Pax5 activates immunoglobulin heavy chain V to DJ rearrangement in transgenic thymocytes.
Mice deficient for the B cell-restricted transcription factor Pax5 show a defect in the VH to DJH rearrangement step of immunoglobulin heavy chain gene assembly even though the expression of the V(D)J recombinase is not diminished in Pax5-/- pro-B cells. To investigate whether Pax5 is limiting for VH to DJH rearrangement, we generated transgenic mice which express Pax5 in developing thymocytes. We show that enforced expression of Pax5 in thymocytes results in a partial block in T cell development due to defective pre-TCR signaling in beta-selection. Moreover, our results demonstrate that expression of Pax5 in early thymocytes is sufficient to induce VH to DJH rearrangements in CD4+CD8+ T cells and lead us to suggest that Pax5 may play a direct role in the lineage-specific regulation of immunoglobulin heavy chain gene rearrangement.


Relationship between Behavior and Periodontal Health Self-Perception in Diabetic and Non-Diabetic Patients from Transylvania, Romania-A Self-Report Study, including The Desire to Use a Mobile App for Oral Care Improvements.
The study aimed to assess self-reported symptoms of periodontal disease (gingival bleeding, tooth mobility and halitosis) among diabetic and non-diabetic patients from Transylvania, Romania. Using statistical analysis methods, correlation between the aforementioned symptoms and diet, oral hygiene habits, stress, physical activity, and BMI (body mass index) were researched. Another secondary objective was to assess the impact of self-reported oral health, aesthetics, and halitosis on their life. Patients' willingness to use a mobile app for generating awareness of oro-dental complications, improving their knowledge of oro-dental health, and reminding them to visit the dentist based on an awareness-raising function, was also assessed. Methods: The study was based on an original self-administered questionnaire, applied to 182 subjects, in an unselected, randomized manner. A total of 110 questionnaires were applied in two dental offices and 72 questionnaires were applied in a public clinic for diabetic patients from Cluj-Napoca, Romania. Results: Warning signs and symptoms relevant to periodontal disease were identified by respondents, having statistically significant associations with the declared oral health-care habits, including interdental aids, vicious habits (nail biting, bruxism), etc. Some of these periodontal signs could be correlated with a certain lifestyle, such as the perceived stress, smoking status, practicing maintenance sports, and alcohol consumption. A total of 66% of the non-diabetics and 68% of the diabetics of the surveyed subjects consider a software application for generating awareness of oro-dental complications useful, and are willing to pay around EUR 6 for it. Conclusions: Having a medical condition such as diabetes makes patients pay more attention to dental health compared with non-diabetic patients. Patients expressed their desire to use a software application to help them to be aware of their condition and for improving their self-report capabilities, including their oral-health-related status.


Live birth rate is associated with oocyte yield and number of biopsied and suitable blastocysts to transfer in preimplantation genetic testing (PGT) cycles for monogenic disorders and chromosomal structural rearrangements.
To investigate whether live birth (LB) is associated with oocyte yield and number of biopsied and suitable blastocyst to transfer following preimplantation genetic testing (PGT) for monogenic disorders (PGT-M) and chromosomal structural rearrangements (PGT-SR). All couples underwent controlled ovarian stimulation, blastocyst biopsy, vitrification and transfer of suitable embryo(s) in a frozen embryo transfer (FET) cycle. Of 175 couples who underwent PGT treatment, 249 oocytes retrievals were carried out and 230 FET were subsequently undertaken. 122/230 (53%, 95% CI 47-59) FET resulted in a LB and 16/230 (7%, 95% CI 4-11) have resulted in ongoing pregnancies. 21/230 (9%, 95% CI 6-14) FET resulted in miscarriage and 69/230 (30%, 95% CI 24-36) concluded with failed implantation. Two (1%, 95% CI 0-3) transfers underwent termination for congenital malformation, with no evidence of misdiagnosis by prenatal testing. The relationship between number of oocytes retrieved and number of blastocysts biopsied and suitable embryos to transfer were significant (p = 0.00; Incidence rate ratio (IRR) 1.05; 95% 1.04-1.06; p = 0.00; IRR 1.04; 95%, 1.03-1.06), respectively. The number of oocytes collected (p = 0.007; OR 1.06; 95% CI 1.01-1.10), the number of blastocysts biopsied (p = 0.001; OR 1.14; 95% 95% CI 1.06-1.23) and the number of suitable embryos to transfer (p = 0.00; OR 1.38; 95% CI 1.17-1.64) were all significantly associated with the odds of achieving a LB. There is a 14% and 38% increased chance of a LB per additional blastocyst biopsied and suitable embryo to transfer, respectively. PGT-M and PGT-SR outcomes are significantly associated with egg yield, number of blastocysts to biopsy and suitable embryos to transfer.


Beta-2-glycoprotein-I IgA antibodies predict coronary plaque progression in rheumatoid arthritis.
To evaluate whether anti-Beta-2-Glycoprotein-I (anti-β2GPI) IgA antibodies associate with progression of coronary atherosclerosis and cardiovascular disease (CVD) events in rheumatoid arthritis (RA). One hundred-fifty patients underwent plaque evaluation (total, non-calcified, mixed and calcified) with coronary computed tomography angiography; 101 were re-imaged within 6.9±0.3 years to assess progression. The Framingham-D'Agostino score assessed cardiovascular risk. Coronary artery calcium (CAC) and segment involvement score quantified plaque burden. Anti-β2GPI IgA were seen in 45 (30%) patients. Despite no link to baseline plaque burden, anti-β2GPI IgA associated with segment involvement score increase (adjusted-RR=1.64 [95%CI 1.02-2.63]), CAC change (adjusted-β=0.33 [95%CI 0.002-0.656]) and developing new extensive or obstructive plaque at follow-up (adjusted-OR=4.24 [95%CI 1.30-13.87]). Adding anti-β2GPI IgA to logistic regression models with conventional risk factors predicting plaque progression outcomes increased Area under the receiver-operator curve and improved Net Reclassification and Integrated Discrimination Improvement indices (all P<0.05). In per-segment analyses, anti-β2GPI IgA predicted mixed plaque formation (adjusted-OR=3.20 [95%CI 1.01-10.09]) and lower likelihood of transition of mixed to calcified plaque (adjusted-OR=0.19 [95%CI 0.04-0.96]). Anti-β2GPI IgA moderated the effect of C-reactive protein on CAC change such that C-reactive protein associated with CAC change (β=0.26 [95%CI 0.14-0.38]) and CVD risk (adjusted-HR=1.89 [95%CI 1.02-3.51]) only in anti-β2GPI IgA positive patients. Anti-β2GPI IgA addition to clinical risk models improved prediction accuracy of CAC, plaque progression and transition to extensive/obstructive disease. They associated with new high-risk mixed plaques and delayed healing to calcified lesions. Anti-β2GPI IgA further modified the effect of inflammation on plaque progression and CVD events.


Altered relative concentrations of high-energy phosphates in patients with uraemic cardiomyopathy measured by magnetic resonance spectroscopy.
Premature sudden cardiovascular death is the commonest cause of death in end-stage renal disease (ESRD) patients and is associated with uraemic cardiomyopathy [left ventricular hypertrophy (LVH), systolic dysfunction (LVSD) or LV dilation]. High-energy phosphates (HEP), quantified using phosphorus-31 magnetic resonance spectroscopy, are reduced in patients with diabetes, heart failure and uraemia. Phosphocreatine:β adenosine triphosphate (PCr:ATP) ratio is an index of metabolic activity. We compared resting HEPs in ESRD patients and hypertensive patients (with and without LVH) who had normal renal function (LVH-only or normal myocardia). We also assessed associations of HEP levels with abnormalities of uraemic cardiomyopathy. Fifty-three ESRD and 30 hypertensive patients (18 with LVH, 12 with normal myocardia) underwent phosphorus magnetic resonance spectroscopy of their left ventricle. PCr:ATP ratios were calculated from (31)P-MR spectra obtained from long-axis views of the left ventricle. There were no significant differences in age, LV mass, chamber sizes and ejection fraction between patient groups. PCr:ATP was significantly lower in ESRD patients compared to hypertensive patients, irrespective of the presence or absence of LVH (P = 0.01). In the ESRD group, PCr:ATP was significantly lower in patients with LVSD (P = 0.05) and LV dilation (P = 0.01). LVH was not associated with significant difference in PCr:ATP. ESRD patients have lower HEP levels compared to hypertensive patients. Lower PCr:ATP ratio, indicating altered myocardial metabolic function in ESRD patients, is associated with features of uraemic cardiomyopathy.


Effects of homologous and heterologous rich platelets plasma, compared to poor platelets plasma, on cutaneous healing of rabbits.
To evaluate and compare the effects of homologous and heterologous PRP (Platelet-Rich Plasma) on the quality and speed of skin wound healing, compared to Poor Platelet Plasma (PPP). Twenty-one male adult rabbits were used; two for preparing homologous PRP, with the rest of them separated randomly in three groups, according to the treatment received: PPP - control (n=5), homologous PRP (n=7), heterologous (n=7). Excisional skin wounds were made on the back of the animals, for the application of homologous and heterologous PPP and PRP. At the 14th post-operative day (POD), the animals were subjected to a new wound, and the treatments were inverted. The wounds were evaluated macroscopically and histologically. A larger percentage of scar retraction was observed on the group treated with heterologous PRP, compared to homologous PRP, at the third POD, an increase of 25.03% (p=0.01). No other statistically significant differences among treatments were observed. Among every group, skin healing was efficient, without local adverse effects. Heterologous PRP contributed with more tissue retraction at the beginning of the wound healing process. After this, there were no differences on the wound healing skin process treated with PRP or PPP. However, our findings suggest the presence of others plasmatic factors, besides platelets, which could also contribute to the wound healing process, and thus, should be further investigated.


Corrections.
Worldwide Antimalarial Resistance Network (WWARN) AL Dose Impact Study Group. The effect of dose on the antimalarial efficacy of artemetherlumefantrine: a systematic review and pooled analysis of individual patient data. Lancet Infect Dis 2015; published online March 13. http://dx.doi. org/10.1016/S1473-3099(15)70024-1— In the WWARN Dose Impact Study Group, the affiliation for S Borrmann was incorrect and has been corrected to Institute for Tropical Medicine, University of Tubingen, Tubingen. The correction has been made to the online version as of April 20.


