Antidepressants for cocaine dependence.
Cocaine dependence is a common and serious condition, which has become nowadays a substantial public health problem. The past decade has witnessed a sustained search for an effective pharmacotherapeutic agent for the treatment of cocaine dependence. While administration of cocaine acutely increases intercellular dopamine, serotonin, and norepinephrine levels by blocking their presynaptic reuptake, chronic cocaine abuse leads to down-regulation of monoamine systems. Post-cocaine use depression and cocaine craving may be linked to this down-regulation. Antidepressant pharmacotherapy, by augmenting monoamine levels, may alleviate cocaine abstinence symptomatology, as well as relieving dysphoria and associated craving by general antidepressant action. To conduct a systematic review of all RCTs on the use of antidepressants for treating cocaine dependence. We searched the Cochrane Controlled Trials Register (Cochrane Library, issue 4, 2000), MEDLINE (from 1966 - 2000), EMBASE (from 1980 - 2000), LILACS (from 1982 - 2000), PsycLIT (from 1974 - 2000), Biological Abstracts (1982 to 2000). Other searches:reference searching; personal communication; conference abstracts; unpublished trials from pharmaceutical industry; book chapters on treatment of cocaine dependence. The inclusion criteria for all randomised controlled trials were that they should focus on the use of antidepressants on the treatment of cocaine dependence. Trials including patients with additional diagnosis such as opiate dependence were also eligible. The reviewers extracted the data independently and Relative Risks, weighted mean difference and number needed to treat were estimated. The reviewers assumed that people who died or dropped out had no improvement and tested the sensitivity of the final results to this assumption. 18 studies were included in the review, with 1177 people randomised. Positive urine sample for cocaine metabolites was the main efficacy outcome, with no significant results obtained regardless the type of antidepressant. Compared to other drugs, desipramine performed better but showing just a non significant trend with heterogeneity present as revealed by the chi-square test (8.6, df=3; p=0.04). One single trial showed imipramine performed better than placebo in terms of clinical response according to patient's self-report. A similar rate of patients remaining in treatment was found for both patients taking desipramine or placebo. Results from one single trial suggest fluoxetine patients on SSRIs are less likely to dropout. Similar results were obtained for trials where patients had additional diagnosis of opioid dependence and/or were in methadone maintenance treatment. There is no current evidence supporting the clinical use of antidepressants in the treatment of cocaine dependence. Given the high rate of dropouts in this population, clinicians may consider adding psychotherapeutic supportive measures aiming to keep patients in treatment.


Seasonal symptom severity in patients with rheumatic diseases: a study of 1,424 patients.
To examine the nature of seasonal symptoms, their prevalence, and differences among rheumatic disorders by examining longitudinal data over a period of up to 24 years. We used a questionnaire assessment of seasonal symptoms using the Seasonal Pattern Assessment Questionnaire (SPAQ) in 1,424 patients with rheumatoid arthritis (RA), osteoarthritis (OA), and fibromyalgia (FM). Clinical status was evaluated with standard assessment measures, and reported symptoms were compared with actual seasonal differences measured for periods of up to 24 years. About 50% of patients with rheumatic disease reported exacerbation of rheumatic symptoms (pain, global severity, and fatigue) by seasonal changes. The presence of seasonal symptoms was not related to diagnosis or to seasonal affective disorder (SAD) symptoms, and symptoms were less common in older patients and in men. The number of symptoms and the severity of allied factors (depression, anxiety, pain, global severity, number of months with seasonal symptoms) were increased in persons with FM and/or complete SAD symptoms. Using circular statistics, the modal months for worse symptoms were December and January, and for best symptoms was July. Bimodal patterns of seasonality were identified for global severity, joint pain, fatigue, and socialization. Seasonal symptoms differed as to the degree at which they were dispersed around the 12 month circle. When pain and global severity measurements obtained over a 24 year period were analyzed, pain was slightly increased in the summer and global severity was not related to season at all. Even when patients who specifically reported worse symptoms in winter and best symptoms in summer were examined, no effect of season could be found. Seasonal rheumatic symptoms are commonly reported across all rheumatic diseases, but appear to reflect perception rather than reality since reported symptoms do not agree with measured clinical scores. In addition, regardless of seasonal complaints, measured pain and global severity scores are not worse in winter. Although patients with FM and Season (+) patients report more severe symptoms, their pattern of reporting and their actual scores do not differ according to season compared to persons without FM or positive seasonality.


Correlation of RNA secondary structure statistics with thermodynamic stability and applications to folding.
The accurate prediction of the secondary and tertiary structure of an RNA with different folding algorithms is dependent on several factors, including the energy functions. However, an RNA higher-order structure cannot be predicted accurately from its sequence based on a limited set of energy parameters. The inter- and intramolecular forces between this RNA and other small molecules and macromolecules, in addition to other factors in the cell such as pH, ionic strength, and temperature, influence the complex dynamics associated with transition of a single stranded RNA to its secondary and tertiary structure. Since all of the factors that affect the formation of an RNAs 3D structure cannot be determined experimentally, statistically derived potential energy has been used in the prediction of protein structure. In the current work, we evaluate the statistical free energy of various secondary structure motifs, including base-pair stacks, hairpin loops, and internal loops, using their statistical frequency obtained from the comparative analysis of more than 50,000 RNA sequences stored in the RNA Comparative Analysis Database (rCAD) at the Comparative RNA Web (CRW) Site. Statistical energy was computed from the structural statistics for several datasets. While the statistical energy for a base-pair stack correlates with experimentally derived free energy values, suggesting a Boltzmann-like distribution, variation is observed between different molecules and their location on the phylogenetic tree of life. Our statistical energy values calculated for several structural elements were utilized in the Mfold RNA-folding algorithm. The combined statistical energy values for base-pair stacks, hairpins and internal loop flanks result in a significant improvement in the accuracy of secondary structure prediction; the hairpin flanks contribute the most.


Mindfulness based stress reduction adapted for depressed disadvantaged women in an urban Federally Qualified Health Center.
In this study we examine the feasibility and preliminary effectiveness of mindfulness based stress reduction adapted for delivery in an urban Federally Qualified Health Center (FQHC). Thirty-one African- American adult women ages 18-65 with depressive symptoms enrolled to participate in an 8-week mindfulness group intervention. The primary outcome (depression) and secondary outcomes (stress, mindfulness, functioning, well-being, and depression stigma) were assessed at baseline, 8 and 16-weeks. Depressive symptoms significantly decreased from baseline to 16 weeks. A significant decrease in stress and significant increase in mindfulness was found from baseline to 8 weeks and baseline to 16 weeks. Additionally, aspects of well-being-self-acceptance and growth-significantly increased from baseline to 8-weeks. Stigma significantly increased from baseline to 8 weeks and significantly decreased from 8 to 16 weeks (all p's < 0.05). Mindfulness-based interventions implemented in FQHCs may increase access to effective treatments for mental health symptoms.


Clinical remission in patients with moderate-to-severe Crohn's disease treated with filgotinib (the FITZROY study): results from a phase 2, double-blind, randomised, placebo-controlled trial.
Filgotinib (GLPG0634, GS-6034) is a once-daily, orally administered, Janus kinase 1 (JAK1)-selective inhibitor. The FITZROY study examined the efficacy and safety of filgotinib for the treatment of moderate-to-severe Crohn's disease. We did a randomised, double-blind, placebo-controlled phase 2 study, which recruited patients from 52 centres in nine European countries. We enrolled eligible patients aged 18-75 years with a documented history of ileal, colonic, or ileocolonic Crohn's disease for 3 months or more before screening, as assessed by colonoscopy and supported by histology, and a Crohn's Disease Activity Index (CDAI) score during screening between 220 and 450 inclusive. Patients were randomly assigned (3:1) to receive filgotinib 200 mg once a day or placebo for 10 weeks. Patients were stratified according to previous anti-tumour necrosis factor alpha exposure, C-reactive protein concentration at screening (≤10 mg/L or >10 mg/L), and oral corticosteroid use at baseline, using an interactive web-based response system. The primary endpoint was clinical remission, defined as CDAI less than 150 at week 10. After week 10, patients were assigned based on responder status to filgotinib 100 mg once a day, filgotinib 200 mg once a day, or placebo for an observational period lasting a further 10 weeks. The filgotinib and placebo treatment groups were compared using ANCOVA models and logistic regression models containing baseline values and randomisation stratification factors as fixed effects. Analyses were done on the intention-to-treat non-responder imputation set. The trial was registered at ClinicalTrials.gov, number NCT02048618. Between Feb 3, 2014, and July 10, 2015, we enrolled 174 patients with active Crohn's disease confirmed by centrally read endoscopy (130 in the filgotinib 200 mg group and 44 in the placebo group). In the intention-to-treat population, 60 (47%) of 128 patients treated with filgotinib 200 mg achieved clinical remission at week 10 versus ten (23%) of 44 patients treated with placebo (difference 24 percentage points [95% CI 9-39], p=0·0077). In a pooled analysis of all periods of filgotinib and placebo exposure over 20 weeks, serious treatment-emergent adverse effects were reported in 14 (9%) of 152 patients treated with filgotinib and three (4%) of 67 patients treated with placebo. Filgotinib induced clinical remission in significantly more patients with active Crohn's disease compared with placebo, and had an acceptable safety profile. Galapagos.


In vivo satellite cell activation via Myf5 and MyoD in regenerating mouse skeletal muscle.
Regeneration of adult skeletal muscle is an asynchronous process requiring the activation, proliferation and fusion of satellite cells, to form new muscle fibres. This study was designed to determine the pattern of expression in vivo of the two myogenic regulatory factors, Myf5 and MyoD during this process. Cardiotoxin was used to induce regeneration in the gastrocnemius and soleus muscles of heterozygous Myf5-nlacZ mice, and the muscles were assayed for the presence of (beta)-galactosidase (Myf5) and MyoD. Adult satellite cells identified by M-cadherin labelling, when activated, initially express either MyoD or Myf5 or both myogenic factors. Subsequently all proliferating myoblasts express MyoD and part of the population is (beta)-galactosidase (Myf5) positive. Furthermore, we demonstrate that activated satellite cells, which express either Myf5 or MyoD, do not accumulate selectively on fast or slow muscle fibres.


