Feasibility and delivery of patient-reported outcomes in clinical practice among racially diverse bladder and prostate cancer patients.
To assess the feasibility of enrollment and collecting patient-reported outcome (PRO) data as part of routine clinical urologic care for bladder and prostate cancer patients and examine overall patterns and racial variations in PRO use and symptom reports over time. We recruited 76 patients (n = 29 Black and n = 47 White) with prostate or bladder cancer at a single, comprehensive cancer center. The majority of prostate cancer patients had intermediate risk (57%) disease and underwent either radiation or prostatectomy. Over half (58%) of bladder cancer patients had muscle invasive disease and underwent cystectomy. Patients were asked to complete PRO symptom surveys using their preferred mode [web- or phone-based interactive voice response (IVR)]. Symptom summary reports were shared with providers during visits. Surveys were completed at 3 time points and assessed urinary, sexual, gastrointestinal, anxiety/depression, and sleep symptoms. Feasibility of enrollment and survey completion were calculated, and linear mixed effects models estimated differences in outcomes by race and time. Sixty three percent of study participants completed all PRO measures at all 3 time points. Black patients were more likely to select IVR as their survey mode (40% vs. 13%, P < 0.05), and less likely to complete all surveys (55% vs. 74%, P = 0.13). Patients using IVR were also less likely to complete all surveys (41% vs. 69%, P = 0.046). Reported preferences for survey mode and completion rates differ by race, which may influence survey completion rates and highlight potential obstacles for equitable implementation of PROs into clinical care.


Digital holographic microscope with automatic focus tracking by detecting sample displacement in real time.
We propose a new method for focus tracking during the recording of a sequence of digital holograms while the sample experiences axial displacement. Corrected reconstruction distances can be automatically calculated, and well-focused amplitude and phase-contrast images can be obtained for each digitized hologram. The method is demonstrated for inspection of microelectromechanical systems subjected to thermal load. The method can be applied as a quasi-real-time procedure.


[Maxillary advancement osteotomy with sequelae cleft lip and palate: Dilemma between occlusion and aesthetic profile].
Maxillary hypoplasia is a common sequela of cleft lip and palate. Its surgical treatment consists in a maxillary advancement by distraction or by conventional orthognathic surgery but morphological results are unpredictable. Our goal in this study was to see if the esthetical results (on the lip and the nose) of maxillary advancement were correlated to the preservation of lateral incisor space of the cleft side. This retrospective study included 38 patients operated between 2002 and 2013. Unilateral clefts were studied independently from bilateral clefts. Profile aesthetics was evaluated independently and subjectively by two surgeons and scored on an 8-point scale. The result was classified as "good" if the score was superior or equal to 6. The score was correlated to the following parameters: amount of maxillary advancement, upper incisor axis, preservation of the missing lateral incisor space. In the "good result" group, the space of the lateral incisor was less often preserved. The nasolabial angle was more open and the upper central incisor axis more vertical. These results were more pronounced in bilateral clefts, but also found in unilateral clefts. Under reservation of the subjective evaluation and of the small number of patients, it seemed that lateral incisor space closure improved the profile of patients treated by maxillary advancement for cleft lip and palate sequelae.


Colorectal cancer and risk of atrial fibrillation and flutter: a population-based case-control study.
Colorectal cancer has recently been associated with an increased atrial fibrillation risk, but evidence is very sparse. So, we conducted a population-based case-control study in northern Denmark (population 1.7 million) during 1998-2006 to estimate the atrial fibrillation/flutter risk in colorectal cancer patients. We identified 28,333 atrial fibrillation/flutter cases and 283,260 sex-, age-, and county-matched population controls. We searched the databases for a prior colorectal cancer diagnosis, a prior cancer diagnosis other than colorectal cancer, and performance of surgery within 30 days prior to atrial fibrillation/flutter. We used conditional logistic regression to estimate the OR of atrial fibrillation/flutter in patients with colorectal cancer, cancers other than colorectal and in patient with surgery. Among cases, 0.59% (n = 168) had a colorectal cancer diagnosis within 90 days before their atrial fibrillation/flutter diagnosis, compared with 0.05% (n = 155) of controls (adjusted OR = 11.8; 95% CI 9.3-14.9). Beyond the first 90 days after a colorectal cancer diagnosis, atrial fibrillation/flutter risk was no longer increased. There was likewise an increased atrial fibrillation/flutter risk in patients diagnosed with another cancer form in the prior 90 days (OR = 7.0, 95% CI 6.3-7.8). Furthermore, the atrial fibrillation/flutter risk was elevated fivefold in patients who had undergone surgery, whether or not cancer-related. We therefore conclude that colorectal cancer patients are at increased atrial fibrillation/flutter risk exclusively in the first 90 days after cancer diagnosis, but to no greater an extent than are patients with other cancers. The performance of surgery probably plays an important role in this association.


Levels of personhood: a model for dementia care.
"Personhood" is a concept that may be seen as insignificant to health care delivery, yet it has strong relevance to people suffering from dementia in nursing home settings. When the dementia disease process negatively affects residents' cognition, memory, and the ability to communicate effectively, nursing home caregivers may approach care in a paternalistic manner, similar to a parent's authority over a child. Based on attributes of personhood identified in the literature, 3 levels of personhood are defined, discussed, and related to the naturally occurring dementia disease progression. Challenges to, and benefits of, the promotion of personhood in current nursing home dementia care are discussed. The author proposes a Personhood Model for Dementia Care that is based on the 3 identified levels of personhood. The model provides a structure for organizing existing person-centered interventions and strategies in dementia care. In addition, the proposed model provides a framework for understanding and testing the potential value and significance of future person-centered interventions as they are developed and implemented.


Hydroxyapatite-fucoidan nanocomposites for bone tissue engineering.
Hydroxyapatite (HAp) is the promising biomaterials to construct the article bone from the last two decades. In the present study, we have developed hydroxyapatite-fucoidan (HApF) nanocomposite for bone tissue engineering and subsequently characterized by different analytical techniques for bone graft substitute. The chemical characterization suggested that the prepared nanocomposite HApF have amorphous nature, crystal size between 41 and 153 nm was observed. The biochemical characterization inferred that the prepared nanocomposite were non-toxic and mineralization effect of HApF was observed two times higher then HAp. Hence, HApF is the promising biomaterial and could be used for bone tissue construct.


