Metabolomic changes associated with frontotemporal lobar degeneration syndromes.
Widespread metabolic changes are seen in neurodegenerative disease and could be used as biomarkers for diagnosis and disease monitoring. They may also reveal disease mechanisms that could be a target for therapy. In this study we looked for blood-based biomarkers in syndromes associated with frontotemporal lobar degeneration. Plasma metabolomic profiles were measured from 134 patients with a syndrome associated with frontotemporal lobar degeneration (behavioural variant frontotemporal dementia n = 30, non fluent variant primary progressive aphasia n = 26, progressive supranuclear palsy n = 45, corticobasal syndrome n = 33) and 32 healthy controls. Forty-nine of 842 metabolites were significantly altered in frontotemporal lobar degeneration syndromes (after false-discovery rate correction for multiple comparisons). These were distributed across a wide range of metabolic pathways including amino acids, energy and carbohydrate, cofactor and vitamin, lipid and nucleotide pathways. The metabolomic profile supported classification between frontotemporal lobar degeneration syndromes and controls with high accuracy (88.1-96.6%) while classification accuracy was lower between the frontotemporal lobar degeneration syndromes (72.1-83.3%). One metabolic profile, comprising a range of different pathways, was consistently identified as a feature of each disease versus controls: the degree to which a patient expressed this metabolomic profile was associated with their subsequent survival (hazard ratio 0.74 [0.59-0.93], p = 0.0018). The metabolic changes in FTLD are promising diagnostic and prognostic biomarkers. Further work is required to replicate these findings, examine longitudinal change, and test their utility in differentiating between FTLD syndromes that are pathologically distinct but phenotypically similar.


Recent advances in management of laryngeal cancer.
Laryngeal cancers account for approximately 1.5% (1 approximately 2%) of the total cancers in Korea, and 30% of all head and neck cancers, not including thyroid cancer. Early laryngeal cancer is treated by operation, including transoral laser excision or radiotherapy. Advanced laryngeal cancer has been treated with mutilating operations, such as a total laryngectomy. However, a laryngeal preserving approach, which can improve the quality of life, has recently been tried with advanced laryngeal cancer.


Tumor clonal status predicts clinical outcomes of lung adenocarcinoma with EGFR-TKI sensitizing mutation.
Objectives: Intratumoral heterogeneity is one of major causes of resistance to therapeutic. Here, we evaluated clonal status, which may reflect intratumoral heterogeneity, in lung adenocarcinoma with EGFR-TKI sensitizing mutation (mEGFR) and its clinical implications. Materials and Methods: Customized panel comprised of 71 solid tumor-associated genes were applied to the 77 surgically resected lung adenocarcinoma having mEGFR with curative aim. For comparison, whole exome sequencing (WES) data of 45 TCGA-LUAD with mEGFR were extracted from the GDC dataportal. Clonal status was estimated from the allele frequency of the mutated genes using the Maftools package. Results: In the study cohort, the number of mutations per case detected by customized panel was 5 [4-8], and the number of total mutations or subtypes of mutations was not related clinical parameters, including size of tumor and pStage. The number of subclones showed positive correlation with the maximum diameter of primary tumor (Spearman's rho=0.273, P-value = 0.026). Disease-free survival (DFS) was significantly shorter among cases wherein tumors comprised two or more subclones than the cases in which tumors were comprised of one clone (P-value = 0.006, Log-rank test), and multivariate analysis indicated that the number of subclones was an independent determinant of DFS. In the WES of TCGA-LUAD mEGFR, the characteristics of the mutations did not show significant relationship with clinical parameters whereas the cases with clones with two or more showed poorer overall survival than those with one clone (P-value = 0.038, Log-rank test). Conclusions: Number of subclones comprising the primary lesion was positively correlated with tumor size, and was an independent factor affecting clinical outcome, showing that a description of tumor clonality may be helpful for understanding of disease status.


[Validation of two indices of biological integrity (IBI) for the Angulo River subbasin in Central Mexico].
Efforts to halt freshwater ecosystem degradation in central Mexico can benefit from using bio-monitoring tools that reflect the condition of their biotic integrity. We analyzed the applicability of two fish-based indices of biotic integrity using data from lotic and lentic systems in the Angulo River subbasin (Lerma-Chapala basin). Both independent data from our own collections during two consecutive years, and existing information detailing the ecological attributes of each species, were used to calculate indices of biological integrity for 16 sites in lotic and lentic habitats. We assessed environmental quality by combining independent evaluations water and habitat quality for each site. We found sites with poor, regular and good biotic integrity. Our study did not find sites with good environmental quality. Fish-based IBI scores were strongly and significantly correlated with scores from independent environmental assessment techniques. IBI scores were adequate at representing environmental conditions in most study sites. These results expand the area where a lotic system fish-based IBI can be used, and constitute an initial validation of a lentic system fish-based IBI. Our results suggest that these bio-monitoring tools can be used in future conservation efforts in freshwater ecosystems in the Middle Lerma Basin.


Self-reported diabetes is associated with self-management behaviour: a cohort study.
The purposes of this cohort study were to establish how frequently people with physician-diagnosed diabetes self-reported the disease, to determine factors associated with self-reporting of diabetes, and to evaluate subsequent differences in self-management behaviour, health care utilisation and clinical outcomes between people who do and do not report their disease. We used a registry of physician-diagnosed diabetes as a reference standard. We studied respondents to a 2000/01 population-based health survey who were in the registry (n = 1,812), and we determined the proportion who reported having diabetes during the survey. Baseline factors associated with self-report and subsequent behavioural, utilisation and clinical differences between those who did and did not self-report were defined from the survey responses and from linkage with administrative data sources. Only 75% of people with physician-diagnosed diabetes reported having the disease. People who did self-report were more likely to be male, to live in rural areas, to have longer disease duration and to have received specialist physician care. People who did not report having diabetes in the survey were markedly less likely to perform capillary blood glucose monitoring in the subsequent two years (OR 0.05, 95% CI 0.02 to 0.08). They were also less likely to receive specialist physician care (OR 0.55, 95% CI 0.37 to 0.86), and were less likely to require hospital care for hypo- or hyperglycaemia (OR 0.09, 95% CI 0.01 to 0.28). Many people with physician-diagnosed diabetes do not report having the disease, but most demographic and clinical features do not distinguish these individuals. These individuals are much less likely to perform capillary glucose monitoring, suggesting that their diabetes self-management is inadequate. Clinicians may be able to use the absence of glucose monitoring as a screening tool to identify people needing a detailed evaluation of their disease knowledge.


Epigenetic regulation of the X-linked tumour suppressors BEX1 and LDOC1 in oral squamous cell carcinoma.
The strong associations between oral squamous cell carcinoma (OSCC) and dietary habits such as alcohol consumption (A), betel quid chewing (B) and cigarette smoking (C) and its predominance in men have been well documented; however, systemic analysis of OSCC is limited. Our study applied high-throughput screening methods to identify causative epigenetic targets in a cohort of men with ABC-associated OSCC. We identified BEX1 and LDOC1 as two epigenetically silenced X-linked tumour suppressors and demonstrated a functional link between the transcription of BEX1 and LDOC1 and promoter hypermethylation. Methylation of the BEX1 and LDOC1 promoters was associated significantly (p < 0.0001) with OSCC and were detected in 75% (42/56) and 89% (50/56) of the samples, respectively. We observed concordant increases in the methylation of both genes in 71% (40/56) of the tumours, and potent in vitro and in vivo growth inhibitory effects in OSCC cells ectopically expressing BEX1 and/or LDOC1. Restored expression of BEX1 and LDOC1 suppressed the nuclear factor-κB (NF-κB) signalling pathway, which is the most frequently hyperactivated signalling pathway in OSCC. This suppression might result from decreased p50 and p65 expression. These findings suggest that silencing of BEX1 and LDOC1 by promoter hypermethylation might represent a critical event in the molecular pathogenesis of OSCC and account for the oncogenic effects of ABC exposure and the male predominance of OSCC occurrence. Microarray data are available in the Gene Expression Omnibus (GEO; http://www.ncbi.nlm.nih.gov/geo/)


Controversies in screening with mammography.
Screening with mammography in order to detect early curable breast cancer has been widely used during the last 2-3 decades. Especially an overview of 4 randomised trials in Sweden has shown a convincing short-term relative reduction of the breast cancer mortality while the long-term absolute effect on this mortality has been impossible to study due to screening of the control groups after some years. There is, however, rather general consensus about the value of screening in women above 50 years of age whereas screening in the age group 40-49 is still controversial due to the low rate of mammographically demonstrable cancers and the high rate of recalls for supplementary mammography, clinical examinations and biopsies in relation to cancers found. Recent follow-up of the pooled Swedish randomised trials have shown an about 20% almost significant reduction of the breast cancer mortality in women aged 40-49 at randomisation but the design of these trials does not allow an adequate estimation of the extra benefit obtained by starting periodical screening at age 40 instead of at age 50. The author proposes that screening in the age group 40-49 should be regarded as experimental and subject to proper randomised trials of a type on-going in UK and planned within UICC.


A morphometric and biochemical investigation of the vesiculation of kidney microvilli.
The vesiculation of kidney proximal tubule microvilli has been examined in tissue slices, isolated brush borders and isolated microvilli. Vesiculation could be induced in tissue slices by 2,4-dinitrophenol and anoxia. Cycloheximide and fluoride had no effect. In brush borders and microvilli, the vesiculation was found to be essentially temperature-dependent. Whilst an osmotic swelling could be produced by hypo-osmolar media, the temperature-dependent vesiculation could not be prevented in hyper-osmolar media. Of a wide variety of reagents tested, only glutaraldehyde, mercuric chloride and mersalyl were effective in arresting the vesiculation. Electron micrographs show that vesiculation involves a collapse of the internal structure of the microvillus. However, the collapse was not associated with depolymerization of the microvillus actin filaments. Rather it appeared to be due to the parting of cross-bridges between the membrane and the actin filaments. The nature of these cross-bridges is discussed: it is suggested that alpha-actinin possesses the characteristics for the cross-bridging protein and that vesiculation might be explained by the displacement of alpha-actinin by tropomyosin.


