Expression of c-fos in the rat brainstem after chronic intermittent hypoxia.
Chronic intermittent hypoxia (CIH) may cause sustained systemic hypertension by increasing sympathetic neural discharge (SND). We hypothesized that CIH alters brainstem circuits modulating SND. After 30 days of CIH exposure in rats, increased c-fos labeling was seen in the nucleus of the solitary tract and ventrolateral medulla as well as other brainstem regions involved in regulation of SND. Increased expression of c-fos after CIH may indicate changes in neuronal genetic transcription which ultimately modulate SND.


Treatment of hepatitis B virus with combination therapy now and in the future.
Chronic Hepatitis B continues as a significant public health problem despite the availability of safe and effective antivirals and a highly effective protective vaccine. Current therapy, however rarely leads to cure and lifelong therapy is often required, contributing to poor uptake and ongoing morbidity. New insights into the hepatitis B viral life cycle and the host immune response have expanded the potential targets for drug therapies with interesting antiviral candidates and novel immunotherapeutic approaches in early stage development. Yet, HBV persistence is multifactorial - due to an intrahepatic reservoir and ongoing HBV-mediated immune dysregulation, making "cure" unlikely to be realized through even the most efficacious monotherapy. Building on the success seen in the treatment of hepatitis C (HCV) and human immunodeficiency virus (HIV), combination therapy may be an essential strategy to improve efficacy and decrease viral breakthrough. Combinations acting on immune and viral targets are particularly attractive. However, creating synergy while balancing efficacy and safety remains a clear challenge. Various approaches to combination therapy are reviewed, highlighting strengths and challenges of each potential strategy. Overall, combination therapies are attractive as the next step towards cure and are a key strategy for achieving treatment with finite durations and durable endpoints.


Sequential determination of metabolites involved in the biosynthesis of aromatic amino acids after ultrasound-assisted extraction from plants and reverse LC separation.
A dual method is proposed for the determination of metabolites involved in the shikimate pathway which are biomarkers of the effects of glyphosate action on plants exposed to this herbicide. Extraction of the target metabolites (phenylalanine, tryptophan, tyrosine and shikimic acid) from a wheat model plant was accelerated by ultrasound energy. After centrifugation and micro-filtration, 1 μL of extract was injected into the chromatograph in an isocratic regime for 4 min to determine shikimate by absorption at 254 nm. In the mean time, a 130 μL aliquot of extract was subjected to derivatization with o-phthaldialdehyde and 2-mercaptoethanol for 1 min, the reaction stopped and 1 μL of the solution chromatographied in a gradient regime prior to laser-induced fluorescence detection of the derivatized amino acids. The characterization of the dual method provided limits of detection around 0.03 μg mL(-1) for the aromatic amino acids and 1.52 μg mL(-1) for shikimate, whereas the limits of quantitation ranged between 0.084 and 0.093 μg mL(-1) for amino acids and was of 4.56 μg mL(-1) for shikimate. The suitability of the method was checked by application to Triticum aestivum (wheat) plants grown under controlled conditions, sprayed with different doses of glyphosate and collected at different times after exposition to the herbicide.


The neural mechanisms of manual dexterity.
The hand endows us with unparalleled precision and versatility in our interactions with objects, from mundane activities such as grasping to extraordinary ones such as virtuoso pianism. The complex anatomy of the human hand combined with expansive and specialized neuronal control circuits allows a wide range of precise manual behaviours. To support these behaviours, an exquisite sensory apparatus, spanning the modalities of touch and proprioception, conveys detailed and timely information about our interactions with objects and about the objects themselves. The study of manual dexterity provides a unique lens into the sensorimotor mechanisms that endow the nervous system with the ability to flexibly generate complex behaviour.


Sleep bruxism and oromandibular myoclonus in rapid eye movement sleep behavior disorder: a preliminary report.
We aimed to compare rhythmic masticatory muscle activity typical of sleep bruxism and oromandibular myoclonus (OMM) during rapid eye movement (REM) sleep in patients with idiopathic REM sleep behavior disorder (iRBD) and in Parkinson disease (PD) patients with RBD (PD-RBD). Sleep polygraphic data were collected from 9 age-matched controls and 28 patients (mean±standard error of the mean, 66.0±1.7 y) with a clinical and sleep laboratory diagnosis of RBD. Patients were divided into two groups: 13 patients with iRBD and 15 patients with PD-RBD. Rhythmic masticatory muscle activity, a marker of sleep bruxism, and OMM were scored blind to subject's diagnosis from jaw electromyographic recordings during sleep. The rhythmic masticatory muscle activity index was significantly higher during REM sleep in iRBD subjects compared to controls (P<.01) and was significantly higher during non-REM (NREM) sleep in both subject groups compared to controls (P < or = .03). A positive sleep laboratory diagnosis of sleep bruxism was made in 25% of all patients. In iRBD, patients had more OMM during REM sleep than controls (2.4 times higher; P=.01). In the presence of a high frequency of rhythmic masticatory muscle activity during REM sleep, RBD may be suspected and further neurologic assessment is recommended.


Plasma cells arise from differentiation of clonal lymphocytes and secrete IgM in Waldenström macroglobulinemia.
Waldenström macroglobulinemia (WM) is characterized by bone marrow infiltration with malignant lymphoplasmacytic cells (LPCs), a smaller population of plasma cells (PCs), and hypersecretion of IgM monoclonal protein. Here, we show that CD45low, CD38+, and CD138+ PCs and CD45high, CD38-, CD138-, CD19+, and CD20+ LPCs carry a heterozygous L265P mutation in the Toll-like receptor signaling adaptor MYD88. Both PCs and LPCs express the same auto-reactive IgHV sequences, suggesting a similar clonal origin and role for auto-antigens in WM cell survival. PCs are primarily responsible for IgM production even without substantial cell proliferation. When cultured in isolation, LPCs give rise to more differentiated PCs and secrete less IgM. Our analyses suggest that malignant PCs arise from the clonal LPC population, and are primarily responsible for IgM secretion in WM. Targeting malignant PCs may have therapeutic benefits in the treatment of WM and improve the duration of response and potentially, survival.


[The conquest for non-smoking zones confronted with industry tactics: scientific misinformation and front groups. The Canadian experience].
"Cigarette smuggling: a wide scope phenomenon only there to serve the interests of big tobacco manuafacturers" uses industry officials' quotes and documents to describe how tobacco manufacturers are involved in the organisation of smuggling and how manufacturers use smuggling in two ways: on one hand, to flood markets with cheap cigarettes and defeat governements' efforts to reduce tobacco consumption by adopting one of the most efficient public health measures (ie: high taxation of tobacco products) and on the other hand, by using the false threat of increased contraband to scare politicians and prevent them from adopting strong fiscal policies. The Framework Convention on Tobacco Control (FCTC) with a protocol on smuggling and the collaboration between international agencies is a means to counter and defeat the tobacco industry attemps at sabotaging efficient public health measures.


Thermal conductivity enhancement in electrospun poly(vinyl alcohol) and poly(vinyl alcohol)/cellulose nanocrystal composite nanofibers.
The thermal conductivity enhancement of neat poly(vinyl alcohol) and poly(vinyl alcohol) (PVA)/cellulose nanocrystal (CNC) composite was attempted via electrospinning. The suspended microdevice technique was applied to measure the thermal conductivity of electrospun nanofibers (NFs). Neat PVA NFs and PVA/CNC NFs with a diameter of approximately 200 nm showed thermal conductivities of 1.23 and 0.74 W/m-K, respectively, at room temperature, which are higher than that of bulk PVA by factors of 6 and 3.5, respectively. Material characterization by Fourier transform infrared spectroscopy, differential scanning calorimetry, and thermogravimetric analysis confirmed that the thermal conductivity of the PVA/CNC NFs was enhanced by the reinforcement of their backbone rigidity, while that of the neat PVA NFs was attributed to the increase in their crystallinity that occurred during the electrospinning.


Rumination mediates the relationship between overgeneral autobiographical memory and depression in patients with major depressive disorder.
Overgeneral autobiographical memory has been identified as a risk factor for the onset and maintenance of depression. However, little is known about the underlying mechanisms that might explain overgeneral autobiographical memory phenomenon in depression. The purpose of this study was to test the mediation effects of rumination on the relationship between overgeneral autobiographical memory and depressive symptoms. Specifically, the mediation effects of brooding and reflection subtypes of rumination were examined in patients with major depressive disorder. Eighty-seven patients with major depressive disorder completed the 17-item Hamilton Depression Rating Scale, Ruminative Response Scale, and Autobiographical Memory Test. Bootstrap mediation analysis for simple and multiple mediation models through the PROCESS macro was applied. Simple mediation analysis showed that rumination significantly mediated the relationship between overgeneral autobiographical memory and depression symptoms. Multiple mediation analyses showed that brooding, but not reflection, significantly mediated the relationship between overgeneral autobiographical memory and depression symptoms. Our results indicate that global rumination partly mediates the relationship between overgeneral autobiographical memory and depressive symptoms in patients with major depressive disorder. Furthermore, the present results suggest that the mediating role of rumination in the relationship between overgeneral autobiographical memory and depression is mainly due to the maladaptive brooding subtype of rumination.


An RNA reset button.
In this issue of Molecular Cell, single-cell analyses by Bumgarner et al. (2012) reveal how two antagonistic long noncoding RNAs at the FLO11 locus define a toggle responsible for morphological heterogeneity in genetically identical populations of budding yeast.


The effect of tooth brushing, irrigation, and topical tetracycline administration on the reduction of oral bacteria in mechanically ventilated patients: a preliminary study.
One of the main causes of ventilator-associated pneumonia (VAP) is thought to be aspiration of oropharyngeal fluid containing pathogenic microorganisms. The aim of this study was to examine the effects of various oral care methods on the reduction of oral bacteria during intubation. First, the effect of mechanical oral cleaning was investigated. The bacterial count on the tongue and in the oropharyngeal fluid was measured after tooth brushing, irrigation, and three hours after irrigation in mechanically ventilated patients at the intensive care unit (ICU). Next, the efficacy of topical administration of tetracycline and povidone iodine on the inhibition of bacterial growth on the tongue and in the oropharyngeal fluid was examined in oral cancer patients during neck dissection. The number of bacteria in the oropharyngeal fluid was approximately 10(5)-10(6) cfu/mL before surgery, but increased to 10(8) cfu/mL after intubation. Oral care with tooth brushing and mucosal cleaning did not reduce oral bacteria, while irrigation of the oral cavity and oropharynx significantly decreased it to a level of 10(5) cfu/mL (p < 0.001). However, oral bacteria increased again to almost 10(8) cfu/mL within three hours of irrigation. Oral bacteria did not decrease by topical povidone iodine application. In contrast, 30 min after topical administration of tetracycline, the number of oral bacteria decreased to 10(5) cfu/mL, and remained under 10(6) cfu/mL throughout the entire experimental period of 150 min. While the present studies are only preliminary, these results indicate that irrigation of the oral cavity and oropharynx followed by topical antibiotic administration may reduce oral bacteria in mechanically ventilated patients. UMIN000018318 , 1 August 2015.