Case and care complexity in the medically ill.
The authors have argued that complexity in general health care is increasingly prevalent because of the increase in patients who have multimorbid conditions, and the increased professional and technical possibilities of medicine. In the increasingly complex care systems, it is necessary-specifically when treating patients in need of integrated care by several providers-that an optimal match between case and care complexity be found in order to prevent poor outcomes in this vulnerable group. The authors discussed several approaches to case complexity that can be identified in the literature. Most of them seem unsuitable for adjusting case and care complexity, and inadequate for designing multidisciplinary care. Theoretic approaches to case complexity may be of interest, but did not result in clinically meaningful information. The INTERMED, which can be considered the first empirically based instrument to link case and care complexity, is an attempt to improve care delivery and outcomes for the complex medically ill.


Varicose Veins: Approach, Assessment, and Management to the Patient with Chronic Venous Disease.
Varicose veins are tortuous and dilated veins commonly seen in chronic venous disease. This article will review chronic venous disease, including its differential diagnosis, workup, and treatment.


Rabbit liver pyridoxamine (pyridoxine) 5'-phosphate oxidase. Purification and properties.
Pyridoxamine (pyridoxine) 5'-phosphate oxidase (EC 220.127.116.11) has been purified 2000-fold from rabbit liver. The enzyme preparation migrates as a single protein and activity band on analytical disc gels containing 4,7, or 9 percent acrylamide, and as a single protein band on sodium dodecyl sulfate acrylamide gels. The oxidase is, therefore, homogeneous by these criteria. The pure enzyme catalyzes the following reactions in the presence of FMN: (See journal for formula). These activities copurify in the ratio of 1:1:1. Apparent K-m values are 10 muM for pyridoxamine-P, 30 muM for pyridoxine-P, and 40 nM for FMN. Apparent K-m values for N-(phosphopyridoxyl)amines range from 3.1 times 10-5 M to 1.6 times 10-3 M. The dissociation constant for FMN binding, determined by quenching of protein fluorescence, is 20 nM. The pH optima for all three types of substrates are broad, with maxima near pH 9. The pH dependence of FMN binding, measured by quenching of flavin fluorescence, has the same shape as the substrate activity profile. The holoenzyme has absorption maxima red-shifted from those of FMN to 380 nm and 448 nm, and exhibits spectral changes typical of flavoproteins upon reduction with dithionite. Its oxidation-reduction potential at pH 7 in phosphate buffer is -0.131 volt. The native enzyme has a molecular weight of 54,000 and is made up of two possibly identical polypeptide chains with molecular weights of 27,000. The applicability of proposed mechanisms of flavin catalysis to this flavoprotein is discussed.


Surveillance of transmitted HIV drug resistance using matched plasma and dried blood spot specimens from voluntary counseling and testing sites in Ho Chi Minh City, Vietnam, 2007-2008.
During 2007-2008, surveillance of transmitted human immunodeficiency virus (HIV) drug resistance (TDR) was performed following World Health Organization guidance among clients with newly diagnosed HIV infection attending voluntary counseling and testing (VCT) sites in Ho Chi Minh City (HCMC), Vietnam. Moderate (5%-15%) TDR to nonnucleoside reverse-transcriptase inhibitors (NNRTIs) was observed among VCT clients aged 18-21 years. Follow-up surveillance of TDR in HCMC and other geographic regions of Vietnam is warranted. Data generated will guide the national HIV drug resistance surveillance strategy and support selection of current and future first-line antiretroviral therapy and HIV prevention programs.


Endarterectomy of the left main coronary artery stenosis by a 'transpulmonary artery approach'.
For better visualization of the left main coronary artery, a new technique involving transection of the main pulmonary artery is described. With this new method it was possible to perform endarterectomy of the left main coronary artery in 35 patients from February 1981 to July 1987. The endarterectomy incision was closed with a pericardial or venous patch. We had no mortality, and 91% are free from angina at a mean follow-up of 31 months. Angiographic evaluation was performed in 19 patients revealing good patency of the left main artery. This procedure is safe, and we recommend it in isolated left main coronary artery stenosis without distal involvement and with good left ventricular function.


A novel machine learning method for evaluating the impact of emission sources on ozone formation.
Ambient ozone air pollution is one of the most important environmental challenges in China today, and it is particularly significant to identify pollution sources and formulate control strategies. In present study, we proposed a novel method of positive matrix factorization-SHapley Additive explanation (PMF-SHAP) for evaluating the impact of emission sources on ozone formation, which can quantify the main emission sources of ozone pollution. In this method, we first used the PMF model to identify the source of volatile organic compounds (VOCs), and then quantified various emission sources using a combination of machine learning (ML) models and the SHAP algorithm. The R2 of the optimal ML model in this method was as high as 0.96, indicating that the prediction performance was excellent. Furthermore, we explored the impact of different emission sources on ozone formation, and found that ozone formation in Shenzhen was more affected by VOCs, of which vehicle emission sources may have the greatest impact. Our results suggest that the appropriate combination of traditional models with ML models can well address environmental pollution problems. Moreover, the conclusions obtained based on the PMF-SHAP method were different from the traditional ozone formation potential (OFP) results, providing valuable clues for related mechanism studies.


Optimization of an Ultra-Sonication Extraction Method for Major Compounds Found in Mondia whitei Using Design of Experiment.
Optimum extraction conditions are vital in quality control methods to enable accurate quantification of the compounds of interest. An ultra-sonication method was developed for the extraction of seven major compounds found in Mondia whitei. Extraction temperature, time, power, frequency, percentage of ethanol in water and solvent to sample ratio were screened to access their significance on the percentage recovery of the compounds of interest. These parameters were screened using Descriptive screening design. Extraction temperature, solvent to sample ratio and the interaction between temperature and percentage ethanol in water were found to have a significant effect on the response. These parameters were then optimized using central composite design. The optimum conditions were found to be 66.1% ethanol in water, 70 °C temperature and 3 mL: 5 mg solvent to sample ratio. This method was successfully applied in the development of a quality control method for the seven compounds in Mondia whitei samples.


Myocardial salvage with trolox and ascorbic acid for an acute evolving infarction.
Both Trolox (a water-soluble analogue of alpha-tocopherol) and ascorbic acid were more effective than superoxide dismutase or catalase in protecting myocyte cell cultures from free radical attack (induced by hypoxanthine and xanthine oxidase). In a canine model of two hours of left anterior descending coronary artery occlusion followed by four hours of reperfusion, Trolox and ascorbic acid reduced the area of infarction within the area at risk. The Trolox group received 500 mL of deoxygenated saline solution containing 2.0 g of Trolox, 3.0 g of ascorbic acid, and 18 mg of EDTA (ethylenediaminetetraacetic acid) infused into the ascending aorta 30 seconds before and four minutes after reperfusion. Saline controls received 500 mL of deoxygenated saline solution containing 18 mg of EDTA. The angioplasty group had unmodified reperfusion by simple release of the occlusion. The area at risk and the area infarcted were estimated with Evans blue and triphenyl tetrazolium hydrochloride stains, respectively. The ratio of the area infarcted to the area at risk was significantly lower with Trolox (angioplasty, 30.4% +/- 5.1%; saline, 20.8% +/- 2.9%; and Trolox, 8.7% +/- 4.0%; p less than 0.01). In summary, the antioxidants Trolox and ascorbic acid effectively reduced myocardial necrosis after ischemia.


Comparison of the efficacy of ALA-PDT using an excimer-dye laser (630 nm) and a metal-halide lamp (600 to 740 nm) for treatment of Bowen's disease.
Topical 5-aminolevulinic acid-based photodynamic therapy (ALA-PDT) is an effective treatment for Bowen's disease (BD). In order to compare the efficacy of two different light sources, using either an excimer-dye laser (EDL) (630 nm) or a metal-halide lamp (MHL) (600 to 740 nm) a protocol for topical ALA-PDT for treatment of BD of the extremities was established, and responses during 12 months follow-up were assessed. From 25 patients a total of 26 lesions that had been histopathologically diagnosed as BD from 2005 to 2010 in the Department of Dermatology at the Aichi Medical University Hospital were randomly selected. The light source used for the topical ALA-PDT was EDL in 17 lesions and MHL in 9 lesions. The photosensitizing protoporphyrin IX that is produced within BD lesions 4 h after application of 20% ALA cream was mostly consumed after exposure to 100 J/cm(2) irradiation using 630 nm EDL. Each lesion was irradiated once a week for 3 weeks, for a total dosage of 300 J/cm(2) (100 mW/cm(2)). Patients were followed up clinically every 3 months for 12 months, and at 1 month after the final treatment lesions were evaluated histopathologically. Histologically, the complete response (CR) rate at 1-month follow-up was 82% (14/17 lesions) in the EDL treatment group and 100% (9/9 lesions) in the MHL treatment group (P > 0.05). The recurrence rate at 12 months after PDT was 46% (6/13 lesions, one patient lost to follow-up) in the EDL group and 0% in the MHL group (P < 0.05) (χ(2) test with Fisher's exact test). The average period before recurrence after EDL treatment was 6.5 months. A novel protocol for topical ALA-PDT in Japanese in Asian patients with BD was developed and implemented. The protocol improved the CR rate compared with previous studies. Moreover, the present results indicate that the efficacy of topical ALA-PDT using MHL was superior to that using EDL for BD patients.


A fully automated approach involving neuroimaging and deep learning for Parkinson's disease detection and severity prediction.
Three-dimensional magnetic resonance imaging has been proved to detect and predict the severity of progressive neurodegenerative disorders such as Parkinson's disease. The application of pre-processing with neuroimaging methods plays a vital role in post-processing for these problems. The development of technology over the years has enabled the use of deep learning methods such as convolutional neural networks (CNN) on magnetic resonance imaging (MRI) . In this study, the detection of Parkinson's disease and the prediction of disease severity were studied with 2D and 3D CNN using T1-weighted MRIs that were pre-processed with FLIRT image registration and BET non-brain tissue scraper. For 2D CNN, the median slices of the MR images in the sagittal, coronal, and axial planes were used separately and in combination. In addition, the whole brain for 3D CNN has been downsized. Considering the performance of the proposed methods, the highest results achieved for detecting Parkinson's disease were measured as 0.9620, 0.9452, 0.9407, and 0.9536 for Accuracy, F1 score, precision, and Recall, respectively. The highest result achieved for estimating the severity of Parkinson's disease was that 3D CNN was fed three times with a downsized whole MRI, which were measured for R, and R2 as 0.9150 and 0.8372, respectively. When the results obtained with the methods suggested within the scope of the study were examined, it was observed that the applied methods yielded promising performance.


Hybrid surgical technique for open abdominal aortic aneurysm repair in the setting of severe iliac artery calcification.
In the present report, we describe the case of a patient with an infrarenal abdominal aortic aneurysm that had been incidentally noted on an imaging study. Treatment decisions for this case were complicated by the presence of a hostile infrarenal aortic neck and significant bilateral iliac artery circumferential calcification, precluding iliac artery clamping and standard distal anastomotic techniques. We performed a hybrid surgical procedure, deploying bilateral iliac stent grafts into the distal aneurysmal aorta and sewing our aortic graft to the proximal extent of these stents. The findings from the present case add to the previously reported techniques of hybrid surgical management of abdominal aortic aneurysms with iliac disease and expand the technique to a larger application.


