therapy at a mean interval of 17 years, with an average radiation dose of 6300 rad. Severe scarring of the skin or radiation fibrosis were present in two thirds of the patients, with 4 patients having permanent tracheostomies. The indications for carotid surgery included cerebral or monocular transient ischemic attack (58%), asymptomatic high-grade stenosis (27%), prior stroke (12%), and tumor invasion of the carotid artery (4%). General anesthesia was used with selective shunting on the basis of carotid artery back pressure or electroencephalography monitoring. Patch angioplasty closure was used in 79% of the patients. The operations included standard carotid endarterectomy (n = 20), external carotid endarterectomy (n = 2), carotid patch angioplasty alone (n = 2), aortocarotid bypass grafting (n = 1), and carotid interposition grafting (n = 1). Four patients required skin grafting or myocutaneous flaps. No deaths or strokes occurred within 30 days of the operations. Six patients had transient cranial nerve palsy, and two had wound infections. The patients were followed from 1 to 156 months, with six patients being followed for longer than 18 months. No strokes were seen at late follow-up examination. Duplex scan examination documented one occlusion, in a patient with primary closure, and two restenoses, one of which necessitated reoperation. The remainder of the grafts were widely patent. Carotid surgery after neck irradiation is safe and durable. The long-term patency rates and the protection against subsequent neurologic events are similar to the results obtained in the absence of radiation therapy. Problems of wound healing were not found in this series.


Carbon nanofiber electrode for neurochemical monitoring.
The ability to rapidly detect neurotransmitter release has broad implications in the study of a variety of neurodegenerative diseases. Electrochemical detection methods using carbon nanofiber nanoelectrodes integrated into the Wireless Instantaneous Neurotransmitter Concentration Sensing System (WINCS) offer many important advantages including biocompatibility, selectivity, sensitivity, and rapid adsorption kinetics. Carbon nanofiber nanoelectrodes exhibit greater selectivity and sensitivity in the electrochemical detection of neurotransmitters compared to macroelectrodes and are able to resolve a ternary mixture of dopamine (DA), serotonin (5-HT), and ascorbic acid as well as to detect individual neurotransmitters in concentrations as low as 50 nM for DA and 100 nM for 5-HT using differential pulse voltammetry. Adsorption kinetics studies and isopropyl alcohol treatments modeled on previous studies on carbon fiber microelectrodes were conducted to investigate the analogous properties on carbon nanofiber electrodes using fast-scan cyclic voltammetry with WINCS and showed analogous results in carbon nanofiber electrodes compared with carbon fiber microelectrodes.


Transcriptional auto-regulation of the dopamine receptor regulating factor (DRRF) gene.
The murine dopamine receptor regulating factor (DRRF) gene is transcribed from a TATA-less promoter that has several putative Sp1 binding sites. The present investigation identifies functional transcription factors that modulate the expression of this gene. In the D2-dopamine receptor expressing NB41A3 cells, Sp1 potently activates transcription from the DRRF promoter in pCAT-DRRF-1153/+17, while DRRF itself effectively inhibits it. Sp1 also activates this promoter in pCAT-DRRF-310/+17. In competitive co-transfection experiments, DRRF represses the transcriptional activation induced by Sp1, while Sp1 de-represses the inhibitory effect of DRRF. Deletion of the 31 bp fragment between -1153 and -1122 decreased basal transcription down to about 60%. This fragment contains a functional AP1 binding site. In addition, deletion of the 129 bp region between -901 and -772 further decreased transcription. The latter region has a functional AP2 binding site. The present observations suggest that DRRF auto-regulates its own promoter by competing with Sp1 and that both AP1 and AP2 modulate expression of this gene.


Cardiogenic shock following electro-cardioversion of new onset atrial flutter.
Transient hypotension and atrial stunning are known complications of electro-cardioversion for supra-ventricular tachyarrhythmias, however, a clinically significant cardiac failure is extremely rare in this setting. We, herein, present a 77-year-old African American male who underwent electro-cardioversion following an unremarkable transesophageal echocardiogram (TEE) for a symptomatic atrial flutter of a new onset. Immediately post-cardioversion, he suffered severe hypotension with a depressed LV systolic function. IV dobutamine stabilized his blood pressure.


Lamellar interface fluid accumulation following traumatic corneal perforation and laser in situ keratomileusis.
A 41-year-old man with myopic astigmatism had laser in situ keratomileusis (LASIK) in each eye in April 2002. Ten months later, he sustained a central perforating corneal injury to the right eye. One day following repair of the corneal wound, he presented with diffuse corneal epithelial microcystic edema, lamellar interface fluid accumulation, and 20/400 visual acuity. Additional sutures were placed to close a presumed posterior wound gape with complete resolution of the corneal edema and lamellar interface fluid collection. One year later, his best corrected visual acuity measured 20/20+ in the right eye. This case is the first to document lamellar interface fluid accumulation following LASIK owing to traumatic disruption of the corneal endothelium.


Target of serine inhibition in Escherichia coli.
L-serine has long been known to inhibit growth of Escherichia coli cells cultured in minimal medium supplemented with glucose, lactate, or another carbohydrate as the sole source of carbon. However, the target of serine inhibition was not known. The growth inhibition was released by adding isoleucine, 2-ketobutyric acid, threonine or homoserine, but not by aspartate. Thus the inhibition site must be between aspartate and homoserine in the isoleucine biosynthetic pathway. We found that homoserine dehydrogenase I was strongly inhibited by serine. We isolated serine-resistant mutants, and found that in these mutants homoserine dehydrogenase I was resistant to serine. Thus, we conclude that the target of serine inhibition in Escherichia coli is homoserine dehydrogenase I.