Acetylsalicyclic acid restores acute insulin response reduced by furosemide in man.
Prostaglandin E (PGE) infusion in normal man inhibits the acute insulin response to glucose. In order to determine whether endogenously released PGE might also inhibit insulin secretion, glucose-stimulated insulin responses were investigated in normal volunteers after furosemide (40 mg i.v.), a stimulator of endogenous PGE synthesis. Acute insulin response to glucose (20 g i.v.) was significantly reduced by furosemide (response before furosemide: 36 +/- 5 muU/ml; after furosemide: 26 +/- 5 muU/ml, m +/- SE, mean change 3--10 min, N = 8, P less than 0.01), whereas glucose disappearance rates were not modified after furosemide. Infusion of lysine acetylsalicylate (LAS), an inhibitor of endogenous PGE synthesis, completely reversed the inhibitory effect of furosemide on insulin secretion and also augmented acute insulin response to glucose (response before furosemide + LAS: 41 +/- 6 muU/ml; during furosemide + LAS: 50 +/- 7 muU/ml, N = 10, P less than 0.02). This effect was associated with an increase in glucose disappearance rates (P less than 0.05). These findings demonstrate that (1) furosemide inhibits glucose-induced acute insulin responses and (2) LAS completely reverses the inhibitory effect of furosemide and also accelerates glucose disposal. It is suggested that furosemide acts via the release of endogenous PGEs, which are known to inhibit insulin responses in man.


EGFR and KRAS in colorectal cancer.
The epidermal growth factor receptor (EGFR) is recognized as an important player in colorectal cancer (CRC) initiation and progression. This membrane-bound receptor tyrosine kinase (RTK) has therefore become a key target of therapeutic strategies designed to treat metastatic CRC, in particular with monoclonal antibodies (mAbs) against the extracellular domain of the receptor. KRAS is an effector molecule responsible for signal transduction from ligand-bound EGFR to the nucleus. Activating mutations in KRAS are recognized as a strong predictor of resistance to EGFR-targeted mAbs. Routine testing of all patients with CRC for KRAS mutations is now recommended; only those harboring wild-type (WT) KRAS should be candidates for such therapies, thus improving outcomes, and minimizing unnecessary toxicity and cost. Even though the identification of the importance of KRAS status has marked a turning point in the treatment of metastatic CRC (mCRC), it is becoming apparent that other critical elements in the complex signaling pathways related to EGFR may also contribute vital information that will aid in treatment decisions and ultimately benefit patients.


[Telangiectasia during amlodipine therapy].
Calcium inhibitors are recommended as first-line treatment in hypertension. We report the development of telangiectasia on the trunk and upper limbs in a female patient on amlodipine (Amlor(®)) that subsided on treatment discontinuation. A 63-year-old woman consulted for numerous asymptomatic stellate telangiectasias on her upper trunk and shoulders, with sparing of the face. No Darier's sign was seen and clinical examination was otherwise normal. The patient had been treated with amlodipine (Amlor(®)) and a combination of bisoprolol and hydrochlorothiazide (Lodoz(®)) for 5years for essential hypertension. Laboratory tests, which included serum tryptase assay, were normal. Histological analysis showed a normal epidermis with dilated superficial dermal capillaries and no inflammatory infiltrate or dermal elastosis. Amlodipine was discontinued and replaced with ramipril (an ACE inhibitor). The other treatments were changed over and the telangiectasias regressed spontaneously within several months, with no relapse being seen at one year of follow-up. Reports of telangiectasia associated with calcium inhibitors most commonly involve the dihydropyridine family, of which amlodipine is a member. Inhibition of muscular contraction induced by this treatment results in vasodilatation, accounting for the associated antihypertensive properties, and this could play a role in telangiectasia formation. The literature contains reports of cases of photo-distributed telangiectasia, suggesting that as well as vasodilatation, calcium inhibitors may in certain cases cause abnormal sensitivity of blood vessels to ultraviolet radiation. The absence of facial lesions rules out the hypothesis of photo-induced lesions in our patient.


Langerhans' cell histiocytosis with bilateral temporal bone involvement.
Langerhans' cell histiocytosis (LCH) is a rare disease with variable clinical appearance. The etiology of LCH remains unclear to date. It is currently believed that clonal accumulation and proliferation of CD1a-positive Langerhans' cells are causative. A 2-year-old boy presented with hypacusis and disturbance of balance. Auditory brainstem-evoked responses (ABRs) revealed severe bilateral labyrinthine hearing loss. Magnetic resonance imaging (MRI) showed inflammatory changes with bone erosion in both temporal bones including labyrinthine systems and mastoid processes. During bilateral surgical exploration, fragile slightly yellowish tissue with necrotic areas was found that turned out to be LCH on histology. Chemotherapy with vinblastine and prednisone was subsequently initiated, leading to continuing complete remission. The initial presentation of LCH with bilateral temporal bone involvement is a very rare condition. The signs and symptoms of otologic histiocytosis can mimic those of acute and chronic infectious ear disease. Only a surgically obtained biopsy leads to definitive diagnosis and appropriate therapy.