Evolving functional and structural dynamism in coupled Boolean networks.
This article uses a recently presented abstract, tunable Boolean regulatory network model to further explore aspects of mobile DNA, such as transposons. The significant role of mobile DNA in the evolution of natural systems is becoming increasingly clear. This article shows how dynamically controlling network node connectivity and function via transposon-inspired mechanisms can be selected for to significant degrees under coupled regulatory network scenarios, including when such changes are heritable. Simple multicellular and coevolutionary versions of the model are considered.


Survival of younger cervical carcinoma patients treated by radical radiotherapy in the west of Scotland 1964-1984.
Between 1964 and 1984, 2011 patients in the West of Scotland were treated by radical radiotherapy for carcinoma of cervix. In keeping with the rise in incidence amongst younger patients nationally, the number of women aged less than 35 years seen during the 20-year period has doubled. Younger women (aged less than 35 or less than 45) have a better prognosis mainly because more present with earlier disease. Stage for stage there has been no change in survival of women of all ages treated by identical radiotherapy during this period. The rise in mortality of younger patients from carcinoma of cervix may be due to the increased incidence of the condition rather than a more virulent form of the disease.


Elder Abuse.
Elder abuse, defined as "harm inflicted on an older person in a relationship where there is an expectation of trust, and/or when the person is targeted based on age or disability," can be challenging for clinicians to identify. Radiologists can help raise appropriate suspicion for elder abuse based on a patient's imaging. This article reviews common distributions and radiographic patterns of injury sustained in physical elder abuse. It also discusses limitations and unique challenges to the radiologic assessment of elder abuse, including issues of communication with frontline providers, and broad overlap in the appearance of abusive and accidental injuries in the setting of old age and deconditioning.


Brief Report: Antimalarial Benefit of HIV Antiretroviral Therapy in Areas of Low to Moderate Malaria Transmission Intensity.
We previously used mathematical modeling to predict reduced malaria incidence in children with protease inhibitor (PI)-, compared with nonnucleoside reverse transcriptase inhibitor-, based highly active antiretroviral therapy (HAART), in moderate to high malaria transmission areas. These effects were accounted for, in part, by pharmacokinetic (PK) interactions between PIs and artemether-lumefantrine (AL). Because of potentially reduced malaria transmission reservoirs in HIV-infected children due to PI/AL PK interactions impacting non-HIV-infected children, we estimate the antimalarial benefit of PI-based HAART in all children, and in HIV-infected children only residing in low to moderate malaria transmission areas. A dynamic model of malaria transmission was developed to evaluate the PK interaction of PI-based HAART with the antimalarial, AL for preventing malaria. To evaluate the benefit of HIV PI-based HAART on malaria incidence, a malaria transmission model with varying degrees of HIV newborn prevalence was developed using recent pediatric clinical trial data in Lilongwe, Malawi. Comparing situations of low to high HIV newborn prevalence, and low to moderate malaria transmission intensities, our model predicts the combination of PI-based HAART with AL-treated malaria prevents 0.04-24.8 and 0.05-34.5 annual incidences of malaria overall per 1000 children, and saves 0.003-1.66 and 0.003-2.30 disability-adjusted life years per 1000 children, respectively. When incorporating seasonality, 0.01-7.3 and 0.01-5.9 annual incidences of malaria overall per 1000 children, and 0.0-0.5 and 0.001-0.41 disability-adjusted life years per 100 children, are prevented, respectively. In low to moderate malaria transmission intensity areas, PI-based HAART may reduce malaria events in children when AL is used.


Endoplasmic reticulum retention and degradation of T cell antigen receptor beta chain.
The T cell antigen receptor-CD3 (TCR/CD3) complex is assembled in the endoplasmic reticulum (ER) of T cells after synthesis of individual chains, and is transported to the cell surface for immune recognition and regulation. Partially assembled or unassembled TCR chains are retained and rapidly degraded in the ER. These processes are strictly regulated in the ER at post-translational level for the maintenance of cellular homeostasis. In order to identify the region responsible for the ER retention and rapid degradation of the TCR beta chain, number of mutants were engineered and their fates, after synthesis in the ER of the HeLa cells, were investigated. Extensive mutagenic analysis of TCR beta chain, including changing the charged amino acid residues and two tyrosine residues of the transmembrane region into hydrophobic amino acid residues, did not alter the ER retention and rapid degradation. Soluble TCR beta chain and cytoplasmic tail truncation mutant were also rapidly degraded in the ER. However, N-glycosylation rate of soluble TCR beta chain in the ER was significantly increased possibly due to the increased exposure of the N-glycosylation site. These results suggest that the ER retention of TCR beta chain is mediated through its extracellular and transmembrane-cytoplasmic regions and that the rapid ER degradation can be caused by an exposure of unassembled subregion of TCR beta chain, either extracellular domain or hydrophobic transmembrane region to the hydrophilic environment (lumen of the ER) rather than by presence of a specific degradation signal.


What am I supposed to be looking at? Controls and measures in inter-modal preferential looking.
Intermodal preferential looking (IMPL) is widely used in experimental studies of infant development, especially language development. Control measures vary, and it is not clear how these affect findings. We examined effects of parental awareness of stimuli. Infants (17-19 months) looked at paired pictures, one name-known and one name-unknown, each assigned target status in 50 % of trials. Infants looked longer at a name-known than a name-unknown target, regardless of parents' awareness. When parents were aware, looking to a name-unknown target increased over a paired name-known non-target. There is evidence that infants' looking at pictures in this paradigm is not due to direct matching of targets to novel names, but is influenced by additional cues present, in a way that could alter the conclusions of studies of infant word learning and other aspects of infant learning. Implications of these findings are discussed, emphasising replicability and theoretical conclusions drawn from studies using this method.


Cloning and molecular characterization of the myxoma virus genome.
Restriction enzyme cleavage maps of the genomes of the Uriarra (Ur), Glenfield (GV), and Lausanne (Lu) strains of myxoma virus were deduced for the enzymes EcoRI, KpnI, BamHI, SalI, HindIII, BglI, PstI, and PvuII. Restriction maps for the three strains were indistinguishable with the exception of an additional KpnI site in the Lu genome at map position 38.8. Genomic DNA fragments were cloned into the plasmid vector pGEM-3 and the viral genome was determined to be 163.6 (+/- 0.2) kb in length. Covalently closed terminal fragments were identified by electrophoresis of "snapback" fragments and the 5.3 kb BglI end fragment was cloned after S1 nuclease digestion of the hairpin structure.


The paradox of mental health: over-treatment and under-recognition.
The PLOS Medicine editors discuss the paradox of mental health, where over-diagnosis and treatment of some mental health issues exists alongside profound under-recognition of mental health conditions in the developing world.


[A comparative clinical study of the efficacy of computer cognitive training in patients with post-stroke cognitive impairments].
To assess the effectiveness of neuropsychological computer programs in comparison with entertainment computer games. Patients (n=68), aged 40-65 years, were randomized into three groups: an intervention group (neuropsychological computer programs), an active control group (entertaining computer games), a passive control group (conventional treatment). An analysis of the coefficient of effectiveness showed significant improvements in the intervention group comparing with the passive control group (MoCA, MMSE, Schulte test) and the active control group (MoCA). Neuropsychological computer programs confirmed their effectiveness for recovery of post stroke cognitive impairments comparing with conventional treatment and entertainment computer games as well.


Stimulation of nuclear receptor REV-ERBs regulates tumor necrosis factor-induced expression of proinflammatory molecules in C6 astroglial cells.
Under physiological conditions, astrocytes maintain homeostasis in the CNS. Following inflammation and injury to the CNS, however, activated astrocytes produce neurotoxic molecules such as cytokines and chemokines, amplifying the initial molecular-cellular events evoked by inflammation and injury. Nuclear receptors REV-ERBα and REV-ERBβ (REV-ERBs) are crucial in the regulation of inflammation- and metabolism-related gene transcription. The current study sought to elucidate a role of REV-ERBs in rat C6 astroglial cells on the expression of inflammatory molecules following stimulation with the neuroinflammatory cytokine tumor necrosis factor (TNF). Stimulation of C6 cells with TNF (10 ng/ml) significantly increased the mRNA expression of CCL2, interleukin-6 (IL-6), inducible nitric oxide synthase (iNOS), and matrix metalloprotease (MMP)-9, but not fibroblast growth factor-2 (FGF-2), cyclooxygenase-2 (COX-2) and MMP-2. Treatment with either REV-ERB agonists GSK4112 or SR9009 significantly blocked TNF-induced upregulation of CCL2 mRNA and MMP-9 mRNA, but not IL-6 mRNA and iNOS mRNA expression. Furthermore, treatment with RGFP966, a selective histone deacetylase 3 (HDAC3) inhibitor, potently reversed the inhibitory effects of GSK4112 on TNF-induced expression of MMP-9 mRNA, but not CCL2 mRNA. Expression of Rev-erbs mRNA in C6 astroglial cells, primary cultured rat cortical and spinal astrocytes was confirmed by reverse transcription polymerase chain reaction. Together, the findings demonstrate an anti-inflammatory effect, downregulating of MMP-9 and CCL2 transcription, of astroglial REV-ERBs activation through HDAC3-dependent and HDAC3-independent mechanisms.