Prophylactic amifostine prevents a pathologic vascular response in a murine model of expander-based breast reconstruction.
Although expander-based breast reconstruction is the most commonly used method of reconstruction worldwide, it continues to be plagued with complication rates as high as 60% when radiotherapy is implemented. We hypothesized that quantitative measures of radiotherapy-induced vascular injury can be mitigated by utilizing amifostine in a murine model of expander-based breast reconstruction. 30 rats were divided into three groups: expander placement (Control), expander placement followed by radiotherapy (XRT), and expander placement followed by radiotherapy with amifostine (AMF/XRT). All groups underwent placement of a sub-latissimus tissue expander. After a 45 day recovery period, all groups underwent vascular perfusion and micro-CT analysis. Micro-CT analysis was used to calculate vessel volume fraction (VVF), vessel number (VN), and vessel separation (VSp). A significant increase in VN was seen in the XRT group as compared to the Control (p = 0.021) and the AMF/XRT (p = 0.027). There was no difference between Control and AMF/XRT (p = 0.862). VVF was significantly higher in XRT than either Control (p = 0.043) and AMF/XRT (p = 0.040), however no difference was seen between Control and AMF/XRT (p = 0.980). VSp of XRT was smaller when compared to both Control and AMF/XRT specimens (p = 0.05 and p = 0.048, respectively), and no difference was seen between Control and AMF/XRT (p = 0.339). Amifostine administered prior to radiotherapy preserved vascular metrics similar to those of non-radiated specimens. Elevated vascularity demonstrated within the XRT group was not seen in either the Control or AMF/XRT groups. These results indicate that amifostine protects soft tissue in our model from a radiotherapy-induced pathologic vascular response.


Leisure-time physical activity interventions for children and adults with cerebral palsy: a scoping review.
To summarize current evidence on the effects and reach of leisure-time physical activity (LTPA) interventions among children and adults with cerebral palsy (CP). Systematic searches were conducted in PubMed, CINAHL, and Google Scholar to identify randomized controlled trials (RCTs) of LTPA interventions in CP. Data from eligible studies were extracted for qualitative synthesis. Forty-nine studies enrolled a total of 1513 participants (mean [SD] age 13y [7y], range 5-43y; 818 males, 655 females, 40 not reported) and primarily included ambulatory children. RCTs underrepresented adults and people in Gross Motor Function Classification System (GMFCS) levels IV and V. Forty-one studies reported at least one favorable benefit from LTPA. Benefits included improvements to musculoskeletal strength, cardiorespiratory fitness, quality of life, spasticity, participation, and core aspects of physical function. Regarding reach, only 34% of people that were contacted to participate enrolled within a study. A smaller percentage of participants dropped out from intervention (8%) and follow-up periods (3%). Study findings highlight effective interventions to improve health, fitness, and function. To enhance the reach and generalizability of LTPA trials for CP, future studies should examine how to increase study sample sizes and aim to include a better representation of adults and people in GMFCS levels IV and V. People with cerebral palsy (CP) may experience improvements in health, fitness, and physical function from leisure-time physical activity (LTPA) interventions. Effective interventions include exercise training, active video games, recreation activities, behavioral coaching, and motor skills training. Interventions that incorporate telehealth technology, behavioral coaching, and community resources may enhance LTPA. Interventions primarily include children in Gross Motor Functional Classification System (GMFCS) levels I to III. Adults, wheelchair users, and those in GMFCS levels IV and V are underrepresented.


Frontal-temporal functional connectivity of EEG signal by standardized permutation mutual information during anesthesia.
Quantifying brain dynamics during anesthesia is an important challenge for understanding the neurophysiological mechanisms of anesthetic drug effect. Several single channel Electroencephalogram (EEG) indices have been proposed for monitoring anesthetic drug effect. The most commonly used single channel commercial index is the Bispectral index (BIS). However, this monitor has shown some drawbacks. In this study, a nonlinear functional connectivity measure named Standardized Permutation Mutual Information (SPMI) is proposed to describe communication between two-channel EEG signals at frontal and temporal brain regions during a controlled propofol-induced anesthesia and recovery design from eight subjects. The SPMI index has higher correlation with estimated propofol effect-site concentration and has better ability to distinguish three anesthetic states of patient than the other functional connectivity indexes (cross-correlation, coherence, phase analysis) and also the BIS index. Moreover, the SPMI index has a faster reaction to the effect of drug concentration, less variability at the consciousness state and better robustness to noise than BIS.


Significance of Serum Uric Acid in Pregnancy Induced Hypertension.
Hypertension is one of the common medical complications of pregnancy and contributes significantly to maternal and perinatal morbidity and mortality. Uric acid (UA) is filtered, reabsorbed and secreted by the kidney. Thus, this study was conducted to assess the serum UA levels in PIH and to evaluate the diagnostic value of serum UA level in PIH. This is a hospital based comparative cross-sectional study conducted in BPKIHS. Ninety study participants were included; forty five participants were diagnosed of PIH and forty five in control group after obtaining informed consent from study participants from August 2014 to May 2015. Serum UA was done by Uricase method and serum creatinine was done by Jaffe's alkaline picrate method in cobas c311 autoanalyser. Data were expressed in frequency, percentage, mean ± S.D., median (IQR), and Independent t-test, Mann-Whitney U test were applied. p Value <0.05 is considered to be significant. Mean serum UA levels was higher in PIH compared to control group (5.46 ± 1.51 vs 4.03 ± 0.69) respectively. ROC curve demonstrated that serum UA showed a superior diagnostic efficiency (Sensitivity - 79.07%, Specificity - 71.19%) compared to creatinine (Sensitivity - 62.75%, Specificity - 27.45%) in PIH respectively. The present study shows that serum UA is significantly raised in PIH compared to the control group. Assessment of uric acid is a convenient and cost-effective method for determination of severity in PIH. Thus, serum uric acid can still be used as prevalent marker for risk assessment in PIH.


