Development of sonic technology for the daily cleansing of the skin.
Even though many skin cleansing products are commercially available, the cleansing of the skin is dependent upon the user's diligence, compliance, and technique, which often results in inconsistent cleansing. When the skin is inadequately or excessively cleansed, the skin becomes compromised, sometimes leading to acute or chronic conditions that may require medical attention. A sonic skincare brush was developed to enhance and provide consistent skin cleansing while preventing the skin from becoming compromised. Utilizing a technology previously used to cleanse the oral cavity, the sonic skincare brush is optimized to work with the skin's own elasticity providing rapid oscillatory flexing of the infundibular opening. By oscillating at sonic speed the net result is the inelastic comedones become loosened and detached from the infundibular wall and are then cleared from the acroinfundibulum. Although additional clinical research into the various applications of sonic skin care technology is needed, utilization of sonic technology is now available for effectively and consistently cleansing the skin.


Ambulatory monitoring of respiration in anxiety.
An ambulatory monitor, body suit, and calibration procedure were developed to compare the respiration of seven patients with panic disorder and twelve normal volunteers. Subjects wore a body suit with Respitrace bands, connected to a portable respiratory monitor for a period of 24 hours. Breath by breath values for respiratory rate and tidal volume were computed every two minutes. There was a significant difference between patients and controls in their patterns of minute ventilation during sleep. Tidal volume, rather that respiratory rate increases characterized the periods of anxiety and limited symptom attacks.


The impact of fruit and soybean by-products and amaranth on the growth of probiotic and starter microorganisms.
The ability of different fruit by-products, okara, and amaranth flour, to support the growth of probiotic and non-probiotic strains was evaluated. The tests were conducted with three commercial starter cultures (Streptococcus thermophilus), ten probiotic strains (seven Lactobacillus spp. and three Bifidobacterium spp. strains), and two harmful bacteria representative of the intestinal microbiota (Escherichia coli and Clostridium perfringens). In vitro fermentability assays were performed using a modified MRS broth supplemented with different fruits (acerola, orange, passion fruit, and mango), and soy (okara) by-products or amaranth flour. Orange and passion-fruit by-products were the substrates that most promoted the growth of bacterial populations, including pathogenic strains. On the other hand, the acerola by-product was the substrate that showed the highest selectivity for beneficial bacteria, since the E. coli and Cl. perfringens populations were lower in the presence of this fruit by-product. Although the passion fruit by-product, okara, and amaranth stimulated the probiotic strains, the growth of the pathogenic strains studied was higher compared to other substrates. Different growth profiles were verified for each substrate when the different strains were compared. Although pure culture models do not reflect bacterial interaction in the host, this study reinforces the fact that the ability to metabolize different substrates is strain-dependent, and acerola, mango, and orange by-products are the substrates with the greatest potential to be used as prebiotic ingredients.


ADAMTS12 acts as a cancer promoter in colorectal cancer via activating the Wnt/β-catenin signaling pathway in vitro.
ADAMTS12, a member of the ADAMTS family, is reported to be associated with the clinic outcome of colorectal cancer (CRC) patients. However, the functions and precise mechanism in CRC progression have yet to be fully understood. By analyzing The Cancer Genome Atlas (TCGA) database, we examined the mRNA level of ADAMTS12 and assessed the prognostic value of ADAMTS12 in CRC patients using a tissue microarray containing 41 CRC patient samples. Cell Counting Kit-8 (CCK-8), colony formation, and transwell assays were used to quantify the impact of ADAMTS12 on cell proliferation and migration in ADAMTS12-overexpressing and ADAMTS12-deficient cell lines. The signaling pathways that ADAMTS12 mediated were identified by dual-luciferase reporter assays, and confirmed by western blotting and quantitative teal-time polymerase chain reaction (qRT-PCR). The ADAMTS12 mRNA level was upregulated in CRC tissues, and CRC patients with a high level of ADAMTS12 showed worse prognosis when compared with the patients with a low level of ADAMTS12. In vitro functional assays demonstrated that overexpression of ADAMTS12 significantly boosted cell proliferation and migration while ADAMTS12 deficiency remarkably impaired both tumor cell behaviors. Mechanical studies further verified that ADAMTS12 overexpression enhanced the transcriptional activity of β-catenin in the Wnt/β-catenin signaling pathway. In the ADAMTS12-deficient context, the downstream gene expression of myc and cyclin D1 was significantly reduced compared with that in wild-type cancer cells. ADAMTS12 fulfills the tumor-promotor role by activating Wnt/β-catenin signaling pathway in colon cells and may represent a new option in CRC target treatment.


[Timosaponins E1 and E2].
By means of silica gel chromatography and HPLC, two compounds were isolated from Anemarrhena asphodeloides Bge.. On the basis of chemical and spectral (MS, 1H, 13CNMR, IR) analyses, their structures were elucidated as (25S)-26-O-beta-D-glucopyranosyl-22-hydroxy-5 beta-furost-3 beta, 15 alpha, 26-triol-3-O-beta-D-glucopyranosyl (1-->2)-beta-D-galactopyranoside (1), and (25S)-26-O-beta-D-glucopyranosyl-22-methoxy-5 beta-furost-3 beta, 15 alpha, 26-triol-3-O-beta-D-glucopyranosyl (1-->2)-beta-D-galactopyranoside (2). They are named as timosaponin E1 (1) and timosaponin E2 (2) respectively. The structure of anemarrhenasaponin-I (A) is briefly discussed. Timosaponins are the main active constituents of Anemarrhena asphodeloides, most of them were shown to can inhibit platelet aggregation.


Low-Cost GNSS and PPP-RTK: Investigating the Capabilities of the u-blox ZED-F9P Module.
GNSS has become ubiquitous in high-precision applications, although the cost of high-end GNSS receivers remains a major obstacle for many applications. Recent advances in GNSS receiver technology have led to the development of low-cost GNSS receivers, making high-precision positioning available to a wider range of users. One such technique for achieving high-precision positioning is Precise Point Positioning-Real Time Kinematic (PPP-RTK). It is a GNSS processing technique that combines the PPP and RTK approaches to provide high-precision positioning in real time without the need for a base station. In this work, we aim to assess the performance of the low-cost u-blox ZED-F9P GNSS module in PPP-RTK mode using the low-cost u-blox ANN-MB antenna. The experiment was designed to investigate both the time it takes the receiver to resolve the phase ambiguity and to determine the positioning accuracies achievable. Results showed that the u-blox ZED-F9P GNSS module could achieve centimeter-level positioning accuracy in about 60 s in PPP-RTK mode. These results make the PPP-RTK technique a good candidate to fulfill the demand for mass-market accurate and robust navigation since uses satellite-based corrections to provide accurate positioning information without the need for a local base station or network. Furthermore, due to its rapid acquisition capabilities and accurate data georeferencing, the technique has the potential to serve as a valuable method to improve the accuracy of the three-S techniques (GIS, remote sensing, and GPS/GNSS).


Developing a person-centred approach in dentistry beyond NHS recall intervals: a commentary.
Person-centred care (PCC) is acknowledged as a fundamental dimension of quality within health care and provides significant benefits for patients and clinicians. Models of PCC have primarily been developed from the medical literature, with limited consideration of their application within dentistry. The Personalised Care Institute was established to deliver education and training on PCC and is working with the Office of the Chief Dental Officer for England to develop resources on shared decision-making (SDM) to promote tailored recall intervals.This paper seeks to promote the value of PCC and SDM in delivering high-quality care but cautions against the use of generic models or training in view of the potential differences which may exist within dentistry, particularly general dental practice. The authors highlight the need to develop materials and training which are appropriate, contextualised and relevant to dentistry. The capacity and desire to deliver PCC is strongly influenced by the healthcare system which is in operation. The current units of dental activity (UDA) system operating in England would appear to act as a barrier to the delivery of PCC. Unless significant and rapid changes are introduced to the NHS Contract, UDA targets will continue to take precedence over PCC, SDM and tailored recall intervals.


Atrial fibrillation in the elderly: a review.
Atrial fibrillation (AF) is common in the elderly population. Elderly patients with AF are often asymptomatic, may have atypical presentation or may present with heart failure or thromboembolic complications. The optimal management strategy of AF in the elderly population is challenging. We present an overview of AF in elderly patients, in particular addressing the pros and cons of various management strategies, and provide a practical approach within the guidelines.


Identification of novel key molecular signatures in the pathogenesis of experimental diabetic retinopathy.
Deep mining of the molecular mechanisms underlying diabetic retinopathy (DR) is critical for the development of novel therapeutic targets. This study aimed to identify key molecular signatures involved in experimental DR on the basis of integrated bioinformatics analysis. Four datasets consisting of 37 retinal samples were downloaded from the National Center of Biotechnology Information Gene Expression Omnibus. After batch-effect adjustment, bioinformatics tools such as Networkanalyst, Enrichr, STRING, and Metascape were used to evaluate the differentially expressed genes (DEGs), perform enrichment analysis, and construct protein-protein interaction networks. The hub genes were identified using Cytoscape software. The DEGs of interest from the meta-analysis were confirmed by quantitative reverse transcription-polymerase chain reaction in diabetic rats and a high-glucose-treated retinal cell model, respectively. A total of 743 DEGs related to lens differentiation, insulin resistance, and high-density lipoprotein (HDL) cholesterol metabolism were obtained using the meta-analysis. Alterations of dynamic gene expression in the chloride ion channel, retinol metabolism, and fatty acid metabolism were involved in the course of DR in rats. Importantly, H3K27m3 modifications regulated the expression of most DEGs at the early stage of DR. Using an integrated bioinformatics approach, novel molecular signatures were obtained for different stages of DR progression, and the findings may represent distinct therapeutic strategies for DR patients.


Dupilumab for treatment of atopic dermatitis.
Dupilumab is a new treatment option for patients with moderate-to-severe atopic dermatitis. It blocks IL-4/IL13-signaling and thereby inhibits receptor signaling downstream the JAK-STAT-pathway. Three of the main disease mechanisms of atopic dermatitis are affected by blocking this pathway; the decrease of skin barrier function, the class switch to IgE and the TH2-differentiation. Areas Covered: Dupilumab showed promising results in clinical trials of phase I-III. Clinical outcome parameters such as SCORAD, EASI, IGA and BSA improved with dupilumab. A positive effect on patient-reported outcomes like DLQI or pruritus-rating-scales was also demonstrated. The safety profile of dupilumab is superior to conventional immunosuppressive drugs, such as cyclosporine or methotrexate. Injection-site reactions and conjunctivitis were the most relevant side-effects. Skin infections were less frequently observed compared to placebo. Data on the use of dupilumab during pregnancy or in children are not published to date. Expert Commentary: Dupilumab was approved by the FDA in April 2017 for the treatment of adult patients with moderate-to-severe atopic dermatitis whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable.