Prescription opioid abuse among enrollees into methadone maintenance treatment.
A multi-state survey of 5663 opioid dependent persons enrolling in 72 methadone maintenance treatment programs (MMTPs) was conducted to determine the prevalence of prescription opioid (PO) abuse, factors associated with PO abuse and sources for POs. Regions where PO abuse was believed to be prevalent were oversampled; primary opioid was defined as the drug used the most before coming to the MMTP. Among primary heroin abusers, 69% reported abusing POs. Opioid abuse frequencies among primary PO abusers were oxycodone (79%), hydrocodone (67%), methadone (40%), morphine (29%), heroin (13%), hydromorphone (16%), fentanyl (9%) and buprenorphine (1%). Correlates (p < or = .01) of PO abuse, using general estimating equations, were: low urbanicity (MMTPs located in comparatively low population density counties), white ethnicity, no history of injecting primary drug, no previous methadone treatment, younger age, chronic pain, and pain as a reason for enrollment. The most frequent sources of POs were dealer, friend or relative, and doctor's prescription; least frequent were Internet and forged prescription. One-third of PO abusers reported a history of injecting their primary drug. PO abuse is highly prevalent among MMTP patients. Future studies should describe HIV/HCV needle injection practices, characteristics that predict treatment outcomes, and factors that contribute to higher prevalence of persistent pain among PO abusers.


Analytical expression for femtosecond-pulsed Z scans on instantaneous nonlinearity.
By employing the Gaussian decomposition method, the analytical formulas of the Gaussian-beam Z-scan traces have been derived for an optically thin material exhibiting both refractive and absorptive parts of third-order nonlinearity, with Gaussian or hyperbolic secant squared laser pulses of femtosecond duration. The formulas have been verified experimentally with femtosecond-pulsed Z scans on a carbon disulfide and acetone solution of a chalcone derivative (0.95C(18)H(17)ClO(4) . 0.05C(17)H(14)Cl(2)O(3)). An efficient yet accurate analytical technique has been demonstrated for extracting both the nonlinear refraction coefficient and the nonlinear absorption coefficient from a single closed-aperture Z-scan trace.


Supplemental control of lepidopterous pests on Bt transgenic sweet corn with biologically-based spray treatments.
Biologically-based spray treatments, including nucleopolyhedroviruses, neem, and spinosad, were evaluated as supplemental controls for the fall armyworm, Spodoptera frugiperda (J. E. Smith), and corn earworm, Helicoverpa zea (Boddie) (Lepidoptera: Noctuidae), on transgenic sweet corn, Zea mays (L.) (Poales: Poaceae), expressing a Cry1Ab toxin from Bacillus thuringiensis Berliner (Bacillales: Bacillaceae) (Bt). Overall, transgenic corn supported lower densities of both pests than did nontransgenic corn. Control of the fall armyworm was improved in both whorl-stage and tassel-stage corn by the use of either a nucleopolyhedrovirus or neem, but the greatest improvement was seen with spinosad. Only spinosad consistently reduced damage to ears, which was caused by both pest species. In general, efficacy of the spray materials did not differ greatly between transgenic and nontransgenic corn.


Auditory middle latency responses (MLRs) in patients with cortical lesions.
Auditory middle latency response (MLRs) and auditory brain stem responses (ABRs) were simultaneously recorded in 24 patients with cortical lesions primarily affecting the temporal lobes. Site of lesion was documented by computerized tomography (CT) scan and behavioral profiles assessing language and other higher cortical functions were obtained. In patients with normal ABRs and either left or right hemisphere lesions, MLR components Na and Pa obtained at the vertex were of normal shape and latency. Exceptions to this occurred in 2 patients: one with bilateral temporal lobe lesions, the second with an infraventricular left temporal lobe lesion extending into the thalamic radiations. Although Na and Pa shape and latency were for the most part unaltered, Pa amplitude tended to cluster at the low end and below normal values. MLR recorded in the coronal plate showed Pa amplitude to be attenuated or absent over the damaged temporal lobe relative to the vertex or the intact hemisphere. This finding contrasts with data from normal subjects where Pa amplitude is largest at the vertex and essentially symmetrical about the temporal lobes. Patients showing an atypical amplitude distribution tended to have lesions involving auditory cortex and adjacent white matter projections. No obvious correlations between MLR abnormalities and behavioral findings regarding receptive and expressive language processes were found. Pa appears to be affected by temporal lobe lesions involving auditory cortex and thalamic projections. Our findings support the hypothesis that Pa is bilaterally generated by two symmetrical, vertically oriented dipole sources located about the temporal lobes.


Semantic feature production norms for a large set of living and nonliving things.
Semantic features have provided insight into numerous behavioral phenomena concerning concepts, categorization, and semantic memory in adults, children, and neuropsychological populations. Numerous theories and models in these areas are based on representations and computations involving semantic features. Consequently, empirically derived semantic feature production norms have played, and continue to play, a highly useful role in these domains. This article describes a set of feature norms collected from approximately 725 participants for 541 living (dog) and nonliving (chair) basic-level concepts, the largest such set of norms developed to date. This article describes the norms and numerous statistics associated with them. Our aim is to make these norms available to facilitate other research, while obviating the need to repeat the labor-intensive methods involved in collecting and analyzing such norms. The full set of norms may be downloaded from www.psychonomic.org/archive.


Calpain-Mediated Processing of Adenylate Cyclase Toxin Generates a Cytosolic Soluble Catalytically Active N-Terminal Domain.
Bordetella pertussis, the whooping cough pathogen, secretes several virulence factors among which adenylate cyclase toxin (ACT) is essential for establishment of the disease in the respiratory tract. ACT weakens host defenses by suppressing important bactericidal activities of the phagocytic cells. Up to now, it was believed that cell intoxication by ACT was a consequence of the accumulation of abnormally high levels of cAMP, generated exclusively beneath the host plasma membrane by the toxin N-terminal catalytic adenylate cyclase (AC) domain, upon its direct translocation across the lipid bilayer. Here we show that host calpain, a calcium-dependent Cys-protease, is activated into the phagocytes by a toxin-triggered calcium rise, resulting in the proteolytic cleavage of the toxin N-terminal domain that releases a catalytically active "soluble AC". The calpain-mediated ACT processing allows trafficking of the "soluble AC" domain into subcellular organella. At least two strategic advantages arise from this singular toxin cleavage, enhancing the specificity of action, and simultaneously preventing an indiscriminate activation of cAMP effectors throughout the cell. The present study provides novel insights into the toxin mechanism of action, as the calpain-mediated toxin processing would confer ACT the capacity for a space- and time-coordinated production of different cAMP "pools", which would play different roles in the cell pathophysiology.


Medically unexplained otorhinolaryngological symptoms: Towards integrated psychiatric care.
To evaluate the presence of medically unexplained otorhinolaryngological symptoms in a patient cohort and propose an interdisciplinary approach for their care. Prospective cohort study. The study describes the population of patients presenting consecutively at the Department of Otorhinolaryngology at the Maastricht University Medical Center. Patients with symptoms who did not meet clear "medical" criteria and were associated with psychological distress and high health care utilization were enrolled in the study by two experienced otorhinolaryngologists following informed consent. The aim of the study is 1) to specify the presence of medically unexplained otorhinolaryngological symptoms and 2) to evaluate the integration of otorhinolaryngological and psychiatric treatment in an interdisciplinary approach in order to help otorhinolaryngologists improve patient care. Of the 102 patients included, 41% (N = 42) did not have a proven somatic otorhinolaryngological diagnosis. For only 10.8% (N = 4) of the latter, no psychiatric diagnosis had been established. Overall, 78% of the study population (N = 80) was diagnosed with psychiatric morbidity/comorbidity, as defined in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. The preliminary data suggest that the majority of patients with these unexplained complaints may suffer from under- or undiagnosed psychiatric morbidity. Therefore, easy access to integrated interdisciplinary care (otorhinolaryngology and psychiatry) should be offered to patients with medically unexplained otorhinolaryngological symptoms after detailed information is made available to them about the pathogenesis of the complaints and the foreseen psychosomatic approach.


Dual jets from binary black holes.
The coalescence of supermassive black holes--a natural outcome when galaxies merge--should produce gravitational waves and would likely be associated with energetic electromagnetic events. We have studied the coalescence of such binary black holes within an external magnetic field produced by the expected circumbinary disk surrounding them. Solving the Einstein equations to describe black holes interacting with surrounding plasma, we present numerical evidence for possible jets driven by these systems. Extending the process described by Blandford and Znajek for a single, spinning black hole, the picture that emerges suggests that the electromagnetic field extracts energy from the orbiting black holes, which ultimately merge and settle into the standard Blandford-Znajek scenario. Emissions along these jets could potentially be observable at large distances.


The Benefits of Rental Assistance for Children's Health and School Attendance in the United States.
Programs that provide affordable and stable housing may contribute to better child health and thus to fewer missed days of school. Drawing on a unique linkage of survey and administrative data, we use a quasi-experimental approach to examine the impact of rental assistance programs on missed days of school due to illness. We compare missed school days due to illness among children receiving rental assistance with those who will enter assistance within two years of their interview, the average length of waitlists for federal rental assistance. Overall, we find that children who receive rental assistance miss fewer days of school due to illness relative to those in the pseudo-waitlist group. We demonstrate that rental assistance leads to a reduction in the number of health problems among children and thus to fewer days of school missed due to illness. We find that the effect of rental assistance on missed school days is stronger for adolescents than for younger children. Additionally, race-stratified analyses reveal that rental assistance leads to fewer missed days due to illness among non-Hispanic White and Hispanic/Latino children; this effect, however, is not evident for non-Hispanic Black children, the largest racial/ethnic group receiving assistance. These findings suggest that underinvestment in affordable housing may impede socioeconomic mobility among disadvantaged non-Hispanic White and Hispanic/Latino children. In contrast, increases in rental assistance may widen racial/ethnic disparities in health among disadvantaged children, and future research should examine why this benefit is not evident for Black children.