MTTP variants and body mass index, waist circumference and serum cholesterol level: Association analyses in 7582 participants of the KORA study cohort.
The microsomal triglyceride transfer protein (MTTP) is a key regulator in the assembly and secretion of chylomicrons and very low density lipoprotein (VLDL) in the intestine and in liver. Associations between MTTP variants and traits of the metabolic syndrome are carried out in relatively small cohorts and are not consistent. We analysed MTTP polymorphisms in 7582 participants of the KORA study cohort. Seven htSNPs covering a 52kb region of the MTTP locus and two cSNPs (I128T, H297Q) were selected. A MTTP haplotype containing the minor allele of H297Q showed a significant decrease of -0.636 (95% CI: -1.226, -0.046; p=0.035) BMI units in females but not in males. In comparison to homozygous H-carriers for the major allele of the MTTP H297Q polymorphism, homozygous Q297Q carriers showed a significant decrease in BMI of -0.425B MI units (95% CI: -0.74, -0.12; p=0.007), in waist circumference of -0.990 cm (95% CI: 1.74, -0.24; p=0.01) and in total cholesterol of -0.039 mmol/l (95% CI: -0.07, 0; p=0.03). Heterozygous Q-carriers displayed a reduction in BMI of -0.183 BMI unit (95% CI: -0.33, -0.04; p=0.012), in waist circumference of -0.45 cm (95% CI: 0.8, -0.1; p=0.01) and in total cholesterol of -0.103 mmol/l (95% CI: -0.18, -0.03; p=0.01). Gender stratified statistics revealed a significant reduction of -0.657 BMI units (95% CI: -1.14, -0.18; p=0.007), -1.437 cm waist circumference (95% CI: -2.55, -0.32; p=0.01) and -0.052 mmol/l total cholesterol (95% CI: -0.1, -0.01; p=0.03) for females homozygous for the Q297Q polymorphism. Females carrying the Q-allele showed a decrease of -0.259 BMI unit (95% CI: -0.48, -0.04; p=0.023), -0.662 cm waist circumference (95% CI: -1.18, -0.14; p=0.01) and -0.111 mmol/l total cholesterol (95% CI: -0.21, -0.01; p=0.03). Our association analysis in a large population based study cohort provides evidence that the minor allele of the MTTP H297Q polymorphism is associated with lower BMI, waist circumference and total cholesterol in females but not in males.


A comprehensive analysis of the potential role of necroptosis in hepatocellular carcinoma using single-cell RNA Seq and bulk RNA Seq.
Necroptosis plays an essential role in oncogenesis and tumor progression in hepatocellular carcinoma (HCC). This study aimed to investigate the role of necroptosis in the development and progression of HCC. Specifically, we constructed a prognostic prediction model using necroptosis-associated genes (NAGs) to predict patient outcomes. Using data from The Cancer Genome Atlas (TCGA) database, we analyzed gene expression and clinical data. We identified a 5-gene model associated with NAGs and explored genetic features and immune cell infiltration using the CIBERSORT algorithm. In addition, we conducted single-cell RNA sequencing to investigate the potential role of necroptosis in HCC. We constructed a 5-gene prognostic model based on NAGs that demonstrated excellent predictive accuracy in both training and validation sets. Using multifactorial cox regression analysis, we confirmed the risk score derived from the model as an independent predictor of prognosis, surpassing other clinical characteristics. Patients with high risk scores had significantly worse prognosis than those with low risk scores. To enhance the clinical utility of the necroptosis score, we constructed an accurate nomogram. Additionally, we compared metabolic pathway and immune microenvironment differences between HCC tumors with high and low risk scores. Our single-cell RNA sequencing analyses revealed that necroptosis in HCC was primarily associated with a specific subset of macrophages. Our study revealed the presence of two distinct necroptosis subtypes in HCC and developed a robust prognostic model with exceptional predictive accuracy. We observed significantly higher infiltration of M0 macrophages in the high-risk group. We propose that rescuing cytochrome c metabolism in HCC could serve as a potential therapeutic strategy. Furthermore, at a single-cell resolution, our analysis identified myeloid cells as the primary cells exhibiting necroptosis. Specifically, macrophages expressing CD5L, CETP, and MARCO, which may belong to a subset of tissue-resident macrophages, were found to be highly susceptible to necroptosis. These findings suggest the involvement of this specific macrophage subset in potential antitumor therapies. Our study provides novel insights into predicting patient prognosis and developing personalized therapeutic approaches for HCC.


[Apoptosis of renal cell carcinoma and apoptotic related genes bcl-2 and bax].
To explore the mechanism of renal cell carcinoma (RCC). We detected the apoptotic status and the expression of apoptotic related gene bcl-2 and bax protein in 48 cases of RCC with TdT-mediated dUTP-biotin nick end labeling (TUNEL) and immunohistochemistry methods. 22 cases showed low expression of bcl-2 protein with an average apoptotic index (AI) of 1.35 and 26 cases had high expression of bcl-2 with an AI of 1.04 (P < 0.05). 34 cases showed low expression of bax protein with average AI of 1.03 and 14 cases had high expression of bax protein with an average AI of 1.63 (P < 0.01). The stronger bcl-2 expression, the weaker bax expression and the less number of apoptotic cells. both bcl-2 and bax take part in the occurrence and progression of RCC.


Crocetin ester improves myocardial ischemia via Rho/ROCK/NF-κB pathway.
Crocetin ester (CE) is the active ingredient of Crocus sativus L. stigmas and Gardenia jasminoides Ellis fruit. The main purpose of the present study was to investigate the protective effect of CE on isoproterenol (ISO)-induced acute myocardial ischemia (AMI) through Rho/ROCK/NF-κB pathway and explore its underlying mechanism. Administration of CE (25 and 50mg/kg) could significantly reduce the serum contents of pro-inflammatory cytokines including tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β) and interleukin-6 (IL-6). In addition, pretreatment with CE attenuated the contents of creatine kinase (CK), malondialdehyde (MDA) and the activities of lactate dehydrogenase (LDH), superoxide dismutase (SOD) in serum. Treatment with CE also improved the histopathological alteration and decreased the ST elevation. Furthermore, CE could ameliorate the cardiac expressions of Cu, Zn-superoxide dismutase (SOD1), MDA5, Rho, ROCK, p-IκB and p-NF-κBp65 in ISO-induced rats. It was assumed that CE might be a new therapeutic candidate for the treatment of AMI possibly through the inhibition of Rho/ROCK/NF-κB pathway.


The first version of nation-wide open 3D soil database for Sri Lanka.
Soil data for Sri Lanka are available through semi-detailed series maps that were developed based on limited soil profile data combined with expert knowledge. This data plays a vital role in decisions at national and regional levels. However, the present format of this database does not allow for their wider use in crop simulation modelling and other related agricultural research that require finer scale data. This is due to the fact that cross-country profile data are not harmonised based on standard depths. Several attempts were made to produce digital soil data for Sri Lanka at different geographic scales, however, a completely harmonised data that covers variability across depths and properties is yet to be made available. In this article, we describe the first version of the open digital soil database that was developed using a database of 122 locations across the country. Soil properties were harmonised for standard depths using equal-area quadratic smoothing splines. Out of several interpolation methods that were evaluated for univariate interpolation, maps which were produced with the least overall error (RMSE) in the process of cross-validation were selected. The newly developed digital soil database contains 9 soil properties; pH, bulk density, cation exchange capacity, organic carbon, volumetric moisture content at 0.33 and 15 bars levels, sand silt and clay content. Moreover, the data are available for five standard depth layers as 0-5, 5-15, 15-30, 30-60 and 60-100 cm in raster format at 1 km spatial resolution. Both interpolated property maps and their error maps were stored in an open repository and made available for public use. The first version of all maps is also showcased online through open web mapping services. The repository will be gradually updated with higher resolution and more accurate maps as more samples become available and better interpolation method are used. This data could provide complementary information for insight generation at finer scales where limited local informaiton about soils hinders agricultural development.


TP53/p53 Facilitates Stress-Induced Exosome and Protein Secretion by Adipocytes.
Besides the secretion of fatty acids, lipolytic stimulation of adipocytes results in the secretion of triglyceride-rich extracellular vesicles and some free proteins (e.g., fatty acid binding protein 4) that, in sum, affect adipose homeostasis as well as the development of metabolic disease. At the mechanistic level, lipolytic signals activate p53 in an adipose triglyceride lipase-dependent manner, and pharmacologic inhibition of p53 attenuates adipocyte-derived extracellular vesicle (AdEV) protein and FABP4 secretion. Mass spectrometry analyses of the lipolytic secretome identified proteins involved in glucose and fatty acid metabolism, translation, chaperone activities, and redox control. Consistent with a role for p53 in adipocyte protein secretion, activation of p53 by the MDM2 antagonist nutlin potentiated AdEV particles and non-AdEV protein secretion from cultured 3T3-L1 or OP9 adipocytes while the levels of FABP4 and AdEV proteins were significantly reduced in serum from p53-/- mice compared with wild-type controls. The genotoxin doxorubicin increased AdEV protein and FABP4 secretion in a p53-dependent manner and DNA repair-depleted ERCC1-/Δ-haploinsufficient mice expressed elevated p53 in adipose depots, along with significantly increased serum FABP4. In sum, these data suggest that lipolytic signals, and cellular stressors such as DNA damage, facilitate AdEV protein and FABP4 secretion by adipocytes in a p53-dependent manner.


Covariation of distributions of callosal cell bodies and callosal axon terminals in layer III of cat primary auditory cortex.
Primary auditory cortex in the cat is both the source and target of callosal fibers. Injection of horseradish peroxidase (HRP) in the high frequency representation of AI in one hemisphere retrogradely labels callosal cell bodies and anterogradely labels callosal axon terminals in AI of the opposite hemisphere. In tissue sections cut through layer III parallel to the cortical surface, elongated patches composed of dense aggregates of callosal cell bodies and callosal axon terminals alternate with regions containing lower concentrations of these elements. Labeling in AI is most dense in regions corresponding to the frequency representation of the injected site. In layer III of the densely labeled region, patches of high concentrations of labeled callosal axon terminals correspond with high concentrations of labeled callosal cell bodies. On the other hand, little correspondence is apparent between the distributions of the two elements in layer III in the surrounding area of lighter labeling. Layers V and VI contain relatively few labeled callosal axon terminals and cell bodies, and our data do not suggest whether the two distributions covary in these layers.


Primary and Secondary Diastolic Dysfunction in Heart Failure With Preserved Ejection Fraction.
Approximately 50% of patients with symptoms and signs of heart failure have a left ventricular ejection fraction (LVEF) ≥50% and are often simply referred to as 'heart failure with preserved EF', 'HFpEF'. Many of such patients have HF secondary to specific cardiac conditions (i.e., valvular or pericardial disease) in which the symptoms and signs occur despite the LVEF being preserved due to diastolic dysfunction secondary to the underlying disease (secondary HFpEF), differently from those HFpEF patients in which the impaired LV filling is due to a primary diastolic dysfunction (primary HFpEF). When primary HFpEF patients are properly diagnosed, they appear to have a milder form of HF with a lower cardiovascular mortality compared with HFrEF and secondary HFpEF population, but a risk of HF hospitalization that is significantly higher than patients with similar cardiovascular risk factors but without the diagnosis of HFpEF. We herein review the diagnostic approach to HFpEF and present a differential diagnosis of HFpEF in a primary and secondary form.


