Antimonato polyoxovanadate based three-dimensional framework exhibiting ferromagnetic exchange interactions: synthesis, structural characterization, and magnetic investigation of {[Fe(C6H14N2)2]3[V15Sb6O42(H2O)]}·8H2O.
The new polyoxovanadate {[Fe(C6H14N2)2]3[V15Sb6O42(H2O)]}·8H2O (1) was obtained under solvothermal conditions using the amine that acts at the same time as the ligand, solvent, and reducing agent. The central structural motif of 1, [V15Sb6O42(H2O)](6-), is related to the {V18O42}-archetype cluster by replacing three VO5 square pyramids with three O2Sb-O-SbO2 moieties. Every [V15Sb6O42(H2O)](6-) cluster anion is expanded by six FeN4O2 octahedra, thus generating a rare three-dimensional network with differently sized pores hosting the crystal water molecules. In 1, two [V15Sb6O42(H2O)](6-) cluster anions with different orientations coexist. According to bond-valence-sum calculations, the anionic cluster can be formulated as [V(IV)15Sb(III)6O42(H2O)](6-), i.e., in line with the valence states of all other known {V15Sb6} clusters. The optical band gap of 1 was determined as 2.47 eV. Investigation of the magnetic behavior indicates dominating ferromagnetic exchange interactions between the V(4+) centers of the cluster and the Fe(2+) d(6) cations.


Genes and Athletic Performance: An Update.
Humans vary in their ability to achieve success in sports, and this variability mostly depends on genetic factors. The main goal of this work was to review the current progress in the understanding of genetic determinism of athlete status and to describe some novel and important DNA polymorphisms that may underlie differences in the potential to be an elite athlete. In the past 19 years, at least 155 genetic markers (located within almost all chromosomes and mtDNA) were found to be linked to elite athlete status (93 endurance-related genetic markers and 62 power/strength-related genetic markers). Importantly, 41 markers were identified within the last 2 years by performing genome-wide association studies (GWASs) of African-American, Jamaican, Japanese, and Russian athletes, indicating that GWASs represent a promising and productive way to study sports-related phenotypes. Of note, 31 genetic markers have shown positive associations with athlete status in at least 2 studies and 12 of them in 3 or more studies. Conversely, the significance of 29 markers was not replicated in at least 1 study, raising the possibility that several findings might be false-positive. Future research, including multicentre GWASs and whole-genome sequencing in large cohorts of athletes with further validation and replication, will substantially contribute to the discovery of large numbers of the causal genetic variants (mutations and DNA polymorphisms) that would partly explain the heritability of athlete status and related phenotypes.


The bispectral index and explicit recall during the intraoperative wake-up test for scoliosis surgery.
In this prospective study, we evaluated the bispectral index (BIS) and postoperative recall during the intraoperative wake-up examination in 34 children and adolescents undergoing scoliosis surgery. Each anesthesiologist was blinded to BIS values throughout surgery and the wake-up test. The BIS, mean arterial blood pressure, and heart rate were compared at: before starting the wake-up test, patient movement to command, and after the patient was reanesthetized. The anesthetic technique for Group 1 was small-dose isoflurane, nitrous oxide, fentanyl, and midazolam and for Group 2 was nitrous oxide, fentanyl, and midazolam. Controlled hypotension was used for all cases. At patient movement to command, the patients were told a specific color to remember (teal) and on the second postoperative day were interviewed for explicit recall of the color and other intraoperative events. A total of 37 wake-up tests were performed in 34 patients. There was a significant increase in both groups of BIS (P < 0.001), mean arterial blood pressure (P < 0.001), and heart rate (P < 0.01) at the time of purposeful patient movement followed by a significant decline in BIS after reintroduction of anesthesia (P < 0.01). No patient recalled intraoperative pain, one patient recalled the wake-up test but not the color, and five patients recalled the specified color. We conclude that BIS may be a useful clinical monitor for predicting patient movement to command during the intraoperative wake-up test, particularly when controlled hypotension is used and hemodynamic responses to emergence of anesthesia are blunted. The relationship between bispectral index (BIS) and purposeful intraoperative patient movement is consistent with previous BIS utility studies. We conclude that BIS may be a useful clinical monitor for predicting patient movement to command during the intraoperative wake-up test, particularly when controlled hypotension is used and hemodynamic responses to emergence of anesthesia are blunted.


Pharmacological treatment of knee osteoarthritis: Special considerations of the new German guideline.
The pharmacological treatment of knee osteoarthritis (OA) is a purely symptomatic therapy, which often ensures that the mobility of the patient is successfully retained. This article refers to the recommendations and opinions regarding the pharmacotherapy of knee OA contained in the new guideline of the Association of the Scientific Medical Societies in Germany (AWMF), highlighting several important aspects and describing the considerations underlying the decision-making process. With this article it is hoped that therapeutic effectiveness can be realistically estimated, that any risks of medication errors and avoidable side effects can be reduced, and that further helpful measures can be taken into consideration.


Depression and Insomnia in Patients With Psoriasis and Psoriatic Arthritis Taking Tumor Necrosis Factor Antagonists.
Psoriasis patients with moderate to severe disease often present with depression and insomnia. Treatment targeting both psoriasis and psychological comorbidities is needed to improve the quality of life of these patients.In this nationwide cohort study, a total of 980 patients with psoriatic arthritis or psoriasis who had received nonbiological disease-modifying antirheumatic drugs and biologics therapy between 2009 and 2012 were identified. The prevalence rates of patients taking medications for depression and insomnia were compared before and after biologics therapy. Logistic regression method was used to investigate the risk factors for depression and insomnia. Further stratified analyses were performed to examine the prevalence of use of medications for depression and insomnia among different patient subgroups.The prevalence of patients taking regular antidepressants before starting biologics therapy was about 20%. There was a more than 40% reduction in this prevalence after biologics therapy for 2 years. Age higher than 45 years, female sex, presence of comorbidities, and psoriatic arthritis were independently associated with depression and insomnia. Further stratified analyses revealed a more rapid and significant reduction in depression/insomnia in those undergoing continuous biologics therapy, younger than 45 years, without psoriatic arthritis and not taking concomitant methotrexate, when compared with their counterparts.The results suggest that biologics therapy may be associated with reduced rates of depression and insomnia, and a reduced rate of regular antidepressants use in psoriasis patients.


Early selection versus late correction: Age-related differences in controlling working memory contents.
We examined whether a reduced ability to ignore irrelevant information is responsible for the age-related decline of working memory (WM) functions. By means of event-related brain potentials, we will show that filtering is not out of service in older adults but shifted to a later processing stage. Participants performed a visual short-term memory task (change-detection task) in which targets were presented along with distractors. To allow early selection, a cue was presented in advance of each display, indicating where the targets were to appear. Despite this relatively easy selection criterion, older adults' filtering was delayed as indicated by the amplitude pattern of the contralateral delay activity. Importantly, WM-equated younger adults did not show a delay indicating that the delay is specific to older adults and not a general phenomenon that comes with low WM capacity. Moreover, the analysis of early visual potentials revealed qualitatively different perceptual/attentional processing between the age groups. Young adults exhibited stronger distractor sensitivity that in turn facilitated filtering. Older adults, in contrast, seemed to initially store distractors and to suppress them after the fact. These early selection versus late-correction modes suggest an age-related shift in the strategy to control the contents of WM. (PsycINFO Database Record


[Bacteriolytic enzymes produced by actinomycetes. I. The physicochemical properties of the enzymes and the spectrum of their lytic action].
This review is devoted to the bacteriolytic enzymes produced by many actinomycetes, mainly by Streptomyces genus. The bacteriolytic enzymes hydrolyse the specific bonds in bacterial peptidoglycans and cause the solubilization of the cellular walls and the disintegration of the bacterial cells. Many of the enzymes are purified to the electrophoretic homogeneity. The actinomycetes form the endo-N-acetylmuramidases more often, then the endopeptidases follow according to the frequency of occurrence, while the amidases and endo-N-acetylglucosaminidases are met rather seldom among the streptomycete-producers. The known amidases and exo-enzymes which are also produced by some species of actinomycetes are not related to the lytic enzymes proper. Almost all known endopeptidases from streptomyces hydrolyse the bridge peptide bonds in which the carboxyl group of terminal D-alanyl of peptide chain is involved. The bacteriolytic spectra of the different muramidases differ from each other and essentially differ from the spectrum of the egg-white lysozyme. Some endomuramidases from streptomyces are able to hydrolyse streptococci and some other important from the practical point of view microorganisms resistant to the action of lysozyme.


Developing a benchmark for emotional analysis of music.
Music emotion recognition (MER) field rapidly expanded in the last decade. Many new methods and new audio features are developed to improve the performance of MER algorithms. However, it is very difficult to compare the performance of the new methods because of the data representation diversity and scarcity of publicly available data. In this paper, we address these problems by creating a data set and a benchmark for MER. The data set that we release, a MediaEval Database for Emotional Analysis in Music (DEAM), is the largest available data set of dynamic annotations (valence and arousal annotations for 1,802 songs and song excerpts licensed under Creative Commons with 2Hz time resolution). Using DEAM, we organized the 'Emotion in Music' task at MediaEval Multimedia Evaluation Campaign from 2013 to 2015. The benchmark attracted, in total, 21 active teams to participate in the challenge. We analyze the results of the benchmark: the winning algorithms and feature-sets. We also describe the design of the benchmark, the evaluation procedures and the data cleaning and transformations that we suggest. The results from the benchmark suggest that the recurrent neural network based approaches combined with large feature-sets work best for dynamic MER.


High-dose methadone produces superior opioid blockade and comparable withdrawal suppression to lower doses in opioid-dependent humans.
The efficacy of methadone for treating heroin dependence derives, in part, from suppression of opiate withdrawal and attenuation of the effects of heroin. The purpose of this double-blind, within-subject, inpatient study was to determine whether larger doses of methadone, which are more effective in the treatment of opioid dependence, produce greater or longer-lasting blockade of the effects of heroin in addition to adequate withdrawal suppression. Participants were maintained on 30, 60, and 120 mg methadone (ascending order) for approximately 3 weeks at each dose. During each maintenance period, heroin challenges were administered at 4, 28, and 52 h after the last methadone dose. Opioid agonist effects and opioid withdrawal symptoms were assessed prior to heroin challenge. Challenge sessions consisted of three doses of heroin (0, 10, and 20 mg/70 kg; ascending order) 45 min apart. All three methadone maintenance doses produced similar agonist effects. Participants tested 4 h after receiving 120 mg methadone showed complete suppression of withdrawal symptoms and full attenuation of the effects of heroin. Thirty and 60 mg methadone suppressed withdrawal for up to 52 h, but failed to block completely the effects of heroin. The effects of heroin increased slightly at longer post-methadone intervals. Heroin use may persist during methadone treatment because low to moderate doses of methadone suppress withdrawal, but fail to eliminate the effects of heroin. These results provide a mechanism for the clinical observation that higher methadone doses are more effective at reducing heroin use.


