NeuroD1 mediates nicotine-induced migration and invasion via regulation of the nicotinic acetylcholine receptor subunits in a subset of neural and neuroendocrine carcinomas.
Cigarette smoking is a major risk factor for acquisition of small cell lung cancer (SCLC). A role has been demonstrated for the basic helix-loop-helix transcription factor NeuroD1 in the pathogenesis of neural and neuroendocrine lung cancer, including SCLC. In the present study we investigate the possible function of NeuroD1 in established tumors, as well as actions early on in pathogenesis, in response to nicotine. We demonstrate that nicotine up-regulates NeuroD1 in immortalized normal bronchial epithelial cells and a subset of undifferentiated carcinomas. Increased expression of NeuroD1 subsequently leads to regulation of expression and function of the nicotinic acetylcholine receptor subunit cluster of α3, α5, and β4. In addition, we find that coordinated expression of these subunits by NeuroD1 leads to enhanced nicotine-induced migration and invasion, likely through changes in intracellular calcium. These findings suggest that aspects of the pathogenesis of neural and neuroendocrine lung cancers may be affected by a nicotine- and NeuroD1-induced positive feedback loop.


Fast mapping of words and story recall by individuals with Down syndrome.
This study compared adolescents with Down syndrome to nonverbal mental-age matched controls in their ability to fast map new noun vocabulary in spoken story contexts. Context for novel words varied within subjects in the distance between mentions (close-distant) and the ease of inferring a real word for the referent (specificity). The 23 participants with Down syndrome (DS) were aged 12.8-20.3 years. The 24 typically developing (TD) children, matched on visual nonverbal mental age (MA), were 4.1 to 6.1 years old. Participants listened to 4 tape-recorded stories, each containing 3 mentions of 2 novel words in close or distant proximity and with clear or uncertain reference, and recalled each story after presentation. Fast-mapping production was measured by the occurrence of the novel word in story recall. Fast-mapping comprehension was measured by asking children to define the novel words. The DS group did not differ from the TD group in novel word production but seemed to have more difficulty with novel word definition. For both groups, novel word production was higher in the nonspecific than the specific referent condition, suggesting that availability of a real word label interfered with fast mapping. Recall of story propositions was poorer for the DS group. For both groups, story recall was better for text units not directly associated with novel words than for text units containing novel words, suggesting a trade-off effect in processing. Regression analyses indicated that syntax comprehension, rather than mean length of utterance, predicted novel word production in both groups; MA additionally contributed to predict DS story recall.


Nerolidol and its Pharmacological Application in Treating Neurodegenerative Diseases: A Review.
Research on natural bioactive compounds has increased exponentially over the last decades. The discovery of new phytochemicals that possess pharmaceutical properties is useful in the development of therapeutic alternatives. The nerolidol (3,7,11-trimetil-1,6,10-dodecatrien-3-ol or 3,7,11-trimetildodeca-1,6,10-trien-3-ol) has been extensively studied for its therapeutic potential because of its pharmacological activities in the treatment of neurodegenerative diseases. All articles and patents regarding nerolidol and its pharmacological properties were revised, focusing mainly on the important properties in the treatment of neurodegenerative diseases. A thorough search in article databases (Science Direct, MEDLINE/PubMed, Scopus and Scielo) and patent database (WIPO, EPO, ESPTO, LATIPAT and INPI) was performed over the course of this study. Several studies stood out for their relevance regarding the treatment of neurodegenerative diseases. Nerolidol demonstrated anticholinesterasic, antioxidant, antinociceptive, anti-inflammatory and anxiolytic activities, thus classifying it as a promising phytochemical for the development of therapeutic drugs. Analysis suggested that nerolidol is a promising target for new drugs and treatment of neurodegenerative diseases.


Somatostatin receptor subtype 2-mediated uptake of radiolabelled somatostatin analogues in the human kidney.
Renal irradiation is a dose-limiting factor in peptide receptor radionuclide therapy using radiolabelled somatostatin analogues. This irradiation is mainly caused by reabsorption of radiolabelled peptides in the proximal tubule. In the human kidney, somatostatin receptors are expressed in the vasa recta, tubuli and glomeruli. It is not clear to what extent these receptors contribute to the total kidney radioactivity uptake. Retrospectively, [(111)In-DTPA(0)]octreotide scans of ten selected patients with carcinoids (well-differentiated gastrointestinal endocrine tumour) with liver metastases were evaluated. For each patient, two scans were obtained: one scan was performed without (control) and one during treatment with unlabelled octreotide. Kidney, tumour, spleen and liver uptake was measured in both scans. The interval between the two scans per patient varied from 50 to 397 days. Octreotide treatment substantially lowered kidney [(111)In-DTPA(0)]octreotide uptake in eight out of ten patients. Kidney uptake in all patients was reduced to 82%+/-15% of control, (p < 0.01). A correlation between kidney uptake and spleen uptake was found (r=0.67, p < 0.05). Serum creatinine was unchanged. Surprisingly, tumour and liver [(111)In-DTPA(0)]octreotide uptake was not significantly influenced by unlabelled octreotide therapy, but spleen uptake was significantly lowered by treatment (30.6% of control, p < 0.002). We conclude that the somatostatin receptor plays a role in the total renal uptake of radiolabelled somatostatin analogues. The long interval between scans might explain the finding that tumour and liver metastasis uptake of [(111)In-DTPA(0)]octreotide was unchanged. Further studies are needed to confirm and eludicate the results of this study.


Chronic granulomatous disease: lessons from a rare disorder.
Chronic granulomatous disease (CGD) is a rare primary immunodeficiency with X-linked or autosomal recessive inheritance involving defects in genes encoding phox proteins, which are the subunits of the phagocyte NADPH oxidase. This results in failure to produce superoxide anion and downstream antimicrobial oxidant metabolites and to activate antimicrobial proteases. Affected patients are susceptible to severe, life-threatening bacterial and fungal infections and excessive inflammation characterized by granulomatous enteritis resembling Crohn's disease and genitourinary obstruction. Early diagnosis of CGD and rapid treatment of infections are critical. Prophylaxis with antibacterial and mold-active antifungal agents and the administration of interferon-γ has significantly improved the natural history of CGD. Currently, the only cure is allogeneic hematopoietic cell transplant (HCT), although there remains controversy as to which patients with CGD should get a transplant. Allele-based HLA typing of alternative donors, improved supportive care measures, and use of reduced toxicity conditioning have resulted in event-free survival (EFS) of at least 80% even with an unrelated donor and even better when the patient has no active infections/inflammation. Gene correction of CGD would eliminate the risks of graft-versus-host disease (GVHD) and the immunoablative chemotherapy required for allogeneic HCT. Based on gene therapy trials in patients with SCID-X1, ADA-SCID, and the early experience with CGD, it is clear that at least some degree of myeloablation will be necessary for CGD as there is no inherent selective growth advantage for gene-corrected cells. Current efforts for gene therapy focus on use of lentivector constructs, which are thought to be safer from the standpoint of insertional mutagenesis and more efficient in transducing hematopoietic stem cells (HSCs).


Aid effectiveness and programmatic effectiveness: a proposed framework for comparative evaluation of different aid interventions in a particular health system.
Against a backdrop of changing concepts of aid effectiveness, development effectiveness, health systems strengthening, and increasing emphasis on impact evaluation, this article proposes a theory-driven impact evaluation framework to gauge the effect of aid effectiveness principles on programmatic outcomes of different aid funded programs in the health sector of a particular country. The foundation and step-by-step process of implementing the framework are described. With empirical evidence from the field, the steps involve analysis of context, program designs, implementation mechanisms, outcomes, synthesis, and interpretation of findings through the programs' underlying program theories and interactions with the state context and health system. The framework can be useful for comparatively evaluating different aid interventions both in fragile and non-fragile state contexts.


Testing for food-borne parasites, their metabolic products and symbionts.
Microscopic animals associated with foods include free-living and saprophytic invertebrates, parasites of hosts other than humans, and parasitic animals specifically designated as food-borne that can infect a human host by the gastrointestinal route. The first general method used to screen for food-borne species was digestion with pepsin and hydrochloric acid at 36 degrees C, based on the "artificial stomach juice" technique for recovering larvae of the nematode Trichinella spiralis from muscle. This method selects for forms capable of surviving a mammalian digestive enzyme at mammalian temperatures. It has been used successfully to recover a variety of food-borne helminths, not only from mammalian flesh but also from fish, shellfish and molluscs, and can be adapted to greatly reduce the "background of living animals" associated with soils and the crops grown in them. However, not all animal forms that survive digestion are food-borne parasites, and all that succumb are not necessarily noninfectious. Methodology to test for food-borne parasites is, in general, not as efficient as that for food-borne bacteria. Recent developments in food parasitology indicate a need to identify not only the parasite, but also its metabolic products and associated symbionts.


Dendritic silica nanomaterials (KCC-1) with fibrous pore structure possess high DNA adsorption capacity and effectively deliver genes in vitro.
The pore size and pore structure of nanoporous materials can affect the materials' physical properties, as well as potential applications in different areas, including catalysis, drug delivery, and biomolecular therapeutics. KCC-1, one of the newest members of silica nanomaterials, possesses fibrous, large pore, dendritic pore networks with wide pore entrances, large pore size distribution, spacious pore volume and large surface area--structural features that are conducive for adsorption and release of large guest molecules and biomacromolecules (e.g., proteins and DNAs). Here, we report the results of our comparative studies of adsorption of salmon DNA in a series of KCC-1-based nanomaterials that are functionalized with different organoamine groups on different parts of their surfaces (channel walls, external surfaces or both). For comparison the results of our studies of adsorption of salmon DNA in similarly functionalized, MCM-41 mesoporous silica nanomaterials with cylindrical pores, some of the most studied silica nanomaterials for drug/gene delivery, are also included. Our results indicate that, despite their relatively lower specific surface area, the KCC-1-based nanomaterials show high adsorption capacity for DNA than the corresponding MCM-41-based nanomaterials, most likely because of KCC-1's large pores, wide pore mouths, fibrous pore network, and thereby more accessible and amenable structure for DNA molecules to diffuse through. Conversely, the MCM-41-based nanomaterials adsorb much less DNA, presumably because their outer surfaces/cylindrical channel pore entrances can get blocked by the DNA molecules, making the inner parts of the materials inaccessible. Moreover, experiments involving fluorescent dye-tagged DNAs suggest that the amine-grafted KCC-1 materials are better suited for delivering the DNAs adsorbed on their surfaces into cellular environments than their MCM-41 counterparts. Finally, cellular toxicity tests show that the KCC-1-based materials are biocompatible. On the basis of these results, the fibrous and porous KCC-1-based nanomaterials can be said to be more suitable to carry, transport, and deliver DNAs and genes than cylindrical porous nanomaterials such as MCM-41.