A rare case: Branch retinal vein occlusion associated with the use of tamoxifen.
Tamoxifen-induced ocular complications including cataracts, keratopathies, retinopathy, impaired visual acuity, ocular irritation, optical neuritis, and retinal vein occlusion are uncommonly reported in the literature. Herein, we report on a premenopausal patient with right-side breast carcinoma who received adjuvant tamoxifen therapy (20 mg/day) for 1.5 years and developed sudden visual loss. Fundal examination revealed an obstruction in the branch of the retinal vein. The diagnosis was confirmed by fluorescein angiography and optical coherence tomography. Thus, tamoxifen was switched to an aromatase inhibitor. Tamoxifen-induced ocular complications should be kept in mind when visual symptoms are seen in patients undergoing tamoxifen therapy. In such cases, a complete ocular examination should be performed.


Thymoquinone ameliorates lead-induced suppression of the antioxidant system in rat kidneys.
Objective Alteration of the antioxidant status in the kidneys may be related to lead (Pb) intoxication. The present study aimed to investigate the possible beneficial effect of thymoquinone (TQ), the major active ingredient of the volatile oil of Nigella sativa seeds, on Pb-induced renal antioxidant defense system impairment. Methods A total of thirty two healthy adult male Wistar rats were randomly divided into four equal groups as follows: a control group, which received no treatment; a Pb group, which was exposed to 2,000 ppm of Pb acetate in drinking water; a Pb-TQ group, which was cotreated with Pb plus TQ (5 mg/kg/day, per os); and a TQ group receiving only TQ. All treatments were applied for five weeks. Results TQ alone did not induce any significant changes in the antioxidant defense system. By contrast, Pb exposure significantly decreased reduced glutathione level and superoxide dismutase, glutathione peroxidase, catalase, and glutathione reductase activities in the renal tissue. Interestingly, supplementation with TQ significantly improved the affected antioxidant parameters. Conclusion Our data are the first to provide evidence on the protective effect of TQ against Pb-induced renal antioxidant capacity impairment and suggest that this component might be a clinically promising alternative in Pb nephrotoxicity.


Regulation of proline 3-hydroxylation and prolyl 3-hydroxylase and 4-hydroxylase activities in transformed cells.
Prolyl 3-hydroxylase activity and the extent of collagen proline 3-hydroxylation were studied in six transformed and three control human cell lines. In the transformed cell lines, the enzyme activity was markedly high in two, similar to that in control cells in two and significantly low in two. The extent of proline 3-hydroxylation was markedly high in cell lines with high enzyme activity, but it was also significantly high in some transformed cell lines with enzyme activities similar to those in the controls. The results thus suggest that, in addition to the amount of enzyme activity present, the rate of collagen synthesis also affects the extent of proline 3-hydroxylation in the newly synthesized collagen. The effect of acute cell transformation on prolyl 3-hydroxylase and 4-hydroxylase activities was studied by infecting chick-embryo fibroblasts with Rous sarcoma virus mutant NY68, temperature-sensitive for transformation. At the permissive temperature prolyl 3-hydroxylase activity showed a more rapid increase and decrease than did prolyl 4-hydroxylase activity, the maximal activity for both enzymes being about 2.5 times that in the control chick fibroblasts. When the transformed cells were shifted to the non-permissive temperature the decays in the elevated enzyme activities were similar, suggesting identical half-lives.


Closely related species of birds differ more in body size when their ranges overlap--in warm, but not cool, climates.
Differences in body size are widely thought to allow closely related species to coexist in sympatry, but body size also varies as an adaptive response to climate. Here, we use a sister lineage approach to test the prediction that body size differences between closely related species of birds worldwide are greater for species whose ranges are sympatric rather than allopatric. We further test if body size differences among sympatric versus allopatric species vary with geography, evolutionary distance, and environmental temperatures. We find greater differences in size among sympatric compared with allopatric lineages, but only in closely related species that live where mean annual temperatures are above 25°C. These size differences in warm environments declined with the evolutionary distance between sister lineages. In species living in cooler regions, closely related allopatric and sympatric species did not differ significantly in size, suggesting either that colder temperatures constrain the evolutionary divergence of size in sympatry, or that the biotic selective pressures favoring size differences in sympatry are weaker in colder environments. Our results are consistent with suggestions by Wallace, Darwin, and Dobzhansky that climatic selective pressures are more important in cooler environments (e.g., high elevations and latitudes) whereas biotic selective pressures dominate in warm environments (e.g., lowland tropics).


Effect of plasma membrane fluidity on serotonin transport by endothelial cells.
To evaluate the effect of plasma membrane fluidity of lung endothelial cells on serotonin transport, porcine pulmonary artery endothelial cells were incubated for 3 h with either 0.1 mM cholesterol hemisuccinate, 0.1 mM cis-vaccenic acid, or vehicle (control), after which plasma membrane fluidity and serotonin transport were measured. Fluorescence spectroscopy was used to measure fluidity in the plasma membrane. Serotonin uptake was calculated from the disappearance of [14C]-serotonin from the culture medium. Cholesterol decreased fluidity in the subpolar head group and central and midacyl side-chain regions of the plasma membrane and decreased serotonin transport, whereas cis-vaccenic acid increased fluidity in the central and midacyl side-chain regions of the plasma membrane and also increased serotonin transport. Cis-vaccenic acid had no effect on fluidity in the subpolar head group region of the plasma membrane. These results provide evidence that the physical state of the central and midacyl chains within the pulmonary artery endothelial cell plasma membrane lipid bilayer modulates transmembrane transport of serotonin by these cells.


Absence of classical and atypical (H- and L-) BSE infectivity in the blood of bovines in the clinical end stage of disease as confirmed by intraspecies blood transfusion.
While the presence of bovine spongiform encephalopathy (BSE) infectivity in the blood of clinically affected sheep has been proven by intraspecies blood-transfusion experiments, this question has remained open in the case of BSE-affected cattle. Although the absence of infectivity can be anticipated from the restriction of the agent to neuronal tissues in this species, evidence for this was still lacking. This particularly concerns the production and use of medicinal products and other applications containing bovine blood or preparations thereof. We therefore performed a blood-transfusion experiment from cattle in the clinical end stage of disease after experimental challenge with either classical (C-BSE) or atypical (H- and l-) BSE into calves at 4-6 months of age. The animals were kept in a free-ranging group for 10 years. Starting from 24 months post-transfusion, a thorough clinical examination was performed every 6 weeks in order to detect early symptoms of a BSE infection. Throughout the experiment, the clinical picture of all animals gave no indication of a BSE infection. Upon necropsy, the brainstem samples were analysed by BSE rapid test as well as by the highly sensitive Protein Misfolding Cyclic Amplification (PMCA), all with negative results. These results add resilient data to confirm the absence of BSE infectivity in the donor blood collected from C-, H- and l-BSE-affected cattle even in the final clinical phase of the disease. This finding has important implications for the risk assessment of bovine blood and blood products in the production of medicinal products and other preparations.


The fructose survival hypothesis as a mechanism for unifying the various obesity hypotheses.
The pathogenesis of obesity remains contested. Although genetics is important, the rapid rise in obesity with Western culture and diet suggests an environmental component. Today, some of the major hypotheses for obesity include the energy balance hypothesis, the carbohydrate-insulin model, the protein-leverage hypothesis, and the seed oil hypothesis. Each hypothesis has its own support, creating controversy over their respective roles in driving obesity. Here we propose that all hypotheses are largely correct and can be unified by another dietary hypothesis, the fructose survival hypothesis. Fructose is unique in resetting ATP levels to a lower level in the cell as a consequence of suppressing mitochondrial function, while blocking the replacement of ATP from fat. The low intracellular ATP levels result in carbohydrate-dependent hunger, impaired satiety (leptin resistance), and metabolic effects that result in the increased intake of energy-dense fats. This hypothesis emphasizes the unique role of carbohydrates in stimulating intake while fat provides the main source of energy. Thus, obesity is a disorder of energy metabolism, in which there is low usable energy (ATP) in the setting of elevated total energy. This leads to metabolic effects independent of excess energy while the excess energy drives weight gain.


Rapid measurement of serum water to assess pseudohyponatremia.
Pseudohyponatremia is caused by an increased serum protein or lipid concentration producing a "space-occupying lesion" in serum water. Its presence and magnitude must be assessed in hyponatremic patients with, for example, paraproteinemia or hyperlipemic diabetic coma. In the absence of a direct-reading ion-selective electrode system, a method for measuring the water content of serum is required. We describe two rapid methods for measuring the diffusible water of serum: osmometry before and after dilution and chloride measurement before and after ultrafiltration. Either of these methods allows the true sodium status of a patient's serum to be determined.


Traumatic brain injury probability of survival assessment in adults using iterative random comparison classification.
Trauma brain injury (TBI) is the most common cause of death and disability in young adults. A method to determine the probability of survival (Ps) in trauma called iterative random comparison classification (IRCC) was developed and its performance was evaluated in TBI. IRCC operates by iteratively comparing the test case with randomly chosen subgroups of cases from a database of known outcomes (survivors and not survivors) and determines the overall percentage match. The performance of IRCC to determine Ps in TBI was compared with two existing methods. One was Ps14 that uses regression and the other was predictive statistical diagnosis (PSD) that is based on Bayesian statistic. The TBI database contained 4124 adult cases (mean age 67.9 years, standard deviation 21.6) of which 3553 (86.2%) were survivors and 571 (13.8%) were not survivors. IRCC determined Ps for the survivors and not survivors with an accuracy of 79.0 and 71.4%, respectively, while the corresponding values for Ps14 were 97.4% (survivors) and 40.2% (not survivors) and for PSD were 90.8% (survivors) and 50% (not survivors). IRCC could be valuable for determining Ps in TBI and with a suitable database in other traumas.


Anatomical boundary of the tympanic membrane pars flaccida of the Meriones unguiculatus (Mongolian gerbil).
The pars flaccida of the Meriones unguiculatus (Mongolian gerbil) was in previous studies shown to bulge almost spherically when pressurized, a behavior suggesting that it is suspended by a fixed circular boundary. The question arises whether this "functional" boundary is based on an underlying circular anatomical boundary, an important issue for modeling the middle-ear mechanics. In this article, the boundaries of the Mongolian gerbil pars flaccida were visualized in situ with otomicroscopy and in slides with light microscopy and by micro-CT radiology. For the major part of its circumference, the pars flaccida was found to be suspended by rigid bone, that is, the tympanic legs. The remaining boundary is made up of the terminal portion of the handle of the malleus and the soft tissue of the terminal arches. The attachment to these structures is simple and uncomplicated, and the geometry is regular and symmetric: deviating by only 3.5% from a perfect circular shape. The findings justify the use of a fixed circular boundary as a good approximation for the modeling of pars flaccida deformation in the Mongolian gerbil.