First trimester uterine artery Doppler abnormalities predict subsequent intrauterine growth restriction.
This study was undertaken to evaluate the association between uterine artery Doppler velocimetry performed between 10 and 14 weeks gestation and intrauterine growth restriction (IUGR). Uterine artery Doppler velocimetry data were collected on 1067 women enrolled in the FASTER trial at the University of Colorado site. The data were analyzed by using univariate and multivariable logistic regression analysis. The uterine artery mean resistance index (RI) for the entire cohort was equal on the right and left sides (0.59 +/- 0.14). Of the 1067 women, 34.2% had unilateral or bilateral diastolic notches, 1 notch was observed in 23.8%, and bilateral notches in 10.4%. Women with a high uterine artery mean RI (> or = 75th percentile) were 5.5 times more likely to have IUGR (95% CI 1.6-18.7). There was no significant relationship between notching and IUGR. Elevated first trimester uterine artery mean RI is significantly associated with IUGR.


A mitochondrial ubiquitin ligase MITOL controls cell toxicity of polyglutamine-expanded protein.
Expansion of a polyglutamine tract in ataxin-3 (polyQ) causes Machado-Joseph disease, a late-onset neurodegenerative disorder characterized by ubiquitin-positive aggregate formation. Several lines of evidence demonstrate that polyQ also accumulates in mitochondria and causes mitochondrial dysfunction. To uncover the mechanism of mitochondrial quality-control via the ubiquitin-proteasome pathway, we investigated whether MITOL, a novel mitochondrial ubiquitin ligase localized in the mitochondrial outer membrane, is involved in the degradation of pathogenic ataxin-3 in mitochondria. In this study, we used N-terminal-truncated pathogenic ataxin-3 with a 71-glutamine repeat (ΔNAT-3Q71) and found that MITOL promoted ΔNAT-3Q71 degradation via the ubiquitin-proteasome pathway and attenuated mitochondrial accumulation of ΔNAT-3Q71. Conversely, MITOL knockdown induced an accumulation of detergent-insoluble ΔNAT-3Q71 with large aggregate formation, resulting in cytochrome c release and subsequent cell death. Thus, MITOL plays a protective role against polyQ toxicity, and thereby may be a potential target for therapy in polyQ diseases. Our findings indicate a protein quality-control mechanism at the mitochondrial outer membrane via a MITOL-mediated ubiquitin-proteasome pathway.


Impact of the K24N mutation on the transactivation domain of p53 and its binding to murine double-minute clone 2.
The level of the p53 transcription factor is negatively regulated by the E3 ubiquitin ligase murine double-minute clone 2 (MDM2). The interaction between p53 and MDM2 is essential for the maintenance of genomic integrity for most eukaryotes. Previous structural studies revealed that MDM2 binds to p53 transactivation domain (p53TAD) from residues 17 to 29. The K24N mutation of p53TAD changes a lysine at position 24 to an asparagine. This mutation occurs naturally in the bovine family and is also found in a rare form of human gestational cancer called choriocarcinoma. In this study, we have investigated how the K24N mutation affects the affinity, structure, and dynamics of p53TAD binding to MDM2. Nuclear magnetic resonance studies of p53TAD show that the K24N mutant is more flexible and has less transient helical secondary structure than the wild type. Isothermal titration calorimetry measurements demonstrate that these changes in structure and dynamics do not significantly change the binding affinity for p53TAD-MDM2. Finally, free-energy perturbation and standard molecular dynamic simulations suggest the negligible affinity change is due to a compensating interaction energy between the K24N mutant and the MDM2 when it is bound. Overall, the data suggest that the K24N-MDM2 complex is able to, at least partly, compensate for an increase in the conformational entropy in unbound K24N with an increase in the bound-state electrostatic interaction energy.


Amino acids in the synaptic vesicle fraction from calf brain: content, uptake and metabolism.
A synaptic vesicle fraction was prepared from calf brain cortex, containing 10 identified amino acids and two unidentified ninhydrin-positive compounds, one of which is apparently a peptide. The most plentiful amino acids were taurine (1.8 nmol/g original tissue), glutamic acid (1.8), serine (0.9), aspartic acid (0.8) and GABA (0.8); the others identified were cysteic acid (or cysteinesulphinic acid), glutamine, alanine, glycine and lysine. The unknown peptide occurred in a high concentration (about 16 alanine equivalents/g), and contained mainly aspartic acid and serine. Cysteic acid (or cysteinesulphinic acid) also occurred in relatively high amounts, but its peak contained acid-labile impurities. The influx of [14C]glutamate into the vesicles took place by means of non-saturable migration, while two saturable systems having very similar properties were dominant only at low glutamate concentrations. Influx constants for these quantitatively low uptake systems were Km, 34 and 92 micrometer, and Vmax, 33 and 49 nmol/min/g obtained by v versus v/S plot. Almost the same values were also obtained by a 1/v versus 1/S plot. GAD and GABA-T activities in the vesicles were only 1/200th of those in the synaptosomes.


