Distinguishing characteristics of exposure to biguanide and sulfonylurea anti-diabetic medications in the United States.
Biguanides and sulfonylureas are anti-hyperglycemic drugs commonly used in the United States. Poisoning with these drugs may lead to serious consequences. The diagnosis of biguanide and sulfonylurea poisoning is based on history, clinical manifestations, and laboratory studies. This study is a six-year retrospective cohort analysis based on the National Poison Data System. Clinical effects of 6183 biguanide and sulfonylurea exposures were identified using binary logistic regression. The mean age of patients with biguanide and sulfonylurea exposure was 39.27 ± 28.91 and 28.91 ± 30.41 years, respectively. Sulfonylurea exposure is most commonly seen via unintentional exposure, while biguanide exposure frequently occurs as a result of intentional ingestion. Minor and moderate outcomes commonly developed following biguanide and sulfonylurea exposure, respectively. Sulfonylurea exposure was less likely to develop clinical effects abdominal pain, metabolic acidosis, diarrhea, nausea, vomiting, and elevated creatinine than patients ingesting biguanides. However, sulfonylurea exposure was more likely to cause dizziness or vertigo, tremor, drowsiness or lethargy, agitation, diaphoresis, and hypoglycemia. Our study is the first to use a wide range of national data to describe the clinical characteristics that differentiate the toxicologic exposure to biguanides and sulfonylureas. Sulfonylurea exposure is commonly seen via unintentional exposure, while metformin exposure is frequently seen via intentional exposure. Sulfonylurea toxicity is more likely to cause agitation, dizziness or vertigo, tremor, diaphoresis, and hypoglycemia, while metformin exposure induces abdominal pain, acidosis, diarrhea, nausea, vomiting, and elevated creatinine.


Effects of naltrexone on learning and performance of conditional fear-induced freezing and opioid analgesia.
In the presence of Pavlovian conditional aversive stimuli rats engage in defensive freezing and exhibit a decreased sensitivity to painful stimulation. Administration of the opioid antagonist naltrexone (7 mg/ml/kg) prior to training in a context fear conditioning procedure using footshock caused an increase in freezing but did not affect suppression of formalin-induced recuperative behaviors relative to controls during a test session 24 hr later. The same dose of naltrexone given during the test session reversed conditional analgesia without altering the level of freezing. These results suggest that full expression of endogenous opioid analgesia during training is not necessary for conditional responding.


Accuracy and reproducibility of strain by speckle tracking in pediatric subjects with normal heart and single ventricular physiology: a two-dimensional speckle-tracking echocardiography and magnetic resonance imaging correlative study.
Myocardial strain is a sensitive measure of ventricular systolic function. Two-dimensional speckle-tracking echocardiography (2DSE) is an angle-independent method for strain measurement but has not been validated in pediatric subjects. The aim of this study was to evaluate the accuracy and reproducibility of 2DSE-measured strain against reference tagged magnetic resonance imaging-measured strain in pediatric subjects with normal hearts and those with single ventricles (SVs) of left ventricular morphology after the Fontan procedure. Peak systolic circumferential strain and longitudinal strain (LS) in segments (n = 16) of left ventricles in age-matched and body surface area-matched 20 healthy and 12 pediatric subjects with tricuspid atresia after the Fontan procedure were measured by 2DSE and tagged magnetic resonance imaging. Average (global) and regional segmental strains measured by the two methods were compared using Spearman's and Bland-Altman analyses. Global strains measured by 2DSE and tagged magnetic resonance imaging demonstrated close agreements, which were better for LS than circumferential strain and in normal left ventricles than in SVs (95% limits of agreement, +0.0% to +3.12%, -2.48% to +1.08%, -4.6% to +1.8%, and -3.6% to +1.8%, respectively). There was variability in agreement between regional strains, with wider limits in apical than in basal regions in normal left ventricles and heterogeneity in SVs. Strain values were significantly (P < .05) higher in normal left ventricles than in SVs except for basal LS, which were similar in both cohorts. The regional strains in normal left ventricles demonstrated an apicobasal magnitude gradient, whereas SVs showed heterogeneity. Reproducibility was the most robust for images obtained with frame rates between 60 and 90 frames/sec, global LS in both cohorts, and basal strains in normal left ventricles. Strains measured by 2DSE agree with strain measured by magnetic resonance imaging globally but vary regionally, particularly in SVs. Global strain may be a more robust tool for cardiac functional evaluation than regional strain in SV physiology. The reliability of 2DSE-measured strain is affected by the frame rate, the nature of strain, and ventricular geometry.


Long-term effects of serum cholesterol on bone mineral density in women and men: the Framingham Osteoporosis Study.
Laboratory studies have suggested a role for cholesterol in the pathogenesis of both osteoporosis and atherosclerosis. The purpose of this prospective study was to assess whether cholesterol levels, repeatedly measured over three decades in young and middle-aged adult women and men, predicted bone mineral density (BMD) at advanced age. Study participants included 712 women and 450 men enrolled in the Framingham Osteoporosis Study, aged 32-61 years at baseline (1953-55) who underwent bone densitometry 34 years later (1988-1989). BMD was measured at the proximal femur (neck, trochanter, and Ward's triangle) and lumbar spine using dual-photon absorptiometry and at the one-third radial shaft and ultradistal radius using single-photon absorptiometry. Sex-specific multivariable linear regression was used to model each BMD site as a function of total cholesterol level, adjusted for age, cigarette smoking, alcohol consumption, body mass index, systolic blood pressure, diabetes, and estrogen use (women). No significant association between total cholesterol and BMD was found in women for any of the bone sites considered. For example, adjusted mean BMD at the lumbar spine was similar in women from the lowest to highest quartile of total cholesterol, respectively, 1.07, 1.08, 1.06, 1.07 g/cm2; P for trend=0.98. Similarly, the findings in men largely showed no association between cholesterol and BMD, although there was an isolated finding of a statistically significant trend in decreasing mean radial shaft BMD with increasing total cholesterol, 0.73, 0.72, 0.72, 0.70 g/cm2, lowest to highest quartile, P for trend=0.02. Cholesterol levels in women and men from young adulthood to middle age years do not appear to have long-term clinical implications for osteoporosis later in life.


An AI-Based Algorithm for the Automatic Classification of Thoracic Radiographs in Cats.
An artificial intelligence (AI)-based computer-aided detection (CAD) algorithm to detect some of the most common radiographic findings in the feline thorax was developed and tested. The database used for training comprised radiographs acquired at two different institutions. Only correctly exposed and positioned radiographs were included in the database used for training. The presence of several radiographic findings was recorded. Consequenly, the radiographic findings included for training were: no findings, bronchial pattern, pleural effusion, mass, alveolar pattern, pneumothorax, cardiomegaly. Multi-label convolutional neural networks (CNNs) were used to develop the CAD algorithm, and the performance of two different CNN architectures, ResNet 50 and Inception V3, was compared. Both architectures had an area under the receiver operating characteristic curve (AUC) above 0.9 for alveolar pattern, bronchial pattern and pleural effusion, an AUC above 0.8 for no findings and pneumothorax, and an AUC above 0.7 for cardiomegaly. The AUC for mass was low (above 0.5) for both architectures. No significant differences were evident in the diagnostic accuracy of either architecture.


Use of Topical Steroids in Dermatology: A Questionnaire Based Study.
Topical steroids, the most widely prescribed drugs in dermatology are being increasingly misused. This study was conducted to assess knowledge and practices regarding the use of topical steroids and to analyze prescriptions containing topical steroids. Following approval from the institutional ethics committee, participants were recruited as per the selection criteria and divided into those treated in the institution and those having outside prescription. They were administered a pre-validated questionnaire to assess knowledge and practices regarding the use of topical steroids. Comparison of awareness between two patient categories was done using Chi-square test. Prescription variables were analyzed using descriptive statistics. Significance of P value was set at 0.05. Out of 400 patients, 167 had external prescriptions whereas 233 were institutional patients. Only 5.5% of all patients knew about the type of drug prescribed whereas 31.25% were aware of the indication. A total of 33.75% of the patients knew topical steroids required a prescription and 5.6% said they were aware that topical steroid use was associated with side effects. Side effects were reported by 96 patients. Awareness regarding knowledge, indication, and need for prescription were significantly better in institutional patients whereas knowledge about side effects was lacking in both groups. Psoriasis was the most common indication overall whereas tinea was the most common indication (51.5%) among externally prescribed. Although this study showed that institutional patients had comparatively better knowledge than community-treated patients, there is a need to create more awareness among patients overall and implement measures to stop irrational prescribing practices in the community.


An extremely rare case of pituitary functioning gonadotroph microadenoma accompanied by ovarian hyperstimulation syndrome in a woman of reproductive age.
To report a case of pituitary functioning gonadotroph microadenoma accompanied by ovarian hyperstimulation syndrome (OHSS) in a woman of reproductive age. A case report. Tertiary care unit of a university hospital. A 42-year-old parous woman with bilateral ovarian enlargement presumed to be secondary to a functioning gonadotroph pituitary microadenoma. Oral contraceptives and endoscopic transsphenoidal surgery for adenoma that initially could not be visualized on a magnetic resonance imaging (MRI) scan. Medical and radiographic assessment of endogenously induced OHSS and its resolution after treatment. The patient was diagnosed with OHSS secondary to elevations in endogenous levels of follicle-stimulating hormone (FSH). The cranial contrast-enhanced MRI scan did not show any apparent tumor in the pituitary gland. She was, therefore, treated with oral contraceptives, which resulted in a modest resolution of ovarian enlargement; however, this treatment became ineffective 3 years later. A small pituitary adenoma (maximum diameter of 8 mm) was suspected on repeated MRI (2 years after the first MRI). Selective adenomectomy was performed, which resulted in normalization of the ovarian size and resumption of regular menstrual cycles. We report a case of a functional pituitary microadenoma secreting FSH in quantities significant enough to result in OHSS. The excessive FSH production was resistant to medical therapy; however, surgical treatment was ultimately successful.