Quantum Effects in the Thermoelectric Power Factor of Low-Dimensional Semiconductors.
We theoretically investigate the interplay between the confinement length L and the thermal de Broglie wavelength Λ to optimize the thermoelectric power factor of semiconducting materials. An analytical formula for the power factor is derived based on the one-band model assuming nondegenerate semiconductors to describe quantum effects on the power factor of the low-dimensional semiconductors. The power factor is enhanced for one- and two-dimensional semiconductors when L is smaller than Λ of the semiconductors. In this case, the low-dimensional semiconductors having L smaller than their Λ will give a better thermoelectric performance compared to their bulk counterpart. On the other hand, when L is larger than Λ, bulk semiconductors may give a higher power factor compared to the lower dimensional ones.


[The behavioral disorders in epilepsy].
The behavioral disorders are more frequent in the epilepsy patients, children and adults, than in the general population. They have been extensively studied by numerous authors, as well as the underlying various factors. These factors are neurobiological and psychological. From the neurobiological point of view, the importance of the brain damages, their nature, their topography, their lateralization, their date of occurrence during the development have been underlined. Specific personality and behavior features have been linked to the temporal localization of the epilepsy, but many controversies continue about this topic and a behavioral temporal syndrome is not proven. The frontal epilepsies are also responsible for psychological and behavioral disturbances. The epilepsy per se is an etiologic factor, through the ictal events and the interictal changes in the neuronal functioning. One example is that of the endogenous production of opioïd substances during the seizures. However the organic factors cannot be dissociated from the psychological ones. The neuropsychological deficits are significantly linked to the appearance of behavioral disorders in children. The stigma stuck to the epilepsy and the imprevisible character of the seizures have a deep resounding upon the subject, his family and his environment. The pharmacological medications are useful for the depressive and psychotic episodes, but have little efficacy on the character disorders, the aggressiveness and the psychogenic seizures. They need a careful assessment of the situation and a strict super vision of the seizure number (risk of worsening) and of the pharmacocinetic interactions. A comprehensive, social and psychological management of the epilepsy patients is always indicated, knowing that every person is unique and has to be understood and helped in his singularity.


Sodium replacement of potassium in physiological processes of olive trees (var. Barnea) as affected by drought.
Potassium (K) is a macro-nutrient understood to play a role in the physiological performance of plants under drought. In some plant species, sodium (Na) can partially substitute K. Although a beneficial role of Na is well established, information regarding its nutritional role in trees is scant and its function under conditions of drought is not fully understood. The objective of the present study was to evaluate the role of K and its possible replacement by Na in olive's (Olea europaea L.) response to drought. Young and bearing olive trees were grown in soilless culture and exposed to gradual drought. In the presence of Na, trees were tolerant of extremely low K concentrations. Depletion of K and Na resulted in ∼50% reduction in CO2 assimilation rate when compared with sufficiently fertilized control plants. Sodium was able to replace K and recover the assimilation rate to nearly optimum level. The inhibitory effect of K deficiency on photosynthesis was more pronounced under high stomatal conductance. Potassium was not found to facilitate drought tolerance mechanisms in olives. Moreover, stomatal control machinery was not significantly impaired by K deficiency, regardless of water availability. Under drought, leaf water potential was affected by K and Na. High environmental K and Na increased leaf starch content and affected the soluble carbohydrate profile in a similar manner. These results identify olive as a species capable of partly replacing K by Na. The nutritional effect of K and Na was shown to be independent of plant water status. The beneficial effect of Na on photosynthesis and carbohydrates under insufficient K indicates a positive role of Na in metabolism and photosynthetic reactions.


[Efficacy of combined local therapy especially with hepatic arterial infusion for liver metastasis from gastric cancer].
Herein, we report four cases of a single liver metastasis after gastric cancer resection. Initially, we chose to perform hepatic arterial infusion( HAI) with high-dose 5-fluorouracil( 5-FU)( 6,000 mg/week) or weekly 500-750 mg of 5-FU. Three patients showed a partial response (PR) and one patient showed no change (NC). Therefore, we performed hepatectomy or radiofrequency ablation( RFA) 300-350 days after HAI. All four patients received postoperative HAI. Two patients survived without recurrence for 12 and 21 months. One patient developed prostate cancer but survived for 22 months as an outpatient. Finally, one patient experienced recurrence in the residual liver, but at a site not supplied by the hepatic artery. This patient survived for 36 months as an outpatient. In conclusion, HAI, liver resection, and RFA are effective in the management of single liver metastasis from gastric cancer.


[Cervical lymph nodes metastases in patients with differentiated thyroid cancer].
Loco-regional recurrences of the differentiated thyroid cancer have been reported to be located in cervical lymph nodes in 60-75% of cases. The widespread use of neck ultrasonography (US) during the follow-up of patients with papillary thyroid carcinoma (PTC) has led to the discovery of small cervical lymph nodes (LN). Although US has a high sensitivity for diagnosing LN, fine needle aspiration biopsy (FNA) and measurement of thyroglobulin in fine needle aspirates (FNA-Tg) have proven to be invaluable tools. The aim of this paper is to review the importance of the early diagnosis of lymph node metastases in the follow-up of patients with differentiated thyroid cancer.


Pilot study of oral metformin in cancer-bearing cats.
A prospective dose escalation pilot study was performed in cancer-bearing cats to assess toxicity and surrogate biomarkers of pharmacologic activity of oral metformin hydrochloride. Nine cats with measurable spontaneous cancer were treated with oral metformin for 14 days. Monitoring included complete blood count (CBC), serum biochemistry, lactate, pH, insulin-like growth factor-1, and vascular endothelial growth factor serially until study completion. At the maximum tolerated dose of 10 mg kg-1 q12 h side effects were primarily mild to moderate gastrointestinal upset (anorexia, vomiting, and/or weight loss). All cats developed a reduction in haematocrit. Six of nine cats developed new or progressive hyperlactatemia and one cat developed asymptomatic lactic acidosis. There were no clinical responders and two cats had modest measurable reduction in tumour size. In conclusion, we demonstrate potential pharmacologic activity of metformin at a clinically relevant dose and identify parameters for clinical monitoring and supportive care. Further investigation of metformin in cancer-bearing cats is warranted.


Cerebral Effect of Intratracheal Aerosolized Surfactant Versus Bolus Therapy in Preterm Lambs.
Aerosolization has been proposed as a useful alternative to rapid intratracheal instillation for the delivery of exogenous surfactant in neonatal respiratory distress syndrome. However, there is a lack of information regarding the likely safety of this new therapeutic approach for the neonatal brain. We aimed to compare the cerebral effects of aerosolized versus bolus surfactant administration in premature lambs with respiratory distress syndrome. Prospective randomized study. BioCruces Institute Animal Research Facility. Fourteen intensively monitored and mechanically ventilated preterm lambs. Preterm lambs were randomly assigned to receive intratracheal aerosolized surfactant or bolus surfactant. Brain hemodynamics (cerebral and regional cerebral blood flow) and cerebral oxygen metabolism (cerebral oxygen delivery, cerebral metabolic rate of oxygen, and oxygen extraction fraction) were measured every 30 minutes for 6 hours. We also performed cerebral biochemical and histological analysis. In preterm lambs with respiratory distress syndrome, cerebral blood flow, regional cerebral blood flow, cerebral oxygen delivery, and cerebral metabolic rate of oxygen increased significantly in the bolus surfactant group during the first 5 minutes, without changes in cerebral oxygen extraction fraction. By 60 minutes, all parameters had decreased in both groups, cerebral blood flow and regional cerebral blood flow (in inner and cerebellum brainstem regions) remaining higher in the bolus surfactant than in the aerosolized surfactant group. Overall, the impact of aerosol surfactant was not significantly different to that of bolus surfactant in terms of cerebral necrosis, edema, inflammation, hemorrhage, infarct, apoptosis, or oxidative stress. In preterm lambs with severe respiratory distress syndrome, aerosol surfactant administration seems to be as safe as bolus administration, showing more stable cerebral hemodynamics and cerebral oxygen metabolism to the same dose of surfactant administered as a standard bolus.


Treating gonococcal urethritis in men: oral amoxycillin potentiated by clavulanate compared with intramuscular procaine penicillin.
In a study of 121 men with uncomplicated gonococcal urethritis, 64 were treated orally with a single dose of 3 g amoxycillin and 250 mg of the specific beta-lactamase inhibitor, clavulanic acid, and 57 with a single intramuscular injection of 2.4 MU procaine penicillin. After seven days, six (9.4%) patients treated with amoxycillin and clavulanic acid were still culture positive for Neisseria gonorrhoeae, compared with 26.3% of those treated with procaine penicillin.


Temporal activation of p42/44 mitogen-activated protein kinase and c-Jun N-terminal kinase by acetaldehyde in rat hepatocytes and its loss after chronic ethanol exposure.
Several cell-damaging effects of ethanol are due to its major metabolite acetaldehyde but its mechanisms are not known. We have studied the effect of acetaldehyde on p42/44 mitogen-activated protein kinase (MAPK) and p46/p54 c-Jun N-terminal kinase (JNK 1/2) in rat hepatocytes. Acetaldehyde caused peak activation of p42/44 MAPK at 10 min followed by JNK activation at 1 h. These responses were acetaldehyde dose-dependent (0.2-5 mM). There was a consistently higher activation of p46 JNK than p54 JNK. Ethanol also activated both p42/44 MAPK and p46/p54 JNK. The activation of JNK by ethanol, however, was not significantly affected by treatment of hepatocytes with 4-methylpyrazole, an alcohol dehydrogenase inhibitor. Cells treated with 200 mM ethanol for 1 h accumulated 0.35 +/- 0.02 mM acetaldehyde, but the magnitude of JNK activation was greater than that expected with 0.35 mM acetaldehyde. Thus, ethanol-activated JNK may be both acetaldehyde-dependent and -independent. The activation of JNK by ethanol or acetaldehyde was insensitive to the treatment of hepatocytes with genistein (tyrosine kinase inhibitor) and 2-[1-(3-dimethylaminopropyl)-1H-indol-3-yl]-3-(1H-indol-3-yl)maleimide (GF109203X) (protein kinase C inhibitor). Remarkably, in contrast to the above-mentioned effects on normal hepatocytes, acetaldehyde was unable to increase JNK activity in hepatocytes isolated from rats chronically fed ethanol for 6 weeks and indicated a loss of this acetaldehyde response. Thus, temporal activation of the p42/44 MAPK and p46/p54 JNK, the greater activation of p46 JNK than p54 JNK, and loss of JNK activation after chronic ethanol exposure indicate that these kinases are differentially affected by ethanol metabolite acetaldehyde.