Transcriptome Profiling Provides Insight into the Genes in Carotenoid Biosynthesis during the Mesocarp and Seed Developmental Stages of Avocado (Persea americana).
Avocado (Persea americana Mill.) is an economically important crop because of its high nutritional value. However, the absence of a sequenced avocado reference genome has hindered investigations of secondary metabolism. For next-generation high-throughput transcriptome sequencing, we obtained 365,615,152 and 348,623,402 clean reads as well as 109.13 and 104.10 Gb of sequencing data for avocado mesocarp and seed, respectively, during five developmental stages. High-quality reads were assembled into 100,837 unigenes with an average length of 847.40 bp (N50 = 1725 bp). Additionally, 16,903 differentially expressed genes (DEGs) were detected, 17 of which were related to carotenoid biosynthesis. The expression levels of most of these 17 DEGs were higher in the mesocarp than in the seed during five developmental stages. In this study, the avocado mesocarp and seed transcriptome were also sequenced using single-molecule long-read sequencing to acquired 25.79 and 17.67 Gb clean data, respectively. We identified 233,014 and 238,219 consensus isoforms in avocado mesocarp and seed, respectively. Furthermore, 104 and 59 isoforms were found to correspond to the putative 11 carotenoid biosynthetic-related genes in the avocado mesocarp and seed, respectively. The isoform numbers of 10 out of the putative 11 genes involved in the carotenoid biosynthetic pathway were higher in the mesocarp than those in the seed. Besides, alpha- and beta-carotene contents in the avocado mesocarp and seed during five developmental stages were also measured, and they were higher in the mesocarp than in the seed, which validated the results of transcriptome profiling. Gene expression changes and the associated variations in gene dosage could influence carotenoid biosynthesis. These results will help to further elucidate carotenoid biosynthesis in avocado.


Use of near-infrared spectroscopy in the adult.
Adult near-infrared spectroscopy is a potential method for observing changes in cerebral oxygenation non-invasively. Access of light to the adult brain requires requires penetration through extracranial tissues; hence the detection of changes in cerebral chromophore concentration can only be achieved by using near-infrared spectroscopy in the reflectance-mode thereby adding variables which are difficult to control. These include the effects of variable anatomy, different intra-optode distances and the presence of an extra- to intracranial collateral blood supply. Although movements of oxygenated haemoglobin concentration following specific cerebral stimuli can be demonstrated, the challenge of separating changes which occur within the extracranial compartment from those occurring in the intracranial compartments remains. Our experience with near-infrared spectroscopy in the three adult clinical scenarios of carotid endarterectomy, head injury and carbon dioxide stress testing will be presented. The influence of extracranial contamination is demonstrated, as are the methods we have developed to help control for extracranial contamination. Provisional experience with spatially resolved spectroscopy technology will also be presented.


The melliferous potential of forest and meadow plant communities on Mount Tara (Serbia).
The apiflora of 34 forest and meadow plant communities in Tara National Park was studied with the aim of assessing their melliferous potential and their contribution to bee pasture during the vegetation period. The melliferous plants were analyzed individually from the aspect of their flowering phenology, abundance, and the intensity of nectar and pollen production, as well as the production of honeydew. The melliferous potential of each investigated plant community was theoretically assessed on the basis of the coenotic coefficient of melliferousness incorporating a phytocoenotic analysis, the coenotic coefficients of nectar and pollen production, and the percentage of melliferous species in relation to the total number of species that characterize the association. The highest percentage of the melliferous species was noted in the meadow association Petasitetum hybridi (70%) and the forest association Piceetum-Abietis serpentinicum (63.6%). The highest values of the coenotic coefficient of melliferousness were established for the forest association Querco-Carpinetum iliricum, and the meadow association Rhinantho-Cynosuretum cristati. Trees notable for their honeydew production in good quantities were Pinus nigra Arnold, Picea sp. Fagus sylvatica Linnaeus, Populus tremula Linnaeus, and Quercus cerris Linnaeus. Because, the vegetation in the study area is forest dominated, forest bee pasture including early flowering herbaceous and woody plants, is of the greatest significance for the honey bee, both in the early spring because of pollen and nectar production, and in the autumn as a source of honeydew.


Using cAMP Sensors to Study Cardiac Nanodomains.
3',5'-cyclic adenosine monophosphate (cAMP) signalling plays a major role in the cardiac myocyte response to extracellular stimulation by hormones and neurotransmitters. In recent years, evidence has accumulated demonstrating that the cAMP response to different extracellular agonists is not uniform: depending on the stimulus, cAMP signals of different amplitudes and kinetics are generated in different subcellular compartments, eliciting defined physiological effects. In this review, we focus on how real-time imaging using fluorescence resonance energy transfer (FRET)-based reporters has provided mechanistic insight into the compartmentalisation of the cAMP signalling pathway and allowed for the precise definition of the regulation and function of subcellular cAMP nanodomains.


Assessment of early and delayed responses in vitamin B12 absorption during antibiotic therapy in tropical malabsorption.
1. Vitamin B12 absorption was measured in 18 patients with tropical malabsorption. 2. Absorption was particularly impaired in patients with severe mucosal lesions. 3. Sequential measurements with 57Co- and 58Co-labelled vitamin B12 were made before and 48 h after the start of tetracycline therapy. A rapid improvement (on average 22% increase in absorption) occurred in four of six patients with marked mucosal lesions. Further improvement occurred in four of five patients measured after 4 weeks' tetracycline, including the two who failed to improve initially. 4. These rapid changes in vitamin B12 absorption after antibiotics occur too early to be due to mucosal recovery and suggest that bacterial metabolism is an important factor in the malabsorption in these patients.


Establishment of orthotopic mouse superficial bladder tumor model for studies on intravesical treatments.
Various animal models of bladder tumor have been developed for the preclinical evaluation of therapeutic modalities for the treatment of bladder cancers. The ideal model for the investigation of therapeutic effects of proposed novel intravesical treatments requires the mass of the implanted tumor to be confined to the urothelium of the bladder at least for the initial phase. However, previously reported bladder tumor models are not suitable for the evaluation of intravesical therapies for the treatment of superficial bladder cancer, since the muscle invasive tumors have developed from the beginnings of the experiments. These models are too aggressive to study local treatment effects. In the current study, we demonstrated that careful instillation of MBT-2 mouse bladder cancer cells into the bladder of a syngenic C3H/HeJ mouse could establish a superficial bladder tumor with an incidence of 100%. The procedure and technique for handling animals are simple for standard animal investigators. Maintenance of the in vitro conditions of MBT-2 cells without contamination of Mycoplasma and careful selection of the substrain of C3H mouse seem to be essential for stable tumor establishment. This bladder tumor model appeared to be easy to reproduce among several investigators in different institutions. The orthotopic bladder tumor model, which was confined to urothelium, lets us evaluate various intravesical treatment strategies.


Optimal dose of aripiprazole for augmentation therapy of antidepressant-refractory depression: preliminary findings based on a systematic review and dose-effect meta-analysis.
Aripiprazole augmentation is proven effective for antidepressant-refractory depression, but its licensed dose range is wide and optimal dosage remains unclear. To find the optimal dosage of aripiprazole augmentation. Multiple electronic databases were searched (from inception to 16 February 2021) to identify all assessor-masked randomised controlled trials evaluating aripiprazole augmentation therapy in adults (≥18 years old, both genders) with major depressive disorder showing inadequate response to at least one antidepressant treatment. A random-effects, one-stage dose-effect meta-analysis with restricted cubic splines was conducted. Outcomes were efficacy (treatment response: ≥50% reduction in depression severity), tolerability (drop-out due to adverse effects) and acceptability (drop-out for any reason) after 8 weeks of treatment (range 4-12 weeks). Ten studies met the inclusion criteria. All were individually randomised, placebo-controlled, multi-centre, parallel studies including 2625 participants in total. The maximum target dose-efficacy curve showed an increase up to doses between 2 mg (odds ratio OR = 1.46, 95% CI 1.15-1.85) and 5 mg (OR = 1.93, 95% CI 1.33-2.81), and then a non-increasing trend through the higher licensed doses up to 20 mg (OR = 1.90, 95% CI 1.52-2.37). Tolerability showed a similar trend with greater uncertainty. Acceptability showed no significant difference through the examined dose range. Certainty of evidence was low to moderate. Low-dose aripiprazole as augmentation treatment might achieve the optimal balance between efficacy, tolerability and acceptability in the acute treatment of antidepressant-refractory depression. However, the small number of included studies and the overall moderate to high risk of bias seriously compromise the reliability of the results. Further research is required to investigate the benefits of low versus high dose.


A phylogenetic approach to test for evidence of parental conflict or gene duplications associated with protein-encoding imprinted orthologous genes in placental mammals.
There are multiple theories on the evolution of genomic imprinting. We investigated whether the molecular evolution of true orthologs of known imprinted genes provides support for theories based on gene duplication or parental conflicts (where mediated by amino-acid changes). Our analysis of 34 orthologous genes demonstrates that the vast majority of mammalian imprinted genes have not undergone any subsequent significant gene duplication within placental species, suggesting that selection pressures against gene duplication events could be operating for imprinted loci. As antagonistic co-evolution between imprinted genes can regulate offspring growth, proteins mediating this interaction could be subject to rapid evolution via positive selection. Supporting this, we detect evidence of site specific positive selection for the imprinted genes OSBPL5 (and GNASXL), and detect lineage-specific positive selection for 14 imprinted genes where it is known that the gene is imprinted in a specific lineage, namely for: PLAGL1, IGF2, SLC22A18, OSBPL5, DCN, DLK1, RASGRF1, IGF2R, IMPACT, GRB10, NAPIL4, UBE3A, GATM and GABRG3. However, there is an overall lack of concordance between the known imprinting status of each gene (i.e. whether the gene is imprinted or biallelically expressed in a particular mammalian lineage) and positive selection. While only a small number of orthologs of imprinted loci display evidence of positive selection, we observe that the majority of orthologs of imprinted loci display high levels of micro-synteny conservation and have undergone very few cis- or trans-duplications in placental mammalian lineages.