Effects of vitamin D3 metabolites on bone cell calcium transport.
The vitamin D3 metabolite, 25-hydroxycholecalciferol, at concentrations of 0.01 to 10.0 microgram/ml, decreased calcium uptake by isolated bone cells. The effect occurred within 1 min after the simultaneous addition of metabolite and 45Ca. Lactic acid and ATP production by the cells was not affected. 24(R), 25-dihydroxycholecalciferol produced a similar decrease in calcium uptake. Vitamin D3 had no effect at concentrations from 0.01 to 10.0 micrograms/ml. No effect of 1,25-dihydroxycholecalciferol on calcium uptake was observed with concentrations from 0.1 to 100 ng/ml and various preincubation periods extending to 2 h. None of the agents had any effect on calcium efflux. The effects of 25-hydroxycholecalciferol and 24(R), 25-dihydroxycholecalciferol on calcium uptake were not seen in isolated fetal rat skin cell preparations.


The inhibitory effects of pudendal nerve stimulation on bladder overactivity in spinal cord injury dogs: is early stimulation necessary?
To determine the inhibitory effects of pudendal nerve stimulation (5 Hz) on bladder overactivity at early and late stages of spinal cord injury in dogs. The study was performed in eight dogs with chronic spinal cord transection at the T9-T10 level. Group 1 (four dogs) underwent electrical stimulation of pudendal nerve one month after spinal cord transection. Group 2 (four dogs) underwent stimulation six months after spinal cord transection. The bladders were removed for histological examination of fibrosis after the stimulation. The bladder capacity and the compliance were significantly increased (p < 0.05) by pudendal nerve stimulation in group 1, but not in group 2. The nonvoiding contractions were inhibited in both groups by electrical stimulation. Collagen fiber was increased, while elastic fiber was significantly decreased (p < 0.05) in group 2 when compared with group 1. Pudendal nerve stimulation can increase the bladder capacity and compliance only during the early period before the bladder wall becomes fibrosit and can inhibit the nonvoiding contraction during two stages.


Hospital falls: development of a predictive model for clinical practice.
A retrospective case-control study related to falls was conducted at an 1,120-bed acute care tertiary hospital. The case (fall) sample consisted of 102 falls and 236 control (nonfall) charts during a 1-month period. An instrument developed by Hendrich (1988) was modified for use in the study. Demographic data and risk factors were recorded. Descriptive statistics included risk factor percentages for each sample and the corresponding univariate relative risks. Logistic regression was used to develop a multivariate risk factor model with seven risk factors. The significant risk factors were recent history of falls, depression, altered elimination patterns, dizziness or vertigo, primary cancer diagnosis, confusion, and altered mobility. The adjusted relative risks were converted to risk points to be used to assess a patient's level of fall risk. Within the data set, a sensitivity of 77% (79 of 102) and specificity of 72% (169 of 236) were calculated. The model was cross-validated in a 1987 data set with a sensitivity of 83% (59 of 71) and specificity of 66% (106 of 161).


Incidence of Cell-Saver contamination during cardiopulmonary bypass.
During regular bacteriological surveillance of cardiac surgical equipment and patients, the Cell Saver apparatus (CSA) was prospectively evaluated to determine if it represented an additional risk for infection. Nineteen patients were studied. After each operation, the effluent from the CSA was sterilely sealed for subsequent culture. A total of 42 aerobic and 42 anaerobic cultures were made. Postoperatively all patients were evaluated daily for four days and before discharge for clinical evidence of infection. Four patients had positive CSA cultures without evidence of postoperative clinical infection. Five patients in whom postoperative infectious complications developed had negative CSA cultures. Ten patients had negative CSA cultures and no evidence of postoperative infection. We conclude that the CSA does not appear to contribute to the risk of infection in cardiac surgical patients and that it is a safe adjunct to cardiac surgery.


The effects of public health insurance on health behaviors: Evidence from the fifth year of Medicaid expansion.
This study examines the longer term relationship between public health insurance expansions and health behaviors. I leverage geographic and temporal variation in the implementation of the Affordable Care Act-facilitated Medicaid expansions and provide the first estimates of the expansions' behavioral impacts during their first 5 years. Using national survey data from the 2010 to 2018 Behavioral Risk Factors Surveillance System and a difference-in-differences regression design, I show that the Medicaid expansions increase utilization of certain forms of preventive care, while reducing heavy drinking. I also find suggestive evidence that the expansions reduce smoking and increase the probability of exercise. These results stand in contrast with earlier studies that used only 2 or 3 years of postexpansion data and found no detectable effect of the Medicaid expansions on health behaviors in the short run. My results, combined with evidence from previous studies, suggest that public insurance expansions may not prompt an immediate change in health behaviors, but newly eligible populations do increase investments in healthy behaviors over time. In the long run, Medicaid expansions may help reduce engagement in risky behaviors like drinking and smoking among low-income people.


Quality of life issues in hypertension: consequences of diagnosis and considerations in management.
Most patients with mild to moderate hypertension are asymptomatic. Any adverse response to nonpharmacologic or pharmacologic therapies can negatively influence some aspect of the patient's sense of well-being and life satisfaction; this will likely limit the compliance with and the resultant benefits of therapy. The diagnosis of hypertension itself is associated with psychological consequences, termed the "labeling effect," that impair life quality. A number of life-style modifications and a variety of highly effective and safe classes of antihypertensive agents can satisfactorily control blood pressure in most patients. Evaluation of the patient's response to an antihypertensive regimen should, in addition to measurement of the level of blood pressure and review of laboratory test values, include assessment of quality of life outcomes: impact of therapy on the patient's daily routine, fatigue or activity limitation, sexual dysfunction, impairment of memory, alertness, mood, or cognitive ability, sleep dysfunction, work performance and satisfaction, and satisfaction with family, social, and leisure time activities.


Large-scale purification of factor VIII by affinity chromatography: optimization of process parameters.
The optimization of a new process for the extraction of human coagulation factor VIII (FVIII) from plasma with the tailor-made affinity matrix dimethylamino-propylcarbamylpentyl-Sepharose CL-4B (C3-C5 matrix) is described. First, plasma is applied to DEAE-Sephadex A-50 anion exchanger in order to separate a number of proteins, including coagulation factors II, IX and X (prothrombin complex), from FVIII. Subsequently, the unbound fraction of the ion exchanger, containing FVIII, is contacted with the C3-C5 affinity matrix. Optimization of the FVIII affinity chromatographic procedure is accomplished in terms of the ligand density of the matrix, adsorption mode (batch-wise versus column-wise adsorption and matrix to plasma ratio), and conditions of pH and conductivity to be applied on washing and desorption. In scale-up experiments, by processing 20 l of plasma, the recovery (340 U VIII:C/kg plasma) and the specific activity (s.a.) (1.2 U VIII:C/mg protein) are better than those obtained by cryoprecipitation (recovery 300 U VIII:C/kg plasma, s.a. 0.3 U VIII:C/mg protein). The newly developed process using the specially designed C3-C5 affinity matrix has potential application in the process-scale purification of FVIII.


A comparison of alprazolam with amitriptyline in the treatment of patients with neurotic or reactive depression. A report of a randomised, double blind study by a General Practitioner Working Party.
104 patients suffering from neurotic or reactive depression were treated with either alprazolam or amitriptyline in randomised, double-blind fashion. Seventeen patients were either lost to follow-up or withdrawn before week 2 (13 due to side effects and 1 because she was feeling better). A further 7 patients did not comply with the protocol, giving a total of 24 patients whose data were not considered suitable for inclusion in the analysis of therapeutic assessments. Evaluation of the 80 patients (40 in each group) who completed at least 2 weeks of the 4-week study demonstrate that both treatments produced a statistically significant response rate. There was a more rapid effect in those patients who received amitriptyline, but there was no significant difference in response between the treatment groups after 4 weeks treatment. Analysis of safety and side effect data on 101 patients (50 treated with alprazolam and 51 with amitriptyline) shows no statistically significant difference in the overall number of side effects experienced in each group, although 11 of those patients who received amitriptyline withdrew because of adverse reactions before completing the study compared to 6 in the alprazolam group. These results suggest that alprazolam may be a useful treatment for patients with neurotic or reactive depression not requiring hospitalisation.


Molecular and cellular mechanisms of protective immunity to coccidioidomycosis.
Coccidioides immitis is endemic in the soil of the desert Southwest. It causes a respiratory infection that is usually mild, but can last months and may disseminate beyond the lung. Disseminated infections can be fatal or require life-long therapy. Development of an effective vaccine may be a successful method of preventing serious disease. In this paper, we show that immunostimulatory-oligodeoxynucleotides (ISS-ODN) are an effective adjuvant for a recombinant coccidioidal protein known as antigen 2/proline rich antigen. Protective immunity induced by this ISS-ODN-based vaccine requires IL-12, interferon-gamma and MHC Class II-restricted T-cells. Cytotoxic CD8 T-cells are not required. This study elucidates the mechanisms needed to elicit successful immunity against coccidioidomycosis, and holds promise for development of an effective coccidioidal vaccine against coccidioidomycosis.


Autophagy induced by silibinin protects human epidermoid carcinoma A431 cells from UVB-induced apoptosis.
Ultraviolet B (UVB) in the sun light is a major cause of skin damage, which accompanies complex alterations in irradiated skin cells, including DNA lesions, oxidative stress, inflammation and caspase activation. The protection against UVB damage requires multiple interruptions such as repair of the DNA lesions, scavenging of the reactive oxygen species (ROS), repression of the inflammation and others. Silibinin is suggested as an anti-UVB reagent, but the underlying mechanisms have not been fully elucidated. In this study, we found a role of autophagy in the anti-UVB effect of silibinin in A431 cells. Autophagy was reduced after UVB-irradiation while restored by silibinin through the suppression of the IGF-1R signalling pathway. The protective effect of silibinin in UVB-irradiated A431 cells was further enhanced by pre-treatment with an autophagy inducer, rapamycin, while it was reversed by an autophagy inhibitor, wortmannin, indicating that elevated autophagy contributed to the cell survival. Consistently, cell apoptosis was augmented by siRNAs targeting Beclin 1 and Atg5, supporting the hypothesis that autophagy induced by silibinin plays a protective role against UVB-induced epidermal apoptosis.