Can body surface microvolt T-wave alternans distinguish concordant and discordant intracardiac alternans?
There is convincing experimental evidence that cellular action potential duration (APD) alternans is arrhythmogenic but its relationship with body surface microvolt T-wave alternans (MTWA) remains unclear. We investigated the relationship between MTWA and APD alternans induced by alternating cycle length (CL) pacing in a pig model. In 10 pigs, catheters in the right atrium (RA) and right (RV) and left ventricle (LV) allowed pacing and recording of monophasic action potentials (MAP). During RA pacing at stable 500-ms CL, LV was paced at alternating CL (505 ms and 495 ms). Changing the alternating LV (A-LV) pacing delay changes the size of the region with alternating ventricular activation. Spectral analysis of intracardiac MAP was correlated with body surface MTWA. In a similar setup (during alternating pacing in RV and LV), we investigated concordant versus discordant APD alternans. Pacing the LV with subtle alternating cycle lengths at short A-LV delay leads to broad QRS (97 ± 10 ms), body surface MTWA (mean Valt 4.2 ± 1.8 µV), and positive RR-interval alternans. At longer A-LV delay, not resulting in QRS widening (68 ± 5 ms), body surface RR alternans was absent but MTWA remained detectable and was even more pronounced (8.7 ± 5.1 µV, P < 0.01). During both concordant and discordant pacing MTWA was present. The precordial leads were better for detecting discordant APD alternans (8.0 ± 2.9 µV and 12.8 ± 4.52 µV, P = 0.02). MTWA is a potent technique to detect subtle and isolated intracardiac APD alternans that is artificially induced by alternating pacing. In the same model, discordant activation alternans can only be discriminated from concordant when using a quantifying approach of MTWA analysis.


Oral hairy leukoplakia among HIV-positive intravenous drug abusers: a clinicopathologic and ultrastructural study.
During a prospective investigation of oral lesions of 120 consecutive patients positive for human immunodeficiency virus, belonging to the intravenous drug abuser risk group and other risk categories, we observed hairy leukoplakia (HL) in 23 cases (19%). The median age of the patients was 27 years (range, 20 to 50 years). Twenty patients were men and three were women. All but two of the twenty three patients used intravenous drugs for a median period of 6 years (range, 5 to 18 years) and were involved in several episodes of needle sharing. Eight men were also bisexual, one man was homosexual, and one man was hemophiliac and bisexual. Eleven patients had asymptomatic infection, five had lymphadenopathy syndrome, six had AIDS-related complex, and one had acquired immunodeficiency syndrome. In all patients, HL lesions were localized on the lateral borders of the tongue. In twelve patients, the lesion was unilateral, and in eleven patients, it was bilateral. Microscopically, hyperparakeratosis and the presence of koilocytes were observed in all cases. Surface candidiasis could be detected with staining with periodic acid-Schiff in two thirds of the cases. In four cases, electron microscopy showed the presence of intracellular and extracellular hyphae of Candida albicans in the parakeratin layer associated with coccobacilli in the spaces between surface epithelial cells. The spinous layer included koilocytes, which had a clear cytoplasmic matrix, sparse organelles and tonofilaments, and dispersed chromatin. These cells were found to be infected by a herpes-type virus in all cases examined. There was no ultrastructural evidence of human papillomavirus in the nuclei of the epithelial cells.(ABSTRACT TRUNCATED AT 250 WORDS)


Low temperature storage alleviates internal browning of 'Comte de Paris' winter pineapple fruit by reducing phospholipid degradation, phosphatidic acid accumulation and membrane lipid peroxidation processes.
To uncover the mechanism underlying membrane lipid metabolism of low temperature induced internal browning tolerance in pineapple, membrane phospholipid alterations of harvested 'Comte de Paris' winter pineapple fruit stored at either 10 °C or 25 °C was investigated. Fruit stored at 10 °C developed low levels of internal browning as compared to fruit stored at 25 °C and was associated with high contents of phosphatidylcholine, phosphatidylglycerol, phosphatidylinositol, phosphatidylserine, and phosphatidylethanolamine, and low levels of phosphatidic acid. Storage at 10 °C down-regulated the expression levels of phospholipase As. Fruit stored at 10 °C also exhibited high ratio of unsaturated fatty acid to saturated fatty acid and index of unsaturated fatty acid level. These findings suggest that maintenance phospholipid abundance, reduction in phosphatidic acid accumulation and membrane lipid peroxidation may have contributed to the enhanced internal browning tolerance in 'Comte de Paris' winter pineapple fruit at low temperature storage.


Effect of target animacy on hand preference in Sichuan snub-nosed monkeys (Rhinopithecus roxellana).
Twenty-eight captive Sichuan snub-nosed monkeys (Rhinopithecus roxellana) were involved in the current study. Many individuals showed handedness, with a modest tendency toward left-hand use especially for animate targets, although no group-level handedness was found. There was no significant gender difference in the direction and strength of hand preference for both targets. Females showed a significantly higher overall rate of actions toward animate targets than inanimate targets for both hands, whereas males displayed almost the reversed pattern. There were no significant interactions between lateral hand use and target animacy for either males or females. Most individuals showed rightward or leftward laterality shift trends between inanimate and animate targets. These findings to some extent support the existence of a potential trend concerning a categorical neural distinction between targets demanding functional manipulation (inanimate objects) and those demanding social manipulation (animate objects), even though specialized hand preference based on target animacy has not been fully established in this arboreal Old World monkey species.


Warming-induced changes in denitrifier community structure modulate the ability of phototrophic river biofilms to denitrify.
Microbial denitrification is the main nitrogen removing process in freshwater ecosystems. The aim of this study was to show whether and how water warming (+2.5 °C) drives bacterial diversity and structuring and how bacterial diversity affects denitrification enzymatic activity in phototrophic river biofilms (PRB). We used water warming associated to the immediate thermal release of a nuclear power plant cooling circuit to produce natural PRB assemblages on glass slides while testing 2 temperatures (mean temperature of 17 °C versus 19.5 °C). PRB were sampled at 2 sampling times during PRB accretion (6 and 21days) in both temperatures. Bacterial community composition was assessed using ARISA. Denitrifier community abundance and denitrification gene mRNA levels were estimated by q-PCR and qRT-PCR, respectively, of 5 genes encoding catalytic subunits of the denitrification key enzymes. Denitrification enzyme activity (DEA) was measured by the acetylene-block assay at 20 °C. A mean water warming of 2.5 °C was sufficient to produce contrasted total bacterial and denitrifier communities and, therefore, to affect DEA. Indirect temperature effect on DEA may have varied between sampling time, increasing by up to 10 the denitrification rate of 6-day-old PRB and decreasing by up to 5 the denitrification rate of 21-day-old PRB. The present results suggest that indirect effects of warming through changes in bacterial community composition, coupled to the strong direct effect of temperature on DEA already demonstrated in PRB, could modulate dissolved nitrogen removal by denitrification in rivers and streams.


In Vitro Analysis of mtDNA Replication.
Human mitochondrial DNA is a small circular double-stranded molecule that is essential for cellular energy production. A specialized protein machinery replicates the mitochondrial genome, with DNA polymerase γ carrying out synthesis of both strands. According to the prevailing mitochondrial DNA replication model, the two strands are replicated asynchronously, with the leading heavy-strand initiating first, followed by the lagging light-strand. By using purified recombinant forms of the replication proteins and synthetic DNA templates, it is possible to reconstitute mitochondrial DNA replication in vitro. Here we provide details on how to differentially reconstitute replication of the leading- and lagging-strands.


[Primary lymphoma of the heart. Report of a case with immunohistochemical study].
A case of primary cardiac lymphoma (PCL) is reported in a patient presenting with chest pains. This PCL was treated with surgery. The histology showed a large cell lymphoma. The immunohistochemical study demonstrated the B cell origin of this PCL.


[Literature review of the toxicology of the fire-extinguishing agents halon 1301 and 1211 and their decomposition products].
This review sums up the results of the examinations concerning the toxicity of the fire extinguishing agents Bromotrifluoromethane and Bromochlorodifluoromethane. Besides the toxicity of the pure substances decomposition products are subject to this paper.


Amyloid precursor protein: from synaptic plasticity to Alzheimer's disease.
The amyloid precursor protein (APP) has been shown to be implicated in age-associated plastic changes at synapses that might contribute to memory loss in Alzheimer's disease. As APP has previously been reported to have multiple functions during normal development, and as human and avian APP share 95% homology in amino acid sequence, we have employed a one-trial passive avoidance task in day-old chicks to study its role in the process of memory formation. Administration of anti-APP antibodies, raised against human APP, APP-antisense, and Abeta during pre-training, prevented memory formation without effects on general behavior or initial acquisition. Amnesia is apparent by 30 min post-training and lasts for at least 24 hours. Injection of APP-derived peptides RERMS (APP(328-332)) and RER (APP(328-330)) homologous to the short stretches of amino acids in the Kang sequence (APP(319-335)), rescue the memory in animals rendered amnestic by previous (anti-APP antibody, antisense, and Abeta pretreatments. The protected form of RER, with a prolonged half-life (acetylated RER), proved to be effective when injected intracranially and peripherally. The tripeptide RER exerts its biological activity by binding to two neuronal plasma membrane proteins (60 and 110 kDa). The results obtained in this study suggest that RER alleviates memory deficits via receptor-mediated events, and that short APP-derived peptides might represent a novel group of therapeutically active molecules for the alleviation of memory deficits in age-related dementias.


The magnitude of HIV-1 resistance to the CCR5 antagonist maraviroc may impart a differential alteration in HIV-1 tropism for macrophages and T-cell subsets.
Human immunodeficiency virus type 1 (HIV-1) resistance to CCR5 antagonists, including maraviroc (MVC), results from alterations in the HIV-1 envelope glycoproteins (Env) enabling recognition of antagonist-bound CCR5. Here, we characterized tropism alterations for CD4+ T-cell subsets and macrophages by Envs from two subjects who developed MVC resistance in vivo, which displayed either relatively efficient or inefficient recognition of MVC-bound CCR5. We show that MVC-resistant Env with efficient recognition of drug-bound CCR5 displays a tropism shift for CD4+ T-cell subsets associated with increased infection of central memory T-cells and reduced infection of effector memory and transitional memory T-cells, and no change in macrophage infectivity. In contrast, MVC-resistant Env with inefficient recognition of drug-bound CCR5 displays no change in tropism for CD4+ T-cell subsets, but exhibits a significant reduction in macrophage infectivity. The pattern of HIV-1 tropism alterations for susceptible cells may therefore be variable in subjects with MVC resistance.


The influence of petroleum products on the methane fermentation process.
In this study the influence of the petroleum products: diesel fuel and spent engine oil on the sewage sludge digestion process and biogas production efficiency was investigated. Microbiological, chemical and enzymatic analyses were applied in the survey. It was revealed that the influence of the petroleum derivatives on the effectiveness of the methane fermentation of sewage sludge depends on the type of the petroleum product. Diesel fuel did not limit the biogas production and the methane concentration in the biogas, while spent engine oil significantly reduced the process efficacy. The changes in physical-chemical parameters, excluding COD, did not reflect the effect of the tested substances. The negative influence of petroleum products on individual bacterial groups was observed after 7 days of the process, while after 14 days probably some adaptive mechanisms appeared. The dehydrogenase activity assessment was the most relevant parameter to evaluate the effect of petroleum products contamination. Diesel fuel was probably used as a source of carbon and energy in the process, while the toxic influence was observed in case of spent engine oil.