The kinetics of adenovirus infection and spread in cell cultures infected with low multiplicity.
The cause for the long "incubation period" required till the appearance of the CPE in cell cultures inoculated with small amounts of adenovirus was investigated with adenovirus type 5 in HeLa cell cultures. The spread of virus in a culture from cell to cell is minimal, as shown in cultures with antiserum in the medium. The spread by spontaneously released virus via the medium is more important. It can be accelerated by repeated subcultivation after freezing and thawing the cells in 2 or 3 days' intervals. The quantity of virus produced by one infected HeLa cell was found to be 200 TCID50 within 48 hours, independent of the MOI. The growth cycle too is largely independent of the virus dose. The data suggest that the long duration of the "incubation period" is fully explained by a burst size of 200, a cycle length of 40 to 48 hours and the assumption of a slow and steadily working process of spontaneous release of virus into the medium. Some other possible causes, like impurities in the inoculum or slow and asynchronous early stages of infection, have been ruled out by appropriate experiments.


Interleukin 1 and tumour necrosis factor increase phosphorylation of fibroblast proteins.
Interleukin 1 (IL1) or tumour necrosis factor (TNF) stimulated phosphorylation of a triad of 27 kDa phosphoproteins (pI 6.0, 5.7 and 5.5) in human dermal fibroblasts. The change was dependent on the dose of cytokine in the range 0.1-20 ng, was detectable between 3 and 5 min after stimulation and was maximal by 10 min. The proteins were found in the cytosol after subcellular fractionation. The 32P was removed from them by alkali, indicating the presence of phosphoserine and/or phosphothreonine. The results suggest that early changes in serine/threonine protein kinase activity may be involved in responses of fibroblasts to IL1 and TNF.


[COPD and alpha-1-antitrypsin deficiency].
Alpha-1-antitrypsin deficiency (AATD) is the main genetic factor related to the development of emphysema. This protein has numerous variants, some of which are clinically relevant because their anomalous conformation implies that they fail to reach the target organs as they are polymerized in the hepatocyte. The main abnormal variant is PiZ. In a small percentage of individuals, the accumulation of Z polymers in the liver leads to the development of liver disease. The lack of AATD in the lung favors the development of emphysema, since the proteolytic effect of elastases - the main biological function of AATD - is not counteracted. In Spain, approximately 400 persons are diagnosed with severe AATD deficiency, representing less than 10 % of those expected by epidemiological studies. The principal prognostic factor in these patients is forced expiratory volume in one second (FEV(1)), which is affected mainly by exposure to tobacco smoke. Thus, life expectancy in nonsmokers is similar to that in the general population while lung function decreases faster in smokers than in other patients with chronic obstructive pulmonary disease (COPD). The treatment of the lung disease is the same, although exogenous AATD augmentation is indicated when lung function deteriorates.


Intravaginal and intranasal immunizations are equally effective in inducing vaginal antibodies and conferring protection against vaginal candidiasis.
Oophorectomized, estrogen-treated rats were immunized by the intravaginal or intranasal route with a mannoprotein extract (MP) or secreted aspartyl proteinases (Sap) of Candida albicans, with or without cholera toxin as a mucosal adjuvant. Both routes of immunization were equally effective in (i) inducing anti-MP and anti-Sap vaginal antibodies and (ii) conferring a high degree of protection against the vaginal infection by the fungus. These data suggest that appropriate fungal antigens and adjuvant can be used to protect against candidal vaginitis, by either route.


Theory of mind in adults with traumatic brain injury: A meta-analysis.
Studies of abnormal theory of mind (ToM) performance in adult patients with traumatic brain injury (TBI) have reported inconsistent results. Therefore, we conducted a meta-analysis to characterize ToM performance in adult patients with TBI. Random-effects models were employed to estimate the overall effect size and the differential effect sizes across different ToM aspects. Based on a sample of 28 studies (1031 patients and 865 healthy controls), the meta-analytic findings revealed that ToM was significantly impaired in adult patients with TBI compared to healthy controls (g = -1.13). Besides, patients with TBI showed significant impairments in individual ToM tasks, as well as for different stimulus modes and contents involved in these ToM tasks. A meta-regression indicated a positive association between ToM performance and Glasgow Coma Scale score. The results of the current meta-analysis suggest that the performance in ToM tasks may be a good predictor of functional outcomes in adults with TBI, which is important for the identification of targets for cognitive interventions and the development of useful training intervention programs.


Dopaminergic regulation of glutamic acid decarboxylase mRNA expression and GABA release in the striatum: a review.
1. The majority of neurons in the striatum (caudate-putamen, dorsal striatum; nucleus accumbens, ventral striatum) and in striatal projection regions (the pallidum, the entopeduncular nucleus and substantia nigra reticulata) use gamma-aminobutyric acid (GABA) as transmitter and express glutamic acid decarboxylase (GAD; rate limiting enzyme) in the synthesis of GABA. GABA is the major inhibitory transmitter in the mammalian brain. 2. GAD in brain is present as two isoenzymes, GAD65 and GAD67. GAD65 is largely present as an inactive apoenzyme, which can be induced by nerve activity, while most GAD67 is present as a pyridoxal phosphate-bound permanently active holoenzyme. Thus GAD65 and GAD67 seem to provide a dual system for the control of neuronal GABA synthesis. 3. GAD mRNA expression can be visualised and quantified using in situ hybridisation, and GABA release can be quantified using in vivo microdialysis. 4. Different populations of GABA neurons can be distinguished in both dorsal and ventral striatum as well as in other parts of the basal ganglia. 5. Inhibition of dopaminergic transmission in the striatum by lesion of dopamine neurons or by neuroleptic treatment is followed by an increased release of GABA and increased expression of GAD67 mRNA in a subpopulation of striatal medium-sized neurons which project to the globus pallidus, and increased striatal GAD enzyme activity. 6. Increased dopaminergic transmission by repeated but not single doses of amphetamine is followed by decreased striatal GABA release and decreased GAD67 mRNA expression in a subpopulation of medium-sized neurons in the striatum. 7. Two populations of medium-sized GABA neurons in the striatum seem to be under tonic dopaminergic influence. The majority of these GABA neurons are under inhibitory influence, whereas a small number seem to be stimulated by dopamine. 8. Specific changes in activity in subpopulations of striatal GABA neurons probably mediate the dopamine-dependent hypokinetic syndrome seen in Parkinson's disease and following neuroleptic treatment.


Mediation of annexin 1 secretion by a probenecid-sensitive ABC-transporter in rat inflamed mucosa.
Annexin 1 is secreted by mammalian cells but lacks a leader signal sequence necessary to lead it to the classical secretory pathway via the endoplasmic reticulum. The mechanisms involved in the secretion of leaderless proteins remain uncertain. It has been suggested to involve membrane translocation via an ABC-transporter (ATP binding cassette). Using cultured inflamed mucosa from rectocolitis induced in rats, we studied if annexin 1 secretion followed the two main characteristics of ABC-transporter substrates: dependency on ATP hydrolysis and competitive inhibition by several other ABC-transporter substrates. Annexin 1 secretion is inhibited in a dose-dependent manner by two ATPase inhibitors. The inhibition reached 63.2+/-3.2%, 66.1+/-3.73% and 88.6+/-1.4% in the presence of 2mM vanadate, 0.5 and 1mM pervanadate, respectively. The efflux of calcein, a known ABC-transporter substrate, is similarly inhibited by 69.4+/-2.8% in the presence of 1mM pervanadate. Probenecid, an inhibitor of several ABC-transporters of the subfamilly ABCC or MRP (multidrug resistant associated protein), also inhibited annexin 1 secretion in a dose-dependent manner. As compared to control, 10mM probenecid reduced annexin 1 secretion by 72+/-20% and 20mM by 95.0+/-9%. By contrast, annexin 1 secretion is not blocked by other inhibitors of MRP1 (indomethacin, MK571), MRP2 (ochratoxin A1 or MK571), MRP5 (trequinsin or sulfinpyrazone) or by verapamil, cyclosporin A or glyburide. Taken together, our results show that annexin 1 secretion appears to share the efflux properties of ABC-transporter substrates.


The Reference Intervals of Hair Trace Element Content in Hereford Cows and Heifers (Bos taurus).
The objective of the present study was to assess hair trace element content in Hereford heifers and cows (Bos taurus) living in South Ural region and calculate the site-specific reference intervals. Hair trace element content in 150 cows and heifers farmed in the Southern Urals of Russia was assessed using inductively coupled plasma mass-spectrometry. Dietary trace element content corresponded to the adequate values as estimated by recommendations of USSR State Agriculture Committee and U.S. National Research Council. Comparative analysis demonstrated that heifers are characterized by significantly higher hair Se (3-fold), Hg (4-fold), and Sn (46%) content, whereas cows had significantly higher levels of hair Co (56%), I (33%), Si (2-fold), V (27%), B (55%), Cd (19%), Pb (47%), and Sr (23%). At the same time, no significant group difference in hair Cr, Cu, Fe, Li, Mn, Zn, As, and Ni was detected between Hereford cows and heifers. The reference intervals and 90% confidence intervals for the lower and upper limits were calculated in agreement with the American Society for Veterinary Clinical Pathology Quality Assurance and Laboratory Standard Guidelines.


Interpretations of the "balanced meal" household food security indicator.
The study objective was to quantify interpretations of the term "balanced meals" used in food security status assessments. Telephone interviews included 77 charitable food recipients in Hawaiì. After participants first responded to the question of whether they could afford to eat balanced meals, they next defined what a "balanced meal" meant. Qualitative responses were categorized into common themes. Forty-one (53%) indicated that a balanced meal consisted of at least three food groups.Thirty-one (40%) indicated something other than three food groups; five (6%) had no idea what a "balanced meal" meant. The findings question the validity and reliability of responses to "balanced meal" food security indicators in Hawaiì.


Soybean agglutinin stimulated cholecystokinin release from cultured rabbit jejunal cells requires calcium influx via L-type calcium channels.
We have studied the mechanism of soybean agglutinin (SBA) mediated cholecystokinin (CCK) release in enriched cultured cholecystokinin-secreting cells. 12-O-Tetradecanoylphorbol-13-acetate 1 mM significantly stimulated release of CCK-like-immunoreactivity (CCK-LI) by 55%+/-17% (p < 0.05), which was blocked by the protein kinase C inhibitor staurosporine 100 nM. Forskolin 10 mM stimulated CCK-LI by 82%+/-12% (p < 0.05) and this was inhibited by somatostatin 1 nM. 1-Phenylalanine 20 mM and Bay K 8644 1 mM stimulated CCK-LI by 69%+/-22% and 60%+/-19% respectively (p < 0.05), these responses were completely abolished by the L-type calcium channel antagonist verapamil 10 mM. SBA 10 and 100 microg/ml stimulated CCK-LI by 65%+/-22% and 74%+/-24% respectively (p < 0.05). The effect of SBA was inhibited by verapamil and N-acetylgalactosamine. We conclude that SBA stimulates CCK-LI through calcium flux via L-type calcium channels.