Biomarkers of An Autoimmune Skin Disease--Psoriasis.
Psoriasis is one of the most prevalent autoimmune skin diseases. However, its etiology and pathogenesis are still unclear. Over the last decade, omics-based technologies have been extensively utilized for biomarker discovery. As a result, some promising markers for psoriasis have been identified at the genome, transcriptome, proteome, and metabolome level. These discoveries have provided new insights into the underlying molecular mechanisms and signaling pathways in psoriasis pathogenesis. More importantly, some of these markers may prove useful in the diagnosis of psoriasis and in the prediction of disease progression once they have been validated. In this review, we summarize the most recent findings in psoriasis biomarker discovery. In addition, we will discuss several emerging technologies and their potential for novel biomarker discovery and diagnostics for psoriasis.


The fidelity of visual memory for faces and non-face objects.
The fidelity of visual working memory was assessed for faces and non-face objects. In two experiments, four levels of memory load (1, 2, 3, or 4 items) were combined with four perceptual distances between probe and study items, with maximum item confusability occurring for the minimum memory load. Under these conditions, recognition memory for multiple faces exceeded that of a single face. This result was primarily due to the higher false alarm rates for faces than non-face objects, even though the two classes of stimuli had been matched for perceptual discriminability. Control experiments revealed that this counterintuitive result emerged only for old-new recognition choices based on near-threshold image differences. For non-face objects, instead, recognition performance decreased with increasing memory load. It is speculated that the low memorial discriminability of the transient properties of a face may serve the purpose of enhancing recognition at the individual-exemplar level.


The effect of livestock on the physiological condition of roe deer (Capreolus capreolus) is modulated by habitat quality.
Free-range livestock grazing is a widespread human activity that not only modifies natural vegetation but also leads to interactions with wild ungulates. Most commonly, the interactions between cattle and wild ungulates have been studied with a focus on competition for high-quality forage. However, other mechanisms, such as the risk of parasite infection, might better describe this interaction. We aim to determine whether livestock affect roe deer (Capreolus capreolus Linnaeus, 1758) by reducing habitat quality and increasing the probability of infection by shared parasites. We measured noninvasive fecal cortisol metabolites as an indicator of habitat quality as well as the lung nematode larvae burden from the Dictyocaulus genus. A higher Dictyocaulus larvae load was found in the presence of livestock in pines, and feces collected in winter had a higher parasite load than feces collected in autumn. Additionally, fecal cortisol metabolite levels in the roe deer were affected by the interaction between habitat quality and livestock presence and were higher in the poorest habitat and when living in sympatry with cattle. Our results suggest that physiological stress responses in roe deer were mediated by the habitat type and the presence of competitors. The long-term implications of altered physiological responses such as those demonstrated here should be considered in management strategies for deer.


Temperature sensitivity and decomposition rate of 101 leaf litter types from Mediterranean ecosystems.
Litter decomposition is a fundamental process, and the number of published studies has steadily increased in recent decades. However, few experiments have systematically compared a large number of litter types and evaluated their temperature sensitivity. We conducted a two-year experiment on the decomposition of litter bags containing 101 leaf litter sampled in Mediterranean ecosystems and incubated under laboratory conditions at 4 °C, 14 °C, and 24 °C. Litter was chemically characterized and analysed for carbon (C), nitrogen (N), cellulose and lignin concentration, C/N, and lignin/N ratios, which serve as predictors of decomposition rate. The sensitivity of litter decay rate to temperature was evaluated using Q10. Leaf litter chemistry varied widely in nitrogen content (range 0.52-6.80 %), lignin content (range 1.53-49.31 %), C/N ratio (range 5.21-77.78), and lignin/N ratio (range 0.34-34.90). Litter decomposition rate was negatively related to initial lignin concentration, lignin/N ratio, and C/N ratio, but only in the early stage. In the late stages of decomposition, litter decay rate was negatively correlated with initial N concentration but positively correlated with C/N and lignin/N ratios. Temperature sensitivity was negatively correlated with N concentration and positively correlated with lignin and lignin/N ratio. It is noteworthy that, contrary to expectations, temperature sensitivity exhibited a hump-shaped relationship with decay rate. N, C/N, and lignin/N ratios should be used with caution because their predictive power is reversed with respect to decomposition rate during the decomposition process. In addition, the new finding that temperature sensitivity has a hump-shaped relationship with decomposition rate deserves further confirmation and could be considered in ecosystem-level organic C modeling.


Proteolytic activation of Bacillus thuringiensis Vip3Aa protein by Spodoptera exigua midgut protease.
Proteolysis of Vip3Aa by insect midgut proteases is essential for their toxicity against target insects. In the present study, proteolysis of Vip3Aa was evaluated by Spodoptera exigua midgut proteases (MJ). Trypsin was verified involved in the activation of Vip3Aa and three potential cleavage sites (Lys195, Lys197 and Lys198) were identified. Four Vip3Aa mutants (KKK195197198AAA, KK197198AA, KK195198AA and KK195197AA) were designed and constructed by replacing residues Lys195,197,198, Lys197,198, Lys195,198 and Lys195,197 with Ala, respectively. Proteolytic processing assays revealed that mutants KK197198AA, KK195198AA and KK195197AA could be processed into 66kDa activated toxins by trypsin or MJ while mutant KKK195197198AAA was not cleaved by trypsin and less susceptible to MJ. Bioassays demonstrated that mutants KK197198AA, KK195198AA and KK195197AA were toxic against S. exigua resembled that of wild-type Vip3Aa, however, the LC50 of mutant KKK195197198AAA against S. exigua was higher than wild-type. Those results suggested that proteolysis by MJ was associated with the insecticidal toxicity of Vip3Aa against S. exigua. It also revealed that trypsin played an important role in the formation of Vip3Aa activated toxin. Our studies characterized the proteolytic processing of Vip3Aa and provided new insight into the activation of this novel Bt toxin.


The applications of deep learning algorithms on in silico druggable proteins identification.
The top priority in drug development is to identify novel and effective drug targets. In vitro assays are frequently used for this purpose; however, traditional experimental approaches are insufficient for large-scale exploration of novel drug targets, as they are expensive, time-consuming and laborious. Therefore, computational methods have emerged in recent decades as an alternative to aid experimental drug discovery studies by developing sophisticated predictive models to estimate unknown drugs/compounds and their targets. The recent success of deep learning (DL) techniques in machine learning and artificial intelligence has further attracted a great deal of attention in the biomedicine field, including computational drug discovery. This study focuses on the practical applications of deep learning algorithms for predicting druggable proteins and proposes a powerful predictor for fast and accurate identification of potential drug targets. Using a gold-standard dataset, we explored several typical protein features and different deep learning algorithms and evaluated their performance in a comprehensive way. We provide an overview of the entire experimental process, including protein features and descriptors, neural network architectures, libraries and toolkits for deep learning modelling, performance evaluation metrics, model interpretation and visualization. Experimental results show that the hybrid model (architecture: CNN-RNN (BiLSTM) + DNN; feature: dictionary encoding + DC_TC_CTD) performed better than the other models on the benchmark dataset. This hybrid model was able to achieve 90.0% accuracy and 0.800 MCC on the test dataset and 84.8% and 0.703 on a nonredundant independent test dataset, which is comparable to those of existing methods. We developed the first deep learning-based classifier for fast and accurate identification of potential druggable proteins. We hope that this study will be helpful for future researchers who would like to use deep learning techniques to develop relevant predictive models.


Neuroleptic malignant syndrome and compulsive drinking of water.
In spite of multiple authoritative reviews in recent years on the subject of neuroleptic malignant syndrome, the association of neuroleptic malignant syndrome with excessive fluid consumption has received little attention. This association is described and comments are made as to its possible origins. Further investigations are required to determine the strength and nature of the association. Such findings may have implications not only for clinical management but also for the poorly-understood neurochemistry of the neuroleptic malignant syndrome.


Analysis of Claims that the Brain Extracellular Impedance Is High and Non-resistive.
Numerous measurements in the brain of the impedance between two extracellular electrodes have shown that it is approximately resistive in the range of biological interest, <10 kHz, and has a value close to that expected from the conductivity of physiological saline and the extracellular volume fraction in brain tissue. Recent work from Gomes et al. has claimed that the impedance of the extracellular space is some three orders of magnitude greater than these values and also displays a 1/f frequency dependence (above a low-frequency corner frequency). Their measurements were performed between an intracellular electrode and an extracellular electrode. It is argued that they incorrectly extracted the extracellular impedance because of an inaccurate representation of the large confounding impedance of the neuronal membrane. In conclusion, no compelling evidence has been provided to undermine the well-established and physically plausible consensus that the brain extracellular impedance is low and approximately resistive.


An audit of expedited treatment for uncomplicated Chlamydia trachomatis index cases at the community pharmacy.
Expedited treatment of index patients testing positive for uncomplicated Chlamydia trachomatis via paper treatment vouchers that can be redeemed at a community pharmacy is feasible.


A multivariate study of determinants of vigorous exercise in a community sample.
The purpose of this study was to explore the associations between several social learning theory variables and self-reported vigorous exercise and to consider the implications for exercise promotion. A random sample of adults in San Diego, California, was surveyed by mail. The 2,053 respondents (response rate, 43.4%) overrepresented Caucasian, affluent, and well-educated groups. A model of 24 variables accounted for 0.27 of the variance in exercise, and results strongly supported social learning theory. The strongest correlates were self-efficacy (i.e., confidence in the ability to exercise in specific situations), perceived barriers to exercise, modeling, dietary habits, support from friends, and age. Smoking was inversely associated with exercise in men only. We encourage researchers to conduct intervention trials to test the hypotheses generated in this study.


The whole-cell proteome shows the characteristics of macrolides-resistant Bordetella pertussis in China linked to the biofilm formation.
The macrolides-resistant Bordetella pertussis (MR-Bp) isolates in China evolved from the ptxP1/fhaB3 allele and rapidly became predominant, suggestive of an adaptive transmission ability. This was different from the global prevalent ptxP3 strains, in which MR-Bp was rarely reported. The study aimed to determine the underlying mechanism responsible for fitness and resistance in these two strains. We identify proteomic differences between ptxP1/fhaB3 and ptxP3/fhaB1 strains using tandem mass tag (TMT)-based proteomics. We then performed in-depth bioinformatic analysis to determine differentially expressed genes (DEGs), followed by gene ontology (GO), and protein-protein interaction (PPI) network analysis. Further parallel reaction monitoring (PRM) analysis confirmed the expression of four target proteins. Finally, the crystal violet method was used to determine biofilm-forming ability. The results showed that the main significantly different proteins between the two represent isolates were related to biofilm formation. Furthermore, we have confirmed that ptxP1/fhaB3 showed hyperbiofilm formation in comparison with ptxP3/fhaB1. It is suggested that the resistance and adaptability of ptxP1/fhaB3 strains may be related to the formation of biofilm through proteomics. In a word, we determined the significantly different proteins between the ptxP1/fhaB3 and ptxP3/fhaB1 strains through whole-cell proteome, which were related to biofilm formation.