Regulatory component analysis: a semi-blind extraction approach to infer gene regulatory networks with imperfect biological knowledge.
With the advent of high-throughput biotechnology capable of monitoring genomic signals, it becomes increasingly promising to understand molecular cellular mechanisms through systems biology approaches. One of the active research topics in systems biology is to infer gene transcriptional regulatory networks using various genomic data; this inference problem can be formulated as a linear model with latent signals associated with some regulatory proteins called transcription factors (TFs). As common statistical assumptions may not hold for genomic signals, typical latent variable algorithms such as independent component analysis (ICA) are incapable to reveal underlying true regulatory signals. Liao et al. [1] proposed to perform inference using an approach named network component analysis (NCA), the optimization of which is achieved by a least-squares fitting approach with biological knowledge constraints. However, the incompleteness of biological knowledge and its inconsistency with gene expression data are not considered in the original NCA solution, which could greatly affect the inference accuracy. To overcome these limitations, we propose a linear extraction scheme, namely regulatory component analysis (RCA), to infer underlying regulatory signals even with partial biological knowledge. Numerical simulations show a significant improvement of our proposed RCA over NCA, not only when signal-to-noise-ratio (SNR) is low, but also when the given biological knowledge is incomplete and inconsistent to gene expression data. Furthermore, real biological experiments on E. coli are performed for regulatory network inference in comparison with several typical linear latent variable methods, which again demonstrates the effectiveness and improved performance of the proposed algorithm.


Gut Bacteria Composition Drives Primary Resistance to Cancer Immunotherapy in Renal Cell Carcinoma Patients.
The development of immune checkpoint blockade (ICB) has revolutionized the clinical outcome of renal cell carcinoma (RCC). Nevertheless, improvement of durability and prediction of responses remain unmet medical needs. While it has been recognized that antibiotics (ATBs) decrease the clinical activity of ICB across various malignancies, little is known about the direct impact of distinct intestinal nonpathogenic bacteria (commensals) on therapeutic outcomes of ICB in RCC. To evaluate the predictive value of stool bacteria composition for ICB efficacy in a cohort of advanced RCC patients. We prospectively collected fecal samples from 69 advanced RCC patients treated with nivolumab and enrolled in the GETUG-AFU 26 NIVOREN microbiota translational substudy phase 2 trial (NCT03013335) at Gustave Roussy. We recorded patient characteristics including ATB use, prior systemic therapies, and response criteria. We analyzed 2994 samples of feces from healthy volunteers (HVs). In parallel, preclinical studies performed in RCC-bearing mice that received fecal transplant (FMT) from RCC patients resistant to ICB (NR-FMT) allowed us to draw a cause-effect relationship between gut bacteria composition and clinical outcomes for ICB. The influence of tyrosine kinase inhibitors (TKIs) taken before starting nivolumab on the microbiota composition has also been assessed. Metagenomic data (MG) from whole genome sequencing (WGS) were analyzed by multivariate and pairwise comparisons/fold ratio to identify bacterial fingerprints related to ATB or prior TKI exposure and patients' therapeutic response (overall response and progression-free survival), and compared with the data from cancer-free donors. Recent ATB use (n = 11; 16%) reduced objective response rates (from 28% to 9%, p < 0.03) and markedly affected the composition of the microbiota, facilitating the dominance of distinct species such as Clostridium hathewayi, which were also preferentially over-represented in stools from RCC patients compared with HVs. Importantly, TKIs taken prior to nivolumab had implications in shifting the microbiota composition. To establish a cause-effect relationship between gut bacteria composition and ICB efficacy, NR-FMT mice were successfully compensated with either FMT from responding RCC patients or beneficial commensals identified by WGS-MG (Akkermansia muciniphila and Bacteroides salyersiae). The composition of the microbiota is influenced by TKIs and ATBs, and impacts the success of immunotherapy. Future studies will help sharpen the role of these specific bacteria and their potential as new biomarkers. We used quantitative shotgun DNA sequencing of fecal microbes as well as preclinical models of fecal or bacterial transfer to study the association between stool composition and (pre)clinical outcome to immune checkpoint blockade. Novel insights into the pathophysiological relevance of intestinal dysbiosis in the prognosis of kidney cancer may lead to innovative therapeutic solutions, such as supplementation with probiotics to prevent primary resistance to therapy.


Lumbo-costo-vertebral syndrome with posterior spinal dysraphism.
Lumbo-costo-vertebral syndrome, which includes abnormalities of the vertebral bodies, ribs and trunk musculature, is very rare and only few cases have been reported. We report a case of 18-month-old female child with absent ribs, hemivertebrae, superior lumbar hernia (features of lumbo-costo-vertebral syndrome) and posterior spinal dysraphism, which to our knowledge is the first case in the English literature with such a combination of defects. Embryology and management of the case is discussed.


A path analysis of some determinants of infant growth in Khartoum.
The interrelationships between some socioeconomic and behavioural characteristics of mothers and the growth and illness experience of their infants in poor Khartoum townships have been examined by path analysis. For both infant body weight and supine length it is shown that weaning age and illness experience are important determinants of growth. It is also shown that greater maternal income has disadvantageous effects through encouraging early weaning. Most importantly the infants of housewives have later weaning, less illness and greater weight and length at 1 year of age than the infants of mothers with jobs, showing the value of time for caring in the prevailing environmental circumstances.


Hypercholesterolemia in renal transplantation.
We conducted this study to evaluate the prevalence, and risk factors of hypercholesterolemia (HC) in renal transplant population. We reviewed the records of the active renal transplant patients at two large transplant centers in Riyadh and Jeddah in Saudi Arabia transplanted between 1979 and November 1998. The patients were grouped according to the measurement of serum cholesterol level; group I (normal): below or equal 5.2 mmol/L, group II (mild HC): from 5.3-6.0 mmol/L, group III (moderate HC): from 6.1-8.0 mmol/L group IV (severe HC): above 8.0 mmol/L. There were 1096 patients' records included in the study. According to the level of measured serum cholesterol, there were 421 (38.4%) patients is group I, 256 (23.3%) patients in group II, 363 (33.1%) patients in group III and 57 (5.2%) patients group IV. We found no significant difference between the study groups in terms of gender (60% males, 40% females), mean duration of transplantation (66.9 months), between those transplanted before 1990 and those transplanted after 1990, donor type, prevalence of hypertension (85%), history of hypertension on dialysis, original kidney disease, frequency of rejections in the first year (28%), mean serum creatinine (220 mumol/L), cyclosporine mean dose (3.2 mg/kg/day) mean prednisone dose (0.15 mg/kg/day), number of patients on azathioprine (65%), the mean proteinuria (0.6 G/L) or number of antihypertensives. In comparison with the group with normal serum cholesterol level, the group with severe hypercholesterolemia had significantly higher mean age (40.6 versus 37.4 years), higher mean weight (72 versus 65.8 kg), rate of retransplantation (8.8% versus 3.1%), higher frequency of diabetics (35% versus 20%) and higher frequency of abnormal electrocardiogram (18.2% versus 5.2%). That hypercholesterolemia is a significant problem in the renal transplant population in Saudi Arabia. Risk factors for the development of hypercholesterolemia are mainly related to weight, age, diabetes and retransplantation.


Co-existing infantile hepatic hemangioma and mesenchymal hamartoma in a neonate.
Infantile hepatic hemangioma (IHH) and mesenchymal hamartoma (MH) form the first and second most common benign hepatic tumors in children. In this case report, we present a newborn child in whom a growing hepatic mass was discovered at the age of 7 days. She suffered also from anemia, respiratory and renal failure. No signs of heart disease or cutaneous lesions were detected. Alpha-fetoprotein was elevated for her age (3562.2 ng/ml). Imaging studies showed multifocal large cystic lesions associated with heterogeneous small solid lesions with arterial enhancement of the liver. Non-anatomical liver resection was performed initially and synchronous MH and IHH GLUT-1 positive were discovered in the pathological analysis. Segmental IV hepatic resection and later on selective cysts excision were done for persistent hepatic lesion despite medical treatment. After 14 months of beta-blockers treatment, clinical follow-up shows a healthy child with no residual cystic lesions.


[Proteomic Analyses of Purified Particles of the Rabies Virus].
The rabies virus (RABV) is an enveloped RNA virus. It mainly damages the central nervous system and causes anencephaly in mammals and humans. There is now compelling evidence that enveloped virions released from infected cells can carry many host proteins, some of which may play an important part in viral replication. Several host proteins have been reported to be incorporated into RABV particles. However, a systematic study to reveal the proteomics of RABV particles has not been conducted. In the present study, after virus culture and purification by sucrose density gradient ultracentrifugation, a proteomics approach was used to analyze the protein composition of purified RABV particles to understand the molecular mechanisms of virus-cell interactions. Fifty host proteins, along with five virus-encoded structural proteins, were identified in purified RABV particles. These proteins could be classified into ten categories according to function: intracellular trafficking (14%), molecular chaperone (12%), cytoskeletal (24%), signal transduction (8%), transcription regulation (12%), calcium ion-binding (6%), enzyme binding (6%), metabolic process (2%), ubiquitin (2%) and other (14%). Of these, four proteins (beta-actin, p-tubulin, Cofilin, Hsc70) were validated by western blotting to be present in purified RABV particles. This novel study of the composition of host proteins in RABV particles may aid investigation of the mechanism of RABV replication.


Anthropometric, physiological and performance characteristics of elite team-handball players.
The objective of this study was to provide anthropometric, physiological, and performance characteristics of an elite international handball team. Twenty-one elite handball players were tested and categorized according to their playing positions (goalkeepers, backs, pivots, and wings). Testing consisted of anthropometric and physiological measures of height, body mass, percentage body fat and endurance (VO(2max)), performance measures of speed (5, 10, and 30 m), strength (bench press and squat), unilateral and bilateral horizontal jumping ability, and a 5-jump horizontal test. Significant differences were found between player positions for some anthropometric characteristics (height and percentage body fat) but not for the physiological or performance characteristics. Strong correlations were noted between single leg horizontal jumping distances with 5-, 10-, and 30-m sprint times (r = 0.51-0.80; P < 0.01). The best predictors of sprint times were single leg horizontal jumping with the dominant leg and the distance measured for the 5-jump test, which when combined accounted for 72% of the common variance associated with sprint ability. In conclusion, performance abilities between positions in elite team-handball players appear to be very similar. Single leg horizontal jumping distance could be a specific standardized test for predicting sprinting ability in elite handball players.