The complex relationship between iron status and anemia in pregnant and postpartum women in India: Analysis of two Indian study cohorts of uncomplicated pregnancies.
Low hemoglobin is widely used as an indicator of iron deficiency anemia in India and other low-and-middle income counties, but anemia need not accurately reflect iron deficiency. We examined the relationship between hemoglobin and biomarkers of iron status in antenatal and postnatal period. Secondary analysis of uncomplicated singleton pregnancies in two Indian study cohorts: 1132 antenatal women in third trimester and 837 postnatal women 12-72 h after childbirth. Associations of hemoglobin with ferritin in both data sets, and with sTfR, TSAT, and hepcidin in the postnatal cohort were examined using multivariable linear regression. Multinomial logistic regression was used to examine the association between severity of anemia and iron status. Regression models were adjusted for potential confounders. Over 55% of the women were anemic; 34% of antenatal and 40% of postnatal women had low ferritin, but 4% antenatal and 6% postnatal women had high ferritin. No evidence of association between hemoglobin and ferritin was observed (antenatal: adjusted coefficient [aCoef] -0.0004, 95% confidence interval [CI] -0.001, 0.001; postnatal: aCoef -0.0001, 95% CI -0.001, 0.001). We found a significant linear association of hemoglobin with sTfR (aCoef -0.04, 95% CI -0.07, -0.01), TSAT (aCoef -0.005, 95% CI -0.008, -0.002), and hepcidin (aCoef 0.02, 95% CI 0.02, 0.03) in postnatal women. Likelihood of low ferritin was more common in anemic than non-anemic women, but high ferritin was also more common in women with severe anemia in both cohorts. Causes of anemia in pregnant and postpartum women in India are multifactorial; low hemoglobin alone is not be a useful marker of iron deficiency.


An approach to the postpartum office visit.
The postpartum period (typically the first six weeks after delivery) may underscore physical and emotional health issues in new mothers. A structured approach to the postpartum office visit ensures that relevant conditions and concerns are discussed and appropriately addressed. Common medical complications during this period include persistent postpartum bleeding, endometritis, urinary incontinence, and thyroid disorders. Breastfeeding education and behavioral counseling may increase breastfeeding continuance. Postpartum depression can cause significant morbidity for the mother and baby; a postnatal depression screening tool may assist in diagnosing depression-related conditions. Decreased libido can affect sexual functioning after a woman gives birth. Physicians should also discuss contraception with postpartum patients, even those who are breastfeeding. Progestin-only contraceptives are recommended for breastfeeding women. The lactational amenorrhea method may be a birth control option but requires strict criteria for effectiveness.


Brief motivational interventions for heavy college drinkers: A randomized controlled trial.
In this randomized controlled trial, the authors evaluated brief motivational interventions (BMIs) for at-risk college drinkers. Heavy drinking students (N = 509; 65% women, 35% men) were randomized into 1 of 6 intervention conditions formed by crossing the baseline Timeline Followback (TLFB) interview (present versus absent) and intervention type (basic BMI, BMI enhanced with a decisional balance module, or none). Assessments completed at baseline, 1, 6, and 12 months measured typical and risky drinking as well as drinking-related problems. Relative to controls, the TLFB interview reduced consumption but not problems at 1 month. The basic BMI improved all drinking outcomes beyond the effects of the TLFB interview at 1 month, whereas the enhanced BMI did not. Risk reduction achieved by brief interventions maintained throughout the follow-up year.


Miniaturized Radiochemical Purity Testing for 99mTc-HMPAO, 99mTc-HMDP, and 99mTc-Tetrofosmin.
Quick methods are functional in clinical practice to ensure the fastest availability of radiopharmaceuticals. For this purpose, we investigated the radiochemical purity of the widely used 99mTc-hydroxymethylene diphosphonate, 99mTc-hexamethylpropyleneamine oxime, and 99mTc-tetrofosmin by reducing time as compared with the manufacturer's method. Methods: We applied a miniaturized chromatographic method with a reduced strip development from 18 cm to 9 cm for all 3 radiopharmaceuticals. The specific support medium and solvent system of the manufacturer's methods was kept unchanged for 99mTc-hydroxymethylene diphosphonate and 99mTc-tetrofosmin, whereas for 99mTc-hexamethylpropyleneamine oxime the instant thin-layer chromatography (ITLC) polysilicic gel (silicic acid [SA]) was replaced with a monosilicic gel (silicic gel [SG]) in the chromatographic system that uses methyl ethyl ketone as solvent. The method was applied and compared with the routine ITLC insert method in a total of 30 batches for each radiopharmaceutical. The precision of repeated tests was determined by comparison with the results of 10 replications on the same batch. Small volumes of concentrated 99mTcO4-, and 99mTc-albumin nanocolloid were used to produce potential radiochemical impurities. Correlation between the quick methods and the insert methods was analyzed using a nonparametric 2-tailed test and a 2 × 2 contingency table with the associated Fisher exact test to evaluate sensitivity and specificity. A receiver-operating-characteristic analysis was performed to evaluate the best cutoff. Results: The percentage radiochemical purity of the quick methods agreed with the standard chromatography procedures. We found that 99mTcO4 and colloidal impurities are not the only common radiochemical impurities with 99mTc-tetrofosmin, and shortening of the ITLC strip with respect to the manufacturer's method will worsen system resolution and may produce inaccuracy. Conclusion: The miniaturized methods we described represent a fast and reliable alternative for 99mTc-exametazime and 99mTc-oxidronate quality control, with the upper cutoff for acceptable radiochemical purity values being 84% and 95%, respectively. For 99mTc-tetrofosmin radiochemical purity testing, a longer strip as described in the standard method is warranted.


Gastronomic Paradigms in Contemporary Western Cuisine: From French Haute Cuisine to Mass Media Gastronomy.
Thomas Kuhn brings the concept of "paradigm" as the fundamental engine in the progress of humanity. Kuhn defines paradigms as the set of formal theories, experiments and work methods that define a process (scientific, economic, social, and in this case, contemporary haute cuisine), in a given time. According to Kuhn, progress does not happen by gradual accumulation of knowledge, but rather by abrupt advances. In this review, the conceptual evolution experienced by contemporary gastronomy (from the French Revolution to today) is analyzed applying the paradigm structure in light of the scientific knowledge of each era. It is thus reviewed how the first and second gastronomic paradigms, proposed, respectively, by Carême and Escoffier and based on food smell and taste the first and the flavor of the sauces the second, have been replaced by the third and fourth paradigms, led, respectively, by the Nouvelle Cuisine in France and Ferrán Adriá in Spain, and in whose development touch, sight, and sound have become increasingly prominent in gastronomic pleasure. Finally, it is analyzed how new trends in gastronomy: (1) worldwide diffusion of the Spanish tapas; (2) globalization of ethnic and fusion cuisines; (3) the growing disappearance of the professional gastronomic critique and its replacement by mass media influencers; (4) the increase of sustainability in cooking with development of local-, vegan-, and paleo-cooking, comfort, and smart food and finally, (5) the growing role of social networks and the self-itis linked to photography or foodstagramming in the gastronomic experience are leading toward a new gastronomic paradigm based on the global socialization of classic gastronomy.


Methylmercury and the health of autochthons in northwest Quebec.
We conducted a cross-sectional epidemiologic and clinical study to evaluate the nature, magnitude, and frequency of unfavourable health states among residents of northwest Quebec. Of particular interest were the possible occurrence of Minamata disease and any other neurological abnormalities. We also sought to determine whether industrial or naturally-occurring mercury in the region's environment were causally associated with any disorders that might be detected. A total of 321 subjects were studied in four groups with contrasting exposure to point-source mercury from a chlor-alkali plant in the area. Methylmercury in hair served as the marker of subject's ingestion of any organic mercury (natural or industrial). Ten pre-chosen target variables, seven clinical and three neurophysiological, were assessed in all subjects. Relationships between mercury in hair and each target variable were calculated. We determined whether gradients in target variables corresponded to gradients in potential exposure of the subjects to the aquatic emissions of the chlor-alkali plant. Minamata disease was not found. Diabetes and alcohol-related health problems assessed as important clinically plausible confounders, were common. Differences in frequency or magnitude of clinical, toxicological, and physiological findings among the contrast groups were small and not of clinical or statistical significance. There were definite relationships between mercury in hair and four target variables despite the low values of mercury measured and the mild nature of the health problems observed. This would suggest that verifiable biological threshold levels for clinical effects, if such exist, may be substantially lower among Canadians than those currently adopted as policy for adults elsewhere. A gradient was found only for two of the ten target variables. Clinically meaningful alternate hypotheses for observed health effects emerge in the data and agree with observations in the field made by consulting clinical experts.


Neutralization of blood group A-antigen by a novel anti-A antibody: overcoming ABO-incompatible solid-organ transplantation.
The major barrier to ABO-incompatible solid-organ transplantation is acute humoral rejection. It is known to be triggered by antidonor blood group A/B antibodies, which might bind to A/B-antigen on the endothelium of the graft. Various strategies to reduce antiblood group antibody by overcoming ABO-incompatible transplantation have been tried. However, antigen-suppressing procedures have not been performed. We produced a novel anti-A antibody (K7508) by immunizing mice with salivary mucin of a blood group A individual, thereby clarifying that blood group A-antigen is expressed in endothelial cells of the liver. We investigated whether K7508 can mask A-antigen on the cells in vitro. Next, we immunized mice with A-antigen-expressing cells coated with K7508 or its Fab fragment, and measured anti-A antibody production in the mice. Blood group A-antigen-expressing cells, such as blood group A-red blood cells (A-RBCs) and A431 cells, coated with K7508 were not recognized by another anti-A antibody in flow cytometry, indicating that A-antigen was masked by K7508 in vitro. The A-antigen on the paraffin-embedded liver tissue was also masked by K7508. Furthermore, the production of anti-A antibody in mice immunized with A-antigen-expressing cells coated with K7508 or its Fab fragment was significantly suppressed compared to that in mice immunized with non-coated cells alone, indicating that A-antigen was neutralized by K7508 in vivo. The neutralization of blood group antigen by antiblood group antibody and especially its Fab fragment might represent one strategy to overcome ABO-incompatible organ transplantation.