A simple approximation within the framework of the hybrid methods for the calculation of the electronic structure of solids is presented. By considering only the diagonal elements of the matrix of the perturbation operator (Hartree-Fock exchange minus semilocal exchange) calculated in the basis of the semilocal orbitals, the computational time is drastically reduced, while keeping very well in most studied cases the accuracy of the results obtained with hybrid functionals when applied without any approximations.


Treatment of Active Crohn's Disease with Exclusive and Partial Enteral Nutrition: A Pilot Study in Adults.
Enteral nutrition (EN) is not commonly used for the treatment of adults with active Crohn's disease (CD), despite patient interest in nutrition-based alternatives to corticosteroids and evidence of efficacy in paediatric CD. The aim of this study was to assess the impact of 2 different EN regimens on disease symptoms, nutrition and inflammatory markers in young adults with active CD. A prospective non-randomized pilot study of adults aged 16-40 years with active CD on endoscopy or imaging was undertaken. Patients were sequentially recruited to use 2 weeks of exclusive EN (EEN) followed by either 6 weeks of EEN or partial EN (PEN) with usual diet. Assessments of disease symptoms, nutrition and inflammatory markers were undertaken at baseline and throughout the treatment. Thirty-eight patients with active disease were recruited. Thirty-two (84$) patients completed 2 weeks of EEN and had significant improvements in disease symptoms (p = 0.003), serum c-reactive protein (CRP; p = 0.005), insulin-like growth factor-1 (p = 0.006) and faecal calprotectin (FC; p = 0.028). During the following 6 weeks, 21 patients continued EEN (14 [67$] completed treatment) and 11 patients used PEN (9 [82$] completed treatment). Initial improvements in symptoms, CRP and nutrition markers were sustained over the next 6 weeks on both treatments. FC non-significantly increased in 5 out of 9 patients who used PEN and at week 8 FC was greater than 500 µg/g in 9 out of 14 and 7 out of 9 patients who used exclusive or PEN respectively. There was no significant difference in clinical outcomes between the 2 groups at week 8. Two weeks of EEN significantly improved disease symptoms, nutrition and inflammatory markers. Further treatment with exclusive or PEN maintained initial improvements.


Opioid receptors and their interacting proteins.
The opioid receptors are among the most highly studied members of the family of G protein-coupled receptors. As for many other members of this family, recent studies have indicated that they do not exist in isolation but are able to interact with a substantial range of other polypeptides. Such interactions can alter the effectiveness of agonist-mediated cell signalling, determine the signals generated, alter the intracellular trafficking routes of the receptors and potentially determine cellular localization by providing a scaffold to link the receptors to the cytoskeletal network. Although virtually all studies on these interactions to date have employed expression into simple heterologous cell lines, the availability of knock-out mouse lines and the capacity to knock-down levels of opioid receptor-interacting proteins using techniques such as siRNA suggest that information on the functional consequences of such protein-protein interactions in a physiological setting will soon be forthcoming.


Warming-induced northwestward migration of the East Asian monsoon rain belt from the Last Glacial Maximum to the mid-Holocene.
Glacial-interglacial changes in the distribution of C3/C4 vegetation on the Chinese Loess Plateau have been related to East Asian summer monsoon intensity and position, and could provide insights into future changes caused by global warming. Here, we present δ(13)C records of bulk organic matter since the Last Glacial Maximum (LGM) from 21 loess sections across the Loess Plateau. The δ(13)C values (range: -25‰ to -16‰) increased gradually both from the LGM to the mid-Holocene in each section and from northwest to southeast in each time interval. During the LGM, C4 biomass increased from <5% in the northwest to 10-20% in the southeast, while during the mid-Holocene C4 vegetation increased throughout the Plateau, with estimated biomass increasing from 10% to 20% in the northwest to >40% in the southeast. The spatial pattern of C4 biomass in both the LGM and the mid-Holocene closely resembles that of modern warm-season precipitation, and thus can serve as a robust analog for the contemporary East Asian summer monsoon rain belt. Using the 10-20% isolines for C4 biomass in the cold LGM as a reference, we derived a minimum 300-km northwestward migration of the monsoon rain belt for the warm Holocene. Our results strongly support the prediction that Earth's thermal equator will move northward in a warmer world. The southward displacement of the monsoon rain belt and the drying trend observed during the last few decades in northern China will soon reverse as global warming continues.


A rapid procedure for the production and purification of vesicular stomatitis virus.
Ehrlich ascites tumour(EAT) cells were infected with vesicular stomatitis virus (VSV) within the peritoneal cavity of mice and used to prepare milligram quanities of purified virus. The protein pattern, endogenous transcriptase activity, and specific infectivity of this virus were comparable to viral preparations from HeLa and BHK cells. A total of 2-4 x 10(11) p.f.u. of VSV were obtained routinely from one mouse. The initial high concentration of VSV grown in EAT cells in the peritoneal cavity of mice facilitates virus isolation and allows its purification by a single gradient centrifugation step.


Interleukin 1 as a tumor cytostatic mediator released from tumor ascites-treated macrophages.
Peritoneal macrophages from DBA/2 mice, elicited by injection of Corynebacterium parvum (C.p.), were in vitro activated to Eb tumor cytostasis by incubation with tumor-induced ascites that was harvested 7 days after intraperitoneal Eb injection. The active cytostasis-mediating compound was found to be interleukin 1 (IL 1). When tumor ascites was fractionated according to molecular weight size, the most active IL 1-inducing fraction was found to comprise molecules of greater than 100,000 daltons. The data show that tumor-bearing hosts are capable of producing compounds that induce a high IL 1 secretion which may enable macrophages to mount an antiproliferative effect against tumor cells.