Genetic diversity of begomoviruses in Pakistan captured through a vector based survey.
Begomoviruses (Geminiviridea), transmitted by whiteflies, constitute one of the most dangerous groups of plant viruses posing a severe threat to economically important crops in tropical and sub-tropical areas. In this study, whiteflies were collected from various locations all over Pakistan. The begomoviruses carried by these whiteflies were detected by PCR with the degenerative primers pair AV94/Dep3. Analysis of the 177 sequences obtained in our study, revealed 14 distinct begomovirus species, including five which were not previously reported in this country. Putative novel strains of Corchorus yellow vein virus (CoYVV) and Chilli leaf curl virus (ChiLCV) showing less than 90% identity with the previously available taxa were also identified. The greatest number of begomoviruses per single site was detected in Sindh province, where up to five different begomovirus species were identified from the same cropping field. Moreover, Cotton leaf curl Multan virus - Rajasthan (CLCuMuV-Ra) was found prevalent in all the cotton growing areas. The data reported here may be useful in the development of control measures against begomoviruses.


AMPK Inhibits the Stimulatory Effects of TGF-β on Smad2/3 Activity, Cell Migration, and Epithelial-to-Mesenchymal Transition.
AMP-activated protein kinase (AMPK), an important downstream effector of the tumor suppressor liver kinase 1 (LKB1) and pharmacologic target of metformin, is well known to exert a preventive and inhibitory effect on tumorigenesis; however, its role in cancer progression and metastasis has not been well characterized. The present study investigates the potential roles of AMPK in inhibiting cancer-cell migration and epithelial-to-mesenchymal transition (EMT) by regulating the canonical transforming growth factor β (TGF-β) signaling pathway, an important promoting factor for cancer progression. Our results showed that activation of AMPK by metformin inhibited TGF-β-induced Smad2/3 phosphorylation in cancer cells in a dose-dependent manner. The effect of metformin is dependent on the presence of LKB1. A similar effect was obtained by expressing a constitutive active mutant of AMPKα1 subunit, whereas the expression of a dominant negative mutant of AMPKα1 or ablation of AMPKα subunits greatly enhanced TGF-β stimulation of Smad2/3 phosphorylation. As a consequence, expression of genes downstream of Smad2/3, including plasminogen activator inhibitor-1, fibronectin, and connective tissue growth factor, was suppressed by metformin in a LKB1-dependent fashion. In addition, metformin blocked TGF-β-induced inteleukin-6 expression through both LKB1-dependent and -independent mechanisms. Our results also indicate that activation of LKB1/AMPK inhibits TGF-β-stimulated cancer cell migration. Finally, TGF-β induction of EMT was inhibited by phenformin and enhanced by knockdown of LKB1 expression with shRNA. Together, our data suggest that AMPK could be a drug target for controlling cancer progression and metastasis.


Submicrometric Films of Surface-Attached Polymer Network with Temperature-Responsive Properties.
Temperature-responsive properties of surface-attached poly(N-isopropylacrylamide) (PNIPAM) network films with well-controlled chemistry are investigated. The synthesis consists of cross-linking and grafting preformed ene-reactive polymer chains through thiol-ene click chemistry. The formation of surface-attached and cross-linked polymer films has the advantage of being well-controlled without any caution of no-oxygen atmosphere or addition of initiators. PNIPAM hydrogel films with same cross-link density are synthesized on a wide range of thickness, from nanometers to micrometers. The swelling-collapse transition with temperature is studied by using ellipsometry, neutron reflectivity, and atomic force microscopy as complementary surface-probing techniques. Sharp and high amplitude temperature-induced phase transition is observed for all submicrometric PNIPAM hydrogel films. For temperature above LCST, surface-attached PNIPAM hydrogels collapse similarly but without complete expulsion of water. For temperature below LCST, the swelling of PNIPAM hydrogels depends on the film thickness. It is shown that the swelling is strongly affected by the surface attachment for ultrathin films below ∼150 nm. For thicker films above 150 nm (to micrometers), surface-attached polymer networks with the same cross-link density swell equally. The density profile of the hydrogel films in the direction normal to the substrate is confronted with in-plane topography of the free surface. It results that the free interface width is much larger than the roughness of the hydrogel film, suggesting pendant chains at the free surface.


Synaptophysin depletion and intraneuronal Aβ in organotypic hippocampal slice cultures from huAPP transgenic mice.
To date, there are no effective disease-modifying treatments for Alzheimer's disease (AD). In order to develop new therapeutics for stages where they are most likely to be effective, it is important to identify the first pathological alterations in the disease cascade. Changes in Aβ concentration have long been reported as one of the first steps, but understanding the source, and earliest consequences, of pathology requires a model system that represents all major CNS cell types, is amenable to repeated observation and sampling, and can be readily manipulated. In this regard, long term organotypic hippocampal slice cultures (OHSCs) from neonatal amyloid mice offer an excellent compromise between in vivo and primary culture studies, largely retaining the cellular composition and neuronal architecture of the in vivo hippocampus, but with the in vitro advantages of accessibility to live imaging, sampling and intervention. Here, we report the development and characterisation of progressive pathological changes in an organotypic model from TgCRND8 mice. Aβ1-40 and Aβ1-42 rise progressively in transgenic slice culture medium and stabilise when regular feeding balances continued production. In contrast, intraneuronal Aβ continues to accumulate in close correlation with a specific decline in presynaptic proteins and puncta. Plaque pathology is not evident even when Aβ1-42 is increased by pharmacological manipulation (using calpain inhibitor 1), indicating that soluble Aβ species, or other APP processing products, are sufficient to cause the initial synaptic changes. Organotypic brain slices from TgCRND8 mice represent an important new system for understanding mechanisms of Aβ generation, release and progressive toxicity. The pathology observed in these cultures will allow for rapid assessment of disease modifying compounds in a system amenable to manipulation and observation.


Serological analysis of the Abbad Tribe of Jordan.
The Abbad are one of the largest tribes in Jordan with a complex structure dictated by historical and cultural factors. To study the genetic variability within the tribe, we examined four samples representing different levels of tribal structure for the polymorphisms of five blood groups, five erythrocyte enzymes, and seven serum proteins. The obtained allele distributions indicate a wide range of genetic variability within the tribe. An allelic heterogeneity test revealed significant differences between the examined samples, yet a gene diversity analysis revealed no significant substructuring. The observed genetic relationships among the four samples appear to agree with the tribal organization. Endogamous mating within the tribe and inbreeding within the subunits are believed to be the main factors that influenced the observed variability. This was confirmed by the results of the R matrix analysis, which summarized the genetic relationships in concordance with intertribal admixture, when affiliation and historical and maternal links were considered. The study is also an example of gene diffusion and of a negative relationship between the FY A-B- phenotype and endemicity of malaria.


Effects of Early-Stage Blood Pressure Variability on the Functional Outcome in Acute Ischemic Stroke Patients With Symptomatic Intracranial Artery Stenosis or Occlusion Receiving Intravenous Thrombolysis.
Studies exploring the relationship between blood pressure (BP) fluctuations and outcome in acute ischemic stroke (AIS) patients treated with intravenous thrombolysis (IVT) are limited. We aimed to investigate the influence of blood pressure variability (BPV) during the first 24 h after IVT on early neurological deterioration (END) and 3-month outcome after IVT in terms of different stroke subtypes. Clinical data from consecutive AIS patients who received IVT were retrospectively analyzed. The hourly systolic BP of all patients were recorded during the first 24 h following IVT. We calculated three systolic BPV parameters, including coefficient of variability (CV), standard deviation of mean BP (SD) and successive variation (SV), within the first 6, 12, and 24 h after IVT. END was defined as neurological deterioration with an increase in the National Institutes of Health Stroke Scale (NIHSS) score ≥ 4 points within the first 72 h after admission. Follow-up was performed at 90 days after onset, and favorable and poor outcomes were defined as a modified Rankin Scale scores (mRS) of ≤1 or ≥2, respectively. A total of 339 patients, which were divided into those with (intracranial artery stenosis or occlusion group, SIASO group) and without (non-SIASO group) SIASO, were included. Among them, 110 patients (32.4%) were with SIASO. Patients in SIASO group had higher NIHSS on admission and difference in term of mRS at 90 days compared with non-SIASO group (P < 0.001). In SIASO group, patients in favorable outcome group were younger and had lower NIHSS on admission, lower SV-24 h (14.5 ± 4.3 vs. 11.8 ± 3.2, respectively) and lower SD-24 h (12.7 ± 3.8 vs. 10.9 ± 3.3, respectively), compared with patients with poor outcome (all P < 0.05). In the multivariable logistic regression analysis, compared with the lowest SV (SV < 25% quartile), SV50-75% [odds ratio (OR) = 4.449, 95% confidence interval (CI) = 1.231-16.075, P = 0.023] and SV>75% (OR = 8.676, 95% CI = 1.892-39.775, P = 0.005) were significantly associated with poor outcome at 3 months in patients with SIASO, adjusted for age, NIHSS on admission and atrial fibrillation. No BPV parameters were associated with END in SIASO group. In non-SIASO group, there were no significant association between BPV patterns and END or 90-day outcome. SV-24 h had a negative relationship with 3-month outcome in AIS patients with SIASO treated with IVT, indicating that BPV may affect the outcome of AIS.


Indomethacin causes prostaglandin D(2)-like and eotaxin-like selective responses in eosinophils and basophils.
We investigated the actions of a panel of nonsteroidal anti-inflammatory drugs on eosinophils, basophils, neutrophils, and monocytes. Indomethacin alone was a potent and selective inducer of eosinophil and basophil shape change. In eosinophils, indomethacin induced chemotaxis, CD11b up-regulation, respiratory burst, and L-selectin shedding but did not cause up-regulation of CD63 expression. Pretreatment of eosinophils with indomethacin also enhanced subsequent eosinophil shape change induced by eotaxin, although treatment with higher concentrations of indomethacin resulted in a decrease in the expression of the major eosinophil chemokine receptor, CCR3. Indomethacin activities and cell selectivity closely resembled those of prostaglandin D(2) (PGD(2)). Eosinophil shape change in response to eotaxin was inhibited by pertussis toxin, but indomethacin- and PGD(2)-induced shape change responses were not. Treatment of eosinophils with specific inhibitors of phospholipase C (U-73122), phosphatidylinositol 3-kinase (LY-294002), and p38 mitogen-activated protein kinase (SB-202190) revealed roles for these pathways in indomethacin signaling. Indomethacin and its analogues may therefore provide a structural basis from which selective PGD(2) receptor small molecule antagonists may be designed and which may have utility in the treatment of allergic inflammatory disease.