[A non-Q wave myocardial infarct with an up or down shift of the ST segment in the acute phase: the clinical, echocardiographic, ergometric and coronary angiographic correlates].
To assess the significance of ST segment shift during the acute phase of non-Q myocardial infarction we studied the clinic echocardiographic, ergometric and coronarographic findings of 46 patients with a first non-Q wave myocardial infarction. The study population was subdivided in 2 subgroups on the basis of acute electrocardiographic change (Group I with ST elevation, Group II with ST depression). Patients with ST elevation had little myocardial infarction with enzymatic (early CPK peak) and coronarographic (low prevalence of coronary occlusion) signs of early spontaneous fibrinolysis. The second group had more diffuse myocardial infraction, higher prevalence of multivessel coronary disease and positive stress test. The ECG changes in this subgroup an probably due to subendocardial necrosis for the presence of collateral flow. The worse intrahospital prognosis of patients with ST segment depression may be related to cardiac function and age.


Clinical phenotypes and survival of pre-capillary pulmonary hypertension in systemic sclerosis.
Pre-capillary pulmonary hypertension (PH) in systemic sclerosis (SSc) is a heterogeneous condition with an overall bad prognosis. The objective of this study was to identify and characterize homogeneous phenotypes by a cluster analysis in SSc patients with PH. Patients were identified from two prospective cohorts from the US and France. Clinical, pulmonary function, high-resolution chest tomography, hemodynamic and survival data were extracted. We performed cluster analysis using the k-means method and compared survival between clusters using Cox regression analysis. Cluster analysis of 200 patients identified four homogenous phenotypes. Cluster C1 included patients with mild to moderate risk pulmonary arterial hypertension (PAH) with limited or no interstitial lung disease (ILD) and low DLCO with a 3-year survival of 81.5% (95% CI: 71.4-88.2). C2 had pre-capillary PH due to extensive ILD and worse 3-year survival compared to C1 (adjusted hazard ratio [HR] 3.14; 95% CI 1.66-5.94; p = 0.0004). C3 had severe PAH and a trend towards worse survival (HR 2.53; 95% CI 0.99-6.49; p = 0.052). Cluster C4 and C1 were similar with no difference in survival (HR 0.65; 95% CI 0.19-2.27, p = 0.507) but with a higher DLCO in C4. PH in SSc can be characterized into distinct clusters that differ in prognosis.


Lipoamide dehydrogenase deficiency due to a novel mutation in the interface domain.
An infant with a neurodegenerative disorder accompanied by lactic acidemia is described. In muscle homogenate, the activity of lipoamide dehydrogenase (LAD), the third catalytic subunit of pyruvate dehydrogenase complex (PDHc), alpha-ketoglutarate dehydrogenase complex (KGDHc), and branched-chain keto acid dehydrogenase complex was reduced to 15% of the control. The activity of PDHc was undetectable and the activity of KGDHc was 2% of the control mean. The immunoreactive LAD protein was reduced to about 10% of the control. Direct sequencing of LAD cDNA revealed only one mutation, substituting Asp for Val at position 479 of the precursor form. The mutation resides within the interface domain and likely perturbs stable dimerization. The phenotypic heterogeneity in LAD deficiency is not directly correlated with the residual LAD activity but rather with its impact on the multienzymatic complex activity.


Associations between untargeted plasma metabolomic signatures and gut microbiota composition in the Milieu Intérieur population of healthy adults.
Host-microbial co-metabolism products are being increasingly recognised to play important roles in physiological processes. However, studies undertaking a comprehensive approach to consider host-microbial metabolic relationships remain scarce. Metabolomic analysis yielding detailed information regarding metabolites found in a given biological compartment holds promise for such an approach. This work aimed to explore the associations between host plasma metabolomic signatures and gut microbiota composition in healthy adults of the Milieu Intérieur study. For 846 subjects, gut microbiota composition was profiled through sequencing of the 16S rRNA gene in stools. Metabolomic signatures were generated through proton NMR analysis of plasma. The associations between metabolomic variables and α- and β-diversity indexes and relative taxa abundances were tested using multi-adjusted partial Spearman correlations, permutational ANOVA and multivariate associations with linear models, respectively. A multiple testing correction was applied (Benjamini-Hochberg, 10 % false discovery rate). Microbial richness was negatively associated with lipid-related signals and positively associated with amino acids, choline, creatinine, glucose and citrate (-0·133 ≤ Spearman's ρ ≤ 0·126). Specific associations between metabolomic signals and abundances of taxa were detected (twenty-five at the genus level and nineteen at the species level): notably, numerous associations were observed for creatinine (positively associated with eleven species and negatively associated with Faecalibacterium prausnitzii). This large-scale population-based study highlights metabolites associated with gut microbial features and provides new insights into the understanding of complex host-gut microbiota metabolic relationships. In particular, our results support the implication of a 'gut-kidney axis'. More studies providing a detailed exploration of these complex interactions and their implications for host health are needed.


Body mass index and percent body fat in a New Zealand multi-ethnic adolescent population.
Abstract Objective. Previous studies show that body mass index (BMI) does not fully explain differences in percent body fat (%BF) between ethnic groups and few studies have investigated this in adolescents. We sought to compare %BF for a given BMI between adolescents from four ethnic groups and to explain ethnic differences in this relationship. Methods. Weight, height and waist circumference were measured in 202 boys and 197 girls (age range 12-19 years; 129 Pacific Island, 91 European, 90 Maori and 89 Asian Indian). Fat mass, appendicular skeletal muscle mass (ASMM), leg length, bone mineral content (BMC), and fat distribution measures were derived from dual-energy X-ray absorptiometry. Results. For the same BMI and age, compared with European boys, %BF in Maori, Pacific Island and Asian Indian boys was 2.8% lower (P=0.017), 5.2% lower (P<0.0001), and 3.5% higher (P=0.0025), respectively. Compared with European girls, %BF, adjusted for BMI, for Maori, Pacific Island and Asian Indian girls was 1.9% lower (P=0.024), 4.1% lower (P<0.0001) and 3.6% higher (P<0.0001), respectively. Adjustment for ASMM, BMC and fat distribution variables, in particular, significantly reduced the differences between ethnic groups. In boys, readily measured variables, conicity index and waist circumference/height, had notable effects on ethnic differences in %BF. Conclusions. Our results show that BMI is not an equivalent measure of %BF between adolescent Europeans, Maori, Pacific Islanders and Asian Indians. Differences in muscularity, bone mass, relative leg length, fat distribution and body shape contribute to this disparity.


Microarray analysis provides new insights into the function of apolipoprotein O in HepG2 cell line.
Apolipoprotein O (apoO) is a new member of the apolipoprotein family. However, data on its physiological functions are limited and inconsistent. Using a microarray expression analysis, this study explored the function of apoO in liver cells. HepG2 cells were treated either with oleic acid or tumor necrosis factor-α for 24 h. mRNA and protein expression of apoO were assessed by quantitative real-time PCR (qRT-PCR) and Western blot respectively. An efficient lentiviral siRNA vector targeting the human apoO gene was designed and constructed. The gene expression profile of HepG2 human hepatocellular carcinoma cells transfected with the apoO silencing vector was investigated using a whole-genome oligonucleotide microarray. The expression levels of some altered genes were validated using qRT-PCR. ApoO expression in HepG2 cells was dramatically affected by lipid and inflammatory stimuli. A total of 282 differentially expressed genes in apoO-silenced HepG2 cells were identified by microarray analysis. These genes included those participating in fatty acid metabolism, such as ACSL4, RGS16, CROT and CYP4F11, and genes participating in the inflammatory response, such as NFKBIZ, TNFSF15, USP2, IL-17, CCL23, NOTCH2, APH-1B and N2N. The gene Uncoupling protein 2 (UCP2), which is involved in both these metabolic pathways, demonstrated significant changes in mRNA level after transfection. It is likely that apoO participates in fatty acid metabolism and the inflammatory response in HepG2 cells, and UCP2 may act as a mediator between lipid metabolism and inflammation in apoO-silenced HepG2 cells.


Cardiorespiratory Fitness as a Moderator of Sleep-Related Associations with Hippocampal Volume and Cognition.
The objective of this study was to understand the associations of sleep and cardiorespiratory fitness with hippocampal volume and global cognition among older adults (n = 30, age = 65.8 years, female = 73.3%). Wrist actigraphy provided objective measures of nighttime sleep including sleep duration, average wake bout length (WBL; sleep disturbance), and wake-to-sleep transition probability (WTSP; sleep consolidation). Cardiorespiratory fitness was quantified via cycle exercise using a modified heart rate recovery approach. Magnetic resonance imaging was used to determine hippocampal volume and the Mini-Mental State Examination was used to assess global cognition. Fitness moderated associations of sleep with hippocampal volume and cognitive performance, whereby the association of WBL-an index of poor sleep-with hippocampal atrophy was stronger among less-fit individuals, and the association of sleep duration with cognitive performance was stronger among more-fit individuals. Across the fitness levels, a longer WBL was associated with lower cognitive performance, and a higher WTSP-an index of more consolidated sleep-was associated with greater hippocampal volume. Sleep and fitness were unrelated to the volume of an amygdala control region, suggesting a degree of neuroanatomical specificity. In conclusion, higher cardiorespiratory fitness may attenuate sleep disturbance-related hippocampal atrophy and magnify the cognitive benefits of good sleep. Prospective studies are needed to confirm these findings.


Visual hallucinations (Charles Bonnet syndrome) associated with neurosarcoidosis.
The Charles Bonnet syndrome (CBS) refers to lucid and complex visual hallucinations in cognitively normal patients with acquired vision loss. It can be associated with any type of vision loss including that related to macular degeneration, corneal disease, diabetic retinopathy, and occipital infarct. Neurosarcoidosis, a multi-systemic inflammatory granulomatous disease affecting both the central and peripheral nervous systems, is rarely associated with CBS. We report a patient with biopsy-confirmed neurosarcoidosis who experienced visual hallucinations following the development of a right seventh-nerve palsy, right facial paresthesia, and bilateral progressive visual loss. This case highlights the importance of recognizing that the CBS can occur in visual loss of any etiology.