Anti-GQ1b antibody as a factor predictive of mechanical ventilation in Guillain-Barré syndrome.
Compared with 87 unventilated patients with Guillain-Barré syndrome (GBS), 44 ventilated patients with GBS more frequently had multiple cranial nerve involvement (91 vs 50%; p < 0.001) and IgG anti-GQ1b antibody (27 vs 8%; p = 0.006). In GBS patients without ophthalmoparesis, the presence of IgG anti-GQ1b antibody was associated with respiratory failure (12 [3/25] vs 0% [0/67]; p = 0.04). The presence of the antibody may be a factor predictive of respiratory failure in GBS.


A novel anti-cancer agent Icaritin suppresses hepatocellular carcinoma initiation and malignant growth through the IL-6/Jak2/Stat3 pathway.
Tumor-initiating cell (TIC) is a subpopulation of cells in tumors that are responsible for tumor initiation and progression. Recent studies indicate that hepatocellular carcinoma-initiating cells (HCICs) confer the high malignancy, recurrence and multi-drug resistance in hepatocellular carcinoma (HCC). In this study, we found that Icaritin, a prenylflavonoid derivative from Epimedium Genus, inhibited malignant growth of HCICs. Icaritin decreased the proportion of EpCAM-positive (a HCICs marker) cells, suppressed tumorsphere formation in vitro and tumor formation in vivo. We also found that Icaritin reduced expression of Interleukin-6 Receptors (IL-6Rs), attenuated both constitutive and IL-6-induced phosphorylation of Janus-activated kinases 2 (Jak2) and Signal transducer and activator of transcription 3 (Stat3), and inhibited Stat3 downstream genes, such as Bmi-1 and Oct4. The inhibitory activity of Icaritin in HCICs was augmented by siRNA-mediated silencing of Stat3 but attenuated by constitutive activation of Stat3.Taken together, our results indicate that Icaritin is able to inhibit malignant growth of HCICs and suggest that Icaritin may be developed into a novel therapeutic agent for effective treatment of HCC.


Diagnostic accuracy of interleukin-2 receptor in sarcoidosis: a systematic review and meta-analysis.
Soluble interleukin-2 receptor (sIL-2 R), a valuable diagnostic biomarker for sarcoidosis, has been reported with variable results. Based on the literatures currently accessible, a systematic review and meta-analysis of the diagnostic performance of serum sIL-2 R for sarcoidosis were performed. Relevant studies investigating sIL-2 R for sarcoidosis diagnosis in several databases were searched and data on sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), and diagnostic odds ratio (DOR) were pooled by STATA 16.0 software. Overall test performance was assessed using summary receiver operating characteristic curves and the area under the curve (AUC). Potential publication bias was assessed by Deeks test. We included eleven studies involving 1,424 subjects, with 1,099 cases of sarcoidosis and 325 of non-sarcoidosis. The pooled parameters of sIL-2 R in diagnosing sarcoidosis were summarized as follows: sensitivity, 0.85 (95% CI: 0.72-0.93); specificity, 0.88 (95% CI: 0.72-0.96); PLR, 7.3 (95% CI: 2.7-20.1); NLR, 0.17 (95% CI:0.08-0.36); DOR, 44 (95% CI: 8-231); and the AUC, 0.93 (95% CI: 0.90-0.95). No publication bias was identified (P = 0.64). Evidence suggests sIL-2 R performs well in diagnosing sarcoidosis. Nevertheless, results of sIL-2 R assay should be interpreted with other diagnostic examinations.


Design principles and mechanistic explanation.
In this essay I propose that what design principles in systems biology and systems neuroscience do is to present abstract characterizations of mechanisms, and thereby facilitate mechanistic explanation. To show this, one design principle in systems neuroscience, i.e., the multilayer perceptron, is examined. However, Braillard (2010) contends that design principles provide a sort of non-mechanistic explanation due to two related reasons: they are very general and describe non-causal dependence relationships. In response to this, I argue that, on the one hand, all mechanisms are more or less general (or abstract), and on the other, many (if not all) design principles are causal systems.


Best New Flaps and Tips for Success in Microsurgery.
After reviewing this article, the participant should be able to: 1. Understand the trends in reconstruction using flaps. 2. Understand the surgical anatomy and elevation of the three best flaps: superficial circumflex iliac artery perforator, profunda artery perforator, and thin anterolateral thigh perforator. 3. Understand the core principle and the modern evolution of microsurgery. 4. Be acquainted with new microsurgical tips to maximize outcomes. Plastic surgery has a long history of innovation expanding the conditions we can treat, and microsurgical reconstruction has played a pivotal role. Freestyle free flaps now create another paradigm shift in reconstructive surgery, relying on a better understanding of anatomy and physiology, opening the door to patient-specific customized reconstruction. This article aims to provide information regarding useful and practical new advances in the field of microsurgery.