Long-term safety and efficacy results of once-daily emtricitabine-based highly active antiretroviral therapy regimens in human immunodeficiency virus-infected pediatric subjects.
The purpose of this work was to obtain long-term safety and efficacy data for antiretroviral regimens containing emtricitabine in HIV-infected pediatric subjects and confirm that a pediatric dose of 6 mg/kg once daily would provide steady-state emtricitabine concentrations comparable to those observed in adults given 200 mg of emtricitabine once daily. HIV-infected subjects between 3 months and 16 years of age were enrolled, including 71 antiretroviral-naïve subjects and 45 antiretroviral-experienced subjects. Naive subjects received emtricitabine plus stavudine plus lopinavir or ritonavir. Experienced subjects replaced the lamivudine in their existing regimens with emtricitabine. Tolerance, safety, disease progression, and virologic and immunologic responses were evaluated. The Kaplan-Meier probability of persistent virologic response in the intent-to-treat population through week 164 at < or = 400 copies per mL and < or = 50 copies per mL was 74% and 62%, respectively. Three subjects (3%) discontinued the study for adverse events, 8 (7%) for virologic failure, and 1 died through a median follow-up of 164 weeks. The annualized incidence rate of grade 3 to 4 adverse events and grade 3 to 4 laboratory abnormalities was 6% and 3%, respectively. The annualized incidence rate of serious adverse events was 9%, with 1% attributed as related to emtricitabine. Genotypic analysis showed the emergence of the M184V mutation in 4 of the 15 subjects who experienced virologic failure through week 164. Pharmacokinetic evaluation demonstrated plasma drug exposures in these children comparable to adults receiving the approved dose of 200 mg once daily. These results demonstrate the safety and efficacy of emtricitabine in pediatric patients. They also support that the safety and efficacy profile of emtricitabine in children is similar to that demonstrated in adults.


Prevalence of brain and spinal cord inclusions, including dipeptide repeat proteins, in patients with the C9ORF72 hexanucleotide repeat expansion: a systematic neuropathological review.
The current literature shows no consensus on the localization and number of characteristic neuronal inclusions [p62 and dipeptide repeat proteins (DRPs) positive, TDP-43-negative and TDP-43 positive] in the brain and spinal cord of patients with the hexanucleotide repeat expansion on chromosome 9 (C9ORF72-positive patients). This may be due to small sample sizes. A valid brain map of the inclusions in C9ORF72-positive patients may improve clinicopathological correlations and may serve as a reference for neuropathologists. We performed a systematic review on 42 pathological studies to assess the pooled prevalence rates and density (a measure of the number of inclusions per brain region) of (phosphorylated)-TDP-43, p62 and DRP neuronal inclusions in seven brain regions and the spinal cord of 261 C9ORF72-positive patients with amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and ALS-FTD. In the cerebellum and hippocampus, the pooled prevalence rates of TDP-43 neuronal cytoplasmic inclusions (NCIs; cerebellum: 3.9%; hippocampus: 68.3%) were lower than those of DRP (cerebellum: 97.2%; hippocampus 97.1%). Moreover, TDP-43 inclusion density was lower compared with p62 inclusion density in these regions. The pooled prevalence rate of TDP-43 NCI in the substantia nigra was high (94.4%). The findings of this systematic review largely confirm findings of previous smaller studies on the localization and prevalence of inclusions in the central nervous system of C9ORF72-positive patients. The high prevalence of TDP-43 inclusions in the substantia nigra is a relatively new finding and is probably related to the relatively high prevalence of parkinsonism in C9ORF72-positive patients.


Optical coherence tomography of basal cell carcinoma: density and signal attenuation.
Basal cell carcinoma (BCC) is the most prevalent malignancy in Caucasians. Optical coherence tomography (OCT) is a non-invasive optical imaging technology using the principle of interferometry. OCT has shown a great potential in diagnosing, monitoring, and follow-up of BCC. So far most OCT studies on the subject of BCC have had a qualitative focus, i.e. on morphological analysis of the OCT images. The aim of this study was to explore the use of quantitative OCT measurements, density, and attenuation coefficient in BCC lesions as a way to improve the OCT evaluation of BCC. The study was based on OCT images of 58 histologically verified BCC lesions and the corresponding normal adjacent skin. The study population was divided into two groups based on the OCT morphology of the BCC lesions: the "Disrupt BCC group" and the "Nodular BCC group". Density and attenuation coefficients were measured in the OCT images by specially designed software and the regions of interests (ROI) were placed directly on (ROI1) and under the visible BCC lesions (ROI2). The results were compared to the OCT images of normal adjacent skin. Disrupt BCC group: The densities of BCC lesions were significant lower (P = 0.002), than the normal skin in ROI1. Attenuation measurements were found to be significantly greater (P = 0.012) in BCC lesions compared to normal skin in ROI1. Nodular BCC group: Attenuation measurements were found to be significantly lower (P = 0.017) in BCC lesions compared to normal skin in ROI1. Our study suggests a quantitative potential of OCT in the context of BCC. This study is exploratory and requires independent verification.


Edoxaban treatment in atrial fibrillation in routine clinical care: One-year outcomes of the prospective observational ETNA-AF study in South Korean patients.
The real-world outcomes of edoxaban treatment in patients with atrial fibrillation (AF) were analyzed in the ETNA-AF (Edoxaban Treatment in Routine Clinical Practice) study involving data from multiple regional registries. This report addresses effectiveness and safety of edoxaban in the Korean ETNA-AF population. One-year data from 1887 Korean ETNA-AF participants were analyzed according to edoxaban dose and patient age and compared with results of other ETNA-AF registries. Approximately 70% of patients received the recommended doses of edoxaban (60 mg/30 mg); non-recommended 60 mg and 30 mg doses were prescribed to 9.6% and 19.8% of the patients, respectively. The proportions of reference age (<65 years), youngest-old (65-74 years) and middle-old/oldest-old (≥75 years) groups were 21.4%, 40.2%, and 38.4%, respectively. Incidence of major or clinically relevant nonmajor bleeding was similar within dose (0.57%-1.71%) and age subgroups (1.26%-1.63%). Incidence of net clinical outcome, a composite of stroke, systemic embolic event, major bleeding, and all-cause mortality, was also comparable among dose subgroups (1.14%-3.10%) and age subgroups (2.28%-2.78%). The percentage of Korean patients receiving non-recommended 30 mg (19.8%) was over twice that of the European population (8.4%). However, the clinical outcomes were generally similar among different populations included in the ETNA-AF study. The outcomes in the Korean ETNA-AF population are like those in the global ETNA-AF population, with overall low event rates of stroke, major bleeding and all-cause mortality across age and dose subgroups. Edoxaban can be used effectively and safely in specific populations of Korean AF patients, including the elderly.