Aldosterone increases urine production and decreases apical AQP2 expression in rats with diabetes insipidus.
Vasopressin and aldosterone are essential hormones in the regulation of water and sodium balance. Aldosterone regulates sodium reabsorption, although synergistic effects on collecting duct water permeability have been shown. We investigated the effects of 7-day aldosterone infusion or oral spironolactone treatment on water balance and aquaporin (AQP) 2 expression in rats with 21 days of lithium-induced nephrogenic diabetes insipidus (Li-NDI). In rats with Li-NDI, aldosterone markedly increased (271 +/- 14 ml/24 h), whereas spironolactone decreased (74 +/- 11 ml/24 h) urine production compared with rats treated with lithium only (120 +/- 11 ml/24 h). Aldosterone increased free-water clearance and creatinine clearance, whereas spironolactone caused a decreased creatinine clearance but unchanged free-water clearance. Immunoblotting showed unchanged AQP2 expression in cortex/outer stripe of the outer medulla and inner medulla. In the inner stripe of the outer medulla aldosterone caused a decreased AQP2 expression, whereas spironolactone caused an increase compared with rats treated with lithium only. Semiquantitative confocal immunofluorescence microscopy of AQP2 immunolabeling showed reduced AQP2 expression in the apical plasma membrane domain in connecting tubule (CNT) and initial cortical collecting ducts (iCCD) in response to aldosterone-treated rats compared with rats treated with lithium only. Spironolactone significantly increased apical AQP2 expression in the iCCD compared with rats treated with lithium only. We also tested whether similar changes could be observed in vasopressin-deficient BB rats and found similar changes in urine production and subcellular AQP2 expression in the CNT and iCCD in response to aldosterone and spironolactone. This study shows that aldosterone treatment perturbs diabetes insipidus and is associated with AQP2 redistribution in CNT and iCCD likely mediated by the spironolactone-sensitive mineralocorticoid receptor.


MdMYB9 and MdMYB11 are involved in the regulation of the JA-induced biosynthesis of anthocyanin and proanthocyanidin in apples.
Anthocyanin and proanthocyanidin (PA) are important secondary metabolites and beneficial to human health. Their biosynthesis is induced by jasmonate (JA) treatment and regulated by MYB transcription factors (TFs). However, which and how MYB TFs regulate this process is largely unknown in apple. In this study, MdMYB9 and MdMYB11 which were induced by methyl jasmonate (MeJA) were functionally characterized. Overexpression of MdMYB9 or MdMYB11 promoted not only anthocyanin but also PA accumulation in apple calluses, and the accumulation was further enhanced by MeJA. Subsequently, yeast two-hybrid, pull-down and bimolecular fluorescence complementation assays showed that both MYB proteins interact with MdbHLH3. Moreover, Jasmonate ZIM-domain (MdJAZ) proteins interact with MdbHLH3. Furthermore, chromatin immunoprecipitation-quantitative PCR and yeast one-hybrid assays demonstrated that both MdMYB9 and MdMYB11 bind to the promoters of ANS, ANR and LAR, whereas MdbHLH3 is recruited to the promoters of MdMYB9 and MdMYB11 and regulates their transcription. In addition, transient expression assays indicated that overexpression of MdJAZ2 inhibits the recruitment of MdbHLH3 to the promoters of MdMYB9 and MdMYB11. Our findings provide new insight into the mechanism of how MeJA regulates anthocyanin and PA accumulation in apple.


Elevation of serum MAGE-4 protein levels and prediction of hepatocellular carcinogenesis in patients with liver cirrhosis.
Early detection of hepatocellular carcinoma (HCC) is clinically important because advanced HCC limits treatment modalities for the cancer. We have previously reported that serum levels of MAGE-4 protein are strongly associated with the development of HCC. The present study was designed to determine whether elevated serum MAGE-4 protein levels can predict hepatocellular carcinogenesis in patients with liver cirrhosis before clinical diagnosis. Among 62 cirrhotic patients, 28 patients were diagnosed with HCC during the follow-up period. The levels of MAGE-4 protein and alpha-fetoprotein (AFP) were significantly elevated in cirrhotic patients with HCC. Univariate and multivariate analyses suggest that elevated serum MAGE-4 protein is more significant than AFP. Importantly, retrospective analysis of prefrozen sera of cirrhotic patients revealed a transient or continuous elevation of serum MAGE-4 protein levels in 14 of 28 cirrhotic patients with HCC (50%) before clinical diagnosis. In contrast, elevated serum MAGE-4 protein levels were observed in 3 of 33 cirrhotic patients without HCC (9%), and in 2 of 34 hepatitic patients (6%). These results indicate that elevated serum MAGE-4 protein levels can be a predictive marker of hepatocellular carcinogenesis in cirrhotic patients, thereby enabling us to treat patients at an earlier stage.


Enhanced S-Cone Syndrome: Elevated Cone Counts Confer Supernormal Visual Acuity in the S-Cone Pathway.
To measure photoreceptor packing density and S-cone spatial resolution as a function of retinal eccentricity in patients with enhanced S-cone syndrome (ESCS) and to discuss the possible mechanisms supporting their supernormal S-cone acuity. We used an adaptive optics scanning laser ophthalmoscope (AOSLO) to characterize photoreceptor packing. A custom non-AO display channel was used to measure L/M- and S-cone-mediated visual acuity during AOSLO imaging. Acuity measurements were obtained using a four-alternative, forced-choice, tumbling E paradigm along the temporal meridian between the fovea and 4° eccentricity in five of six patients and in seven control subjects. L/M acuity was tested by presenting long-pass-filtered optotypes on a black background, excluding wavelengths to which S-cones are sensitive. S-cone isolation was achieved using a two-color, blue-on-yellow chromatic adaptation method that was validated on three control subjects. Inter-cone spacing measurements revealed a near-uniform cone density profile (ranging from 0.9-1.5 arcmin spacing) throughout the macula in ESCS. For comparison, normal cone density decreases by a factor of 14 from the fovea to 6°. Cone spacing of ESCS subjects was higher than normal in the fovea and subnormal beyond 2°. Compared to the control subjects (n = 7), S-cone-mediated acuities in patients with ESCS were normal near the fovea and became increasingly supernormal with retinal eccentricity. Beyond 2°, S-cone acuities were superior to L/M-cone-mediated acuity in the ESCS cohort, a reversal of the trend observed in normal retinas. Higher than normal parafoveal cone densities (presumably dominated by S-cones) confer better than normal S-cone-mediated acuity in ESCS subjects.


A system dynamics-based synergistic model of urban production-living-ecological systems: An analytical framework and case study.
Human-land coordination represents urbanization and is a key component of urban modernization. In this study, the theory of system dynamics was introduced, in which a "production-living-ecological" complex system was used based on the human-land coordination concept. Moreover, the characteristics of system dynamics of causal cycle, dynamic and sustainable development, man-land synergy, integrity and openness, and self-organization and adaptability were analyzed by dividing it into three subsystems: urban production, urban living, and urban ecological subsystems. Here, causal feedback and system structure flow diagrams were designed using causal loop diagrams and system structure flow diagrams to evaluate the causal relationships between variables and quantitatively analyzing their interactions between variables and predicting the future development of variables. Changsha City, China was selected as the case study area, where we constructed system dynamics practice equation model was then constructed to determine the interaction between the subsystems. Our findings indicate that by the year 2035 in the future, the overall trend of factors influencing the function of the subsystems such as population, GDP and built-up area are positively correlated with an increasing trend, and there are interactions between. Furthermore, these factors interact with each other, and a mutual correlation was found among the production-living-ecological functions system, Therefore, this study provides a novel perspective and exploratory practice for the study of the synergistic coupling of ecological, production, and living functions of cities and evaluating high-quality development of cities. Thus, the coupling and coordination of urban production, living and ecological functions reflects the coupling and coordination of the "people-land" relationship, which is the key to high-quality urban development.


A test of the multiple connections model of reading acquisition.
Within the framework of Society of Mind Theory (Minsky, 1986), learning to read is conceptualized as a process of creating new communication links or neural connections between an existing visual society and an existing linguistic society. Four visual-linguistic connections may become functional: letter-phonemic code, whole word-semantic code, whole word-name code, letter sequence-aural syllabic code. The hypothesis was tested that more than one of these visual-linguistic connections must be taken into account in predicting reading achievement. Results showed that the combination of the composite letter-phoneme variable and the composite whole word-semantic code variable accounted for significantly more variance in oral reading than did either single variable at the end of the first grade. Groups with large absolute discrepancy (1 or more standard scores) or small absolute discrepancy (1/3 standard score or less) on corresponding visual and linguistic skills differed significantly in both oral (whole word-semantic code composite) and silent reading (whole word-semantic code and letter sequence-aural syllabic code composites). There was a relationship between the number of large discrepancies and reading achievement. Results are discussed in reference to neuropsychological models of connectionism (Rumelhart & McClelland, 1986) and working brain systems (Luria, 1973).


Batrachochytrium dendrobatidis haplotypes on the hellbender Cryptobranchus alleganiensis are identical to global strains.
To determine whether the chytrid fungus Batrachochytrium dendrobatidis (Bd) found on the hellbender Cryptobranchus alleganiensis in the southern US is endemic or exotic, we identified the genetic type of this fungus using partial DNA sequences of the internal transcribed spacer (ITS) region. We identified 3 genetic types, which are found on Japanese amphibians other than the Japanese giant salamander Andrias japonicus, a species that belongs to the same family (Cryptobranchidae) as hellbenders. The fungus collected from hellbenders exhibited low genetic diversity and matched the common Bd genetic types which have been detected from around the world. These results support that the chytrid fungus on the hellbender is a novel pathogen, as proposed by previous studies. Although we have not observed disease symptoms directly linked to this fungus on this endangered salamander, further evaluation of the influence of this exotic fungus on this species is warranted.