[Two cases of Buschke-Löwenstein tumor].
We report two cases of Buschke-Löwenstein Tumor on 39- and 55-year-old males. Both patients presented with mass and pain of glans penis. Pathological diagnosis of biopsy specimens were condyloma acuminatum in both cases. Bleomycin was not effective. Therefore, tumor resection in the first case and partial penectomy on second case were performed. Pathological examination revealed hyperkeratosis, acanthosis and downward growth of the prickle cell layer. But cellular atypia were not seen. Pathological diagnosis was Buschke-Löwenstein tumor. Our two patients are alive with no evidence of disease after 10 years. Pathological and clinical problems of Buschke-Löwenstein tumor were discussed by review of the literature.


[Cognitive function in patients with severe carotid stenosis--evaluation of RBANS, WAIS-R and NART before treatment of carotid revascularization--].
To evaluate the cognitive function in preoperative patients with severe carotid stenosis. Twenty-five patients with severe carotid stenosis were examined on their cognitive function by RBANS (Japanese version), WAIS-R (Japanese version), and NART (Japanese version) before treatment of carotid revascularization (endarterectomy or stenting). They had full activities of daily living without any hemiparesis, aphasia, agnosia, and apraxia at the time of the examinations. Mean intelligent quotient (IQ) measured by WAIS-R and NART was 104.0 +/- 10.7 and 101.3 +/- 13.4, (ns) respectively. Mean total scale of RBANS was 90.0 +/- 13.4, which was significantly lower than both the results of WAIS-R and NART. A mean value of each RBANS index was 91.3 +/- 11.7 in immediate memory, 102.0 +/- 18.2 in visuospatial/constructional, 93.2 +/- 8.7 in language, 84.6 +/- 14.7 in attention, and 92.1 +/- 14.4 in delayed memory. RBANS index significantly declined in immediate memory, language, attention and delayed memory than visuospatial/constructional. Qualitative evaluation was available in RBANS, WAIS-R, and NART, which enabled the investigators to make a precise comparison between these methods. WAIS-R and NART showed a comparatively preserved function and were presumed to be useful for the evaluation of the baseline of cognitive function in preoperative patients. RBANS demonstrated a slight decrease in memory and attention in those patients and was expected to be useful to detect the cognitive dysfunction when compared with WAIS-R and NART.


Prevalence of Dental Fear and Anxiety and Its Triggering Factors in the Dental Office among School-going Children in Al Ahsa.
To estimate the prevalence of dental fear and anxiety (DFA) among school-going children in Al Ahsa.To identify the factors that trigger DFA in the dental office. A cross-sectional questionnaire-based study was conducted. Eight hundred and sixteen, 7-12-year-old children studying in government and private schools spread across the city of Al-Ahsa, Saudi Arabia, participated in the study. A self-reported questionnaire with 15 close-ended questions pertaining to DFA in logical order was distributed to all the participants. Each question had three options as responses with images. The children were asked to choose the option that best fitted their response. The prevalence of DFA among boys and girls was found to be 50.4 and 71.28%, respectively. The majority of the boys studying in government schools reported DFA when informed about the treatment in advance, while most of those studying in private schools reported DFA at the sight of the dental chair and dental injections, while walking into the clinic, in the waiting room, when informed about the treatment in advance and their tooth being drilled. On the contrary, the responses were very similar among girls irrespective of their school. Most of the boys and girls did not experience any DFA when their parents were allowed to accompany them. Hence, a tailor-made approach for the management of the child in the dental office is warranted. A tailor-made approach for the management of DFA in the dental office plays a significant role in successful treatment. Alshuaibi AF, Aldarwish M, Almulhim AN, et a l. Prevalence of Dental Fear and Anxiety and Its Triggering Factors in the Dental Office among School-going Children in Al Ahsa. Int J Clin Pediatr Dent 2021;14(2):286-292.


Novel Genetic Subtypes of Urothelial Carcinoma With Differential Outcomes on Immune Checkpoint Blockade.
Immune checkpoint blockade (ICB) therapy has significantly improved clinical outcomes in bladder cancer. Identification of correlates of benefit is critical to select appropriate therapy for individual patients. To reveal genetic variables associated with benefit from ICB, we performed whole-exome sequencing on tumor specimens from 88 patients with advanced bladder cancer treated with ICB. We identified several genetic factors that correlated with progression-free and overall survival after ICB therapy including ARID1A mutation, tumor mutational burden, intratumoral heterogeneity, the ratio of nonsynonymous to synonymous mutations in the immunopeptidome (immune dN/dS), and tumor cell purity. In addition, we noted that neutrophil-to-lymphocyte ratio and smoking history were negatively associated with overall survival. These genetic characteristics define four molecular subtypes demonstrating differential sensitivity to ICB. We validated the association of these four subtypes with clinical benefit from ICB in an independent cohort (IMvigor210). Finally, we showed that these molecular subtypes also correlate with outcome, although with distinct relationships, among patients not treated with ICB using The Cancer Genome Atlas (TCGA) bladder cancer cohort. Using parallel RNA sequencing data, the subtypes were also shown to correlate with immune infiltration and inflammation, respectively, in the IMvigor210 and TCGA cohorts. Together, our study defines molecular subgroups of bladder cancer that influence benefit from ICB.


Ultrasonographic diagnosis of a fibrinonecrotic colonic cast in a kitten with feline panleukopenia virus.
Ultrasonography of a cat with diarrhoea and vomiting revealed a multi-layered, discrete linear structure within the large intestine with retention of the intestinal layers which could potentially be confused with an intestinal intussusception. The structure was ultimately expelled from the large intestine during defecation, and confirmed as a fibrinonecrotic cast. The origin of the fibrinonecrotic cast was assumed to be an intestinal pseudo-membrane formed in enteritis caused by immune suppression due to the panleukopenia virus. To our knowledge, this is the first ultrasonographic description of a fibrinonecrotic cast and spontaneous passage of the colonic cast in the veterinary field.


Antipsychotic combinations in schizophrenia.
In the treatment of resistant schizophrenia, a number of meta-analyses attempted to quantify the efficacy and tolerability of antipsychotic (AP) polypharmacy v. monotherapy with contradictory results. Recently, a systematic review and meta-analysis of randomised controlled trials investigated the efficacy and tolerability of AP combination v. monotherapy in schizophrenia. It included 31 studies: 21 double-blind (considered high-quality studies) and 10 open-label (considered low-quality studies). The meta-analysis showed that, overall, the combination of two APs was more effective than monotherapy in terms of symptom reduction (standardised mean difference (SMD) = -0.53, 95% confidence interval (CI) -0.87 to -0.19); however, this result was confirmed only in the subgroup of low-quality studies. Negative symptoms improved when combining a D2 antagonist with a D2 partial agonist (SMD = -0.41, 95% CI -0.79 to -0.03) both in double-blind and open-label studies. In the present commentary, the results of this systematic review are critically discussed in terms of their clinical and research implications.


Incidence of metabolic bone disease in rheumatoid arthritis and osteoarthritis.
Bone biopsy specimens from the iliac crest were obtained during surgical operations from 45 patients with rheumatoid arthritis (RA) and 41 with osteoarthritis (OA). Control material was obtained from 20 cases of sudden death due to cardiovascular disease. By both conventional histology and image analysis techniques about a quarter of all patients showed some osteoporosis. This was equally common among the OA and RA patients. It was more common among those with transparent skin and those taking corticosteroids. The only case showing mild osteomalacia suffered from OA. No gross differences were apparent between the groups in relation to plasma biochemical studies, diet, or exposure to sunlight. These results are in striking contrast to the high incidence of osteomalacia in RA reported from the west of England; moreover they do not confirm reports of hypercalcaemia among rheumatoid subjects. We conclude that the differences regarding osteomalacia are due to selection of cases. We find no evidence that osteomalacia is specifically associated with RA.


Assessing the genotoxic effects of two lipid peroxidation products (4-oxo-2-nonenal and 4-hydroxy-hexenal) in haemocytes and midgut cells of Drosophila melanogaster larvae.
Lipid peroxidation products can induce tissue damage and are implicated in diverse pathological conditions, including aging, atherosclerosis, brain disorders, cancer, lung and various liver disorders. Since in vivo studies produce relevant information, we have selected Drosophila melanogaster as a suitable in vivo model to characterise the potential risks associated to two lipid peroxidation products namely 4-oxo-2-nonenal (4-ONE) and 4-hydroxy-hexenal (4-HHE). Toxicity, intracellular reactive oxygen species production, and genotoxicity were the end-points evaluated. Haemocytes and midgut cells were the evaluated targets. Results showed that both compounds penetrate the intestine of the larvae, affecting midgut cells, and reaching haemocytes. Significant genotoxic effects, as determined by the comet assay, were observed in both selected cell targets in a concentration/time dependent manner. This study highlights the importance of D. melanogaster as a model organism in the study of the different biological effects caused by lipid peroxidation products entering via ingestion. This is the first study reporting genotoxicity data in haemocytes and midgut cells of D. melanogaster larvae for the two selected compounds.


How applicable are clinical practice guidelines to elderly patients with comorbidities?
To examine the applicability of 10 common clinical practice guidelines (CPGs) to elderly patients with multiple comorbidities. Content analysis of published Canadian CPGs for the following chronic diseases: diabetes, dyslipidemia, dementia, congestive heart failure, depression, osteoporosis, hypertension, gastroesophageal reflux disease, chronic obstructive pulmonary disease, and osteoarthritis. Presence or absence of 4 key indicators of applicability of CPGs to elderly patients with multiple comorbidities. These indicators include any mention of older adults or people with comorbidities, time needed to treat to benefit in the context of life expectancy, and barriers to implementation of the CPG. Out of the 10 CPGs reviewed, 7 mentioned treatment of the elderly, 8 mentioned people with comorbidities, 4 indicated the time needed to treat to benefit in the context of life expectancy, 5 discussed barriers to implementation, and 7 discussed the quality of evidence. This study shows that although most CPGs discuss the elderly population, only a handful of them adequately address issues related to elderly patients with comorbidities. In order to make CPGs more patient centred rather than disease driven, guideline developers should include information on elderly patients with comorbidities.