Tumor characteristics in screen-detected and symptomatic breast cancers.
The natural course of early breast cancer has changed as a result of the introduction of mammographic screening. The present aim was a prospective analysis of screen-detected and symptomatic operable breast cancers in the era of mammographic service screening. The mode of detection (screen-detected, symptomatic or interval cancer), the type of mammographic image and other characteristics (the invasive tumor size, histological tumor type, grade, nodal, hormone receptor and HER2 status and the presence of lymphovascular invasion) of 569 invasive breast cancers were studied. Screen-detected cancers were significantly more frequently of grade I, < 10 mm of size and node-negative (p < 0.001, respectively). Symptomatic/interval cancers were significantly more frequently of grade 3, >20 mm of size (p < 0.001), and exhibited lymphovascular invasion (p = 0.001). Screening-detection of the tumor favored breast-conserving surgery, sentinel lymph node biopsy and the avoidance of chemotherapy (p < 0.001). Cancers associated with casting-type calcifications on the mammogram were typically of ductal type (p = 0.043), of grade 2-3, estrogen receptor and progesterone receptor-negative and HER2-positive (p < 0.001). Interval cancers occurred significantly more often at a younger age and remained mammographically occult as compared with other cancers. Mammographic screen-detected cancers demonstrate more favorable prognostic features, and need less extensive treatment than symptomatic or interval cancers. The mammographic appearance of the tumor reflects its biological behavior, and this should be considered in the management optimization.


Oscillating contractions in protoplasmic strands of Physarum: effects of externally applied ouabain, sodium-, potassium- and calcium-ions.
1. Concentrations of 0.1-10 mM Ouabain do not affect oscillating contractions, when applied externally in physiological solutions. 2. Ouabain has no effect, when applied in solutions of increased sodium- (100 mM) and lowered potassium-concentration (0.1 or zero mM). 3. De novo generation of oscillating contractions in protoplasmic drops is not suppressed in Ouabain-solutions. 4. Biochemical studies of Na-K-ATPase did not show any Ouabain sensitive ATPase-activity. 5. Reaction of veins on high concentrations (300 mosm) is discussed as to be a physical effect. 6. It is concluded that no Na-K-ATPase is engaged in triggering oscillating contraction automaticity.


The degraded polysaccharide from Pyropia haitanensis represses amyloid beta peptide-induced neurotoxicity and memory in vivo.
An antioxidant polysaccharide, porphyran, from red algae Pyropia haitanensis, is introduced as a protective agent against neurotoxicity-induced amyloid β peptide (Aβ) of Alzheimer's disease (AD) mice. Then the activity of acetylcholinesterase (AChE) and choline acetyltransferase (CHAT) in the cortical and hippocampal tissue were examined by colorimetric method. Results showed that porphyran significantly ameliorated the learning and memory impairment induced by Aβ1-40. Biochemical analysis showed that porphyran increased ChAT activity and decreased AChE activity in the cortical and hippocampal tissue. The mechanism may be related with the increase of cerebral acetylcholine content. Porphyran has a potential of developing anti-aging drug.


Potent bicyclic lactam inhibitors of thrombin: Part I: P3 modifications.
Peptidomimetic inhibitors of general structure 1 have been prepared. Optimization of the binding affinities of these compounds through variation of the P3 hydrophobic residue is described. Selected substituted bicylic lactams displayed interesting pharmacological profiles both in vitro and in vivo.


Successful use of oligopeptides as immunogens in the preparation of antisera to immediate-early gene products of herpes simplex virus type 1.
Antisera to two herpes simplex virus-type 1 (HSV-1) immediate-early gene products ( IE12 and IE175 ) have been produced using oligopeptides, constructed on the basis of proposed DNA coding sequences, as immunogens. In both cases the synthetic peptides were linked to bovine serum albumin via an N-terminal tyrosine prior to immunization. Both the IE12 and the IE175 antisera reacted with their respective HSV-1 antigens and with antigens produced by the HSV-1 immediate-early mutant tsK but not with functionally equivalent antigens induced by HSV-2. IE12 induced by tsK was found to have an altered mobility with respect to the wild-type IE12 and its precipitation was accompanied by a second, minor, component of lower mobility. Revertants of tsK gave similar results. Labelling IE12 with a variety of amino acids indicated that the first of three possible initiation codons was used in its translation from mRNA. The results imply that the other initiation codons were not used. Wildtype IE12 is produced for at least 3 h after release of cycloheximide block and appears to be turned over rapidly.


N-(2,3,4-Trifluoro-phen-yl)morpholine-4-carboxamide.
In title mol-ecule, C(11)H(11)F(3)N(2)O(2), the central -N-C(=O)-N- unit is essentially planar [maximum deviation = 0.013 (2) Å] and forms a dihedral angle of 57.33 (9)° with the benzene ring. The morpholine ring is in a chair conformation. In the crystal, mol-ecules are linked into chains along [001] by N-H⋯O hydrogen bonds.