Health State Utilities and Disease Duration in Systemic Sclerosis: Is There an Association?
Health state utility values (HSUV) are used as weightings to calculate quality-adjusted life years in economic evaluations. Evidence suggests that patients' perceptions of a new diagnosis for a chronic disease, while initially poor, may improve over time. The objective of this study was to examine the association between disease duration and direct HSUV scores in patients with systemic sclerosis (SSc). Our study included patients with SSc from a US SSc center. An interviewer administered direct HSUV techniques including the visual analog scale (VAS), time tradeoff (TTO), and standard gamble (SG). We calculated the Short Form 6D HSUV from the Medical Outcomes Study Short Form-36. Additional clinical and demographic variables were collected. The mean age of the SSc sample (n = 223) was 51 years (SD 16) with the majority being women (84%). Median disease duration was 5 years (interquartile range 1.5-9). Mean (SD) HSUV scores were 0.67 (0.19) for the VAS, 0.76 (0.28) for the TTO, 0.84 (0.22) for the SG, and 0.65 (0.13) for the SF-6D. In patients with early disease (defined as ≤ 2 yrs, n = 78), the mean HSUV values were 0.64 (VAS), 0.70 (TTO), 0.80 (SG), and 0.63 (SF-6D) versus for those with a longer disease duration: 0.69, 0.79, 0.87, and 0.67, respectively. In multivariate analysis, the SG measure showed a significant and positive association with disease duration measured as a continuous variable and using a threshold of 2 years (p = 0.047 and p = 0.023, respectively). Greater disease duration showed a positive association with a direct measure (SG) of utility elicitation after a period of 2 years.


Regulation of the extrarenal CYP27B1-hydroxylase.
Provided here is a collective review of research on the extrarenal CYP27B1-hydroxylase that shapes our current and expanding vision of the role this enzyme plays in the intracrinology and paracrinology, as opposed to the traditional endocrinology, of vitamin D to regulate the innate and adaptive immune responses, particularly in human granuloma-forming diseases like tuberculosis. Special emphasis is placed on soluble factors (i.e., cytokines) in the local microenvironment of these human diseases that coordinate amplification and feedback inhibition of the macrophage CYP27B1-hydroxylase. Principal among these factors are Type I and Type II interferons (IFNs); the Type II IFN, IFN-γ, stimulates the production of 1,25-dihydroxyvitamin D (1,25(OH)2D) from 25-hydroxyvitamin D (25OHD) by the granuloma-forming disease-activated macrophage, while the Type I IFNs, IFN-α and IFN-β, block the hydroxylation reaction. The Type I IFN response is associated with more aggressive disease, while the Type II IFN response, the one that promotes 1,25(OH)2D production by the macrophage, is associated with more confined disease. Tilting the balance in the human immune response toward a confined disease phenotype is enabled by the presence of sufficient extracellular 25OHD to modulate IFN-γ-promoted and substrate 25OH-driven intracellular synthesis of 1,25(OH)2D. This article is part of a Special Issue entitled 'Vitamin D Workshop'.


[Rocuronium anesthesia induced anaphylactic shock: a case report].
Anaphylaxis is an acute and fatal systemic allergic reaction to an allergen, and it could be an unpredictable and life-threatening cause during anesthesia. The main purpose of this paper is to report a case of anaphylactic shock during the anesthesia induction and to review the prophylaxis and treatment of anaphylactic reactions and anaphylactoid reactions during the anesthesia period. A 63-year-old man, with a mass on his adrenal, was scheduled to a laparoscopic adrenal tumor excision. During the anesthesia induction period, after administrated sulfentanil, propofol and rocuronium, the blood pressure was decreased and the heart rate was increased. Then, the patient had rash on his whole body and developed an anaphylactic shock. After being treated with the anti-allergic agents and norepinephrine, the rash disappeared and the vital sign become stable. The patient felt nothing uncomfortable during the two weeks'follow-up. Anaphylactic reactions and anaphylactoid reactions are not rare during the anesthesia period. The most common inducements are muscle relaxant, latex and antibiotics. Anaphylactic reactions in the perioperative period are often serious and potentially life-threatening conditions, involving multiple organ systems in which the clinical manifestations are the consequence of the release of preformed mediators from mast cells and basophils. Before anesthesia, we should acquire the allergic history. During the anesthesia period, the vital sign and the skin should be observed carefully.


Demarcating and highlighting in Papuan Malay phrase prosody.
Phrase-level prosody serves two essential functions in many languages of the world: chunking information into units (demarcating) and marking important information (highlighting). Recent work suggests that prosody has a mainly demarcating function in the Trade Malay language family. That is, the use of pitch accents in these languages is limited or absent, as the main prosodic events occur on the final two syllables in a phrase. The current study investigates the extent to which Papuan Malay phrase prosody is used for demarcating and highlighting, taking into account the potential influence of word stress. This is done by means of acoustic analyses on a corpus of spontaneous speech. Both the form (F0 movement) and the possible functions (demarcating and highlighting) of the final two syllables in Papuan Malay phrases are investigated. Although most results favor the demarcating function of Papuan Malay phrase prosody, a highlighting function cannot be ruled out. The results suggest that Papuan Malay might hold an exceptional position in the typology of prosodic prominence.


[Iatrogenic streptococcal sepsis-- a case report].
A case study of iatrogenic streptococcal sepsis is presented. That was caused by the stomatological device left in a dental alveolus at time of dental treatment and prosthetic restoration. Systemic inflammatory response because of dentigenous spread endangered the patients life.


High Performance and Structural Stability of K and Cl Co-Doped LiNi0.5Co0.2Mn0.3O2 Cathode Materials in 4.6 Voltage.
The high energy density lithium ion batteries are being pursued because of their extensive application in electric vehicles with a large mileage and storage energy station with a long life. So, increasing the charge voltage becomes a strategy to improve the energy density. But it brings some harmful to the structural stability. In order to find the equilibrium between capacity and structure stability, the K and Cl co-doped LiNi0.5Co0.2Mn0.3O2 (NCM) cathode materials are designed based on defect theory, and prepared by solid state reaction. The structure is investigated by means of X-ray diffraction (XRD), rietveld refinements, scanning electron microscope (SEM), XPS, EDS mapping and transmission electron microscope (TEM). Electrochemical properties are measured through electrochemical impedance spectroscopy (EIS), cyclic voltammogram curves (CV), charge/discharge tests. The results of XRD, EDS mapping, and XPS show that K and Cl are successfully incorporated into the lattice of NCM cathode materials. Rietveld refinements along with TEM analysis manifest K and Cl co-doping can effectively reduce cation mixing and make the layered structure more complete. After 100 cycles at 1 C, the K and Cl co-doped NCM retains a more integrated layered structure compared to the pristine NCM. It indicates the co-doping can effectively strengthen the layer structure and suppress the phase transition to some degree during repeated charge and discharge process. Through CV curves, it can be found that K and Cl co-doping can weaken the electrode polarization and improve the electrochemical performance. Electrochemical tests show that the discharge capacity of Li0.99K0.01(Ni0.5Co0.3Mn0.2)O1.99Cl0.01 (KCl-NCM) are far higher than NCM at 5 C, and capacity retention reaches 78.1% after 100 cycles at 1 C. EIS measurement indicates that doping K and Cl contributes to the better lithium ion diffusion and the lower charge transfer resistance.


An RNA interference knock-down of nitrate reductase enhances lipid biosynthesis in the diatom Phaeodactylum tricornutum.
When diatoms are stressed for inorganic nitrogen they remodel their intermediate metabolism and redirect carbon towards lipid biosynthesis. However, this response comes at a significant cost reflected in decreased photosynthetic energy conversion efficiency and growth. Here we explore a molecular genetics approach to restrict the assimilation of inorganic nitrogen by knocking down nitrate reductase (NR). The transformant strain, NR21, exhibited about 50% lower expression and activity of the enzyme but simultaneously accumulated over 40% more fatty acids. However, in contrast to nitrogen-stressed wild-type (WT) cells, which grow at about 20% of the rate of nitrogen-replete cells, growth of NR21 was only reduced by about 30%. Biophysical analyses revealed that the photosynthetic energy conversion efficiency of photosystem II was unaffected in NR21; nevertheless, the plastoquinone pool was reduced by 50% at the optimal growth irradiance while in the WT it was over 90% oxidized. Further analyses reveal a 12-fold increase in the glutamate/glutamine ratio and an increase NADPH and malonyl-CoA pool size. Transcriptomic analyses indicate that the knock down resulted in changes in the expression of genes for lipid biosynthesis, as well as the expression of specific transcription factors. Based on these observations, we hypothesize that the allocation of carbon and reductants in diatoms is controlled by a feedback mechanism between intermediate metabolites, the redox state of the plastid and the expression and binding of transcription factors related to stress responses.


In vitro procoagulant and anticoagulant properties of Naja naja naja venom.
Bites by the Indian cobra (Naja naja naja) are common in India and Sri Lanka because of its close association with humans. Cobra venoms are complex and contain several toxic components, including neurotoxins that cause post-synaptic neuromuscular blockade with respiratory paralysis and even death. Bites may also cause extensive local necrosis by mechanisms not fully elucidated. Although no significant coagulopathy has been reported, N.n. naja venom can form blood clots in vitro by activating prothrombin as demonstrated by thrombin-specific chromogenic substrate. Scanning electron microscopy demonstrates that the clots formed by venom lack the thin fibrin strands of normal blood clots formed by thromboplastin or glass contact. Rheometry shows that clots formed by venom have abnormally low elasticity over an extended period and then, as the platelets contract, a retarded and more feeble increase in elasticity. Purified N.n. naja venom PLA2 inhibits platelet aggregation in PRP and explains the decreased clot retraction and retarded and compromised elasticity build up. The present study shows that the PLA2 and the prothrombin activator from N.n. naja venom have effects on haemostasis and blood clotting, although such effects are not observed systemically in envenomed humans.


The pathophysiology, medical management, and dental implications of children and young adults having attention-deficit hyperactivity disorder.
Attention-deficit hyperactivity disorder is considered to be the most common neurobehavioral disorder among school-aged children. Children who have ADHD exhibit symptoms of inattention, hyperactivity, and impulsivity that are extreme for their age. These symptoms adversely affect academic performance, vocational success, and social-emotional development. The disorder is usually treated with stimulant medications, but on occasion antidepressants and certain antihypertensive agents are used. Dentists caring for individuals with ADHD must be familiar with the manifestations of the disease and its associated features so they can garner the maximum level of cooperation from the patient. They must also be familiar with the drugs used to treat the disorder because many of these pharmaceuticals cause adverse orofacial and systemic reactions and may interact with dental therapeutic agents.


Evaluating Interactive Graphical Encodings for Data Visualization.
User interfaces for data visualization often consist of two main components: control panels for user interaction and visual representation. A recent trend in visualization is directly embedding user interaction into the visual representations. For example, instead of using control panels to adjust visualization parameters, users can directly adjust basic graphical encodings (e.g., changing distances between points in a scatterplot) to perform similar parameterizations. However, enabling embedded interactions for data visualization requires a strong understanding of how user interactions influence the ability to accurately control and perceive graphical encodings. In this paper, we study the effectiveness of these graphical encodings when serving as the method for interaction. Our user study includes 12 interactive graphical encodings. We discuss the results in terms of task performance and interaction effectiveness metrics.