A history of natural membranes in dialysis.
Nature uses various natural membranes to eliminate toxic substances from the blood, mainly in renal failure. The membranes used for this purpose are predominantly those of the gastrointestinal system and the skin. Humans tried to imitate nature, and employed the same membranes for blood purification in patients with renal failure. The beginning of the practice can be dated to at least 4,000 years ago. However, the initiative for such clearing maneuvers was given by the human mind's conception for purifying the cosmos, the polis and the soul. This article traces similarities between such metaphysical tactics and procedures of the applied sciences. It also describes the historical evolution of the use of natural membranes for medical reasons in nephrological patients.


Inhibition of FABP5 attenuates inflammatory bowel disease by modulating macrophage alternative activation.
Fatty acid binding protein 5 (FABP5) is an intracellular chaperone of fatty acid molecules that regulates lipid metabolism and cell growth. However, its role in intestinal inflammation remains enigmatic. Through examination of human tissue samples and single-cell data, we observed a significant upregulation of FABP5 within the mucosa of patients afflicted with ulcerative colitis (UC) and Crohn's disease (CD), predominantly localized in intestinal macrophages. Herein, we investigate the regulation of FABP5-IN-1, a FABP5 inhibitor, on various cells of the gut in an inflammatory environment. Our investigations confirmed that FABP5 ameliorates DSS-induced colitis in mice by impeding the differentiation of macrophages into M1 macrophages in vitro and in vivo. Furthermore, following FABP5-IN-1 intervention, we observed a notable restoration of intestinal goblet cells and tuft cells, even under inflammatory conditions. Additionally, FABP5-IN-1 exhibits a protective effect against DSS-induced colitis by promoting the polarization of macrophages towards the M2 phenotype in vivo. In summary, FABP5-IN-1 confers protection against DSS-induced acute colitis through a multifaceted approach, encompassing the reduction of inflammatory macrophage infiltration, macrophage polarization, regulating Th17/Treg cells to play an anti-inflammatory role in IBD. The implications for IBD are underscored by the comprehensive in vivo and in vitro experiments presented in this article, thereby positioning FABP5 as a promising and novel therapeutic target for the treatment of IBD.


Ancient mitochondrial DNA and ancestry of Paquimé inhabitants, Casas Grandes (A.D. 1200-1450).
The Casas Grandes (Paquimé) culture, located in the Northwest of Chihuahua, Mexico reached its apogee during the Medio Period (A.D. 1200-1450). Paquimé was abandoned by the end of the Medio Period (A.D. 1450), and the ancestry of its inhabitants remains unsolved. Some authors suggest that waves of Mesoamerican immigrants, possibly merchants, stimulated Paquimé's development during the Medio Period. Archaeological evidence suggests possible ties to groups that inhabited the Southwestern US cultures. This study uses ancient DNA analysis from fourteen samples to estimate genetic affinities of ancient Paquimé inhabitants. DNA was extracted from 14 dental ancient samples from Paquimé. PCR and Sanger sequencing were used to obtain mitochondrial control region sequences. Networks, PCoA, and Nei genetic distances were estimated to compare Paquimé haplotypes against available past haplotypes data from Southwestern and Mesoamerican groups. Haplogroups were characterized for 11 of the samples, and the results revealed the presence of four distinct Amerindian mitochondrial lineages: B (n = 5; 45%), A (n = 3; 27%), C (n = 2; 18%) and D (n = 1; 10%). Statistical analysis of the haplotypes, haplogroup frequencies, and Nei genetic distances showed close affinity of Paquimé with Mimbres. Although our results provide strong evidence of genetic affinities between Paquimé and Mimbres, with the majority of haplotypes shared or derived from ancient Southwest populations, the causes of cultural development at Paquimé still remain a question. These preliminary results provide evidence in support of other bioarchaeological studies, which have shown close biological affinities between Paquimé and Mimbres, a Puebloan culture, in the Southwestern US.


Pharmacological interventions for non-ulcer dyspepsia.
The commonest cause of upper gastrointestinal symptoms is non-ulcer dyspepsia (NUD) and yet the pathophysiology of this condition has been poorly characterised and the optimum treatment is uncertain. It is estimated that pound450 million is spent on dyspepsia drugs in the UK each year. This review aims to determine the effectiveness of six classes of drugs (antacids, histamine H2 antagonists, proton pump inhibitors, prokinetics, mucosal protecting agents and antimuscarinics) in the improvement of either the individual or global dyspepsia symptom scores and also quality of life scores patients with non-ulcer dyspepsia. Trials were located through electronic searches of the Cochrane Controlled Trials Register (CCTR), MEDLINE, EMBASE, CINAHL and SIGLE, using appropriate subject headings and text words, searching bibliographies of retrieved articles, and through contacts with experts in the fields of dyspepsia and pharmaceutical companies. All randomised controlled trials (RCTs) comparing drugs of any of the six groups with each other or with placebo for non-ulcer dyspepsia (NUD). Data were collected on dyspeptic symptom scores either individual or global symptom assessments and also quality of life scores and adverse effects. A total of 11775 citations were obtained. 144 trials were retrieved and 94 trials fulfilled our eligibility criteria. However, subsequent data extraction was not possible in 37 trials. Fifty trials were excluded as they did not meet our eligibility criteria. The final 57 trials were included in the final meta-analysis. Prokinetics (12 trials with dichotomous outcomes generating 829 patients; relative risk reduction [RRR] = 50%; 95% confidence intervals [CI] = 30 to 65%) and H2RAs (8 trials generating 1,125 patients; RRR = 30%; 95% CI = 4 to 48%) were significantly more effective than placebo. Proton pump inhibitors (4 trials generating 1,248 patients; RRR = 12%; 95% CI = -1 to 24%) and Bismuth salts (6 trials generating 311 patients; RRR = 40%; 95% CI = -3 to 65%) were superior to placebo but this was of marginal statistical significance. Antacids (one trial generating 109 patients; RRR = -2%; 95% CI = -36% to 24%) and sucralfate (two trials generating 246 patients; RRR = 29%; 95% CI = -40% to 64%) were not statistically significantly superior to placebo. A funnel plot suggested that the prokinetic result could be due to publication bias. The funnel plot of H2RAs did not show any evidence of publication bias but the quality of the trials was generally poor. There is some evidence that anti-secretory therapy may be effective in NUD. The trials evaluating prokinetic therapy are difficult to interpret as the meta-analysis result could have been due to publication bias. Further research using prokinetics and anti-secretory therapy is required before any firm conclusions can be reached. The effect of these drugs is likely to be small and many patients will need to take them on a long-term basis so the therapies assessed need to be inexpensive and well tolerated.


A unique junctional palindromic sequence in mitochondrial DNA from a patient with progressive external ophthalmoplegia.
A polymerase chain reaction (PCR) based procedure was modified to determine the deletion of mitochondrial DNA (mtDNA). The protocol consists of coamplification both of deleted and wild-type segments of mtDNA using a long PCR technique; evaluation of the deleted portion within the amplified DNA segments by restriction enzyme digestion followed by densitometrical analysis; and direct subcloning into a plasmid vector for DNA sequencing. The procedure revealed a 5.3 kb deletion of mtDNA in the biopsied muscle tissue obtained from a patient clinically diagnosed with progressive external ophthalmoplegia. The 5' and 3' sequences at both sides of the breakpoint comprise a 17 bp palindrome and 5 bp tandem repeats, suggesting that the deletion might occur through slipped mispairing and other novel mechanisms. This improved procedure has the potential to detect deletions occurring in the entire length of mtDNA, and mighty be useful for clinical screening of progressive external ophthalmoplegia.


Study of therapy resistance in cancer cells with functional proteome analysis.
Different types of cancer are naturally resistant to many anticancer drugs. Additionally, these tumours develop acquired drug resistance, which includes the classical multidrug resistance (MDR) accompanied by the synthesis of P-glycoprotein, a member of the superfamily of ATP-binding cassette (ABC) transporters. Furthermore, atypical MDR is mediated by several different, some unknown, mechanisms. To overcome chemoresistance problems, antineoplastic drugs are often combined with other modes of therapy, e.g. hyperthermia, where good response has been reported in several experimental tumour models and in advanced cancer patients. The success of this combined anticancer treatment may be limited by an increase in chemoresistance and thermoresistance. A model system to study resistance phenomena is the use of chemoresistant and thermoresistant cancer cell lines. We have established chemoresistant cancer cell lines (gastric and pancreatic carcinoma, fibrosarcoma, melanoma) and now thermoresistant cell lines derived from gastric and pancreatic carcinoma cells and their counterparts that were resistant towards daunorubicin (classical MDR) and mitoxantrone (atypical MDR). Using proteomics, in this paper we evaluate the drug resistance of chemoresistant melanoma cells (parental cell line MeWo and sublines exhibiting drug resistance towards etoposide, cisplatin, fotemustine and vindesine) as a paradigm for analysis of drug resistance phenomena. Additionally, we investigate heat resistance and the interaction of chemoresistance and thermoresistance to identify common pathways using the parental and drug resistant stomach cancer cell lines EPG85-257, EPG85-257RNOV, EPG85-257RDB and their thermoresistant counterparts. Possible implications of differential protein expression will be discussed.