Tissue recommendations for precision cancer therapy using next generation sequencing: a comprehensive single cancer center's experiences.
To generate accurate next-generation sequencing (NGS) data, the amount and quality of DNA extracted is critical. We analyzed 1564 tissue samples from patients with metastatic or recurrent solid tumor submitted for NGS according to their sample size, acquisition method, organ, and fixation to propose appropriate tissue requirements.Of the 1564 tissue samples, 481 (30.8%) consisted of fresh-frozen (FF) tissue, and 1,083 (69.2%) consisted of formalin-fixed paraffin-embedded (FFPE) tissue. We obtained successful NGS results in 95.9% of cases. Out of 481 FF biopsies, 262 tissue samples were from lung, and the mean fragment size was 2.4 mm. Compared to lung, GI tract tumor fragments showed a significantly lower DNA extraction failure rate (2.1 % versus 6.1%, p = 0.04). For FFPE biopsy samples, the size of biopsy tissue was similar regardless of tumor type with a mean of 0.8 × 0.3 cm, and the mean DNA yield per one unstained slide was 114 ng. We obtained highest amount of DNA from the colorectum (2353 ng) and the lowest amount from the hepatobiliary tract (760.3 ng) likely due to a relatively smaller biopsy size, extensive hemorrhage and necrosis, and lower tumor volume. On one unstained slide from FFPE operation specimens, the mean size of the specimen was 2.0 × 1.0 cm, and the mean DNA yield per one unstained slide was 1800 ng.In conclusions, we present our experiences on tissue requirements for appropriate NGS workflow: > 1 mm2 for FF biopsy, > 5 unstained slides for FFPE biopsy, and > 1 unstained slide for FFPE operation specimens for successful test results in 95.9% of cases.


Solar steam generation by heat localization.
Currently, steam generation using solar energy is based on heating bulk liquid to high temperatures. This approach requires either costly high optical concentrations leading to heat loss by the hot bulk liquid and heated surfaces or vacuum. New solar receiver concepts such as porous volumetric receivers or nanofluids have been proposed to decrease these losses. Here we report development of an approach and corresponding material structure for solar steam generation while maintaining low optical concentration and keeping the bulk liquid at low temperature with no vacuum. We achieve solar thermal efficiency up to 85% at only 10 kW m(-2). This high performance results from four structure characteristics: absorbing in the solar spectrum, thermally insulating, hydrophilic and interconnected pores. The structure concentrates thermal energy and fluid flow where needed for phase change and minimizes dissipated energy. This new structure provides a novel approach to harvesting solar energy for a broad range of phase-change applications.


Probing an Allosteric Pocket of CDK2 with Small Molecules.
The availability of well-characterized allosteric modulators is crucial for investigating the allosteric regulation of protein function. In a recently identified inactive conformation of cyclin-dependent kinase 2 (CDK2), an open allosteric pocket was detected and proposed as a site to accommodate allosteric inhibitors. Previous structure-based approaches allowed the identification of a hit compound expected to bind to this pocket. Herein we report the characterization of this compound by X-ray crystallography, which surprisingly provided a chemical structure different from that previously reported. Therefore, the compound was synthesized and completely characterized. X-ray structures of the synthesized and purchased compounds were found to be superimposable. A reaction mechanism was proposed to explain the formation of the structure indicated by crystallography. Moreover, a stereoselective synthesis was developed to evaluate the biological activity of the pure stereoisomers. Modeling studies were performed to unveil the details of the interaction with CDK2. The activity of the obtained compounds was evaluated with various biological assays. Mutagenesis experiments confirmed binding to the allosteric pocket. Finally, the allosteric ligands were shown to inhibit the growth of lung (A549) and ovarian (SKOV3) cancer cell lines. Therefore, this report presents a thorough chemical and biological characterization of the first small-molecule ligands to be used as probes to study the allosteric modulation of CDK2 activity.


Combination of herbivore removal and nitrogen deposition increases upland carbon storage.
Ecosystem carbon (C) accrual and storage can be enhanced by removing large herbivores as well as by the fertilizing effect of atmospheric nitrogen (N) deposition. These drivers are unlikely to operate independently, yet their combined effect on aboveground and belowground C storage remains largely unexplored. We sampled inside and outside 19 upland grazing exclosures, established for up to 80 years, across an N deposition gradient (5-24 kg N ha(-1) yr(-1) ) and found that herbivore removal increased aboveground plant C stocks, particularly in moss, shrubs and litter. Soil C storage increased with atmospheric N deposition, and this was moderated by the presence or absence of herbivores. In exclosures receiving above 11 kg N ha(-1) year(-1) , herbivore removal resulted in increased soil C stocks. This effect was typically greater for exclosures dominated by dwarf shrubs (Calluna vulgaris) than by grasses (Molinia caerulea). The same pattern was observed for ecosystem C storage. We used our data to predict C storage for a scenario of removing all large herbivores from UK heathlands. Predictions were made considering herbivore removal only (ignoring N deposition) and the combined effects of herbivore removal and current N deposition rates. Predictions including N deposition resulted in a smaller increase in UK heathland C storage than predictions using herbivore removal only. This finding was driven by the fact that the majority of UK heathlands receive low N deposition rates at which herbivore removal has little effect on C storage. Our findings demonstrate the crucial link between herbivory by large mammals and atmospheric N deposition, and this interaction needs to be considered in models of biogeochemical cycling.


Long-term pooled analysis of multicenter studies of cooled thermotherapy for benign prostatic hyperplasia results at three months through four years.
To determine the long-term efficacy of cooled thermotherapy in the treatment of lower urinary tract symptoms of clinical benign prostatic hyperplasia. A total of 541 men underwent cooled thermotherapy treatment in six multicenter studies in the United States, England, and Canada. Both fixed and random effects models were used to pool the data across the six studies. The treatment response was measured as the difference between the urinary tract symptoms at baseline versus those at 3, 12, 24, 36, and 48 months after therapy. The treatment response included changes in the American Urological Association Symptom Score (AUA symptom score), peak urinary flow rate in milliliters per second (Qmax), and quality of life (QOL). The baseline measures were comparable across the studies. At 3 months, the AUA symptom score had improved by a mean of 11.6 (55%), Qmax by a mean of 4.0 (51%), and QOL by a mean of 2.3 (53%). These changes persisted with only slight attenuation through 48 months (corresponding mean changes of 43%, 35%, and 50%). These changes were highly statistically significant (P <0.0001 to 0.01). An improvement of at least 25% was achieved for the AUA symptom score and QOL by more than 85% of men and by more than 65% of men for Qmax. This pooled analysis of six multicenter studies of cooled thermotherapy, involving 541 men, found highly significant improvements in AUA symptom score, Qmax, and QOL. The results were highly consistent across the studies. The improvements reflected changes from baseline values of 45% to 50% for AUA symptom score and QOL and 35% to 40% for Qmax at a follow-up duration up to 48 months after therapy. The level of improvement for all three measures remained high at 48 months, indicating that the response is durable.


MR imaging-guided cryoablation for the treatment of benign prostatic hyperplasia.
A patient with benign prostatic hyperplasia presented with chronic lower urinary tract symptoms despite prior surgery and continued medical therapy. Using a magnetic resonance imaging-guided transperineal approach, two cryoprobes were placed into the transition zone of the prostate gland, and two cryoablation freeze-thaw cycles were performed. At 10 weeks after treatment, the frequency of nocturia had decreased from once every 1.5 hours to once per night, urinary peak flow rates had increased from 5.1 mL/s to 10.3 mL/s, and postvoid residual urinary bladder volume had decreased from 187 mL to 58 mL. Improved flow rates and symptoms remained stable 16 weeks after treatment.


Microfluidic device for on-chip isolation and detection of circulating exosomes in blood of breast cancer patients.
Tumor-derived circulating exosomes have been recognized as a promising biomarker source for cancer diagnosis via a less invasive procedure. The integration of isolation and detection of exosomes in routine clinical settings is still challenging. In this study, we developed a new microfluidic device for immunomagnetic separation and detection of blood exosomes in situ. The microfluidic device may empower the integration of target exosome analysis via high surface to volume ratios of immunomagnetic beads and highly precise fluid control with the aid of microvalves. The obtained microfluidic device was capable of on-chip isolation and detection of circulating exosomes within 1.5 h. The captured exosomes could be directly visualized with an inverted fluorescence microscope in situ by tetramethylbenzidine-based colorimetric sensing. It was revealed that a statistically significant increase (p < 0.01) in EpCAM-positive exosomes was captured for cancer patients (n = 10) on the device when compared to healthy individuals (n = 10). The device also demonstrated high predicting accuracy for tumor exosomal markers with a sensitivity of 90% and a specificity of >95% using receiver operating characteristic curves. The microfluidic device might provide a new platform to assist cancer diagnosis and molecular classification in an automated and simple fashion.


WRN helicase and mismatch repair complexes independently and synergistically disrupt cruciform DNA structures.
The Werner Syndrome helicase, WRN, is a promising therapeutic target in cancers with microsatellite instability (MSI). Long-term MSI leads to the expansion of TA nucleotide repeats proposed to form cruciform DNA structures, which in turn cause DNA breaks and cell lethality upon WRN downregulation. Here we employed biochemical assays to show that WRN helicase can efficiently and directly unfold cruciform structures, thereby preventing their cleavage by the SLX1-SLX4 structure-specific endonuclease. TA repeats are particularly prone to form cruciform structures, explaining why these DNA sequences are preferentially broken in MSI cells upon WRN downregulation. We further demonstrate that the activity of the DNA mismatch repair (MMR) complexes MutSα (MSH2-MSH6), MutSβ (MSH2-MSH3), and MutLα (MLH1-PMS2) similarly decreases the level of DNA cruciforms, although the mechanism is different from that employed by WRN. When combined, WRN and MutLα exhibited higher than additive effects in in vitro cruciform processing, suggesting that WRN and the MMR proteins may cooperate. Our data explain how WRN and MMR defects cause genome instability in MSI cells with expanded TA repeats, and provide a mechanistic basis for their recently discovered synthetic-lethal interaction with promising applications in precision cancer therapy.