Flushing time and storage effects on the accuracy and precision of carbon and oxygen isotope ratios of sample using the Gasbench II technique.
Continuous-flow isotope ratio mass spectrometry interfaced with a Gasbench II is used for automated and faster analyses of delta(13)C and delta(18)O in water, carbonate, and air samples that are accurate and highly precise. Prior to online chemistry and measurement using the Gasbench technique, rubber septa-capped glass vials are routinely flushed to remove air. Due to the small amounts of sample gas required for isotope analyses using current techniques, care should be taken to properly flush these vials to avoid contamination of sample gas with air. Our results indicate that isotopic composition of sample CO(2) gas remains constant when 10 mL vials are flushed (rate of 100 mL/min) for > or =600 s, whereas for vials flushed <600 s, the isotopic composition becomes substantially lighter with decreasing time of flushing, which affects the accuracy of analyses. This largely depends on the isotopic composition (and volume) of air that still remains after flushing. This effect is more pronounced on delta(18)O than on delta(13)C of sample CO(2) gas because there is very little carbon in the air. After 24 h storage in vials with punctured septa, both delta(13)C and delta(18)O of CO(2) become isotopically heavier compared with first day analyses, suggesting time-dependent changes in isotopic composition. The magnitude of shift depends on the concentration and the isotopic composition of CO(2) in laboratory air as well as on fractionation due to outflow of sample gas or inflow of air via punctured septa. Contamination of sample gas with air can be observed as a secondary peak on chromatograms that precedes sample peaks, and the intensity of these peaks depends on the amount of air. Such peaks are always present with short flushing times. For accuracy and better precision, irrespective of the magnitude of the secondary peaks, the analyses should be discarded if these appear in the chromatograms.


[Genetics of dystonia].
The dystonias comprise a heterogeneous group of movement disorders. In contrast to the frequent sporadic forms, a variety of rare familial forms are caused by genetic mutations with mendelian inheritance. In recent years, significant progress has been made with regard to the identification of genes causing dystonia, and to the molecular pathophysiology underlying dystonic symptoms. Currently, 18 gene loci have been described causing primary dystonia, dystonia-plus syndromes or paroxysmal dystonia. The most frequent form of inherited dystonia, according to current knowledge, is early-onset generalized DYT1 dystonia, caused by a deletion of three basepairs, GAG, in the DYT1 (TOR1A) gene. It is thought that the protein encoded by this gene, torsinA, participates in association of the endoplasmatic reticulum and the nuclear envelope with the cytoskeleton and hereby might influence the reaction of cells to various stresses and/or the development of specific neuronal populations involved in movement control in the brain. Other genes which have only recently been identified include: THAP1, causing adolescent-onset primary dystonia of mixed type (DYT6); ATP1A3, responsible for Rapid-Onset Dystonia-Parkinsonism (RDP, DYT12); PRKRA, causing young-onset dystonia-parkinsonism (DYT16); and SLC2A1, causing paroxysmal exertion-induced dystonia with haemolytic anemia (DYT18). Further, five other loci for primary dystonia (DYT2, DYT4, DYT7, DYT13 and DYT17) have been identified, for which the causative genes remain to be discovered.


Revisiting and Implementing the Weber and Ventilatory Functional Classifications in Heart Failure by Cardiopulmonary Imaging Phenotyping.
Background In heart failure, the exercise gas exchange Weber (A to D) and ventilatory classifications (VC-1 to VC-4) historically define disease severity and prognosis. However, their applications in the modern heart failure population of any left ventricular ejection fraction combined with hemodynamics are undefined. We aimed at revisiting and implementing these classifications by cardiopulmonary exercise testing imaging. Methods and Results 269 patients with heart failure with reduced (n=105), mid-range (n=88) and preserved (n=76) ejection fraction underwent cardiopulmonary exercise testing imaging, primarily assessing the cardiac output (CO), mitral regurgitation, and mean pulmonary arterial pressure (mPAP)/CO slope. Within both classes, a progressively lower exercise CO, higher mPAP/CO slopes, and mitral regurgitation (P<0.01 all) were observed. After adjustment for age and sex, Cox proportional hazard regression analyses showed that Weber (hazard ratio [HR], 2.9; 95% CI, 1.8-4.7; P<0.001) and ventilatory classes (HR, 1.4; 95% CI, 1.1-2.0; P=0.017) were independently associated with outcome. The best stratification was observed when combining Weber (A/B or C/D) with severe ventilation inefficiency (VC-4) (HR, 2.7; 95% CI, 1.6-4.8; P<0.001). At multivariable analysis the best hemodynamic determinants of peak oxygen consumption and ventilation to carbon dioxide production slope were CO (β-coefficient, 0.72±0.16; P<0.001) and mPAP/CO slope (β-coefficient, 0.72±0.16; P<0.001), respectively. Conclusions In the contemporary heart failure population, the Weber and ventilatory classifications maintain their prognostic ability, especially when combined. Exercise CO and mPAP/CO slope are the best predictors of peak oxygen consumption and ventilation to carbon dioxide production slope classifications representing the main targets of interventions to impact functional class and, likely, event rate.


Translational Research in Cutaneous Melanoma: New Therapeutic Perspectives.
Melanoma is an aggressive form of skin cancer characterized by poor prognosis and high mortality. The development of targeted agents based on the discovery of driver mutations as well as the implementation of checkpoint inhibitor-based immunotherapy represents a major breakthrough in the treatment of metastatic melanoma. However, in both cases the development of drug resistance and immune escape mechanisms as well as the lack of predictive biomarkers limits their extraordinary clinical efficacy. In this article, we summarize the available therapeutic options for patients with metastatic melanoma, outline the mechanisms implicated in the resistance to both targeted agents and immunotherapy, discuss potential predictive biomarkers and outline future therapeutic approaches under investigation.


[Role of genetic factors in the formation of trace reactions in man].
Trace processes due to presentation of visual nonverbal information, and the dynamics of the bioelectrical parameter (mean level of asymmetry of EEG-waves) were studies in 32 pairs of monozygote and 38 pairs of dizygote twins with twins method. Statistical processing of the data revealed a significant effect of genetic factors on the formation of individual variability of the characteristics of trace processes in humans. The results obtained showed that with increased functional load the intrapair similarity of trace reactions increased in monozygote twins and did not change or decrease in dizygote twins and in unrelated pairs. This fact is interpreted at a dependence of appearance of geneticly determined neurophysiological characteristics on the level of functional activity of the nervous system.


An improved P300-based brain-computer interface.
A brain-computer interface (BCI) is a system for direct communication between brain and computer. The BCI developed in this work is based on a BCI described by Farwell and Donchin in 1988, which allows a subject to communicate one of 36 symbols presented on a 6 x 6 matrix. The system exploits the P300 component of event-related brain potentials (ERP) as a medium for communication. The processing methods distinguish this work from Donchin's work. In this work, independent component analysis (ICA) was used to separate the P300 source from the background noise. A matched filter was used together with averaging and threshold techniques for detecting the existence of P300s. The processing method was evaluated offline on data recorded from six healthy subjects. The method achieved a communication rate of 5.45 symbols/min with an accuracy of 92.1% compared to 4.8 symbols/min with an accuracy of 90% in Donchin's work. The online interface was tested with the same six subjects. The average communication rate achieved was 4.5 symbols/min with an accuracy of 79.5 % as apposed to the 4.8 symbols/min with an accuracy of 56 % in Donchin's work. The presented BCI achieves excellent performance compared to other existing BCIs, and allows a reasonable communication rate, while maintaining a low error rate.


Effects of alpha-tocopheryl acetate and beta-carotene dietary supplementation on the antioxidant enzymes, TBARS and sensory attributes of turkey meat.
1. The aim of the study was to evaluate the effects of alpha-tocopheryl acetate (50 mg/kg) and beta-carotene (15 mg/kg) dietary supplementation on the oxidative status of raw turkey breast and leg muscles assessed by thiobarbituric acid test values, the vitamin E levels and the antioxidant enzyme activities. In parallel, a quantitative descriptive sensory analysis was carried out on cooked, stored and reheated samples. 2. Vitamin E was present in sufficient quantity to reduce oxidation, since iron-induced reactive substances (TBARS) were significantly lower in antioxidant-supplemented treatments. The results suggested that the presence of beta-carotene in the diet limits the accumulation of alpha-tocopherol in turkey muscles. 3. In the present study, there was no conclusive relationship between dietary antioxidant supplementation and endogenous antioxidant enzyme activities. 4. Sensory evaluation showed that a longer supplementation time and dose may be necessary in turkeys to prevent meat from rancidity and warmed-over flavour (WOF). Leg pastiness and stringiness were modified by dietary antioxidant supplementation, indicating the possible synergism between antioxidants and cysteine proteinases in the perception of meat quality. 5. Given the modern trends that lead consumers to increase their consumption of poultry meat, it would be interesting to evaluate the commercial potential and cost effectiveness of routine dietary antioxidant supplementation.


Methodological quality and synthesis of case series and case reports.
Case reports and case series are uncontrolled study designs known for increased risk of bias but have profoundly influenced the medical literature and continue to advance our knowledge. In this guide, we present a framework for appraisal, synthesis and application of evidence derived from case reports and case series. We propose a tool to evaluate the methodological quality of case reports and case series based on the domains of selection, ascertainment, causality and reporting and provide signalling questions to aid evidence-based practitioners and systematic reviewers in their assessment. We suggest using evidence derived from case reports and case series to inform decision-making when no other higher level of evidence is available.