Pollen proteomics: from stress physiology to developmental priming.
Pollen development and stress. In angiosperms, pollen or pollen grain (male gametophyte) is a highly reduced two- or three-cell structure which plays a decisive role in plant reproduction. Male gametophyte development takes place in anther locules where diploid sporophytic cells undergo meiotic division followed by two consecutive mitotic processes. A desiccated and metabolically quiescent form of mature pollen is released from the anther which lands on the stigma. Pollen tube growth takes place followed by double fertilization. Apart from its importance in sexual reproduction, pollen is also an interesting model system which integrates fundamental cellular processes like cell division, differentiation, fate determination, polar establishment, cell to cell recognition and communication. Recently, pollen functionality has been studied by multidisciplinary approaches which also include OMICS analyses like transcriptomics, proteomics and metabolomics. Here, we review recent advances in proteomics of pollen development and propose the process of developmental priming playing a key role to guard highly sensitive developmental processes.


Effectiveness, safety, and pharmacokinetics of quetiapine in aggressive children with conduct disorder.
To provide an initial description of the effectiveness and pharmacokinetics (PK) of quetiapine in aggressive children with conduct disorder (CD). This 8-week, open-label outpatient trial, enrolled patients ages 6 to 12 years with CD. Outcome measures included the Rating of Aggression Against People and/or Property Scale (RAAPPS), Nisonger Child Behavior Rating Form (NCBRF), and the Conners Parent Rating Scale (CPRS-48). Blood sampling for PK analyses occurred at the end of weeks 2 and 8. Seventeen children (16 boys, mean age 8.9 years) were treated. The mean dose at week 8 was 4.4 mg/kg (SD = 1.1 mg/kg). Significant decreases in the baseline scores of the RAAPPS, and several subscales of the NCBRF and the CPRS were found by the end of the study (p <.05). No patients discontinued because of an adverse event. No patients experienced extrapyramidal side effects. Quetiapine disposition was linear over the dose range studied. The elimination half-life of the drug averaged 3.9 and 2.9 hours and total body clearance averaged 3.5 and 3.0 L/hr/kg after study weeks 2 and 8, respectively. These preliminary data suggest that aggressive children with CD may benefit from quetiapine. The PK of quetiapine supports twice-daily dosing in children with CD.


Role of intestinal mucus in crystal biogenesis: an electron-microscopical, diffraction and X-ray microanalytical study.
In the posterior intestine of the sea-water eel, mucus plays an important role in biocrystallization of calcium ions. By means of transmission and scanning electron microscopy associated with X-ray microanalysis and X-ray diffraction it has been possible to determine the role of mucous fibers as nucleation sites. Biocrystallization occurs in 2 steps: (1) Calcification of mucus. As soon as mucus is excreted in the intestinal lumen, it is loaded with calcium, as shown by lanthanum affinity and X-ray microanalysis on freeze-dried tissues. (2) Genesis of crystals. Needle-shaped crystallites build up in coalescent spherites in the intestinal lumen near the microvilli. Genesis occurs as follows: (a) crystallite mineralization by nucleation in an organic matrix composed of glycoproteinaceous mucous fibers, followed by the appearance of spherites; (b) coalescence in spherites and association of spherites in rhombohedra; (c) extrusion of organic material during the final step of crystallization.


Mutagenic effects of thiram in mammalian somatic cells.
The dimethylthiocarbamate fungicide thiram has been found to be a potent and direct inducer of point mutations at the hypoxanthine-guanine phosphoribosyl transferase (HGPRT) locus in Chinese hamster cells in vitro. It also increased the incidence of micronuclei in polychromatic erythrocytes in the bone marrow of mice given a single ip dose of 100 mg/kg. Both the in vitro and the in vivo mutagenic responses were observed with doses of thiram that were cytotoxic.


Synthesis and regional rat brain distribution of [11C]MDL 72222: a 5HT3 receptor antagonist.
MDL 72222, an antagonist of 5HT3 receptors, was labeled with a specific radioactivity of 340-400 mCi/mumol by alkylation of the nor-precursor with [11C]CH3I. The yield of the synthesis, starting from [11C]methyliodide to the purified product and corrected for decay, was good approximately 70-75%. After i.v. injection, [11C]MDL 72222 diffuses readily in the central nervous system but is not detected as metabolites in brain and blood, during 1 h study carried out in rats. The time course and distribution of [11C]MDL 72222 was assessed in various organs (liver, lung, kidney, heart, whole brain) and in blood; the organ uptake was rapid and large; the highest accumulation was found in the lung. The regional brain distribution shows initial uptake and subsequent retention of tracer in favor of the cerebral cortex. The level of brain radioactivity was not reduced by pretreatment with a 1000-fold excess of unlabeled MDL 72222. These results suggest that [11]MDL 72222 is of limited interest for 5HT3 receptor binding studies in brain in vivo, presumably mainly because of large non-specific binding.


Quality and equity of primary care with patient-centered medical homes: results from a national survey.
The patient-centered medical home (PCMH) model has gained support, but the impact of this model on the quality and equity of care merits further evaluation. To determine if PCMHs are associated with improved quality and equity in pediatric primary care. Using the 2007/2008 National Survey of Children's Health, a nationally representative survey of parents/guardians of children (age, 0-17 y), we evaluated the association of PCMHs with 10 quality-of-care measures using multivariable regression models, adjusting for demographic and socioeconomic covariates. For quality indicators that were significantly associated with medical homes, we determined if this association differed by race/ethnicity. Compared with children without medical homes, those with medical homes had significantly better adjusted rates for 6 of 10 quality measures (all P≤0.02), such as obtaining a developmental history [adjusted rates % (SE): 41.7 (1.3) vs. 52.0 (1.1), P<0.001]. Having a medical home was associated with better adjusted rates of receiving a developmental history exam for both white and black children, but the disparity between these groups was not significantly narrowed [difference in risk differences (SE): 0.9 (4.3) for whites vs. blacks; P=0.83]. Our results underscore the benefits of the medical home model for children while highlighting areas for improvement, such as narrowing disparities. Our findings also emphasize the key role of patient experience measures in the evaluation of medical homes.