Comparison of predictability of Marshall and Rotterdam CT scan scoring system in determining early mortality after traumatic brain injury.
Marshall computed tomographic (CT) classification is widely used as a predictor of outcome. However, this grading system lacks the following variables, which are found to be useful predictors: subarachnoid/intraventricular hemorrhage, extradural hematoma, and extent of basal cistern compression. A new classification called the Rotterdam grading system, incorporating the above variables, was proposed later. In the original paper, this system was found to have superior discrimination as compared to Marshall grading, however, Rotterdam grading has not been validated widely. We aimed to compare the discriminatory power of both grading systems. This is a prospective study of patients with moderate and severe TBI (Glasgow coma scale (GCS) 3-12) who presented to our casualty. All the patients were followed up for 2 weeks to determine early mortality. The discriminatory power of each grading system was determined using area under the receiver operating characteristic curve (AUC). A total of 134 patients, mean age 38.3 (±15.7) years, were recruited for study. The overall mortality was 11.2 %. The mean GCS of these patients was 9.6 (±2.3). There was good correlation between Marshall and Rotterdam grading, r = 0.68 (significant at 0.01 level). The Marshall CT classification had reasonable discrimination (AUC - 0.707), and Rotterdam grading had good discrimination (AUC - 0.681). Both Marshal and Rotterdam grading systems are good in predicting early mortality after moderate and severe TBI. As the Rotterdam system also includes additional variables like subarachnoid hemorrhage, it may be preferable, particularly in patients with diffuse injury.


Pharmacoresistent Partial Epilepsy Secondary to Progressive Inflammatory Poliodystrophy.
Epilepsy with progressive cortical volume loss is described secondary to energy failure such as mitochondrial disorders, infectious, or inflammatory etiologies and associated with temporal lobe epilepsy. Postmortem studies do not support that spontaneous seizures even if present for prolonged periods universally result in cortical volume loss. We describe two children with extratemporal pharmacoresistent epilepsy, slowly progressive gray matter volume loss over several years, and evidence of central nervous system inflammation. Brain magnetic resonance imaging changes and antibody profiles were not typical of a well-defined, antibody-mediated central nervous system syndrome such as N-methyl-D-aspartate receptor encephalitis. These patients illustrate a novel presentation of a subacute inflammatory central nervous system process with epilepsy and progressive cortical volume loss, supporting the role of sequential brain imaging in children with epilepsy.


Myospherulosis in the operated temporal bone.
Myospherulosis is an unusual foreign-body reaction occurring in tissues exposed to petrolatum-based products. Histopathologically this disorder is characterized by the presence of large and small tissue spaces containing amorphous debris and peculiar sac-like structures enclosing numerous brown spherical bodies. A rare case of myospherulosis of the middle ear and mastoid is presented and the literature is reviewed.


Detection of epigenetic alterations using tiling arrays.
The epigenetic status of cancer cells is a consequence of the neoplastic transformation of their normal counterpart. Epigenetic changes directly influence gene expression and chromatin organization, which consequently leads to escape from the tumor-suppression mechanisms. Global mapping for specific epigenetic modifications (e.g., DNA methylation) of the entire genome is required to reveal epigenetic hotspots associated with a cancer type/stage. DNA tiling arrays may be applied for genome-wide analysis of different epigenetic marks. Tiling arrays are high-density DNA microarrays that can be custom-made to survey regions of interest (e.g., gene promoters) or permit whole-genome analysis. To identify the genomic alterations associated with testicular cancers we used tiling arrays to profile their methylome. We successfully identified numerous epigenetically modified loci that arose as a consequence of tumor progression.


Clinical features of pulmonary tuberculosis in young and old veterans.
Pulmonary tuberculosis (TB) continues to pose a health threat to the elderly population. In order to delineate age-related differences in disease presentation a comparison between young and old male veterans hospitalized over a five-year period with culture proven Mycobacterium tuberculosis is reported. The study sample included 27 patients 60 years of age and older (range, 60 to 85; mean, 70) and 52 patients under 60 years of age (range, 22 to 59; mean, 51). The elderly were significantly less likely to demonstrate cavitary lesions on admission radiographs or present with hemoptysis but were more likely to present with right lower lobe infiltrates and complaints of dyspnea. Symptoms prior to admission occurring with equal frequency in both young and old subjects included fever, anorexia, weight loss, and cough. Although treatment was delayed in the elderly, there were no age-related differences in mortality. Skin testing was underutilized in all patients regardless of age. The results support the notion that the clinical presentation of pulmonary TB is remarkably similar in young and old males.


Factors and their origins in mate selection and choice among humans: implications for individual psychotherapy and counseling.
A mechanism of mate selection in humans is proposed and elaborated. It is further proposed that this mechanism constitutes one of the important factors for stability and the necessary longevity of the procreational dyad and therefore the procreational success of humans as a species. The concepts and mechanisms of assortative mating (homogamy) and that of complementarity of temperaments of the mates (heterogamy) which guide such selections are described, the relationships between the two are explored, and finally their possible early developmental origins are proposed. Evidence from a small study of 20 married couples' responses in temperament tests is offered as well as some illustrative case histories all pointing to those mechanisms. The argument is based mainly on principles of evolutionary psychology.


Incidence, risk factors and prevention of melanoma.
The incidence of cutaneous malignant melanoma steadily increased between 1940 and 1990 in both sexes. However, this increase appears to have peaked in females in Scotland. Excessive exposure to ultraviolet radiation among Caucasians is the main etiologic factor implicated in the incidence of melanoma. Mortality due to melanoma also increased between 1940 and 1990, but the rate of increase is less than that of the incidence of melanoma. This may be due to earlier diagnosis and treatment of melanoma as a result of public education campaigns. Independent risk factors for developing melanoma include the presence of benign melanocytic naevi (moles), the development of lentigines or freckles, three or more dysplastic naevi and a history of three or more severe sunburns that resulted in peeling or blistering. Approximately 2% of melanoma patients have a family history of the disease and research into potential melanoma susceptibility genes is ongoing. Primary prevention campaigns, initiated mainly in Australia, are aimed at encouraging sensible sun exposure. Secondary prevention campaigns are directed at preventing death from melanoma by encouraging early diagnosis and treatment. Additional prospective studies are needed to determine if the incidence of melanoma has peaked and whether the recent trends observed in females will also occur in males.


Defining Failure in Primary Total Joint Arthroplasty: The Minimal Clinically Important Difference for Worsening Score.
We define the value of the Minimal Clinically Important Difference for Worsening (MCID-W) for Patient-Reported Outcomes Measurement Information System Physical Function short form 10-a (PROMIS-PF-10a) score for primary total joint arthroplasty (TJA) of the hip and knee and describe the risk factors for patients scoring worse than the MCID-W. This retrospective study was performed using 3414 primary TJA patients. PROMIS-PF-10a scores were collected at the preoperatively and postoperatively, and patients were classified based on reaching Minimal Clinically Importance Difference for Improvement (MCID-I), MCID-W, or "no significant change" after TJA (scores betweex`n MCID-W and MCID-I). MCID-W and MCID-I values were determined by a distribution method. The association between numerous variables and scoring worse than the MCID-W of PROMIS-PF-10a was then evaluated through multiple logistic regression. A threshold for preoperative PROMIS-PF-10a score predicting decline past MCID-W was determined using the Youden index and receiver operating characteristic curve. The MCID-W for TJA was -1.89. Notably, increasing length of stay (odds ratio [OR] 1.073, 95% confidence interval [CI] 1.029-1.119, P < .001) and increasing preoperative PROMIS-PF-10a scores (OR 1.117, 95% CI 1.091-1.144, P < .001) were associated with increased likelihood of decline past the MCID-W of the PROMIS-PF-10a for TJA compared with patients who achieved the MCID-I. A community hospital with a dedicated joint replacement center was associated with a decreased risk for decline past the MCID-W (OR 0.601, 95% CI 0.402-0.899; P = .013). We described the MCID-W value (-1.89) for the PROMIS-PF-10a questionnaire for knee and hip TJA and associated patient- and hospital-level risk factors for failure after TJA. Healthcare funding initiatives should be directed toward modifiable factors associated with clinically significant worse outcomes after TJA.


Testing for validity and bias in the use of GPA and the MCAT in the selection of medical school students.
In the 1988 study reported here, Medical College Admissions test (MCAT) scores and grade point averages for undergraduate science courses (S-GPAs) were examined for predictive validity and differential prediction of National Board of Medical Examiners Part I scores. Data from 579 medical students from the classes of 1979-80 through 1983-84 attending a midwestern medical college were analyzed via moderated multiple regression. The findings indicated that using the S-GPA and a composite MCAT score based on the Biology Knowledge, Chemistry Knowledge, Physics Knowledge, Science Problems, and Reading subtests was valid and equally predictive for the minority and majority groups studied. These results are discussed in terms of past findings on cognitive tests in general, and the MCAT and the S-GPA specifically.


Revisiting the human capital-economic growth nexus in Africa.
This study examines the impact of human capital on economic growth in 48 African countries from 2000 to 2019. The methodological approach involves the system GMM technique to address the problem of potential sources of endogeneity. The findings reveal that economic growth in Africa is positively influenced by human capital development. The findings also indicate that both the male and the female genders for human capital development are important for the economic growth of African countries. Similarly, internet penetration and foreign direct investments interact with human capital to produce positive net effects on economic growth. The study recommends policymakers attribute more resources to the education and health sectors to enhance human capital development as a prerequisite to ensure a stable economic growth. The online version contains supplementary material available at 10.1007/s43546-023-00494-5.


