Identification of core genes, critical signaling pathways, and potential drugs for countering BPA-induced hippocampal neurotoxicity in male mice.
Although the neurotoxicity of the common chemical bisphenol A (BPA) to the mouse hippocampus has been often reported, the mechanism underlying BPA-induced depression-like behavior in mice remains unclear. We evaluated BPA's role in inducing depressive-like behavior by exposing male mice to different BPA concentrations (0, 0.01, 0.1, and 1 μg/mL) and using the forced swimming test (FST) and tail suspension test (TST). We aimed to identify critical gene and anti-BPA-neurotoxicity compounds using RNA sequencing combined with bioinformatics analysis. Our results showed that 1 μg/mL BPA exposure increased mouse immobility during the FST and TST. Based on BPA-induced hippocampal transcriptome changes, we identified NADH: ubiquinone oxidoreductase subunit AB1 (Ndufab1) as a critical and potential therapeutic target gene, and Ndufab1 mRNA and protein levels were downregulated in the BPA-exposed groups. Furthermore, molecular docking identified phenelzine as a compound that could counteract BPA-related neurotoxicity. Conclusively, our analyses confirmed that BPA triggers depressive behavior in male mice by downregulating Ndufab1 expression and suggested that phenelzine might reduce BPA-induced neurotoxicity.


Sorting out the p63 signaling network.
p63 is a transcription factor required for normal epidermal development and differentiation. Because of the complexity of these processes, p63 is expected to regulate a myriad of target genes, providing impetus to many laboratories to identify these genes. p63 target genes have been shown to encode a diverse group of proteins, including structural proteins, proteins that control cell cycle withdrawal, and proteins that regulate the epidermal differentiation program. In this issue, Antonini et al., describe a novel p63 target gene whose evolutionary conservation suggests a critical role for this gene in the epidermis.


Effectiveness of Alcohol and Aldehyde Spray Disinfectants on Dental Impressions.
The gold standard for disinfection of dental impressions is by immersion although spray techniques are also available. This study compared the effectiveness of alcohol and aldehyde spray disinfectants on analogue dental impressions in a hospital setting. Impressions were swabbed after removal from the mouth (pre-disinfection) and after spraying (post-disinfection) with either a non-aldehyde alcohol-based disinfectant, Bossklein (Silsden, W Yorks, BD20 0EF, UK) or a glutaraldehyde-based alcohol-free disinfectant, MD520 (Dürr Dental, 74321 Bietigheim-Bissingen, Germany). Swabs were transported to the microbiology laboratory in Amies medium and plated onto sheep blood agar within 2 hrs. Plates were incubated for 3 days at 37°C then at room temperature for 3 days. After incubation, all plates were examined for microbial growth. A total of 87 impressions were assessed (alginate = 41; poly-vinyl siloxane (PVS) = 31; polyether = 15). The counts were categorized into two groups: no growth or growth present. Post-disinfection contamination was present on six alginate and six PVS impressions but only one polyether impression (x2 = 1.27, P > 0.05, NSS). Analysis of post-disinfection growth according to impression and disinfectant found significantly more contaminated PVS impressions with the alcohol-based spray than with the aldehyde spray (x2 = 5.37, p < 0.05). Disinfection with the aldehyde-based spray resulted in only two contaminated impressions, both in alginate. Alcohol-based spray disinfection of dental impressions may be less effective than aldehyde spray and full immersion of impressions is recommended. Careful wetting or soaking of all surfaces of impressions is very important when using a spray.


[Collagenolytic activity of neoplastic and rapidly proliferating normal tissue].
By means of a biological collagenase assay the activity of this protease was examined in 12 invasive adenocarcinomas of the colon and compared to that in 10 normal thymus tissue biopsies. Collagenolytic activity at dimensions of 10(-3) units/mm diameter tissue could be revealed in all carcinomas, which significantly (p less than 0.001) surpassed the also regularly detectable activity in thymi. While 0-Phenantrolin and D-Penicillamin totally inhibited lysis of each sample, EDTA and normal human serum, remarkably inhibiting collagenase of normal thymus, only were able to reduce the lysis by cancer at 19 and 23% in the average leading to enzyme: inhibitor imbalance in malignancy. It can be suggested that collagenolysis displayed by adenocarcinomas is derived from the tumor itself, and is different from that of normal thymus--a rapidly proliferating organ--by means of enzymatic quantity and quality.


Phase I and pharmacokinetic study of 5-aza-2'-deoxycytidine (NSC 127716) in cancer patients.
A phase I trial and pharmacokinetic study of 5-aza-2'-deoxycytidine (5-aza-dCyd) were conducted in 21 patients with advanced solid tumors. The drug was given as three 1-h infusions, separated by intervals of 7 h. Treatment was repeated every 3-6 weeks. Forty-six cycles of 5-aza-dCyd were administered at 7 dose levels ranging from 25 to 100 mg/m2 in three infusions. The dose-limiting toxicity was myelosuppression, with a delayed white blood cell nadir, occurring at Day 22. Other toxicities included a mild, reversible elevation of serum creatinine in three patients, minimal nausea and vomiting in six patients, and transient fatigue in three patients. In this study one partial response in a patient with an undifferentiated carcinoma of the ethmoid sinus was observed. Plasma and urinary concentrations of 5-aza-dCyd were measured using a bioassay based on growth inhibition of L1210 leukemia cells in vitro. For 75 and 100 mg/m2 given as 1-h infusions, mean peak plasma concentrations of 0.93 and 2.01 microM, respectively, were attained. In seven of nine courses at doses of 25-60 mg/m2, plasma 5-aza-dCyd concentration was less than 0.01 microM. In one case at 30 mg/m2 and another at 60 mg/m2, peak plasma drug concentrations were determined to be 0.244 and 0.409 microM, respectively. Following cessation of the infusion rapid disappearance of drug from plasma was observed with a t1/2 alpha and t1/2 beta of 7 and 35 min, respectively. High clearance values and a total urinary excretion of less than 1% of the administered dose suggest that 5-aza-dCyd is eliminated rapidly and largely by metabolic processes. For the present schedule studied, a dose of 75 mg/m2 in three infusions, every 5 weeks, is recommended for phase II trials in solid tumors.


[Peculiarities of performing hybrid operation in a patient with atherosclerosis of lower limbs and developed critical ischaemia].
Currently, there is a tendency towards an increase in the incidence rate of cardiovascular disease. According to the data of the World Health Organization the incidence rate of obliterating diseases of peripheral arteries varies from 5 to 10%. Diseases of peripheral arteries manifest themselves by such a severe condition as lower-limb critical ischaemia. Most often lower-limb chronic critical ischaemia develops in patients with multi-level lesions of the arterial bed. Treatment of such patients constitutes a serious problem since it requires large-scope revascularization. The authors describe a clinical example of a hybrid operation in a patient with atherosclerosis of lower-limb arteries on the background of critical ischaemia of the lower extremities on the background of type 2 diabetes mellitus. The hybrid intervention was performed in the scope of balloon angioplasty and stenting of the right deep femoral artery with simultaneous loop semiclosed thromboendarterectomy from the right common femoral artery, superficial femoral and popliteal artery with balloon angioplasty of the right superficial femoral artery with mechanic recanalization and balloon angioplasty of the popliteal artery, anterior tibial artery, and peroneal artery. The next stage consisted in amputation of the anterior portion of the right foot according to the Chopart s technique with skin plasty. Resulting from the operation on the background of further angiotropic and rheological active therapy with PGE-1 preparation VAP-20 we managed to save the patient s limb and to limit to minor amputation. Hybrid operative interventions should be carried out in order to achieve maximal revascularization when it is not possible to obtain a favourable result by a reconstructive or endovascular intervention alone.


Lipopolysaccharide (LPS) attenuates the primary conditioning of lithium chloride (LiCl)-induced context aversion but not the secondary conditioning of context aversion or taste avoidance.
A first-order association can be formed between toxin-induced nausea and a context, as well as nausea and a taste cue. However, comparatively little is understood about second-order associations. The present study examined if the bacterial endotoxin, LPS, could impair the first- and second-order conditioning of context aversion (anticipatory nausea paradigm) and subsequent conditioned taste avoidance (two-bottle task). Adult male Long Evans rats were treated with LiCl (127 mg/kg, intraperitoneal [i.p.]) or vehicle control (NaCl) and then exposed to a distinct context for 4 first-order conditioning trials. LPS (200 μg/kg, i.p.) or NaCl were administered 24 h after each trial. Seventy-two h after the final first-order conditioning trial, rats underwent 2 second-order conditioning trials where they were treated with 2% saccharin (i.p.) and then exposed to the same context. Twenty-four h after the final second-order conditioning trial, rats were tested in a two-bottle task (2 trials), where they were given a choice between water and a palatable 0.2% saccharin solution. LiCl-treated rats demonstrated a context aversion by the 3rd conditioning trial in the anticipatory nausea paradigm. Rats previously exposed to LiCl also displayed a conditioned taste avoidance of saccharin within the two-bottle task. LPS attenuated first-order context aversion but did not alter either second-order context aversion or conditioned taste avoidance in the two-bottle task. This study demonstrated that a secondary association formed within an aversive context could result in a conditioned taste avoidance. Further, LPS may be able to attenuate primary conditioning, but not secondary conditioning.


A late presentation of Loeys-Dietz syndrome associated with an aortic root aneurysm.
Loeys-Dietz syndrome (LDS) is characterised by a mutation in the transforming growth factor beta receptor, and is strongly associated with aortic aneurysms and rupture. Most cases of LDS present in the second decade of life, with the average life expectancy being 37 years. We report a case of suspected LDS (owing to significant family history of the disorder) that presented in the seventh decade of life. Our patient had aortic root dilation and was initially believed to have Marfan syndrome. However, subsequent tests were negative. On further investigation of her family history, it was revealed that she had a strong positive family history of aortic rupture and aneurysms associated with genetically confirmed atypical LDS. By reporting this case, we aim to highlight the importance of considering inherited connective tissue disorders when a patient presents with aortic aneurysms or dissections associated with a strong family history of aortic pathology.