Presence and location of TP53 mutation determines pattern of CDKN2A/ARF pathway inactivation in bladder cancer.
Transformation and immortalization require the inactivation of key cell cycle regulatory genes. We examined 19 bladder cancer cell lines derived from 17 patients for alterations in TP53, RB1, CDKN2A, and ARF. Twelve cell lines had a mutation in exons 5-11 of TP53 and, with only one exception, a concomitant loss of RB1 protein expression. Another group of seven cell lines had a wild-type TP53 gene or a mutation in exons 1-4 of TP53 and concomitant alterations in both CDKN2A and ARF in every case. This demonstrates the requirement, in all but one line, for inactivation of both the CDKN2A/RB1 and ARF/TP53 pathways in bladder cancer cell lines and provides the first evidence for potential differences in the penetrance of mutations in the transactivation and DNA-binding domains of TP53.


Benign familial pemphigus--premenstrual exacerbation suppressed by goserelin and oophorectomy.
We report the case of premenstrually exacerbated benign familial pemphigus which showed dramatic improvement with subcutaneous goserelin, a gonadotrophin-releasing hormone analogue. Total abdominal hysterectomy and bilateral salpingo-oophorectomy and oestrogen replacement therapy sustained the improvement.


Analysis of rhG-CSF-effects on platelets by in vitro bleeding test and transcranial Doppler ultrasound examination.
Experimental evidence suggests a stimulatory effect of recombinant human granulocyte colony-stimulating factor (rhG-CSF) on both platelets and coagulation. RhG-CSF is increasingly used to stimulate healthy volunteer donors for blood stem cell mobilization. We therefore assessed 25 healthy donors receiving rhG-CSF for changes in in vitro bleeding test (IVBT), coagulation parameters and cerebral microembolism by transcranial Doppler (TCD) ultrasound. A significant shortening of IVBT was found on day 4 of rhG-CSF administration together with increased levels of fibrinogen and factor VIII and reduced activities of protein C and protein S. Although these changes are quite small it is possible that they may lead to a hypercoagulable state especially in donors with other risk factors for thromboembolism. However, TCD examination failed to detect any signs of microembolism. We therefore conclude that rhG-CSF leads to significant changes in coagulation parameters, but has no effect on TCD detectable microembolism as a stroke risk factor. However donors receiving rhG-CSF should be examined carefully to detect pre-existing changes in the coagulation system and we would like to suggest a routine thrombophilia screen.


[Immunoaffinity purification of alpha 1-protease inhibitor from human plasma].
A single-step procedure is described for isolation of alpha 1-inhibitor of proteases (alpha 1-IP) from human blood plasma using affinity chromatography on immunosorbent containing monoclonal antibodies against alpha 1-IP. Activity of the alpha 1-IP preparation, estimated by means of specific trypsin inhibition, was increased 61.1-fold after the chromatography, with a yield of the end product 20%. The preparation of alpha 1-IP obtained exhibited electrophoretic and immunochemical homogeneity.


PIM1/STAT3 axis: a potential co-targeted therapeutic approach in triple-negative breast cancer.
Triple-negative breast cancer lacks an expression of ER, PR, and Her-2, has a poor prognosis, and there are no target therapies available. Therapeutic options to treat TNBC are limited and urgently needed. Strong evidence indicates that molecular signaling pathways have a significant function to regulate biological mechanisms and their abnormal expression endows with the development of cancer. PIM kinase is overexpressed in various human cancers including TNBC which is regulated by various signaling pathways that are crucial for cancer cell proliferation and survival and also make PIM kinase as an attractive drug target. One of the targets of the STAT3 signaling pathway is PIM1 that plays a key role in tumor progression and transformation. In this review, we accumulate the current scenario of the PIM-STAT3 axis that provides insights into the PIM1 and STAT3 inhibitors which can be developed as potential co-inhibitors as prospective anticancer agents.


Five-to-five clear aligner therapy: predictable orthodontic movement for general dentist to achieve minimally invasive dentistry.
Esthetic dentistry has become a very important aspect of every dental treatment from the patient perspective, whether it is orthodontics or implant therapy. The aim of this article is to describe the advantages of a newly developed branch of five-to-five clear aligner therapy (CAT) (Invisalign Go, Align Technology, San Jose, Calif) in interdisciplinary treatments especially in terms of minimally invasive interventions. Two case reports are presented together with a comprehensive analysis using the SAFE (Safety, Assessment, Function, Ethics) assessment. This paper aims to introduce a new systematic in CAT. Invisalign Go (Align Technology, Santa Clara, California, USA) allows orthodontic treatment from second premolar and second premolar in both arches. It is specially designed for general practitioners devoted to restorative dentistry for a better planning of a multidisciplinary and mini-invasive treatment plan. The clinical results demonstrate how CAT is extremely useful in multidisciplinary treatment plan in order to straighten teeth especially in a pre-restorative phase to allow minimally invasive and adhesive restorations.


Detection of proximal coronary occlusion in acute coronary syndrome: a feasibility study using computerized electrocardiographic analysis.
Rapid identification of a proximal occlusion site of a major coronary artery is of paramount importance in the care of myocardial infarction (MI). It is increasingly recognized that routine electrocardiogram (ECG) can be used for that purpose, provided that expert interpretation is available. Computer-based signal analysis has potential to enhance early ECG interpretation but its performance must be validated against manual algorithms. We therefore set out to develop a computer-assisted model to detect proximal occlusion of the left anterior descending coronary artery (LAD) in patients with suspected acute coronary syndrome (ACS). Based on manual anatomical interpretation of the ECG, obtained from 216 consecutive patients who were admitted due to suspected ACS, an automatic computerized ECG model to detect LAD occlusion was constructed. Agreement between manual evaluation of the ECG by two cardiologists and a computerized ECG algorithm to detect occlusion of the LAD and the site of occlusion was determined. Using an expert electrocardiographer's anatomical interpretation as the gold standard, the computer model recognized patients fulfilling ECG criteria for any occlusion of the LAD with a specificity of 99% and a sensitivity of 67% (kappa= 0.71). However, proximal LAD occlusion was detected with 100% specificity and 86% sensitivity (kappa= 0.72). The computer program detected a distal occlusion in the LAD with a specificity of 99% and a sensitivity of 40% (kappa= 0.72). Computerized anatomical interpretation of the ECG is feasible and allows detection of a proximal LAD occlusion with excellent accuracy.


[Mouth floor and mobile tongue epidermoid carcinomas thickness: prognostic value].
Most cancers of the oral cavity are epidermoid carcinomas. The prognosis is made on the patient's general health status and the tumoral stage. The UICC TNM staging classification system is one of the most important factors taken in consideration for the prognosis. But this classification in oral epidermoid carcinomas does not include the tumor thickness (except for T4 tumors). Several studies demonstrated that tumor thickness could influence the prognosis in epidermoid carcinoma and other types of cancers. The aim of our retrospective study was to assess the prognostic value of tumor thickness in oral epidermoid carcinoma. The study included patients with mouth floor or mobile tongue epidermoid carcinoma classified T1N0, T2N0 and T3N0 between 1985 and 2005. All patients were treated with a curative intention. A pathologist analysed the tumor thickness and cervical lymph nodes. All the slides were examined to measure tumor thickness in millimetres. Three hundred and five patient files were reviewed and 124 patients were included, with 94 men (75.8%), and a mean age of 59.3 years (17-93). The mean and median tumor thickness were respectively 7.7 and 6.5 mm (0.4-30). The median tumor thickness was chosen for the study. There was a statistically significant link between the five-year probability of global survival and the initial tumor thickness and between neck node invasion and tumor thickness (p<0.05). This study suggests that tumor thickness should be taken in consideration in T1N0, T2N0 and T3N0 mouth floor and mobile tongue epidermoid carcinomas. In the future, the clinical evaluation of tumor thickness will help determine the therapeutic management.


Thermodynamics, kinetics and isothermal studies of tartrazine adsorption onto microcline/MWCNTs nanocomposite and the regeneration potentials.
The quest for a cheap, effective, and eco-friendly wastewater treatment technique that is free of secondary toxic byproducts, calls for the fabrication of a nature-friendly adsorbent with a robust capacity to decontaminate polluted water sources and be recycled. To this end, we report the fabrication of novel nanocomposite (KMCM) from microcline (KMC) and multiwall carbon nanotubes (MWCNTs). The adsorbents (KMC and KMCM) were characterized using XRD, BET, SEM, TGA and FTIR. The novel and low-cost nano sorbent were designed for the elimination of tartrazine (Tatz) from wastewater. The adsorption of Tatz onto KMC and KMCM was influenced by adsorbent dose, initial Tatz concentration, contact time and solution pH. Experimental data acquired from the equilibrium studies were well addressed by the Langmuir isotherm model. The maximum uptake capacity of 37.96 mg g-1 and 67.17 mg g-1 were estimated for KMC and KMCM. The kinetics for the adsorption of Tatz onto KMC and KMCM was best expressed by pseudo-second-order and Elovich models. The thermodynamic parameters revealed that the uptake of Tatz onto KMC and KMCM was an endothermic (ΔH: KMC = 35.0 kJ mol-1 and KMCM = 42.91 kJ mol-1), entropy-driven (ΔS: KMC = 177.6 J K-1 mol-1 and KMCM = 214.2 J K-1 mol-1) and spontaneous process. Meanwhile, KMCM demonstrated good reusability potential and superior adsorption efficiency when compared to other adsorbents.