Successful use of add - on topiramate for antipsychotic - induced weight gain.
Antipsychotic induced weight gain is the most common and distressing side effect. This also affects the compliance toward the treatment and hence the prognosis. Non - pharmacological interventions such as exercise and diet modifications alone might not be sufficient most of the times; also ensuring compliance toward this is difficult in patients with psychiatric illness. So, the role of weight - reducing drugs become important. In this case report, we describe the use of low - dose topiramate as a weight - reducing agent, in a patient with a bipolar affective disorder - mania with psychotic symptoms, who had significant risperidone - induced weight gain.


End of life care - the importance of culture and ethnicity.
Australia is a culturally and ethnically diverse country. Within such diversity there will be differing beliefs systems about death and dying. This may be a challenging prospect for health professionals. This article discusses how cultural diversity may impact care and provides some strategies for the general practitioner when considering the provision of end of life care. This article does not attempt to provide GPs with a prescriptive approach to multicultural care, as this would run the risk of stereotyping individuals. Rather, it discusses the barriers to end of life care among different cultural and ethnic groups, and suggests ways in which to improve understanding of different cultural needs in end of life care.


Glyceryl monooleate-based otic delivery system of ofloxacin: release profile and bactericidal activity.
This study investigated the preparation and characterization of glyceryl monooleate- (GMO) based drug delivery system containing ofloxacin for the treatment of otitis externa. Acetate buffer (pH 4.5) containing dissolved ofloxacin was added to molten GMO as an aqueous phase, this resulted in the formation of a cubic and a reverse hexagonal phases. The release behavior of ofloxacin from the drug delivery system was studied using three different methods. The mechanism of drug release using paddles/dissolution apparatus and Franz diffusion cells followed Higuchi and Fickian diffusion models; whereas intrinsic release rate method showed zero-order kinetics. The intrinsic release rate was estimated and found to be 187.2 µg/cm(2)/h. The release mechanisms were similar irrespective of the loaded ofloxacin amount, however, the higher drug load displayed higher release rate. The drug delivery system was proven to be microbiologically effective by using agar diffusion method, against Staphylococcus aureus, and Pseudomonas aeruginosa. The GMO/ofloxacin formulation was stable for 6 months after preparation at room temperature as measured with respect to phase stability and antibacterial activity.


Induction of Lipin1 by ROS-Dependent SREBP-2 Activation.
Lipin1 was identified as a phosphatidate phosphatase enzyme, and it plays a key role in lipid metabolism. Since free radicals contribute to metabolic diseases in the liver, this study investigated the effects of free radicals on the regulation of Lipin1 expression in Huh7 and AML12 cells. Hydrogen peroxide induced mRNA and protein expression of Lipin1 in Huh7 cells, which was assayed by quantitative RT-PCR and immunoblotting, respectively. Induction of Lipin1 by hydrogen peroxide was confirmed in AML12 cells. Hydrogen peroxide treatment significantly increased expression of sterol regulatory element-binding protein (SREBP)-2, but not SREBP-1. Moreover, nuclear translocation of SREBP-2 was detected after hydrogen peroxide treatment. Hydrogen peroxide-induced Lipin1 or SREBP-2 expression was significantly reduced by N-acetyl-l-cysteine treatment, indicating that reactive oxygen species (ROS) were implicated in Lipin1 expression. Next, we investigated whether the hypoxic environments that cause endogenous ROS production in mitochondria in metabolic diseases affect the expression of Lipin1. Exposure to hypoxia also increased Lipin1 expression. In contrast, pretreatment with antioxidants attenuated hypoxia-induced Lipin1 expression. Collectively, our results show that ROS activate SREBP-2, which induces Lipin1 expression.


Glial modulation of synaptic transmission in culture.
Accumulating evidence has demonstrated the existence of bidirectional communication between glial cells and neurons, indicating an important active role of glia in the physiology of the nervous system. Neurotransmitters released by presynaptic terminals during synaptic activity increase intracellular Ca(2+) concentration in adjacent glial cells. In turn, activated glia may release different transmitters that can feed back to neuronal synaptic elements, regulating the postsynaptic neuronal excitability and modulating neurotransmitter release from presynaptic terminals. As a consequence of this evidence, a new concept of the synaptic physiology, the tripartite synapse, has been proposed, in which glial cells play an active role as dynamic regulatory elements in neurotransmission. In the present article we review evidence showing the ability of astrocytes to modulate synaptic transmission directly, with the focus on studies performed on cell culture preparations, which have been proved extremely useful in the characterization of molecular and cellular processes involved in astrocyte-mediated neuromodulation.


Evaluation and Comparison of the Early Outcomes of Open and Laparoscopic Surgery of Liver Hydatid Cyst.
Surgery is the mainstay for treatment of liver hydatid cyst. Different surgical procedures have been suggested, but it is important to select the most appropriate treatment to obtain the best results with the lowest rate of recurrence and minimal morbidity and mortality. The aim of this study was to evaluate the early outcomes of open and laparoscopic surgery of hydatidosis. In this study, 75 patients with uncomplicated liver hydatid cyst were assigned prospectively to either groups of laparoscopic surgery (37, 50.68%) or open procedure (36, 49.32%) during the period of 2007 to 2012. Conversion to open surgery was required in 2 patients (2.67%), who were excluded from the study. Patients were followed for about 17.86±17.64 months. Participants included 73 patients: 49 (67.12%) female and 24 (32.88%) male patients, with the mean age of 38.97±16.48 years. There was no statistically significant difference between the 2 groups with regard to the sex, the occupation, and the mean diameter of the cysts. Bilious staining of the cyst content was observed in 23 (35.94%) patients during surgery, and a maximum diameter of 91 mm was considered as a cut point for predicting postoperative fistula with 69.2% sensitivity and 41.1% specificity. The mean duration of operation, postoperative pain, the hospitalization time, and the time to return to work were significantly lower in the laparoscopic group. Postoperative biliary fistula, cyst cavity infection, and wound infection were not different between the 2 groups. Laparoscopic surgery seems to be effective and safe, with low morbidity rates for uncomplicated cysts in accessible segments of the liver.


Epidemiological, Clinical, and Oncological Outcomes of non-Alcohol Drinking and non-Smoking Laryngeal Squamous Cell Carcinoma Patients: A Distinct Entity.
Purpose: To explore the discrepancy in clinicopathological and prognostic features between smoking and alcohol drinking (SA) and non-smoking and non-alcohol drinking (NSNA) patients with laryngeal squamous cell carcinoma (LSCC). Methods: This retrospective study including 1735 patients with LSCC was conducted from January 2005 to December 2010, which were categorized into 4 groups, NSNA group, smoking only group, alcohol-drinking only group, and SA group. We compared overall survival (OS) and disease-free survival (DFS) using the Kaplan-Meier method and indicated clinicopathological features by Cox proportional hazards regression models before and after propensity score matching (PSM). Results: A total of 415 patients (23.92%) were identified as NSNA. The SA group was predominantly patients ≤60 years old (46.63%) while the NSNA group was more older (58.07%). NSNA group was more likely to present at earlier disease stage and more female. No significant difference in OS (P = .685) and DFS (P = .976) was found between the 2 groups. In addition to age and recurrence and metastasis being common independent prognostic factors in terms of OS in both groups of patients, NSNA group also exhibited other factors, namely tumor area >3.7 cm2 and positive resection margin. For DFS, N + stage, tumor size >3.7 cm2, and positive resection margin were prognostic features specific to NSNA group. Conclusion: The outcome is similar in LSCC patients with and without SA. NSNA group shows a distinct profile from that found in SA group. Clinicopathological features from NSNA group should be considered for LSCC management.


The Mutagenic Consequences of DNA Methylation within and across Generations.
DNA methylation is an epigenetic modification with wide-ranging consequences across the life of an organism. This modification can be stable, persisting through development despite changing environmental conditions. However, in other contexts, DNA methylation can also be flexible, underlying organismal phenotypic plasticity. One underappreciated aspect of DNA methylation is that it is a potent mutagen; methylated cytosines mutate at a much faster rate than other genetic motifs. This mutagenic property of DNA methylation has been largely ignored in eco-evolutionary literature, despite its prevalence. Here, we explore how DNA methylation induced by environmental and other factors could promote mutation and lead to evolutionary change at a more rapid rate and in a more directed manner than through stochastic genetic mutations alone. We argue for future research on the evolutionary implications of DNA methylation driven mutations both within the lifetime of organisms, as well as across timescales.


The nuclear-cytoplasmic trafficking of a chromatin-modifying and remodelling protein (KMT2C), in osteosarcoma.
Osteosarcoma is the most common paediatric primary non-hematopoietic bone tumor; the survival is related to the response to chemotherapy and development of metastases. KMT2C is a chromatin-modifying and remodelling protein and its expression has never been studied in osteosarcoma. The aim of this study was to understand the role of KMT2C in the osteosarcoma carcinogenesis and metastatic progression to identify a new molecular target and to provide new therapeutic approach. We performed the immunohistochemical and gene expression analysis of KMT2C in 32 samples of patients with diagnosis of osteosarcoma with known clinic-pathological data and we analysed the expression of genes involved in the metastatic pathway in four osteosarcoma cell lines by blocking the KMT2C expression using siRNA. We found a nuclear-cytoplamic trafficking of KMT2C and the cytoplasmic localization was higher than the nuclear localization (p < 0.0001). Moreover, the percentage of cells with cytoplasmic positivity increased from low grade primary tissue to metastatic tissues. The cytoplasmic localization of KMT2C could lead to a change in its function supporting osteosarcoma carcinogenesis and progression. Our hypothesis is that KMT2C could affect the enhancer activity of genes influencing the invasive properties and metastatic potential of osteosarcoma.


A Moral Foundation for Anti-Doping: How Far Have We Progressed? Where Are the Limits?
Clarity about the ethical justification of anti-doping is essential. In its absence, critics multiply and confusion abounds. Three broad reasons are typically offered in anti-doping's defense: to protect athletes' health; to promote fairness; and to preserve meaning and values in sport - what the World Anti-Doping Agency (WADA) Code refers to as the spirit of sport. Protecting health is itself an important value, but many sports encourage athletes to take significant risks. The case against doping is buttressed by concern for athletes' health, but it cannot be the sole foundation. Promoting fairness is vital in all sports as the metaphor of the level playing field attests. But playing fields can be leveled by providing performance-enhancing drugs to all competitors. When doping is prohibited, fairness is aided by effective anti-doping. But the fundamental justification for anti-doping is found in the meanings and values we pursue in and through sport.