Nucleosome-positioning sequence repeats impact chromatin silencing in yeast minichromosomes.
Eukaryotic gene expression occurs in the context of structurally distinct chromosomal domains such as the relatively open, gene-rich, and transcriptionally active euchromatin and the condensed and gene-poor heterochromatin where its specific chromatin environment inhibits transcription. To study gene silencing by heterochromatin, we created a minichromosome reporter system where the gene silencer elements were used to repress the URA3 reporter gene. The minichromosome reporters were propagated in yeast Saccharomyces cerevisiae at a stable copy number. Conduction of gene silencing through nucleosome arrays was studied by placing various repeats of clone-601 DNA with high affinity for histones between the silencer and reporter in the yeast minichromosomes. High-resolution chromatin mapping with micrococcal nuclease showed that the clone-601 nucleosome positioning downstream of the HML-E gene silencing element was not significantly altered by chromatin silencing. Using URA3 reporter assays, we observed that gene silencing was conducted through arrays of up to eight nucleosomes. We showed that the shorter nucleosome repeat lengths, typical of yeast (167 and 172 bp), were more efficient in conducting silencing in vivo compared to the longer repeats (207 bp) typical of higher eukaryotes. Both the longer and the shorter repeat lengths were able to conduct silencing in minichromosomes independently of clone-601 nucleosome positioning orientations vs. the silencer element. We suggest that the shorter nucleosome linkers are more suitable for conducting gene silencing than the long repeats in yeast due to their higher propensity to support native-like chromatin higher-order folding.


Mortality in adult patients with epilepsy in Taiwan.
To investigate mortality in adult patients with epilepsy in Taiwan, a total of 263 patients with epilepsy aged > or = 17 years, referred to the outpatient epilepsy clinic between 1 Jan and 31 December 1991, were prospectively enrolled and followed up until 31 December 2000. A total of 32 deaths were reported. Overall case-fatality rate was 12.2%. The age-adjusted standard mortality ratio (SMR) was calculated to compare the risk of death in patients with epilepsy to the general population. Patients with epilepsy had a 3.5-fold higher risk of death as compared with the general population (SMR: 3.47, 95% CI: 2.46-4.91). The Cox proportional hazards regression model was used to assess relevant clinical contributions to death. Patients with an age-at-onset > or = 40 years had a 4-fold higher risk of death as compared with those with an earlier onset. The multivariate analysis revealed that age-at-onset between 40 and 59 years, tumor etiology, and being male increased the risk of death in epilepsy. One-third of the deaths in patients with age-at-onset between 40-59 years died of liver cirrhosis and hepatoma. Hepatitis B virus infection is endemic in Taiwan, and this is closely associated with liver cirrhosis and hepatoma. Whether anticonvulsants contributed to the hepatotoxicity that led to fatal liver disease in this group needs further investigation.


[Tonic inhibitory effect of the cat brain on spinal interneurons].
Cord dorsum potentials were recorded in the acute experiments on cats. The relationship between the N-component of the cord dorsum potentials and the strength of stimulation of the big femoral nerve was studied. After the transsection of the half of midbrain tegmentum the increased curve slope indicating the rise in cord interneuron excitability was mainly observed on the contralateral side. The same results were observed after the removal of the contralateral somatosensory cortex or contralateral section of midbrain basis. The data indicate the tonic inhibitory influence of cortical structures on cord interneurons, which participate in the transmission of somatosensory signals.


The indistinguishability of epitopes from protein surface is explained by the distinct binding preferences of each of the six antigen-binding loops.
General protein-protein interfaces are known to be enriched, compared with other surface patches, with amino acids that can form stabilizing interactions. However, several studies reported that there are hardly any differences between the amino acid composition of B-cell epitopes and that of antigen surface residues. If the amino acid composition of epitopes is indistinguishable from other surface patches, how do antibodies (Abs) identify epitopes? Here, we analyze the antigen binding regions (ABRs, roughly corresponding to the complementarity determining regions) and the epitopes in a non-redundant set of all known Ab-antigen complexes. We find that the ABRs differ significantly from each other in their amino acid composition and length. Analysis of the energetic contribution of each ABR to antigen binding reveals that, while H3 often plays a key role in antigen binding, in many antibodies other ABRs are more important. Moreover, each ABR has a distinct propensity to bind different amino acids on the antigen. The combined binding preferences of the ABRs yield a total preference to amino acids with a composition that is virtually identical to that of surface residues. These results suggest that antibodies evolved to recognize protein surfaces. They may help in improving Ab engineering and B-cell epitope prediction.


[The macrosystematics of mammals according to energy metabolism criteria].
Criteria of evolutionary progress and complexity of organization have been proposed on the basis of the data on energetic metabolism. These criteria can serve as a basis of macrosystematics of mammals at the level of orders. The orders with the known data on energetic metabolism have been ranged.


Carotid near-occlusion frequently has high peak systolic velocity on Doppler ultrasound.
Carotid near-occlusion is a tight atherosclerotic stenosis of the internal carotid artery (ICA) resulting in decrease in diameter of the vessel lumen distal to the stenosis. Near-occlusions can be classified as with or without full collapse, and may have high peak systolic velocity (PSV) across the stenosis, mimicking conventional > 50% carotid artery stenosis. We aimed to determine how frequently near-occlusions have high PSV in the stenosis and determine how accurately carotid Doppler ultrasound can distinguish high-velocity near-occlusion from conventional stenosis. Included patients had near-occlusion or conventional stenosis with carotid ultrasound and CT angiogram (CTA) performed within 30 days of each other. CTA examinations were analyzed by two blinded expert readers. Velocities in the internal and common carotid arteries were recorded. Mean velocity, pulsatility index, and ratios were calculated, giving 12 Doppler parameters for analysis. Of 136 patients, 82 had conventional stenosis and 54 had near-occlusion on CTA. Of near-occlusions, 40 (74%) had high PSV (≥ 125 cm/s) across the stenosis. Ten Doppler parameters significantly differed between conventional stenosis and high-velocity near-occlusion groups. However, no parameter was highly sensitive and specific to separate the groups. Near-occlusions frequently have high PSV across the stenosis, particularly those without full collapse. Carotid Doppler ultrasound does not seem able to distinguish conventional stenosis from high-velocity near-occlusion. These findings question the use of ultrasound alone for preoperative imaging evaluation.


The reorganized brain: how treatment strategies for stroke and amblyopia can inform our knowledge of plasticity throughout the lifespan.
Neural plasticity plays a crucial role in human development. During development, neural networks are shaped by experience-dependent processes that selectively strengthen and prune connections so that those that remain match the environment and process it optimally. Over time, neural connections become more stable, forming widely distributed, interconnected networks involving balanced excitation and inhibition and structural stabilizers like myelin. It was long believed that the potential for organization or reorganization existed only during early development. However, the successful treatments for adults with stroke or amblyopia discussed in this issue suggest that the potential for significant reorganization persists well into adulthood. Thus, development can be thought of as the stabilization of connections to match the current environment but with considerable residual plasticity that can be revealed if there is a shift in the excitatory: inhibitory balance or the removal of the structural stabilizers.


[The reactivity of laboratory mice in pharmacological tests as dependent on their zoosocial status].
The study was conducted on dominant and inferior albino laboratory mice united in small groups according to linear hierarchy. Naloxone, amphetamine, and 5-hydroxytryptophan were used in the pharmacological tests, estimating, respectively, the pain response in the hot plate test, motor activity in the actometer, and the appearance of the specific stereotyped "head-twitching" response. The dominant subjects were less sensitive to amphetamine and 5-hydroxytryptophan than the inferior of animals, whereas the effect of naloxone depended on the level of the zoosocial stress. Therefore, the rank of the animal in the group is the factor modulating the behavioral effect of the pharmacological agents and should be taken into account in studying the individual sensitivity to them.


Role of myosin light chain kinase in regulation of basal blood pressure and maintenance of salt-induced hypertension.
Vascular tone, an important determinant of systemic vascular resistance and thus blood pressure, is affected by vascular smooth muscle (VSM) contraction. Key signaling pathways for VSM contraction converge on phosphorylation of the regulatory light chain (RLC) of smooth muscle myosin. This phosphorylation is mediated by Ca(2+)/calmodulin-dependent myosin light chain kinase (MLCK) but Ca(2+)-independent kinases may also contribute, particularly in sustained contractions. Signaling through MLCK has been indirectly implicated in maintenance of basal blood pressure, whereas signaling through RhoA has been implicated in salt-induced hypertension. In this report, we analyzed mice with smooth muscle-specific knockout of MLCK. Mesenteric artery segments isolated from smooth muscle-specific MLCK knockout mice (MLCK(SMKO)) had a significantly reduced contractile response to KCl and vasoconstrictors. The kinase knockout also markedly reduced RLC phosphorylation and developed force. We suggest that MLCK and its phosphorylation of RLC are required for tonic VSM contraction. MLCK(SMKO) mice exhibit significantly lower basal blood pressure and weaker responses to vasopressors. The elevated blood pressure in salt-induced hypertension is reduced below normotensive levels after MLCK attenuation. These results suggest that MLCK is necessary for both physiological and pathological blood pressure. MLCK(SMKO) mice may be a useful model of vascular failure and hypotension.


Low prevalence of high risk human papillomavirus in normal oral mucosa by hybrid capture 2.
High risk human papillomavirus (HR-HPV) are recognized as a necessary factor to development cervical cancer. During the last decade many studies have found HR-HPV in oral squamous cell carcinoma (OSCC) and normal oral mucosa, however the association between HR-HPV and OSCC is still uncertain. The aim of the study was to determine DNA HR-HPV in normal oral cavity of healthy adults. A cross-sectional study was performed; samples from 77 patients with normal oral cavity were collected at the Dentistry school, Autonomous University of Yucatan, Merida, Yucatan, México. HR-HPV was detected by hybrid capture 2. One sample out of 77(1.2%) was positive for HR-PVH. It was from a man of 50 years old. HRHPV is present in low rate among healthy oral mucosa. Hybrid capture 2 could be a good methodology for large epidemiology studies.


Drosophila protamine-like Mst35Ba and Mst35Bb are required for proper sperm nuclear morphology but are dispensable for male fertility.
During spermiogenesis, histones are massively replaced with protamines. A previous report showed that Drosophila males homozygous for a genomic deletion covering several genes including the protamine-like genes Mst35Ba/b are surprisingly fertile. Here, we have precisely deleted the Mst35B locus by homologous recombination, and we confirm the dispensability of Mst35Ba/b for fertility.