Factorial, Construct, and Predictive Validity of the Motivation for Treatment Scale in Alcohol-Use Disorder Withdrawal Treatment.
The aim of the present study was to examine for the first time the factorial, construct, and predictive validity of the motivation for treatment (MfT) scale in a cohort of patients undergoing inpatient-qualified alcohol withdrawal treatment with the goal of referring patients to further treatment. The MfT scale has previously been evaluated in different settings of substance abuse treatment, revealing factorial ambiguity. To the best of our knowledge, the present study is the first study that conducted comprehensive factor analyses versus separate analyses of the factors conducted in prior studies in order to clarify the aforementioned factorial ambiguity. A total of 249 patients (mean age 45.2 years (SD = 10.3); 34.4% females) with alcohol dependence were assessed. Data were obtained from four inpatient clinics specialized in qualified alcohol withdrawal treatment in Germany. First, confirmatory factor analyses were carried out to examine the fit of the four models discussed in the literature. Second, an exploratory factor analysis was conducted. Correlations of the new factors with other motivational constructs and referral to a subsequent treatment were investigated as measures of construct and predictive validity. None of the four models showed an acceptable fit to the data in confirmatory analyses. The exploratory analysis suggested to eliminate seven items because of inappropriate factor loadings and resulted in a shortened MfT scale, which consists of three factors based on 17 items. For the latent variables "problem recognition," "desire for help," and "treatment readiness," satisfactory composite reliability was found with 0.82, 0.80, and 0.78, respectively. Evidence for predictive validity was found in the correlation between "treatment readiness" and referral to a subsequent treatment. The new shortened MfT scale exhibited remarkable parsimony, which is desirable in settings such as withdrawal treatment, where patients frequently are cognitively or physically impaired. Despite its briefness, construct and predictive validity were better than in the original version of the MfT scale. The factorial validity of the suggested scale needs to be corroborated in further research.


Primary structure of cholera toxin beta-chain: a glycoprotein hormone analog?
The completed sequence of the beta-chain of cholera toxin (103 amino acid residues) was compared to the beta-chains of chorionic gonadotropin, thyrotropin, luteinizing, and follicle stimulating hormones. The overall chemical similarity of the toxin beta-chain to the hormones was not statistically different from random; however, a comparison of the first 40 residues of the toxin beta-chain to the glycoprotein hormones revealed a segment of the hormones which was significantly chemically similar. The probability was less than .003 that the similarity was due to chance.


Hospital variation in episiotomy use and the risk of perineal trauma during childbirth.
Episiotomies are the most frequently performed surgical procedure among United States women, but there are no published epidemiological studies of the extent of variation in episiotomy use among different obstetrical providers, or the outcomes associated with different levels of use. The objective of this study was to assess the extent of hospital variation in the use of episiotomy and the relationship between hospital episiotomy use and the incidence and risk of perineal trauma among women residing in a large urban area in the United States. Linked birth certificate and hospital discharge data pertaining to births to nulliparous women without prolonged labor or obstructed deliveries, and with infants weighing between 2500 and 4000 g, were analyzed for 18 major maternity hospitals. The relationship between episiotomy use and perineal trauma at the hospital level was examined using regression analysis. Hospital episiotomy rates ranged from approximately 20 to 73 percent. The rate of third or fourth degree perineal lacerations varied from a low of 4 percent to a high of more than 13 percent among hospitals. Rates of episiotomy were significantly correlated with rates of a third or fourth degree perineal laceration (r = 0.70; p < 0.01), and with the hospital-specific, adjusted odds ratios for such lacerations (r = 0.65; p < 0.01). Findings from the analysis of epidemiological data for this study population were consistent with those from clinical studies, indicating that liberal as opposed to restrictive use of episiotomy is unwarranted, and probably even harmful. Hospital episiotomy rates exceeded 20 percent in all cases, but such rates appear difficult to justify in face of the evidence.


A novel gene derived from a segmental duplication shows perturbed expression in Alzheimer's disease.
Alzheimer's disease (AD) is a disabling neurodegenerative disorder with onset commonly in late life. Three genes have been identified causing earlier onset AD, and a fourth has been shown to be a risk factor for late onset AD (LOAD), while many more yet unrecognized genes are thought to contribute to susceptibility. Many studies have reported linkage to LOAD on human chromosome 10, where we have identified a parent of origin effect [Bassett SS, Avramopoulos D, Perry RT, Wiener H, Watson B Jr, Go RC, Fallin MD. Am J Med Genet B Neuropsychiatr Genet 141:537-540, (2006), Bassett SS, Avramopoulos D, Fallin D. Am J Med Genet 114:679-686, (2002)]. In this paper, we report on a gene in this region that shows reduced expression with increasing age, reduced expression in females across ages, and further reduction in LOAD patients. In concordance with the observed parent of origin effect on the linkage, this reduction is more pronounced in patients with an affected mother. We discovered this gene while studying the alkaline ceramidase gene (ASAH2); it is a partial paralog of ASAH2, and we call it ASAH2L. It is the result of a partial duplication of ASAH2 on chromosome 10q11.23, just downstream from the sequence with promoter activity. ASAH2L has a polymorphic start codon with a single nucleotide change of the original ASAH2 sequence plus other putative translation start sites that might produce novel proteins. It is expressed in all the tissues we tested including the brain and is an interesting example of the generation of a new gene. Comparison of primate and other mammal genomes suggests that ASAH2L is human specific. Further research would be necessary to determine the function of the ASAH2L transcript and explore any possible involvement in neurodegeneration.


Pilot-scale formation of whey protein aggregates determine the stability of heat-treated whey protein solutions-Effect of pH and protein concentration.
Denaturation and consequent aggregation in whey protein solutions is critical to product functionality during processing. Solutions of whey protein isolate (WPI) prepared at 1, 4, 8, and 12% (wt/wt) and pH 6.2, 6.7, or 7.2 were subjected to heat treatment (85°C × 30 s) using a pilot-scale heat exchanger. The effects of heat treatment on whey protein denaturation and aggregation were determined by chromatography, particle size, turbidity, and rheological analyses. The influence of pH and WPI concentration during heat treatment on the thermal stability of the resulting dispersions was also investigated. Whey protein isolate solutions heated at pH 6.2 were more extensively denatured, had a greater proportion of insoluble aggregates, higher particle size and turbidity, and were significantly less heat-stable than equivalent samples prepared at pH 6.7 and 7.2. The effects of WPI concentration on denaturation/aggregation behavior were more apparent at higher pH where the stabilizing effects of charge repulsion became increasingly influential. Solutions containing 12% (wt/wt) WPI had significantly higher apparent viscosities, at each pH, compared with lower protein concentrations, with solutions prepared at pH 6.2 forming a gel. Smaller average particle size and a higher proportion of soluble aggregates in WPI solutions, pre-heated at pH 6.7 and 7.2, resulted in improved thermal stability on subsequent heating. Higher pH during secondary heating also increased thermal stability. This study offers insight into the interactive effects of pH and whey protein concentration during pilot-scale processing and demonstrates how protein functionality can be controlled through manipulation of these factors.


The forgotten variable? Does the euthanasia method and sample storage condition influence an organisms transcriptome - a gene expression analysis on multiple tissues in pigs.
Transcriptomic studies often require collection of fresh tissues post euthanasia. The chosen euthanasia method might have the potential to induce variations in gene expressions that are unlinked with the experimental design. The present study compared the suitability of 'nitrogen gas in foam' (ANOXIA) in comparison to a non-barbiturate anaesthetic, T-61® (T61), for euthanizing piglets used in transcriptome research. Further, the effect of common tissue storage conditions, RNAlater™ (RL) and snap freezing in liquid nitrogen (LN2), on gene expression profiles were also analysed. On comparison of the 3'mRNA-Seq data generated from pituitary, hypothalamus, liver and lung tissues, no significant differential expression in the protein coding genes were detected between the euthanasia methods. This implies that the nitrogen anoxia method could be a suitable alternative for euthanasia of piglets used in transcriptomic research. However, small nuclear RNAs (snRNAs) that constitute the eukaryotic spliceosomal machinery were found to be significantly higher (log2fold change ≥ 2.0, and adjusted p value ≤ 0.1) in pituitary samples collected using ANOXIA. Non-protein coding genes like snRNAs that play an important role in pre-mRNA splicing can subsequently modify gene expression. Storage in RL was found to be superior in preserving RNA compared to LN2 storage, as evidenced by the significantly higher RIN values in representative samples. However, storage in RL as opposed to LN2, also influenced differential gene expression in multiple tissues, perhaps as a result of its inability to inhibit biological activity during storage. Hence such external sources of variations should be carefully considered before arriving at research conclusions. Source of biological variations like euthanasia method and storage condition can confound research findings. Even if we are unable to prevent the effect of these external factors, it will be useful to identify the impact of these variables on the parameter under observation and thereby prevent misinterpretation of our results.


An in vitro evaluation of the effect of dentin deproteinization on coronal microleakage in endodontically treated teeth.
The most common cause of failure of endodontic therapy is inadequate apical and coronal seal. Proper coronal seal reduces the risk of endodontic failure. Hence, the present study was done to test the role of self-etching primers in reducing microleakage through coronal seal. Following root canal preparation and obturation, 46 specimen teeth were subjected to one of the test methods as follows: Group I - deproteinization with 3% sodium hypochlorite and etching with 37% phosphoric acid; Group II - deproteinization with 3% sodium hypochlorite and chelation with 15% ethylenediaminetetraacetic acid (EDTA) (Glyde) without etching. Group I and Group II were further divided into two subgroups with 10 specimens in each: In subgroup A, Clearfil Liner Bond 2V was used and in subgroup B, Excite was used. Group III (obturated without access restorative material) had six specimens. Spectrophotometric analysis was done to quantitatively analyze the amount of dye leakage. Microleakage values obtained in Group I and Group II were comparable. In Group I, marginally better values were obtained with the Clearfil Liner Bond 2V in comparison with Excite. In Group II, microleakage values obtained with Clearfil Liner Bond 2V and Excite were similar and statistically not significant. In Group III (control) where no access restoratives were placed, maximum leakage was observed. Maximum leakage values were observed in Group III, when obturated without access restorative and when exposed to artificial saliva. Clearfil Liner Bond 2V as a self-etching primer showed better values in preventing microleakage. Deproteinization may be important to reduce microleakage when using the fifth-generation bonding system (Excite) and sixth-generation bonding system (Clearfil Liner Bond 2V).