A multi-channel hearing prosthesis for profound-to-total hearing loss.
A multi-channel cochlear implant hearing prosthesis providing 22 separate channels of stimulation has been developed. The electronics for the implantable receiver-stimulator have been incorporated on a single chip, using digital circuits and employing CMOS technology. The chip is enclosed in a titanium capsule with platinum/ceramic electrode feed-throughs. A pocket-sized speech processor and directional microphone extract the following speech parameters: signal amplitude, fundamental frequency and formant frequency. The fundamental frequency is coded as electric pulse rate, and formant frequency by electrode position. The speech processor has been realized using hybrid circuits and CMOS gate arrays. The multi-channel prosthesis has undergone a clinical trial on four postlingually deaf patients with profound-total hearing losses. The speech perception results indicate that they were able to obtain open-set speech recognition scores for phonetically balanced words, CID sentences and spondees. In all cases the tests showed significant improvements when using the cochlear prosthesis combined with lipreading compared to lipreading alone.


A study of empyema thoracis and role of intrapleural streptokinase in its management.
Clinical spectrum, microbiology and outcome of empyema thoracis are changing. Intrapleural instillation of fibrinolytic agents is being increasingly used for management of empyema thoracis. The present study was carried out to describe the clinical profile and outcome of patients with empyema thoracis including those with chronic empyema and to study the efficacy and safety of intrapleural streptokinase in its management. Clinical profile, etiological agents, hospital course and outcome of 31 patients (mean age 40 +/- 16 years, M: F 25: 6) with empyema thoracis treated from 1998 to 2003 was analyzed. All patients were diagnosed on the basis of aspiration of frank pus from pleural cavity. Clinical profile, response to therapy and outcome were compared between the patients who received intrapleural streptokinase (n = 12) and those who did not (n = 19). Etiology was tubercular in 42% of the patients (n = 13) whereas the rest were bacterial. Amongst the patients in which organisms could be isolated (n = 13, 42%) Staphylococcus aureus was the commonest (n = 5). Intrapleural streptokinase was instilled in 12 patients. This procedure resulted in increase of drainage of pleural fluid in all patients. Mean daily pleural fluid drainage after streptokinase instillation was significantly higher for patients who received intrapleural streptokinase than those who did not (213 ml vs 57 ml, p = 0.006). Only one patient who was instilled streptokinase eventually required decortication, which had to be done in five patients (16.1%). Mean hospital stay was 30.2 +/- 17.6 days whereas two patients died. Tubercular empyema is common in Indian patients. Intrapleural streptokinase appears to be a useful strategy to preserve lung function and reduce need for surgery in patients with late stage of empyema thoracis.


[Contraceptive choices and experience of sexuality: a comparison between sterilized and non-sterilized women in a metropolitan area of southeastern Brazil].
A cross sectional study involving 357 women, 174 of them sterilized and 183 non-sterilized, with a view to comparing their sexual and reproductive behaviour, was undertaken. The questionnaire was based on previous focus group discussions with both women and men, to find out the best way to approach related questions. The results show that sterilized women-who are older and more often have steady partnerships than non-sterilized women-fulfil traditional gender roles more closely than the others. Furthermore, no sterilized woman had used the condom in the month prior to the interview. It is suggested that public messages for the prevention of the spread of the HIV, sexually-transmissible disease and cervical cancer should target women who have been sterilized for the purpose of increasing the use of the condom in accordance with specific strategies.


Low immunogenicity of the common lipoamide dehydrogenase subunit (E3) of mammalian pyruvate dehydrogenase and 2-oxoglutarate dehydrogenase multienzyme complexes.
The production of high-titre monospecific polyclonal antibodies against the purified pyruvate dehydrogenase and 2-oxoglutarate dehydrogenase multienzyme complexes from ox heart is described. The specificity of these antisera and their precise reactivities with the individual components of the complexes were examined by immunoblotting techniques. All the subunits of the pyruvate dehydrogenase and 2-oxoglutarate dehydrogenase complexes were strongly antigenic, with the exception of the common lipoamide dehydrogenase component (E3). The titre of antibodies raised against E3 was, in both cases, less than 2% of that of the other subunits. Specific immunoprecipitation of the dissociated N-[3H]ethylmaleimide-labelled enzymes also revealed that E3 alone was absent from the final immune complexes. Strong cross-reactivity with the enzyme present in rat liver (BRL) and ox kidney (NBL-1) cell lines was observed when the antibody against ox heart pyruvate dehydrogenase was utilized to challenge crude subcellular extracts. The immunoblotting patterns again lacked the lipoamide dehydrogenase band, also revealing differences in the apparent Mr of the lipoate acetyltransferase subunit (E2) from ox kidney and rat liver. The additional 50 000-Mr polypeptide, previously found to be associated with the pyruvate dehydrogenase complex, was apparently not a proteolytic fragment of E2 or E3, since it could be detected as a normal component in boiled sodium dodecyl sulphate extracts of whole cells. The low immunogenicity of the lipoamide dehydrogenase polypeptide may be attributed to a high degree of conservation of its primary sequence and hence tertiary structure during evolution.


The impact of ADHD persistence, recent cannabis use, and age of regular cannabis use onset on subcortical volume and cortical thickness in young adults.
Both Attention Deficit Hyperactivity Disorder (ADHD) and chronic cannabis (CAN) use have been associated with brain structural abnormalities, although little is known about the effects of both in young adults. Participants included: those with a childhood diagnosis of ADHD who were CAN users (ADHD_CAN; n=37) and non-users (NU) (ADHD_NU; n=44) and a local normative comparison group (LNCG) who did (LNCG_CAN; n=18) and did not (LNCG_NU; n=21) use CAN regularly. Multiple regressions and MANCOVAs were used to examine the independent and interactive effects of a childhood ADHD diagnosis and CAN group status and age of onset (CUO) on subcortical volumes and cortical thickness. After controlling for age, gender, total brain volume, nicotine use, and past-year binge drinking, childhood ADHD diagnosis did not predict brain structure; however, persistence of ADHD was associated with smaller left precentral/postcentral cortical thickness. Compared to all non-users, CAN users had decreased cortical thickness in right hemisphere superior frontal sulcus, anterior cingulate, and isthmus of cingulate gyrus regions and left hemisphere superior frontal sulcus and precentral gyrus regions. Early cannabis use age of onset (CUO) in those with ADHD predicted greater right hemisphere superior frontal and postcentral cortical thickness. Young adults with persistent ADHD demonstrated brain structure abnormalities in regions underlying motor control, working memory and inhibitory control. Further, CAN use was linked with abnormal brain structure in regions with high concentrations of cannabinoid receptors. Additional large-scale longitudinal studies are needed to clarify how substance use impacts neurodevelopment in youth with and without ADHD.


German energy technology prospects.
After more than 25 years of development of nuclear power and almost 10 years of research and development in numerous areas of nonnuclear energy, there is now a good basis for judging the future prospects of energy technologies in the Federal Republic of Germany. The development of nuclear power has provided an important and economically advantageous new source of energy. Further efforts are needed to establish the nuclear fuel cycle in all stages and to exploit the potential of advanced reactors. In all other areas of energy technology, including energy conservation, new energy sources, and coal, economics has turned out to be the key problem, even at today's energy prices. Opportunities to overcome these economic problems through additional R & D are limited. There is some potential for special applications, and there are many technologies that could contribute to the energy supply of developing countries. In general, however, progress in energy conservation and the use of renewable energy sources will depend on the degree to which energy policy measures can improve their economic basis. For some technologies, such as solar thermal power stations and coal liquefaction, large-scale economic deployment cannot be foreseen today. Instead of establishing costly demonstration projects, emphasis will be put on improving key components of these technologies with the aim of having the most advanced technology available when the economic parameters are more favorable.


Interpersonal conflict and sarcasm in the workplace.
Violence and aggression in the workplace are problems that most Americans confront on a daily basis. The present study is an exploration of the predisposition to conflict in a work environment in which personality traits responsible for increased sarcasm and increased anger in response to sarcasm are identified. Participants represented two subdepartments within a city general hospital. The Keirsey Temperament Sorter (D. Keirsey, 1998) test for departmental temperament and a sarcasm survey designed by the author were used to test for frequency of sarcasm and anger in relation to differing categories of sarcasm. Angry reactions were gauged in relation to sarcasm directed at job performance, personal life, behavior, and appearance. Conclusions from this study point to many variables as causes for workplace anger; these include influences from organizational culture, work environment, psychological defense mechanisms, leadership decisions, stress, task orientation, and personality differences. Sarcasm trigger points leading to anger may be predicted based on a work group's personality composition. A homogeneous personality composition within a work group may involve factors such as personality characteristics common to a particular profession, organizational demands, and hiring practices.


The effects of integrated single- and dual-task training on automaticity and attention allocation in Parkinson's disease: A secondary analysis from a randomized trial.
People with Parkinson's disease (PwPD) demonstrate impaired automaticity of motor and cognitive tasks, with unclear prioritization strategies when exposed to dual-task situations. However, no randomized trials have investigated the effects of training on automaticity and prioritization strategies in this population. The purpose of this study was to investigate the effects of training on the automaticity of gait and cognitive processing in PwPD and the allocation of attention between gait and a cognitive task. One-hundred PwPD were randomized to 10 weeks of challenging gait and balance training (including single and dual-task conditions) or to a control group (care as usual). Outcome measure was the absolute dual-task interference (difference between single- and dual-tasks) for gait and cognitive parameters. Differences between baseline and follow-up were compared between the groups. The Mann-Whitney U test was used to assess potential differences. Significance level was set to p = .05. The direction and magnitude of nonparametric effect sizes were used to investigate attention allocation. No significant between-groups differences were found regarding any gait parameter. The training group significantly improved the dual-task interference of the cognitive task. The direction of between-groups effect sizes indicated that the training group primarily allocated attention to the cognitive task, whereas the control group appeared to prioritize gait. The results indicate that challenging training can improve automaticity of cognitive processing during walking. This may have a beneficiary effect on the ability to ambulate safely in the community, thereby improving independence and the quality of life in this population. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Multifocal intraparenchymal hemorrhages after ventriculoperitoneal shunt surgery in infants.
Ventriculoperitoneal (VP) shunt surgery is the most common treatment for hydrocephalus. In certain situations, uncommon complications can occur after shunting procedures. The authors undertook this study to analyze the clinical characteristics of pediatric patients who developed multifocal intraparenchymal hemorrhages (MIPHs) as a complication of shunt surgery. The authors also analyzed the risk factors for MIPH in a large cohort of patients with hydrocephalus. This study included all pediatric patients (age < 18 years) who underwent VP shunt surgery at the authors' institution between January 2001 and December 2012. During this period, 507 VP shunt operations were performed in 330 patients. Four of these patients were subsequently diagnosed as having MIPH. The authors analyzed the clinical characteristics of these patients in comparison with those of the entire group of shunt-treated patients. The incidence of MIPH was 1.2% (4 of 330 cases) for all pediatric patients who underwent VP shunt placement but 2.9% (4 of 140 cases) for infants less than 1 year old. When the analysis was limited to patients whose corrected age was less than 3 months, the incidence was 5.3% (4 of 76 cases). Of the 4 patients with MIPH, 2 were male and 2 were female. Their median age at surgery was 54 days (range 25-127 days), and in all 4 cases, the patients' corrected age was less than 1 month. Three patients were preterm infants, whereas one patient was full-term. None of these patients had a prior history of intracranial surgery (including CSF diversion procedures). All showed severe hydrocephalus during the preoperative period. Their clinical courses as patients with MIPH were comparatively favorable, despite the radiological findings. MIPH is a rare but not negligible complication of VP shunt surgery. This complication might be a unique phenomenon in infants, especially young, preterm infants with severe hydrocephalus. Moreover, the absence of previous intracranial procedures might be one of the risk factors for this complication. The rapid alteration of brain conditions in the setting of immaturity might cause MIPH. To prevent this complication, the authors recommend that pressure settings of programmable valves should be gradually adapted to the target pressure.