Does Cozen's phenomenon warrant surgical intervention?
Proximal tibial metaphyseal fractures can be complicated by a late valgus deformity, referred to as Cozen's phenomenon. We studied children with such fractures to determine whether the child's age at the time of injury influenced the development of Cozen's as well as the occurrence of elongation. In addition, we explored whether the deformity resolved at long-term follow-up. We conducted a retrospective study of 33 patients (six months to 14 years old). Mean follow-up was 8.8 years (3 to 25). We measured angulation of the fractured limb post-treatment, at maximum deformity and final follow-up, as well as elongation and compared them with the uninjured limb. Three of the fractures were treated surgically whereas the rest, nonoperatively. In all, 15 out of 33 fractures developed late valgus deformity between eight and 19 months (mean time 12.5 months). A total of 24 fractures developed elongation. We found no association of either of these with age. Angulation increased to a statistically significant level, from post-treatment to maximum deformity, and then decreased at final follow-up, leaving no statistically significant difference from the initial measurement. The difference in valgus between fractured and uninjured limb increased to a statistically significant level from post-treatment to maximum deformity and then decreased, leaving an excess from the initial measurement. In almost half the patients, late valgus deformity developed within two years post-fracture and corrected to the initial post-treatment angles. Patients should be warned of this possibility and reassured of its natural resolution. IV.


A frog in the throat? An expansile mass presenting in the neck with dysphonia.
A neck mass, which rapidly increases in size over several weeks, is concerning for all involved. When accompanied by other symptoms suggesting sinister underlying pathology, efficient management and rapid diagnosis are vital. The causes may include primary or metastatic carcinoma, or lymphoreticular malignancy. Other non-sinister pathology may account for the swelling such as reactive lymph nodes or benign neoplasms. A benign neoplasm of the lymphatic system known as a lymphangioma may rarely be the cause of a mass in the neck in adults. More commonly found in infants, with approximately 40% found at birth, they are seldom encountered in adults. In children, they have the propensity to infiltrate into and around muscles and neurovascular structures, occasionally leading to difficult surgical excision. The authors present an unusual case of an adult patient with an expansile mass in the supraclavicular fossa of insidious onset. It was associated with dysphagia and hoarseness of voice.


Psychological and Biological Validation of a Novel Digital Social Peer Evaluation Experiment (digi-SPEE).
Negative social evaluation is associated with psychopathology. Given the frequency of evaluation through increasingly prevalent virtual social networks, increased understanding of the effects of this social evaluation is urgently required. A new digital social peer evaluation experiment (digi-SPEE) was developed to mimic everyday online social interactions between peers. Participants received mildly negative feedback on their appearance, intelligence, and congeniality. Two hundred and forty-one young people [58.9% female, aged 18.9 years (15 to 34)] from an ongoing novel general population twin study participated in this study. Positive affect (PA), negative affect (NA), implicit self-esteem, and cortisol were assessed before and after exposure to the social evaluation experiment. The social evaluation experiment decreased PA (B=-5.25, p<.001) and implicit self-esteem (B=-.19; p<.001), whereas it increased NA (B=5.99; p<.001) and cortisol levels (B=.07; p<.001). Females (PA: B=-7.62; p<.001; NA: B=8.28; p<.001) and participants with higher levels of general psychological distress (PA: B=-.04, p=.035; NA: B=.06; p=.028) showed stronger affective responses. Stressor-induced cortisol increase was stronger in adolescents under the age of 18 than in participants 18 years and older (B=-.06, p=.002). The digi-SPEE represents a social evaluation stressor that elicits biological and implicit and explicit mental changes that are relevant to mechanisms of psychopathology.


Cardioprotective time-window of Penehyclidine hydrochloride postconditioning: A rat study.
Pharmacological postconditioning offers a clinical perspective for all patients with ischemic heart disease. Penehyclidine hydrochloride (PHC) is a new type of anticholinergic drug. We previously reported that PHC preconditioning protects against I/R injury in rat hearts in vivo. Ischemic heart disease often occurs suddenly, so postconditioning is more significant than preconditioning. However, studies evaluating myocardial protective effects of PHC postconditioning are unavailable. We explored the effects and time-window of cardioprotection of PHC postconditioning in myocardial I/R injury. PHC was administered by intravenous at various times (t = -5, 0, 5, 10, 15, or 30min) after the onset of reperfusion in addition to I/R rat. We observed five different indicators including infarct size, inflammatory response, myocardial enzyme, oxidative stress, and Ca2+ overload to quantify the effect of cardioprotection. Evans blue and TTC staining were used to measure myocardial infarct size. The expression of NF-κ B and IκB-α was analyzed using Western blot. ELISA was conducted to detect inflammatory and anti-inflammatory mediators. The Ca2+ level was determined using assay kit. PHC postconditioning (from -5 to 10min after the onset of reperfusion) significantly reduced infarct size, downregulated NF-κ B expression, and decreased the release of inflammatory mediators, while significantly upregulating IκB-α expression and increasing the release of anti-inflammatory mediators. All PHC postconditioning groups significantly reduced Ca2+ level. PHC postconditioning is cardioprotective over a larger time-window (from -5 to 10min after the onset of reperfusion). The probable mechanism is inhibition of NF-кB regulated inflammatory response pathway.


The process utility of thermotolerant methylotrophic bacteria: II. An evaluation of transient responses.
In Part II, the process utility of a thermotolerant methylotrophic bacterium is evaluated with respect to its dynamic response when various substrate or nutrient pulses are imposed on it while growing under steady-state conditions in a chemostat. The pulses investigated were methanol pulses on methanol-, methanol/formaldehyde-, and dual methanol/ammonia-limited cultures and an ammonia pulse on a severely nitrogen (ammonia)-limited culture. The results obtained, although exemplifying the complex biochemistry of such bacteria, clearly demonstrate the bacteriums flexibility and versatility in handling process transients. Its lack of fastidiousness in unsteady state continuous culture make it a most promising candidate for inclusion in process cultures for elevated temperature industrial wastewater treatment.


The Mammalian Diving Response: Inroads to Its Neural Control.
The mammalian diving response (DR) is a remarkable behavior that was first formally studied by Laurence Irving and Per Scholander in the late 1930s. The DR is called such because it is most prominent in marine mammals such as seals, whales, and dolphins, but nevertheless is found in all mammals studied. It consists generally of breathing cessation (apnea), a dramatic slowing of heart rate (bradycardia), and an increase in peripheral vasoconstriction. The DR is thought to conserve vital oxygen stores and thus maintain life by directing perfusion to the two organs most essential for life-the heart and the brain. The DR is important, not only for its dramatic power over autonomic function, but also because it alters normal homeostatic reflexes such as the baroreceptor reflex and respiratory chemoreceptor reflex. The neurons driving the reflex circuits for the DR are contained within the medulla and spinal cord since the response remains after the brainstem transection at the pontomedullary junction. Neuroanatomical and physiological data suggesting brainstem areas important for the apnea, bradycardia, and peripheral vasoconstriction induced by underwater submersion are reviewed. Defining the brainstem circuit for the DR may open broad avenues for understanding the mechanisms of suprabulbar control of autonomic function in general, as well as implicate its role in some clinical states. Knowledge of the proposed diving circuit should facilitate studies on elite human divers performing breath-holding dives as well as investigations on sudden infant death syndrome (SIDS), stroke, migraine headache, and arrhythmias. We have speculated that the DR is the most powerful autonomic reflex known.


Colocalized delivery of adjuvant and antigen using nanolipoprotein particles enhances the immune response to recombinant antigens.
Subunit antigen-based vaccines can provide a number of important benefits over traditional vaccine candidates, such as overall safety. However, because of the inherently low immunogenicity of these antigens, methods for colocalized delivery of antigen and immunostimulatory molecules (i.e., adjuvants) are needed. Here we report a robust nanolipoprotein particle (NLP)-based vaccine delivery platform that facilitates the codelivery of both subunit antigens and adjuvants. Ni-chelating NLPs (NiNLPs) were assembled to incorporate the amphipathic adjuvants monophosphoryl lipid A and cholesterol-modified CpG oligodeoxynucleotides, which can bind His-tagged protein antigens. Colocalization of antigen and adjuvant delivery using the NiNLP platform resulted in elevated antibody production against His-tagged influenza hemagglutinin 5 and Yersinia pestis LcrV antigens. Antibody titers in mice immunized with the adjuvanted NLPs were 5-10 times higher than those observed with coadministration formulations and nonadjuvanted NiNLPs. Colocalized delivery of adjuvant and antigen provides significantly greater immune stimulation in mice than coadministered formulations.


Intercellular Transmission of Viral Populations with Vesicles.
A common paradigm holds that during cell-to-cell transmission, viruses behave as lone soldiers. Recently, we discovered not only that enteroviruses are transmitted via vesicles as populations of viral particles but also that this type of transmission enhances their infection efficiency (Y. H. Chen et al., Cell 160: 619-630, 2015). This mechanism could be advantageous for the overall fitness of the viral population, promoting genetic interplay by enabling viral quasispecies to collectively infect a susceptible host cell. Here, we discuss these findings in the context of viral pathogenesis and also propose that this novel type of vesicular transmission is widespread among different virus families and includes populations of both viral particles and naked viral genomes.