The metabolomics side of frailty: Toward personalized medicine for the aged.
Frailty encompasses several domains (i.e., metabolic, physical, cognitive). The multisystem derangements underlying frailty pathophysiology, its phenotypic heterogeneity, and the fluctuations of individuals across severity states have hampered a comprehensive appraisal of the condition. Circulating biomarkers emerged as an alleged tool for capturing this complexity and, as proxies for organismal metabolic changes, may hold the advantages of: 1) supporting diagnosis, 2) tracking the progression, 3) assisting healthcare professionals in clinical and therapeutic decision-making, and 4) verifying the efficacy of an intervention before measurable clinical manifestations occur. Among available analytical tools, metabolomics are able to identify and quantify the (ideally) whole repertoire of small molecules in biological matrices (i.e., cells, tissues, and biological fluids). Results of metabolomics analysis may define the final output of genome-environment interactions at the individual level. This entire collection of metabolites is called "metabolome" and is highly dynamic. Here, we discuss how monitoring the dynamics of metabolic profiles may provide a read-out of the environmental and clinical disturbances affecting cell homeostasis in frailty-associated conditions.


Girls' Stuff? Maternal Gender Stereotypes and Their Daughters' Fear.
One of the most robust findings in psychopathology is the fact that specific phobias are more prevalent in women than in men. Although there are several theoretical accounts for biological and social contributions to this gender difference, empirical data are surprisingly limited. Interestingly, there is evidence that individuals with stereotypical feminine characteristics are more fearful than those with stereotypical masculine characteristics; this is beyond biological sex. Because gender role stereotypes are reinforced by parental behavior, we aimed to examine the relationship of maternal gender stereotypes and children's fear. Dyads of 38 mothers and their daughters (between ages 6 and 10) were included. We assessed maternal implicit and explicit gender stereotypes as well as their daughters' self-reported general fearfulness, specific fear of snakes, and approach behavior toward a living snake. First, mothers' fear of snakes significantly correlated with their daughters' fear of snakes. Second, mothers' gender stereotypes significantly correlated with their daughters' self-reported fear. Specifically, maternal implicit gender stereotypes were associated with daughters' fear of snakes and fear ratings in response to the snake. Moreover, in children, self-reported fear correlated with avoidance of the fear-relevant animal. Together, these results provide first evidence for a potential role of parental gender stereotypes in the development and maintenance of fear in their offspring.


ABCG2 dysfunction increases the risk of renal overload hyperuricemia.
ATP-binding cassette transporter, sub-family G, member 2 (ABCG2/BCRP) is identified as a high-capacity urate exporter, and its dysfunction has an association with serum uric acid levels and gout/hyperuricemia risk. Generally, hyperuricemia has been classified into urate "overproduction type," "underexcretion type," and "combined type" based on only renal urate excretion, without considering an extra-renal pathway such as gut excretion. In this study, we investigated the effects of ABCG2 dysfunction on human urate handling and the mechanism of hyperuricemia. Clinical parameters for urate handling including urinary urate excretion (UUE) were examined in 644 Japanese male outpatients with hyperuricemia. The severity of their ABCG2 dysfunction was estimated by genotype combination of two common ABCG2 variants, nonfunctional Q126X (rs72552713) and half-functional Q141K (rs2231142). Contrary to the general understanding that ABCG2 dysfunction leads to decreased renal urate excretion, UUE was significantly increased by ABCG2 dysfunction (P=3.60×10(-10)). Mild, moderate, and severe ABCG2 dysfunctions significantly raised the risk of "overproduction" hyperuricemia including overproduction type and combined type, conferring risk ratios of 1.36, 1.66, and 2.35, respectively. The present results suggest that common dysfunctional variants of ABCG2 decrease extra-renal urate excretion including gut excretion and cause hyperuricemia. Thus, "overproduction type" in the current concept of hyperuricemia should be renamed "renal overload type," which is caused by two different mechanisms, "extra-renal urate underexcretion" and genuine "urate overproduction." Our new concept will lead to a more accurate diagnosis and more effective therapeutic strategy for hyperuricemia and gout.


Gingers and Their Purified Components as Cancer Chemopreventative Agents.
Chemoprevention by ingested substituents is the process through which nutraceuticals and/or their bioactive components antagonize carcinogenesis. Carcinogenesis is the course of action whereby a normal cell is transformed into a neoplastic cell. This latter action involves several steps, starting with initiation and followed by promotion and progression. Driving these stages is continued oxidative stress and inflammation, which in turn, causes a myriad of aberrant gene expressions and mutations within the transforming cell population and abnormal gene expressions by the cells within the surrounding lesion. Chemoprevention of cancer with bioreactive foods or their extracted/purified components occurs primarily via normalizing these inappropriate gene activities. Various foods/agents have been shown to affect different gene expressions. In this review, we discuss how the chemoprevention activities of gingers antagonize cancer development.


Brain-derived neurotrophic factor overexpression induces precocious critical period in mouse visual cortex.
Brain-derived neurotrophic factor (BDNF) is a candidate molecule for regulating activity-dependent synaptic plasticity on the grounds of its expression pattern in developing visual cortex and that of its receptor, trkB (Castr¿n et al., 1992; Bozzi et al., 1995; Schoups et al., 1995; Cabelli et al., 1996), as well as the modulation of these patterns by activity (Castr¿n et al., 1992; Bozzi et al., 1995; Schoups et al., 1995). Infusing trkB ligands or their neutralizing agents, the trkB-IgG fusion proteins, into visual cortex alters the development and plasticity of ocular dominance columns (Cabelli et al., 1995; Riddle et al., 1995; Galuske et al., 1996 ; Gillespie et al., 1996; Cabelli et al., 1997). To test further the physiological role of BDNF, we studied a transgenic mouse that expresses elevated levels of BDNF in primary visual cortex (V1) postnatally (Huang et al., 1999). We found that unlike the infusion experiments, excess BDNF expressed in mouse visual cortex did not block ocular dominance plasticity. Instead, single neurons in V1 of the BDNF transgenic mice were as susceptible to the effects of monocular deprivation (MD) as neurons in wild-type mice, but only during a precocious critical period. At a time when V1 in the wild-type mouse responded maximally to a 4 d MD with a reduction in its response to deprived eye visual stimulation, the transgenic mouse V1 had already passed the peak of its precocious critical period and no longer responded maximally. This finding suggests a role for BDNF in promoting the postnatal maturation of cortical circuitry.


Effects of droperidol on respiratory drive in humans.
The sensitivity of the respiratory center following a single 0.3 mg X kg-1 iv dose of droperidol was determined in eight healthy volunteers by using carbon dioxide (CO2) rebreathing and mouth occlusion pressure measurements (P0.1). There were no significant differences in the mean slopes of the minute ventilation/partial pressure of CO2 (VE/PCO2) and log P0.1/PCO2 relationships between control measurements and those made 30, 60, 90, 150, and 240 min after droperidol administration. However, individual variations in response were present, one subject showing significant (approximately 50%) depression of respiratory drive.


Notch Signaling Augments BMP9-Induced Bone Formation by Promoting the Osteogenesis-Angiogenesis Coupling Process in Mesenchymal Stem Cells (MSCs).
Mesenchymal stem cells (MSCs) are multipotent progenitors that can differentiate into several lineages including bone. Successful bone formation requires osteogenesis and angiogenesis coupling of MSCs. Here, we investigate if simultaneous activation of BMP9 and Notch signaling yields effective osteogenesis-angiogenesis coupling in MSCs. Recently-characterized immortalized mouse adipose-derived progenitors (iMADs) were used as MSC source. Transgenes BMP9, NICD and dnNotch1 were expressed by adenoviral vectors. Gene expression was determined by qPCR and immunohistochem¡stry. Osteogenic activity was assessed by in vitro assays and in vivo ectopic bone formation model. BMP9 upregulated expression of Notch receptors and ligands in iMADs. Constitutively-active form of Notch1 NICD1 enhanced BMP9-induced osteogenic differentiation both in vitro and in vivo, which was effectively inhibited by dominant-negative form of Notch1 dnNotch1. BMP9- and NICD1-transduced MSCs implanted with a biocompatible scaffold yielded highly mature bone with extensive vascularization. NICD1 enhanced BMP9-induced expression of key angiogenic regulators in iMADs and Vegfa in ectopic bone, which was blunted by dnNotch1. Notch signaling may play an important role in BMP9-induced osteogenesis and angiogenesis. It's conceivable that simultaneous activation of the BMP9 and Notch pathways should efficiently couple osteogenesis and angiogenesis of MSCs for successful bone tissue engineering.


Synthesis of 14-membered enediyne-embedded macrocycles.
A concise and practical strategy towards a novel class of 14-membered macrocycles containing an enediyne (Z-3-ene-1,5-diyne) structural unit is described. A highly modular assembly of various precursors via sequential Ugi/Sonogashira reactions allowed the preparation of hybrid enediyne-peptide macrocycles in most cases as single diastereoisomers. Selected macrocyclic compounds showed moderate antiproliferative activity, and can be considered as templates suitable for further diversification in terms of ring size, shape, and stereochemistry.


Convergent pathways of macrophage polarization: The role of B cells.
The construction of an inflammatory microenvironment provides the fuel for cancer development and progression. Hence, solid tumors promote infiltration of leukocyte populations, among which tumor-associated macrophages (TAM) represent a paradigm for cancer-promoting inflammation. TAM orchestrate various aspects of cancer, including diversion and skewing of adaptive responses, cell growth, angiogenesis, matrix deposition and remodelling, the construction of a metastatic niche and actual metastasis, response to hormones and chemotherapeutic agents. Several lines of evidence indicate that TAM show a remarkable degree of plasticity and functional heterogeneity, suggesting that during tumor progression macrophages undergo a phenotypic "switch", eventually exhibiting the alternatively activated, "M2", phenotype that is associated with immunosuppression, promotion of tumor angiogenesis and metastasis. Although recent studies have attempted to address the role of microenvironmental signals on TAM "reprogramming", the interplay between innate and adaptive immunity is emerging as a crucial step of this event. In this issue of the European Journal of Immunology, a study demonstrates that B1 lymphocytes expressing IL-10 play a key role in promoting a pro-tumoral M2-biased phenotype of macrophages. This article defines a new in vivo pathway of macrophage polarization and suggests that targeting B cells is a possible therapeutic intervention to reinstate anti-cancer functions by TAM.