Microdissection for detecting genetic aberrations in early and advanced human urinary bladder cancer.
Laser microdissection is an essential method for the investigation of the multistep carcinogenic process in the urinary bladder. Reliable detection of tumor-specific alterations which can be compromised by the presence of normal cells, requires microdissection of pure tumor cell populations (>80%) to detect loss of heterozygosity (LOH) by either fluorescence in situ hybridization (FISH) or sequence analysis. Multiple molecular methods need to be performed in the course of studying often-small lesions. This chapter describes in detail the use of laser microdissection, whole-genome amplification by improved primer extension preamplification (I-PEP)-polymerase chain reaction, and subsequent LOH, FISH, and sequencing analysis in the investigation of urothelial tumors and their precursor lesions. The combination of the described methods allows a wide spectrum of molecular investigations of tumor cells and helps to understand the fundamental alterations involved in urothelial carcinogenesis.


Allergen microarrays.
Allergy affects more than 25% of Western populations (1) and is estimated to be the sixth leading cause of chronic disease in the United States and Western Europe. The complexity of the condition is such that hundreds of common allergens have been described, and in order to maximize diagnostic efficiency there is an urgent clinical requirement for assays to provide multiple-allergen determination in a timely and cost-effective manner. Miniaturized immunoassays that utilize protein microarray technology now offer the possibility of circumventing most of the current limitations in the serodiagnosis of allergic disease. The heterogeneous nature of allergens presents many challenges in all aspects of developing such arrays, from immobilization of the capture molecule to detection of the bound ligand. In addition, there is no simple method of protein amplification (such as PCR for nucleic acids), and stabilization is yet a further major consideration. Notwithstanding these challenges, protein microarrays have been developed for the serodiagnosis of allergies and other complex clinical conditions. These assays exhibit good analytical and clinical performance and deliver significant advantages in convenience and cost compared with traditional ELISA test formats. This chapter details the techniques employed in the construction and processing of an allergen array specific for the serodiagnosis of allergic disease. An overview of protein microarray technology is provided and the principles that underpin the suitability for use of this technology in the identification and measurement of particular proteins in patient sera (serum profiling) are discussed.


Improved variable reduction in partial least squares modelling based on predictive-property-ranked variables and adaptation of partial least squares complexity.
The calibration performance of partial least squares for one response variable (PLS1) can be improved by elimination of uninformative variables. Many methods are based on so-called predictive variable properties, which are functions of various PLS-model parameters, and which may change during the variable reduction process. In these methods variable reduction is made on the variables ranked in descending order for a given variable property. The methods start with full spectrum modelling. Iteratively, until a specified number of remaining variables is reached, the variable with the smallest property value is eliminated; a new PLS model is calculated, followed by a renewed ranking of the variables. The Stepwise Variable Reduction methods using Predictive-Property-Ranked Variables are denoted as SVR-PPRV. In the existing SVR-PPRV methods the PLS model complexity is kept constant during the variable reduction process. In this study, three new SVR-PPRV methods are proposed, in which a possibility for decreasing the PLS model complexity during the variable reduction process is build in. Therefore we denote our methods as PPRVR-CAM methods (Predictive-Property-Ranked Variable Reduction with Complexity Adapted Models). The selective and predictive abilities of the new methods are investigated and tested, using the absolute PLS regression coefficients as predictive property. They were compared with two modifications of existing SVR-PPRV methods (with constant PLS model complexity) and with two reference methods: uninformative variable elimination followed by either a genetic algorithm for PLS (UVE-GA-PLS) or an interval PLS (UVE-iPLS). The performance of the methods is investigated in conjunction with two data sets from near-infrared sources (NIR) and one simulated set. The selective and predictive performances of the variable reduction methods are compared statistically using the Wilcoxon signed rank test. The three newly developed PPRVR-CAM methods were able to retain significantly smaller numbers of informative variables than the existing SVR-PPRV, UVE-GA-PLS and UVE-iPLS methods without loss of prediction ability. Contrary to UVE-GA-PLS and UVE-iPLS, there is no variability in the number of retained variables in each PPRV(R) method. Renewed variable ranking, after deletion of a variable, followed by remodelling, combined with the possibility to decrease the PLS model complexity, is beneficial. A preferred PPRVR-CAM method is proposed.


Exposure to methylparaben at environmentally realistic concentrations significantly impairs neuronal health in adult zebrafish.
Methylparaben (MeP) is an emerging aquatic pollutant that is found to impact neural functions. However, it still lacks a comprehensive understanding about its neurotoxicology. The present study exposed adult zebrafish to environmentally realistic concentrations (0, 1, 3, and 10 µg/L) of MeP for 28 days, with objectives to elucidate the neurotoxic effects and mechanisms. Proteomic profiling found that MeP pollutant induced distinct mechanism of neurotoxicity as a function of sex. MeP pollutant appeared to preferentially target the neurotransmission cascade via synapse junctions. In male brain, glutamatergic neural signaling was enhanced by 10 µg/L of MeP in characteristics of higher glutamate neurotransmitter content (by 61.9%) and up-regulated glutamate receptor expression by 2.6-fold relative to the control. In MeP-exposed female brain, biomarker proteins of synapse formation and regeneration had significantly lower abundance, accounting for the blockage of synaptic neurotransmission. Furthermore, under the stress of MeP pollutant, both male and female zebrafish initiated a negative feedback mechanism along stress neuroendocrine axis by down-regulating the transcriptions of corticotropin-releasing hormone and its binding protein, which subsequently decreased blood cortisol concentrations. MeP subchronic exposure also disturbed innate immune function. In particular, significant increases in lipopolysaccharide (LPS) content by 15.6% were caused by MeP exposure in male brain, thereby inducing the synthesis of pro-inflammatory cytokines. In contrast, female brain was able to adaptively up-regulate the protein expression of blood brain barrier to inhibit the infiltration of LPS endotoxin into brain. Overall, the present findings pinpoint the potent neurotoxicity of MeP pollutant even at environmentally realistic concentrations.


Physiologically Based Modelling Framework for Prediction of Pulmonary Pharmacokinetics of Antimicrobial Target Site Concentrations.
Prediction of antimicrobial target-site pharmacokinetics is of relevance to optimize treatment with antimicrobial agents. A physiologically based pharmacokinetic (PBPK) model framework was developed for prediction of pulmonary pharmacokinetics, including key pulmonary infection sites (i.e. the alveolar macrophages and the epithelial lining fluid). The modelling framework incorporated three lung PBPK models: a general passive permeability-limited model, a drug-specific permeability-limited model and a quantitative structure-property relationship (QSPR)-informed perfusion-limited model. We applied the modelling framework to three fluoroquinolone antibiotics. Incorporation of experimental drug-specific permeability data was found essential for accurate prediction. In the absence of drug-specific transport data, our QSPR-based model has generic applicability. Furthermore, we evaluated the impact of drug properties and pathophysiologically related changes on pulmonary pharmacokinetics. Pulmonary pharmacokinetics were highly affected by physiological changes, causing a shift in the main route of diffusion (i.e. paracellular or transcellular). Finally, we show that lysosomal trapping can cause an overestimation of cytosolic concentrations for basic compounds when measuring drug concentrations in cell homogenate. The developed lung PBPK model framework constitutes a promising tool for characterization of pulmonary exposure of systemically administrated antimicrobials.


Emotion processing influences working memory circuits in pediatric bipolar disorder and attention-deficit/hyperactivity disorder.
This functional magnetic resonance imaging (fMRI) study examined how working memory circuits are affected by face emotion processing in pediatric bipolar disorder (PBD) and attention-deficit/hyperactivity disorder (ADHD). A total of 23 patients with PBD, 14 patients with ADHD, and 19 healthy control (HC) subjects (mean age, 13.36 ± 2.55 years) underwent an affective, two-back fMRI task with blocks of happy, angry, and neutral faces. For angry versus neutral faces PBD patients, relative to ADHD patients, exhibited increased activation in the subgenual anterior cingulate cortex (ACC) and orbitofrontal cortex, and reduced activation in the dorsolateral prefrontal cortex (DLPFC) and premotor cortex. Relative to the HC group, the PBD group showed no increased activation and reduced activation at the junction of DLPFC and ventrolateral prefrontal cortex (VLPFC). Relative to HC, the ADHD patients exhibited greater activation in the DLPFC and reduced activation in the ventral and medial PFC, pregenual ACC, striatum, and temporo-parietal regions. For happy versus neutral faces, relative to the ADHD group, the PBD group exhibited greater activation in the bilateral caudate, and relative to the HC group the ADHD group showed increased activation in the DLPFC, striatal, and parietal regions, and no reduced activation. The ADHD group, compared with the HC group, showed no reduced activation and increased activation in regions that were underactive for the angry face condition. Relative to the ADHD group, the PBD group exhibited greater deployment of the emotion-processing circuitry and reduced deployment of working memory circuitry. Commonalities across PBD and ADHD patients, relative to the HC individuals, entailed cortico-subcortical activity that was reduced under negative emotional challenge and increased under positive emotional challenge.


Gene therapy progress and prospects: transcription regulatory systems.
The clinical efficacy and safety as well as the application range of gene therapy will be broadened by developing systems capable of finely modulating the expression of therapeutic genes. Transgene regulation will be crucial for maintaining appropriate levels of a gene product within the therapeutic range, thus preventing toxicity. Moreover, the possibility to modulate, stop or resume transgene expression in response to disease evolution would facilitate the combination of gene therapy with more conventional therapeutic modalities. The development of ligand-dependent transcription regulatory systems is thus of great importance. Here, we summarize the most recent progress in the field.


Patient-perceived side effects to antihypertensive drugs.
The Hypertension Detection and Follow-up Program (HDFP) used two methods to collect data on drug side effects. First, questions were asked during annual home visits by nontherapist interviewers, and second, responses were elicited by questionnaire at each clinic visit. Frequency of side effects as reported by the participants was similar in stepped care and referred care participants. Among the stepped care participants attending clinic, 75 percent continued to report at least one of the side effects reported at baseline. New symptoms (not previously reported) were less frequent, reported by 14 percent. Although medications were discontinued in 17 percent of the HDFP participants due to side effects, less than 2 percent of those reporting side effects had their drug discontinued for the symptom they reported. We concluded that questionnaire-elicited reports of drug side effects are a relatively poor index of side effects.