The size, location, and clinical severity of corneal infiltrative events associated with contact lens wear.
The purpose of this study is to determine the relationship between the size, location, and clinical severity of corneal infiltrative events (CIEs) associated with contact lens wear. We examined a series of contact lens wearers, presenting consecutively to a large hospital clinic, who had any form of CIE. The severity of the CIE was quantified using a clinical severity matrix based on scores attributed to each of 10 signs and symptoms. The infiltrate was accurately drawn on a schematic diagram of the ocular surface, and from this, we determined its size (i.e., largest dimension) and distance from the limbus. Cartograms were constructed to illustrate the size and location of the corneal infiltrates according to wearing modality and lens type. Useable data pertaining to 111 patients were analyzed. A significant positive correlation was found between the distance of the infiltrate from the limbus versus clinical severity (p = 0.002), but not between the distance of the infiltrate from the limbus versus infiltrate size (p = 0.97). The cartograms revealed a tendency for infiltrates to occur in the superior cornea of patients wearing extended wear silicone hydrogel lenses (p = 0.0002) in the central cornea of patients wearing daily wear hydrogel daily disposable lenses (p = 0.007) and in the peripheral cornea of patients wearing daily wear hydrogel (excluding daily disposable) lenses (p = 0.0006). These data statistically validate the previously held anecdotal notion that CIEs which occur in the peripheral cornea are less clinically severe than those which occur in the central cornea. Consideration of the distribution of CIEs may facilitate a better understanding of the etiology of these events and can serve to alert practitioners as to their likely clinical presentation.


Cytochrome c oxidase subunit 4 isoform 2-knockout mice show reduced enzyme activity, airway hyporeactivity, and lung pathology.
Cytochrome c oxidase (COX) is the terminal enzyme of the mitochondrial electron transport chain. The purpose of this study was to analyze the function of lung-specific cytochrome c oxidase subunit 4 isoform 2 (COX4i2) in vitro and in COX4i2-knockout mice in vivo. COX was isolated from cow lung and liver as control and functionally analyzed. COX4i2-knockout mice were generated and the effect of the gene knockout was determined, including COX activity, tissue energy levels, noninvasive and invasive lung function, and lung pathology. These studies were complemented by a comprehensive functional screen performed at the German Mouse Clinic (Neuherberg, Germany). We show that isolated cow lung COX containing COX4i2 is about twice as active (88 and 102% increased activity in the presence of allosteric activator ADP and inhibitor ATP, respectively) as liver COX, which lacks COX4i2. In COX4i2-knockout mice, lung COX activity and cellular ATP levels were significantly reduced (-50 and -29%, respectively). Knockout mice showed decreased airway responsiveness (60% reduced P(enh) and 58% reduced airway resistance upon challenge with 25 and 100 mg methacholine, respectively), and they developed a lung pathology deteriorating with age that included the appearance of Charcot-Leyden crystals. In addition, there was an interesting sex-specific phenotype, in which the knockout females showed reduced lean mass (-12%), reduced total oxygen consumption rate (-8%), improved glucose tolerance, and reduced grip force (-14%) compared to wild-type females. Our data suggest that high activity lung COX is a central determinant of airway function and is required for maximal airway responsiveness and healthy lung function. Since airway constriction requires energy, we propose a model in which reduced tissue ATP levels explain protection from airway hyperresponsiveness, i.e., absence of COX4i2 leads to reduced lung COX activity and ATP levels, which results in impaired airway constriction and thus reduced airway responsiveness; long-term lung pathology develops in the knockout mice due to impairment of energy-costly lung maintenance processes; and therefore, we propose mitochondrial oxidative phosphorylation as a novel target for the treatment of respiratory diseases, such as asthma.


Selective blockade of the inhibitory Fcgamma receptor (FcgammaRIIB) in human dendritic cells and monocytes induces a type I interferon response program.
The ability of dendritic cells (DCs) to activate immunity is linked to their maturation status. In prior studies, we have shown that selective antibody-mediated blockade of inhibitory FcgammaRIIB receptor on human DCs in the presence of activating immunoglobulin (Ig) ligands leads to DC maturation and enhanced immunity to antibody-coated tumor cells. We show that Fcgamma receptor (FcgammaR)-mediated activation of human monocytes and monocyte-derived DCs is associated with a distinct gene expression pattern, including several inflammation-associated chemokines, as well as type 1 interferon (IFN) response genes, including the activation of signal transducer and activator of transcription 1 (STAT1). FcgammaR-mediated STAT1 activation is rapid and requires activating FcgammaRs. However, this IFN response is observed without a detectable increase in the expression of type I IFNs themselves or the need to add exogenous IFNs. Induction of IFN response genes plays an important role in FcgammaR-mediated effects on DCs, as suppression of STAT1 by RNA interference inhibited FcgammaR-mediated DC maturation. These data suggest that the balance of activating/inhibitory FcgammaRs may regulate IFN signaling in myeloid cells. Manipulation of FcgammaR balance on DCs and monocytes may provide a novel approach to regulating IFN-mediated pathways in autoimmunity and human cancer.


Occurrence of Tomato spotted wilt virus in Stevia rebaudiana and Solanum tuberosum in Northern Greece.
Tomato spotted wilt virus (TSWV) (genus Tospovirus, family Bunyaviridae) was first reported in Greece during 1972 (3) and currently is widespread in the central and northern part of the country infecting several cultivated and wild plant species (1,2). In June 2006, virus-like symptoms similar to those caused by TSWV were observed on sweet honey leaf (Stevia rebaudiana (Bertoni) Bertoni, [synonym Eupatorium rebaudianum Bertoni], family Asteraceae) plants in an experimental field in the prefecture of Kilkis and on potato (Solanum tuberosum, family Solanaceae) plants growing close to tobacco in the prefecture of Kozani in northern Greece. Diseased S. rebaudiana plants expressed chlorotic and necrotic rings and line patterns on systemically infected leaves and occasionally a general chlorosis or dwarfing of the plant. Potato plants expressed only necrotic rings or lesions and a mild plant dwarfing. Seven percent of the S. rebaudiana plants, but only 0.1% of the potato plants, were showing symptoms. TSWV was detected by ELISA using polyclonal antisera in all symptomatic plants of both species, but those plants tested negative for Potato Y virus (PVY), Cucumber mosaic virus (CMV), Alfalfa mosaic virus (AMV), and Potato leafroll virus (PLRV); all viruses known to occur in these areas. Sap from symptomatic plants was used to mechanically inoculate Petunia × hybrida cv. Blue magic, Nicotiana tabacum cvs. Samsun NN and Basmas, N. benthamiana, N. glutinosa, N. rustica, Datura stramonium, and Physalis floridana. Sap from both S. rebaudiana and potato produced typical symptoms of TSWV on the diagnostic test plants; all Nicotiana species and cultivars, as well as D. stramonium and P. floridana, reacted with chlorotic and necrotic lesions on the inoculated leaves followed by systemic mosaic and mottling of the leaves. None of the isolates produced systemic infection on P. × hybrida. Adult thrips, identified as Thrips tabaci, were collected from infected plants of both hosts in the field and determined to be infected with TSWV by the petunia leaf disc method (4). Symptoms observed in the field on both hosts where reproduced in the laboratory after infestation of healthy plants with TSWV-infected individuals from a tobacco population of T. tabaci. To our knowledge, this is the first official report of a TSWV infection in S. rebaudiana. Potato is a known host for TSWV, however, to our knowledge, this is the first natural infection detected in Greece. References: (1) E. K. Chatzivassiliou et al. Ann. Appl. Biol. 137:127, 2000. (2) E. K. Chatzivassiliou et al. Plant Dis. 85:40, 2001. (3) J. P. Tsakiridis and G. V. Gooding, Jr. Phytopathol. Mediterr. 11:42, 1972. (4) I. Wijkamp and D. Peters. Phytopathology 83:986,1993.


Safe, long-term hepatic expression of anti-HCV shRNA in a nonhuman primate model.
The hepatitis C virus (HCV) chronically infects 2% of the world population and effective treatment is limited by long duration and significant side-effects. Here, we describe a novel drug, intended as a "single-shot " therapy, which expresses three short hairpin RNAs (shRNAs) that simultaneously target multiple conserved regions of the HCV genome as confirmed in vitro by knockdown of an HCV replicon system. Using a recombinant adeno-associated virus (AAV) serotype 8 vector for delivery, comprehensive transduction of hepatocytes was achieved in vivo in a nonhuman primate (NHP) model following a single intravenous injection. However, dose ranging studies performed in 13 NHP resulted in high-expression levels of shRNA from wild-type (wt) Pol III promoters and dose-dependent hepatocellular toxicity, the first demonstration of shRNA-related toxicity in primates, establishing that the hepatotoxicity arises from highly conserved features of the RNA interference (RNAi) pathway. In the second generation drug, each promoter was re-engineered to reduce shRNA transcription to levels that circumvent toxicity but still inhibit replicon activity. In vivo testing of this modified construct in 18 NHPs showed conservation of hepatocyte transduction but complete elimination of hepatotoxicity, even with sustained shRNA expression for 50 days. These data support progression to a clinical study for treatment of HCV infection.


The Cholera Phone: Diarrheal Disease Surveillance by Mobile Phone in Bangladesh.
Existing methodologies to record diarrheal disease incidence in households have limitations due to a high-episode recall error outside a 48-hour window. Our objective was to use mobile phones for reporting diarrheal episodes in households to provide real-time incidence data with minimum resource consumption and low recall error. From June 2014 to June 2015, we enrolled 417 low-income households in Dhaka, Bangladesh, and asked them to report diarrheal episodes to a call center. A team of data collectors then visited persons reporting the episode to collect data. In addition, each month, the team conducted in-home surveys on diarrhea incidence for a preceding 48-hour period. The mobile phone surveillance reported an incidence of 0.16 cases per person-year (95% CI: 0.13-0.19), with 117 reported diarrhea cases, and the routine in-home survey detected an incidence of 0.33 cases per person-year (95% CI: 0.18-0.60), the incidence rate ratio was 2.11 (95% CI: 1.08-3.78). During focus group discussions, participants reported a lack in motivation to report diarrhea by phone because of the absence of provision of intervening treatment following reporting. Mobile phone technology can provide a unique tool for real-time disease reporting. The phone surveillance in this study reported a lower incidence of diarrhea than an in-home survey, possibly because of the absence of intervention and, therefore, a perceived lack of incentive to report. However, this study reports the untapped potential of mobile phones in monitoring infectious disease incidence in a low-income setting.