Analysis of a taurine-dependent promoter in Sinorhizobium meliloti that offers tight modulation of gene expression.
Genetic models have been developed in divergent branches of the class Alphaproteobacteria to help answer a wide spectrum of questions regarding bacterial physiology. For example, Sinorhizobium meliloti serves as a useful representative for investigating rhizobia-plant symbiosis and nitrogen fixation, Caulobacter crescentus for studying cell cycle regulation and organelle biogenesis, and Zymomonas mobilis for assessing the potentials of metabolic engineering and biofuel production. A tightly regulated promoter that enables titratable expression of a cloned gene in these different models is highly desirable, as it can facilitate observation of phenotypes that would otherwise be obfuscated by leaky expression. We compared the functionality of four promoter regions in S. meliloti (P(araA), P(tauA), P(rhaR), and P(melA)) by constructing strains carrying fusions to the uidA reporter in their genomes and measuring beta-glucuronidase activities when they were induced by arabinose, taurine, rhamnose, or melibiose. P(tauA) was chosen for further study because it, and, to a lesser extent, P(melA), exhibited characteristics suitable for efficient modulation of gene expression. The levels of expression from P(tauA) depended on the concentrations of taurine, in both complex and defined media, in S. meliloti as well as C. crescentus and Z. mobilis. Moreover, our analysis indicated that TauR, TauC, and TauY are each necessary for taurine catabolism and substantiated their designated roles as a transcriptional activator, the permease component of an ABC transporter, and a major subunit of the taurine dehydrogenase, respectively. Finally, we demonstrated that P(tauA) can be used to deplete essential cellular factors in S. meliloti, such as the PleC histidine kinase and TatB, a component of the twin-arginine transport machinery. The P(tauA) promoter of S. meliloti can control gene expression with a relatively inexpensive and permeable inducer, taurine, in diverse alpha-proteobacteria. Regulated expression of the same gene in different hosts can be achieved by placing both tauR and P(tauA) on appropriate vectors, thus facilitating inspection of conservation of gene function across species.


cDNA cloning and sequencing of Ca2+/calmodulin-dependent protein kinase IIalpha subunit and its mRNA expression in diisopropyl phosphorofluoridate (DFP)-treated hen central nervous system.
Diisopropyl phosphorofluoridate (DFP) produces delayed neurotoxicity, known as organophosphorus ester-induced delayed neurotoxicity (OPIDN), in hen, human, and other sensitive species. A single dose of DFP (1.7 mg/kg, se.) produces first mild ataxia followed by paralysis in 7-14 days in hens. DFP treatment also increases in vitro autophosphorylation of Ca2+ calmodulin-dependent protein kinase II (CaM kinase II) and the phosphorylation of several cytoskeletal proteins in the hen brain. To investigate whether increase in CaM kinase II activity is associated with increased expression of its mRNA, we cloned and sequenced CaM kinase II alpha subunit cDNA, and used it to study CaM kinase II expression in brain regions and spinal cord. Hen CaM kinase II alpha subunit differs in 7 amino acids from that of rat CaM kinase II. Its mRNA occurs predominantly as a 6.7 kb message, which is very close to that of human CaM kinase II alpha subunit. Northern blot analysis showed a transient increase in CaM kinase II alpha subunit mRNA in the cerebellum and spinal cord of DFP-treated chickens. The increase in CaM kinase II mRNA expression is consistent with the previously reported increase in its activity in brain and spinal cord, and its increased expression only in cerebellum and spinal cord, which are sensitive to the Wallerian-type degeneration characteristic of OPIDN, suggests the probable role of this enzyme in delayed neurotoxicity.


[A Case of Port Site Recurrence of Gallbladder Carcinoma after Laparoscopic Cholecystectomy].
The patient was a 76-year-old man who underwent laparoscopic cholecystectomy with a diagnosis of cholecystolithiasis. Since the definite diagnosis of gallbladder carcinoma was made after the operation, he underwent additional resection. Four years later, he revisited the hospital complaining of painful swelling of the port site of his epigastrium. Magnetic resonance imaging of the abdomen revealed a mass 3.4 cm in diameter at the epigastrium. Thus, port site recurrence of gallbladder carcinoma was the suspected diagnosis. We resected the peritoneum, rectus abdominis muscle, and skin, as well as the tumor, and the abdominal wall was reconstructed using synthetic composite mesh. Histological examinations revealed recurrence of gallbladder carcinoma. Port site recurrence of gallbladder carcinoma is known to have a poor prognosis, but long survival can be expected in patients after complete resection of the metastatic lesion, if the recurrence develops more than a year after the initial operation.


Phylogeographic Structure in Anastrepha ludens (Diptera: Tephritidae) Populations Inferred With mtDNA Sequencing.
Anastrepha ludens (Loew) (Diptera: Tephritidae), the Mexican fruit fly, is a major pest of citrus and mango. It has a wide distribution in Mexico and Central America, with infestations occurring in Texas, California, and Florida with origins believed to have been centered in northeastern Mexico. This research evaluates the utility of a sequence-based approach for two mitochondrial (COI and ND6) gene regions. We use these markers to examine genetic diversity, estimate population structure, and identify diagnostic information for A. ludens populations. We analyzed 543 individuals from 67 geographic collections and found one predominant haplotype occurring in the majority of specimens. We observed 68 haplotypes in all and see differences among haplotypes belonging to northern and southern collections. Mexico haplotypes differ by few bases possibly as a result of a recent bottleneck event. In contrast to the hypothesis suggesting northeastern Mexico as the origin of this species, we see that specimens from two southern collections show high genetic variability delineating three mitochondrial groups. These data suggest that Central America is the origin for A. ludens. We show that COI and ND6 are useful for phylogeographic studies of A. ludens.


MAO A VNTR polymorphism and variation in human morphology: a VBM study.
The X-linked monoamine oxidase A (MAO A) gene, coding for an enzyme especially involved in the serotonin catabolism, presents a well-characterized functional polymorphism (long and short variants) in the promoter region that alters the transcriptional activity of the gene and hence the function of the corresponding proteins. Using optimized voxel-based morphometry, we studied the effect of this functional polymorphism on brain morphology in normal individuals. Fifty-nine male healthy individuals (33 MAO A-high and 26 MAO A-low) were investigated. Voxel-based morphometry showed that the carriers of the long variant were significantly associated with loss of grey matter in orbitofrontal cortex, bilaterally. This study reveals pronounced genotype-related structural changes in a specific prefrontal region previously observed to mediate neurofunctional responses in behavioral tasks.


Determination of orally coadministered nadolol and its deuterated analogue in human serum and urine by gas chromatography with selected-ion monitoring mass spectrometry.
A cartridge serum and urine extraction procedure of the beta-adrenergic antagonist, nadolol, employing a cross-linked styrene-divinyl benzene macroreticular resin is described. Samples were analyzed as the silylated derivative by gas chromatography-mass spectrometry (GC-MS) using selected-ion monitoring. When nadolol was orally coadministered with its deuterated analogue, relative bioavailability could be demonstrated with six or fewer subjects. Employing a base-deactivated GC phase, the limit of detection is 1 ng and 0.5 ng/mL of serum for nadolol and the deuterated analogue, respectively. For levels of less than 10 ng/mL, the respective coefficients of variation are 4 and 2%. For concentrations of greater than 10 ng/mL, the CV is 1% for nadolol and nadolol-d9.


Contribution of skin thermal sensitivities of large body areas to sweating response.
The thermal sensitivity of different parts of the body was investigated by heating large areas of the body surface while the mean skin temperature calculated from Hardy and DuBois ' formula (1938) was always kept constant. The right arm sweating responses recorded under a local thermal clamp were related to changes in segmental skin temperatures of the different parts of the body. The results show that: 1) the various local peripheral signals are projected into integrating structures in the central nervous system; 2) the thermal sensitivity is greater for the head-and-trunk area in comparison with other parts of the body. For resting nude subjects, the formula of Hardy and DuBois remains a pertinent way for evaluating the role of skin thermal signals in the central drive for sweating. The peripheral contribution to the central sweating drive depends only on the skin temperature change and on the size of the stimulated area.


[Increased DMT1 expression and iron content in MPTP-treated C57BL/6 mice].
Iron plays a key role in Parkinson s disease (PD). To illustrate the mechanism underlying the increase of iron in substantia nigra (SN) in PD, changes of the expression of divalent metal transporter 1 (DMT1) and iron content were examined in SN in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treated mice using immunohistochemistry and histochemistry respectively. Following MPTP treatment for 3 d, elevated iron staining was found in SN. A further increase in iron content was observed after 7 d. In these lesioned animals, tyrosine hydroxylase-immunoreactive DA neurons exhibited a decrease in number and morphological changes as well. There were two isoforms of DMT1 expressed in SN of mice. After MPTP treatment, the expression of DMT1 without IRE form increased in either group, whereas DMT1 with IRE form increased only after 7 d of MPTP treatment. These observations suggest that DMT1 is possibly involved in the process of iron accumulation in SN of MPTP-treated mice, which might be responsible for the subsequent death of DA neurons.


The Urban Emergency Department: A Potential Increased Occupational Hazard for Sharps-related Injuries.
Health care workers are at risk for sharps-related injuries while working in the clinical arena. The authors sought to quantify and compare the frequency of these injuries for all health care personnel between the urban and community emergency department (ED). A retrospective review was performed on the institutional human resources database of all self- or supervisor-reported sharps-related injuries that occurred to ED personnel in a single health system from January 2010 through September 2014. The health system was composed of a single urban academic Level I trauma center and seven community EDs, two of which were academic Level III trauma centers. Each sharps-related injury was reviewed for site of injury, job class, and type of instrument causing the injury. There were 171 sharps-related injuries reported during 447,986 urban and 1,350,623 community patient visits. Of the 171 injuries, 44.4% occurred to physicians, 39.2% to nurses, 12.9% to support staff, and 3.5% to physician assistants. Injuries occurred more frequently at the urban academic medical center when compared to the pooled community sites: 20.3 per 100,000 patient visits (n = 91) versus 5.9 per 100,000 patient visits (n = 80), respectively (odds ratio = 3.43, 95% confidence interval = 2.54 to 4.63, p < 0.001). They also occurred more frequently at the urban site when individually compared to each community site. Physicians accounted for the largest proportion of health care workers reporting sharps-related injuries. These injuries occurred more frequently in the urban ED than in the community EDs.


Accumulation of manganese superoxide dismutase under metal-depleted conditions: proposed role for zinc ions in cellular redox balance.
A diet low in copper results in increased levels of MnSOD (manganese superoxide dismutase), a critical antioxidative enzyme conferring protection against oxidative stress, in rat liver mitochondria. The mechanism for this was investigated using cultured HepG2 cells, a human hepatocellular carcinoma-derived line. MnSOD activity increased 5-7-fold during incubation in a medium supplemented with metal-depleted fetal bovine serum, with a corresponding elevation of its mRNA levels. Metal depletion also decreased CuZnSOD and glutathione peroxidase levels to approx. 70-80% of baseline. When zinc ions were added to the medium at micromolar levels, MnSOD accumulation was suppressed; however, copper ions had essentially no effect on MnSOD expression. Since the intracellular redox status was shifted to a more oxidized state by metal depletion, we examined the DNA-binding activity of NF-kappaB (nuclear factor-kappaB), an oxidative stress-sensitive transactivating factor that plays a primary role in MnSOD induction. A gel shift assay indicated that the DNA-binding activity of NF-kappaB was increased in cells maintained in metal-depleted culture, suggesting the involvement of the transactivating function of NF-kappaB in this induction. This was further supported by the observation that curcumin suppressed both the DNA-binding activity of NF-kappaB and the induction of MnSOD mRNA in cells cultivated under metal-depleted conditions. These results suggest that the level of zinc, rather than copper, is a critical regulatory factor in MnSOD expression. It is possible that a deficiency of zinc in the low-copper diet may be primarily involved in MnSOD induction.