The effect of habitual smoking on measured and predicted VO2(max).
Nonexercise models were developed to predict maximal oxygen consumption (VO2(max)). While these models are accurate, they don't consider smoking, which negatively impacts measured VO2(max). The purpose of this study was to examine the effects of smoking on both measured and predicted VO2(max). Indirect calorimetry was used to measure VO2(max) in 2,749 men and women. Physical activity using the NASA Physical Activity Status Scale (PASS), body mass index (BMI), and smoking (pack-y = packs.day * y of smoking) also were assessed. Pack-y groupings were Never (0 pack-y), Light (1-10), Moderate (11-20), and Heavy (> 20). Multiple regression analysis was used to examine the effect of smoking on VO2(max) predicted by PASS, age, BMI, and gender. Measured VO2(max) was significantly lower in the heavy smoking group compared with the other pack-y groups. The combined effects of PASS, age, BMI, and gender on measured VO2(max) were significant. With smoking in the model, the estimated effects on measured VO2(max) from Light, Moderate, and Heavy smoking were -0.83, -0.85, and -2.56 ml x kg(-1) x min(-1), respectively (P < .05). Given that 21% of American adults smoke and 12% of them are heavy smokers, it is recommended that smoking be considered when using nonexercise models to predict VO2(max).


Leukocyte complement receptors and adhesion proteins in the inflammatory response: insights from an experiment of nature.
The complement receptor type 3 (CR3) mediates phagocytosis and degradation of iC3b-opsonized particles by macrophages and granulocytes. The CR3 is identical to the Mac-1 molecule, which is composed of two non-covalently associated glycoprotein subunits, alpha M of Mr 170,000 and beta of Mr 95,000. Patients with recurring, life-threatening bacterial infections have been identified who have moderate (95%) or severe (greater than 99%) deficiency of Mac-1 and of the related LFA-1 and p150,95 molecules. The primary defect is in the shared beta subunit of these molecules. Patient leukocytes are not only deficient in CR3 but in a wide variety of adhesion-dependent functions, including granulocyte chemotaxis, adherence to surfaces, and aggregation. Monoclonal antibodies to the Mac-1 alpha subunit and to the beta subunit block these functions. The hypothesis will be advanced that Mac-1 functions dually as the CR3 and in 'nonspecific' adherence reactions. Adherence functions are stimulated in normal granulocytes by chemoattractants, which also induce a rapid 5-fold increase in Mac-1 and p150,95 on the cell surface. It is proposed that absence of Mac-1 and p150,95 expression and upregulation by patient granulocytes is causally related to their inability to extravasate and migrate into inflammatory sites.


Clinical Efficacy and Safety Profile of Lofexidine Hydrochloride in Treating Opioid Withdrawal Symptoms: A Review of Literature.
Opioid use disorder (OUD) is a rapidly growing challenge worldwide and is characterized by an increase in dependence on opioids up to a point that a person loses control over the drug use. Multiple drugs are approved for its treatment, including methadone, buprenorphine, and diazepam. Although not approved, clonidine is also used for the treatment of OUD. On May 16, 2018, the United States Food and Drug Administration (FDA) approved a new drug lofexidine hydrochloride for the treatment of opioid withdrawal symptoms. Lofexidine is a centrally acting alpha two receptor agonist. It reduces the neurochemical surge by inhibiting the conversion of adenosine triphosphate (ATP) into cyclic adenosine monophosphate (cAMP) which in turn decrease the sympathetic outflow. This results in the improvement of withdrawal symptoms. When compared with methadone and buprenorphine, it is equally effective in controlling withdrawal symptoms. Its efficacy is also similar to clonidine with a better side effects profile. The adverse effects of lofexidine include bradycardia, hypotension, orthostasis, somnolence, sedation, dry mouth, and rebound elevations in blood pressure and prolongation of QT interval. Lofexidine is contraindicated in patients who are on beta-blockers and angiotensin converting enzyme inhibitors (ACE inhibitors). In our review, we have discussed the clinical efficacy and safety profile of lofexidine in treating opioid withdrawal symptoms and its comparison to other available treatment options.


Multi-task machine learning models for simultaneous prediction of tissue-to-blood partition coefficients of chemicals in mammals.
Tissue-to-blood partition coefficients (Ptb) are crucial for assessing the distribution of chemicals in organisms. Given the lack of experimental data and laborious nature of experimental methods, there is an urgent need to develop efficient predictive models. With the help of machine learning algorithms, i,e., random forest (RF), and artificial neural network (ANN), this study developed multi-task (MT) models that can simultaneously predict Ptb values for various mammalian tissues, including liver, muscle, brain, lung, and adipose. Single-task (ST) models using partial least squares regression, RF, and ANN algorithms for each endpoint were established for comparison. Overall, the performances of MT models were superior to those of ST models. The MT model using ANN algorithms showed the highest prediction accuracy with determination coefficients ranging from 0.704 to 0.886, root mean square errors between 0.223 and 0.410, and mean absolute errors ranging from 0.178 to 0.285 log units. Results showed that lipophilicity and polarizability of molecules significantly influence their partition behavior in organisms. Applicability domains (ADs) of the models were characterized by weighted molecular similarity density, and weighted inconsistency in molecular activities of structure-activity landscapes. When constrained by ADs, the models displayed enhanced predictive accuracy, making them valuable tools for the risk assessment and management of chemicals.


Regulation of myometrial contractivity during pregnancy in the rat: potential role for DDAH.
There has been little information demonstrating the roles of dimethylarginine dimethylaminohydrolase (DDAH), which is the hydrolyzing enzyme of endogenous nitric oxide synthase (NOS) inhibitors and, in turn, modulates the intracellular concentrations of NOS inhibitors, in the myometrium during the course of pregnancy. Therefore, the present experiments were designed to investigate whether or not DDAH activity, protein and mRNA expression levels are altered during gestation of the rat and, if altered, those changes reflect on the levels of endogenous inhibitors and endothelin-1 (ET-1), and NO-dependent cyclic GMP generation in the myometrium. The up-regulated changes in DDAH activity, DDAH-2 protein and DDAH-2 mRNA expression at mid-gestation were accompanied by the reduced monomethylarginine and asymmetric dimethylarginine as NOS inhibitors, and ET-1 levels, and by the enhanced NO-dependent cyclic GMP production. At term gestation, on the other hand, down-regulated changes in DDAH activity, DDAH-2 protein and DDAH-2 mRNA expression were accompanied by the increased NOS inhibitors and ET-1 levels, and decreased NO-dependent cyclic GMP generation. These results suggest that alterations in DDAH/NOS inhibitors/NO-dependent cyclic GMP/ET-1 pathway are possibly involved in maintaining myometrial quiescence during gestation and controlling delivery at term.


3-D wavelet compression and progressive inverse wavelet synthesis rendering of concentric mosaic.
Using an array of photo shots, the concentric mosaic offers a quick way to capture and model a realistic three-dimensional (3-D) environment. We compress the concentric mosaic image array with a 3-D wavelet transform and coding scheme. Our compression algorithm and bitstream syntax are designed to ensure that a local view rendering of the environment requires only a partial bitstream, thereby eliminating the need to decompress the entire compressed bitstream before rendering. By exploiting the ladder-like structure of the wavelet lifting scheme, the progressive inverse wavelet synthesis (PIWS) algorithm is proposed to maximally reduce the computational cost of selective data accesses on such wavelet compressed datasets. Experimental results show that the 3-D wavelet coder achieves high-compression performance. With the PIWS algorithm, a 3-D environment can be rendered in real time from a compressed dataset.


DNA binding by single HMG box model proteins.
The HMG1/2 family is a large group of proteins that share a conserved sequence of approximately 80 amino acids rich in basic, aromatic and proline side chains, referred to as an HMG box. Previous studies show that HMG boxes can bind to DNA in a structure-specific manner. To define the basis for DNA recognition by HMG boxes, we characterize the interaction of two model HMG boxes, one a structure-specific box, rHMGb from the rat HMG1 protein, the other a sequence-specific box, Rox1 from yeast, with oligodeoxynucleotide substrates. Both proteins interact with single-stranded oligonucleotides in this study to form 1:1 complexes. The stoichiometry of binding of rHMGb to duplex or branched DNAs differs: for a 16mer duplex we find a weak 2:1 complex, while a 4:1 protein:DNA complex is detected with a four-way DNA junction of 16mers in the presence of Mg(2+). In the case of the sequence-specific Rox1 protein we find tight 1:1 and 2:1 complexes with its cognate duplex sequence and again a 4:1 complex with four-way branched DNA. If the DNA branching is reduced to three arms, both proteins form 3:1 complexes. We believe that these multimeric complexes are relevant for HMG1/2 proteins in vivo, since Mg(2+) is present in the nucleus and these proteins are expressed at a very high level.