Regional variation of insulin-like growth factor-I gene expression in mature rat bone and cartilage.
Regulation of long bone growth by growth hormone and other endocrine factors is mediated by the local synthesis of IGF-I in the growth plate. Recent evidence suggests that different regions of the growth plate exhibit variable growth rates. To investigate whether IGF-I gene expression in the growth plate differs in relation to growth, we examined the distribution of IGF-I mRNA and peptide using in situ hybridization and immunohistochemistry, respectively, in the tibiae of 18-week-old rats (n = 6). Osteoblasts were identified by osteocalcin immunoreactivity, and osteoclasts by tartrate-resistant acid phosphatase (TRAP) histochemistry. The abundance of IGF-I mRNA in growth plate chondrocytes was quantified by counting the autoradiographic signal associated with each cell. IGF-I mRNA was identified in chondrocytes of both the proliferative and hypertrophic zones of the growth plate. Cells in the marginal regions of both zones contained significantly more IGF-I mRNA than those in the central region (p < 0.05). In addition, IGF-I mRNA levels were greater in the periphery of the growth plate on the medial side of the tibia (p < 0.05) in which there was more active growth than the lateral side. IGF-I immunoreactivity was present predominantly in the hypertrophic zone chondrocytes and no regional differences in its distribution were observed. IGF-I mRNA and peptide were also identified in periosteal fibroblasts, notably at sites of muscle attachment to bone, and in osteoblasts at active sites of bone remodelling in the periosteal, endocortical, and endosteal bone envelopes. In the TRAP-positive osteoclasts, IGF-I immunoreactivity, but not IGF-I mRNA, was detected. In addition, both IGF-I mRNA and peptide were identified in the hemopoietic cells of the metaphyseal bone marrow, whereas only IGF-I immunoreactivity was detectable in the diaphysis. We conclude that, in the tibiae of mature rats: (i) IGF-I gene expression in the growth plate is related to its growth and/or synthetic activity; and (ii) the presence of IGF-I in osteoblasts and osteoclasts suggests its involvement in active bone growth and remodeling.


Effect of nitrofurantoin on meiosis of the male mouse.
The effects of nitrofurantoin [N-(5-nitro-2-furfurylidine)-1-amino-hydantoin] on chromosomes of primary and secondary spermatocytes of mice were studied. No mutagenic activity was detectable after application of either 8 mg/kg or 40 mg/kg nitrofurantoin. An increase in the univalent rates and a decrease in the chiasma frequencies was observed in treated animals. The probable origins of these effects are discussed.


Toxicological analysis and effectiveness of oral Kalanchoe pinnata on a human case of cutaneous leishmaniasis.
Leishmaniasis is an extremely difficult disease to treat. Previously, it was shown that oral Kalanchoe pinnata (Kp) leaf extract is strongly effective against murine leishmaniasis. Here, it is shown that the serum levels of alanine-aminotransferase (ALT), aspartate-aminotransferase (AST), urea and alkaline phosphatase were unchanged in mice orally treated with supraoptimal Kp doses for 30 days, indicating the absence of chronic toxicity to the liver, heart or kidney. Additionally, evidence is presented that human leishmaniasis may also be controlled with oral Kp. A 36-year-old man with an active cutaneous leishmaniasis was orally treated with 30 g wet weight of Kp leaves/day for 14 days. During the Kp treatment, the lesion stopped growing and slightly decreased. No adverse reactions or toxicity was observed. This study reports for the first time that Kalanchoe pinnata contains substances potentially active and safe for the oral treatment of human cutaneous leishmaniasis.


Differences by sex in associations between injection drug risks and drug crime conviction among people who inject drugs in Almaty, Kazakhstan.
The criminalization of drug use leads to high rates of drug crime convictions for engaging in injection drug use behaviors, introducing barriers to HIV prevention and drug treatment for PWID. Females (FWID) face unique vulnerabilities to HIV compared to males (MWID) in Kazakhstan. This study examined sex differences in associations between HIV/HCV infection, HIV knowledge, injection drug risk behaviors, and conviction for a drug crime in a sample of people who inject drugs (PWID) in Almaty, Kazakhstan. Analyses were performed on baseline data from 510 PWID and stratified by males (MWID) (329) and females (FWID) (181) from Kazakhstan in a couples-focused HIV prevention intervention. Logistic regression analyses using mixed effects (AOR) examined associations between HIV/HCV infection, HIV knowledge, injection drug risk behaviors, drug use severity, drug treatment history and conviction for a drug crime. About three quarters of PWID reported drug crime conviction (73.92%, n = 377). HCV infection was associated with increased odds of drug crime conviction for FWID (AOR = 4.35, CI95 = 1.83-10.31, p < .01) and MWID (AOR = 3.62, CI95 = 1.09-12.07, p < .01). HIV transmission knowledge was associated with increased odds of conviction for MWID (AOR = 1.19, CI95 = 1.00-1.41, p < .05). Injection drug risk knowledge was associated with lower odds of conviction (AOR = .75, CI95 = .59-.94, p < .05) for FWID. Receptive syringe sharing (AOR = 3.48, CI95 = 1.65-7.31, p < .01), splitting drug solutions (AOR = 4.12, CI95 = 1.86-7.31, p < .05), and injecting with more than two partners (AOR = 1.89, CI95 = 1.06-3.34, p < .05) was associated with increased odds of conviction for FWID. Receptive syringe or equipment sharing with intimate partners was associated with conviction for both MWID (AOR = 1.90, CI95 = 1.03-3.92, p < .05) and FWID (AOR = 1.95, CI95 = 1.02-3.70, p < .05). For FWID, injection drug use in public spaces was associated with conviction (AORME = 3.25, CI95 = 1.31-7.39, p < .01). Drug use severity was associated with increased odds of conviction for FWID (AOR = 1.29, CI95 = 1.09-1.53, p < .001) and MWID (AOR = 1.24, CI95 = 1.09-1.41, p < .001). Ever receiving drug treatment was associated with conviction for MWID (AOR = 2.31, CI95 = 1.32-4.12, p < .01). High-risk behaviors, HCV infection and more severe substance use disorders are associated with drug crime conviction for PWID, particularly FWID. Structural interventions are necessary to increase the engagement of PWID with drug crime convictions in HIV prevention and substance abuse treatment.