Microbial shifts associated to ENSO-derived thermal anomalies reveal coral acclimation at holobiont level.
The coral microbiome conforms a proxy to study effects of changing environmental conditions. However, scarce information exists regarding microbiome dynamics and host acclimation in response to environmental changes associated to global-scale disturbances. We assessed El Niño Southern Oscillation (ENSO)-derived thermal anomalies shifts in the bacterial microbiome of Pacifigorgia cairnsi (Gorgoniidae: Octocorallia) from the remote island of Malpelo in the Tropical Eastern Pacific. Malpelo is a hot spot of biodiversity and lacks direct coastal anthropogenic impacts. We evaluated the community composition and predicted functional profiles of the microbiome during 2015, 2017 and 2018, including different phases of ENSO cycle. The bacterial community diversity and composition between the warming and cooling phase were similar, but differed from the neutral phase. Relative abundances of different microbiome core members such as Endozoicomonas and Mycoplasma mainly drove these differences. An acclimated coral holobiont is suggested not just to warm but also to cold stress by embracing similar microbiome shifts and functional redundancy that allow maintaining coral's viability under thermal stress. Responses of the microbiome of unperturbed sea fans such as P. cairnsi in Malpelo could be acting as an extended phenotype facilitating the acclimation at the holobiont level.


New surgical techniques and informed consent--safety first.
Surgical techniques always imply uncertainty about risks and outcome. Many law systems explicitly recognise the patient's right with respect to informed decision-making. This right refers to information about the risks and benefits, the experience of the surgeon, and the performance of the surgical team. In practice, the informed consent is difficult to obtain, and patients have often difficulty to recall the adequate information. Especially when risk and benefit assessment has to be done with the focus on a new technology that is expected to prevent disease in the future, safety of this less invasive technique compared with the current strategy is important. Therefore, it is also of importance to look at the mid-term and long-term follow-up. Appropriate knowledge of the technology involved, follow-up data, and risk information provided by a professional safety-committee should be the input of the informed consent procedure.


Mesenchymal stem cell-derived exosomes do not promote the proliferation of cancer cells in vitro.
Nowadays, the use of Mesenchymal stem cells (MSCs) in clinical therapies have an increased acceleration, while it constitutes two sides of yin-yang with its ameliorating effects in regenerative medicine and promoting effects in carcinogenesis. It has been shown that the treatment activities of MSCs are mediated by paracrine factors secreted. These paracrine factors are transmitting via exosomes secreted from MSCs. With the understanding of this mechanism, cell-free therapies have begun to create a new path in MSC based therapies. At this point, two sides of the yin-yang have once again become controversial. In addition, there are conflicting study results in the literature. Due to this contradiction, we have designed this study to demonstrate the role of MSCs in the carcinogenesis process and we investigated the proliferation effect of MSC-derived exosomes on cancer cell lines. Two parallel experimental setups were established, as an experimental group, the four-different epithelial cancer cell lines and Wharton's Jelly (WJ)-MSC derived exosomes were directly co-cultured with in 6 different concentrations and simultaneously in the control group cells were cultured respectively. PKH-26 labelling was performed for detection of exosome locations in co-cultures. Each group were evaluated by WST-1 and xCelligence assays for proliferation and confirmed with PCNA staining. The results were analysed with paired t-test and Newman-Keuls comparison. The relative comparison demonstrated a significant increase in the rate of proliferation only in exosome co-cultures with WJ-MSCs and it was supported by PCNA staining. Cancer cell lines in co-cultures have not shown any significant increase neither in proliferation assays nor in PCNA staining. MSCs regulate their secretions according to the microenvironment, they have more dominant regenerative feature rather than triggering cancer proliferation.


Blood schizontocidal activity of methylene blue in combination with antimalarials against Plasmodium falciparum.
Methylene blue (MB) is the oldest synthetic antimalarial. It is not used anymore as antimalarial but should be reconsidered. For this purpose we have measured its impact on both chloroquine sensitive and resistant Plasmodium strains. We showed that around 5 nM of MB were able to inhibit 50% of the parasite growth in vitro and that late rings and early trophozoites were the most sensitive stages; while early rings, late trophozoites and schizonts were less sensitive. Drug interaction study following fractional inhibitory concentrations (FIC) method showed antagonism with amodiaquine, atovaquone, doxycycline, pyrimethamine; additivity with artemether, chloroquine, mefloquine, primaquine and synergy with quinine. These results confirmed the interest of MB that could be integrated in a new low cost antimalarial combination therapy.


Postnatal growth of tracheobronchial airways of Sprague-Dawley rats.
Rats are widely used for the studies of pulmonary toxicology in both juveniles and adults. To facilitate such studies, investigators have developed models of lung architecture based on manual or computerized airway measurements. However, postnatal growth of conducting airways of rat lungs has never been reported. In this paper, we present conducting airway architecture statistics for male Sprague-Dawley rat lungs at ages 15, 28, 40, and 81 days by analyzing CT images from airway silicon casts. Detailed branching characteristics and intersubject variance are presented. This study shows that (i) airway growth in diameter and length is not linear with age, (ii) growth of airway length is faster than that of diameter during the 15-81-day postnatal period, and (iii) asymmetry in airway diameter (ratio of major to minor daughter diameter) increases with age.


Four-dimensional MRI of renal function in the developing mouse.
The major roles of filtration, metabolism and high blood flow make the kidney highly vulnerable to drug-induced toxicity and other renal injuries. A method to follow kidney function is essential for the early screening of toxicity and malformations. In this study, we acquired high spatiotemporal resolution (four dimensional) datasets of normal mice to follow changes in kidney structure and function during development. The data were acquired with dynamic contrast-enhanced MRI (via keyhole imaging) and a cryogenic surface coil, allowing us to obtain a full three-dimensional image (isotropic resolution, 125 microns) every 7.7 s over a 50-min scan. This time course permitted the demonstration of both contrast enhancement and clearance. Functional changes were measured over a 17-week course (at 3, 5, 7, 9, 13 and 17 weeks). The time dimension of the MRI dataset was processed to produce unique image contrasts to segment the four regions of the kidney: cortex (CO), outer stripe (OS) of the outer medulla (OM), inner stripe (IS) of the OM and inner medulla (IM). Local volumes, time-to-peak (TTP) values and decay constants (DC) were measured in each renal region. These metrics increased significantly with age, with the exception of DC values in the IS and OS. These data will serve as a foundation for studies of normal renal physiology and future studies of renal diseases that require early detection and intervention.


Molecular analysis and physicochemical properties of electrophoretic variants of wild soybean Glycine soja storage proteins.
Cultivated soybeans (Glycine max) are derived from wild soybeans (Glycine soja) and can be crossed with them to produce fertile offspring. The latter exhibit greater genetic variation than the former, suggesting a possibility that wild soybeans contain storage proteins with properties different from and better than those of cultivated soybeans. To identify a wild soybean suitable for breeding a new soybean cultivar, we analyzed seed proteins from 390 lines of wild soybeans by electrophoresis. We found some lines containing electrophoretic variants of glycinin and beta-conglycinin subunits: one line containing a small alpha' subunit of beta-conglycinin and two and five lines containing small A3 and large A4 polypeptides of glycinin, respectively. Beta-Conglycinin and glycinin containing such variant subunits exhibited solubility and emulsifying ability similar to those of the predominant types of wild and cultivated soybeans. Glycinins containing small A3 and large A4 gave a shoulder derived from the start of denaturation at a temperature 4 degrees C lower than that of glycinin from the predominant types of wild and cultivated soybeans, although their thermal denaturation midpoint temperatures were very similar to each other. Cloning and sequencing of the predominant and variant subunit cDNAs revealed that the small alpha' and the small A3 lacked 24 amino acid residues in the extension region and four amino acid residues in the hypervariable region, respectively, and that the large A4 did not have an insert corresponding to the difference in the electrophoretic mobility but Arg279 and Gln305 were replaced by glutamine and histidine, respectively, in the hypervariable region. These suggest that small differences even in the hypervariable region can affect the thermal stability, as well as the electrophoretic mobilities, of the proteins.


Large-scale conformational rearrangement of the α5-helix of Gα subunits in complex with the guanine nucleotide exchange factor Ric8A.
Resistance to inhibitors of cholinesterase 8A (Ric8A) protein is an important G protein-coupled receptor (GPCR)-independent regulator of G protein α-subunits (Gα), acting as a guanine nucleotide exchange factor (GEF) and a chaperone. Insights into the complex between Ric8A and Gα hold the key to understanding the mechanisms underlying noncanonical activation of G-protein signaling as well as the folding of nascent Gα proteins. Here, we examined the structure of the complex of Ric8A with minimized Gαi (miniGαi) in solution by small-angle X-ray scattering (SAXS) and exploited the scattering profile in modeling of the Ric8A/miniGαi complex by steered molecular dynamics (SMD) simulations. A small set of models of the complex featured minimal clash scores, excellent agreement with the experimental SAXS data, and a large-scale rearrangement of the signal-transducing α5-helix of Gα away from its β-sheet core. The resulting interface involved the Gα α5-helix bound to the concave surface of Ric8A and the Gα β-sheet that wraps around the C-terminal part of the Ric8A armadillo domain, leading to a severe disruption of the GDP-binding site. Further modeling of the flexible C-terminal tail of Ric8A indicated that it interacts with the effector surface of Gα. This smaller interface may enable the Ric8A-bound Gα to interact with GTP. The two-interface interaction with Gα described here distinguishes Ric8A from GPCRs and non-GPCR regulators of G-protein signaling.


Anammox activity improved significantly by the cross-fed NO from ammonia-oxidizing bacteria and denitrifying bacteria to anammox bacteria.
Nitric oxide (NO) has been suggested as an obligate intermediate in anaerobic ammonium oxidation (anammox), nitrification and denitrification. At the same time, ammonia-oxidizing bacteria (AOB) and denitrifying bacteria (DNB) are always existed in anammox flora, so what is the role of NO produced from AOB and DNB? Could it accelerate nitrogen removal via the anammox pathway with NO as an electron acceptor? To investigate this hypothesis, nitrogen transforming of an anammox biofilter was analyzed, functional gene expression of anammox bacteria (AnAOB), AOB and DNB were compared, and NO source was verified. For anammox biofilter, anammox contributed to 91.3 % nitrogen removal with only 14.4 % of AnAOB being enriched, while DNB was dominant. Meta-omics analysis and batch test results indicated that AOB could provide NO to AnAOB, and DNB also produced NO via up-regulating nirS/K and down-regulating nor. The activation of the anammox pathway of NH4++NO→N2 caused the downregulation of nirS and nxr in Ca. Kuenenia stuttgartiensis. Additionally, changes in nitrogen transforming pathways affected the electron generation and transport, limiting the carbon metabolism of AnAOB. This study provided new insights into improving nitrogen removal of the anammox system.