Characterization of antihistamine-human serum protein interactions by capillary electrophoresis.
An important topic in the drug discovery and development process is the role of drug binding to plasma proteins. In this paper the characterization of the interaction between antihistamines (cationic drugs) towards human serum albumin (HSA) and alpha(1)-acid glycoprotein (AGP) under physiological conditions by capillary electrophoresis-frontal analysis is presented. Furthermore, the binding of these drugs to all plasma proteins is evaluated by using ultrafiltration and capillary electrophoresis. Antihistamines present a wide-ranging behaviour with respect to their affinities towards plasma proteins. Orphenadrine, phenindamine, tripelenamine and tripolidine principally bind to HSA; carbinoxamine, dimetindene and etintidine principally bind to AGP; brompheniramine, chlorpheniramine and ranitidine present an important binding to lipoproteins and/or globulins and finally, chlorcyclizine, cinarizine, cyclizine, doxylamine, hydroxyzine, perphenazine and terfenadine do not bind to lipoproteins and/or globulins but bind to HSA and AGP in different extension. The interaction of antihistamines with HSA is determined by the hydrophobicity (direct relationship) and the polar surface area (indirect relationship) of the compounds. The steric parameters and hydrogen bonding character of compounds seems to be related with the binding of antihistamines to AGP. The antihistamine-HSA affinity constants were evaluated and the K(1) values ranged from 7 x 10(2)M(-1) (for doxylamine) to 4 x 10(4)M(-1) (for phenindamine).


Comparison of genome-wide binding of MyoD in normal human myogenic cells and rhabdomyosarcomas identifies regional and local suppression of promyogenic transcription factors.
Rhabdomyosarcoma is a pediatric tumor of skeletal muscle that expresses the myogenic basic helix-loop-helix protein MyoD but fails to undergo terminal differentiation. Prior work has determined that DNA binding by MyoD occurs in the tumor cells, but myogenic targets fail to activate. Using MyoD chromatin immunoprecipitation coupled to high-throughput sequencing and gene expression analysis in both primary human muscle cells and RD rhabdomyosarcoma cells, we demonstrate that MyoD binds in a similar genome-wide pattern in both tumor and normal cells but binds poorly at a subset of myogenic genes that fail to activate in the tumor cells. Binding differences are found both across genomic regions and locally at specific sites that are associated with binding motifs for RUNX1, MEF2C, JDP2, and NFIC. These factors are expressed at lower levels in RD cells than muscle cells and rescue myogenesis when expressed in RD cells. MEF2C is located in a genomic region that exhibits poor MyoD binding in RD cells, whereas JDP2 exhibits local DNA hypermethylation in its promoter in both RD cells and primary tumor samples. These results demonstrate that regional and local silencing of differentiation factors contributes to the differentiation defect in rhabdomyosarcomas.


Design of validation studies for estimating the odds ratio of exposure-disease relationships when exposure is misclassified.
We compared several validation study designs for estimating the odds ratio of disease with misclassified exposure. We assumed that the outcome and misclassified binary covariate are available and that the error-free binary covariate is measured in a subsample, the validation sample. We considered designs in which the total size of the validation sample is fixed and the probability of selection into the validation sample may depend on outcome and misclassified covariate values. Design comparisons were conducted for rare and common disease scenarios, where the optimal design is the one that minimizes the variance of the maximum likelihood estimator of the true log odds ratio relating the outcome to the exposure of interest. Misclassification rates were assumed to be independent of the outcome. We used a sensitivity analysis to assess the effect of misspecifying the misclassification rates. Under the scenarios considered, our results suggested that a balanced design, which allocates equal numbers of validation subjects into each of the four outcome/mismeasured covariate categories, is preferable for its simplicity and good performance. A user-friendly Fortran program is available from the second author, which calculates the optimal sampling fractions for all designs considered and the efficiencies of these designs relative to the optimal hybrid design for any scenario of interest.


Efficacy of prophylactic intramuscular ephedrine in prevention of hypotension during caesarean section under spinal anaesthesia: a comparative study.
Hypotension during caesarean section under spinal anaesthesia is a common complication. Several measures are used to reduce the incidence of hypotension but no method is fully effective. Prophylactic intramuscular ephedrine may be effective in reducing the incidence of hypotension in addition to conventional measures. To evaluate the efficacy of prophylactic intramuscular (IM) ephedrine (0.5 mg/kg, maximum up to 45 mg), given 10 minutes and 20 minutes before spinal anaesthesia to prevent hypotension, and to observe the adverse effects of IM ephedrine. A prospective, randomised, double-blind controlled study was undertaken where 150 pregnant mothers aged between 18 and 29 years and belonging to ASA physical status I, posted for elective caesarean section, were randomly allocated into one of the three groups. Group C received only preloading with 15 ml/kg of Ringer lactate (RL) solution, group E10 and group E20 received injection ephedrine 0.5 mg/kg IM 10 minutes and 20 minutes prior to performing spinal anaesthesia respectively along with 15 ml/kg RL preloading. The incidence of hypotension was significantly more in group C compared to other two groups. Mean arterial pressure and heart rate were significantly more in group E10 compared to group C. No significant increase in the incidence of hypertension and tachycardia in any group were observed. The findings of this study indicate that prophylactic IM ephedrine 0.5 mg/kg given 10 minutes before spinal anaesthesia gives better haemodynamic stability during intra-operative period without any significant increase in the incidence of adverse effects.


Short and informative DNA products to indirectly measure vascular plant biodiversity.
Anthropogenic activities are having a deleterious effect on biodiversity. To understand the magnitude of this issue, and ultimately temper its pace, requires reproducible biodiversity measurements at suitable spatio-temporal scales. Procuring such data solely by existing approaches is unachievable because of the costs, time and the taxonomic expertise required. High-throughput molecular biodiversity analysis shows great promise, increasing the breadth of biota sampled and accelerating the rate of data collection. In this issue of Molecular Ecology, Yoccoz et al. (2012) use short informative DNA product 'meta-barcodes' to provide an insight into above-ground vascular plant diversity from boreal, temperate and tropical environments. Interestingly, their molecular analysis was derived from the soils and not the plants themselves, with the molecular signatures of the soils not only strongly reflecting current diversity, but also traces of crops not sown for up to one hundred years. Importantly, the research examines the complexities associated with deriving biomass estimates from molecular data and the need to consider biomass turnover. The use of soil-derived meta-barcodes extends beyond estimating vascular plant diversity, with the approach being suited to the range of ecological applications, especially scenarios where DNA may be degraded.


The impacts of organizational green culture and corporate social responsibility on employees' responsible behaviour towards the society.
Corporate social responsibility (CSR) initiatives and organizational green culture (OGC) play a significant role in developing organizations and society. However, the extent to which these activities encourage organizational employees to act socially responsible outside their workplace is yet to be explored. This study uses the Operant conditioning theory to examine the effect of OGC and CSR activities on employees' responsible behaviour towards the society (ERBS) outside their organizations. To collect data, we focused on employees of public and private manufacturing and services firms and analysed it using the structural equation modelling (SEM) technique). It is found that OGC and CSR activities significantly reshape employees' behaviour, and they tend to behave in a socially responsible manner in society. Moreover, the relationship between OGC and ERBS' is partially mediated by CSR. It is also found that female workers tend to behave more socially responsibly than male workers. This study suggests that firms should adopt a green culture and CSR practices since it promotes socially responsible behaviour (a better citizen) among their employee, which is essential for a sustainable society.


Evidence for the use of urinary albumin as marker of kidney involvement in unselected populations.
The incidence of end-stage renal disease (ESRD) has been increasing, and within a 10-year period it is predicted that it will increase by 40 %. The main cause of death in this population of more than 50,000,000 individuals worldwide is cardiovascular disease. Increased urinary albumin is a predictor of renal failure, type 1 and type 2 diabetes; it correlates closely with mean arterial pressure in hypertensive subjects, predicts cardiovascular events and has a strong association with the metabolic syndrome. Treatment with angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers can reduce progressive renal damage, the beneficial effect being partially independent of the blood pressure lowering actions. Various therapies have proved effective in reducing microalbuminuria and progressive renal damage, demonstrating that the risk factor associated with a clinical outcome decreases with appropriate treatment. Cardiovascular events are the main cause of death in most patients with chronic renal disease. Diabetes, hypertension, obesity and smoking further increase the likelihood of vascular damage. Screening target populations of people with diabetes or hypertension is well recognized. Studies in several countries that have tested for albuminuria in unselected populations have demonstrated associations between microalbuminuria and deteriorating renal function, with the risk of developing ESRD and cardiovascular outcomes. There is some evidence for the use of urinary albumin as a marker of kidney involvement in unselected populations, but this needs to be strengthened and it may be cost effective compared with no screening. This has the potential to have a major impact in developing countries facing the challenges of chronic kidney disease, diabetes and cardiovascular disease.


Waterborne outbreaks reported in the United States.
Epidemic waterborne risks are discussed in this paper. Although the true incidence of waterborne illness is not reflected in the currently reported outbreak statistics, outbreak surveillance has provided information about the important waterborne pathogens, relative degrees of risk associated with water sources and treatment processes, and adequacy of regulations. Pathogens and water system deficiencies that are identified in outbreaks may also be important causes of endemic waterborne illness. In recent years, investigators have identified a large number of pathogens responsible for outbreaks, and research has focused on their sources, resistance to water disinfection, and removal from drinking water. Outbreaks in surface water systems have decreased in the recent decade, most likely due to recent regulations and improved treatment efficacy. Of increased importance, however, are outbreaks caused by the microbial contamination of water distribution systems. In order to better estimate waterborne risks in the United States, additional information is needed about the contribution of distribution system contaminants to endemic waterborne risks and undetected waterborne outbreaks, especially those associated with distribution system contaminants.


[Audiogenic epilepsy: a morphofunctional analysis].
The rats of K-M line with high level of convulsive readiness to sound stimuli were tested. It was established that systemic application of epileptogenic stimulus evoked the decrease of level of convulsive readiness. The phenomena of habituation and normalization of animal behavior were revealed. The intraperitoneal injection of inhibitory transmitter--GABA and taurine (separately or in mixture) blocked the convulsive seizures. The functional influence by KCl-induced spreading depression in the cerebral cortex bilaterally impairs the inhibitory processes, but not the changes the form of epileptiform seizure. In neurophysiological experiments using microelectrophoresis technique it was shown that taurine as inhibitory agent is more effective when applied to dendritic layers II-III; GABA is more effective if it is applied on soma of cortical pyramidal cells. Using the electron microscopic methods, the following changes were observed during the clonic seizure: axo-dendritic and axo-spine synapses in rat auditory cortex were activated. After the habituation to the epileptogenic stimulus, some features evidencing the decrease of activity were observed in ultrastructure of synapses in layers II-III. In 2 days after that the majority of ultrastructural shifts were normalized. Role of calcium ions in generation of epileptic seizures and their depression as main factor of antiepileptic mechanisms is discussed.