Collagen prolyl 4-hydroxylase tetramers and dimers show identical decreases in Km values for peptide substrates with increasing chain length: mutation of one of the two catalytic sites in the tetramer inactivates the enzyme by more than half.
The collagen prolyl 4-hydroxylases (collagen P4Hs, EC 22.214.171.124) play a key role in the synthesis of the extracellular matrix. The vertebrate enzymes are alpha(2)beta(2) tetramers, the beta subunit being identical to protein disulfide isomerase (PDI). The main Caenorhabditis elegans collagen P4H form is an unusual PHY-1/PHY-2/(PDI)(2) mixed tetramer consisting of two types of catalytic alpha subunit, but the PHY-1 and PHY-2 polypeptides also form active PHY/PDI dimers. The lengths of peptide substrates have a major effect on their interaction with the P4H tetramers, the K(m) values decreasing markedly with increasing chain length. This phenomenon has been explained in terms of processive binding of the two catalytic subunits to long peptides. We determined here the K(m) values of a collagen P4H having two catalytic sites, the C. elegans mixed tetramer, and a form having only one such site, the PHY-1/PDI dimer, for peptides of varying lengths. All the K(m) values of the PHY-1/PDI dimer were found to be about 1.5-2.5 times those of the tetramer, but increasing peptide length led to identical decreases in the values of both enzyme forms. The K(m) for a nonhydroxylated collagen fragment with 33 -X-Y-Gly-triplets but only 11 -X-Pro-Gly-triplets was found to correspond to the number of the former rather than the latter. To study the individual roles of the two catalytic sites in a tetramer, we produced mutant PHY-1/PHY-2/(PDI)(2) tetramers in which binding of the Fe(2+) ion or 2-oxoglutarate to one of the two catalytic sites was prevented. The activities of the mutant tetramers decreased to markedly less than 50% of that of the wild type, being about 5-10% and 20-30% with the enzymes having one of the two Fe(2+)-binding sites or 2-oxoglutarate-binding sites inactivated, respectively, while the K(m) values for these cosubstrates or peptide substrates were not affected. Our data thus indicate that although collagen P4Hs do not act on peptide substrates by a processive mechanism, prevention of hydroxylation at one of the two catalytic sites in the tetramer impairs the function of the other catalytic site.


Lessons from game theory about healthcare system price inflation: evidence from a community-level case study.
Game theory is useful for identifying conditions under which individual stakeholders in a collective action problem interact in ways that are more cooperative and in the best interest of the collective. The literature applying game theory to healthcare markets predicts that when providers set prices for services autonomously and in a noncooperative fashion, the market will be susceptible to ongoing price inflation. We compare the traditional fee-for-service pricing framework with an alternative framework involving modified doctor, hospital and insurer pricing and incentive strategies. While the fee-for-service framework generally allows providers to set prices autonomously, the alternative framework constrains providers to interact more cooperatively. We use community-level provider and insurer data to compare provider and insurer costs and patient wellness under the traditional and modified pricing frameworks. The alternative pricing framework assumes (i) providers agree to manage all outpatient claims; (ii) the insurer agrees to manage all inpatient clams; and (iii) insurance premiums are tied to patients' healthy behaviours. Consistent with game theory predictions, the more cooperative alternative pricing framework benefits all parties by producing substantially lower administrative costs along with higher profit margins for the providers and the insurer. With insurance premiums tied to consumers' risk-reducing behaviours, the cost of insurance likewise decreases for both the consumer and the insurer.


Targeting the RAS pathway in melanoma.
Metastatic melanoma is a highly lethal type of skin cancer and is often refractory to all traditional chemotherapeutic agents. Key insights into the genetic makeup of melanoma tumors have led to the development of promising targeted agents. An activated RAS pathway, anchored by oncogenic BRAF, appears to be the central motor driving melanoma proliferation. Although recent clinical trials have brought enormous hope to patients with melanoma, adverse effects and novel escape mechanisms of these inhibitors have already emerged. Definition of the limits of the first successful targeted therapies will provide the basis for further advances in management of disseminated melanoma. In this review, the current state of targeted therapy for melanoma is discussed, including the potent BRAF(V600E) inhibitor vemurafenib.


Patient outcomes in light chain (AL) amyloidosis: The clock is ticking from symptoms to diagnosis.
Symptomology of AL amyloidosis can be vague, with a broad range of manifestations and potential etiologies. We sought to determine whether time from initial patient-reported symptom onset to diagnosis was associated with survival. The Boston University Amyloidosis Patient Database was queried for patients with AL amyloidosis who presented to the Center for initial evaluation from 2010 to 2015. A total of 324 patients with AL amyloidosis were evaluated for initial evaluation. The median time to diagnosis from initial symptom onset was 7.1 months (range, 0-61). At data cutoff, 60.2% (n = 195) of patients were alive; of those, the majority were diagnosed <6 months from initial symptoms (52.3%, n = 102). In contrast, time to diagnosis from symptom onset was >6 months in 63.6% (n = 82) of patients who did not survive at the time of data cutoff (P = .0005). Survival analysis of time from diagnosis to death or data cutoff stratified by time from patient-reported symptom onset to diagnosis (<6, 6-12, and >12 months) showed significant differences among groups (P = .001). Additionally, multivariable regression demonstrated that an increase in time from self-reported symptom onset to diagnosis was significantly associated with an increased risk of death (HR = 1.02, 95% CI = 1.01-1.04, P = .002). These results support the importance of early diagnosis for patients with AL amyloidosis.