Gentiopicroside inhibits retinoblastoma cell proliferation, invasion, and tumorigenesis in nude mice by suppressing the PI3K/AKT pathway.
Retinoblastoma is a prevalent pediatric intraocular tumor. The suppressive effect of gentiopicroside (GPS) has been reported on various tumors. This study sought to determine the effect of GPS on retinoblastoma cell proliferation, apoptosis, invasion, and epithelial-mesenchymal transition (EMT), and tumorigenesis in nude mice. The effect and mechanism of GPS on growth, apoptosis, invasion, and EMT were determined by cell counting kit-8 (CCK-8), western blot, flow cytometry, and transwell assays in retinoblastoma cells. Y79 cells were injected into the vitreous cavity of BALB/c‑nude mice to construct a retinoblastoma mouse model. Tumor growth and mouse weight were monitored for sequential 5 weeks. The effect of GPS in vivo was assessed by immunohistochemistry (IHC), terminal deoxynucleotidyl transferase deoxyuridine triphosphate (dUTP) nick end labeling (TUNEL), and western blot assays. GPS decreased the cell viability of both Y79 and Weri-Rb1 cells with the IC50 of 18.85 μM and 27.57 μM, respectively. Besides, GPS reduced the relative expression of proteins involved in proliferation and EMT, and the number of invading cells, while increased the apoptosis rate and the relative expressions of apoptosis proteins in retinoblastoma cells. Mechanically, GPS decreased the relative protein level of PI3K/AKT pathway, which was then recovered after 740 Y-P was applied. Correspondingly, 740 Y-P reversed the inhibitory effect of GPS on growth, invasion, and EMT, and the increased effect of GPS on apoptosis. Additionally, GPS decreased tumor volume and weight as well as the relative level of Ki-67, VEGF, p-PI3K/PI3K, and p-AKT/AKT, while increased the apoptosis rate in vivo. GPS inhibited retinoblastoma cell proliferation and invasion via deactivating the PI3K/AKT pathway in both cell and animal models.


Chain elongation-desaturation of linoleic acid during the development of the pig. Implications for the supply of polyenoic fatty acids to the developing brain.
Rates of chain elongation-desaturation of C18:2 omega 6 were compared for liver and brain microsomes in fetal, neonatal and postnatal piglets. Rates of chain elongation-desaturation of C18:2 omega 6 were greatest in liver and increased during perinatal development on a per organ basis. These results suggest that fetal liver and brain has the capability to chain elongate and desaturate essential fatty acids to longer chain homologues. For brain rates of synthesis of chain elongation-desaturation products was greatest during the newborn period whereas this metabolic function was greatest in liver in the postnatal stages of life examined.


Anterior segment abnormalities in cicatricial retinopathy of prematurity.
Abnormalities that occur in the anterior segments of patients with retinopathy of prematurity have been studied in 72 eyes of 36 patients. The anterior chamber depth, the placido disc image on the cornea, the distortion of polarized light by corneal stress, and keratometry readings were recorded. There was a highly significant correlation between anterior chamber depth, retinopathy of prematurity, and keratometry readings (p less than .001). These findings emphasize the importance of careful follow-up examinations of the anterior segment in retinopathy of prematurity because cataracts, band keratopathy, acute hydrops, and angle-closure glaucoma can progressively occur as complications.


Evidence for calcium-binding proteins and calcium-dependent regulatory proteins in sensory cells of the organ of Corti.
Calcium is thought to play a major signaling role in outer hair cells to control metabolism, cytoskeletal integrity, cell shape and cell excitability. For this to happen, in resting cells the concentration of free calcium ions must be maintained at low levels so that focal increases can trigger specific events. In this paper, the localization of calcium, calcium-binding and calcium-dependent regulatory proteins in sensory cells from the guinea pig inner ear was demonstrated using immunocytochemical and histochemical techniques. We found the calcium buffer and/or calcium sensor proteins calmodulin, calbindin and calsequestrin predominantly in sensory cells and that when present, these proteins can be enriched in the outer hair cells. Calmodulin is found in the stereocilia, in the cuticular plate and in the cytoplasm and calbindin is found only in the cuticular plate and cytoplasm of both the inner and outer hair cells. The staining for these proteins in the outer hair cells is homogeneous, with no apparent compartmentalization along the lateral wall. Calsequestrin, thought to store and release calcium from membrane bound intracellular storage sites is found only in the cytoplasm of outer hair cells. There, it has a more punctuate staining pattern than does calmodulin or calbindin suggesting that it may be present in calciosomes rather than soluble in the cytoplasm. We did not detect caldesmon and S-100. Using the potassium pyroantimonate technique, we found precipitates containing calcium ions distributed throughout the cytoplasm of outer hair cells, with no evidence that the subsurface cisterns along the lateral wall act as calcium storage sites. Thus, calcium in resting cells is found in the cytoplasm along with calbindin and calmodulin and appears to have a punctate distribution consistent with a co-localization with calsequestrin. The implications of this distribution with respect to the slow shortening and elongation seen in outer hair cells are discussed.


Role of systemic immunosuppression on subglottic stenosis in granulomatosis with polyangiitis: Analysis of a single-centre cohort.
Subglottic stenosis (SGS) is a potentially life-threatening manifestation of granulomatosis with polyangiitis (GPA). Endoscopic dilation is effective, but relapses are frequent and the benefit of systemic immunosuppression in this setting is still controversial. We aimed to investigate the role of immunosuppressive treatment on SGS relapse risk. This is a retrospective observational study based on review of medical charts among our cohort of patients with GPA. Twenty-one patients with SGS-GPA were identified, with a prevalence of 20% among our entire GPA cohort (n = 105). Compared to patients without SGS, patients with SGS-GPA had an earlier disease onset (mean age 30.2 vs. 47.3 years, p<0.001), and lower BVAS (mean 10.5 vs 13.5; p = 0.018). Five patients didn't receive systemic immunosuppression for SGS and they all (100%) relapsed after the first procedure, while among medical treatment group relapse rate was 44% (p = 0.045). When single treatment regimens are considered, rituximab (RTX) and cyclophosphamide (CYC) yielded a protective role towards the need of subsequent dilation procedure after the first if compared with absence of medical treatment. Patients with SGS and generalized disease, who initially received either a RTX- or a CYC-based induction treatment, and higher cumulative doses of glucocorticoids, showed a delayed median time to SGS relapse (36 vs. 12 months, p = 0.024). Subglottic stenosis is highly prevalent in patients with GPA and may define a milder systemic disease subset occurring more frequently in younger patients. Systemic immunosuppression provides benefit in preventing recurrence of SGS in GPA patients and regimens based on cyclophosphamide or rituximab might have a non-redundant role in this setting.


Overexpression of 5-HT(1B) mRNA in nucleus accumbens shell projection neurons differentially affects microarchitecture of initiation and maintenance of ethanol consumption.
Serotonin 1B (5-HT(1B)) heteroreceptors on nucleus accumbens shell (NAcSh) projection neurons have been shown to enhance the voluntary consumption of alcohol by rats, presumably by modulating the activity of the mesolimbic reward pathway. The present study examined whether increasing 5-HT(1B) receptors expressed on NAcSh projection neurons by means of virus-mediated gene transfer enhances ethanol consumption during the initiation or maintenance phase of drinking and alters the temporal pattern of drinking behavior. Animals received stereotaxic injections of viral vectors expressing either 5-HT(1B) receptor and green fluorescent protein (GFP) or GFP alone. Home cages equipped with a three-bottle (water and 6 and 12% ethanol) lickometer system recorded animals' drinking behaviors continuously, capturing either initiation or maintenance of drinking behavior patterns. Overexpression of 5-HT(1B) receptors during initiation increased consumption of 12% ethanol during both forced-access and free-choice consumption. There was a shift in drinking pattern for 6% ethanol with an increase in number of drinking bouts per day, although the total number of drinking bouts for 12% ethanol was not different. Finally, increased 5-HT(1B) expression induced more bouts with very high-frequency licking from the ethanol bottle sippers. During the maintenance phase of drinking, there were no differences between groups in total volume of ethanol consumed; however, there was a shift toward drinking bouts of longer duration, especially for 12% ethanol. This suggests that during maintenance drinking, increased 5-HT(1B) receptors facilitate longer drinking bouts of more modest volumes. Taken together, these results indicate that 5-HT(1B) receptors expressed on NAcSh projection neurons facilitate ethanol drinking, with different effects during initiation and maintenance of ethanol-drinking behavior.


Development of a customized booklet of foot-ankle exercises for people with diabetes mellitus as a management and prevention tool for musculoskeletal complications: A customized booklet of foot-ankle exercises for people with diabetes.
Diabetes mellitus (DM) and diabetic peripheral neuropathy (DPN) compromises the structures of the musculoskeletal system, especially in the foot-ankle complex. Foot-related exercises can be a promising tool to be incorporated in health care programs to manage and prevent musculoskeletal complications resulting from DM and DPN progression. To present the development, validation, and usability evaluation of a booklet that directs training and personalizes the progression of a home-based program of foot-ankle exercises. The booklet containing a foot-ankle exercise program developed in a previous clinical trial was validated using the Delphi technique, with a multi-professional jury of experts who assessed the content of the material, language, individual education, exercise execution, exercise quality, and material implementation. The validated version was evaluated through telephone interview by a convenience sample of 10 individuals with DPN regarding its relevance, health education, comprehension, and usability. The validation process with experts was performed in two rounds achieving 100% agreement in the second round. During the usability evaluation process the main complaint of users was that performing all the exercises was very tiring and took too much time out of their daily routine. Thus, the number of repetitions for each exercise was changed from 30 to 12. The booklet is a material for prevention and management of the impacts of DM and DPN progression by improving the musculoskeletal function of the foot-ankle. This material provides an exercise regime with a personalized progression based on the perceived effort of the users.


The role of monocytes in the suppression of PHA-induced proliferation and IL 2 production of human mononuclear cells by 1,25-dihydroxyvitamin D3.
1,25-dihydroxyvitamin D3 [1,25(OH)2D3] inhibited phytohemagglutinin (PHA)-induced proliferation of human blood mononuclear cells (MNC) at concentrations of 10(-11) M or more. Interleukin 2 (IL 2) production of T cells activated with PHA was also inhibited by 1,25(OH)2D3. Furthermore, 1,25(OH)2D3 suppressed interleukin 1 (IL 1) production of monocytes (Mo), and the agent-treated Mo were unable to promote IL 2 production of non-adherent cells (NAC). Thus, the reduction of proliferative response of MNC to PHA by 1,25(OH)2D3 appeared to have resulted from the inhibitory effects of the agent on both IL 2 and IL 1 production. From these data, 1,25(OH)2D3 appears to play an important role in the immunoregulatory system.