Common and distinct networks for self-referential and social stimulus processing in the human brain.
Self-referential processing is a complex cognitive function, involving a set of implicit and explicit processes, complicating investigation of its distinct neural signature. The present study explores the functional overlap and dissociability of self-referential and social stimulus processing. We combined an established paradigm for explicit self-referential processing with an implicit social stimulus processing paradigm in one fMRI experiment to determine the neural effects of self-relatedness and social processing within one study. Overlapping activations were found in the orbitofrontal cortex and in the intermediate part of the precuneus. Stimuli judged as self-referential specifically activated the posterior cingulate cortex, the ventral medial prefrontal cortex, extending into anterior cingulate cortex and orbitofrontal cortex, the dorsal medial prefrontal cortex, the ventral and dorsal lateral prefrontal cortex, the left inferior temporal gyrus, and occipital cortex. Social processing specifically involved the posterior precuneus and bilateral temporo-parietal junction. Taken together, our data show, not only, first, common networks for both processes in the medial prefrontal and the medial parietal cortex, but also, second, functional differentiations for self-referential processing versus social processing: an anterior-posterior gradient for social processing and self-referential processing within the medial parietal cortex and specific activations for self-referential processing in the medial and lateral prefrontal cortex and for social processing in the temporo-parietal junction.


Identification of potential pseudogenes for predicting the prognosis of hepatocellular carcinoma.
Hepatocellular carcinoma (HCC) remains a highly deadly malignant tumor with high recurrence and metastasis rates. Cancer stem cells (CSCs) are involved in tumor metastasis, recurrence, and resistance to drugs, which have attracted widespread attention in recent years. Research has shown that pseudogenes may regulate stemness to promote the progression of HCC, but its specific mechanisms and impact on prognosis remain unclear. In this study, clinical prognosis information of HCC was first downloaded from The Cancer Genome Atlas (TCGA) database. Then we calculated the mRNA expression-based stemness index (mRNAsi) of HCC. We also screened the differentially expressed pseudogene (DEPs) and conducted univariate Cox regression analysis to investigate their effect on the prognosis of HCC. Further, genomic mutation frequency analysis and weighted gene co-expression network analysis (WGCNA) were performed to compare the role of pseudogenes and stemness in promoting the progression of HCC. Finally, we conducted the correlation analysis to examine the potential mechanism of pseudogenes regulating stemness to promote the progression of HCC and detected the possible pathways through the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Herein, we revealed that the high stemness of HCC correlated with an unfavorable prognosis. We obtained 31 up-regulated and 8 down-regulated DEPs in HCC and screened CTB-63M22.1, a poor prognostic indicator of HCC. In addition, CTB-63M22.1 had a mutation frequency similar to mRNAsi and acted in a module similar to that of mRNAsi on HCC. We then screened two RNA-binding proteins (RBPs) LIN28B and NOP56 with the highest correlation with stemness. We also discovered that they were primarily enriched in the biological process as examples of mitotic nuclear division and cell cycle. Collectively, these results revealed that pseudogenes CTB-63M22.1 may regulate cancer stemness by regulating RBPs, suggesting that CTB-63M22.1 may serve as an innovative therapeutic target and a reliable prognostic marker for HCC.


Interferon alfa-2a in the treatment of exudative age-related macular degeneration.
Nineteen patients (20 eyes) with the exudative form of macular degeneration were treated with parenteral interferon alfa-2a. Fifteen patients (16 eyes) had adequate follow-up for evaluation of outcome of the exudative macular lesion. The average follow-up was 8 months (range 5-11 months). Color photographs and fluorescein angiograms were evaluated independently by two masked readers for change in size, presence of fibrosis, and leakage of the neovascular lesion. During the follow-up, none of the exudative lesions resolved: one lesion became smaller, four remained the same, nine enlarged, and two could not be graded based on the photographs. Visual acuity remained 20/40 or better in four eyes. The proportion of eyes with visual acuity of 20/200 or worse increased from 35% at the initial visit to 59% at the final visit. Ten patients experienced significant but reversible side effects, including weight loss, depression, and/or hematopoietic suppression. The data from these cases do not support any significant treatment benefit from interferon alfa-2a at the doses used in exudative macular degeneration.


Coordinate expression of beta1 integrins and their regulator, TGF beta2 at the floor plate of the medulla oblongata is correlated with the crossing of the fibers of olivocerebellar projection in mice.
During embryonic day 11 (E11) to E16, contact-dependent interacting molecules beta1 integrins and their putative regulator TGF beta2 are coordinately expressed at the floor plate in the caudal part of mouse myelencephalon. Their expression disappears at E18. Consistent with the peak of their expression (E13-E16), olivocerebellar fibers primarily cross the floor plate. These data indicate that spatiotemporal expression of beta1 integrins and TGF beta2 is correlated with the crossing of olivocerebellar fibers.


High-throughput screening assays for antibacterial and antifungal activities of Lactobacillus species.
We describe high-throughput screening techniques to rapidly detect either antimicrobial activity, using an agar-well diffusion assay in microtiter plates, or antifungal activity using an agar-spot assay in 24-well plates. 504 Lactobacillus isolates were screened with minimal laboratory equipment and screening rates of 2000-5000 individual antimicrobial interactions.


Contribution of research networks to a clinical trial of antidepressants in people with dementia.
The Mental Health Research Network and Dementia and Neurodegenerative Diseases Research Network were established in the UK to increase research capacity and activity; the former in mental health generally, and the latter specifically in neurodegenerative disorders including dementia. Little evidence exists on the impact of these networks on research in mental health of older people. To examine research network support to a multi-centre randomised controlled trial of antidepressants in people with depression superimposed on dementia. Method Qualitative questionnaires were completed by principal investigators, trial-funded research workers and clinical study officers (CSOs) of the research networks. Research network contribution was much valued by principal investigators and the nine research teams. CSOs boosted the recruitment campaign in a challenging environment and enhanced assessment processes. Some problems with consistency and staff turnover were raised. Research network input can make an appreciable difference to the process and outcome of a multi-centre clinical trial.