Limb girdle muscular dystrophy type 2A presenting with cardiac arrest.
The occurrence of respiratory failure in progressive neuromuscular disorders is well recognized. This failure is observed most commonly in Duchenne dystrophy but sometimes occurs in Becker's, limb-girdle, and facioscapulohumeral dystrophies. Patients usually present acutely or subacutely with cyanosis and cor pulmonale, with severe decompensation often being precipitated by an acute intercurrent infection. However, cardiopulmonary arrest is an uncommon presentation. A male diagnosed with limb-girdle muscular dystrophy type 2A who presented with cardiopulmonary arrest that was precipitated by an upper respiratory tract infection is presented. The nocturnal application of noninvasive intermittent positive pressure ventilation with a bilevel positive airway pressure (Bi-PAP) device improved his symptoms and quality of life without resorting to more-invasive and more-restrictive forms of support. This report demonstrates an unusual presentation of limb-girdle muscular dystrophy and documents that nocturnal nasal administration of continuous airway pressure using the Bi-PAP device may be sufficient to maintain adequate ventilation in such patients.


Work-related subjective experiences among community residents with schizophrenia or schizoaffective disorder.
To develop a self-report scale of subjective experiences of illness perceived to impact on employment functioning, as an alternative to a diagnostic perspective, for anticipating the vocational assistance needs of people with schizophrenia or schizoaffective disorders. A repeated measures pilot study (n(1) = 26, n(2) = 21) of community residents with schizophrenia identified a set of work-related subjective experiences perceived to impact on employment functioning. Items with the best psychometric properties were applied in a 12 month longitudinal survey of urban residents with schizophrenia or schizoaffective disorder (n(1) = 104; n(2) = 94; n(3) = 94). Construct validity, factor structure, responsiveness, internal consistency, stability, and criterion validity investigations produced favourable results. Work-related subjective experiences provide information about the intersection of the person, the disorder, and expectations of employment functioning, which suggest new opportunities for vocational professionals to explore and discuss individual assistance needs. Further psychometric investigations of test-retest reliability, discriminant and predictive validity, and research applications in supported employment and vocational rehabilitation, are recommended. Subject to adequate psychometric properties, the new measure promises to facilitate exploring: individuals' specific subjective experiences; how each is perceived to contribute to employment restrictions; and the corresponding implications for specialized treatment, vocational interventions and workplace accommodations.


Surface Plasmon Enabling Nitrogen Fixation in Pure Water through a Dissociative Mechanism under Mild Conditions.
Nitrogen fixation in a simulated natural environment (i.e., near ambient pressure, room temperature, pure water, and incident light) would provide a desirable approach to future nitrogen conversion. As the N≡N triple bond has a thermodynamically high cleavage energy, nitrogen reduction under such mild conditions typically undergoes associative alternating or distal pathways rather than following a dissociative mechanism. Here, we report that surface plasmon can supply sufficient energy to activate N2 through a dissociative mechanism in the presence of water and incident light, as evidenced by in situ synchrotron radiation-based infrared spectroscopy and near ambient pressure X-ray photoelectron spectroscopy. Theoretical simulation indicates that the electric field enhanced by surface plasmon, together with plasmonic hot electrons and interfacial hybridization, may play a critical role in N≡N dissociation. Specifically, AuRu core-antenna nanostructures with broadened light adsorption cross section and active sites achieve an ammonia production rate of 101.4 μmol g-1 h-1 without any sacrificial agent at room temperature and 2 atm pressure. This work highlights the significance of surface plasmon to activation of inert molecules, serving as a promising platform for developing novel catalytic systems.


Role of neural barriers in the pathogenesis and outcome of Streptococcus pneumoniae meningitis.
Bacterial meningitis is an inflammatory disease of the meninges of the central nervous system (CNS). Streptococcus pneumoniae (S. pneumoniae), Neisseria meningitidis, and Haemophilus influenzae are the major bacterial pathogens causing meningitis with S. pneumoniae being responsible for two thirds of meningitis cases in the developed world. To reach the CNS following nasopharyngeal colonization and bacteraemia, the bacteria traverse from the circulation across the blood brain barrier (BBB) and choroid plexus. While the BBB has a protective role in healthy individuals by shielding the CNS from neurotoxic substances circulating in the blood and maintaining the homeostasis within the brain environment, dysfunction of the BBB is associated with the pathophysiology of numerous neurologic disorders, including bacterial meningitis. Inflammatory processes, including release of a broad range of cytokines and free radicals, further increase vascular permeability and contribute to the excessive neural damage observed. Injury to the cerebral microvasculature and loss of blood flow auto-regulation promote increased intracranial pressure and may lead to vascular occlusion. Other common complications commonly associated with meningitis include abnormal neuronal hyper-excitability (e.g., seizures) and loss of hearing. Despite the existence of antibiotic treatment and adjuvant therapy, the relatively high mortality rate and the severe outcomes among survivors of pneumococcal meningitis in developing and developed countries increase the urgency in the requirement of discovering novel biomarkers for the early diagnosis as well as novel treatment approaches. The present review aimed to explore the changes in the brain vascular barriers, which allow S. pneumoniae to invade the CNS, and describe the resultant brain injuries following bacterial meningitis.


[Utilization of the Famacha method in individual clinic diagnostic of haemonchosis in sheep of south-west of Minas Gerais State].
The aim of this study was to evaluate the efficacy of Famacha method in individual clinical diagnosis of haemonchosis in sheep from the south-west of Minas Gerais. Fifty crossbred Santa Inês ewes were evaluated during 5 months as for conjunctival mucous colour (Famacha method), Packed Cell Volume (PCV), Faecal Egg Counts (FEC), body score and clinic alterations. The score Famacha observed was from 1 to 3, the body score from 2 to 5, the PCV from 20 to 47%, and FEC from 0 to 7,750. The correlations between the parameters evaluated, except Famacha with body score, were highly significant (P < 0.0001). The main genus identified in the coprocultures was Haemonchus (87-100% of total larvae, +/- 93.5%). We observed reduction of 87.33% in the use of anthelmintics on the property. It was concluded that the Famacha method, associated with other diagnostic methods, is a useful tool to detect hemonchosis in sheep.


Nuclear cGAS restricts L1 retrotransposition by promoting TRIM41-mediated ORF2p ubiquitination and degradation.
Cyclic GMP-AMP synthase (cGAS), initially identified as a cytosolic DNA sensor, detects DNA fragments to trigger an innate immune response. Recently, accumulating evidence reveals the presence of cGAS within the nucleus. However, the biological functions of nuclear cGAS are not fully understood. Here, we demonstrate that nuclear cGAS represses LINE-1 (L1) retrotransposition to preserve genome integrity in human cells. Mechanistically, the E3 ligase TRIM41 interacts with and ubiquitinates ORF2p to influence its stability, and cGAS enhances the association of ORF2p with TRIM41, thereby promoting TRIM41-mediated ORF2p degradation and the suppression of L1 retrotransposition. In response to DNA damage, cGAS is phosphorylated at serine residues 120 and 305 by CHK2, which promotes cGAS-TRIM41 association, facilitating TRIM41-mediated ORF2p degradation. Moreover, we show that nuclear cGAS mediates the repression of L1 retrotransposition in senescent cells induced by DNA damage agents. We also identify several cancer-associated cGAS mutations that abolish the suppressive effect on L1 retrotransposition by disrupting the CHK2-cGAS-TRIM41-ORF2p regulatory axis. Together, these findings indicate that nuclear cGAS exhibits an inhibitory function in L1 retrotransposition which could provide avenues for future interventions in both aging and tumorigenesis.


Development of a Low-Cost Arduino-Based Sonde for Coastal Applications.
This project addresses the need for an expansion in the monitoring of marine environments by providing a detailed description of a low cost, robust, user friendly sonde, built on Arduino Mega 2560 (Mega) and Arduino Uno (Uno) platforms. The sonde can be made without specialized tools or training and can be easily modified to meet individual application requirements. The platform allows for internal logging of multiple parameters of which conductivity, temperature, and GPS position are demonstrated. Two design configurations for different coastal hydrographic applications are highlighted to show the robust and versatile nature of this sensor platform. The initial sonde design was intended for use on a Lagrangian style surface drifter that recorded measurements of temperature; salinity; and position for a deployment duration of less than 24 h. Functional testing of the sensor consisted of a 55 h comparison with a regularly maintained water quality sensor (i.e., YSI 6600 sonde) in Mobile Bay, AL. The temperature and salinity data were highly correlated and had acceptable RMS errors of 0.154 °C and 1.35 psu for the environmental conditions. A second application using the sonde platform was designed for longer duration (~3-4 weeks); subsurface (1.5-4.0 m depths) deployment, moored to permanent structures. Design alterations reflected an emphasis on minimizing power consumption, which included the elimination of the GPS capabilities, increased battery capacity, and power-saving software modifications. The sonde designs presented serve as templates that will expand the hydrographic measurement capabilities of ocean scientists, students, and teachers.


Protonation drives the conformational switch in the multidrug transporter LmrP.
Multidrug antiporters of the major facilitator superfamily couple proton translocation to the extrusion of cytotoxic molecules. The conformational changes that underlie the transport cycle and the structural basis of coupling of these transporters have not been elucidated. Here we used extensive double electron-electron resonance measurements to uncover the conformational equilibrium of LmrP, a multidrug transporter from Lactococcus lactis, and to investigate how protons and ligands shift this equilibrium to enable transport. We find that the transporter switches between outward-open and outward-closed conformations, depending on the protonation states of specific acidic residues forming a transmembrane protonation relay. Our data can be framed in a model of transport wherein substrate binding initiates the transport cycle by opening the extracellular side. Subsequent protonation of membrane-embedded acidic residues induces substrate release to the extracellular side and triggers a cascade of conformational changes that concludes in proton release to the intracellular side.