The use of silica-coated magnetic graphene microspheres as the adsorbent for the extraction of pyrethroid pesticides from orange and lettuce samples followed by GC-MS analysis.
Graphene-grafted ferroferric oxide microspheres were used as the adsorbent to extract some pyrethroid pesticides (bifenthrin, λ-cyhalothrin, cyfluthrin, cypermethrin, fenvalerate, and deltamethrin) from orange and lettuce samples prior to their determination by GC-MS. The main variables that could affect the extraction, including the amount of the adsorbent, pH of the sample solution, extraction time, concentration of salt, and desorption conditions, were investigated and optimized. Under the optimized conditions, a linear response was obtained in the concentration range of 0.3-100.0 ng/g for the analytes with the coefficients of determination ranging from 0.9877 to 0.9925. The LODs for the pyrethroids ranged from 0.01 to 0.02 ng/g. The method provided a good repeatability with RSDs < 10.6%. The recoveries for the six pyrethroid pesticides were in the range from 90.0 to 103.7%. The method was applied to the determination of the pesticides in orange and lettuce samples with a satisfactory result.


A patient with mitochondrial disorder due to a novel mutation in MRPS22.
MRPS22 gene defect is a very rare newly discovered mitochondrial disorder. We report a 4-month-old severely affected male infant with MRPS22 mutation. Whole exome sequencing revealed a novel homozygous splicing mutation c.339 + 5 G > A in MRPS22 gene. He has mild dysmorphism, hypotonia, developmental delay but not hypertrophic cardiomyopathy and tubulopathy which differ from other majority of reported patients. Therefore, hypertrophic cardiomyopathy and tubulopathy may not be considered as constant features of MRPS22. With this case report, we also present first symmetrical bilateral brainstem and medial thalamic lesions, and cerebellar and cerebral atrophy on a brain MR imaging follow-up of ten months.


The technique of percutaneous endoscopic gastrostomy. A safe and cost-effective alternative to operative gastrostomy.
Percutaneous endoscopic gastrostomy (PEG) is an attractive method of providing enteral nutrition to patients who are candidates for operative gastrostomy or nasoenteric tube feeding; it is currently the procedure of choice for selected nutritionally compromised patients. PEG may be considered for patients who need short- or long-term enteral support; those unable to swallow or who cannot maintain adequate oral intake are ideal candidates. Several techniques are used to perform PEG; each involves the placement of a gastrostomy tube at a point where the stomach and abdominal walls are in closest contact. PEG can be done at the bedside without general anesthesia. Feeding can begin within 24 hours of PEG placement. Major complications (peritonitis and pulmonary aspiration) occur infrequently.


MiR-452-5p facilitates retinoblastoma cell growth and invasion via the SOCS3/JAK2/STAT3 pathway.
Retinoblastoma (RB) is an intraocular tumor in children. Accumulated evidence confirms that microRNAs (miRNAs) exert critical functions in RB. This research aimed to investigate the miR-452-5p function in RB. MiR-452-5p expressions in RB were tested with quantitative real-time polymerase chain reaction (PCR). MiR-452-5p functions in RB were evaluated via Cell Counting Kit-8, 5-Ethynyl-2'-deoxyuridine assay, flow cytometry, Western blot, and Transwell. MiR-452-5p mechanism in RB was assessed using bioinformatics software Starbase and dual-luciferase reporter gene assay. Meanwhile, miR-452-5p function in RB in vivo was examined by constructing tumor xenografts in nude mice, immunohistochemistry, and Western blot assays. MiR-452-5p was overexpressed in RB tissues and cells, and miR-452-5p expression was positively correlated with RB clinicopathology including the Largest tumor base (mm) and Differentiation. Functionally, miR-452-5p knockdown restrained RB cell proliferation, invasion, epithelial-mesenchymal transition (EMT), and facilitated cell apoptosis. Mechanistically, suppressors of cytokine signaling (SOCS3) knockdown restored the inhibitory effects of miR-452-5p knockdown on RB cells. Meanwhile, in vivo studies further corroborated that miR-452-5p knockdown reduced RB tumor growth, EMT, and accelerated apoptosis in vivo. Also, miR-452-5p knockdown increased SOCS3 protein levels, and decreased phosphorylated Janus kinase 2/Janus kinase 2 (JAK2), phosphorylated signal transducer and activator of transcription 3/signal transducer and activator of transcription 3 (STAT3) in vivo. MiR-452-5p accelerated RB cell growth and invasion by SOCS3/JAK2/STAT3.


Application of isoabsorption plots generated by high-performance liquid chromatography with diode array detection to the development of multicomponent quantitative analysis of traditional herbal medicines.
Multicomponent quantitative analysis is one of the mainstream quality control methods of traditional herbal medicines. Since the constituents of traditional herbal medicines samples are complex, the development of high-performance liquid chromatography methods is laborious. In this study, an isoabsorption plot, a chromatographic/spectrometric data image plotted by diode array detection was utilized to facilitate the establishment of a high-performance liquid chromatography method by optimizing and validating the detection conditions off-line. Consequently a simple, reliable and accurate method for simultaneous determination of seven active polyphenolic components (protocatechuic acid, chlorogenic acid, caffeic acid, p-coumaric acid, rosmarinic acid, scutellarin, and apigenin) in Qingfei mixture, a long-used Chinese prescription, was developed. The chromatographic separation was performed on a C18 column with gradient elution of phosphoric acid aqueous solution (0.05%, v/v) and acetonitrile, and a wavelength switch program optimized with isoplot was adopted for detection. The method was validated in terms of linearity, sensitivity, precision, repeatability, and accuracy and was successfully applied to the simultaneous determination of the seven polyphenolic components in different production batches of Qingfei Mixture. These results indicated that isoplot is an effective tool to improve the establishment of multicomponent quantitative analysis methods.


Liming poultry manures to decrease soluble phosphorus and suppress the bacteria population.
Stabilizing phosphorus (P) in poultry waste to reduce P losses from manured soils is important to protect surface waters, while pathogens in manures are an emerging issue. This study was conducted to evaluate CaO and Ca(OH)2 for killing manure bacterial populations (pathogens) and stabilizing P in poultry wastes and to investigate the influence on soils following amendment with the treated wastes. Layer manure and broiler litter varying in moisture content were treated with CaO and Ca(OH)2 at rates of 2.5, 5, 10, and 15% by weight. All treated wastes were analyzed for microbial plate counts, pH, and water-soluble phosphorus (WSP), while a few selected layer manures were analyzed by phosphorus X-ray absorption near edge structure (XANES). A loamy sand and a silt loam were amended with broiler litter and layer manure treated with CaO at rates of 0, 2.5, 5, 10, and 15% and soil WSP and pH were measured at times 1, 8, and 29 d. Liming reduced bacterial populations, with greater rates of lime leading to greater reductions; for example 10% CaO applied to 20% solids broiler litter reduced the plate counts from 793,000 to 6500 mL-1. Liming also reduced the WSP in the manures by over 90% in all cases where at least 10% CaO was added. Liming the manures also reduced WSP in soils immediately following application and raised soil pH. The liming process used successfully reduced plate counts and concerns about P losses in runoff following land application of these limed products due to decreased WSP.


The influence of predation on the chronic response of Artemia sp. populations to a toxicant.
Environmental risk assessment of contaminants is conventionally based on toxic effects assessed in organism-level test systems. We suggest that, for the prediction of toxicant effects, population- and community-level effects should be considered. The aim of this study was to investigate how predation could alter a prey population's response to a toxicant to reveal effects at population and community levels.Populations of the brine shrimp Artemia sp. were maintained in the laboratory with and without simulated predation. Individuals were exposed for 1 h to the pyrethroid insecticide esfenvalerate (0, 0.01, 0.04 and 0.08 microg L(-1)) and subsequently observed for 6 weeks.Unpredated exposed populations showed a reduced population density compared with the control. However, even at the highest concentration of insecticide, populations were sustained until the end of the experiment. The lower density in the exposed populations led to reduced competition and subsequently to enhanced development of surviving individuals and an increased proportion of young individuals. In contrast, the combination of predation and short-term toxicant exposure at concentrations of 0.04 and 0.08 microg L(-1) produced extinction of the populations after 39 and 32 days of exposure, respectively.Synthesis and applications. The response of populations of brine shrimp to toxicants at the community level may be stronger when predation is present than the response of populations without predation pressure, as the regulation capacity of the population (measured as an increased production of offspring at reduced population densities) is exhausted when predation is present. Future ecotoxicological risk assessment schemes should consider relevant community characteristics such as predation as part of an environmental risk assessment.


Asymmetric functioning of dimeric metabotropic glutamate receptors disclosed by positive allosteric modulators.
The recent discovery of positive allosteric modulators (PAMs) for G-protein-coupled receptors open new possibilities to control a number of physiological and pathological processes. Understanding the mechanism of action of such compounds will provide new information on the activation process of these important receptors. Within the last 10 years, a number of studies indicate that G-protein-coupled receptors can form dimers, but the functional significance of this phenomenon remains elusive. Here we used the metabotropic glutamate receptors as a model, because these receptors, for which PAMs have been identified, are constitutive dimers. We used the quality control system of the GABA(B) receptor to generate metabotropic glutamate receptor dimers in which a single subunit binds a PAM. We show that one PAM/dimer is sufficient to enhance receptor activity. Such a potentiation can still be observed if the subunit unable to bind the PAM is also made unable to activate G-proteins. However, the PAM acts as a non-competitive antagonist when it binds in the subunit that cannot activate G-proteins. These data are consistent with a single heptahelical domain reaching the active state per dimer during receptor activation.