Attenuation of lower-thoracic, lumbar, and sacral spinal cord motion: implications for imaging human spinal cord structure and function.
Recent literature indicates that cervical and upper-thoracic spinal cord motion adversely affect both structural and functional MR imaging (fMRI; particularly diffusion tensor imaging [DTI] and spinal fMRI), ultimately reducing the reliability of these methods for both research and clinical applications. In the present study, we investigated motion of the lower-thoracic, lumbar, and sacral cord segments to evaluate the incidence of similar motion-related confounds in these regions. Recently developed methods, used previously for measuring cervical and upper-thoracic spinal cord motion, were employed in the present study to examine anteroposterior (A/P) and left-right (L/R) spinal cord motion in caudal regions. Segmented cinematic imaging was applied with a gradient-echo, turbo fast low-angle shot (turbo-FLASH) pulse sequence to acquire midline images of the cord at 24 cardiac phases throughout the lower-thoracic, lumbar, and sacral spinal cord regions. The magnitude of A/P motion was found to be largest in rostral cord regions, whereas in caudal regions (at the level of the T4/T5 vertebrae and below), peak cord motion was uniformly small (routinely < or =0.10 mm). L/R motion, however, was found to be minimal throughout the thoracic, lumbar, and sacral regions. Motion-related errors in spinal fMRI and DTI are expected to be significantly reduced throughout caudal regions of the spinal cord, thus yielding higher sensitivity and specificity compared with rostral regions. The paucity of such errors is expected to provide a means of observing the specific impact of motion (in rostral regions) and to enable the acquisition of uncorrupted DTI and fMRI data for studies of structure and function throughout lumbar and sacral regions.


Scoliosis surgery in cerebral palsy: differences between unit rod and custom rods.
Retrospective review. To evaluate the differences in intraoperative factors and postoperative results between pediatric patients with cerebral palsy (CP) treated with unit rods and those treated with custom-bent rods. No prior study has directly compared unit and custom-bent rods for CP. We retrospectively analyzed the clinical and radiographic data of 157 children with CP who underwent posterior spinal fusion. Of those 157, we treated 79 with unit rods and 78 with custom-bent rods. Minimum follow-up was 2 years. Intraoperatively, unit rod surgeries were associated with significantly shorter mean surgical time (339 and 379 minutes, respectively; P = 0.04), longer mean intensive care unit stay (4 vs. 3 days, respectively; P = 0.001), and longer mean hospital stay (14 vs. 13 days; P = 0.006) than custom-bent rod procedures. The mean estimated blood loss was higher for unit rods (2124 vs. 1885 mL, respectively), but not significantly so. After surgery, unit rod surgeries were associated with significantly more mean pelvic obliquity correction (74% vs. 22%, respectively; P = 0.002), more mean clinically apparent implant prominence at 2-year follow-up (12 vs. 2 instances; P = 0.03; most were proximal), and a higher mean infection rate (15% vs. 5%, respectively; P = 0.03). There were no significant differences in final major Cobb correction, curves with an apex above or below T10, implant-related reoperations, or neurologic complications. The only factor that was statistically correlated with the overall complication rate for both groups was absolute curve magnitude (P = 0.04). Compared with custom-bent rods, unit rods provided superior correction of pelvic obliquity but were associated with higher transfusion requirements, higher infection rates, more proximal fixation problems, and longer intensive care unit and hospital stays.


Biotherapy in the Adjuvant Treatment of Colorectal Cancer.
The use of adjuvant chemotherapy has improved survival in early-stage colon cancer. Ongoing adjuvant clinical trials are evaluating the addition of targeted therapies to standard chemotherapy regimen. Preliminary results with bevacizumab were disappointing. Also, cetuximab added to chemotherapy does not seem to be better than chemotherapy alone, even in selected wild-type KRAS populations. A better understanding of mechanisms of action of drugs, tumor biology, and predictive biomarkers are needed to design future adjuvant trials.


Prevalence of Juvenile Fibromyalgia Syndrome Among Children and Adolescents and its Relationship With Academic Success, Depression and Quality of Life, Çorum Province, Turkey.
This study aims to determine the frequency of juvenile fibromyalgia syndrome (JFMS) among children and adolescents in Çorum Province, Turkey, and its impact by comparing the levels of academic success, depression and quality of life (QoL) in individuals with and without JFMS. This was a cross-sectional study on 476 children and adolescents (245 boys, 231 girls; mean age 13.81±2.3 years; range, 9 to 17 years). The control group (non-JFMS group) consisted of 105 age- and sex-matched healthy participants (75 girls, 30 boys; mean age 14.1±1.8 years; range; 9 to 17 years). Participants' sociodemographic data, parental information, and school achievement in addition to data on chronic illness and drug use were collected via questionnaires (depression and QoL). A tender point (TP) examination was performed on each participant. Thirty-five (7.35%) of the participants (girls, n=25; boys, n=10) were diagnosed with JFMS. The number of minor JFMS diagnostic criteria, number of TPs, depression level and number of days the participants were absent from school were significantly higher in the JFMS group compared with the non-JFMS group (p<0.05). The mean grade point scores of the JFMS group were significantly lower than those of the non-JFMS group (p<0.05). The QoL subgroup scores as assessed by physical functioning, emotional functioning, social functioning and school-related problems of the JFMS group were significantly lower than the non-JFMS group (p<0.05). Age had a statistically significant negative correlation with QoL and school-related problems (r= -0.421, r= -0.494; p<0.05, respectively). Depression was negatively correlated with QoL and school-related problems (r= -0.672, r= -0.731; p<0.05, respectively). Juvenile fibromyalgia syndrome affects QoL and can lead to school absenteeism, poor academic performance, depression and anxiety among the school-age population. Early identification of JFMS and early intervention may be the most effective strategy for preventing problems in later life.


Anticoagulant therapy in pediatrics.
Thromboembolic episodes are disorders encountered in both children and adults, but relatively more common in adults. However, the occurrence of venous thromboembolism and use of anticoagulants in pediatrics are increasing. Unfractionated Heparin (UH) is used as a treatment and prevention of thrombosis in adults and critically ill children. Heparin utilization in pediatric is limited by many factors and the most important ones are Heparin Induced Thrombocytopenia (HIT) and anaphylaxis. However, Low Molecular Weight Heparin (LMWH) appears to be an effective and safe alternative treatment. Hence, it is preferred over than UH due to favorable pharmacokinetic and side effect profile. Direct Thrombin Inhibitors (DTI) is a promising class over the other anticoagulants since it offers potential advantages. The aim of this review is to discuss the differences between adult and pediatric thromboembolism and to review the current anticoagulants in terms of pharmacological action, doses, drug reactions, pharmacokinetics, interactions, and parameters. This review also highlights the differences between old and new anticoagulant therapy in pediatrics.


Implant healing in experimental animal models of diabetes.
Diabetes mellitus is becoming increasingly prevalent worldwide. Additionally, there is an increasing number of patients receiving implantable devices such as glucose sensors and orthopedic implants. Thus, it is likely that the number of diabetic patients receiving these devices will also increase. Even though implantable medical devices are considered biocompatible by the Food and Drug Administration, the adverse tissue healing that occurs adjacent to these foreign objects is a leading cause of their failure. This foreign body response leads to fibrosis, encapsulation of the device, and a reduction or cessation of device performance. A second adverse event is microbial infection of implanted devices, which can lead to persistent local and systemic infections and also exacerbates the fibrotic response. Nearly half of all nosocomial infections are associated with the presence of an indwelling medical device. Events associated with both the foreign body response and implant infection can necessitate device removal and may lead to amputation, which is associated with significant morbidity and cost. Diabetes mellitus is generally indicated as a risk factor for the infection of a variety of implants such as prosthetic joints, pacemakers, implantable cardioverter defibrillators, penile implants, and urinary catheters. Implant infection rates in diabetic patients vary depending upon the implant and the microorganism, however, for example, diabetes was found to be a significant variable associated with a nearly 7.2% infection rate for implantable cardioverter defibrillators by the microorganism Candida albicans. While research has elucidated many of the altered mechanisms of diabetic cutaneous wound healing, the internal healing adjacent to indwelling medical devices in a diabetic model has rarely been studied. Understanding this healing process is crucial to facilitating improved device design. The purpose of this article is to summarize the physiologic factors that influence wound healing and infection in diabetic patients, to review research concerning diabetes and biomedical implants and device infection, and to critically analyze which diabetic animal model might be advantageous for assessing internal healing adjacent to implanted devices.


Do colleagues influence our lifestyle: the matter of smoking, body mass index and leisure-time physical activity?
Previous research has indicated that health behaviours tend to cluster in social networks, but few have studied the cluster effect in workgroups. We examined the effect of workgroups on current state and change in three indicators of health behaviours (smoking, body mass index (BMI) and physical activity). Further, we examined whether health behaviours of the respondents at group level predicted lifestyle changes. In a prospective cohort (n=4730), employees from 250 workgroups in the Danish eldercare sector answered questionnaires at baseline (2005) and follow-up (2006). Multilevel regression models were used to examine the effect of workgroups. Workgroups accounted for 6.49% of the variation in smoking status, 6.56% of amount smoked and 2.62% of the variation in current BMI. We found no significant workgroup clustering in physical activity or lifestyle changes. Furthermore, changes in smoking status (cessation) and weight gain were seen in workgroups with high percentage of smokers and high levels of BMI. We found modest evidence for clustering of some health behaviours within workgroups, which could be due to social learning or selection into and out of workgroups. Future health promotion programmes at worksites should recognize the potential clustering of lifestyle behaviours within workgroups.


The Tyrosine Kinase Inhibitor Gefitinib Restricts Mycobacterium tuberculosis Growth through Increased Lysosomal Biogenesis and Modulation of Cytokine Signaling.
Host-directed therapeutics have the potential to combat the global tuberculosis pandemic. We previously identified gefitinib, an inhibitor of EGFR, as a potential host-targeted therapeutic effective against Mycobacterium tuberculosis infection of macrophages and mice. Here we examine the functional consequences of gefitinib treatment on M. tuberculosis infected macrophages. Using phosphoproteomic and transcriptional profiling, we identify two mechanisms by which gefitinib influences macrophage responses to infection to affect cytokine responses and limit replication of M. tuberculosis in macrophages. First, we find that gefitinib treatment of M. tuberculosis infected macrophages inhibits STAT3, a transcription factor known to repress effective immune responses to M. tuberculosis in vivo. Second, we find that gefitinib treatment of M. tuberculosis infected macrophages leads to increased expression of genes involved in lysosomal biogenesis and function and an increase of functional lysosomes in gefitinib treated cells. Furthermore, we show that gefitinib treatment increases the targeting of bacteria to lysosomes, providing an explanation for the cell intrinsic effects of gefitinib treatment on M. tuberculosis infection. Our data provide novel insights into the effects of gefitinib on mammalian cells and into the possible roles for EGFR signaling in macrophages.