Laparoscopic left colon resection for diverticular disease.
The aim of this study was to review our experience with laparoscopic sigmoid colectomy for diverticular disease. All patients presenting with acute or chronic diverticulitis, obstruction, abscess, or fistula were included. Symptomatic diverticular disease was the main surgical indication (95%). Between March 1992 and August 1999 170 consecutive patients underwent surgery. Of these, 21 patients (12%) had significant obesity, with body mass index (BMI) greater than 30. The average length of surgery was 141 +/- 36 min. In 163 patients (96%), the procedure was performed solely with the laparoscope. The nasogastric tube was removed on postoperative day 2 +/- 1.9, and oral feeding was started on postoperative day 3.4 +/- 2.1. The average length of hospital stay after surgery was 8.5 +/- 3.7 days. During the first postoperative month, there were no deaths. However, 11 patients (6.5%) had surgical complications: 5 anastomotic leaks (2.9%), 1 intraabdominal abscess (0.6%), and 3 wound infections (1.7%). There were four reinterventions (2.4%), with two diverting colostomies. Secondarily, 10 anastomotic stenoses (5.9%) were observed. Eight patients required a reintervention: seven anastomotic resections by open laparotomy and one terminal colostomy. Seven patients (4.1%) reported retrograde ejaculation, and one reported impotence. The feasibility of the laparoscopic approach to diverticular disease is established with a conversion rate of 4%, a low incidence of acute septic complications (5.3%), and a mortality rate of 0%. Therefore, laparoscopic sigmoid colectomy has become our procedure of choice in the treatment of diverticular disease.


Three New Constituents with Anti-Inflammatory and Antimicrobial Activities in Vitro from the Roots of Capsicum annuum L.
Three new compounds, including two new sesquiterpenes (1-2), named Annuumine E-F, and one new natural product, 3-hydroxy-2,6-dimethylbenzenemethanol (3), together with seventeen known compounds (4-20) were isolated from the ethanol extract of the roots of Capsicum annuum L. Among them, five compounds (4, 5, 9, 10 and 20) were isolated from this plant for the first time. The structures of new compounds (1-3) were determined via detailed analysis of the IR, HR-ESI-MS and 1D and 2D NMR spectra. The anti-inflammatory activities of the isolated compounds were evaluated by their ability to reduce NO release by LPS-induced RAW 264.7 cells. Notably, compound 11 exhibited moderate anti-inflammatory activity (IC50 =21.11 μM). Moreover, the antibacterial activities of the isolated compounds were also evaluated.


Comparison of clinical characteristics and vestibular function test results in patients with vestibular migraine and Menière's disease.
The differentiation between Vestibular Migraine (VM) and Meniere's Disease (MD) is difficult because of overlapping symptoms. The study aimed to compare the clinical characteristics and vestibular function test results between VM and MD patients. Seventy-one patients with definite VM and 31 patients with definite unilateral MD were included. All patients received Caloric Test (CT), Video Head Impulse Test (vHIT) and Vestibular Evoked Myogenic Potential (VEMP) test within 7 days after visiting the hospital. Results of these tests were compared between groups. Most VM patients (64.0%) experienced spontaneous internal vertigo, while most MD patients (66.7%) experienced spontaneous external vertigo. MD patients had more severe vestibular symptoms and autonomic responses compared to VM patients during attacks (p = 0.03, p = 0.00, respectively). The nystagmus intensity of CT-induced was greater in VM patients than in MD patients (p = 0.003). More VM patients had CT intolerance and Central Positional Nystagmus (CPN) compared to MD patients (p = 0.002, p = 0.006, respectively). More MD patients had CT(+) and vHIT saccades wave compared to VM patients (p < 0.001, p = 0.002, respectively). The non-elicitation rate of cervical VEMP was higher, and the ocular VEMP amplitudes were lower in MD patients than in VM patients (p = 0.002, p = 0.018). Vestibular symptoms during attacks combined with the results of vestibular function tests may be used to differentiate between VM and MD. The diverse nature of vestibular symptoms (especially internal vertigo), history of motion sickness and CT intolerance may provide clues to the diagnosis of VM, whereas spontaneous external vertigo, CT(+) with vHIT(-), and the presence of saccades may provide clues to the diagnosis of MD.


Estimated plasma volume is not a robust indicator of the severity of congestion in patients with heart failure.
Congestion is the main cause of morbidity and a prime determinant of survival in patients with heart failure (HF). However, the assessment of congestion is subjective and estimation of plasma volume (ePV) has been suggested as a more objective measure of congestion. This study aimed to explore the relationships and interactions between ePV, the severity of congestion and survival using a nationwide registry. Of the 1054 patients with HF enrolled in the registry, 769 had sufficient data to calculate ePV (using the Duarte, Kaplan, and Hakim equations) and relative plasma volume status (rPVS), and these patients were subsequently included in the present analysis. The severity of congestion was assessed using a 6-point congestion score (CS). Patients were divided into three groups according to the degree of congestion. Out of four equations tested, only ePVDuarte and rPVS were statistically higher in patients with severe congestion as compared to patients with no congestion (p<0.001 for both). Both ePVDuarte (r = 0.197, p<0.001) and rPVS (r = 0.153, p<0.001) showed statistically significant correlations with CS and both had a modest accuracy (70.4% for ePVDuarte and 69.4% for rPVS) to predict a CS ≥3. After a median follow up of 496 days, both ePVDuarte (OR:1.14,95%CI:1.03-1.26, p = 0.01) and rPVS (OR:1.02, 95%CI:1.00-1.03, p = 0.03) were associated with all-cause mortality after adjusting for demographic and clinical variables. However, none of the indices were associated with mortality following the introduction of CS to the models (p>0.05 for both). Elevated ePVDuarte and rPVS were indicators of congestion but with a limited robustness, and either parameter could be clinically useful when a comprehensive clinical evaluation of congestion is not feasible.


Comparative genome analyses of the pathogenic Yersiniae based on the genome sequence of Yersinia enterocolitica strain 8081.
This chapter represents a summary of the findings from the Yersinia enterocolitica strain 8081 whole genome sequence and the associated microarray analysis. Section 1 & 2 provide an introduction to the species and an overview of the general features of the genome. Section 3 identifies important regions within the genome which highlight important differences in gene function that separate the three pathogenic Yersinias. Section 4 describes genomic loci conferring important, species-specific, metabolic and virulence traits. Section 5 details extensive microarray data to provide an overview of species-specific core Y. enterocolitica gene functions and important insights into the intra-species differences between the high, low and non-pathogenic Y. enterocolitica biotypes.


Mechanical properties of the human patellar tendon, in vivo.
Mechanical properties of the human patellar tendon are largely based on cadaver studies, which may not necessarily be applicable to the human patellar tendon, in vivo. While ultrasonography is an attractive non-invasive method for studying human, in vivo, muscle-tendon behaviour, it has mostly been used to examine Achilles tendon properties. We examine the accuracy of human patellar tendon elongation, in vivo, and its within-day and between-day reproducibility. Subjects performed four maximal 10-s ramp isometric knee extension trials to examine within-day reproducibility, and the procedure was repeated on a separate day to assess between-day reproducibility. Continuous and simultaneous ultrasonography based measurement of both tibial and patellar movement together with patellar tendon force yielded mechanical estimates. Longitudinal tibial displacement corresponded to 45 (SEM 8) % of the overall tibia-patella displacement. For within-day reproducibility there was no difference between trials for stiffness [trial a, 4334 (SEM 562) N/mm; trial b, 4273 (SEM 533) N/mm], strain [trial a, 6.9 (SEM 0.6) %; trial b, 6.8 (SEM 0.7) %] or elastic modulus [trial a, 1.09 (SEM 0.12) GPa; trial b, 1.09 (SEM 0.10) GPa]. The within day correlation coefficient and typical error were 0.95 and 9.9% for stiffness, 0.97 and 5.5% for strain, and 0.94 and 9.4% for elastic modulus. The corresponding values for between days were 0.94 and 8.7% for stiffness, 0.98 and 3.7% for strain, and 0.86 and 9.6% for elastic modulus. The present methodology of assessing human patellar tendon elongation, strain and stiffness, in vivo, is accurate and reproducible which permits its use in future investigations of patellar tendon biomechanics and the potential effects of various interventions.


An extramural dental education program in a rural setting in Florida.
An extramural dental education experience which is a required component of the University of Florida College of Dentistry is described. The program, established in 1977, is conducted on a contractual basis between the college and the Lafayette-Suwannee Rural Health Corporation, Inc., the governing body of the Dental Center clinic located in the town of Mayo, Florida, which is 65 miles from the dental school. The program has brought high quality comprehensive dental care to a previously underserved population. Dental students are provided with experiences that enhance social sensitization, and that are perceived by them as a help in bridging the gap between dental school and dental practice after graduation. The program has made valued contributions to the education, research, and service components of the dental school's mission.


TIPS prevents further decompensation and improves survival in patients with cirrhosis and portal hypertension in an individual patient data meta-analysis.
Further decompensation represents a prognostic stage of cirrhosis associated with higher mortality compared with first decompensation. A transjugular intrahepatic portosystemic shunt (TIPS) is indicated to prevent variceal rebleeding and for refractory ascites, but its overall efficacy to prevent further decompensations is unknown. This study assessed the incidence of further decompensation and mortality after TIPS vs. standard of care (SOC). Controlled studies assessing covered TIPS compared with SOC for the indication of refractory ascites and prevention of variceal rebleeding published from 2004 to 2020 were considered. We collected individual patient data (IPD) to perform an IPD meta-analysis and to compare the treatment effect in a propensity score (PS)-matched population. Primary outcome was the incidence of further decompensation and the secondary outcome was overall survival. In total, 3,949 individual patient data sets were extracted from 12 controlled studies and, after PS matching, 2,338 patients with similar characteristics (SOC = 1,749; TIPS = 589) were analysed. The 2-year cumulative incidence function of further decompensation in the PS-matched population was 0.48 (95% CI 0.43-0.52) in the TIPS group vs. 0.63 (95% CI 0.61-0.65) in the SOC group (stratified Gray's test, p <0.0001), considering mortality and liver transplantation as competing events. The lower further decompensation rate with TIPS was confirmed by adjusted IPD meta-analysis (hazard ratio 0.44; 95% CI 0.37-0.54) and was consistent across TIPS indication subgroups. The 2-year cumulative survival probability was higher with TIPS than with SOC (0.71 vs. 0.63; p = 0.0001). The use of TIPS for refractory ascites and for prevention of variceal rebleeding reduces the incidence of a further decompensation event compared with SOC and increases survival in highly selected patients. A further decompensation (new or worsening ascites, variceal bleeding or rebleeding, hepatic encephalopathy, jaundice, hepatorenal syndrome-acute kidney injury and spontaneous bacterial peritonitis) in patients with cirrhosis is associated with a poor prognosis. Besides the known role of TIPS in portal hypertension-related complications, this study shows that TIPS is also able to decrease the overall risk of a further decompensation and increase survival compared with standard of care. These results further support the role of TIPS in the management of patients with cirrhosis and portal hypertension-related complications.