Stakeholder perspectives of piloting pre-hospital COVID-19 lateral flow testing and direct admissions pathway: exploring why well-received ideas have low uptake.
In January 2021, Yorkshire Ambulance Service and Hull University Teaching Hospitals implemented a pilot COVID-19 lateral flow testing (LFT) and direct admissions pathway to assess the feasibility of using pre-hospital LFTs to bypass the emergency department. Due to lower than anticipated uptake of the pilot among paramedics, we undertook a process evaluation to assess reasons for low uptake and perceived potential benefits and risks associated with the pilot. We undertook semi-structured telephone interviews with 12 paramedics and hospital staff. We aimed to interview paramedics who had taken part in the pilot, those who had received the project information but not taken part and ward staff receiving patients from the pilot. We transcribed interviews verbatim and analysed data using thematic analysis. Participation in the pilot appeared to be positively influenced by high personal capacity for undertaking research (being 'research-keen') and negatively influenced by 'COVID-19 exhaustion', electronic information overload and lack of time for training. Barriers to use of the pathway related to 'poor timing' of the pilot, restrictive patient eligibility and inclusion criteria. The rapid rollout meant that paramedics had limited knowledge or awareness of the pilot, and pilot participants reported poor understanding of the pilot criteria or the rationale for the criteria. Participants who were involved in the pilot were overwhelmingly positive about the intervention, which they perceived as having limited risks and high potential benefits to the health service, patients and themselves, and supported future roll-out. Ambulance clinician involvement in rapid research pilots may be improved by using multiple recruitment methods (electronic and other), providing protected time for training and increased direct support for paramedics with lower personal capacity for research. Improved communication (including face-to-face approaches) may help understanding of eligibility criteria and increase appropriate recruitment.


Volume image reconstruction for diffuse optical tomography.
Optical tomography is a potential diagnostic method for visualizing optical properties of tissues in vivo. We present an optical tomography method that has been designed for imaging of the human testes, particularly for spectroscopic tumor differentiation. In this application we need to compute three-dimensional distributions of the optical contrast (absorption coefficient) in the tissue in real time. Thus we have given special care to elaborate an efficient inverse algorithm that takes the limitations of spatial resolution and data space point density into account. Our inverse solution is based on a linearization approach and a dedicated object space discretization. Furthermore, we introduce the concept of fuzzy voxels, which enables a reconstruction-inherent image smoothing.


Recurrent Oropharyngeal Squamous Cell Carcinomas Maintain Anti-tumor Immunity and Multinucleation Levels Following Completion of Radiation.
Oropharyngeal squamous cell carcinoma (OPSCC) recurrence is almost universally fatal. Development of effective therapeutic options requires an improved understanding of recurrent OPSCC biology. We analyzed paired primary-recurrent OPSCC from Veterans treated at the Michael E. DeBakey Veterans Affairs Medical Center between 2000 and 2020 who received curative intent radiation-based treatment (with or without chemotherapy). Patient tumors were analyzed using standard immunohistochemistry and automated imaging of infiltrating lymphocytes and multinucleated tumor cells coupled to machine learning algorithms. Primary and recurrent tumors demonstrated high concordance via p16 and p53 immunohistochemistry, with comparable levels of multinucleation. In contrast, recurrent tumors demonstrated significantly higher levels of CD8+ tumor infiltrating lymphocytes (p<0.05) and higher levels of PD-L1 expression (p<0.05). Exposure to chemo-radiation and recurrence following treatment preserves critical features of intrinsic tumor biology and the tumor immune microenvironment suggesting that novel treatment regimens may be as effective in the salvage setting as in the definitive intent setting.


Upper limit of cancer extent on biopsy defining very low-risk prostate cancer.
To investigate how much Gleason pattern 3 cancer prostate biopsy specimens may contain without an increased risk of undetected more aggressive cancer, compared with the risk for cancers fulfilling the National Comprehensive Cancer Network (NCCN) criteria for very low-risk prostate cancer. We identified 1286 men aged <70 years in the National Prostate Cancer Register of Sweden who underwent primary radical prostatectomy (RP) for stage T1c or T2 prostate cancer with Gleason pattern ≤3 only, prostate-specific antigen (PSA) level of <10 ng/mL and a PSA density of <0.15 ng/mL/mL. The association between the extent of cancer in the biopsies (the number and proportion of positive cores and the total cancer length in the cores in millimetres) and the likelihood of Gleason pattern 4-5 in the RP specimen was analysed with logistic regression. In all, 438 (34%) of the 1286 men had Gleason pattern 4-5 in the RP specimen. Increasing number and proportion of positive biopsy cores, as well as increasing biopsy cancer length were both significantly associated with increased risk of upgrading at RP in univariable analysis, but in multivariable analysis only biopsy cancer length remained significant. The 684 men with stage T1c and <8 mm cancer had similar risk of upgrading regardless of whether the number of positive biopsy cores was 1-2 or 3-4 (28% vs 27% risk); upgrading was more common among the remaining men (40%, P < 0.01). Men aged <70 years with stage T1c prostate cancer and 3-4 biopsy cores with Gleason pattern 3 are not more likely to have undetected Gleason pattern 4-5 cancer than men with 1-2 cores with cancer, provided that the total biopsy cancer length is <8 mm. We propose that the definition of very low-risk prostate cancer is widened accordingly.


Epstein-Barr Virus-Associated Vesiculopapular Eruption on the Face of a Patient with Natural Killer T Cell Lymphoma.
Unlike typical hydroa vacciniforme (HV), Epstein-Barr virus (EBV)-associated HV-like eruption is more variable in its clinical manifestations. In some patients, progression to lymphoma or leukemia has been reported, which are characterized by the T-cell immunophenotype. Here, we report the first Korean case of EBV-associated vesiculopapular eruption on the face of a patient with natural killer (NK)/T cell lymphoma. A 32-year-old Korean man presented with a late adolescent-onset recurrent necrotic papulovesicles on his face. The patient was previously diagnosed with EBV-associated NK/T cell lymphoma of the oral cavity and also had childhood-onset hypersensitivity to mosquito bites. Biopsy of his facial skin showed EBV-associated vesiculopapular eruptions, though ultraviolet provocation did not reproduce the skin lesions. EBV viral load in his peripheral blood was detected but low. The patient was treated with systemic chemotherapy. The lymphoma went into remission, but the facial EBV-associated vesiculopapular eruption had a relapsing and remitting course.


Optical coherence tomography-measured pigment epithelial detachment height as a predictor for retinal pigment epithelial tears associated with intravitreal bevacizumab injections.
The purpose was to study preinjection optical coherence tomography-related factors in age-related macular degeneration eyes with retinal pigment epithelial detachment (PED) that may predispose retinal pigment epithelial (RPE) tears associated with intravitreal bevacizumab injections. This multicenter retrospective case series involving 9 retina specialists and 7 centers investigated Stratus optical coherence tomography (Carl Zeiss Meditec, Dublin, CA) parameters in eyes with vascularized PED (vPED) from February 2006 to February 2007. Of the 1,280 eyes in 1,255 patients receiving 2,890 intravitreal injections, there were 125 eyes with vPED. For every vPED eye that developed an RPE tear (Group 1), 3 or more vPED eyes without RPE tears (Group 2) were randomly selected in each study center during the same time period for comparison. The primary outcome measure was PED height (microm), and the secondary measures included volume index (vPED height x surface area), total macular volume, subretinal fluid, cystoid macular edema, center-point thickness, central 1 mm, and pre- and postinjection best-corrected Snellen visual acuities. Twenty-one vPED eyes in 21 patients among 125 vPED eyes (16.8% of all vPED eyes) developed RPE tears. The 21 Group 1 eyes were compared with the 78 randomly selected Group 2 eyes. The vPED height was significantly higher for Group 1 eyes in comparison to Group 2 eyes (mean: 648.9 +/- 245.0 vs. 338.1 +/- 201.6 microm, P < 0.001). The same was true for the following: volume index (P = 0.001), subretinal fluid (P = 0.002), and total macular volume (P = 0.04). The mean preinjection and post-RPE tear best-corrected visual acuity were 0.92 logMAR (20/166) and 0.84 logMAR (20/137), respectively (P = 0.25). Multivariate analysis showed PED height to be the only significant risk factor associated with RPE tears in Group 1 eyes [odds ratio = 0.995 (95% confidence interval: 0.992-0.997), P < 0.001]. Elevated preinjection vPED height is the single most significant predictor for RPE tears after bevacizumab injections for vPED eyes. A vPED height >400 microm is associated with a significant risk for such a complication.


Synchronous neurite branchings in single goldfish retinal ganglion cells.
We have examined the time course of branch formation in neurites of retinal ganglion cells isolated from adult goldfish (Carassius auratus). These neurites elongate at approximately 13 microns/h, and usually branch by bifurcation of growth cones at their tips. The times elapsed between branchings in different neurites of single cells can be described by a Poisson distribution with a mean interval of approximately 2 h. As predicted by this distribution, a relatively large number of branchings occur simultaneously in different neurites of individual cells. Simultaneous branchings of neurites elongating at a common rate generate branch points that lay equidistant from their soma. Since similar branching patterns can be seen in dendrites of retinal ganglion and amacrine cells in situ, these results are consistent with the possibility that dendrites of individual neurons branch synchronously and grow at common rates during development.


The Heterogeneity of Illness Behaviors in Patients with Medically Unexplained Physical Symptoms.
To investigate the heterogeneity of illness behavior in patients with medically unexplained physical symptoms (MUPS), we clustered patients in regard to their degree of engaging in different aspects of illness behavior and identified related variables with these behaviors. A sample of N = 224 patients attending treatment in primary care with a history of MUPS (at least two symptoms) was investigated by analyzing different aspects of illness behavior with the self-reported number of doctor visits during the last 6 months and the Scale for the Assessment of Illness Behavior (SAIB; e.g., expression of symptoms). Two distinct clusters were identified by cluster analysis: a low (n = 106) and a high (n = 118) illness behavior clusters. The high illness behavior cluster exhibited a significantly higher rate of health anxiety than the low illness behavior cluster. Regression analysis revealed a particular effect of sex in the high illness behavior cluster: whereas being male was associated with increased illness behavior as measured by the SAIB, being female was linked to a higher number of doctor visits. Increased health anxiety was associated with the SAIB illness behavior in both clusters. Depression and anxiety did not show incremental associations with all aspects of illness behavior. Knowledge of the pattern of illness behavior in patients with MUPS enables us to improve psychological treatments that directly address specific aspects of illness behavior or health anxiety. Differences between sexes in illness behaviors require more differentiated consideration in future research.