SINGLE MOLECULE ENZYMOLOGY FINDS ITS STRIDE.
More techniques aimed at probing the nature of single molecules are being developed and advanced in biophysics labs. Jeffrey Perkel takes a look at the scientists leading the charge into the micro-world.


Extended reality (XR) virtual practical and educational eGaming to provide effective immersive environments for learning and teaching in forensic science.
Online virtual learning resources have been available for learning and teaching in forensic science for some years now, but the recent global COVID-19 related periods of irregular lockdown have necessitated the rapid development of these for teaching, learning and CPD activities. However, these resources do need to be carefully constructed and grounded in pedagogic theory to be effective. This article details eXtended Reality (XR) learning and teaching environments to facilitate effective online teaching and learning for forensic geoscientists. The first two case studies discussed in this article make use of Thinglink software to produce virtual learning and teaching XR resources through an internet system, which was delivered to undergraduate students in 2021. Case one details a range of XR virtual laboratory-based equipment resources, providing a consistent, reliable and asynchronous learning and teaching experience, whilst the second case study presents an XR virtual learning applied geophysics resource developed for a 12-week CPD training programme. This programme involves recorded equipment video resources, accompanying datasets and worksheets for users to work through. Both case studies were positively received by learners, but there were issues encountered by learners with poor internet connections or computer skills, or who do not engage well with online learning. A third case study showcases an XR educational forensic geoscience eGame that was developed to take the user through a cold case search investigation, from desktop study through to field reconnaissance and multi-staged site investigations. Pedagogic research was undertaken with user questionnaires and interviews, providing evidence that the eGame was an effective learning and teaching tool. eGame users highly rated the eGame and reported that they raised awareness and understanding of the use of geophysics equipment and best practice of forensic geoscience search phased investigations. These types of XR virtual learning digital resources, whilst costly to produce in terms of development time and staff resource, provide a complementary virtual learning experience to in-situ practical sessions, and allow learners to asynchronously familiarise themselves with equipment, environments and techniques resulting in more efficient use of in situ time. The XR resources also allow learners to reinforce learning post in-situ sessions. Finally, XR resources can provide a more inclusive and authentic experience for learners who cannot attend or complete work synchronously.


Chinese herbs nephropathy-associated slimming regimen induces tumours in the forestomach but no interstitial nephropathy in rats.
Chinese herbs nephropathy (CHN), a rapidly progressive interstitial fibrosis of the kidney, has been described in approximately 100 young Belgian women who had followed a slimming regimen containing some Chinese herbs. In 4 patients multifocal transitional cell carcinomas (TCC) were observed. Aristolochic acid (AA), suspected as the causal factor of CHN, is a well known carcinogen but its ability to induce fibrosis has never been demonstrated. The objective of this study was to evaluate the latter using doses of AA, durations of intoxication and delays of sacrifice known to yield tumours in rats. We also tested the hypothesis that a possible fibrogenic role of AA was enhanced by the other components of the slimming regimen. Male and female rats were treated orally with 10 mg isolated AA/kg per day for 5 days/week, or with approximately 0.15 mg AA/ kg per day 5 days/week contained in the herbal powder together with the other components prescribed in the slimming pills for 3 months. The animals were killed respectively 3 and 11 months later. At sacrifice, animals in both groups had developed the expected tumours but not fibrosis of the renal interstitium. Whether the fibrotic response observed in man is due to species and/or strain related differences in the response to AA or to other factors, remains to be determined. Interestingly, despite the addition of fenfluramine and diethylpropion, two drugs incriminated in the development of valvular heart disease, no cardiac abnormalities were observed.


Distribution of extracellular proteolytic activities among various yeast.
A general screening test for extracellular proteolytic activities was carried out on 24 cultures belonging to 14 genera of yeasts. The screening was performed using gelatine and casein as sole nitrogen sources under two sets of pH conditions. Potent proteolytic yeast cultures belonging to both Ascomycetes and Deuteromycetes were detected, particularly certain members of the genera Endomycopsis, Metschnikowia, Debaromyces, Rhodotorula, and Candida spec. Most detected proteolytic cultures were active on both casein and gelatine substrates, possibly suggesting one enzyme system in each case with wide substrate specificity. Physiological studies revealed that maximum proteolysis occurred after 3--4 days of aerobic incubation and that some strains were able to hydrolyze egg albumin.


Ultrastructure of pigmented and unpigmented photoreceptors in cercariae of Trichobilharzia ocellata (Plathelminthes, Trematoda, Schistosomatidae): evidence for the evolution of parasitism in Neodermata.
The lens-covered pigment cup ocelli in free-swimming cercariae of Trichobilharzia ocellata were re-examined and the differentiation of the lenticular elements was studied in cercariae still enclosed in sporocysts. Each eye consists of a single rhabdomeric sensory cell, a single cup cell harboring pigment granules and the lens. This lens is developed step by step by the fusion of numerous dark platelets not enclosed by a bordering membrane. The material is presumably proteinaceous. There is no evidence that the lenses are of mitochondrial origin. Besides the pigment cup ocelli, a special type of unpigmented rhabdomeric photoreceptor was discovered. Three unicellular photoreceptors arranged in a three-dimensional configuration exist. These light-sensing organs show a principle of construction similar to that of phaosomous photoreceptors. We hypothesize that both types of photoreceptors are relevant for distinct reactions in the host-finding behaviour of the cercariae. The special type of lensing in the pigmented eyes seems to be restricted to Trichobilharzia species, whereas the phaosomous-like receptors may be more widespread in members of the Schistosomatidae. The obvious absence of any mitochondrial lensing in T. ocellata, and probably all other species of the Digenea, may be correlated with the evolution of endoparasitism in the Trematoda.


Phase I trial of Adozelesin using the treatment schedule of daily x5 every 3 weeks.
CC-1065 is a unique alkylating agent that preferentially binds in the minor groove of double-stranded DNA at adenine-thymine-rich sites. Although it has broad antitumor activity in preclinical models its development was discontinued because of deaths observed during preclinical toxicology studies. Adozelesin is a potent synthetic analog that was chosen for clinical development because it had a similar preclinical antitumor spectrum, but did not produce deaths similar to CC-1065 at therapeutic doses. Phase I evaluations using a variety of Adozelesin treatment schedules have been conducted. This report describes our experience using a multiple dose treatment schedule. Endpoints including antitumor response, maximum tolerated dose, dose limiting toxicity as well as other toxicities and the recommended Phase II starting dose were determined. Adozelesin was given as a 10 minute IV infusion for 5 consecutive days every 21 days or upon recovery from toxicity. The dose range evaluated was 6-30 mcg/m2/day. All patients had refractory solid tumors and had received prior cytotoxic treatment. Thirty-three patients (22 men: 11 women) were entered onto the study and 87 courses were initiated. Dose limiting toxicity was cumulative myelosuppression (leucopenia, thrombocytopenia). The maximum tolerated dose was 30 mcg/m2/day. The only other significant toxicity was an anaphylactoid syndrome that occurred in 2 patients. A partial response was observed in a patient with refractory soft tissue sarcoma. The recommended Phase II starting dose of Adozelesin using a 10 minute IV infusion for 5 consecutive days is 25 mcg/m2/day to be repeated every 4-6 weeks to allow recovery from myelotoxicity, based on our experience. Additional Phase I and II studies with Adozelesin are recommended.


A miniaturized mechanical antenna based on FEP/THV unipolar electrets for extremely low frequency transmission.
An electret-based mechanical antenna (EBMA), which can transmit extremely low frequency (ELF) electromagnetic signals, has the advantages of miniaturization and high transmitting efficiency, with great potential applications in air, underwater, and underground communications. To improve the charge density of the electret, which is a key factor in determining the radiation performance of an EBMA, this work proposes a fluorinated ethylene propylene/terpolymer of tetrafluoroethylene, hexafluoropropylene and vinylidene fluoride (FEP/THV) unipolar electret exhibiting negative polarity, reaching a total charge density up to -0.46 mC/m2 for each layer of electret. Long transmission distances can be achieved in sea water, soil, and air using a 3-layer-FEP/THV-based EBMA with a compact volume of 5 × 10-4 m3. As an application demonstration, binary ASCII-coded ELF information of "BUAA" is successfully transmitted with a power consumption < 5 W.


Advancing Cancer Immunotherapy: From Molecular Mechanisms to Clinical Applications.
In recent years, cancer immunotherapy research has made remarkable progress, completely transforming the cancer treatment landscape [...].


Mirror exposure therapy for body image disturbances and eating disorders: A review.
Mirror exposure therapy is a clinical trial validated treatment component that improves body image and body satisfaction. Mirror exposure therapy has been shown to benefit individuals with high body dissatisfaction and patients with eating disorders (ED) in clinical trials. Mirror exposure is an optional component of cognitive behavioral therapy (CBT), an effective treatment for body dysmorphic disorder (BDD). However, most clinical trials of mirror exposure therapy have been small or uncontrolled and have included few male subjects. Adverse events have been reported during mirror exposure clinical trials. We discuss how individuals respond when looking in a mirror and how mirrors can be used therapeutically, and we critically evaluate the evidence in favor of mirror exposure therapy. We discuss clinical indications and technical considerations for the use of mirror exposure therapy.