Clinical, biological, and microbiological pattern associated with ventriculostomy-related infection: a retrospective longitudinal study.
Our aim was to describe the pattern of ventriculostomy-related infection (VRI) development using a dynamic approach. Retrospective longitudinal study. We analyzed the files of 449 neurosurgical patients who underwent placement of external ventricular drain (EVD). During the study period, CSF sampling was performed on a daily base setting. VRI was defined as a positive CSF culture resulting in antibiotic treatment. For VRI patients, we arbitrary defined day 0 (D0) as the day antibiotic treatment was started. In these patients, we compared dynamic changes in clinical and biological parameters at four pre-determined time points: (D-4, D-3, D-2, D-1) with those of D0. For all CSF-positive cultures, we compared CSF biochemical markers' evolution pattern between VRI patients and the others, considered as a control cohort. Thirty-two suffered from VRI. Peripheral white blood cell count did not differ between D-4-D0. Median body temperature, CSF cell count, median Glasgow Coma Scale, CSF protein, and glucose concentrations were significantly different between D-4, D-3, D-2, and D0. At D0, 100 % of CSF samples yielded organisms in culture. The physician caring for the patient decided to treat VRI based upon positive CSF culture in only 28 % (9/32) of cases. In the control cohort, CSF markers' profile trends to normalize, while it worsens in the VRI patients. We showed that clinical symptoms and biological abnormalities of VRI evolved over time. Our data suggest that VRI decision to treat relies upon a bundle of evidence, including dynamic changes in CSF laboratory exams combined with microbiological analysis.


A pilot study of nitric oxide blood levels in patients with chronic orofacial pain.
Control of pain is the major goal in the management of chronic orofacial pain (COP) patients. The pathogenesis of COP is currently not well understood. Consequently, the treatment of COP may be suboptimal or even harmful. Based on independent observations, we propose that local elevated levels of nitric oxide (NO) may have a central role in the pathogenesis of COP. NO level in the orofacial region of COP patients is elevated. A regional increased level of NO causes excessive vasodilatation. This hyperperfusion is manifested by hyperthermia of the overlying skin, while NO enhances nociception, aggravating orofacial pain. An alternative mechanism involving NO as a neurotransmitter at the CNS level may contribute to orofacial pain, but seems not to account for all the known clinical observations. Two groups of subjects were studied: 5 patients with COP and 59 control subjects. For each subject we collected blood samples for analysis of nitrite\nitrate (or NOx). (1) NOx blood levels for 5 patients diagnosed with COP was 65.9 microM (SD of 10.4) verses 42.7 microM (SD of 24.2) for 59 control subjects, the difference being statistically significant, t-statistic = -2.12 (P > .05). (2) No statistical difference was found for NOx blood levels for 59 control subjects divided by gender (male vs female), with 23 female controls having NOx blood levels of 42.6 microM (SD of 25.2) and male controls having NOx blood levels of 42.8 microM (SD of 24.0), t-statistic = -0.03, P = .98. This pilot study suggests that NO blood levels may have an association with COP. A better understanding of the mechanism of chronic orofacial pain is expected to lead to more precise diagnostic staging and management of this disorder.


[Testicular torsion in the 15-year records of our clinic].
Six cases of testicular torsion treated in the last 15 years are described and attention is drawn to the importance of thorough examination and early treatment.


MIF as a glucocorticoid-induced modulator of cytokine production.
Glucocorticoid hormones are important for vital functions and act to modulate inflammatory and immune responses. Yet, in contrast to other hormonal systems, no endogenous mediators have been identified that can directly counter-regulate their potent anti-inflammatory and immunosuppressive properties. Recent investigations of the protein macrophage migration inhibitory factor (MIF), which was discovered originally to be a T-lymphocyte-derived factor, have established it to be a pro-inflammatory pituitary and macrophage cytokine and a critical mediator of septic shock. Here we report the unexpected finding that low concentrations of glucocorticoids induce rather than inhibit MIF production from macrophages. MIF then acts to override glucocorticoid-mediated inhibition of cytokine secretion by lipopolysaccharide (LPS)-stimulated monocytes and to overcome glucocorticoid protection against lethal endotoxaemia. These observations identify a unique counter-regulatory system that functions to control inflammatory and immune responses.


Brain metabolism after electroshock seizure in the neonatal dog: a [31P]NMR study.
In vivo [31P] nuclear magnetic resonance (NMR) spectroscopy disclosed that a 10 second electroshock seizure in oxygenated neonatal dogs produced prolonged alteration of brain phosphocreatine (PCr), inorganic phosphate (Pi), and lactate. The slow return of these metabolites to baseline may be related to lower endogenous stores of high energy phosphates, or less developed pathways for their regeneration.


Alkaline ceramidase 2 regulates beta1 integrin maturation and cell adhesion.
The polypeptide core of the integrin beta1 subunit (beta1) is glycosylated sequentially in the endoplasmic reticulum and the Golgi complex to form beta1 precursor and mature beta1, respectively. The beta1 precursor to mature beta1 conversion, termed beta1 maturation, regulates the cell surface levels and function of beta1-containing integrins, beta1 integrins. Here we demonstrate that the human alkaline ceramidase 2 (ACER2), a Golgi enzyme, regulates beta1 maturation by controlling the generation of sphingosine. ACER2 overexpression inhibited beta1 maturation, thus leading to a decrease in the levels of mature beta1 in T-REx HeLa cells, whereas RNA interference-mediated knockdown of ACER2 enhanced beta1 maturation in MCF-7 cells. ACER2 overexpression decreased the cell surface levels of beta1 integrins, thus inhibiting cell adhesion to fibronectin or collagen, whereas ACER2 knockdown has the opposite effects. Treatment with all-trans retinoic acid (ATRA) increased both the expression of ACER2 and the generation of sphingosine in HeLa cells and inhibited beta1 maturation. ACER2 knockdown attenuated the inhibitory effects of ATRA on both beta1 maturation and cell adhesion. In contrast, treatment with phorbol myristate acetate (PMA), a protein kinase C activator, decreased the expression of ACER2 and sphingosine in T-REx HeLa cells, thus enhancing beta1 maturation. ACER2 overexpression inhibited the stimulatory effects of PMA on both beta1 maturation and cell adhesion. These results suggest that the ACER2/sphingosine pathway plays an important role in regulating beta1 maturation and cell adhesion mediated by beta1 integrins.


miR-10b promotes aortic aneurysm formation and aortic rupture in angiotensin II-induced ApoE-deficient mice.
Abdominal aortic aneurysm (AAA) is associated with increased plasma levels of microRNA (miR) -10b. 5 nmols of miR-10b or miR control was administrated to Apolipoprotein E-deficient mice three days prior implantation of osmotic mini-pumps containing angiotensin II, and for three additional times once a week, which increased expression of miR-10b in plasma. Animals receiving miR-10b had a mortality rate due to aortic rupture of 61% compared to 11% in the miR controls (p < 0.05). Further, miR- 10b resulted in an increased aneurysm formation and growth (p < 0.05), which was accompanied by increased elastin degradation, neutrophil and mast cell markers (p < 0.05). In conclusion, miR-10b is functionally affecting aneurysm development and rupture and not only a marker of AAA. More mechanistic studies are required to better understand miR-10b's role in AAA formation.


CO2 retention as a basis for increased toxicity of salicylate with acetazolamide: avoidance of increased toxicity with benzolamide.
Two carbonic anhydrase inhibitors, acetazolamide and benzolamide, are capable of increasing the toxicity of sodium salicylate in mice. Beginning at about 2 mg/kg, each of the inhibitors, in combination with a fixed (400 mg/kg) dose of salicylate, generates a dose-mortality curve that reaches a plateau at about 60% deaths at 6 to 8 mg/kg. This effect can be duplicated by 8 to 10% inspired CO2. It appears that the respiratory acidosis secondary to the inhibition of red cell carbonic anhydrase is responsible for the increased toxicity; earlier work by others shows that acidosis increases the concentration of salicylate in the brain. In the treatment of salicylate poisoning by carbonic anhydrase inhibitors, the goal is to alkalinize the urine and increase the excretion of salicylate. With the newer inhibitor, benzolamide, it is possible to dissociate the respiratory acidosis from the renal effect. Maximal alkalinization of the urine is possible with a dose (about 1 mg/kg) below that which generates a respiratory acidosis. With this dose, there is no increase in the early toxicity of salicylate.


Activation of p42/p44 mitogen-activated protein kinases (MAPK) and p38 MAPK by tumor necrosis factor (TNF) is mediated through the death domain of the 55-kDa TNF receptor.
In the mouse fibrosarcoma cell line L929sA, tumor necrosis factor (TNF) stimulates activation of the stress-responsive p38 mitogen-activated protein kinase (MAPK), as well as the classical p42 and p44 MAPK. TNF signaling can be mediated by p55 or p75 TNF receptors. Here, we demonstrate that TNF-R55 is sufficient to activate p42/p44 MAPK and p38 MAPK. Moreover, by expressing different membrane-bound or purely cytoplasmic truncations of TNF-R55, we show that the intracellular death domain of TNF-R55 is the crucial domain involved. The cytoplasmic membrane-proximal region of TNF-R55, known to induce neutral sphingomyelinase activation, is not required for activation of p38 MAPK or p421p44 MAPK.


Assessing the impact of binaural and non-binaural auditory beat intervention to pain and compression in mammography.
Pain and discomfort has a negative impact on a patient's overall experience and may impact on subsequent re-attendance to mammography. Pain during mammography remains a significant issue. Assessment of interventions to reduce levels of pain associated with mammography are essential to increase attendance to breast services and improve user experience. Participants (n = 60) were invited to take part in the study at one hospital Trust within the UK. Postal invitations were sent 2 weeks prior to appointment to patients older than 40 years with previous mammography attendance at the same Trust to allow for comparison of previous and current pain scores/compression values. Patients were randomised into 3 groups: Binaural music (BM), non-binaural music (NBM) and standard care (C). A numerical rating scale (NRS) was used to rate pain. Patient tolerance is increased by the application of both the non-binaural and binaural music. Binaural music was most effective in improving patient tolerance (p = 0.02). When applied compression increased some patients recorded less pain, which may have implications to image quality and radiation dose for patients. Binaural music reduces the perception of mammographic pain within this data set. 5 min exposure to binaural music improves patient experience and tolerance for mammography which could be utilised to improve attendance rates in screening and symptomatic services. There is an indication for further research looking at application prior and during interventional biopsies. Music intervention can be offered to patients in the severe pain category who refuse mammography. It is acknowledged from these findings that the introduction of BM and NBM prior to mammography would be a low risk, cost effective intervention within the hospital setting.