Metabolism of ether glycolipids with potentially antineoplastic activity by Ehrlich ascites tumor cells.
Ehrlich ascites tumor cells were incubated in vitro with rac-1-O-[1'-14C]octadecyl-2-O-methylglycero-3-beta-D-glucopyranosi de for 24 h. The potentially antineoplastic ether glycolipid was rapidly metabolized by the cells to radioactive 1-O-octadecyl-2-O-methylglycerol (70 pmol/10(6) cells per h) and further acylated to 1-O-octadecyl-2-O-methyl-3-acylglycerols. Incubation of Ehrlich ascites cells with synthetic rac-1-O-[1'-14C]octadecyl-2-O-methyl-3-palmitoylglycerol showed that this metabolite is reconverted by deacylation to 14C-labeled 1-O-octadecyl-2-O-methylglycerol. The latter compound or a metabolite derived therefrom may be the 'toxic principle' of both the ether glyceroglycolipids and ether glycerophospholipids having a 1-O-alkyl-2-O-methylglyceryl moiety, as suggested by Unger et al. (J. Natl. Cancer Inst. 78 (1987) 219-222).


Differential immunolocalization of VEGF in rat and human adult lung, and in experimental rat lung fibrosis: light, fluorescence, and electron microscopy.
Vascular endothelial growth factor (VEGF) is a cytokine with main angiogenetic functions in embryonic development and tumor-formation. In the adult lung, reports of the localization of VEGF were controversial. A precise cell typing of VEGF-positive pulmonary cells is still lacking. Nothing is known about a potential role in pulmonary fibrosis. Immunohistochemistry (IH), double immunofluorescence microscopy (DIF), and immunoelectron microscopy (IEM) were used to study the differential distribution of VEGF in paraffin-embedded (IH, DIF) and in cryo-substituted, Lowicryl-embedded (IEM) specimens of normal rat and human lungs and fibrotic rat lungs. Fibrosis was induced by intratracheal bleomycin treatment. IH and DIF showed that VEGF was present in surfactant protein (SP) D-positive alveolar type II pneumocytes, bronchiolar Clara cells, smooth muscle (SM) cells, and alpha-SM actin-positive myofibroblasts of normal rat and human lungs. Fibrotic lesions in bleomycin-treated rat lungs were rich in VEGF-positive cells presenting with a heterogeneous phenotype (mainly SP-D-positive type II pneumocytes, alpha-SM actin-positive myofibroblasts). There were no signs of angiogenesis. Post-embedding immunogold labeling using protein A-gold and IgG-gold technique revealed a specific localization of VEGF to mitochondria, Clara cell secretory granules, and capillary interendothelial cell junctions. The predominant localization of VEGF to bronchiolar and alveolar epithelial and alpha-SM actin-positive cells, and the marked increase of VEGF-positive type II pneumocytes and myofibroblasts in fibrotic lung lesions, indicate that in adult lungs VEGF is involved in processes other than angiogenesis.


mTOR Inhibitors Prevent CMV Infection through the Restoration of Functional αβ and γδ T cells in Kidney Transplantation.
The reported association of mTOR-inhibitor (mTORi) treatment with a lower incidence of cytomegalovirus (CMV) infection in kidney transplant recipients (KTR) who are CMV seropositive (R+) remains unexplained. The incidence of CMV infection and T-cell profile was compared between KTRs treated with mTORis and mycophenolic acid (MPA), and in vitro mTORi effects on T-cell phenotype and functions were analyzed. In KTRs who were R+ and treated with MPA, both αβ and γδ T cells displayed a more dysfunctional phenotype (PD-1+, CD85j+) at day 0 of transplantation in the 16 KTRs with severe CMV infection, as compared with the 17 KTRs without or with spontaneously resolving CMV infection. In patients treated with mTORis (n=27), the proportion of PD-1+ and CD85j+ αβ and γδ T cells decreased, when compared with patients treated with MPA (n=44), as did the frequency and severity of CMV infections. mTORi treatment also led to higher proportions of late-differentiated and cytotoxic γδ T cells and IFNγ-producing and cytotoxic αβ T cells. In vitro, mTORis increased proliferation, viability, and CMV-induced IFNγ production of T cells and decreased PD-1 and CD85j expression in T cells, which shifted the T cells to a more efficient EOMESlow Hobithigh profile. In γδ T cells, the mTORi effect was related to increased TCR signaling. Severe CMV replication is associated with a dysfunctional T-cell profile and mTORis improve T-cell fitness along with better control of CMV. A dysfunctional T-cell phenotype could serve as a new biomarker to predict post-transplantation infection and to stratify patients who should benefit from mTORi treatment. Proportion of CMV Seropositive Kidney Transplant Recipients Who Will Develop a CMV Infection When Treated With an Immunosuppressive Regimen Including Everolimus and Reduced Dose of Cyclosporine Versus an Immunosuppressive Regimen With Mycophenolic Acid and Standard Dose of Cyclosporine A (EVERCMV), NCT02328963.


Renal involvement and circulating immune complexes in dermatitis herpetiformis.
A fine-needle kidney biopsy was performed on eleven patients with dermatitis herpetiformis (DH) who had no previous signs or symptoms of renal disease. Of the eight patients whose biopsy specimens were representative, electron microscopic examination showed mesangial deposits in five. A subsequent conventional renal biopsy was obtained from one of these five, and immunofluorescence microscopy revealed IgA and complement deposits in the glomeruli. Renal involvement was not related either to the degree of jejunal villous atrophy or to the deposition of IgA and complement in the skin. Glomerular deposits, however, were associated with a high frequency of circulating IgA and IgG class immune complexes and IgA class antigliadin and antireticulin antibodies. These results suggest that, in DH, immune complexes or antibodies derived from the gut can be deposited in the kidney.