Contamination, transport, and ecological risks of pharmaceuticals and personal care products in a large irrigation region.
Pharmaceuticals and personal care products (PPCPs) have attracted widespread attention owing to their extensive use and potential adverse effects on human and ecosystem health. There is a lack of information regarding the occurrence and environmental fate of PPCPs in large agricultural irrigation areas in China. In this study, we conducted a comprehensive survey on 30 PPCPs in water from Hetao Irrigation District, one of the three largest irrigation areas in China. The ΣPPCP-concentrations ranged 82.13-1409.24 ng/L in August and 40.53-887.20 ng/L in November, with caffeine (CAF), norfloxacin (NOR), erythromycin (ERY), sulfamethoxazole (SMX) and ofloxacin (OFL) being the predominant compositions. Spatially, the average ΣPPCP concentrations increased from irrigation to drainage water, and then decreased in Wuliangsuhai Lake. Less PPCP mass loading (55.05 kg/y) migrated from Wuliangsuhai Lake to Yellow River than that from the Yellow River to Hetao Irrigation District (425.88 kg/y), indicating that Wuliangsuhai Lake plays an important role in improving water quality. An ecological risk assessment showed that it is worthwhile to consider the presence of CAF, ERY, NOR, and OFL in natural surface water and to control their potential risks.


Pet ownership among homeless youth: associations with mental health, service utilization and housing status.
As many as 25 % of homeless persons have pets. To our knowledge, pet ownership has not been studied quantitatively with homeless youth. This study examined pet ownership among 398 homeless youth utilizing two Los Angeles drop-in centers. Twenty-three percent of homeless youth had a pet. The majority of pet owners reported that their pets kept them company and made them feel loved; nearly half reported that their pets made it more difficult to stay in a shelter. Pet owners reported fewer symptoms of depression and loneliness than their non-pet owning peers. Pet ownership was associated with decreased utilization of housing and job-finding services, and decreased likelihood of currently staying in a shelter. These findings elucidate many of the positive benefits of pet ownership for homeless youth, but importantly highlight that pet ownership may negatively impact housing options. Housing and other services must be sensitive to the needs of homeless youth with pets.


Maternal restriction of polyphenols and fetal ductal dynamics in normal pregnancy: an open clinical trial.
We have recently demonstrated reversal of fetal ductal constriction after dietary maternal restriction of polyphenol-rich foods (PRF), due to its inhibitory action on prostaglandin synthesis. To test the hyphotesis that normal third trimester fetuses also improve ductus arteriosus dynamics after maternal restriction of polyphenols. Open clinical trial with 46 fetuses with gestational age (GA) > 28 weeks submitted to 2 Doppler echocardiographic studies with an interval of at least 2 weeks, being the examiners blinded to maternal dietary habits. A validated food frequency questionnaire was applied and a diet based on polyphenol-poor foods (<30 mg/100 mg) was recommended. A control group of 26 third trimester fetuses was submitted to the same protocol. Statistics used t test for independent samples. Mean GA was 33 ± 2 weeks. Mean daily maternal estimated polyphenol intake (DMPI) was 1277 mg, decreasing to 126 mg after dietary orientation (p=0.0001). Significant decreases in systolic (SDV) and diastolic (DDV) ductal velocities, and RV/LV diameters ratio, as well as increase in ductal PI were observed [DSV = 1.2 ± 0.4 m/s (0.7-1.6) to 0.9 ± 0.3 m/s (0.6-1.3) (p = 0.018); DDV = 0.21 ± 0.09 m/s (0.15-0.32) to 0.18 ± 0.06 m/s (0.11-0.25) (p = 0.016); RV/LV ratio = 1.3 ± 0.2 (0.9-1.4) to 1.1 ± 0.2 (0.8-1.3) (p=0.004); ductal PI = 2.2 ± 0.03 (2.0-2.7) to 2.4 ± 0.4(2.2-2.9) (p = 0.04)]. In the control group, with GA of 32 ± 4 weeks, there were no significant differences in DMPI, mean SDV, DDV, PI and RV/LV ratio. The oriented restriction of third trimester maternal ingestion of polyphenol-rich foods for a period of 2 weeks or more improve fetal ductus arteriosus flow dynamics and right ventricular dimensions.


Maturation of the rectoanal response in premature and perinatal infants.
Twenty unselected premature and perinatal infants, and 40 older infants and children with chronic constipation were investigated manometrically. Anorectal pressure studies were found to be a safe and reliable screening method for Hirschsprung's disease. Many unnecessary deep and superficial rectal biopsies were avoided by recording a normal rectoanal response. Failure to record a normal reflex requires further evaluation by tissue diagnosis. A normal reflex does not occur in premature or perinatal infants in whom maturational age (gestational age plus age after birth) has yet to reach 39 wk, and who weigh less than 6 lb.


Anterior cruciate ligament reconstruction with an all-epiphyseal "over-the-top" technique is safe and shows low rate of failure in skeletally immature athletes.
The aim of this study was to follow up, clinically and radiographically, skeletally immature patients who underwent ACL reconstruction with an all-epiphyseal "over-the-top" technique. Twenty athletes aged between 8 and 13 years were enrolled and retrospectively evaluated. The subjects underwent surgical ACL reconstruction between 2009 and 2013. The surgical technique consisted of a single-bundle all-epiphyseal ACL reconstruction with an extra-articular lateral tenodesis. The mean follow-up was 54 months [34-123] after surgery. Clinically, the patients were evaluated pre- and post-operatively with Lysholm and KOOS scores; sport activity level was evaluated using the pre-injury, pre-operative and post-operative Tegner scores. Objective IKDC was calculated post-operatively. The joint laxity was evaluated by KT1000 and Rolimeter arthrometers. Panoramic AP standing radiographs of the lower limbs and lateral knee radiographs were also taken at the follow-up to evaluate limb length discrepancies (LLD) and axial malalignment. Normally distributed parameters were presented as mean ± standard deviation, while the non-normally distributed parameters were presented as median [25° percentile, 75° percentile]. Clinical scores showed significant (P < 0.01) improvement: Lysholm and KOOS scores improved from 40 [22; 65] and 59 [42, 73], respectively, to 100 [95; 100] and 99 [97;100] after surgery. Tegner score improved from 2 [2; 2] pre-operatively to 7 [3; 9] at follow-up (P < 0.01). At follow-up, IKDC score was A for 19 patients and one who scored B. All patients returned to sport activity and had good stability at follow-up: the KT1000 showed a median side-to-side difference of 0.0 mm [- 0.4; 1.0] for the standard force evaluation and 0.0 mm [- 1.0; 0.8] for manual-maximum test. The Rolimeter showed median side-to-site difference of 0.0 mm [- 1.0; 0.8]. Three minor leg length discrepancies and axial deviations were observed at the radiograph: one patient had 0.6 cm lengthening and 4° of varus, one had 1 cm lengthening, and one had 3° of varus (in comparison with the non-operated limb). No re-injury was observed. This study demonstrates that the modified all-epiphyseal single-bundle "over-the-top" technique is a viable and safe option for ACL reconstruction in pediatric subjects. These results support once more that not only ACL reconstruction is a safe procedure in skeletally immature patients, but also it is highly recommended for those who want to pursue an active and sportive life. Case series, IV.


Necrotizing sialometaplasia in two patients with bulimia and chronic vomiting.
The purpose of this report was to present two unusual cases of necrotizing sialometaplasia of the hard palate, in which the patients were suffering from bulimia and chronic self-induced vomiting. It emphasizes the importance of confirming the diagnosis by incisional biopsy and discusses local mucosal trauma as a possible etiologic factor.


Safe injection practices for administration of propofol.
Sepsis and postoperative infection can occur as a result of unsafe practices in the administration of propofol and other injectable medications. Investigations of infection outbreaks have revealed the causes to be related to bacterial growth in or contamination of propofol and unsafe medication practices, including reuse of syringes on multiple patients, use of single-use medication vials for multiple patients, and failure to practice aseptic technique and adhere to infection control practices. Surveys conducted by AORN and other researchers have provided additional information on perioperative practices related to injectable medications. In 2009, the US Food and Drug Administration and the Centers for Disease Control and Prevention convened a group of clinicians to gain a better understanding of the issues related to infection outbreaks and injectable medications. The meeting participants proposed collecting data to persuade clinicians to adopt new practices, developing guiding principles for propofol use, and describing propofol-specific, site-specific, and practitioner-specific injection techniques. AORN provides resources to help perioperative nurses reduce the incidence of postoperative infection related to medication administration.


Calcium sequestration by human platelet acidic organelles is regulated by the actin cytoskeleton and autocrine 5-hydroxytryptamine.
Human platelets regulate agonist-evoked Ca2+ signalling through Ca2+ release from and sequestration into acidic organelles. Previous studies have pharmacologically characterised the presence of a Ca2+-H+ exchanger in these organelles. This exchanger appears to regulate a secondary plateau phase in agonist-evoked cytosolic Ca2+ signals in fura-2-loaded human platelets. Here we demonstrate that cytochalasin D treatment removes the secondary plateau in ADP-evoked Ca2+ signals elicited in the absence of external Ca2+. This effect was reversed by pretreatment with nigericin, a K+/H+ exchanger that short-circuits the Ca2+-H+ exchanger. Using Fluo-5N- or Lysosensor Green-loaded cells, cytochalasin D was found to enhance Ca2+ sequestration into acidic organelles by preventing their alkalinisation. Additional experiments demonstrated that ADP-evoked alkalinisation of acidic organelles and subsequent slowing of acidic organellar Ca2+ sequestration was mediated by autocrine 5-HT signalling. Enhancing this 5-HT signalling using fluoxetine overcame the inhibitory effect of cytochalasin D on ADP-evoked Ca2+ signals, indicating that cytochalasin D interferes with 5-HT autocrine signalling. The ability of Cytochalasin D to interfere with autocrine 5-HT signalling was downstream of the 5-HT2A receptor as secretion of [3H]-5-HT from ADP-stimulated human platelets was not reduced. These data provide the first evidence that the pH gradient across acidic organelles is dynamically regulated upon human platelet activation, and that this can play a significant role in controlling human platelet function by modulating Ca2+-H+ exchange and so [Ca2+]i.


Associations among Alzheimer disease, depressive disorder, and risk of end-stage kidney disease in elderly people.
Alzheimer disease (AD) and depressive disorder (DD) are prevalent among elderly end-stage kidney disease (ESKD) patients. However, whether preexisting mental health disorders increase the risk of ESKD is not well understood. The risk of incident ESKD in patients with or without underlying AD or DD was evaluated in a nationwide cohort of elderly people in Republic of Korea. This study used data from the National Health Insurance Service-Senior cohort in Republic of Korea. Among the 558,147 total subjects, 49,634 and 54,231 were diagnosed with AD (AD group) or DD (DD group), respectively, during the follow-up period. Propensity score matching was conducted to create non-AD and non-DD groups of subjects. AD and DD diagnoses were analyzed as time-varying exposures, and the study outcome was development of ESKD. The incidence rates of ESKD were 0.36 and 1.17 per 1,000 person-years in the non-AD and AD groups, respectively. After adjustment for clinical variables and competing risks of death, the risk of incident ESKD was higher in the AD group than in the nonAD group (hazard ratio [HR], 1.67; 95% confidence interval [CI], 1.34-2.08). The incidence rates of ESKD in the non-DD and DD groups were 0.36 and 0.91 per 1,000 person-years, respectively. The risk of ESKD development was also higher in the DD group than the non-DD group (HR, 1.44; 95% CI, 1.19-1.76). The risk of ESKD development was higher in subjects diagnosed with AD or DD, suggesting that central nervous system diseases can adversely affect kidney function in elderly people.