Survey on environmental monitoring requirements of European ports.
A group of 26 European ports was interviewed to understand their requirements for environmental information and to establish how widespread the use of Earth Observation (EO) data was amongst them. Aspects covered by the research included port profile characterisation, environmental management activities, environmental needs and current monitoring practices. The study reflected the diversity amongst European ports and their environmental performances. Most of the ports were publicly owned and located in estuaries and rivers. General cargo was the most popular commodity handled. Practically all the ports had an environmental policy in place and half of them had been accredited by an external body. The main environmental parameters that ports required to be monitored were marine related issues (currents, waves and tide), water quality, meteorological parameters, turbidity and sediment processes. The principal driver for monitoring was maintaining key port operations, followed by legislation, and local responsibilities. Ports in general collected their own data in situ and only one-third had used remotely sensed data (data from Earth Observation satellites or from airplane mounted sensors) for environmental purposes. Half of them used computer modelling. This study was conducted within the framework of the European funded port environmental information collector project (PEARL).


Augmentation of the in vitro humoral immune response by pharmacologic agents. II: comparison of the effects of antiproliferative agents with DBcAMP.
We have compared the stimulatory activity of DBcAMP with various antiproliferative agents on the induction of the humoral immune response. When they are present only during an early stage of immune induction, DBcAMP, colcemid, cytosine-arabinoside, hydroxy urea, and high specific activity 3H-thymidine can all enhance the primary 19s antibody response to SRBC. In contrast, each of these agents inhibits the PFC response, when they are incubated with the cells during late stages of induction of humoral immunity. Because all of these agents can inhibit proliferation of cultured cells, the results suggested that DBcAMP and other agents that elevate cAMP could augment humoral immunity via their effects on cellular proliferation. However, we also found that although each agent could modulate induction of the immune response to SRBC, only DBcAMP produced a dose- and time-dependent augmentation of the response to DLF. We conclude that although antiproliferative effects of drugs may contribute to augmentation of some humoral antibody responses, this effect alone is insufficient to account for the mechanism by which agents that elevate intracellular levels of cAMP produce enhancement of humoral immunity.


New-onset atrial fibrillation: incidence, characteristics, and related events following a national COVID-19 lockdown of 5.6 million people.
To determine the incidence, patient characteristics, and related events associated with new-onset atrial fibrillation (AF) during a national COVID-19 lockdown. Using nationwide Danish registries, we included all patients, aged 18-90 years, receiving a new-onset AF diagnosis during the first 3 months of 2019 and 2020. The main comparison was between patients diagnosed during lockdown (12 March 12-1 April 2020) and patients diagnosed in the corresponding period 1 year previously. We found a lower incidence of new-onset AF during the 3 weeks of lockdown compared with the corresponding weeks in 2019 [incidence rate ratios with 95% confidence intervals (CIs) for the 3 weeks: 0.66 (0.56-0.78), 0.53 (0.45-0.64), and 0.41 (0.34-0.50)]. There was a 47% drop in total numbers (562 vs. 1053). Patients diagnosed during lockdown were younger and with a lower CHA2DS2-VASc score, while history of cancer, heart failure, and vascular disease were more prevalent. During lockdown, 30 (5.3%) patients with new-onset AF suffered an ischaemic stroke and 15 (2.7%) died, compared with 45 (4.3%) and 14 (1.3%) patients during the corresponding 2019 period, respectively. The adjusted odds ratio of a related event (ischaemic stroke or all-cause death) during lock-down compared with the corresponding weeks was 1.41 (95% CI 0.93-2.12). Following a national lockdown in Denmark, a 47% drop in registered new-onset AF cases was observed. In the event of prolonged or subsequent lockdowns, the risk of undiagnosed AF patients developing complications could potentially translate into poorer outcomes in patients with AF during the COVID-19 pandemic.


Leadless pacemakers: A new era in cardiac pacing.
Cardiac pacemakers are a critical management option for patients with rhythm disorders. Current efforts to develop leadless pacemakers have two primary goals: to reduce lead-associated post-procedural morbidity and to avoid the surgical scar associated with placement. After extensive studies on animal models and technological advancements, these devices are currently under investigation for human use. Herein, we review the evidence from animal studies and the technological advancements that have ushered in the era of use in humans. We also discuss different leadless pacemakers currently under investigation, along with limitations and future developments of this innovative concept.


A crucial role for ATR in the regulation of deoxycytidine kinase activity.
Deoxycytidine kinase (dCK) (EC 22.214.171.124) is a key enzyme for salvage of deoxynucleosides and activation of numerous anticancer and antiviral nucleoside analogs. dCK activity is enhanced in response to several genotoxic treatments, which has been correlated with an increase of dCK phosphorylation at Ser-74. ATM was recently identified as the kinase responsible for Ser-74 phosphorylation and dCK activation after ionizing radiation (IR). Here, we investigated the role of ATM and the related kinase ATR in dCK activation induced by other types of DNA damage. Using ATM-deficient cells or the ATM inhibitor KU-60019, we found that ATM was not required for dCK activation caused by UV light, aphidicolin, cladribine, and unexpectedly also IR. On the other hand, the selective ATR inhibitor VE-821 significantly reduced up-regulation of dCK activity induced by these genotoxic agents, though not IR, and also down-regulated basal dCK activity. A role for ATR in the control of dCK activity was confirmed by using ATR siRNA and ATR-Seckel cells. ATR was also found to directly phosphorylate dCK at Ser-74 in vitro. Further studies revealed that ATR, which is also activated in response to IR, although later than ATM, was responsible for IR-induced dCK activation in ATM-deficient cells or in the presence of KU-60019. Overall, our results demonstrate that ATR controls basal dCK activity and dCK activation in response to replication stress and indicate that ATR can activate dCK after IR if ATM is lacking or inhibited.


Distinct coping strategies differentially predict urge levels and lapses in a smoking cessation attempt.
This study analysed mechanisms through which stress-coping and temptation-coping strategies were associated with lapses. Furthermore, we explored whether distinct coping strategies differentially predicted reduced lapse risk, lower urge levels, or a weaker association between urge levels and lapses during the first week of an unassisted smoking cessation attempt. Participants were recruited via the internet and mass media in Switzerland. Ecological momentary assessment (EMA) with mobile devices was used to assess urge levels and lapses. Online questionnaires were used to measure smoking behaviours and coping variables at baseline, as well as smoking behaviour at the three-month follow-up. The sample consisted of 243 individuals, aged 20 to 40, who reported 4199 observations. Findings of multilevel regression analyses show that coping was mainly associated with a reduced lapse risk and not with lower urge levels or a weaker association between urge levels and lapses. 'Calming down' and 'commitment to change' predicted a lower lapse risk and also a weaker relation between urge levels and lapses. 'Stimulus control' predicted a lower lapse risk and lower urge levels. Conversely, 'task-orientation' and 'risk assessment' were related to higher lapse risk and 'risk assessment' also to higher urge levels. Disengagement coping i.e. 'eating or shopping', 'distraction', and 'mobilising social support' did not affect lapse risk. Promising coping strategies during the initial stage of smoking cessation attempt are targeted directly at reducing the lapse risk and are characterised by engagement with the stressor or one's reactions towards the stressor and a focus on positive consequences instead of health risks.


Aflatoxins in peanut butter in Khartoum State, Sudan.
Forty-three peanut butter samples from Khartoum State, Sudan, were analyzed for aflatoxins (AFs, AFB1 + AFB2 + AFG1 + AFG2) using high performance liquid chromatography (HPLC) with fluorescence detection after extraction with methanol:water (8:1, v/v) and clean-up using chloroform. All samples were contaminated with AFs, with total AF levels ranging between 26.7 and 853 μg/kg, and a mean total AF level of 287 ± 200.5 μg/kg. The highest concentrations were found for AFB1, (28 positive samples, maximum 534 μg/kg), while AFG1 was most frequently detected (43 positive samples, maximum 401 μg/kg). AFB2 (42 positive samples, maximum 3.2 μg/kg) and AFG2 (4 positive samples, maximum 30 μg/kg) were also present in these samples. The mean AF contamination levels found in this study exceeded by far all international regulations concerning maximum levels for this group of toxins. From the data, it is concluded that the levels of AF contamination in peanut butter from the Kartoum area are quite alarming, and may pose serious health hazards to consumers. Therefore, an intervention strategy to manage AF in peanut butter is urgently needed.


Environmental findings and sudden infant death syndrome.
Sudden infant death syndrome (SIDS) death rates show substantial seasonal variation. Analysis of this variation shows that it is due to postnatal factors. Possible variables are temperature, infection, pollution, and the infants' interaction with the social environment. In England and Wales the temporal pattern of pollution levels and the geographical variation of death rates do not suggest pollution is generally an important factor. Social environment appears the most important. One in three high risk infants are in families with multiple social problems compared with 9% of controls. Further studies of why some infants are at greatly increased risk might identify crucial adverse environmental factors and indicate how some deaths could be prevented.


[The effect of total phenolics from abnormal savda munziq on cervical cancer cell lines].
To explore the feasibility of total phenolics from Abnormal Savda Munziq on treating human cervical carcinoma. MTT assay was used to determine the growth inhibition ratio and IC50 on Hela cells and SiHa cells after treated with different concentrations of total phenolics. Morphologic changes of cells were observed by inverted microscope. Total phenolics inhibited the proliferation of Hela cells in the concentration range of 25 - 125 microg/mL; Total phenolics inhibited the proliferation of SiHa cells in the concentration range of 75 - 175 microg/mL; The inhibitory actions of total phenolics on the Hela and SiHa appeard dose-effect relationship and time-effect relationship obviously (P < 0.01); The IC50 of Hela was (125.26 +/- 16.15) microg/mL after 48h total phenolics treatment; The IC50 of SiHa was (134.51 +/- 2.55) microg/mL after 48h total phenolics treatment. And there was no statistical sense in the disparation of them (P > 0.05); Both of the cells showed apoptosis character evidently after total phenolics treatment, Along with the increasing of the concentration and the action time, morphologic changes of cells were more obviously. Total phenolics could inhibit the growth of Hela cells and SiHa cells and the inhibitory actions of total phenolics on the two cells is almostly the same. Therefore, total phenolics from abnormal savda munziq is deserved to be further studied for treating human cervical carcinoma.