Anesthesia for the repeat cesarean section in the parturient with abnormal placentation: what does an obstetrician need to know?
Placenta accreta is an abnormal adherence of the placenta to the uterine wall owing to an absent or faulty decidua basalis. The incidence of this devastating problem is increasing secondary to the increased incidence of Cesarean section. Although rare, the diagnosis of placenta accreta may lead to life-threatening complications (e.g., fatal hemorrhage) and significantly impact the obstetric and anesthetic management of these parturients. I herein present the case of a pregnant patient with abnormal placentation and review the current state-of-the-art obstetric and anesthetic management of this complication.


The differential heritability of regular tobacco use based on method of administration.
Several large studies have demonstrated that the liability to smoke cigarettes is strongly genetically influenced. However, the role of genetic and environmental risk factors in the use of other common forms of tobacco use has yet to be studied. Data on the regular use of cigarettes, cigars, pipes, dip (moist snuff), and chewing tobacco from 2634 male twins were analyzed with ACE structural equation models. Twin similarity for regular cigarette and dip use was largely genetic in origin. However, twin resemblance for chewing tobacco was just about equally the result of genes and shared environment, and twin similarity for use of pipes and cigars was entirely the result of shared environmental factors. Thus, the genetic influences on the liability for regular tobacco use appear to vary based on tobacco type. The causes for the use of different forms of tobacco are complex and worthy of further study.


Statins and Higher Diabetes Mellitus Risk: Incidence, Proposed Mechanisms, and Clinical Implications.
3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors are ubiquitously prescribed for cardiovascular disease (CVD) prevention and treatment. However, the use of statins has been linked to the development of new-onset diabetes mellitus (NODM), which could possibly increase future CVD risk. This phenomenon necessitates a clear discussion of the possible etiologies of this relationship and its broader clinical consequences. We discuss the reported incidence of NODM in statin users through a rigorous review of data from metaanalyses of randomized control trials examining this association. We also highlight the various possible mechanisms responsible for the development of statin-induced diabetes mellitus. Finally, we examine the clinical implications of this effect on future CVD risk and identify specific patient factors that can be used for risk-stratification strategies. Data from 14 randomized control trials metaanalyses suggest a 9-33% higher risk of NODM with statin use. Several cellular, molecular, and genetic mechanisms, as well as lifestyle habits, have been identified as potential underlying factors responsible for this elevated risk. The principle mode of the diabetogenic action of statins is still unclear, though it is likely the result of a complex interplay of pancreatic and extrapancreatic effects. It is understood that patient populations with a greater predisposition to diabetes mellitus, and those with thicker epicardial adiposity are more at risk for the development of statin-induced NODM. Despite these observations, robust data from a variety of investigations suggest that the CVD preventative benefits of statin treatment significantly outweigh the risks associated with the development of NODM. Nevertheless, further study must better identify the causative mechanisms involved in this process, its natural history, and the unique factors that will help clinicians risk stratify and appropriately monitor patients on statin therapy.


Origin of intraventricular haemorrhage in the preterm infant.
A technique has been developed for the injection and stereomicroscopic examination of blood vessels in the preterm newborn brain. Using this technique it can be seen that in the immature brain there is a rich capillary bed in the germinal layer region supplied mainly by Heubner's artery. Capillary channels drain directly into the terminal vein and its main branches. Study of 19 cases with spontaneous germinal layer haemorrhage (GLH) with or without intraventricular haemorrhage (IVH) failed to show rupture of the terminal vein or germinal layer infarction. In babies of up to 28 weeks' gestation GLH developed most frequently over the body of the caudate nucleus, whereas in babies of 29 weeks' gestation or more the haemorrhages were usually over the head of the caudate nucleus. Histological study of 10 cases of GLH failed to show rupture either of arteries or veins, though evidence of rupture at a capillary-vein junction was seen in one case and masses of fibrin adjacent to the vein wall in 2 others. Injection through the carotid artery caused prominent leaks of injection mass within the germinal layer capillary bed, often adjacent to the veins. Injection through the jugular veins in 2 cases failed to rupture the terminal vein but caused multiple vein ruptures at the junction of deep and cortical venous systems. Additional small ruptures in the germinal layer occurred in one of the cases only. It is suggested that the capillaries within the germinal layer may be ruptured by a rise in arterial pressure, particularly in conditions of hypercapnia and hypoxia.


Blue-Phosphorescent Pt(II) Complexes of Tetradentate Pyridyl-Carbolinyl Ligands: Synthesis, Structure, Photophysics, and Electroluminescence.
Blue phosphorescent tetradentate pyridyl-carbolinyl Pt(II) complexes, Pt(ppzOclpy-Me), Pt(ppzOclpy-iPr), and Pt(ppzOclpy-mesi), were purposefully synthesized and investigated with their photophysical and luminescent properties. The complexes, incorporating with carbolinyl moieties, have twisted planar structure. X-ray crystallography revealed that the intraligand N···H-C hydrogen bond reversely turned the twisty pyridyl moiety back into the chelating plane. Computational analyses confirmed that the metal-to-ligand charge-transfer transition character appears in the singlet manifolds. However, the ligand-centered transitions rule in their triplet states, which accounts for the phosphorescent emission. The Pt(II) complexes emit blue light with peak wavelengths (λmax) of 461-481 nm and moderate photoluminescent quantum yields (Φ = 34-46% in dichloromethane and Φ = 44-52% in films). The electroluminescent devices were fabricated by solution processes, giving blue emissions peaking at around 470 nm.


Specific-ion effects on the aggregation mechanisms and protein-protein interactions for anti-streptavidin immunoglobulin gamma-1.
Non-native protein aggregation is common in the biopharmaceutical industry and potentially jeopardizes product shelf life, therapeutic efficacy, and patient safety. The present article focuses on the relationship(s) among protein-protein interactions, aggregate growth mechanisms, aggregate morphologies, and specific-ion effects for an anti-streptavidin (AS) immunoglobulin gamma 1 (IgG1). Aggregation mechanisms of AS-IgG1 were determined as a function of pH and NaCl concentration with sodium acetate buffer and compared to previous work with sodium citrate. Aggregate size and shape were determined using a combination of laser light scattering and small-angle neutron or X-ray scattering. Protein-protein interactions were quantified in terms of the protein-protein Kirkwood-Buff integral (G22) determined from static light scattering and in terms of the protein effective charge (Zeff) measured using electrophoretic light scattering. Changing from citrate to acetate resulted in significantly different protein-protein interactions as a function of pH for low NaCl concentrations when the protein displayed positive Zeff. Overall, the results suggest that electrostatic repulsions between proteins were lessened because of preferential accumulation of citrate anions, compared to acetate anions, at the protein surface. The predominant aggregation mechanisms correlated well with G22, indicating that ion-specific effects beyond traditional mean-field descriptions of electrostatic protein-protein interactions are important for predicting qualitative shifts in protein aggregation state diagrams. Interestingly, while solution conditions dictated which mechanisms predominated, aggregate average molecular weight and size displayed a common scaling behavior across both citrate- and acetate-based systems.


Energetics and longevity in birds.
The links between energy expenditure and ageing are different at different levels of enquiry. When studies have examined the relationships between different species within a given class the association is generally negative--animals with greater metabolism per gram of tissue live shorter lives. Within species, or between classes (e.g. between birds and mammals) the association is the opposite--animals with higher metabolic rates live longer. We have previously shown in mammals that the negative association between lifespan and metabolic rate is in fact an artefact of using resting rather than daily energy expenditure, and of failing to adequately take into account the confounding effects of body size and the lack of phylogenetic independence of species data. When these factors are accounted for, across species of mammals, the ones with higher metabolism also have the largest lifetime expenditures of energy-consistent with the inter-class and intra-specific data. A previous analysis in birds did not yield the same pattern, but this may have been due to a lack of sufficient power in the analysis. Here we present an analysis of a much enlarged data set (>300 species) for metabolic and longevity traits in birds. These data show very similar patterns to those in mammals. Larger individuals have longer lives and lower per-gram resting and daily energy expenditures, hence there is a strong negative relationship between longevity and mass-specific metabolism. This relationship disappears when the confounding effects of body mass and phylogeny are accounted for. Across species of birds, lifetime expenditure of energy per gram of tissue based on both daily and resting energy expenditure is positively related to metabolic intensity, mirroring these statistical relationships in mammals and synergizing with the positive associations of metabolism with lifespan within species and between vertebrate classes.


[Amyloid positron-emission-tomography with [18 F]-florbetaben in the diagnostic workup of dementia patients].
To this day the definite diagnosis of Alzheimer's disease still relies on post-mortem histopathological detection of neurofibrillary tangles and beta-amyloid deposits. Amyloid positron emission tomography (PET) is a new diagnostic tool that enables the in vivo quantification of pathological beta-amyloid deposits. The aim of the current study was to evaluate to what extent 18F-florbetaben-PET (FBB-PET) influences the diagnosis of patients with dementia. Imaging with FBB-PET was performed on 33 patients from our outpatient department for cognitive neurology. Beforehand all patients underwent a comprehensive clinical, neuropsychiatric and laboratory examination as well as imaging by means of magnetic resonance imaging (MRI) and fluorodeoxyglucose-PET. The working diagnoses before and after FBB-PET imaging were compared. 17 out of 33 patients were scored as FBB-PET positive. In four cases the initial diagnosis had to be changed to Alzheimer's disease (three cases) and cerebral amyloid angiopathy (one case) due to the positive FBB-PET scan. 16 patients showed a negative FBB-PET scan. In three patients the initial diagnosis of Alzheimer's disease could be ruled out due to the negative FBB-PET scan. Overall, in 7 out of 33 examined patients the initial diagnosis had to be changed because of the findings of the FBB-PET scan. In 24 patients the initial diagnosis was confirmed by the results of the FBB-PET scan. Amyloid-PET is currently no standard procedure in the diagnosis of dementia; however, it can be a helpful additional diagnostic tool when used according to the "Appropriate Use Criteria" and the S3 guidelines on dementia in cases of unclear clinical presentation, atypically early age of onset as well as in patients with persistent or progressive unexplained mild cognitive impairment. By facilitating early diagnosis amyloid-PET imaging allows patient selection for therapeutic drug trials.