Hyperinsulinemic hypoglycemia with nesidioblastosis: histologic features and growth factor expression.
Hypoglycemia secondary to nesidioblastosis is rare in adults, and the pathogenesis of this condition is unknown. To determine factors leading to nesidioblastosis in adults, we analyzed 36 cases of nesidioblastosis including 27 cases of postgastric bypass nesidioblastosis and 9 cases of idiopathic nesidioblastosis in adults by immunohistochemistry using antibodies to insulin-like growth factor 1, insulin-like growth factor 2 (IGF2), insulin-like growth factor one receptor-alpha epidermal growth factor receptor, transforming growth factor-beta1 and 2, and transforming growth factor-beta receptor type 3. Fifty-two surgically excised pancreatic specimens from patients with benign exocrine tumors and no evidence of hypoglycemia were used as controls. There was increased IGF2, insulin-like growth factor receptor 1 receptor-alpha and transforming growth factor-beta receptor 3 expression in islets from nesidioblastosis patients compared to controls. Peliosis-type vascular ectasia was more common in nesidioblastosis patients compared to controls. These findings suggest that increased production of growth factors and growth factor receptors may contribute to the development of nesidioblastosis in adults.


Hsa_circ_0058129 regulates papillary thyroid cancer development via miR-873-5p/follistatin-like 1 axis.
Papillary thyroid cancer (PTC) is an endocrine malignancy with a high incidence. Circular RNAs (circRNAs) participate in regulating PTC. Here, we analyzed the role of hsa_circ_0058129 (circ_0058129) in PTC. The expression of circ_0058129, fibronectin 1 (FN1) mRNA, microRNA-873-5p (miR-873-5p), and follistatin-like 1 (FSTL1) was detected by qRT-PCR and western blot. Cell proliferation was analyzed by CCK-8, EdU, and flow cytometry analysis assays. Cell migration and invasion were evaluated by Transwell assay. The targeting relationship of miR-873-5p and circ_0058129 or FSTL1 was identified through dual-luciferase reporter assay, RIP assay, and RNA pull-down assay. Xenograft mouse model assay was implemented to determine the effect of circ_0058129 on tumor formation in vivo. The circ_0058129 and FSTL1 abundances were increased, while the miR-873-5p content was decreased in PTC tissues and cells compared with control groups. Circ_0058129 shortage inhibited PTC cell proliferation, migration, and invasion. Moreover, miR-873-5p repressed PTC cell malignancy by binding to FSTL1. Circ_0058129 targeted miR-873-5p to regulate FSTL1. Circ_0058129 expedited PTC progression through the miR-873-5p/FSTL1 pathway.


Lithium: poisonings and suicide prevention.
This study concerns 81 cases of lithium poisoning and shows that deliberate intoxications are prevalent during the first 3 years of lithium treatment as well as in cases with a previous history of suicide attempt. Therapeutic intoxications could generally be avoided by education concerning hygiene and diet and careful monitoring in cases of intercurrent diseases.


Will the COVID-19 Epidemic Reshape Cardiology?
The emergence of the novel coronavirus infection (COVID-19) began a series of unparalleled changes in health care systems worldwide. In the United States, the rapid evolution of the epidemic poses unprecedented challenges to hospitals, medical staff, training programs, policy makers, and professional societies1. For cardiology, COVID-19 brings substantial changes to the way we conceptualize and practice medicine. As others have observed, the abrupt change of our routines and priorities offers us the opportunity for reinvention; in this space, we can critically examine several facets of our profession. In this perspective, we discuss key questions resonating in the cardiology community in the midst of the epidemic. The discussion is structured around three domains: clinical practice, education and training, and professional values. We describe the immediate ramifications and potential long-term impact of COVID-19 on each domain.


Non-tuberculous mycobacterium bacteraemia in a pregnant systemic lupus erythematosus (SLE) patient: a case review and pooled case analysis.
Non-tuberculous mycobacteria (NTM) are recognized as an important cause of human diseases and infections. It is commonly known to cause infections of the skin, soft tissue infections, and pulmonary infection as well as bacteraemia. We report a challenging case of severe mycobacterium abscessus bacteraemia in a pregnant lady with active systemic lupus erythematous (SLE). A comprehensive literature review of NTM infection among SLE patients was also performed, and pooled analysis of the reported cases, including our case, was done to determine the clinical characteristics and factors associated with poor outcome of NTM infection.


Comparative studies of Iodo-bead and chloramine-T methods for the radioiodination of human alpha-fetoprotein.
Human alpha-fetoprotein (h-AFP) of iodination grade was radiolabeled with Na125I by chloramine-T (conventional method) and by Iodo-bead (solid-phase method) in our laboratory under standard and varied conditions, such as quantity of h-AFP and volume of the reaction mixture. We have slightly modified the chloramine-T method and developed a protocol for the Iodo-bead method of iodination. Our results show that while the chloramine-T method yields radiolabeled h-AFP of apparently 40% higher specific radioactivity (SR) than those of the Iodo-bead method, the latter appears to be a simpler, more controllable and milder method, giving rise to a more stable population of [125I]h-AFP. This is supported by the results of radioactive counting of [125I]h-AFP collected from a Sephadex G-50 column after radioiodination, storage stability and immunoreactivity with anti-h-AFP.


A Resampling Based Grid Search Method to Improve Reliability and Robustness of Mixture-Item Response Theory Models of Multimorbid High-Risk Patients.
There are many statistics available to the applied statistician for assessing model fit and even more methods for assessing internal and external validity. We detail a useful approach using a grid search technique that balances the internal model consistency with generalizability and can be used with models that naturally lend themselves to multiple assessment techniques. Our method relies on resampling and a simple grid search method over 3 commonly used statistics that are simple to calculate. We apply this method in a latent traits framework using a mixture Item Response Theory (MIXIRT) model of common chronic health conditions. Model fit is assessed using Akaike's Information Criteria (AIC), latent class similarity is measured with the Variance of Information (VI), and the consistency of condition complexity and prevalence across latent classes is compared using Kendall's τ rank order statistic. From two patient cohorts at high risk for hospitalization in 2014 and 2018, we generated 19 MIXIRT models (allowing 2-20 latent classes) on 21 common comorbid conditions identified via healthcare encounter diagnosis codes. We ran these models on 100 bootstrap samples of size 10% for each cohort. Among the resulting models, combined AIC and VI statistics identified 5-7 latent classes, but the rank order correlation of condition complexity revealed that only the 5 class solutions had consistent condition complexity. The 5 class solutions were combined to produce a single parsimonious MIXIRT solution that balanced clinical significance with model fit, cluster similarity, and consistency of condition complexity.