Plasma testosterone levels in the rapist.
Plasma testosterone level was measured in 52 rapists and 12 child molesters who had completed the Buss-Durkee Hostility Inventory, the Megargee Overcontrolled Hostility Scale, and the Michigan Alcoholism Screening Test. The rapists were classified according to the degree of violence during the commission of the rape. The ranges and means of the plasma testosterone level for the rapist and child molester controls were within normal limits. The group of rapists who were judged to be most violent had a significantly higher mean plasma testosterone level than normals, child molesters, and other rapists in this study. Mean Buss-Durkee hostility rating scores for rapists were significantly higher than the mean for normals, but there was no correlation between individual hostility scores and plasma testosterone levels. There was no correlation between age, race, or length of incarceration and plasma testosterone level.


Galactosyltransferase isoenzyme II in the detection of pancreatic cancer: comparison with radiologic, endoscopic, and serologic tests.
We assessed the value of several serologic markers in detecting pancreatic carcinoma in a prospective study of 270 patients. The sensitivity and specificity of galactosyltransferase isoenzyme II (GT-II), carcinoembryonic antigen (CEA), alpha-fetoprotein, ferritin, C1q binding, and ribonuclease were determined. GT-II was the most sensitive (67.2 per cent) and specific (98.2 per cent) for discriminating between benign and malignant disease and was more sensitive and specific than CEA, the next most useful marker. Sensitivity was 64 per cent for ultrasound, 79.4 per cent for computerized body tomography (CBT), and 92.8 per cent for endoscopic retrograde cholangiopancreatography (ERCP). As a single test, only ERCP was more sensitive than GT-II, but more sensitive diagnoses resulted when GT-II was combined with ultrasound (92 per cent), CBT (88 per cent), or ERCP (100 per cent). Serum GT-II may be useful both by itself and in combination with imaging techniques in distinguishing benign from malignant pancreatic disease; however, this test does not discriminate between pancreatic carcinoma and other gastrointestinal neoplasms.


ALDH1L1 variant rs2276724 and mRNA expression predict post-operative clinical outcomes and are associated with TP53 expression in HBV-related hepatocellular carcinoma.
Aldehyde dehydrogenase 1 family member L1 (ALDH1L1) is downregulated in hepatocellular carcinoma (HCC) tumors, and its decreased expression is associated with the poor prognosis of HCC patients. We, therefore, evaluated the effect of single nucleotide polymorphisms (SNPs) of ALDH1L1, and its mRNA expression on the survival of hepatitis B virus (HBV)‑related HCC patients and the association with tumor protein p53 (TP53) expression. ALDH1L1 SNPs in 415 HBV-related HCC patients were genotyped via direct sequencing. Expression profile chip datasets and survival information were obtained from GSE14520. The C allele (CT/CC) carriers of rs2276724 were significantly associated with a favorable prognosis [adjusted P=0.040; adjusted hazard ratio (HR)=0.725; 95% confidence interval (CI)=0.533-0.986]. Joint-effect analyses suggested that the CT/CC genotype of rs2276724 in TP53-negative patients was significantly associated with a decreased risk of death, compared to the TT genotype of rs2276724 in TP53-positive patients (adjusted P=0.037; adjusted HR=0.621; 95% CI=0.396-0.973). Furthermore, low expression of ALDH1L1 predicted a poor prognosis for the HBV-related HCC patients (adjusted P=0.04 for disease-free survival; adjusted P=0.001 for overall survival). Patients with high ALDH1L1 expression and low TP53 expression were significantly associated with a decreased risk of recurrence and death, and patients with a high TP53 expression were also significantly associated with a decreased risk of death in HBV-related HCC, compared with low ALDH1L1 and low TP53 expression. Our results suggest that ALDH1L1 may be a biomarker for predicting postoperative clinical outcomes. Moreover, ALDH1L1-rs2276724 and mRNA expression were associated with TP53 expression in HBV-related HCC patients.


Misoprostol effects on diclofenac-induced cardiorenal changes in salt-sensitive patients with hypertension: the MEDIC Study.
To determine whether coadministration of misoprostol with the nonsteroidal antiinflammatory drug diclofenac lessens the increase in blood pressure and improves the alterations in renal hemodynamics induced by diclofenac. Prospective, randomized, double-blind, placebo-controlled, crossover study. Two university research centers. Nineteen senior (mean age 62 yrs [range 55-73 yrs]), salt-sensitive patients with stage 1 or 2 hypertension. After a 3-week antihypertensive withdrawal lead-in phase, patients received either diclofenac 75 mg alone or diclofenac 75 mg plus misoprostol 200 microg twice/day for 14 days. After a 10-day washout period, patients received the alternate treatment. Blood pressure was measured by 24-hour ambulatory blood pressure monitoring, effective renal plasma flow (ERPF) rate was determined by para-aminohippurate clearance, and glomerular filtration rate (GFR) was measured by iothalamate clearance. Mean arterial pressure (MAP = diastolic blood pressure + 0.33[systolic - diastolic blood pressure]) and rate-pressure product (RPP = systolic blood pressure x heart rate x 10(-2)) were also used to compare treatment groups. Diclofenac alone increased MAP by a mean +/- SEM of 5.0 +/- 1.0 mm Hg and RPP by 337 +/- 181 units compared with baseline. The ERPF rate and GFR decreased by 40.5 +/- 26.9 ml/minute and 14.1 +/- 6.5 ml/minute, respectively. Diclofenac plus misoprostol decreased the diclofenac-induced increase in MAP by 3.3 +/- 1.0 mm Hg (95% confidence interval [CI] 1.1-5.3 mm Hg, p=0.004) and decreased the RPP by 724 +/- 238 units (95% CI 225-1223 units, p=0.007). The ERPF rate increased by 56.1 +/- 35.0 ml/minute (95% CI -24.7-137.0 ml/min, p=0.15) and GFR by 18.1 +/- 7.1 ml/minute (95% CI 1.9-34.5 ml/min, p=0.03). Diclofenac alone was relatively well tolerated; no adverse effects were reported with diclofenac plus misoprostol. In senior salt-sensitive patients with hypertension, coadministration of misoprostol with diclofenac attenuated the blood pressure elevation and renal vasoconstrictive effects of diclofenac and was well tolerated.


Speech production variability in fricatives of children and adults: results of functional data analysis.
This study investigates token-to-token variability in fricative production of 5 year olds, 10 year olds, and adults. Previous studies have reported higher intrasubject variability in children than adults, in speech as well as nonspeech tasks, but authors have disagreed on the causes and implications of this finding. The current work assessed the characteristics of age-related variability across articulators (larynx and tongue) as well as in temporal versus spatial domains. Oral airflow signals, which reflect changes in both laryngeal and supralaryngeal apertures, were obtained for multiple productions of /h s z/. The data were processed using functional data analysis, which provides a means of obtaining relatively independent indices of amplitude and temporal (phasing) variability. Consistent with past work, both temporal and amplitude variabilities were higher in children than adults, but the temporal indices were generally less adultlike than the amplitude indices for both groups of children. Quantitative and qualitative analyses showed considerable speaker- and consonant-specific patterns of variability. The data indicate that variability in /s/ may represent laryngeal as well as supralaryngeal control and further that a simple random noise factor, higher in children than in adults, is insufficient to explain developmental differences in speech production variability.


Primary induction of human CD8+ cytotoxic T lymphocytes and interferon-gamma-producing T cells after smallpox vaccination.
This study measured the ability of a standard smallpox vaccine, given by scarification (by bifurcated needle), to induce primary human vaccinia virus-specific cytotoxic and interferon (IFN)-gamma-producing T lymphocyte responses. Because protection against smallpox may be mediated in part by T cell memory responses induced by vaccination, an analysis of the induction of primary human cytotoxic T lymphocytes (CTL) and IFN-gamma-producing T cell responses was performed. Although smallpox is no longer an epidemic threat under natural conditions, vaccination is still recommended for persons working with vaccinia viruses in the laboratory and for those who may be at risk from the potential use of smallpox virus as a bioterrorism agent. The results demonstrate that smallpox vaccine given by bifurcated needle induces strong vaccinia virus-specific CD8(+) CTL and IFN-gamma-producing T cell responses and provide baseline information useful for planning the immunologic assessment of future smallpox vaccines.


Vibrational effects in laser-driven molecular wires.
The influence of an electron-vibrational coupling on the laser control of electron transport through a molecular wire that is attached to several electronic leads is investigated. These molecular vibrational modes induce an effective electron-electron interaction. In the regime where the wire electrons couple weakly to both the external leads and the vibrational modes, we derive within a Hartree-Fock approximation a nonlinear set of quantum kinetic equations. The quantum kinetic theory is then used to evaluate the laser driven, time-averaged electron current through the wire-leads contacts. This formalism is applied to two archetypical situations in the presence of electron-vibrational effects, namely, (i) the generation of a ratchet or pump current in a symmetrical molecule by a harmonic mixing field and (ii) the laser switching of the current through the molecule.


Inherent variations in CO-H2S-mediated carotid body O2 sensing mediate hypertension and pulmonary edema.
Oxygen (O2) sensing by the carotid body and its chemosensory reflex is critical for homeostatic regulation of breathing and blood pressure. Humans and animals exhibit substantial interindividual variation in this chemosensory reflex response, with profound effects on cardiorespiratory functions. However, the underlying mechanisms are not known. Here, we report that inherent variations in carotid body O2 sensing by carbon monoxide (CO)-sensitive hydrogen sulfide (H2S) signaling contribute to reflex variation in three genetically distinct rat strains. Compared with Sprague-Dawley (SD) rats, Brown-Norway (BN) rats exhibit impaired carotid body O2 sensing and develop pulmonary edema as a consequence of poor ventilatory adaptation to hypobaric hypoxia. Spontaneous Hypertensive (SH) rat carotid bodies display inherent hypersensitivity to hypoxia and develop hypertension. BN rat carotid bodies have naturally higher CO and lower H2S levels than SD rat, whereas SH carotid bodies have reduced CO and greater H2S generation. Higher CO levels in BN rats were associated with higher substrate affinity of the enzyme heme oxygenase 2, whereas SH rats present lower substrate affinity and, thus, reduced CO generation. Reducing CO levels in BN rat carotid bodies increased H2S generation, restoring O2 sensing and preventing hypoxia-induced pulmonary edema. Increasing CO levels in SH carotid bodies reduced H2S generation, preventing hypersensitivity to hypoxia and controlling hypertension in SH rats.