Use of alternative test methods in a tiered testing approach to address photoirritation potential of fragrance materials.
The safety assessment of fragrance materials for photoirritation utilized by The Research Institute for Fragrance Materials has recently been modified and is described in detail. Materials demonstrating significant absorbance in the ultraviolet and visible light (UV/VIS) range (290-700 nm) may present a concern for photoirritation and require further investigation. If there are no photoirritation data or data are insufficient, then data on read-across materials are considered before a tiered approach for testing begins. The hazard-based 3T3-Neutral Red Uptake (NRU) Phototoxicity Test (OECD TG 432) is used as a first-tier assay; if it predicts photoirritation, it is followed by the reconstructed human epidermis (RhE) phototoxicity assay (OECD TG 498). The RhE phototoxicity assay is used to determine a No Observed Effect Level (NOEL) for photoirritation that is used in a confirmatory human photoirritation test. Data are presented on 108 fragrance materials exhibiting significant UV/VIS absorbance and evaluated in the 3T3-NRU Phototoxicity Assay. Twenty-one materials were predicted to be phototoxic; twenty were evaluated in the RhE Phototoxicity Assay to establish a NOEL. Fourteen materials were then evaluated in a confirmatory human phototoxicity test. The tiered testing approach presented represents a scientifically pragmatic method to minimize the likelihood of photoirritation from fragrance materials.


CRY-BARs: Versatile light-gated molecular tools for the remodeling of membrane architectures.
BAR (Bin, Amphiphysin, and Rvs) protein domains are responsible for the generation of membrane curvature and represent a critical mechanical component of cellular functions. Thus, BAR domains have great potential as components of membrane-remodeling tools for cell biologists. In this work, we describe the design and implementation of a family of versatile light-gated I-BAR (inverse BAR) domain containing tools derived from the fusion of the Arabidopsis thaliana cryptochrome 2 photoreceptor and I-BAR protein domains ("CRY-BARs") with applications in the remodeling of membrane architectures and the control of cellular dynamics. By taking advantage of the intrinsic membrane-binding propensity of the I-BAR domain, CRY-BARs can be used for spatial and temporal control of cellular processes that require induction of membrane protrusions. Using cell lines and primary neuron cultures, we demonstrate here that the CRY-BAR optogenetic tool evokes membrane dynamic changes associated with cellular activity. Moreover, we provide evidence that ezrin, an actin and phosphatidylinositol 4,5-bisphosphate-binding protein, acts as a relay between the plasma membrane and the actin cytoskeleton and therefore is an important mediator of switch function. Overall, we propose that CRY-BARs hold promise as a useful addition to the optogenetic toolkit to study membrane remodeling in live cells.


ADMIRE: analysis and visualization of differential methylation in genomic regions using the Infinium HumanMethylation450 Assay.
DNA methylation at cytosine nucleotides constitutes epigenetic gene regulation impacting cellular development and a wide range of diseases. Cytosine bases of the DNA are converted to 5-methylcytosine by the methyltransferase enzyme, acting as a reversible regulator of gene expression. Due to its outstanding importance in the epigenetic field, a number of lab techniques were developed to interrogate DNA methylation on a global range. Besides whole-genome bisulfite sequencing, the Infinium HumanMethylation450 Assay represents a versatile and cost-effective tool to investigate genome-wide changes of methylation patterns. Analysis of DNA Methylation In genomic REgions (ADMIRE) is an open source, semi-automatic analysis pipeline and visualization tool for Infinium HumanMethylation450 Assays with a special focus on ease of use. It features flexible experimental settings, quality control, automatic filtering, normalization, multiple testing, and differential analyses on arbitrary genomic regions. Publication-ready graphics, genome browser tracks, and table outputs include summary data and statistics, permitting instant comparison of methylation profiles between sample groups and the exploration of methylation patterns along the whole genome. ADMIREs statistical approach permits simultaneous large-scale analyses of hundreds of assays with little impact on algorithm runtimes. The web-based version of ADMIRE provides a simple interface to researchers with limited programming skills, whereas the offline version is suitable for integration into custom pipelines. ADMIRE may be used via our freely available web service at https://bioinformatics.mpi-bn.mpg.de without any limitations concerning the size of a project. An offline version for local execution is available from our website or GitHub (https://github.molgen.mpg.de/loosolab/admire).


Coping mediates and moderates the relationship between executive functions and psychological adjustment in multiple sclerosis.
To identify the moderating and mediating relationship of different coping strategies between executive function and stress, depression and anxiety in people with multiple sclerosis (PwMS). Participants were 107 people with relapsing remitting or secondary progressive multiple sclerosis who were administered tasks of executive function and completed self-report measures of stress, depression, anxiety, and coping. An indirect relationship was found between executive function and psychosocial adjustment through maladaptive coping strategies: behavioral and mental disengagement, and substance abuse; adaptive coping strategies: acceptance, active, positive reinterpretation, and growth, as well as for an index of adaptive coping. In general, a relationship was found between better performance on tasks of executive function and psychosocial adjustment when adaptive coping strategies were low, as opposed to high, or maladaptive coping strategies were high, as opposed to low. Some unexpected findings are also discussed. Executive function and psychosocial adjustment is mediated and moderated by coping strategies used by PwMS. Well-preserved executive function provides relative protection from poorer adjustment in the presence of high maladaptive or low adaptive coping. PwMS who perform poorly on tasks of executive function benefit from using less cognitively demanding adaptive coping strategies to enhance adjustment outcomes and further research in this area would be advantageous to underpin effective intervention strategies.


Racial Differences in Insurance Stability After Health Insurance Reform.
One of the potential benefits of insurance reform is greater stability of insurance and reduced coverage disparities by race and ethnicity. We examined the temporal trends in insurance coverage by racial/ethnic group before and after Massachusetts Insurance Reform by abstracting records across 2 urban safety net hospital systems. We examined adjusted odds of being uninsured and incident rate ratios of gaining and losing insurance over time by race and ethnicity. We used billing records to capture the payer for each episode of care. We included data from January 2005 through December 2013 on patients with hypertension between the ages of 21 and 64 years. We compared 4 racial and ethnic groups: non-Hispanic white, non-Hispanic Black, non-Hispanic Asian, and Hispanic. We examined individual patients' insurance coverage status in 6-month intervals. We compared odds of being uninsured in the transition and postinsurance reform period to the prereform period, adjusting for age, sex, comorbidities practice location and education, and income by Census tract. Among 48,291 patients with hypertension, reduction in rates of uninsurance with insurance reform was greater for Hispanic (29.7%), non-Hispanic Black (24.8%), and non-Hispanic Asian (26.8%) than non-Hispanic white (14.9%) patients. The odds of becoming uninsured were reduced in all racial and ethnic groups (odds ratio, 0.27-0.41). Massachusetts Insurance Reform resulted in stable insurance coverage and a reduction in disparities in insurance instability by race and ethnicity.


Upregulated tumor necrosis factor-alpha gene expression in the hypoplastic lung in patients with congenital diaphragmatic hernia.
Recent studies using animal models of congenital diaphragmatic hernia (CDH) have reported a reduction in both surfactant (SF) phospholipids and proteins in CDH lungs compared to controls, resulting in biophysical and physiologic impairment of SF function in the hypoplastic CDH lung. Furthermore, SF replacement has been shown to improve physiological function in CDH lungs. Tumor necrosis factor-alpha (TNF-alpha) is a polypeptide whose overproduction has been implicated in the pathogenesis of a number of pathological conditions, such as neonatal and adult respiratory distress syndrome. TNF-alpha has been shown to selectively inhibit the de-novo synthesis of SF phospholipid components in type II pneumocytes. It has been demonstrated that TNF-alpha is synthesized locally in lung and functions in an autocrine/paracrine mode. The aim of this study was to investigate TNF-alpha messenger RNA (mRNA) expression in hypoplastic CDH lung using in-situ hybridization histochemistry, to determine the molecular basis of the SF deficiency in the hypoplastic CDH lung. Lung-tissue samples were obtained at autopsy from 7 full-term newborns (age range: 1-21 days) with CDH and 4 stillborns with CDH. Normal lung tissue from eight infants with sudden infant death syndrome (age range: 5-30 days) acted as controls. In-situ hybridization was performed using TNF-alpha specific and digoxigenin-labeled oligonucleotide probe and visualized by nitroblue tetrazolium staining. In control lung tissue, mRNA expression of TNF-alpha was absent or weak in type II pneumocytes and alveolar macrophages. In contrast, mRNA expression of TNF-alpha was markedly increased in both type II pneumocytes and alveolar macrophages in hypoplastic CDH lung. Our findings of up-regulated TNF-alpha gene expression in CDH lung suggest that the SF deficiency observed in hypoplastic CDH lung may be the result of increased local production of TNF-alpha.


A Lifelong Passion for All Things Ribonucleic.
This year's Lasker-Koshland Special Achievement Award is given to Joan Argetsinger Steitz for her RNA research discoveries and her exemplary international leadership.


Purinergic signalling in the kidney: In physiology and disease.
Historically, the control of renal vascular and tubular function has, for the most part, concentrated on neural and endocrine regulation. However, in addition to these extrinsic factors, it is now appreciated that several complex humoral control systems exist within the kidney that can act in an autocrine and/or paracrine fashion. These paracrine systems complement neuroendocrine regulation by dynamically fine-tuning renal vascular and tubular function to buffer rapid changes in nephron perfusion and flow rate of tubular fluid. One of the most pervasive is the extracellular nucleotide/P2 receptor system, which is central to many of the intrinsic regulatory feedback loops within the kidney such as renal haemodynamic autoregulation and tubuloglomerular feedback (TGF). Although physiological actions of extracellular adenine nucleotides were reported almost 100 years ago, the conceptual framework for purinergic regulation of renal function owes much to the work of Geoffrey Burnstock. In this review, we reflect on our >20-year collaboration with Professor Burnstock and highlight the research that is still unlocking the potential of the renal purinergic system to understand and treat kidney disease.