Treatment of primary headache disorders with intravenous valproate: initial outpatient experience.
To evaluate the effectiveness of intravenous valproate in managing moderate to severe headaches. Despite major strides in the understanding of primary headache disorders, there have been few additions to acute headache management other than introduction of the triptans. An intravenous antiepileptic preparation, sodium valproate, has been reported to be effective in the management of status epilepticus and acute headache. Between March 13, 2000 and October 11, 2000, we prospectively treated, in a nonrandomized and open-label study, every patient with a moderate to severe headache (4 or greater on a visual analog scale of head pain from 1 to 10) who wanted treatment with intravenous valproate. Using a verbal visual analog scale for pain (0 = no headache and 10 = most severe headache), we measured head pain before treatment and at time of discharge. The treating nurse monitored vital signs and side effects. A positive response was defined as a 50% or greater reduction at discharge in baseline pain. Information was collected regarding patient demographics, type of headache (according to criteria of the International Headache Society and that recently proposed for chronic headache), observation time in the treatment suite, cumulative dose of valproate, and use of concurrent medications. Univariable and multivariable correlates of response to treatment were identified using logistic regression analysis. One hundred thirty treatments were given to 89 women and 17 men, aged 17 to 76 years; 92 patients received only one treatment. Valproate doses ranged between 300 and 1200 mg. Thirty-three patients (31%) presented with episodic migraine, with or without aura; 45 patients (42%) presented with chronic daily headache with a history of episodic migraine, with or without aura (transformed migraine); 22 (21%) with unclassifiable chronic headache; 2 (2%) with episodic cluster headache; and 4 (4%) with chronic tension-type headache. For first treatments only, 61 patients (57.5%) responded to treatment, whereas for all treatments, 82 patients (63.1%) responded. Age and gender did not affect likelihood of response, whereas increasing duration of treatment (P=.003) and the additional use of analgesics (P=.021) were each negatively associated with response. Among headache types, unclassifiable chronic headache segregated from all other classified headaches in terms of poor response. Aside from rare dizziness (n = 2) and one spell interpreted as a pseudoseizure, no side effects were noted. Intravenous valproate is a safe, rapidly effective, abortive headache agent. It appears to be an effective analgesic for identifiable primary headaches, especially episodic headache, and less effective for unclassifiable chronic headache. Randomized, double-blind, controlled studies are warranted.


Care of the Hepatology Patient in the COVID-19 Era.
The COVID-19 pandemic has resulted in over 800,000 deaths worldwide and resulted in fundamental changes in practice in nearly every aspect of medicine. The majority of symptomatic patients experience liver-associated enzyme (LAE) elevations which appear to be correlated to disease severity. Furthermore, there are unique considerations of COVID-19 on chronic liver disease. Background, including epidemiology, pathophysiologic mechanisms and therapeutics, as well as the impact of COVID-19 on specific chronic liver disease, is discussed. Studies suggest that degree of LAE elevation correlates with illness severity, although it is unclear whether this represents true liver injury. Numerous proposed treatments for COVID-19 have been linked with drug induced liver injury and may have clinically significant drug-drug interactions. Others may have unintended consequences on chronic liver disease treatment including reactivation of hepatitis B. The risk of severe COVID-19 in patients with chronic liver disease is largely unknown; metabolic dysfunction-associated fatty liver disease may be linked to higher risk for severe illness. Implications for cirrhosis of other etiologies, autoimmune hepatitis, and viral hepatitis are less well defined. The treatment of chronic liver disease has been severely impacted by the pandemic. The societal factors created by the pandemic have led to decreased in person visits, evolving access to invasive screening modalities, food and financial insecurity, and likely increased alcohol use. The impacts of COVID-19 on the liver range from a potential increased risk of severe infection in chronic liver disease patients, to hepatotoxic effects of proposed treatments, to second and third order impacts on the care of patients with chronic liver disease.


Reply to L.M. Brown et al. "Brief history of the Cambridge STEM aberration correction project and its progeny" in Ultramicroscopy 157, 88 (2015).
We comment on a Short Communication recently published in Ultramicroscopy in which Brown et al. criticize our description of the time sequence of events in the development of aberration correction systems in electron optics during the 1990s put forward in the introduction to the Ultramicroscopy April 2015 Special Issue. We present an analysis of the published literature furnishing evidence that our description is correct.


The prognostic roles of initial glucose level and functional outcomes in patients with ischemic stroke: difference between diabetic and nondiabetic patients.
To identify the prognostic roles of initial glucose level in the emergency department among patients with acute ischemic stroke, and to evaluate whether or not the impact varied with diabetes. A total of 774 first-ever ischemic stroke patients admitted to the emergency department of a tertiary hospital in Taiwan. Participants were stratified into tertiles by initial glucose level in the emergency department. The Barthel Index (BI) and modified Rankin Scale (mRS) were used to assess functional outcome 3 months after the ischemic stroke. Initial glucose level was significantly associated with functional outcome 3 months after ischemic stroke. Compared with the 1st tertile, adjusted odds ratios for 2nd and 3rd tertiles of initial glucose level were 1.84 (95% confidence interval [CI], 1.15-2.95) and 4.57 (95% CI, 2.87-7.29), for BI of less than 60, 2.07 (95% CI, 1.28-3.36) and 4.45 (95% CI, 2.76-7.18) for mRS score of >2. The association was apparent among the nondiabetic stroke patients compared with diabetic patients. A positive association was found between initial glucose level and poor functional outcome at 3 months in patients with acute ischemic stroke, particularly among nondiabetic patients.


Association between clinical findings and the presence of lumbar spine osteoarthritis imaging features: A systematic review.
Spinal osteoarthritis is difficult to study and diagnose, partly due to the lack of agreed diagnostic criteria. This systematic review aims to give an overview of the associations between clinical and imaging findings suggestive of spinal osteoarthritis in patients with low back pain to make a step towards agreed diagnostic criteria. We searched MEDLINE, Embase, Web of Science, and CINAHL from inception to April 29, 2021 to identify observational studies in adults that assessed the association between selected clinical and imaging findings suggestive of spinal osteoarthritis. Risk of bias was assessed using the Newcastle Ottawa Scale and the quality of evidence was graded using an adaptation of the GRADE approach. After screening 7902 studies, 30 met the inclusion criteria. High-quality evidence was found for the longitudinal association between low back pain (LBP) intensity, and both disc space narrowing and osteophytes, as well as for the association between LBP-related physical functioning and lumbar disc degeneration, the presence of spinal morning stiffness and disc space narrowing and for the lack of association between physical functioning and Schmorl's nodes. There is high- and moderate-quality evidence of associations between clinical and imaging findings suggestive of spinal osteoarthritis. However, the majority of the studied outcomes had low or very low-quality of evidence. Furthermore, clinical and methodological heterogeneity was a serious limitation, adding to the need and importance of agreed criteria for spinal osteoarthritis, which should be the scope of future research.


Acute viral bronchiolitis in infancy: epidemiology and management.
Acute bronchiolitis due to viral agents (RSV, parainfluenza, influenza, adenovirus) is a relatively frequent disease of infancy. Seasonal epidemic pattern have been recognized, and nosocomial infections in pediatric wards occur. Until age 2 years most children have experienced some form of airway disease attributable to RSV. Some patients require hospital treatment; about 15% of our patients had to be transferred to the intensive care unit. Bronchiolitis seems to be frequently the first manifestation of asthma and we found higher IgG antibody titers to viruses causing bronchiolitis in children with asthma than in controls. Retrospective analysis of the charts of 147 cases of bronchiolitis revealed considerable uncertainty regarding therapeutic concepts. Mainstays of conservative therapy include oxygen, adequate hydration (often IV), and sometimes bronchodilators (based on the clinical impression of effectiveness in the individual patient). Mist therapy and secretolytic agents remain popular, although no clinical effect has been demonstrated. Attention should be directed toward the relief of upper airway obstruction caused by swelling, secretions, and nasogastric tubes. Oxygen administration in infants with coexisting chronic airway disease (e.g., BPD) and bronchiolitis may cause CO2 retention. Bronchodilators can cause hypoxia and increase bronchial compressibility by reducing smooth muscle tone. However, in severe cases a trial under pulse oximetry control seems worthwhile. Steroids seem to bring no clinical improvement, except in infants with protracted wheezing after bronchiolitis and patients with preexisting BPD.


Spinal glial activation contributes to pathological pain states.
Chronic pain, a pathological state, affects millions of people worldwide. Despite decades of study on the neuronal processing of pain, mechanisms underlying the creation and maintenance of enhanced pain states after injury or inflammation remain far from clear. In the last decade, however, the discovery that glial activation amplifies pain has challenged classic neuronal views of "pain". This review focuses on recent developments in understanding that spinal cord glia are involved in pathological pain. We overview the action of spinal glia (both microglia and astrocytes) in several persistent pain models, and provide new evidence that spinal glia activation contributes to the development and maintenance of arthritic pain facilitation. We also attempt to discuss some critical questions, such as how signals are conveyed from primary afferents to spinal glia following peripheral nerve injury and inflammation. What causes glia to become activated after peripheral/central injury/inflammation? And how the activated glia alter neuronal sensitivity and pain processing? Answers to these questions might open a new approach for treatment of pathological pain.


Evolutionary trends in carotid atherosclerotic plaques: results of a two-year follow-up study using an ultrasound imaging system.
A two-year follow-up on 118 atherosclerotic lesions of the extracranial carotid tract observed in 70 patients was carried out using real-time high-resolution echotomography. The following plaque characteristics were monitored: the echogenic patterns (soft, intermediate, hard, and mixed), the surface aspects, and the degree of stenosis. The aim of the study was to evaluate plaque evolution, in relation both to the degree of vessel stenosis produced and to the echostructural characteristics of the lesion. After two years 68% of the lesions remained unchanged while the degree of vessel stenosis increased in 32%; no case of regression was observed. Intrinsic factors appearing to condition an increase in degree of stenosis were "mixed" and "hard" echogenic pattern, an irregular lesion surface, and an initial degree of stenosis of more than 50%. A modification in the echogenic pattern, which generally tended to progress toward more highly reflecting echogenic levels was observed in 27% of the lesions studied.


Duties and responsibilities of laboratory scientists.
The duties and responsibilities of laboratory scientists are still evolving. In this paper, I briefly summarize some of the classical duties and responsibilities of Clinical Chemists in the areas of research, education and service. Furthermore, I developed some general rules of success for younger laboratorians. It is clear that we are living in exciting times and Clinical Chemists must learn to adapt very quickly to the continuing changes in our discipline. The new developments in science and technology suggest that we are yet to realize the best times of this exciting profession.


Reptile Soft Tissue Surgery.
The surgical approach to reptiles can be challenging. Reptiles have unique physiologic, anatomic, and pathologic differences. This may result in frustrating surgical experiences. However, recent investigations provided novel, less invasive, surgical techniques. The purpose of this review was to describe the technical aspects behind soft tissue surgical techniques that have been used in reptiles, so as to provide a general guideline for veterinarians working with reptiles.