CD154 expression and mRNA stability of activated CD4-positive T cells in patients with systemic lupus erythematosus.
Abstract The expression of CD154 (CD40 ligand) on activated CD4+ T cells is known to be transient and tightly regulated for antigen-specific immune responses, and is increased and prolonged among patients with systemic lupus erythematosus (SLE). We investigated the regulation of CD154 expression by determining the protein and mRNA expression with PMA and ionomycin stimulation in CD4+ T cells, and confirmed their increase and prolongation in SLE T cells. Treatment with actinomycin D, a transcription inhibitor, after PMA and ionomycin stimulation was performed, and the findings revealed that the stability of CD154 mRNA increased significantly in activated SLE T cells compared with that of controls. However, alternations or abnormal sequences were not identified in the 3″ untranslated region, including AU-rich elements and CU-rich sequences, while their partial involvement in the posttranscriptional regulation of CD154 mRNA stability has been reported. With 96 h culture in vitro, the destabilization of CD154 mRNA was demonstrated, resulting in a corresponding decrease and normalization of surface expression on activated SLE T cells. We speculate that the CD154 expression on T cells from SLE patients may be increased and prolonged, with mRNA stabilization being related to a continuous stimulation in vivo.


The four classes of endogenous murine leukemia virus: structural relationships and potential for recombination.
The process by which leukemogenic viruses are generated during the lifetime of certain strains of mice is poorly understood. We have therefore set out to define all the murine leukemia virus-related endogenous proviruses of HRS/J mice. We have cloned 34 different proviral fragments and their flanking cellular sequences. These have been characterized by restriction enzyme analysis, by fingerprinting in vitro-synthesized RNA, and by DNA sequencing. We conclude that all the proviruses can be assigned into one of four different classes: the previously characterized ecotropic, xenotropic, and polytropic viruses, as well as a new class we have termed modified polytropic viruses. The xenotropic, polytropic, and modified polytropic classes are closely related to one another, but as a group they differ considerably from the ecotropic class. Sequence analyses show that both polytropic and modified polytropic sequences can contribute env sequences to recombinant viruses.


Streptococcus pneumoniae-Induced Oxidative Stress in Lung Epithelial Cells Depends on Pneumococcal Autolysis and Is Reversible by Resveratrol.
Streptococcus pneumoniae is the most common cause of community-acquired pneumonia worldwide. During pneumococcal pneumonia, the human airway epithelium is exposed to large amounts of H2O2 as a product of host and pathogen oxidative metabolism. Airway cells are known to be highly vulnerable to oxidant damage, but the pathophysiology of oxidative stress induced by S. pneumoniae and the role of nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated antioxidant systems of the host are not well characterized. For gluthation/gluthathion disulfide analysis BEAS-2B cells, primary broncho-epithelial cells (pBEC), explanted human lung tissue and mouse lungs were infected with different S. pneumoniae strains (D39, A66, R6x, H2O2/pneumolysin/LytA- deficient mutants of R6x). Cell death was proven by LDH assay and cell viability by IL-8 ELISA. The translocation of Nrf2 and the expression of catalase were shown via Western blot. The binding of Nrf2 at the catalase promoter was analyzed by ChIP. We observed a significant induction of oxidative stress induced by S. pneumoniae in vivo, ex vivo, and in vitro. Upon stimulation, the oxidant-responsive transcription factor Nrf2 was activated, and catalase was upregulated via Nrf2. The pneumococci-induced oxidative stress was independent of S. pneumoniae-derived H2O2 and pneumolysin but depended on the pneumococcal autolysin LytA. The Nrf2 inducer resveratrol, as opposed to catalase, reversed oxidative stress in lung epithelial cells. These observations indicate a H2O2-independent induction of oxidative stress in lung epithelial cells via the release of bacterial factors of S. pneumoniae. Resveratrol might be an option for prevention of acute lung injury and inflammatory responses observed in pneumococcal pneumonia.


Equine sarcoidosis: clinical signs, diagnosis, treatment and outcome of 22 cases.
Equine sarcoidosis may present as a generalized or localized exfoliative dermatitis and/or as a granulomatous inflammation of multiple organs. To report the clinical signs, diagnosis, treatment and outcome for 22 horses with histologically confirmed sarcoidosis. Twenty-two horses of different breeds, between 3 and 17 years of age. Diagnosis was based on clinical signs and histopathological findings. The following three forms of equine sarcoidosis were identified: generalized (13.6%), partially generalized (18.2%) and localized (68.2%). High-dose systemic corticosteroids were used as the initial treatment in all three forms, followed by lower doses for a variable number of weeks. No local treatment was prescribed. Case outcome was variable; one of three cases of generalized sarcoidosis was euthanized immediately and the remaining two were euthanized after 2-3 months of unsuccessful treatment; all four cases of partially generalized sarcoidosis deteriorated despite treatment and were euthanized after 3.5-12 months; two cases with localized disease showed no response or insufficient response to treatment and were euthanized; four cases recovered fully with or without treatment, and one showed partial recovery without treatment; and eight cases improved whilst receiving prednisolone but required continuous low doses to maintain remission. Recognition of the different forms of sarcoidosis based on history, clinical appearance and histopathology assisted in making an informed choice between treatment and euthanasia and prevented unnecessary local treatment. Equine sarcoidosis should be included in the differential diagnosis of a localized exfoliative dermatitis of unknown origin.


ECT in acute delirium and related clinical states.
A retrospective investigation of electroconvulsive therapy (ECT)-treated patients in 1992-94 at the Psychiatric Hospital in Aarhus, Denmark showed that en bloc treatment had been given in 39 cases of 420 patient series. The basic diagnoses (according to ICD-10) were severe depressive disorder, bipolar affective disorder mixed state, manic disorder, acute transient psychotic disorder, schizoaffective disorder, and schizophrenia; all patients were in a severely psychotic condition. Eight patients were diagnosed with acute delirium. Delirious symptoms disappeared completely after the first few ECT treatments. Patients were subsequently given supplementary treatment for the underlying disease. ECT is an effective treatment for psychoses complicated by acute delirium.


Pseudotumor Cerebri and Glymphatic Dysfunction.
In contrast to virtually all organ systems of the body, the central nervous system was until recently believed to be devoid of a lymphatic system. The demonstration of a complex system of paravascular channels formed by the endfeet of astroglial cells ultimately draining into the venous sinuses has radically changed this idea. The system is subsidized by the recirculation of cerebrospinal fluid (CSF) through the brain parenchyma along paravascular spaces (PVSs) and by exchanges with the interstitial fluid (IF). Aquaporin-4 channels are the chief transporters of water through these compartments. This article hypothesizes that glymphatic dysfunction is a major pathogenetic mechanism underpinning idiopathic intracranial hypertension (IIH). The rationale for the hypothesis springs from MRI studies, which have shown many signs related to IIH without evidence of overproduction of CSF. We propose that diffuse retention of IF is a direct consequence of an imbalance of glymphatic flow. This imbalance, in turn, may result from an augmented flow from the arterial PVS into the IF, by impaired outflow of the IF into the paravenous spaces, or both. Our hypothesis is supported by the facts that (i) visual loss, one of the main complications of IIH, is secondary to the impaired drainage of the optic nerve, a nerve richly surrounded by water channels and with a long extracranial course in its meningeal sheath; (ii) there is a high association between IIH and obesity, a condition related to paravascular inflammation and lymphatic disturbance, and (iii) glymphatic dysfunction has been related to the deposition of β-amyloid in Alzheimer's disease. We conclude that the concept of glymphatic dysfunction provides a new perspective for understanding the pathophysiology of IIH; it may likewise entice the development of novel therapeutic approaches aiming at enhancing the flow between the CSF, the glymphatic system, and the dural sinuses.


A compensating income variation approach to valuing 34 health conditions in Iceland.
Using data from an Icelandic health-and-lifestyle survey carried out in 2007, 2009, and 2012, we employ a compensating income variation (CIV) approach to estimate the monetary value sufficient to compensate individuals for the presence of various sub-optimal health conditions. This method is inexpensive and easy on subjects and has been applied to several desiderata that do not have revealed market prices. The CIV literature is, however, still limited in its application to health and thus information about its suitability is limited. With the aim of shedding light on the method́s appropriateness we thus provide a broad-view analysis including a spectrum of diseases and conditions that can be held up against more traditionally used methods. CIV for physical conditions vary greatly, but paralysis, fibromyalgia, chronic back pain, rheumatoid arthritis, urinary incontinence, severe headache and thyroid disease were among those consistently associated with substantial well-being reductions. Mental-health results using this method should be read with caution. The societal value of health interventions is multidimensional, including for example increased productivity in the population. However, one of the main positive aspects of increased health is undoubtedly the increased well-being of the treated subjects. Such quality-of-life effects should thus preferably be taken into account. For this reason, information on the value individuals place on recovery from various sub-optimal health conditions is useful when it comes to prioritizing scarce capital in the health sector. It is therefore vital to estimate the importance individuals place on various health states and hold them up against each other. Furthermore, this paper has scientific value as it sheds light on attributes of a potentially useful method in health evaluations.


Serum alpha-fetoprotein estimations and doubling time in hepatocellular carcinoma: influence of therapy and possible value in early detection.
Serial alpha-fetoprotein (AFP) levels, measured from 32 to more than 500 days in 40 patients with hepatocellular carcinoma, accurately reflected a response to chemotherapy or surgery. In patients who failed to respond to chemotherapy and in those who relapsed after initially successful chemotherapy or surgery, AFP concentration rose exponentially with time. The rate of rise as characterized by the doubling time ranged from 6.5 to 112 days (mean, 41 days), correlated positively with survival time, and proved a useful guide to prognosis. Falls in AFP concentrations were associated with a decrease in tumor mass, although the achievement of a normal level did not necessarily imply complete tumor clearance as shown in 2 patients who had been treated by transplantation and in whom the tumor recurred. Data based on AFP concentrations at the time of clinical presentation and AFP doubling time suggest that increasing concentrations of AFP detectable by radioimmunoassay may be present up to 18 months before appearance of symptoms. In this way screening of high-risk groups, i.e., men with cirrhosis, could lead to significantly earlier diagnosis.