Phenyl-hydrazinium (6-carb-oxy-pyridine-2-carboxyl-ato)(pyridine-2,6-dicarboxyl-ato)cobaltate(II)-pyridine-2,6-dicarb-oxy-lic acid-water (1/1/3).
The asymmetric unit of the title compound, (C(6)H(9)N(2))[Co(C(7)H(3)NO(4))(C(7)H(4)NO(4))]·C(7)H(5)NO(4)·3H(2)O, contains one (6-carb-oxy-pyridine-2-carboxyl-ato)(pyridine-2,6-dicarboxyl-ato)cobaltate(II) anion, one phenyl-hydrazinium cation, one pyridine-2,6-dicarb-oxy-lic acid mol-ecule and three uncoordin-ated water mol-ecules, part of which are disordered. The Co(II) ion is coordinated by a pyridine-2,6-dicarboxyl-ate ion and a 6-carb-oxy-pyridine-2-carboxyl-ate ligand almost perpendicular to each other [the angle between the least-squares planes is 87.38 (4)°] and is surrounded by two O atoms and two N atoms in the equatorial plane and two O atoms in axial positions, resulting in a distorted octa-hedral coordination geometry. There is an extensive three-dimensional network of O-H⋯O and N-H⋯O hydrogen bonds, which link the components.


Different Molecular Interaction between Collagen and α- or β-Chitin in Mechanically Improved Electrospun Composite.
Although collagens from vertebrates are mainly used in regenerative medicine, the most elusive issue in the collagen-based biomedical scaffolds is its insufficient mechanical strength. To solve this problem, electrospun collagen composites with chitins were prepared and molecular interactions which are the cause of the mechanical improvement in the composites were investigated by two-dimensional correlation spectroscopy (2DCOS). The electrospun collagen is composed of two kinds of polymorphs, α- and β-chitin, showing different mechanical enhancement and molecular interactions due to different inherent configurations in the crystal structure, resulting in solvent and polymer susceptibility. The collagen/α-chitin has two distinctive phases in the composite, but β-chitin composite has a relatively homogeneous phase. The β-chitin composite showed better tensile strength with ~41% and ~14% higher strength compared to collagen and α-chitin composites, respectively, due to a favorable secondary interaction, i.e., inter- rather than intra-molecular hydrogen bonds. The revealed molecular interaction indicates that β-chitin prefers to form inter-molecular hydrogen bonds with collagen by rearranging their uncrumpled crystalline regions, unlike α-chitin.


Learning from women veterans who navigate invisible injuries, caregiving, and reintegration challenges.
As women comprise a greater proportion of military service members, there is growing recognition of how their experiences in the early phase of military to civilian transitions have an important influence on their health and reintegration outcomes. Qualitative accounts of women veterans can inform programs that support transitioning service members. We examined narratives of civilian reintegration among women veterans to understand their experiences of adjusting to community life while coping with mental health challenges. We interviewed 16 post-911 era women who were within 5 years of separating from military service and developed a case study based on three participants. Interviews were audio-recorded and transcribed verbatim. Inductive thematic analysis was conducted to establish categories about reintegration. Immersion/crystallization techniques were used to identify exemplary cases that illustrated salient themes. Women veterans identified establishing a future career direction, drawing on social support, and navigating health care services as major factors influencing how they adjusted to civilian life. In addition, participants also highlighted the navigation of complex and intersecting identities (i.e., wife, mother, employee, friend, veteran, patient, etc.), further magnified by gender inequalities. These women performed emotional labor, which is often rendered invisible and oriented toward their family and loved ones, while simultaneously monitoring self-care activities. During the early period of reintegration, they described how they felt marginalized in terms of accessing healthcare compared to their military spouses and male veteran peers. Our case study suggests that there are key gaps in addressing healthcare and readjustment needs for women servicemembers, a high priority VA group, as they transition into post-military life. It is important to consider innovative ways to address specific needs of women in veteran-focused policies and programs.


Characterizing the microbiome of patients with myeloproliferative neoplasms during a Mediterranean diet intervention.
Myeloproliferative neoplasms (MPNs) are a class of rare hematological malignancies that result in the overproduction of myeloid lineage cells. These malignancies result in increased cytokine production and inflammation, which correlate with worsened symptom burden and prognosis. Other than bone marrow transplantation, there is no cure for myeloproliferative neoplasms. As such, treatments focus on reducing thrombotic risk, inflammation, and symptom burden. Because current pharmacological treatments carry significant side effects, there is a need to explore low-risk therapies that may modulate inflammation and alleviate symptom burden. One potential way to achieve this is adherence to a Mediterranean (MED) diet, which is rich in anti-inflammatory foods, reduces inflammatory biomarkers, and beneficially alters the gut microbiome. We performed a 15-week clinical trial of 28 individuals with MPN who were randomized to dietary counseling based on either a Mediterranean diet or standard U.S. Guidelines for Americans. Our primary objective was to determine whether MPN patients could adopt a Mediterranean eating pattern when supported with dietician counseling. As exploratory endpoints, we investigated the impact of diet and inflammation on the gut microbiome. Using shotgun metagenomic sequencing, we found that microbiome diversity and composition were stable throughout the study duration in both cohorts. Furthermore, we discovered significant differences in the microbiomes between MPN subtypes, such as increased beta-dispersion in subjects with myelofibrosis. Lastly, we found several significant correlations between the abundance of multiple bacterial taxa and cytokine levels. Together, this study provides insight into the interaction between diet, inflammation, and the gut microbiome. IMPORTANCE The gut microbiome serves as an interface between the host and the diet. Diet and the gut microbiome both play important roles in managing inflammation, which is a key aspect of myeloproliferative neoplasm (MPN). Studies have shown that a Mediterranean (MED) diet can reduce inflammation. Therefore, we longitudinally characterized the gut microbiomes of MPN patients in response to Mediterranean or standard 2020 US Guidelines for Americans dietary counseling to determine whether there were microbiome-associated changes in inflammation. We did not find significant changes in the gut microbiome associated with diet, but we did find several associations with inflammation. This research paves the way for future studies by identifying potential mechanistic targets implicated in inflammation within the MPN gut microbiome.


Spatial and topographic trends in forest expansion and biomass change, from regional to local scales.
Natural forest growth and expansion are important carbon sequestration processes globally. Climate change is likely to increase forest growth in some regions via CO2 fertilization, increased temperatures, and altered precipitation; however, altered disturbance regimes and climate stress (e.g. drought) will act to reduce carbon stocks in forests as well. Observations of asynchrony in forest change is useful in determining current trends in forest carbon stocks, both in terms of forest density (e.g. Mg ha(-1) ) and spatially (extent and location). Monitoring change in natural (unmanaged) areas is particularly useful, as while afforestation and recovery from historic land use are currently large carbon sinks, the long-term viability of those sinks depends on climate change and disturbance dynamics at their particular location. We utilize a large, unmanaged biome (>135 000 km(2) ) which spans a broad latitudinal gradient to explore how variation in location affects forest density and spatial patterning: the forests of the North American temperate rainforests in Alaska, which store >2.8 Pg C in biomass and soil, equivalent to >8% of the C in contiguous US forests. We demonstrate that the regional biome is shifting; gains exceed losses and are located in different spatio-topographic contexts. Forest gains are concentrated on northerly aspects, lower elevations, and higher latitudes, especially in sheltered areas, whereas loss is skewed toward southerly aspects and lower latitudes. Repeat plot-scale biomass data (n = 759) indicate that within-forest biomass gains outpace losses (live trees >12.7 cm diameter, 986 Gg yr(-1) ) on gentler slopes and in higher latitudes. This work demonstrates that while temperate rainforest dynamics occur at fine spatial scales (<1000 m(2) ), the net result of thousands of individual events is regionally patterned change. Correlations between the disturbance/establishment imbalance and biomass accumulation suggest the potential for relatively rapid biome shifts and biomass changes.


Male Age Affects Female Mate Preference, Quantity of Accessory Gland Proteins, and Sperm Traits and Female Fitness in D. melanogaster.
For species in which mating is resource-independent and offspring do not receive parental care, theoretical models of age-based female mate preference predict that females should prefer to mate with older males as they have demonstrated ability to survive. Thus, females should obtain a fitness benefit from mating with older males. However, male aging is often associated with reductions in quantity of sperm. The adaptive significance of age-based mate choice is therefore unclear. Various hypotheses have made conflicting predictions concerning this issue, because published studies have not investigated the effect of age on accessory gland proteins and sperm traits. D. melanogaster exhibits resource-independent mating, and offspring do not receive parental care, making this an appropriate model for studying age-based mate choice. In the present study, we found that D. melanogaster females of all ages preferred to mate with the younger of two competing males. Young males performed significantly greater courtship attempts and females showed least rejection for the same than middle-aged and old males. Young males had small accessory glands that contained very few main cells that were larger than average. Nevertheless, compared with middle-aged or old males, the young males transferred greater quantities of accessory gland proteins and sperm to mated females. As a result, females that mated with young male produced more eggs and progeny than those that mated with older males. Furthermore, mating with young male reduced female's lifespan. These studies indicate that quantity of accessory gland proteins and sperm traits decreased with male age and females obtain direct fitness benefit from mating with preferred young males.


Radial Head Subluxation: Possible Effective Factors on Time to Re-use the Affected Limb.
Radial head subluxation (RHS) is a common disorder in children. Although it is not accompanied by any important short- or long-term sequel, it could make the parents worried about. The purpose of this study was to determine the possible effective factors that may influence time to use the affected limb. This cross-sectional study was conducted prospectively during the years 2014 to 2016. All children under the age of 6 years who visited the emergency department (ED) and were diagnosed as having RHS were eligible. The patients' baseline information was recorded. After the reduction, the time until the affected arm use returned was recorded. The possible relationship between the baseline data and time to re-use the affected limb was assessed. During the study period, 112 children with a mean age of 30.18 ± 18.18 months were evaluated (53% male). Among the children who visited the ED during the first 4 hours and thereafter, 84% and 60%, respectively, re-used their limb in less than 10 minutes after reduction (p = 0.004). Also, 55% of children less than or equal to 24 months and 89% over the age of 24 months re-used the arm in 10 minutes (p < 0.001). The success rate of the first reduction maneuver was significantly lower in children with a recurrent dislocation (p = 0.001). It is likely that age less than or equal to 24 months and ED visit after 4 hours of the event lead to a longer duration for re-using the affected arm following reduction.