Utility of a Wisconsin Card Sorting Test short form in persons with Alzheimer's and Parkinson's disease.
The utility of administering only the first deck of 64 cards from the Wisconsin Card Sorting Test (WCST-64) in persons with Alzheimer's (AD) and Parkinson's disease (PD) was evaluated. There were 35 elderly subjects matched for gender, age, and education in each of four groups: controls, PD without dementia (PDN), PD with dementia (PDD), and AD. Additionally, the control and PDN subjects were matched for level of cognitive functioning as were the PDD and AD groups. Results revealed that demented persons performed significantly worse than nondemented subjects. The WCST-64 was also sensitive to the subtle executive deficits demonstrated by persons with PD without dementia. The findings support the use of the WCST-64 in elderly persons with AD and PD.


Frequency, sensitivity, and specificity of individual signs of diverticulitis on thin-section helical CT with colonic contrast material: experience with 312 cases.
The aim of our study was to determine the frequency, sensitivity, and specificity of the individual signs of diverticulitis using helical CT with colonic contrast material. Between March 1997 and September 1999, 312 patients with suspected diverticulitis were examined on helical CT using rectally administered colonic contrast material. CT scans that were positive for diverticulitis or indeterminate were rereviewed by two radiologists; CT interpretations were correlated with patients' clinical courses and surgical findings. One hundred fourteen (37%) of the 312 CT scans were interpreted as positive for diverticulitis; 192 scans (61%), as negative; six scans (2%), as indeterminate. Of the 114 scans that were positive for diverticulitis, 109 (96%; sensitivity 96%, specificity 91%) showed bowel wall thickening; 108 (95%; sensitivity 96%, specificity 90%), fat stranding; 104 (91%; sensitivity 91%, specificity 67%), diverticula; 57 (50%; sensitivity 50%, specificity 100%), fascial thickening; 51 (45%; sensitivity 45%, specificity 97%), free fluid; 49 (43%; sensitivity 43%, specificity 100%), inflamed diverticula; 34 (30%; sensitivity 30%, specificity 100%), free air; 18 (16%; sensitivity 16%, specificity 100%), "arrowhead" signs; nine (8%; sensitivity 8%, specificity 99%), abscesses; four (4%; sensitivity 4%, specificity 100%,), phlegmons; five (4%; sensitivity 4%, specificity 99%), intramural air; two (2%; sensitivity 2%, specificity 100%), intramural sinus tracts. Overall CT interpretation had a sensitivity of 99%, a specificity of 99%, a positive predictive value of 99%, a negative predictive value of 99%, and an overall accuracy of 99%. The two most frequent signs of diverticulitis were bowel wall thickening (96%) and fat stranding (95%). Less frequent but highly specific signs were fascial thickening (50%), free fluid (45%), and inflamed diverticula (43%).


Neutral defects in SrTiO3 studied with screened hybrid density functional theory.
The properties of neutral defects in SrTiO3 are calculated using the screened hybrid density functional of Heyd, Scuseria, and Ernzerhof. The formation energies, the crystal field splittings affecting the SrTiO3 band structure, and the relaxation geometries around each defect are discussed. Oxygen vacancies introduced in SrTiO3 are found to cause a small tetragonal elongation of the lattice along the z-axis. The resulting conduction band minimum electron effective masses deviate from the bulk values and support the proposal of enhanced electron mobility along the direction of the compressive strain. The locations of the various defect bands within the SrTiO3 gap are estimated without introducing any post hoc corrections, thus allowing a more reliable comparison with experiment.


Survey of US Patients with Multiple Sclerosis: Comparison of the New Electronic Interferon Beta-1b Autoinjector (BETACONNECT™) With Mechanical Autoinjectors.
Patients with multiple sclerosis (MS) generally undergo long-term treatment with disease-modifying therapies (DMTs). In the US, patients taking glatiramer acetate, interferon beta-1a, or interferon beta-1b, typically use a mechanical autoinjector. Recent survey results have shown that using an electronic autoinjector, such as BETACONNECT™ (Bayer Pharma AG) for interferon beta-1b/Betaseron® (Bayer Pharma AG) may reduce injection discomfort and increase patient satisfaction with treatment. The aim of the current survey was to assess patient perceptions of BETACONNECT compared with mechanical autoinjectors using a survey integrated with demonstrations and simulated injections with BETACONNECT. Patients with MS currently using mechanical autoinjectors for glatiramer acetate/Copaxone® (Teva Pharmaceuticals USA, Inc.), interferon beta-1a/Rebif® (EMD Serono Inc.), or interferon beta-1b/Extavia® (Novartis Pharmaceuticals Corp.), participated in a 60-min in-person interview. Patients rated the importance of 18 ideal autoinjector attributes, and the performance of their current autoinjectors across these attributes. BETACONNECT was demonstrated and patients performed simulated injections with BETACONNECT before rating it across the same attributes. Patient overall autoinjector preference was assessed. Ninety patients completed the survey: 63 were using autoinjectors for Copaxone, 25 for Rebif, and 2 for Extavia. BETACONNECT scored higher than mechanical autoinjectors across all 18 attributes. The top attributes of an ideal autoinjector were the injection process is easy overall, easy to push the button to start the injection, and autoinjector is comfortable to hold during injections. Unique BETACONNECT features most valued by patients were the built-in dwell time, self-check function, greater ability to customize injections, adjustment of injection speed, low injection noise, and automatic needle retraction. Overall, 75 out of 90 patients (83%) expressed a preference for BETACONNECT over their current autoinjector. BETACONNECT attributes and features were highly rated by patients, compared with both an ideal autoinjector and their current mechanical autoinjectors. These findings suggest that the use of BETACONNECT may increase patient satisfaction and potentially increase overall medication adherence. Bayer HealthCare Pharmaceuticals.


[Mutational landscape of prostate tumors revealed by whole-exome sequencing].
The results of the whole-exome DNA sequencing of eight prostate adenocarcinoma patients are presented. DNA was isolated from the peripheral blood as well as healthy and tumor prostate tissue from each patient. Bioinformatics analysis was conducted and the most significant mutations in prostate cancer patients were revealed. The obtained data could be important for understanding of the molecular mechanisms of prostate cancer pathogenesis and facilitate development of new approaches for treatment of the disease.


Simultaneous chromate and sulfate removal by Streptomyces sp. MC1. Changes in intracellular protein profile induced by Cr(VI).
The purpose of this study was to investigate the influence of increasing sulfate concentrations on chromium removal, to evaluate the effect of the presence of Cr(VI) on sulfate removal by Streptomyces sp. MC1 and to analyze the differential protein expression profile in the presence of this metal for the identification of proteins repressed or overexpressed. In the presence of Cr(VI) but in the absence of sulfate ions, bacterial growth was negligible, showing the Cr(VI) toxicity for this bacterium. However, the sulfate presence stimulated bacterium growth and Cr(VI) removal, regardless of its concentrations. Streptomyces sp. MC1 showed ability to remove chromium and sulfate simultaneously. Also, the sulfate presence favored the decrease of total chromium concentration from supernatants reaching a decrease of 50% at 48 h. In presence of chromium, seven proteins were down-expressed and showed homology to proteins involved in protein biosynthesis, energy production and free radicals detoxification while two proteins involved in oxidation-reduction processes identified as dihydrolipoamide dehydrogenase and S-adenosyl-l-methionine synthase were overexpressed.


Cognitive Impairment following use of Anaesthetic Agents: a Review of the Literature, and Implications for Future Practice.
Emerging data suggest that both inhalational and intravenous anaesthetics are associated with cognitive decline, particularly in the elderly. Of particular concern, is the phenomenon known as post-operative cognitive decline (POCD), characterised by a transient impairment of memory, concentration, language comprehension and social integration. Implicated in the pathophysiology of POCD is the accumulation of Aβ peptide, and inhibition of cholinergic neurotransmission. Currently used anaesthetic agents differ in their propensity for causing POCD as a result of their differing pharmacological profiles. Coupled with increasing knowledge of patient susceptibility factors, this information allows for modification of clinical practice to minimise the long-term disability that may otherwise accompany POCD.


Functional uncoupling of the platelet alpha 2-adrenergic receptor-adenylate cyclase complex in the elderly.
Elderly humans demonstrate decreased responsiveness in several hormone-receptor systems, including adrenergic receptors. Studies of the beta-adrenergic receptor (beta-AR) system have shown that reduced beta-adrenergic sensitivity in the elderly may be due to reduced beta-AR affinity for agonists. To determine the mechanisms underlying altered alpha-adrenergic sensitivity in the elderly, we assessed the relationships between age and platelet membrane alpha 2-adrenergic receptor (alpha 2-AR)-binding properties, receptor-linked adenylate cyclase (AC) activity, and the affinity of the alpha 2-AR-AC complex for agonists in 18 young (mean age, 24 yr; range 19-34) and 13 elderly (mean age, 69 yr; range, 63-85) normal subjects. In platelet membrane preparations from elderly compared to young subjects, we found similar antagonist-binding properties and similar activity of the catalytic unit of platelet AC, as indicated by the cAMP response to sodium fluoride stimulation. However, mean epinephrine-mediated inhibition of sodium fluoride-stimulated platelet AC activity was less in the elderly [20 +/- 4% (+/- SEM) vs. 31 +/- 2% inhibition; P less than 0.005). In addition, platelet alpha 2-AR affinity for agonist was lower in the elderly, as indicated by the higher concentration of epinephrine needed to inhibit 50% of specific [3H]yohimbine binding (IC50, 3.2 +/- 0.6 vs. 1.4 +/- 0.3 microM; P less than 0.02). These data provide evidence that platelet membranes from elderly humans have decreased responsiveness to alpha-adrenergic stimulation, which can be attributed to reduced alpha 2-AR-AC affinity for agonists. Similarly to reported age-related alterations in beta-adrenergic receptor function, these results suggest that there is also functional uncoupling of the alpha 2-AR-AC complex in elderly humans.