Cardiopulmonary Responses During Clinical and Laboratory Gait Assessments in People With Chronic Stroke.
The 6-Minute Walk Test (6MWT) is a common clinical assessment used to evaluate locomotor function in patients after stroke. Previous work suggests the 6MWT can estimate peak metabolic capacity (VO2peak) without cardiorespiratory assessments during graded exercise tests (GXTs), which may assist with exercise prescription. However, selected research also indicated increased heart rates (HRs) during 6MWTs beyond levels considered safe without GXTs. The goal of this study was to examine cardiorespiratory responses during 6MWTs and GXTs in individuals with chronic stroke and their associations with demographic or clinical characteristics. The study used a cross-sectional observational design. Cardiorespiratory responses were assessed during 6MWTs at self-selected velocity (SSV) and fastest velocity (FV), and during GXTs. Secondary assessments included the lower extremity Fugl-Meyer Assessment, Functional Gait Assessment, gait speeds, and daily stepping activity. Correlation and regression analyses were used to evaluate associations between locomotor performance, cardiorespiratory responses, and clinical and demographic characteristics. Average HRs during 6MWT-FV were 72% to 76% of the age-predicted maximum (HRmax), with 20% of participants exceeding 85% predicted HRmax. When normalized to HRs during GXTs, HRs during 6MWT-FV were 86% to 88% of observed HRmax. Primary predictors of increased HRs during 6MWTs were resting HR, body mass index, and daily stepping. Distance during 6MWT-FV was a significant predictor of VO2peak in combination with other variables. Electrocardiographic abnormalities were observed in >80% of participants at rest and 31% demonstrated distinct abnormalities during GXTs, which were not related to 6MWT or GXT performance. In addition to sample size, a primary limitation involved the ability to accurately predict or measure HRmax in patients with motor dysfunction after stroke. Cardiac responses were higher than anticipated during 6MWTs and often exceeded recommended HR thresholds. Clinicians should closely monitor cardiorespiratory responses during 6MWTs.


Single immunoglobulin IL-1 receptor-related protein attenuates the lipopolysaccharide-induced inflammatory response in A549 cells.
The lipopolysaccharide (LPS)-Toll-like receptor 4 (TLR4) signaling pathway in alveolar epithelial cells plays an important role in many pathologic processes such as acute lung injury (ALI). The single immunoglobulin IL-1 receptor-related protein (SIGIRR) is an inhibitor of LPS-TLR4 signaling, but its expression and function in alveolar epithelial cells are still unknown. In this study, we examined the expression of SIGIRR in normal human lung tissue using immunohistochemistry, reverse transcription-PCR (RT-PCR) and Western blot and found that SIGIRR was expressed in alveolar epithelial cells. Treatment of an alveolar epithelial cell line, A549, with LPS and we observed a downregulation of SIGIRR mRNA, which returned to normal levels 24h after LPS exposure. A549 cells were then transfected with a SIGIRR eukaryotic expression vector to over-express SIGIRR or, as a control, with an empty vector. Following LPS exposure, the transcriptional activity of NF-kappaB was measured using a dual-luciferase reporter assay system, and the concentration of IL-1beta, TNF-alpha and IL-6 was determined by ELISA, and cell proliferation was measured by MTT. In A549 cells that over-expressed SIGIRR, LPS treatment resulted in a significant decrease in the transcriptional activity of NF-kappaB and cell growth inhibition ratio, as well as lower levels of secreted IL-1beta, TNF-alpha and IL-6. In conclusion, SIGIRR in A549 cells inhibits the transcriptional activity of NF-kappaB and reduces the amount cytokines produced, protecting these cells from acute LPS-induced damage.


[Establishment of the plague control system in Russia].
The specialized plague control facilities which began being founded as a system of institutions in Russia in 1897 have made a great contribution to epidemiological well-being against quarantine and particularly menacing diseases. The developmental stages of plague control service in different periods of the country's social life and its place in the general governmental preventive and antiepidemic measures are shown. The paper emphasizes that it is expedient to maintain the antiepidemic readiness of plaque control facilities due the fact that the epidemic situation is due menacing and zoonosis is expected to aggravate in the late 20th to the early 21st centuries.


Progressive solitary sclerosis: Gradual motor impairment from a single CNS demyelinating lesion.
To report patients with progressive motor impairment resulting from an isolated CNS demyelinating lesion in cerebral, brainstem, or spinal cord white matter that we call progressive solitary sclerosis. Thirty patients were identified with (1) progressive motor impairment for over 1 year with a single radiologically identified CNS demyelinating lesion along corticospinal tracts, (2) absence of other demyelinating CNS lesions, and (3) no history of relapses affecting other CNS pathways. Twenty-five were followed prospectively in our multiple sclerosis (MS) clinic and 5 were identified retrospectively from our progressive MS database. Patients were excluded if an alternative etiology for progressive motor impairment was found. Multiple brain and spinal cord MRI were reviewed by a neuroradiologist blinded to the clinical details. The patients' median age was 48.5 years (range 23-71) and 15 (50%) were women. The median follow-up from symptom onset was 100 months (range 15-343 months). All had insidiously progressive upper motor neuron weakness attributable to the solitary demyelinating lesion found on MRI. Clinical presentations were hemiparesis/monoparesis (n = 24), quadriparesis (n = 5), and paraparesis (n = 1). Solitary MRI lesions involved cervical spinal cord (n = 18), cervico-medullary/brainstem region (n = 6), thoracic spinal cord (n = 4), and subcortical white matter (n = 2). CSF abnormalities consistent with MS were found in 13 of 26 (50%). Demyelinating disease was confirmed pathologically in 2 (biopsy, 1; autopsy, 1). Progressive solitary sclerosis results from an isolated CNS demyelinating lesion. Future revisions to MS diagnostic criteria could incorporate this presentation of demyelinating disease.


The role of violence in street crime: a qualitative study of violent offenders.
Studies on the motivation for violent street crime, such as robbery and assault, have tended to draw on either the rational choice or the subcultural perspective. This study explores the extent to which violence on the street can be explained by rational factors associated with the successful commission of the offence or social factors related to street culture. The study is based on qualitative interviews with 55 violent street offenders who were serving sentences for street robbery and assault in six prisons in the United Kingdom. The findings, based on accounts of 101 incidents of street violence, identified four main explanations for street violence: (a) successful offence enactment, (b) buzz and excitement, (c) status and honor, and (d) informal justice. The article concludes that there might be benefits in combining the insights of both perspectives by generating an integrated theory that would properly explain both the rational and the seemingly irrational components of street violence.


Salmonella infection of afferent lymph dendritic cells.
The interactions of Salmonella enterica subspecies I serotype Abortusovis (S. Abortusovis) with ovine afferent lymph dendritic cells (ALDCs) were investigated for their ability to deliver Maedi visna virus (MVV) GAG p25 antigens to ALDCs purified from afferent lymph. Salmonellae were found to enter ALDC populations by a process of cell invasion, as confirmed by electron and confocal microscopy. This led to phenotypical changes in ALDC populations, as defined by CD1b and CD14 expression. No differences in the clearance kinetics of intracellular aroA-negative Salmonella from CD1b+ CD14lo and CD1b+ CD14(-) ALDC populations were noted over 72 h. ALDCs were also shown to present MVV GAG p25 expressed by aroA-negative S. Abortusovis to CD4+ T lymphocytes. Thus, the poor immune responses that Salmonella vaccines elicited in large animal models compared with mice are neither a result of an inability of Salmonella to infect large animal DCs nor an inability of these DCs to present delivered antigens. However, the low efficiency of infection of ALDC compared with macrophages or monocyte-derived DCs may account for the poor immune responses induced in large animal models.


Face lifting in the massive weight loss patient: modifications of our technique for this population.
The authors evaluated their experience with facial rejuvenation in the massive weight loss patient. A retrospective chart review of the senior author's (R.J.R) face-lift patients was conducted. Data on patient age and body mass index, surgical techniques used (when available), and intraoperative and postoperative complications were collected. Of the senior author's 25-year database of 1089 patients, 22 were identified (15 women and seven men). Nineteen patients had primary face lifts performed; three patients were secondary cases. Average age at face lift was 52.7 years (range, 41.0 to 67.0 years). Body mass index at the time of surgery was 26.0. There were no intraoperative complications. Postoperative complications included one hematoma that responded to drainage. Nineteen patients (86 percent) had volume loss in the midface and nasolabial groove regions. Thirteen patients (59 percent) had perioral volume loss, all had skin excess and redundancy in the jowl and submental region, and 18 (82 percent) had documented platysmal bands. The superficial musculoaponeurotic system (SMAS) was addressed in 20 patients (91 percent) with a SMASectomy. Fat augmentation was performed in all patients. On average, almost twice as much fat was used (22 ml versus 12 ml in non-massive weight loss patients). In the massive weight loss population, there are common techniques that can enhance results. (1) Individualized components analysis can be used; (2) to treat laxity of skin and deflation of fat compartments, twice as much fat augmentation is needed; (3) SMASectomy is used for redundant skin; and (4) SMAS neck suspension sutures are used in thicker-skinned patients. Therapeutic, IV.


[The place of sexual health in general medicine].
Objective : Assessment of the practices and knowledge of general practitioners in Bouche du Rhône and Vaucluse regarding their patients's sexual health. Method : A descriptive cross-sectional study was conducted among general practitioners in Bouche du Rhône and Vaucluse from January 12, 2023 to February 9, 2023. A questionnaire was developed and sent to general practitioners practicing in Bouche du Rhône and Vaucluse. It was distributed by personal and professional emails and numbers, and Bouche du Rhône and Vaucluse's medical order. The questionnaire was divided into three parts : the first collected demographic and epidemiological data, the second assessed knowledge and practices of general practitioners regardind the sexual health, and the last evaluated practitioners's obstacles to talking about sexual health. Results : 99 general practitioners responded to the questionnaire (99/276, 35,9%). 30,3% obtained a rate of correct answers> 60%. The general practitioners with the best response rates had training in sexology or a degree in gynecology (p=0,0109). In their practices, some topics such as contraception for adolescents, the reassessment of contraception, the search for vulvuvaginal disorders in postmenopausal patients are more addresses by doctors and in particular those of the female sex. Other topics such as sexual violence, male sexual dysfunction and sexual health in patients over 70 are less discussed in consultation. Conclusion : The care of sexual health is an important part of global health, specific to the profession of general practitioner. The results of our study suggest that the knowledge and practices of general practitioners in Bouche du Rhône and Vaucluse, is perfectible. The establishment of professionnel training, consultation dedicated to prevention, or even better awareness of sexual health professionals would promote a better screening.