Lipopolysaccharide inhibits the binding of colony-stimulating factor (CSF-1) to murine peritoneal exudate macrophages.
These studies demonstrate the potent effect of bacterial endotoxin (LPS) on the inhibition of iodinated colony-stimulating factor- (125I-CSF-1) binding by murine peritoneal exudate macrophages (PEM) from C3H/An and C57BL/6 mice. As small an amount as 0.1 ng/ml LPS is sufficient to cause a significant inhibitory effect; this effect is temperature-, time- and concentration-dependent. LPS, however, causes minimal or no inhibition of 125I-CSF-1-binding by PEM from LPS-resistant C3H/HeJ mice. Inhibition of 125I-CSF-1-binding does not appear to be a result of a direct occupancy by LPS of CSF-1 receptors present on the cell membrane and is most likely due to a progressive loss of available CSF-1-binding sites. The effect can be neutralized by the addition of the antibiotic polymyxin B, which binds to the lipid A portion of LPS. The action of LPS on PEM is transient; treated cells recover their 125I-CSF-1-binding activity whether or not LPS is later removed. The restoration of 125I-CSF-1-binding activity can be blocked completely by the addition of cyclohexamide. These findings suggest the rapid, LPS-induced disappearance of CSF-1 receptors from the cell surface may be related to the activation of macrophages by LPS.


The association of socioeconomic status and symptom severity in persons with fibromyalgia.
Although persons with lower socioeconomic status (SES) generally have poorer health status for many medical conditions, the association of SES with symptom severity in fibromyalgia (FM) is unknown. The subjective symptoms of FM may be influenced by personal perceptions, and environmental and psychosocial factors. Therefore SES may influence symptom expression and severity. Data for this cross-sectional analysis were obtained from a real-life prospective cohort of 246 patients with FM categorized according to level of education: high school graduates or less (Group 1; n = 99), college graduates (Group 2; n = 84), and university graduates (Group 3; n = 63). The association between level of education, a well-validated measure of SES, and disease severity, functional status, and quality of life were examined. Lower education was significantly associated with older age (p = 0.039), current unemployment (p < 0.001), and more severe disease, as measured by patient global assessment disease activity (p = 0.019), McGill Pain Questionnaire (p = 0.026), Pain Disability Index (p = 0.031), Pain Catastrophizing Scale (p = 0.015), Health Assessment Questionnaire (p = 0.001), and Fibromyalgia Impact Questionnaire (p = 0.002), but not pain level, anxiety, or depression. These associations remained significant even upon adjusting for age and sex differences. Patients with FM and lower SES, as assessed by education level, reported greater symptom severity and functional impairment, despite reporting similar levels of pain, depression, and anxiety. Although FM spans all socioeconomic groups, factors other than specific disease characteristics or mental status, appear to play an important role in patients' perception of illness.


Differences in the expression of GABA(A) receptors between functionally innervated and non-innervated granule neurons in neonatal rat cerebellar cultures.
We had earlier found that granule neurons in cultures of small explants of neonatal rat cerebellar cortex could be placed in two groups: cells in one group showed spontaneous synaptic activity and also had a large response to applications of 1 microM gamma-aminobutyric acid (GABA) while cells in the other lacked spontaneous activity and also showed much lower sensitivity to GABA [25]. For convenience, the more responsive cells will be termed A-type neurons, while the less responsive cells will be termed B-type. We have undertaken a comparison of the responses mediated by activation of GABA A receptors for the two types of neurons. A-type neurons have a larger maximal response to GABA (about 10 times that for B-type neurons), suggesting that they express more functional GABA(A) receptors. The concentration of GABA producing half-maximal activation of A-type neurons is somewhat less (12 mu M) than that for B-type neurons (41 microM), while the Hill coefficients are similar. Responses of both types of cell desensitize to prolonged applications of GABA. At a given concentration of GABA the responses of A-type neurons desensitize more rapidly than the responses of B-type neurons, indicating that the physiological properties of the receptors differ. Responses of A-type neurons are also potentiated to a significantly lesser extent by either chlordiazepoxide or alphaxalone than are the responses of B-type neurons, indicating that the pharmacological properties of the receptors differ. These data indicate that A-type and B-type granule neurons in our cultures express GABA(A) receptors which differ in number, physiological properties and pharmacological responsiveness. We have also confirmed the observation that almost all A-type neurons also show spontaneous synaptic currents, while almost no B-type neurons do.


[Role of SPP1 in acute kidney injury induced by renal ischemia-reperfusion in rats].
To investigate the role of SPP1 gene in acute kidney injury induced by renal ischemia-reperfusion injury (IRI). Twelve Sprague-Dawley rats were randomly divided into sham group and IRI group (n=6) and subjected to sham operation and renal ischemia for 30 min induced by penal pedicle clamping using non-traumatic microvascular clamps, respectively.Serum creatinine and blood urea nitrogen levels were detected, and PAS staining was used for pathological examination of the kidneys in the two groups.The renal expressions of SPP1, α-SMA and caspase-3 were detected using immunohistochemistry and immunofluorescent staining.In cultured renal tubular epithelial cells (HK-2 cells), Western blotting was performed to detect the changes in expressions of SPP1, caspase-3, and Kim-1 proteins following hypoxiareoxygenation (H/R) and transfection with si-NC or si-SPP1;flow cytometry was employed to analyze apoptosis of the treated cells. Renal IRI caused significant elevations of serum creatinine and blood urea nitrogen levels (P<0.05) and induced severe shedding and necrosis of the renal tubular epithelial cells in the rats, resulting also in significantly up-regulated renal expressions of SPP1, α-SMA and caspase-3(P<0.05).In HK-2 cells, H/R significantly increased the protein expression levels of SPP1, caspase-3, and Kim-1(P<0.05), and compared si-NC transfection, transfection with SPP1 obviously reduced caspase-3 and Kim-1 expressions and lowered apoptosis rate of the cells with H/R exposure (P<0.05). SPP1 is up-regulated in the kidneys of rats with renal IRI, and down-regulation of SPP1 expression can inhibit H/R-induced apoptosis of renal tubular epithelial cells.


Specification of the peroxisome targeting signals type 1 and type 2 of plant peroxisomes by bioinformatics analyses.
To specify the C-terminal peroxisome targeting signal type 1 (PTS1) and the N-terminal PTS2 for higher plants, a maximum number of plant cDNAs and expressed sequence tags that are homologous to PTS1- and PTS2-targeted plant proteins was retrieved from the public databases and the primary structure of their targeting domains was analyzed for conserved properties. According to their high overall frequency in the homologs and their widespread occurence in different orthologous groups, nine major PTS1 tripeptides ([SA][RK][LM]> without AKM> plus SRI> and PRL>) and two major PTS2 nonapeptides (R[LI]x5HL) were defined that are considered good indicators for peroxisomal localization if present in unknown proteins. A lower but significant number of homologs contained 1 of 11 minor PTS1 tripeptides or of 9 minor PTS2 nonapeptides, many of which have not been identified before in plant peroxisomal proteins. The region adjacent to the PTS peptides was characterized by specific conserved properties as well, such as a pronounced incidence of basic and Pro residues and a high positive net charge, which probably play an auxiliary role in peroxisomal targeting. By contrast, several peptides with assumed peroxisomal targeting properties were not found in any of the 550 homologs and hence play--if at all--only a minor role in peroxisomal targeting. Based on the definition of these major and minor PTS and on the recognition of additional conserved properties, the accuracy of predicting peroxisomal proteins can be raised and plant genomes can be screened for novel proteins of peroxisomes more successfully.


Elucidating the Inhibitory Potential of Designed Peptides Against Amyloid Fibrillation and Amyloid Associated Cytotoxicity.
Inhibition of fibrillation process and disaggregation of mature fibrils using small peptide are the promising remedial strategies to combat neurodegenerative diseases. However, designing peptide-based drugs to target β-sheet-rich amyloid has been a major challenge. The current work describes, for the first time, the amyloid inhibitory potential of the two short peptides (selected on the basis of predisposition of their amino acid residues toward β-sheet formation) using combination of biophysical, imaging methods, and docking approaches. Results showed that peptides employed different mechanisms to inhibit the amyloid fibrillation. Furthermore, they were also effective in blocking the amyloid fibrillation pathway. In contrary to the insulin fibrillar mesh, significantly less fibrillar species appeared in the presence of peptides, as confirmed by transmission electron microscopy. Circular dichroism analysis indicated that although peptides did not stabilize the native state of insulin, they inhibited amyloid aggregation by reducing the formation of β-sheet rich structures. Hemolytic assay revealed the non-hemolytic nature of the species formed when insulin was co-incubated with the peptides. Therefore, despite the inherent potential to form β-sheet structure, these peptides inhibited the amyloid formation and potentially can be used as therapeutics for the treatment of amyloid-related diseases.


Synthesis of phosphaisocoumarin amidates via DIBAL-H-mediated selective amidation of phosphaisocoumarin esters.
A series of phosphaisocoumarin amidates were synthesized for the first time via DIBAL-H-mediated direct amidation of phosphaisocoumarin esters under mild conditions in good to excellent yields. The present reaction showed high selectivity. In each case, the phostone ring was intact and only the exocyclic ethoxy group was amidated. A plausible mechanism of the reaction was provided.


Fusion of the lumbar spine with a free vascularized fibular bone graft: case report.
Spinal fusion with either non-vascularized or vascularized bone grafts has been well documented for inflammatory, degenerative, post-oncological and post-traumatic reconstruction Vascularized bone graft has been proven to have more rapid healing and better clinical results. A few reports have indicated that free vascularized fibular bone grafts have been used for reconstruction of the cervical and thoracic spine with good clinical results. We report a case of a third lumbar vertebra burst fracture successfully treated with a free vascularized fibula graft after failure of an initial conventional bone graft. The neurological symptoms improved significantly. The strong and straight bone quality makes the vascularized fibula an ideal choice for reconstruction of the spine. Vascularized fibula bone graft is an option in cases with failed nonvascularized bone grafts, in cases where an iliac bone is not suitable for reconstruction, or in cases where a poor recipient bed makes having well-vascularized bone necessary. This report describes our surgical approach and demonstrates the versatility of the free fibular osteoseptocutaneous flap for reconstruction of any portion of the spine.