Absorption, disposition, metabolism and excretion of [14C]mizagliflozin, a novel selective SGLT1 inhibitor, in rats.
The pharmacokinetic and metabolite profiles of mizagliflozin, a novel selective sodium glucose co-transporter 1 inhibitor designed to act only in the intestine, were investigated in rats. Mizagliflozin administrated intravenously (0.3 mg/kg) and orally (3 mg/kg) declined with a short half-life (0.23 and 1.14 h, respectively). The absolute bioavailability was only 0.02%. Following intravenous administration of [14 C]mizagliflozin (0.3 mg/kg), radioactivity in plasma was also rapidly declined. Up to 24 h after oral administration of [14 C]mizagliflozin (1 mg/kg), radioactivity was recovered in the faeces (98.4%) and in the urine (0.8%). No remarkable accumulation of radioactivity in tissues was observed using tissue dissection technique and whole body autoradiography. Orally dosed [14 C]mizagliflozin was mostly metabolised to its aglycone, KP232, in the intestine. In the plasma, KP232 and its glucuronide were predominant. KP232 glucuronide was also prominent in the bile and was recovered as KP232 in the faeces possibly because of the deconjugation by gut microflora. Mizagliflozin was observed neither in the urine nor the faeces. These findings suggest that orally administered mizagliflozin is poorly absorbed, contributing to low systemic exposure; if absorbed, mizagliflozin is rapidly cleared from circulation.


Effect of omalizumab as add-on therapy to Quality of Life Questionnaire for Korean Asthmatics (KAQLQ) in Korean patients with severe persistent allergic asthma.
Omalizumab is the first biologic known to be effective in patients with severe allergic asthma. This study was conducted as a multicenter, single-group, open trial to evaluate the improvement in the quality of life with the additional administration of omalizumab for 24 weeks in Korean patients with severe persistent allergic asthma. Of the 44 patients, 31.8% were men and the mean age was 49.8 ± 11.8 years. A score improvement of 0.5 points or more in the Quality of Life Questionnaire for Korean Asthmatics (KAQLQ) was noted in 50.0% (22/44) of the patinets. In the improved group, the baseline total immunoglobulin E (IgE) level and the amount of omalizumab used were higher, and the day and night asthma symptoms were more severe, compared to those in the non-improved group. According to the Global Evaluation of Treatment Effectiveness, favorable outcomes were found in 78.6% of patients. The Korean asthma control test (p < 0.005) and forced expiratory volume in 1 second % predicted (FEV1%; p < 0.01) improved significantly in patients who received omalizumab treatment, compared to that at week 0, and the total dose of rescue systemic corticosteroids significantly decreased (p < 0.05). The improved group on KAQLQ showed a significant improvement in FEV1% (p < 0.001). Omalizumab can be considered a biological treatment for Korean patients with severe allergic asthma. It is recommended to consider omalizumab as add-on therapy in patients with high baseline total IgE levels and severe asthma symptoms.


Structure of major surface determinants and DNA diagnosis of Pneumocystis carinii.
Pneumocystis carinii is a pathogen which causes fatal pneumonia in patients with the acquired immune deficiency syndrome (AIDS). To facilitate the basic study of P. carinii, we have analyzed its major surface proteins by both immunochemical and biochemical methods. The major protein components of both cysts and trophozoites are a group of proteins called "P115" with apparent masses of 105-120 kd. It includes 6 isoelectric variants. A monoclonal antibody raised against cysts recognizes all 6 variants and reacts with epitopes located in the cell wall indicating that P115 is an immunoreactive surface component. The isoelectric variants contain identical or closely related protein components and they are mannose-rich glycoproteins. The isoelectric variation may be due primarily to differences in glycosylation. The majority of sera from humans with diagnosed pneumocystosis that were tested reacted strongly with the P115 proteins. To develop probes for DNA diagnosis and to facilitate molecular studies, a genomic DNA library of P. carinii has been constructed. Some of these clones were used for DNA hybridization analysis of rat and human lungs.


Relationship of expansion of CGG repeats and X-inactivation with expression of fra(X)(q27.3) in heterozygotes.
Expression of the fragile site Xq27.3 was investigated in 82 heterozygotes (58 normal and 24 mentally impaired) diagnosed by DNA analysis. EcoRI and EagI DNA digests were probed with StB12.3. This allowed the detection of the expansion of the CGG repeat of the FMR1 gene and the methylation pattern of the adjacent CpG island. Heterozygotes with delta < or = 400 bp (52/82) were all mentally normal and manifested fra(X) in less than 3% of the cells or did not express it. Unmethylated mutant alleles were always observed. About two thirds of females with delta > 500 bp (21/30) showed fra(X) frequencies above 3% (3 normal and 18 mentally impaired). Lower frequencies of fra(X) or negative results were observed in the remaining 9 females (3 normal and 6 affected). The large mutant alleles were always methylated. Therefore, while delta < or = 400 bp is always associated with negative or low expression of fra(X), larger expansions are not present exclusively in heterozygotes with high frequencies of fra(X). In 25 of 30 heterozygotes with delta > 500 bp, active and inactive normal alleles were observed. Three fra(X)-negative or low manifesting heterozygotes showed completely skewed X-inactivation, with the normal allele either active or inactive. Two females with high frequencies of fra(X) always had the normal allele inactivated. Densitometry studies showed no difference in the inactivation of the normal allele between heterozygotes who manifested fra(X) or not. Thus fra(X) expression does not seem to be influenced by X-inactivation.


Immunolocalization of matrix metalloproteinases and tissue inhibitors of metalloproteinases in human subconjunctival tissues.
To evaluate the roles of fibroblast proteins in the remodeling of the subconjunctival connective tissue, we immunohistochemically assessed the expression of matrix metalloproteinases (MMP)-1 and -2, and the tissue inhibitors of matrix metalloproteinases (TIMP)-1 and -2 in cultured human subconjunctival fibroblasts and in normal and healing human subconjunctival connective tissue. Cultured fibroblasts derived from human subconjunctival connective tissue and surgical specimens of normal and healing conjunctiva were immunostained with monoclonal antibodies directed against human MMPs and TIMPs and examined by light and electron microscopy. In the cultured fibroblasts, MMP-1 and TIMP-1 antibodies stained the cytoplasm in a fine granular pattern, suggesting localization of those proteins in the endoplasmic reticulum (ER) and Golgi apparatus. Antibodies to MMP-2 and TIMP-2 reacted with fibroblast cytoplasm in a granular pattern. Electron microscopy of those fibroblasts revealed MMP-1 and TIMP-1 immunoreactivity in the ER cisternae or on the membrane of the ER. In surgical samples, MMP-1 and TIMP-1 were immunohistochemically detected in healing subconjunctival tissue, but not in conjunctival epithelium or normal subconjunctival tissue. MMPs and TIMPs may be involved in remodeling of subconjunctival connective tissue and in fibroblast population after surgical interventions. These proteins may play a crucial role in the post-operative fibrotic process occurring during scar formation in subconjunctival tissue.


Ribosomopathies: mechanisms of disease.
Ribosomopathies are diseases caused by alterations in the structure or function of ribosomal components. Progress in our understanding of the role of the ribosome in translational and transcriptional regulation has clarified the mechanisms of the ribosomopathies and the relationship between ribosomal dysfunction and other diseases, especially cancer. This review aims to discuss these topics with updated information.


Implications of intercorrelation between hepatic CYP3A4-CYP2C8 enzymes for the evaluation of drug-drug interactions: a case study with repaglinide.
Statistically significant positive correlations are reported for the abundance of hepatic drug-metabolizing enzymes. We investigate, as an example, the impact of CYP3A4-CYP2C8 intercorrelation on the predicted interindividual variabilities of clearance and drug-drug interactions (DDIs) for repaglinide using physiologically based pharmacokinetic (PBPK) modelling. PBPK modelling and simulation were employed using Simcyp Simulator (v15.1). Virtual populations were generated assuming intercorrelations between hepatic CYP3A4-CYP2C8 abundances derived from observed values in 24 human livers. A repaglinide PBPK model was used to predict PK parameters in the presence and absence of gemfibrozil in virtual populations, and the results were compared with a clinical DDI study. Coefficient of variation (CV) of oral clearance was 52.5% in the absence of intercorrelation between CYP3A4-CYP2C8 abundances, which increased to 54.2% when incorporating intercorrelation. In contrast, CV for predicted DDI (as measured by AUC ratio before and after inhibition) was reduced from 46.0% in the absence of intercorrelation between enzymes to 43.8% when incorporating intercorrelation: these CVs were associated with 5th/95th percentiles (2.48-11.29 vs. 2.49-9.69). The range of predicted DDI was larger in the absence of intercorrelation (1.55-77.06) than when incorporating intercorrelation (1.79-25.15), which was closer to clinical observations (2.6-12). The present study demonstrates via a systematic investigation that population-based PBPK modelling incorporating intercorrelation led to more consistent estimation of extreme values than those observed in interindividual variabilities of clearance and DDI. As the intercorrelations more realistically reflect enzyme abundances, virtual population studies involving PBPK and DDI should avoid using Monte Carlo assignment of enzyme abundance.


Electrochemical and structural characterization of polymer gel electrolytes based on a PEO copolymer and an imidazolium-based ionic liquid for dye-sensitized solar cells.
Polymer electrolytes based on mixtures of poly(ethylene oxide-co-propylene oxide) and 1-methyl-3-propyl-imidazolium iodide (MPII) were investigated, aiming at their application in dye-sensitized solar cells (DSSC). The interactions between the copolymer and the ionic liquid were analyzed by infrared spectroscopy and (1)H NMR. The results show interactions between the ether oxygen in the polymer and the hydrogen in the imidazolium cations. The ionic conductivities, electrochemical behaviors, and thermal properties of the electrolytes containing different concentrations of MPII were investigated. The electrolyte containing 70 wt % MPII presented the highest ionic conductivity (2.4 x 10(-3) S cm(-1)) and a diffusion coefficient of 1.9 x 10(-7) cm(2) s(-1). The influence of LiI addition to the electrolytes containing different concentrations of MPII was also investigated. The DSSC assembled with the electrolyte containing 70 wt % MPII showed an efficiency of 3.84% at 100 mW cm(-2). The stability of the devices for a period of 30 days was also evaluated using sealed cells. The devices assembled with the electrolyte containing less ionic liquid showed to be more stable.


Regional cerebral glucose metabolism in late-life depression and Alzheimer disease: a preliminary positron emission tomography study.
Eight subjects with late-life depression, eight subjects with probable Alzheimer disease, and eight healthy age-matched controls were studied using 2-[18F]fluoro-2-deoxy-D-glucose positron emission tomography in the resting state with their eyes open and ears unoccluded. The depressed subjects showed widespread reductions in the regional cerebral metabolic rate for glucose in most major neocortical, subcortical, and paralimbic regions that were significantly different from control values (P < 0.01). The metabolic decrements in the depressed group were comparable in magnitude to those seen in the Alzheimer disease group. These data demonstrate widespread nonfocal decline in glucose metabolism in late-life depression that is comparable to the hypometabolism seen in Alzheimer disease. These findings have pathophysiological implications in major depressive disorder in the elderly.