GFI1-Dependent Repression of SGPP1 Increases Multiple Myeloma Cell Survival.
Multiple myeloma (MM) remains incurable for most patients due to the emergence of drug resistant clones. Here we report a p53-independent mechanism responsible for Growth Factor Independence-1 (GFI1) support of MM cell survival by its modulation of sphingolipid metabolism to increase the sphingosine-1-phosphate (S1P) level regardless of the p53 status. We found that expression of enzymes that control S1P biosynthesis, SphK1, dephosphorylation, and SGPP1 were differentially correlated with GFI1 levels in MM cells. We detected GFI1 occupancy on the SGGP1 gene in MM cells in a predicted enhancer region at the 5' end of intron 1, which correlated with decreased SGGP1 expression and increased S1P levels in GFI1 overexpressing cells, regardless of their p53 status. The high S1P:Ceramide intracellular ratio in MM cells protected c-Myc protein stability in a PP2A-dependent manner. The decreased MM viability by SphK1 inhibition was dependent on the induction of autophagy in both p53WT and p53mut MM. An autophagic blockade prevented GFI1 support for viability only in p53mut MM, demonstrating that GFI1 increases MM cell survival via both p53WT inhibition and upregulation of S1P independently. Therefore, GFI1 may be a key therapeutic target for all types of MM that may significantly benefit patients that are highly resistant to current therapies.


Reduction of testosterone, androstendione and their derivatives by Aphanocladium album.
A strain of Aphanocladium album reduces the C-3 carbonyl group in testosterone or androstendione to to 3 alpha-allyl alcohol. In some derivatives of these steroids the same carbonyl group is reduced to allyl alcohol with stereospecificity, depending on whether chlorine at C-4 or a 17 alpha-methyl group is present. On the other hand, the presence of C-4 methyl group, a C-19 hydroxy group, a C-17 acetyl one, or a double bond conjugated with the 4-en-3- ketone system totally inhibits the formation of allyl alcohols at C-3. At the same time, the C-17 carbonyl group in androstendione or in its derivatives is reduced to a respective 17 beta-alcohol. In the derivatives with an additional 2-exomethylene group the double bond at this group is reduced.


Comparison of cone pathologic changes in idiopathic macular telangiectasia types 1 and 2 using adaptive optics scanning laser ophthalmoscopy.
To compare pathologic changes in the photoreceptors of eyes with idiopathic macular telangiectasia types 1 and 2 using adaptive optics scanning laser ophthalmoscopy (AO-SLO). Prospective cross-sectional study. Eleven eyes with idiopathic macular telangiectasia type 1, 14 eyes with type 2, and 10 normal eyes underwent a full ophthalmologic examination, spectral-domain optical coherence tomography (SD-OCT), and imaging with an original prototype AO-SLO system. All eyes with idiopathic macular telangiectasia were examined with fluorescein angiography (FA), confocal blue reflectance, and microperimetry. Compared with normal eyes (29 017 ± 5507 cones/mm(2)), those with idiopathic macular telangiectasia type 1 had significantly lower cone density on the temporal side (18 427 ± 4908 cones/mm(2), P = .010). The FA leakage area (5.90 ± 3.23 mm(2)) was larger than the dark regions (2.45 ± 2.40 mm(2)) on AO-SLO (P = .003)-which were observed only in the FA leakage area. Compared with normal eyes, those with idiopathic macular telangiectasia type 2 had significantly lower cone density in all areas (P < .05 for all). Patchy dark regions were also seen in areas without FA abnormalities in 12 eyes. Higher mean retinal sensitivity correlated with greater mean cone density 0.5 mm from the center of the fovea (type 1: P = .010; type 2: P < .001). Idiopathic macular telangiectasia type-specific differences in the distribution of photoreceptor abnormalities were shown in the AO-SLO images. For both idiopathic macular telangiectasia types 1 and 2, visual impairment was associated with cone damage.


A program to improve detection of undiagnosed dementia in primary care and its association with healthcare utilization.
Alzheimer's disease and related dementias are common and costly, with increased healthcare utilization for patients with these disorders. The current study describes a novel dementia detection program for veterans and examines whether program-eligible patients have higher healthcare utilization than age-matched comparison patients. Using a telephone-based case-finding approach, the detection program used risk factors available in the electronic medical record (EMR) and telephone-based brief cognitive screening. Holding illness severity constant, dementia detection and healthcare utilization were compared across age-matched groups with and without program risk factors. Five Veterans Affairs Healthcare Network Upstate New York primary care clinics. Veterans aged 70 years and older. EMR data and the Charlson comorbidity index. Program-eligible patients (n = 5,333) demonstrated significantly greater levels of medical comorbidity relative to comparison patients and were on average more than twice as likely to be admitted to the hospital. They also had nearly double the number of outpatient visits to several services. Similar patterns were seen in those who screened positive on a brief cognitive measure, compared with those who screened negative. A novel program using EMR data to assist in the detection of newly diagnosed dementia in a clinical setting was found to be useful in identifying older veterans with multiple comorbid medical conditions and increased utilization of hospital and clinic services. Results suggest undetected cognitive impairment and dementia may significantly contribute to healthcare utilization and costs of care in older veterans.


The potentials of the in vitro protein biosynthesis system.
Recent developments indicate that with the in vitro protein biosynthesis system a new technology emerges, which will find in the future its application in biotechnology. Up to date the best system described produces 2 mg of proteins per 0.5 ml after 100 h. The potentials of the in vitro protein biosynthesis system include not only the production of proteins, but especially the synthesis of proteins, which are toxic to living cells, or proteins with unnaturally modified or isotope-labelled amino acids in specific positions. Among the advantages of the in vitro system, when compared to current cloning techniques, are the purity of the proteins synthesized and their superior biological activities. Thus, the application of this technology will be manifold ranging from the production of proteins with improved or even new characteristics to the potentials of improving the methods of protein design and structural characterization.


Hopelessness in Patients with Early-Stage Relapsing-Remitting Multiple Sclerosis.
Hopelessness is a risk factor for depression and suicide. There is little information on this phenomenon among patients with relapsing-remitting multiple sclerosis (RRMS), one of the most common causes of disability and loss of autonomy in young adults. The aim of this study was to assess state hopelessness and its associated factors in early-stage RRMS. A multicenter, non-interventional study was conducted. Adult patients with a diagnosis of RRMS, a disease duration ≤ 3 years, and an Expanded Disability Status Scale (EDSS) score of 0-5.5 were included. The State-Trait Hopelessness Scale (STHS) was used to measure patients´ hopelessness. A battery of patient-reported and clinician-rated measurements was used to assess clinical status. A multivariate logistic regression analysis was conducted to determine the association between patients' characteristics and state hopelessness. A total of 189 patients were included. Mean age (standard deviation-SD) was 36.1 (9.4) years and 71.4% were female. Median disease duration (interquartile range-IQR) was 1.4 (0.7, 2.1) years. Symptom severity and disability were low with a median EDSS (IQR) score of 1.0 (0, 2.0). A proportion of 65.6% (n=124) of patients reported moderate-to-severe hopelessness. Hopelessness was associated with older age (p=0.035), depressive symptoms (p=<0.001), a threatening illness perception (p=0.001), and psychological and cognitive barriers to workplace performance (p=0.029) in the multivariate analysis after adjustment for confounders. Hopelessness was a common phenomenon in early-stage RRMS, even in a population with low physical disability. Identifying factors associated with hopelessness may be critical for implementing preventive strategies helping patients to adapt to the new situation and cope with the disease in the long term.


Zinc tolerant plant growth promoting bacteria alleviates phytotoxic effects of zinc on maize through zinc immobilization.
The increasing heavy metal contamination in agricultural soils has become a serious concern across the globe. The present study envisages developing microbial inoculant approach for agriculture in Zn contaminated soils. Potential zinc tolerant bacteria (ZTB) were isolated from zinc (Zn) contaminated soils of southern Rajasthan, India. Isolates were further screened based on their efficiency towards Zn tolerance and plant growth promoting activities. Four strains viz. ZTB15, ZTB24, ZTB28 and ZTB29 exhibited high degree of tolerance to Zn up to 62.5 mM. The Zn accumulation by these bacterial strains was also evidenced by AAS and SEM-EDS studies. Assessment of various plant growth promotion traits viz., IAA, GA3, NH3, HCN, siderophores, ACC deaminase, phytase production and P, K, Si solubilization studies revealed that these ZTB strains may serve as an efficient plant growth promoter under in vitro conditions. Gluconic acid secreted by ZTB strains owing to mineral solubilization was therefore confirmed using high performance liquid chromatography. A pot experiment under Zn stress conditions was performed using maize (Zea mays) variety (FEM-2) as a test crop. Zn toxicity reduced various plant growth parameters; however, inoculation of ZTB strains alleviated the Zn toxicity and enhanced the plant growth parameters. The effects of Zn stress on antioxidant enzyme activities in maize under in vitro conditions were also investigated. An increase in superoxide dismutase, peroxidase, phenylalanine ammonia lyase, catalase and polyphenol oxidase activity was observed on inoculation of ZTB strains. Further, ZIP gene expression studies revealed high expression in the ZIP metal transporter genes which were declined in the ZTB treated maize plantlets. The findings from the present study revealed that ZTB could play an important role in bioremediation in Zn contaminated soils.


[Definition of a brain reference line in magnetic resonance imaging: the chiasmato-commisural line].
Proposes and defines a cephalic reference plane that joins the chiamatic notch to the posterior commissure, easily shown on a mid-sagittal cut using magnetic resonance. The horizontal cuts obtained prove to be very close to those oriented according to the lateral fissure, and orthogonal the great axis of the brainstem.


Increase in SP-like immunoreactivity in nerve fibres of rabbit iris and ciliary body one to four months following sympathetic denervation.
Substance P (SP) levels in rabbit iris-ciliary body preparations were found to be significantly elevated 30 days after removal of the superior cervical ganglion when compared with the contralateral unoperated side. These elevated levels were still apparent after two and three months. Immunohistochemical studies, using a monoclonal antibody to SP, revealed an increase in the density of SP-immunoreactive nerve fibres in the region of the iris dilator muscle and in the ciliary processes one to four months after sympathectomy, although the density of these fibres in other regions of the iris was not altered.


Predictors of impact of a minority program upon a medical school.
The race of the respondents, and the racial orientation of the white respondents, were found to be predictors of how the individuals perceived the impact of the minority program at the University of Michigan Medical School.


Diffusion-weighted Magnetic Resonance Imaging in the Early Diagnosis of Neonatal Adrenoleukodystrophy.
A newborn baby girl developed seizures right after birth. On the fourth day, the baby was examined using diffusion sequence magnetic resonance imaging (MRI) and diagnosed to have neonatal adrenoleukodystrophy. Laboratory findings confirmed the diagnosis. This is the first case of neonatal adrenoleukodystrophy (NALD) where diffusion MRI sequence helped in the diagnosis. We find association of NALD with seizures at birth is an extremely rare occurrence, and so far, only one case has been mentioned in the literature.