Approach to investigating the spherical aberration variation with the object position in an aplanatic system.
In a general optical system, spherical aberration will arise when the on-axis position of an object is changed from its optimum position to another point. Induced spherical aberration can be used to compensate the aberration caused by inserting or removing a medium plate with any thickness that has a refractive index that differs from that of the original. To generate a degree of adequate aberration to balance the aberration from a thin layer, it is necessary to estimate the amount of arising aberration correctly when a point object deviates from its aberration-free position. We analytically induce the exact form of an arising spherical aberration with an on-axis object position for general optical systems that satisfy the Abbe sine condition and express a fourth-order approximation of that form using simple parameters that are conventionally used for the aberration of a thin lens. To verify the correctness of the proposed formula, a comparison between this analysis and simulation results is applied to several sample optical systems using commercial lens-design software.


Epidemiology report: trends in sex-specific cerebrovascular disease mortality in Europe based on WHO mortality data.
There have been substantial declines in cerebrovascular disease mortality across much of Europe, mirroring trends in deaths from cardiovascular disease as a whole. No study has investigated trends in cerebrovascular disease, and its subtypes within all European countries. This study aimed to examine sex-specific trends in cerebrovascular disease, and three of its sub-types: ischaemic stroke, haemorrhagic stroke, and subarachnoid haemorrhage (SAH), in Europe between 1980 and 2016. Sex-specific mortality data for each country of the World Health Organization (WHO) Europe region were extracted from the WHO global mortality database and analysed using Joinpoint software to examine trends. The number and location of significant joinpoints for each country by sex and subtype was determined using a log-linear model. The annual percentage change within each segment was calculated along with the average annual percentage change over the duration of all available data. The last 35 years have seen large overall declines in cerebrovascular disease mortality rates in the majority of European countries. While these declines have continued steadily in more than half of countries, this analysis has revealed evidence of recent plateauing and even increases in stroke mortality in a number of countries, in both sexes, and in all four geographical sub-regions of Europe. Analysis by stroke sub-type revealed that recent plateauing was most common for haemorraghic stroke and increases were most common for ischaemic stroke. These findings highlight the need for continued research into the inequalities in both current stroke mortality outcomes and trends across Europe, as well as the causes behind any recent plateauing of total cerebrovascular disease or its subtypes.


Implementation of a model for identifying Essentially Derived Varieties in vegetatively propagated Calluna vulgaris varieties.
Variety protection is of high relevance for the horticultural community and juridical cases have become more frequent in a globalized economy due to essential derivation of varieties. This applies equally to Calluna vulgaris, a vegetatively propagated species from the Ericaceae family that belongs to the top-selling pot plants in Europe. We therefore analyzed the genetic diversity of 74 selected varieties and genotypes of C. vulgaris and 3 of Erica spp. by means of RAPD and iSSR fingerprinting using 168 mono- and polymorphisms. The same data set was utilized to generate a system to reliably identify Essentially Derived Varieties (EDVs) in C. vulgaris, which was adapted from a method suggested for lettuce and barley. This system was developed, validated and used for selected tests of interest in C. vulgaris. As expected following personal communications with breeders, a very small genetic diversity became evident within C. vulgaris when investigated using our molecular methods. Thus, a dendrogram-based assay to detect Essentially Derived Varieties in this species is not suitable, although varieties are propagated vegetatively. In contrast, the system applied in lettuce, which itself applies pairwise comparisons using appropriate reference sets, proved functional with this species. The narrow gene pool detected in C. vulgaris may be the genetic basis for juridical conflicts between breeders. We successfully tested a methodology for identification of Essentially Derived Varieties in highly identical C. vulgaris genotypes and recommend this for future proof of essential derivation in C. vulgaris and other vegetatively propagated crops.


Making the Moon from a fast-spinning Earth: a giant impact followed by resonant despinning.
A common origin for the Moon and Earth is required by their identical isotopic composition. However, simulations of the current giant impact hypothesis for Moon formation find that most lunar material originated from the impactor, which should have had a different isotopic signature. Previous Moon-formation studies assumed that the angular momentum after the impact was similar to that of the present day; however, Earth-mass planets are expected to have higher spin rates at the end of accretion. Here, we show that typical last giant impacts onto a fast-spinning proto-Earth can produce a Moon-forming disk derived primarily from Earth's mantle. Furthermore, we find that a faster-spinning early Earth-Moon system can lose angular momentum and reach the present state through an orbital resonance between the Sun and Moon.


Fluid Management During Kidney Transplantation: A Consensus Statement of the Committee on Transplant Anesthesia of the American Society of Anesthesiologists.
Intraoperative fluid management may affect the outcome after kidney transplantation. However, the amount and type of fluid administered, and monitoring techniques vary greatly between institutions and there are limited prospective randomized trials and meta-analyses to guide fluid management in kidney transplant recipients. Members of the American Society of Anesthesiologists (ASA) committee on transplantation reviewed the current literature on the amount and type of fluids (albumin, starches, 0.9% saline, and balanced crystalloid solutions) administered and the different monitors used to assess fluid status, resulting in this consensus statement with recommendations based on the best available evidence. Review of the current literature suggests that starch solutions are associated with increased risk of renal injury in randomized trials and should be avoided in kidney donors and recipients. There is no evidence supporting the routine use of albumin solutions in kidney transplants. Balanced crystalloid solutions such as Lactated Ringer are associated with less acidosis and may lead to less hyperkalemia than 0.9% saline solutions. Central venous pressure is only weakly supported as a tool to assess fluid status. These recommendations may be useful to anesthesiologists making fluid management decisions during kidney transplantation and facilitate future research on this topic.


Requirement of histone deacetylase activity for signaling by STAT1.
STAT1 is a transcription factor that plays a crucial role in signaling by interferons (IFNs). In this study we demonstrated that inhibitors of histone deacetylase (HDAC) activity, butyrate, trichostatin A, and suberoylanilide hydroxamic acid, prevented IFNgamma-induced JAK1 activation, STAT1 phosphorylation, its nuclear translocation, and STAT1-dependent gene activation. Furthermore, we showed that silencing of HDAC1, HDAC2, and HDAC3 through RNA interference markedly decreased IFNgamma-driven gene activation and that overexpression of HDAC1, HDAC2, and HDAC3 enhanced STAT1-dependent transcriptional activity. Our data therefore established the essential role of deacetylase activity in STAT1 signaling. Induction of IRF-1 by IFNgamma requires functional STAT1 signaling and was abrogated by butyrate, trichostatin A, suberoylanilide hydroxamic acid, and STAT1 small interfering RNA. In contrast, silencing of STAT1 did not interfere with IFNgamma-induced expression of STAT2 and caspase-7, and HDAC inhibitors did not preclude IFNgamma-induced expression of STAT1, STAT2, and caspase-7, suggesting that HDAC inhibitors impede the expression of IFNgamma target genes whose expression depends on STAT1 but do not interfere with STAT1-independent signaling by IFNgamma. Finally, we showed that inhibitors of deacetylase activity sensitized colon cancer cells to IFNgamma-induced apoptosis through cooperative negative regulation of Bcl-x expression, demonstrating that interruption of the balance between STAT1-dependent and STAT1-independent signaling significantly alters the biological activity of IFNgamma.


Hypermethylation of XIAP-associated factor 1, a putative tumor suppressor gene from the 17p13.2 locus, in human gastric adenocarcinomas.
X-linked inhibitor of apoptosis (XIAP) is the most potent member of the IAP family that exerts antiapoptotic effects by interfering with the activities of caspases. Recently, XIAP-associated factor 1 (XAF1) and two mitochondrial proteins, Smac/DIABLO and HtrA2, have been identified to negatively regulate the caspase-inhibiting activity of XIAP. To explore the candidacy of XAF1, Smac/DIABLO, and HtrA2 as a tumor suppressor in gastric tumorigenesis, we investigated the expression and mutation status of the genes in 123 gastric tissues and 15 cancer cell lines. Whereas Smac/DIABLO and HtrA2 transcripts were normally expressed in all cancer specimens we examined, XAF1 transcript was not expressed or present at extremely low levels in 40% (6 of 15) of cancer cell lines and in 23% (20 of 87) of primary carcinomas. Abnormal reduction of XAF1 expression showed a strong correlation with stage and grade of tumors, and a tumor-specific down-regulation of XAF1 was observed in 45% (9 of 20) of matched sets. Unlike XAF1, XIAP expression exhibited no detectable alteration in cancers. Whereas loss of heterozygosity within the XAF1 region or somatic mutations of the gene was not detected, expression of XAF1 transcript was reactivated in all nonexpressor cell lines after 5-aza-2-deoxycytidine treatment. The 5' upstream region of the XAF1 gene encompasses no gastric cell-rich region that rigorously satisfies the formal criteria for CpG islands. However, bisulfite DNA sequencing analysis for 34 CpG sites in the promoter region revealed a strong association between hypermethylation and gene silencing. Moreover, transcriptional silencing of XAF1 was tightly associated with hypermethylation of seven CpGs located in the 5' proximal region (nucleotides -23 to -234). Additionally, loss or abnormal reduction of XAF1 expression was found to inversely correlate with p53 mutations, suggesting that epigenetic inactivation of XAF1 and mutational alteration of p53 might be mutually exclusive events in gastric tumorigenesis. Collectively, our study suggests that epigenetic silencing of XAF1 by aberrant promoter methylation may contribute to the malignant progression of human gastric tumors.


Migratory paths of neurons and glia in the embryonic chick spinal cord.
To study the migration of chick spinal cord neurons, we labeled individual cells in the ventricular zone with recombinant retroviruses, then identified their progeny histochemically. First, we analyzed cell mixing in the ventricular zone. Some clones labeled at early neural tube stages spread widely along both the dorsoventral and rostrocaudal axes. However, clones labeled later were confined to narrow domains along both axes. These results imply that displacement of cells within the ventricular zone becomes progressively restricted. Second, we studied the migration of cells out of the ventricular zone by infecting embryos at a fixed stage and varying the time of analysis. At first, most clones consisted of radial arrays of cells, suggesting that the initial migration is predominantly radial. In many clones, however, neurons turned orthogonally from parental radial arrays and migrated along the path of circumferentially oriented axons. By hatching, clonally related cells in the gray matter were usually distributed in narrow transverse slabs, but some white matter glial cells had migrated longitudinally for up to several segments. We conclude that the dispersal of clonally related cells results from (1) early mixing of progenitors within the neural tube; (2) radial stacking of progeny in the ventricular zone; (3) migration of progeny from the ventricular zone in spoke-like routes; (4) circumferential migration of some neurons along axons; (5) short-distance dispersal of differentiating neurons; and (6) a late, longitudinal migration of glia through white matter tracts. Finally, we show that floor plate cells differ from other spinal cord cells in both their lineage and migration patterns.