[New merge of knowledge of the acu-moxibustion academic in the Republican period].
During the republican period, western science and technology as well as western medicine spread quickly in China, and inevitably had a profound influence on the academic of acu-moxibustion. The confluence of Chinese and western medicine with the scientification of acu-moxibustion had left an obvious mark on the academic of acu-moxibustion. No matter whether the theory involves science of channels and collaterals, acupoints and methods of needling and moxibustion or the improvement of acu-moxibustion apparatus and new therpy methods, all carrying remarkable characteristic of new merge of knowledge, and providing solid foundation and valuable reference for the development of contemporary academic of acu-moxibustion.


Ancestry dynamics in a South American population: The impact of gene flow and preferential mating.
European ancestry in many populations in Latin America at autosomal loci is often higher than that from X-linked loci indicating more European male ancestry and more Amerindian female ancestry. Generally, this has been attributed to more European male gene flow but could also result from an advantage to European mating or reproductive success. Population genetic models were developed to investigate the dynamics of gene flow and mating or reproductive success. Using estimates of autosomal and X-chromosome European ancestry, the amount of male gene flow or mating or reproductive advantage for Europeans, or those with European ancestry, was estimated. In a population from Antioquia, Colombia with an estimated 79% European autosomal ancestry and an estimated 69% European X-chromosome ancestry, about 15% male gene flow from Europe or about 20% mating or reproductive advantage of Europeans over Amerindians resulted in these levels of European ancestry in the contemporary population. Combinations of gene flow and mating advantage were nearly additive in their impact. Gene flow, mating advantage, or a combination of both factors, are consistent with observed levels of European ancestry in a Latin American population. This approach provides a general methodology to determine the levels of gene flow and mating differences that can explain the observed contemporary differences in ancestry from autosomes and X-chromosomes.


Heavy Metal Induced Antibiotic Resistance in Bacterium LSJC7.
Co-contamination of antibiotics and heavy metals prevails in the environment, and may play an important role in disseminating bacterial antibiotic resistance, but the selective effects of heavy metals on bacterial antibiotic resistance is largely unclear. To investigate this, the effects of heavy metals on antibiotic resistance were studied in a genome-sequenced bacterium, LSJC7. The results showed that the presence of arsenate, copper, and zinc were implicated in fortifying the resistance of LSJC7 towards tetracycline. The concentrations of heavy metals required to induce antibiotic resistance, i.e., the minimum heavy metal concentrations (MHCs), were far below (up to 64-fold) the minimum inhibition concentrations (MIC) of LSJC7. This finding indicates that the relatively low heavy metal levels in polluted environments and in treated humans and animals might be sufficient to induce bacterial antibiotic resistance. In addition, heavy metal induced antibiotic resistance was also observed for a combination of arsenate and chloramphenicol in LSJC7, and copper/zinc and tetracycline in antibiotic susceptible strain Escherichia coli DH5α. Overall, this study implies that heavy metal induced antibiotic resistance might be ubiquitous among various microbial species and suggests that it might play a role in the emergence and spread of antibiotic resistance in metal and antibiotic co-contaminated environments.


VLA-4 blockade suppresses endotoxin-induced uveitis: in vivo evidence for functional integrin up-regulation.
Leukocyte adhesion to the vascular wall is a critical early step in the pathogenesis of inflammatory diseases and is mediated in part by the leukocyte integrin, VLA-4, which binds to endothelial vascular cell adhesion molecule (VCAM) -1. Here, we investigate VLA-4's role in endotoxin-induced uveitis (EIU). At various time points (6-48 h) after EIU induction, the severity of the inflammation was evaluated by quantifying cell and protein content in the aqueous fluid, firm leukocyte adhesion in the retinal vessels, and the number of extravasated leukocytes into the vitreous. Functional activation of VLA-4 in vivo was investigated in our previously introduced autoperfused micro flow chamber assay. Firm adhesion of EIU leukocytes to immobilized VCAM-1 under physiological blood flow conditions was significantly increased compared with normal controls (P<0.05), suggesting an important role for VLA-4 in EIU. VLA-4 blockade in vivo significantly suppressed all uveitis-related inflammatory parameters studied, decreasing the clinical score by 45% (P<0.01), protein content in the aqueous fluid by 21% (P<0.01), retinal leukostasis by 68% (P<0.01), and leukocyte accumulation in the vitreous by 75% (P<0.01). Our data provide novel evidence for functional up-regulation of VLA-4 during EIU and suggest VLA-4 blockade as a promising therapeutic strategy for treatment of acute inflammatory eye diseases.


Serum Level of Growth Arrest-Specific 6 (Gas6) Protein and Genetic Variations in the Gas6 Gene in Patients with Type 2 Diabetes Mellitus.
Growth arrest-specific protein 6 (Gas6) belongs to a family of vitamin K-dependent coagulation proteins. Plasma levels of Gas6 are associated to altered glucose tolerance. This study aimed at determining whether c.843+7G>A Gas6 polymorphism is associated with the development of type 2 diabetes mellitus. The study included 50 patients with type 2 diabetes and 40 matched controls. The Gas6 protein was measured in serum using ELISA and Gas6 gene polymorphism by polymerase chain reaction-Restriction Fragment Length Polymorphism. The GG genotype was the most prevalent in the diabetic patient. The frequency of A allele in the diabetic group was lower than the control group (P < 0.05). Serum concentrations of Gas6 were lower among type 2 diabetes patients than controls (P < 0.001). Since the AA genotype was expressed at a lower frequency in type2 diabetes patients compared to controls, a protective role for this Gas6 variant in type 2 diabetic patients may be concluded.


Elevated Bmi-1 expression is associated with dysplastic cell transformation during oral carcinogenesis and is required for cancer cell replication and survival.
Bmi-1 is a polycomb group protein that was identified as c-myc cooperating oncogene in murine lymphomagenesis. The current study was undertaken to determine the role of Bmi-1 in human oral carcinogenesis. Bmi-1 protein and RNA expression levels were markedly enhanced in the cells of oral squamous cell carcinomas (OSCC) compared with that of normal human oral keratinocytes (NHOK). Enhanced-Bmi-1 expression was also detected in situ in the archived oral mucosal tissues with cancerous and precancerous histopathology, including that of mild epithelial dysplasia. Thus, Bmi-1 expression occurs at a very early stage in oral carcinogenesis. To determine the biological role of Bmi-1 in cell proliferation, endogenous Bmi-1 was knocked down in actively proliferating SCC4 cells and NHOK by RNA interference. After Bmi-1 knockdown, cell replication was severely retarded. However, the expression of p16(INK4A), a known cellular target of Bmi-1, was not changed in cells with or without Bmi-1 knockdown. Furthermore, Bmi-1 knockdown in HOK-16B-BaP-T cells, in which the p16(INK4A)/pRb pathway was abrogated, led to immediate arrest of replication and loss of viable cells. Thus, our data suggest that Bmi-1 may act through p16(INK4A)-independent pathways to regulate cellular proliferation during oral cancer progression.


Evaluation of the MALDI-TOF MS profiling for identification of newly described Aeromonas spp.
The genus Aeromonas comprises primarily aquatic bacteria and also serious human and animal pathogens with the occurrence in clinical material, drinking water, and food. Aeromonads are typical for their complex taxonomy and nomenclature and for limited possibilities of identification to the species level. According to studies describing the use of MALDI-TOF MS in diagnostics of aeromonads, this modern chemotaxonomical approach reveals quite high percentage of correctly identified isolates. We analyzed 64 Aeromonas reference strains from the set of 27 species. After extending the range of analyzed Aeromonas species by newly described ones, we proved that MALDI-TOF MS procedure accompanied by Biotyper tool is not a reliable diagnostic technique for aeromonads. We obtained quite high percentage of false-positive, incorrect, and uncertain results. The identification of newly described species is accompanied with misidentifications that were observed also in the case of pathogenic aeromonads.


Design, synthesis, and characterization of PROTACs targeting the androgen receptor in prostate and lung cancer models.
Although the androgen receptor (AR) is a validated target for the treatment of prostate cancer, resistance to antiandrogens necessitates the development of new therapeutic modalities. Exploiting the ubiquitin-proteasome system with proteolysis-targeting chimeras (PROTACs) has become a practical approach to degrade specific proteins and thus to extend the portfolio of small molecules used for the treatment of a broader spectrum of diseases. Herein, we present three subgroups of enzalutamide-based PROTACs in which only the exit vector was modified. By recruiting cereblon, we were able to demonstrate the potent degradation of AR in lung cancer cells. Furthermore, the initial evaluation enabled the design of an optimized PROTAC with a rigid linker that degraded AR with a DC50 value in the nanomolar range. These results provide novel AR-directed PROTACs and a clear rationale for further investigating AR involvement in lung cancer models.


Assessment of heavy-metal profile of the New Calabar River and its impact on juvenile Clarias gariepinus.
We have determined the heavy-metal status of the lower reaches of the New Calabar River in the Niger Delta region over a 40-km-long distance, and its impact on the development of catfish (juvenile Clarias gariepinus). The total mean concentrations of dissolved trace metals in the river were 0.01, 0.85, 0.56, 2.08, 0.05, 12.0, and 6.59 mg/l for Hg, Pb, Cd, Cu, Cr, Fe, and Zn, respectively. The accumulated concentration of trace metals in the muscles of different mature fish caught from the river were examined, and the results fell within the action levels adopted in most countries. To evaluate the contributions of trace metals to fisheries depletion, eggs of C. gariepinus were hatched in dilution water spiked with the total mean metal levels determined in the river water. Our results indicate substantive inhibition of egg hatch even at very low concentrations of the majority of the trace metals studied, with mortality rates well above 50% after 216 h of exposure (Table 5). These findings suggest that trace metals (except for Zn), even at very low concentrations, negatively affect fish hatch and fry rearing, implying that aquatic milieus contaminated by trace metals are not suitable as nursery grounds for fish cultures.


Toxicity and bioaccumulation of lead in marine protozoa communities.
The toxicity and bioaccumulation of lead has been studied using marine protozoa communities developed in laboratory microecosystems. The concentrations tested were 500 and 1000 micrograms.L-1 of lead as lead acetate. The protozoan was able to bioaccumulate 27.02-504 micrograms Pb.g-1 dry weight. Bacteria also bioaccumulated lead, but always to a lesser degree than protozoa. Lead caused a significant reduction in the density of protozoa, which could be an indirect response to the cellular increase of lead. On the other hand, the toxicant did not determine a decrease in the number of bacterial cells; this could be due to their capacity to bioaccumulate a lesser amount of lead, the increase in the number of dead cells, and the elimination of their predators by the toxicant. After 120 h, a recovery of the community was observed.