Novel imidazole derivatives with subtype-selective antimuscarinic activity (1).
A series of N-substituted 4-amino-2,2-diphenylbutyramide derivatives was prepared as part of a search for subtype-selective antimuscarinic agents. The representative compound KRP-197, bearing a 2-methylimidazole ring as a surrogate of aliphatic amine, was found to be a highly potent and both M1- and M3-selective antimuscarinic agent.


Recent innovations in the structural analysis of heparin.
Heparin, the widely used anticoagulant drug, is unusual among major pharmaceutical agents being neither single chemical entity nor a defined mixture of compounds. Its composition, while conforming to approximate average disaccharide composition or sulfation levels, exhibits heterogeneity and variability depending on the source, as well as its geographical origin. Furthermore, individual polysaccharide chains, whose physico-chemical properties are extremely similar, cannot be separated with current state-of-the-art techniques, presenting a challenge to those interested in the quality control of heparin, in ensuring its provenance and safety, and those with an interest in investigating the relationships between its structure and biological activity. The review consists of two main sections: The first is the Introduction, comprising (i) The History, Occurrence and Use of Heparin and (ii) Approaches to Structure-Activity Relationships. The second section is Improved Techniques for Structural Analysis, comprising; (i) Separation and Identification, (ii) Spectroscopic Methods, (iii) Enzymatic Approaches and (iv) Other Physico-Chemical Approaches. The ~60 references cover recent technological advances in the study of heparin structural analysis, largely since 2010.


Understanding and managing RAC.
It takes time, money and staff, but hospitals can get their arms around the RAC process.


Associations between hurtful weight-related comments by family and significant other and the development of disordered eating behaviors in young adults.
Research has found that weight-teasing is associated with disordered eating in adolescents. This study expands on the existing research by examining associations between hurtful weight comments by family and a significant other and disordered eating in young adults. Data come from 1,902 young adults (mean age 25) who completed surveys in 1998, 2003 and 2009. Correlations were examined between receiving hurtful comments from family and significant others, and four disordered eating behaviors in young adulthood, adjusting for prior disordered eating and prior teasing. Disordered eating behaviors were common in young adulthood, and were associated with hearing hurtful weight-related comments from family members and a significant other, for both females and males. Disordered eating prevention activities, which include messages about the potential harm associated with hurtful weight-related comments, should be expanded to address young adults, and programs may want to target relationship partners.


Burn and trauma associated proteinuria: the role of lipid peroxidation, renin and myoglobin.
Ten trauma patients and 13 burns patients were studied intensively for the first 36 h and subsequent 6 days post injury in order to investigate the mechanism of trauma and burn associated proteinuria. Burns patient's initial maximum proteinuria occurred between 4 and 8 h post injury, whilst trauma patients showed greatest proteinuria within 4 h. In both groups coexisting myoglobinuria or marked elevation of serum renin activity was not found during the first 36 h. Following admission serum lipid peroxides rose in burns patients reaching a maximum between 2 and 8 h following injury, after which levels fell rapidly; in contrast trauma patient's values were initially within normal limits, but rose sharply after 12 h with peaks occurring between 16 h and 7 days post injury. Some patients within both groups showed a recurrent protein leak 2 to 5 days post injury. The data suggest that myoglobinuria or raised renin levels do not play an important role in trauma associated proteinuria.


Analysis of hsa-miR-30a-5p expression in human gliomas.
Our previous study demonstrated that miR-30a-5p was upregulated in six malignant glioma cell lines by microRNA(miRNA) array. For further verification of this finding, the expression of miR-30a-5p in 7 more malignant glioma cell lines, 43 freshly resected glioma samples and 75 archival paraffin embedded glioma specimens with different grade of malignancy were examined by qRT-PCR and in situ hybridization(ISH). Here, we present the first evidence that miR-30a-5p is overexpressed in glioma cell lines and glioma samples as compared to the normal brain tissues (NBTs), and its expression level is positively correlated with tumor grade of malignancy. It is concluded that miR-30a-5p may have the potential as a diagnostic or prognostic marker of gliomas and as the target of miRNA-based glioma therapy in further studies.


The natural product peiminine represses colorectal carcinoma tumor growth by inducing autophagic cell death.
Autophagy is evolutionarily conservative in eukaryotic cells that engulf cellular long-lived proteins and organelles, and it degrades the contents through fusion with lysosomes, via which the cell acquires recycled building blocks for the synthesis of new molecules. In this study, we revealed that peiminine induces cell death and enhances autophagic flux in colorectal carcinoma HCT-116 cells. We determined that peiminine enhances the autophagic flux by repressing the phosphorylation of mTOR through inhibiting upstream signals. Knocking down ATG5 greatly reduced the peiminine-induced cell death in wild-type HCT-116 cells, while treating Bax/Bak-deficient cells with peiminine resulted in significant cell death. In summary, our discoveries demonstrated that peiminine represses colorectal carcinoma cell proliferation and cell growth by inducing autophagic cell death.


Structural characterisation of the photoisomers of reactive sulfonated azo dyes by NMR spectroscopy and DFT calculations.
1H NMR spectroscopy coupled with in situ laser irradiation has been used together with density functional theory (DFT) computation to examine the structures of the photoisomers of a series of sulfonated reactive azo dyes. Assignment of 1H NMR spectra acquired at the photostationary state has allowed, for the first time, NMR characterisation of unstable cis isomers of commercially relevant water-soluble azo dyes. Structural features of the two isomeric forms predicted by DFT calculations are clearly reflected in the experimental NMR data. The trans-cis photoisomerisation process could be unambiguously identified in each case, based on the large chemical shift change observed for resonances associated with aromatic protons adjacent to the azo linkage.


Release of the self-quenching of fluorescence near silver metallic surfaces.
Fluorescein is one of the most widely used fluorescent probes in microscopy, biotechnology, and clinical assays. One difficulty with fluorescein is its self-quenching, which results in decreased intensities with increasing labeling density. In this study we examined human serum albumin (HSA), which contained one to nine covalently linked fluorescein molecules per molecule of HSA. The occurrence of homo resonance energy transfer for labeling ratios greater than 1 were confirmed by decreases in the relative quantum yields, anisotropies, and lifetimes. We found that most of the self-quenching can be partially eliminated by proximity of the labeled protein to metallic silver particles. These results suggest the use of heavily labeled proteins and metallic colloids to obtain ultrabright reagents for use in immunoassays, imaging, and other applications.


The healing power of art: is it just for patients?
To be a caring professional one must learn to care for oneself. This article is an exemplar of one nurse's discovery of the use of music to cope with stress and grief.


A randomised prospective study of split skin graft donor site dressings: AWBAT-D™ vs. Duoderm®.
To assess patient comfort and wound-healing efficacy of a new, purpose-designed biosynthetic material (AWBAT-D™) in the healing of split-skin graft donor sites in comparison with our standard dressing, Duoderm(®). We conducted a prospective randomised controlled trial of donor site dressings, comparing AWBAT-D™ with our standard dressing, Duoderm(®). Patients were randomly allocated to have their donor site dressed with one of these materials. Outcome measures included pain scores at rest and during dressing changes, time to re-epithelialisation, time to discharge, scarring and infection. Results were assessed for significance using the Mann-Whitney U-test (non-parametric data) and the Chi-Square test (parametric data). Fourteen patients were recruited with 8 donor sites in each group. The mean pain scores at rest and during dressing changes were not found to be significantly different between the two groups (P=0.99 and P=0.90 respectively). The median time to re-epithelialisation was shorter in the Duoderm(®) group at 11 days compared to 17 days in the AWBAT-D™ group (P=0.007). The median time to discharge was not significantly different (P=0.38). No infection or scarring has been observed. Based on these early results, AWBAT-D™ appears to have slower donor site healing and does not provide significant improvements in postoperative pain or discharge time compared to Duoderm(®). There is no evidence at this stage that our standard donor site dressing should be changed.


Controlling Nutritional Status (CONUT) score and the risk of mortality or impaired physical function in stroke patients: A systematic review and meta-analysis.
The Controlling Nutritional Status (CONUT) score is a tool for assessing the risk of malnutrition (undernutrition) that can be calculated from albumin concentration, total peripheral lymphocyte count, and total cholesterol concentration. CONUT score has been proposed as a promising prognostic marker in several clinical settings; however, a consensus on its prognostic value in patients with stroke is lacking. The aim of this systematic review and meta-analysis was to evaluate the relationship between CONUT score and clinical outcomes in patients with stroke based on all current available studies. Systematic research on PubMed, Scopus and Web of Science from inception to February 2023 was performed on the association between CONUT score and clinical outcomes in patients with stroke. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses were followed. Methodological quality was evaluated using the Newcastle-Ottawa Scale quality assessment tool. Pooled effect estimation was calculated by a random-effect model. Through the initial literature search, 15 studies (all high-quality) including 16 929 patients were found to be eligible and analysed in the meta-analysis. A significant risk of malnutrition (in most studies defined by a CONUT score ≥5) was directly associated with mortality, higher risk of poor functional outcome according to the modified Rankin Scale and total infection development. Evidence was consistent for acute ischaemic stroke and preliminary for acute haemorrhagic stroke. CONUT score is an independent prognostic indicator, and it is associated with major disability and infection development during hospitalisation. CRD42022306560.


Chromosomal aberrations in rat lymphocytes treated in vivo with 1-phenyl-3, 3-dimethyltriazene and n-nitrosomorpholine. A further report on a possible method for carcinogenicity screening.
This paper reports the results of screening two carcinogens, N-nitrosomorpholine (NM) and 1-phenyl-3, 3-dimethyltriazene (PDT), for their ability to cause an increase in chromosomal aberrations in rat lymphocytes cultured in vitro after treatment in vivo. NM is a hepatocarcinogen and PDT induces tumours mainly of the central and peripheral nervous system. Both these chemicals gave only weakly positive results in certain other established short term screening tests for carcinogenicity, despite having been shown to cause a significant increase in the number of chromosomal aberrations after a single administration of doses of 250 mg/kg and above. These aberrations were mainly of the isolocus type as opposed to the chromatid type. Significant increases in the number of aberrations of both the isolocus and chromatid types were found after single applications of PDT of 35 and 50 mg/kg. The results obtained are compared with those of other workers using the same compounds in different test systems. Modifications of the system to increase its sensitivity are suggested.