Secondary cancers after bone marrow transplantation for leukemia or aplastic anemia.
To determine the incidence of secondary cancers after bone marrow transplantation, we reviewed the records of all patients at our center who received allogeneic, syngeneic, or autologous transplants for leukemia (n = 1926) or aplastic anemia (n = 320). Thirty-five patients were given a diagnosis of secondary cancer between 1.5 months and 13.9 years (median, 1.0 year) after transplantation. Sixteen patients had non-Hodgkin's lymphomas, 6 had leukemias, and 13 had solid tumors (including 3 each with glioblastoma, melanoma, and squamous-cell carcinoma). There were 1.2 secondary cancers per 100 exposure-years during the first year after transplantation (95 percent confidence interval, 0.7 to 2.0). The rate declined to 0.4 (95 percent confidence interval, 0.2 to 0.7) after one year. The age-adjusted incidence of secondary cancer was 6.69 times higher than that of primary cancer in the general population. In a multivariate model, the predictors (and relative risks) of any type of secondary cancer were acute graft-versus-host disease treated with either antithymocyte globulin (relative risk, 4.2) or an anti-CD3 monoclonal antibody (13.6) and total-body irradiation (3.9). Two additional factors were associated with secondary non-Hodgkin's lymphomas: T-lymphocyte depletion of donor marrow (12.4) and HLA mismatch (3.8). We conclude that recipients of bone marrow transplantation have a low but significant risk of a secondary cancer, particularly non-Hodgkin's lymphoma.


Hyperlipidemia in rats fed retinoic acid.
This report describes a series of experiments that attempt to characterize the lipidemia accompanying retinoic acid administration. After feeding young adult male Sprague-Dawley rats, 1.2 Retinol Equivalents (R.E.) retinyl acetate plus supplemental retinoic acid (100 microgram/g dry diet) for three days and fasting for 6-8 hr, triglyceride, cholesterol, and phospholipid content of various serum lipoprotein fractions were determined. When compared to unsupplemented controls, both the serum very low density lipoprotein (VLDL) and the high density lipoprotein (HDL) fractions of the retinoic acid-fed rats were found to harbor an elevated triglyceride content. While VLDL cholesterol and phospholipid content were also elevated, total serum cholesterol and phospholipids were not statistically altered. The detergent Triton WR-1339 was used to depress serum triglyceride clearance in order to assess the effects of retinoic acid feeding on serum triglyceride levels. Triglyceride accumulation started earlier after Triton treatment and was greater when rats were fed 100 microgram/g retinoic acid for three days prior to testing. Red and white gastrocnemius muscle, cardiac ventricular muscle, and perirenal adipose tissue were removed from rats following retinoic acid feeding. Analysis of these tissues for lipoprotein lipase (EC 22.214.171.124) activity showed a decrease in adipose tissue, a large depression in both areas of gastrocnemius muscle and no change in cardiac muscle as a result of retinoic acid feeding.


Tubulocisternal endoplasmic reticulum in human eccrine sweat glands.
Human eccrine sweat glands, including those expressing the gene for cystic fibrosis, were stained sequentially en bloc with uranyl acetate, lead citrate and copper sulfate, and osmium tetroxide for the ultrastructural demonstration of tubulocisternal endoplasmic reticulum (TER). This organelle has been associated with water and electrolyte transport in other epithelia. TER was present in the apical cytoplasm and basolateral cytoplasm circumscribing intercellular canaliculi of clear cells in the secretory coil and in the apical cuticular cytoplasm of luminal cells in the coiled duct. In both the secretory coil and duct, TER was situated strategically around the tight junctions. Together, the TER and tight junctions may regulate the secretory and absorptive permeability of the eccrine sweat gland to NaCl and water. The dark cell of the coil which is exocrine, and the deep cell of the duct which lacked tight junctions, did not contain TER. In sweat glands obtained from three cases of cystic fibrosis, elements of TER were more prevalent and complex in luminal cells of the secretory duct than was the TER in normal sweat glands. This difference may be a consequence of the basic electrolyte abnormality of cystic fibrosis.


When Trustworthy Information Becomes Inaccessible: The Search Behaviour of Users with Dyslexia in an Online Encyclopedia.
The ability to search for trustworthy information has become increasingly important. Access to information is key for a democratic, inclusive society. However, poorly designed search user interfaces exclude certain user groups. For instance, search systems with high demands for correctly spelled queries have been reported to be challenging for people with reading and spelling difficulties, such as dyslexia. In a qualitative pre-study, four adults with dyslexia were interviewed about their search experiences in an encyclopedia with low tolerance for spelling errors. The participants regarded the encyclopedia as highly credible and preferred using this source for factual queries. Nevertheless, the users with dyslexia were highly dependent on Google due to high spelling demands in the encyclopedia search interface. Although the participants found relevant information on Google, they reported the search process as tiresome, since the result list assessment required a significant amount of reading. In contrast, searching the encyclopedia provided direct access to neutral, evaluated information, thus removing the evaluation phase. Moreover, searching was frequently associated with feelings such as fatigue, frustrations and failure. Results from this study imply that search user interface design affects the information searching behavior of people with dyslexia.


Mindfulness of the kindness of others: The contemplative practice of Naikan in cultural context.
Mindfulness in the Buddhist tradition involves a variety of practices, and contemporary secular forms of mindfulness practices, therapies, and interventions can similarly be broadened to include more of these forms. The Japanese practice of Naikan takes one mindfulness practice from the Buddhist tradition--that of recollecting the kindness of others--and asks clients to engage in this practice for 1 solid week, 15 hours per day. Difficult interpersonal relationships and a perceived lack of social support are chief sources of stress, and Japanese selfhood in particular has been described as interdependent and highly social in nature. It is unsurprising therefore that Japanese would be drawn to relational forms of practice like Naikan, and that they would find particular benefit from such practices. Recent ethnographic and survey work I have conducted at 2 Naikan centers suggests that Naikan significantly improves positive mental health, perceived connection with others, and perceived meaning in life, even up to 6 months later, thereby potentially undercutting factors contributing to depression and suicide. Naikan practice is not entirely limited to Japan, however, and its use in Europe and North America prompts us to ask about the culturally specific and universal aspects of mindfulness practices, and how we may construct mindfulness interventions that are best suited for addressing the mental health problems that face our communities.


Precocious and reversible expression of sucrase-isomaltase unrelated to intestinal cell turnover.
The effect of starvation and refeeding on the developmental pattern of intestinal sucrase-isomaltase (SI) was analyzed in preweaned rats. Starvation at postnatal day 12 caused a precocious expression of SI activity and mRNA. Alkaline phosphatase activity was slightly reduced, and no significant change was observed for aminopeptidase and lactase activities. Immunostaining showed that SI molecules appear in cells at the base of the villus. Sucrase expression was further increased by prolonged food deprivation, whereas enzyme activity as well as the amount of SI mRNA dropped to reach the low level found in control sucklings when 48 h-starved pups were refed by returning them to their dams. During the refeeding period, the enterocytes that were committed to produce SI by starvation continued to express the enzyme while migrating up the villi. However, the new epithelial cells arising from the crypts no longer synthesized the disaccharidase. The starvation-evoked appearance of SI was preceded by a transient burst of expression of the protooncogene c-fos, an event that may be correlated to the ontogenic rise of c-fos mRNA observed before weaning. However, in contrast to the normal weaning condition, SI induction by starvation occurred without obvious increase of epithelial cell proliferation and turnover. During the starvation and refeeding period, patterns of sucrase activity and SI mRNA paralleled the serum level of glucocorticoids.(ABSTRACT TRUNCATED AT 250 WORDS)


Cardiac manifestations of HIV infection: an African perspective.
The pericardium, myocardium, coronary arteries and pulmonary arteries are the main targets for cardiac disease in people who are infected with HIV. Geography and access to highly active anti-retroviral therapy (HAART) have a major influence on which of these targets is affected. In sub-Saharan Africa, where tuberculosis is endemic and access to HAART is limited, the dominant forms of HIV-associated heart disease are pericardial tuberculosis and cardiomyopathy. However, in industrialized countries, where tuberculosis is rare and HAART is widely available, coronary artery disease is the main cause of death and disability in these patients. Observational data suggest that HAART, by preserving immune function, reduces the incidence of myopericardial disease and pulmonary hypertension. The result has been that, although optimal strategies to reduce vascular disease in this population continue to be sought and debated in industrialized nations, the focus of prevention and treatment strategies for HIV-related heart disease in developing countries has been to support the active campaigns to get universal access to HAART in the first place. Herein, we review the cardiac manifestations of HIV in sub-Saharan Africa.


Acquired immunodeficiency syndrome. Cerebrospinal fluid findings in patients before and during long-term oral zidovudine therapy.
Fifty-two patients with acquired immunodeficiency syndrome were enrolled in this study to evaluate the relationship between cerebrospinal fluid (CSF) zidovudine concentrations and neurologic and human immunodeficiency virus (HIV) culture findings. Paired HIV-CSF culture and neurologic measurements were available in 30 and 45 patients, respectively. Twenty-nine patients were assessable for zidovudine CSF concentrations. Patients underwent lumbar puncture and neurologic testing before and after 8 weeks or more of oral zidovudine therapy (600 to 1500 mg/d). After 8 weeks of therapy, the frequency of HIV isolation from CSF cultures was unchanged. Significant neurologic improvement by examination was noted in 61.5% (32/52) of the patients. The median CSF zidovudine concentration among 29 patients was 0.047 mg/L (range, 0.015 to 0.198 mg/L). No correlation between CSF zidovudine concentration, cumulative dose, or HIV isolation from CSF and persistence or resolution of neurologic symptoms or signs was observed. The mechanisms by which zidovudine improves neurologic function are unclear and appear unrelated to direct clearance of virus from CSF.