D313Y Variant in Fabry Disease: A Systematic Review and Meta-analysis.
There is accumulating evidence in the literature indicating a strong correlation between Fabry disease (FD) phenotypes and specific sequence variations in the Galactosidase Alpha (GLA) gene. Among them, the potential pathogenicity and clinical relevance of D313Y variation in patients with FD remain debated. We performed a systematic review and meta-analysis of studies reporting D313Y as single occurring variant in the GLA gene and sought to evaluate (1) the prevalence of D313Y variation in different populations with or without clinical manifestations of FD, (2) the clinical FD phenotype in D313Y-positive patients, and (3) the proportion of D313Y-positive patients presenting abnormal laboratory findings (alpha-galactosidase-A deficiency or globotriaosylceramide accumulation). Forty cohorts comprising 211 individuals with D313Y variation among 42,723 participants with available GLA gene-sequencing data were included. Patients highly suspected for FD had a higher prevalence of D313Y variation (4.9%, 95% CI 1.6%-9.9%; I2 = 95.5%) compared with the general population (0%, 95% CI 0%-0.1%; I2 = 1.9%; p = 0.004). The prevalence of D313Y variation was 0.6% (95% CI 0.3%-1%; I2 = 74.1%), 0.4% (95% CI 0.2%-0.7%; I2 = 0%), and 0.3% (95% CI 0.2%-0.4%; I2 = 0%) in patients presenting with neurologic, cardiac, or renal manifestations, respectively. D313Y was associated with a milder, late-onset FD phenotype, as indicated by the mean patient age of 51 years (95% CI 44-59; I2 = 94%) and the evidence of alpha-galactosidase A deficiency and globotriaosylceramide accumulation in 26.7% (95% CI 15.3%-40%; I2 = 34%) and 16.2% (95% CI 8%-26.4%; I2 = 35%) of cases, respectively. D313Y-positive patients displayed predominantly neurologic FD manifestations (58.1%, 95% CI 37.7%-77.1%; I2 = 78%), with central and peripheral nervous system (CNS/PNS) involvement noted in 28.2% (95% CI 15.4%-43.2%; I2 = 51%) and 28.5% (95% CI 17.8%-40.5%; I2 = 61%) of cases, respectively. D313Y variation seems to correlate with an atypical, mild late-onset phenotype with predominantly neurologic FD manifestations. Monitoring for CNS/PNS involvement is thus paramount to identify D313Y-positive patients with latent or early-FD pathology, which may qualify for enzyme-replacement therapy or chaperone treatment.


Mitochondrial quality control mechanisms as therapeutic targets in doxorubicin-induced cardiotoxicity.
Doxorubicin (DOX) is a chemotherapeutic drug that is utilized for solid tumors and hematologic malignancies, but its clinical application is hampered by life-threatening cardiotoxicity including cardiac dilation and heart failure. Mitochondrial quality control processes, including mitochondrial proteostasis, mitophagy, and mitochondrial dynamics and biogenesis, serve to maintain mitochondrial homeostasis in the cardiovascular system. Importantly, recent advances have unveiled a major role for defective mitochondrial quality control in the etiology of DOX cardiomyopathy. Moreover, specific interventions targeting these quality control mechanisms to preserve mitochondrial function have emerged as potential therapeutic strategies to attenuate DOX cardiotoxicity. However, clinical translation is challenging because of obscure mechanisms of action and potential adverse effects. The purpose of this review is to provide new insights regarding the role of mitochondrial quality control in the pathogenesis of DOX cardiotoxicity, and to explore promising therapeutic approaches targeting these mechanisms to aid clinical management.


Central role of defective interleukin-2 production in the triggering of islet autoimmune destruction.
The dynamics of CD4(+) effector T cells (Teff cells) and CD4(+)Foxp3(+) regulatory T cells (Treg cells) during diabetes progression in nonobese diabetic mice was investigated to determine whether an imbalance of Treg cells and Teff cells contributes to the development of type 1 diabetes. Our results demonstrated a progressive decrease in the Treg cell:Teff cell ratio in inflamed islets but not in pancreatic lymph nodes. Intra-islet Treg cells expressed reduced amounts of CD25 and Bcl-2, suggesting that their decline was due to increased apoptosis. Additionally, administration of low-dose interleukin-2 (IL-2) promoted Treg cell survival and protected mice from developing diabetes. Together, these results suggest intra-islet Treg cell dysfunction secondary to defective IL-2 production is a root cause of the progressive breakdown of self-tolerance and the development of diabetes in nonobese diabetic mice.


Nutrient scavenging activity and antagonistic factors of non-photobiont lichen-associated bacteria: a review.
Lichens are defined as the specific symbiotic structure comprising a fungus and a green alga and/or cyanobacterium. Up until recently, non-photobiont endothallic bacteria, while known to be present in large numbers, have generally been dismissed as functionally irrelevant cohabitants of the lichen thallus, or even environmental contaminants. Recent analyses of lichen metagenomes and innovative co-culture experiments have uncovered a functionally complex community that appears to contribute to a healthy lichen thallus in several ways. Lichen-associated bacteriomes are typically dominated by several lineages of Proteobacteria, some of which may be specific for lichen species. Recent work has implicated members of these lineages in several important ecophysiological roles. These include nutrient scavenging, including mobilization of iron and phosphate, nitrogen fixation, cellulase, xylanase and amylase activities, and oxidation of recalcitrant compounds, e.g. aromatics and aliphatics. Production of volatile organic compounds, conferring antibacterial and antifungal activity, has also been demonstrated for several lichen-associated isolates. In the present paper we review the nature of non-phototrophic endolichenic bacteria associated with lichens, and give insight into the current state of knowledge on their importance the lichen symbiotic association.


Predictors of psychological distress in Lebanese hostages of war.
A cross-sectional study addressed the experience of Lebanese hostages of war in Lebanon. It specifically assessed the prevalence of general distress and its relationship to captivity-related factors and selected psychosocial variables. Trained field researchers using standard measurements interviewed 118 Lebanese hostages released from Khiam prison, an Israeli detention center in Lebanon. Questionnaires administered included the GHQ-12 and the Harvard Trauma Questionnaire. Individuals were detained for 3.4 years on average, and 86% were tortured. Psychological distress was present in 42.1% of the sample compared to 27.8% among the control group. In the multivariate analysis, the significant predictors for distress were: years of education and increase in religiosity after release. In conclusion, even after 2 years of release, more than one-third of the Lebanese hostages released from Khiam prison were found to have psychological distress. Caregivers need to pay special attention to the mental health of hostages of war. The paper discusses the meaning and implications of the factors predicting resilience and vulnerability in this particular population.


Pilot study in human healthy volunteers on the mechanisms underlying remote ischemic conditioning (RIC) - Targeting circulating immune cells and immune-related proteins.
Remote ischemic conditioning (RIC) is a novel promising therapy for treatment of neurological diseases, including ischemic stroke. RIC consists of short cycles of ischemia in a distant non-vital organ that may protect other organs against ischemia. Extensive experimental data and some few clinical trials support the neuroprotective role of RIC in ischemic stroke. Nevertheless, the circulating factors involved in this inter-organ communication and neuroprotection are not clarified. This pilot study in humans characterized the innate and adaptive circulating immune cell populations following RIC. This analysis has a particular focus at 24 h after RIC to avoid circadian influence. In silico functional analysis of mass spectrometry data identified 15 immune-related proteins. Our results reveal an immune response following RIC.


Fracture-dislocation of the ankylosed thoracic spine.
A patient with a fracture of an ankylosed thoracic spine was treated initially along conservative lines. Subsequently the fracture displaced, causing paraplegia. Internal fixation proved difficult but stability was obtained by wiring two Sherman plates to the posterior elements. This succeeded in holding the fracture until the death of the patient 13 days postoperatively. The difficulties in the management of these fractures are discussed.


Transmembrane potential of J774.2 mouse macrophage cells measured by microelectrode and ion distribution methods.
The transmembrane potential (Em) of J774.2 macrophage cells measured by microelectrodes was -24.1 +/- 0.7 mV (mean +/- SEM). Em measured by lipophilic ion distribution was -35 +/- 2 mV or -40 +/- 2 mV, using a cation or anion, respectively. By any method, colchicine reduced Em by approximately 3 mV.


Ubiquitination of human leukocyte antigen (HLA)-DM by different membrane-associated RING-CH (MARCH) protein family E3 ligases targets different endocytic pathways.
HLA-DM plays an essential role in the peptide loading of classical class II molecules and is present both at the cell surface and in late endosomal peptide-loading compartments. Trafficking of DM within antigen-presenting cells is complex and is, in part, controlled by a tyrosine-based targeting signal present in the cytoplasmic tail of DMβ. Here, we show that DM also undergoes post-translational modification through ubiquitination of a single lysine residue present in the cytoplasmic tail of the α chain, DMα. Ubiquitination of DM by MARCH1 and MARCH9 induced loss of DM molecules from the cell surface by a mechanism that cumulatively involved both direct attachment of ubiquitin chains to DMα and a functional tyrosine-based signal on DMβ. In contrast, MARCH8-induced loss of surface DM was entirely dependent upon the tyrosine signal on DMβ. In the absence of this tyrosine residue, levels of DM remained unchanged irrespective of whether DMα was ubiquitinated by MARCH8. The influence of MARCH8 was indirect and may have resulted from modification of components of the endocytic machinery by ubiquitination.


Involvement of guanine nucleotide-binding protein in the gating of Ca2+ by receptors.
The introduction of impermeant aqueous solutes into individual cells by microinjection has long been established but the difficulties of manipulating the cytosol composition of large populations of microscopic cells have only recently been overcome. Successful techniques include a dielectric breakdown procedure, treatment with micromolar concentrations of ATP4- (ref. 7) and also with very small (that is nonagglutinating, non-fusogenic) amounts of Sendai virus. So far, attention has been concentrated on the behaviour of the cells (generally their response to applied Ca2+ buffers) at the time when the membrane permeability lesions are open, and thus cytosol and external medium are in contact. I now report a novel technique for monitoring the state of molecular solute permeability in cell membranes and show that the lesions generated by ATP4- in the membrane of mast cells can be closed within seconds of adding Mg2+ so that a cycle of permeabilization and resealing can be used to explore the effect of foreign compounds trapped in the cytosol of effectively intact cells. I show that non-hydrolysable GTP analogues, introduced into the cytosol of mast cells, cause them to undergo exocytotic secretion in response to addition of extracellular Ca2+. This finding is discussed in the light of previous experience relating guanine nucleotide regulatory proteins as intermediaries between receptors and the transducers which they control.