The validity in persons with spinal cord injury of a self-reported functional measure derived from the functional independence measure.
A cross-sectional, mailed survey on impairment and function using 6361 respondents to the Spinal Cord Dysfunction National Veterans Survey who reported spinal cord injury as the sole cause of their spinal cord dysfunction. To establish the concurrent and construct validities of a Self-Reported Functional Measure appropriate for use in patients with spinal cord injuries. Functional assessment is of increasing importance in clinical care, quality assurance, and national health-care planning. There is a conspicuous need for validated functional assessment measures that are rapid, reliable, and appropriate for use in the disabled population. The correlation was examined of hours of personal assistance, number of affected limbs, amount of motor impairment, and amount of combined limb-motor impairment to Self-Reported Functional Measure response tertile (scores, 13-32, 33-45, 46-52; lower scores indicated worse function). There were statistically significant correlations between Self-Reported Functional Measure score and hours of personal assistance (P < 0.001), the number of affected limbs (P < 0.001), the amount of motor impairment (P < 0.001), and the amount of combined limbmotor impairment (P < 0.001). For example, 87% of people with the most limb-motor impairment (four affected limbs and no useful movement) were in the lowest Self-Reported Functional Measure tertile, compared with 3% of people in the least-affected category of limb-motor impairment. Furthermore, visual, sensory, or memory impairment did not influence the correlation between limbmotor impairment and Self-Reported Functional Measure score. The Self-Reported Functional Measure shows good concurrent and construct validities.


Strategies to Circumvent Testosterone Surge and Disease Flare in Advanced Prostate Cancer: Emerging Treatment Paradigms.
The testosterone surge and disease flare is a feared complication from initiation of gonadotropin-releasing hormone (GnRH) agonist treatment in advanced prostate adenocarcinoma. It is a common practice to start an average 7-day pretreatment regimen with an antiandrogen agent before initiating GnRH agonist therapy, to circumvent disease flare from testosterone surge. However, this might not be the best strategy and can be harmful, especially in patients at high risk of imminent organ damage from minimal testosterone surge. Surgical castration is a simple and cost-effective method that should be considered in these scenarios. But most patients refuse this procedure because of the permanent and psychologic impact of surgery. Novel GnRH antagonists, such as degarelix, and cytochrome P450 17 (CYP17) enzyme inhibitors, such as ketoconazole, achieve castrate-equivalent serum testosterone levels much faster than traditional GnRH agonists without the need for coadministration of antiandrogens. This article reports on 3 cases of impending oncologic emergencies in advanced prostate adenocarcinoma treated promptly with degarelix and ketoconazole without any disease flare related to testosterone surge. In the setting of symptomatic hormone-naïve metastatic prostate cancer, the authors suggest clinical trials using abiraterone, orteronel, and other newer agents that target the CYP17 axis (eg, ketoconazole) for fine-tuning the emergent medical castration methods and avoiding the dangers from the flare phenomenon.


Is Abnormal Urine Protein/Osmolality Ratio Associated with Abnormal Renal Function in Patients Receiving Tenofovir Disoproxil Fumarate?
Risk factors for and optimal surveillance of renal dysfunction in patients on tenofovir disoproxil fumarate (TDF) remain unclear. We investigated whether a urine protein-osmolality (P/O) ratio would be associated with renal dysfunction in HIV-infected persons on TDF. This retrospective, single-center study investigated the relationship between parameters of renal function (estimated glomerular filtration rate (eGFR) and P/O-ratio) and risk factors for development of kidney dysfunction. Subjects were HIV-infected adults receiving TDF with at least one urinalysis and serum creatinine performed between 2010 and 2013. Regression analyses were used to analyze risk factors associated with abnormal P/O-ratio and abnormal eGFR during TDF therapy. Patients were predominately male (81%); (65%) were Caucasian. Mean age was 45.1(±11.8) years; median [IQR] TDF duration was 3.3 years. [1.5-7.6]. Median CD4+ T cell count and HIV viral load were 451 cells/μL [267.5-721.5] and 62 copies/mL [0-40,150], respectively. Abnormal P/O-ratio was not associated with low eGFR. 68% of subjects had an abnormal P/O-ratio and 9% had low eGFR. Duration of TDF use, age, diabetes and hypertension were associated with renal dysfunction in this study. After adjustment for age, subjects on TDF > 5 years had almost a four-fold increased likelihood of having an abnormal P/O-ratio than subjects on TDF for < 1yr (OR 3.9; 95% CI 1.2-14.0; p = 0.024). Abnormal P/O-ratio is common in HIV-infected patients on TDF but was not significantly associated with low eGFR, suggesting that abnormal P/O-ratio may be a very early biomarker of decreased renal function in HIV infected patients.


Prevalence of celiac disease in latin america: a systematic review and meta-regression.
Celiac disease (CD) is an immune-mediated enteropathy triggered by the ingestion of gluten in susceptible individuals, and its prevalence varies depending on the studied population. Given that information on CD in Latin America is scarce, we aimed to investigate the prevalence of CD in this region of the world through a systematic review and meta-analysis. This was a two-phase study. First, a cross-sectional analysis from 981 individuals of the Colombian population was made. Second, a systematic review and meta-regression analysis were performed following the Preferred Reporting Items for Systematic Meta- Analyses (PRISMA) guidelines. Our results disclosed a lack of celiac autoimmunity in the studied Colombian population (i.e., anti-tissue transglutaminase (tTG) and IgA anti-endomysium (EMA)). In the systematic review, 72 studies were considered. The estimated prevalence of CD in Latin Americans ranged between 0.46% and 0.64%. The prevalence of CD in first-degree relatives of CD probands was 5.5%. The coexistence of CD and type 1 diabetes mellitus varied from 4.6% to 8.7%, depending on the diagnosis methods (i.e., autoantibodies and/or biopsies). Although CD seems to be a rare condition in Colombians; the general prevalence of the disease in Latin Americans seemingly corresponds to a similar scenario observed in Europeans.


Phosphodiesterase 10A levels are related to striatal function in schizophrenia: a combined positron emission tomography and functional magnetic resonance imaging study.
Pharmacological inhibition of phosphodiesterase 10A (PDE10A) is being investigated as a treatment option in schizophrenia. PDE10A acts postsynaptically on striatal dopamine signaling by regulating neuronal excitability through its inhibition of cyclic adenosine monophosphate (cAMP), and we recently found it to be reduced in schizophrenia compared to controls. Here, this finding of reduced PDE10A in schizophrenia was followed up in the same sample to investigate the effect of reduced striatal PDE10A on the neural and behavioral function of striatal and downstream basal ganglia regions. A positron emission tomography (PET) scan with the PDE10A ligand [11C]Lu AE92686 was performed, followed by a 6 min resting-state magnetic resonance imaging (MRI) scan in ten patients with schizophrenia. To assess the relationship between striatal function and neurophysiological and behavioral functioning, salience processing was assessed using a mismatch negativity paradigm, an auditory event-related electroencephalographic measure, episodic memory was assessed using the Rey auditory verbal learning test (RAVLT) and executive functioning using trail-making test B. Reduced striatal PDE10A was associated with increased amplitude of low-frequency fluctuations (ALFF) within the putamen and substantia nigra, respectively. Higher ALFF in the substantia nigra, in turn, was associated with lower episodic memory performance. The findings are in line with a role for PDE10A in striatal functioning, and suggest that reduced striatal PDE10A may contribute to cognitive symptoms in schizophrenia.


Heterogeneous Effects of Direct Hypoxia Pathway Activation in Kidney Cancer.
General activation of hypoxia-inducible factor (HIF) pathways is classically associated with adverse prognosis in cancer and has been proposed to contribute to oncogenic drive. In clear cell renal carcinoma (CCRC) HIF pathways are upregulated by inactivation of the von-Hippel-Lindau tumor suppressor. However HIF-1α and HIF-2α have contrasting effects on experimental tumor progression. To better understand this paradox we examined pan-genomic patterns of HIF DNA binding and associated gene expression in response to manipulation of HIF-1α and HIF-2α and related the findings to CCRC prognosis. Our findings reveal distinct pan-genomic organization of canonical and non-canonical HIF isoform-specific DNA binding at thousands of sites. Overall associations were observed between HIF-1α-specific binding, and genes associated with favorable prognosis and between HIF-2α-specific binding and adverse prognosis. However within each isoform-specific set, individual gene associations were heterogeneous in sign and magnitude, suggesting that activation of each HIF-α isoform contributes a highly complex mix of pro- and anti-tumorigenic effects.


Alterations in protective enzymes against peroxidation in the central and peripheral nervous system of control and dysmyelinating mutant mice.
The activities of peroxide-detoxifying enzymes such as superoxide dismutase (SOD), glutathione peroxidase, glutathione reductase, and catalase were measured in the nervous system of neurological dysmyelinating mutants: quaking (Qk), shiverer (Shi), and trembler (Tr) mice. Cu/Zn-SOD activity was higher in the cerebellum of Qk and Shi mice (by 53% and 106%, respectively) in comparison with controls, but it was the same in the cerebellum of Tr mice and their corresponding controls. In contrast, there was no difference in the level of Cu/Zn-SOD activity in the cerebrum of Qk, Shi, and Tr mice and their respective controls. Mn-SOD activity was the same among all the mutants compared to control animals in both cerebrum and cerebellum. In Shi cerebellum, glutathione peroxidase and glutathione reductase activities were slightly decreased (a 21.6% and a 13.2% diminution, respectively), whereas catalase activity in cerebrum and cerebellum was the same among mutants and control mice. In the sciatic nerve from Tr mice, all the enzymatic activities were enhanced: sixfold increase for total SOD, and 2.4-fold, 3.5-fold, and 1.8-fold increase for glutathione peroxidase, glutathione reductase, and catalase, respectively.