Hospitalization in South African Adolescents With Perinatally Acquired HIV on Antiretroviral Therapy.
Little is known about hospitalization in African adolescents with perinatally acquired HIV (PHIV+ adolescents). We described the incidence and causes of hospitalization in participants enrolled in the Cape Town Adolescent Antiretroviral Cohort in South Africa. Data collected from July 2013 to October 2018 from PHIV+ and HIV- adolescents were analyzed. Participants were assessed every 6 months and data on intercurrent hospitalization were abstracted. Causes of hospitalizations were classified according to ICD-10 codes. Descriptive statistics, time-to-event analysis and Poisson regression were used to describe causes and incidence and to determine incidence rate ratios for factors associated with hospitalization. Five hundred fifteen PHIV+ and 109 HIV- participants had a median follow-up of 4.1 years [interquartile range (IQR): 3.7-4.6]. At enrollment HIV+ participants had a median duration of ART of 7.6 years (IQR: 4.6-9.2), median CD4 count of 713 cells/mm (IQR: 561.0-957.5) and 387 (75%) had a viral load <50 copies/mL. There were 149 hospital admissions over 64 months. Crude incidence rates for hospitalization were 6.6 [95% confidence interval (CI): 5.7-7.8] and 2.2 (95% CI: 1.2-4.3) per 100-person-years (P = <0.01) in HIV + and HIV-, respectively. Ninety of 149 (60%) admissions in HIV+ participants were classified as non-infectious, 36/149 (24%) were infectious and 23/149 (16%) were "other HIV-related" or "unknown." Older age (15-19 years) and maintaining a CD4 >500 cells/cm were associated with decreased risk of hospitalization: adjusted incidence rate ratios of 0.61 (CI: 0.44-0.86, P = <0.01) and 0.68 (CI: 0.49-0.94, P = 0.02), respectively. PHIV+ adolescents had a high incidence of hospitalization despite ART. Strategies addressing infectious and non-infectious morbidity must be strengthened.


Single-cell Mayo Map ( scMayoMap ): an easy-to-use tool for cell type annotation in single-cell RNA-sequencing data analysis.
Single-cell RNA-sequencing (scRNA-seq) has become a widely used tool for both basic and translational biomedical research. In scRNA-seq data analysis, cell type annotation is an essential but challenging step. In the past few years, several annotation tools have been developed. These methods require either labeled training/reference datasets, which are not always available, or a list of predefined cell subset markers, which are subject to biases. Thus, a user-friendly and precise annotation tool is still critically needed. We curated a comprehensive cell marker database named scMayoMapDatabase and developed a companion R package scMayoMap , an easy-to-use single cell annotation tool, to provide fast and accurate cell type annotation. The effectiveness of scMayoMap was demonstrated in 48 independent scRNA-seq datasets across different platforms and tissues. scMayoMap performs better than the currently available annotation tools on all the datasets tested. Additionally, the scMayoMapDatabase can be integrated with other tools and further improve their performance. scMayoMap and scMayoMapDatabase will help investigators to define the cell types in their scRNA-seq data in a streamlined and user-friendly way.


[Ecology of a focus of cutaneous leishmaniasis in the Thies region (Senegal, West Africa). 2. Epidemiological and clinical peculiarities of the human disease].
During their epidemiological survey of a cutaneous leishmaniasis focus, the authors study the epidemiological and clinical aspects of 60 proven human cases observed in the studied area (Thies region). The disease can occur at any age but is more frequently seen in the pre-adolescent (10-15 years), adolescent (15-20 years) and adult (20-40 years) age classes. During the year, 76.5% of the lesions appear between july and the end of november. The spontaneous evolution of the disease seems to have a one year duration. Less than 10 lesions are observed in the majority of the cases (91.5%). The lesions are mainly located on upper and/or lower limbs and are generally of humid ulcerated type, often covered by a deep scar; a lymphatic nodular dissemination from a lesion occurs in 25% of the cases.


Metabolic profile of PML lesions in patients with and without IRIS: an observational study.
To characterize progressive multifocal leukoencephalopathy (PML) lesions by contrast-enhanced MRI and evaluate their metabolism using proton magnetic resonance spectroscopy ((1)H- MRS) in the setting of immune reconstitution inflammatory syndrome (IRIS). A total of 42 patients with PML underwent a clinical evaluation as well as brain MRI and (1)H-MRS at baseline and 3, 6, and 12 months later. The presence of IRIS was determined based on clinical and laboratory criteria. Ratios of N-acetylaspartate (NAA), choline (Cho), myo-inositol (mI), and lipid/lactate (Lip1 and Lip2) to creatine (Cr) were measured and correlated with the presence of contrast enhancement (CE) in PML lesions. IRIS occurred in 16 of 28 (57.1%) PML survivors (PML-S) and 1 of 14 (7.1%) PML progressors (PML-P). Lesions of patients with PML-IRIS showed significantly higher Cho/Cr (p = 0.0001), mI/Cr (p = 0.02), Lip1/Cr (p < 0.0001), and Lip2/Cr (p = 0.002) ratios and lower NAA/Cr (p = 0.02) ratios than patients with PML who did not have IRIS. An elevated Cho/Cr ratio was associated with CE within the (1)H-MRS voxel, whereas lipid/Cr ratios were elevated in PML-IRIS lesions independently of CE. Follow-up until 33 months from PML onset showed persistent elevation of the mI/Cr ratio in lesions of patients with PML-IRIS. A Lip1/Cr ratio greater than 1.5 combined with the presence of CE yielded a 79% probability of IRIS compared with 13% in the absence of these criteria. (1)H-MRS is a valuable tool to recognize and track IRIS in PML and may prove useful in the clinical management of these patients.


Cloning, sequencing, and recombinant expression of the porcine inhibitor of carbonic anhydrase: a novel member of the transferrin family.
The plasma from many vertebrates contains a component that specifically binds and inhibits carbonic anhydrase II with nanomolar affinity. Amino-terminal sequencing of pICA, the previously identified 79-kDa carbonic anhydrase inhibitor isolated from porcine plasma [Roush, E. D., & Fierke, C. A. (1992) Biochemistry 31, 12536-12542], and sequencing of four proteolytic fragments of pICA revealed that each of the partial sequences has 40-80% sequence identity with members of the transferrin protein family. We describe here the isolation of a full-length cDNA clone of pICA from a lambda gt11 porcine liver cDNA library. Heterologous expression of this cDNA clone in a Pichia pastoris expression system led to the secretion into the medium of 5 mg/L of a 79-kDa protein that specifically reacts with anti-pICA antibodies and binds tightly to a carbonic anhydrase-Sepharose affinity column. Pairwise sequential alignment of pICA with various transferrins reveals an amino acid identity as high as 64% and predicts that 16 transferrin disulfide bonds are conserved. However, despite these structural similarities, the properties of pICA are distinct from the properties of transferrin. pICA exhibits a significantly decreased affinity for iron that can be attributed to the loss of one of the eight amino acids that coordinate iron in the transferrins as well as both of the arginine residues responsible for anion binding. In addition, the antigenic determinants of pICA and the transferrins are not identical. These data imply that pICA, along with saxiphilin, is a member of a diverse superfamily of transferrin-like proteins with functions other than iron binding.


More or Less? The Effect of Symbiont Density in Protective Mutualisms.
AbstractSymbionts can provide hosts with effective protection from natural enemies, but it can sometimes come at a cost. It is unclear to what extent the density of symbionts modulates the cost and benefits of conferred protection. Here, we use a meta-analysis of 103 effect sizes from a broad taxonomic range of protective symbioses to show that the degree of both protection and cost afforded to hosts is a positive function of symbiont density. We found that the effects of symbiont density on protection and cost are robust across ecological contexts. Density-function relationships did not vary with host type, symbiont localization, or transmission mode, nor did they vary with the method of density manipulation. Taken together, our results suggest that symbiont density can be a key variable determining the costs and benefits of a protective interaction.


ENTH domain-dependent membrane remodelling.
Cellular membranes are anything but flat structures. They display a wide variety of complex and beautiful shapes, most of which have evolved for a particular physiological reason and are adapted to accommodate certain cellular demands. In membrane trafficking events, the dynamic remodelling of cellular membranes is apparent. In clathrin-mediated endocytosis for example, the plasma membrane undergoes heavy deformation to generate and internalize a highly curved clathrin-coated vesicle. This process has become a model system to study proteins with the ability to sense and induce membrane curvature and over the last two decades numerous membrane remodelling molecules and molecular mechanisms have been identified in this process. In this review, we discuss the interaction of epsin1 ENTH domain with membranes, which is one of the best-studied examples of a peripheral and transiently membrane bending protein important for clathrin-mediated endocytosis.


[Effect of solutions of salts and glucose on the affinity of hemoglobin for oxygen in rats].
After washing of erythrocytes in the solutions of NaCl, CaCl2, MgSO4 and glucose, their hemoglobin had lower pH and affinity to oxygen as compared to the control values. The solutions used for washing had a higher pH than the control. The dependence of hemoglobin upon several events in the erythrocytes is unspecific and indirect.


Human menstrual blood: a renewable and sustainable source of stem cells for regenerative medicine.
Stem cells (SCs) play an important role in autologous and even allogenic applications. Menstrual blood discharge has been identified as a valuable source of SCs which are referred to as menstrual blood-derived stem cells (MenSCs). Compared to SCs from bone marrow and adipose tissues, MenSCs come from body discharge and obtaining them is non-invasive to the body, they are easy to collect, and there are no ethical concerns. There is, hence, a growing interest in the functions of MenSCs and their potential applications in regenerative medicine. This review presents recent progress in research into MenSCs and their potential application. Clinical indications of using MenSCs for various regenerative medicine applications are emphasized, and future research is recommended to accelerate clinical applications of MenSCs.


Active sodium-urea counter-transport is inducible in the basolateral membrane of rat renal initial inner medullary collecting ducts.
Rat inner medullary collecting ducts (IMCD3s) possess a luminal Na+-dependent, active urea secretory transport process, which is upregulated by water diuresis. In this study of perfused IMCDs microdissected from base (IMCD1), middle (IMCD2), or tip (IMCD3) of the inner medulla, we tested whether furosemide diuresis alters active urea transport. Rats received furosemide (10 mg/d s.c. for 3-4 d) and were compared with pair-fed control rats. Furosemide significantly decreased urine osmolality and urea clearance, and increased blood urea nitrogen. IMCD3s from furosemide-treated rats had significantly lower rates of active urea secretion than IMCD3s from control rats. IMCD2s showed no active urea transport in control or furosemide-treated rats. IMCD1s from control rats had no active urea transport, but IMCD1s from furosemide-treated rats expressed significant rates of active urea reabsorption. In IMCD1s, this active urea reabsorptive transport process was inhibited by: (i) 0. 25 mM phloretin (bath); (ii) 1 mM ouabain (bath); and (iii) replacing bath Na+ with NMDG+; it was stimulated by 10 nM bumetanide (bath). In summary, we found that furosemide decreased active urea secretion in IMCD3s and induced active urea reabsorption in IMCD1s. The new Na+- dependent, active urea reabsorptive transport process may be a basolateral Na+-urea antiporter.