Orthotopic bone induction at sites of Moloney murine sarcoma virus inoculation in mice.
Moloney murine sarcoma virus (M-MSV) induces at the site of inoculation in newborn and adult mice and rats various types of sarcoma, including osteosarcoma. The induced tumours are fatal in newborn, whereas sarcomas developed in adult animals regress spontaneously. The regression is mediated mainly by a cellular response. We have now demonstrated that the presence of sarcomas induced by M-MSV is a powerful stimulus for periosteal osteogenesis around tumour masses. Orthotopically induced osteogenesis by M-MSV may serve as a model for local regulation of bone growth and for cell differentiation studies, and may help explain the aetiology of some human bone disorders.


[Personality changes in patients with periodic psychoses].
The author studied some personality changes in 35 patients with psychoses of periodical development (affective and schizoaffective psychoses), which are important for the rehabilitation period. It was demonstrated that following acute psychotic states there may be a significant distortion of the personality traits giving ground to qualify this state as "a defect", which in the opinion of the author is not justified. Adequate treatment to a large degree removes the personality changes. However, during the remission period there may be some irreversible changes of the personality. The author believes that in some cases there may be peculiar postpsychotic reactions and personality development.


Perioperative complications and mortality after radical cystectomy when using a standardized reporting methodology.
To evaluate, by using a standardized reporting methodology, the perioperative complications and mortality in patients who underwent radical cystectomy. We retrospectively reviewed all data of 404 consecutive patients who underwent radical cystectomy from 1995 to 2009 for nonmetastatic bladder cancer at the same academic center. Perioperative complications and perioperative mortality were defined as any adverse event or death from any cause within 90 days of surgery. All perioperative complications were reported according to the Martin criteria and were graded according to the Clavien system (grade 1-5). Univariate and multivariate analyses for the clinical and pathologic characteristics were used to evaluate predictors of complications. A total of 296 complications occurred in 209 (51.7%) patients. Among them, 139 (34.4% of the entire population) had only a '"minor"' (grade 1-2) complication, whereas 70 (17.3%) had a "major" (grade 3-5) complication. Eighteen (4.5%) patients died within 90 days after surgery. At univariate analysis, age ≥75 years (2P = .018), serum creatinine level ≥1.4 mg/dL (2P = .025), American Society of Anesthesiologists (ASA) score of 3 to 4 (2P < .001) were significant predictors of complications after 30 days from surgery; conversely, the ASA score was the only significant predictor of complications after 90 days. At multivariate analysis, only the ASA score was independently correlated with the development of complications at 30 and 90 days of follow-up (2P < .001). Radical cystectomy is one of the most complex procedures in urology, with a high rate of complications and mortality. The use of a standardized methodology is the only way to estimate the actual rate and the severity of complications.


Orthostatic hypotension and cardiac sympathetic denervation in Parkinson disease patients with REM sleep behavioral disorder.
Rapid eye movement (REM) sleep behavioral disorder (RBD), orthostatic hypotension (OH), and cardiac sympathetic denervation were commonly observed in PD and are related in both the premotor and motor periods. This study is intended to evaluate if the OH and cardiac sympathetic denervation found in PD are associated with RBD. Among 94 non-medicated and mild PD patients, 53 had RBD. Orthostatic vital signs and ambulatory 24-hour blood pressure values were recorded. (123)I-metaiodobenzylguanidine (MIBG) cardiac scintigraphy as obtained in all patients. The association between orthostatic hypotension, supine hypertension, nocturnal hypertension, non-dipping, myocardial MIBG uptake, and RBD was analyzed. RBD was associated with orthostatic hypotension. Patients with RBD had higher systolic blood pressure changes during orthostasis and lower myocardial MIBG uptake than patients without RBD and controls. Patients with OH also had lower mean H/M ratios those in the non-OH group. This study showed that RBD was closely associated with OH and cardiac sympathetic denervation in patients with early and mild PD. The result also suggests that impaired cardiac sympathetic innervation could be the mechanism behind OH in PD. This association may be closely correlated with Braak alpha-synuclein pathogenetic sequences, which would account for the clinical spectrum of PD.


Automatic implantable cardioverter-defibrillator: is early implantation cost-effective?
The evaluation of survivors of sudden cardiac death with serial electrophysiologic studies involves a lengthy and expensive hospitalization, especially when an automatic implantable cardioverter-defibrillator is ultimately necessary. The cost efficacy of this conventional approach was therefore compared with direct implantation of a cardioverter-defibrillator after the first electrophysiologic study. Thirty-two survivors of sudden death who had inducible ventricular tachycardia during their initial electrophysiologic study underwent serial drug trials. At discharge 12 (37%) were taking an antiarrhythmic drug found to prevent induction of ventricular tachycardia and 20 underwent cardioverter-defibrillator implantation after serial drug trials proved ineffective. The average length of hospitalization for this group that had undergone serial drug testing was 20.2 +/- 9.3 days at an average cost of $48,900 +/- $31,600. Seven survivors of sudden death had no inducible ventricular tachycardia during their initial electrophysiologic study and underwent direct cardioverter-defibrillator implantation. Their average length of hospitalization was 12.6 +/- 6.2 days at an average cost of $40,400 +/- $8,300. It is concluded that automatic implantable cardioverter-defibrillator implantation as an early intervention is not more costly and indeed may be cost-effective compared with therapy guided by serial electrophysiologic testing. As antitachycardia devices become more versatile, long lived and easier to implant, earlier implantation is likely to compare even more favorably with drug therapy.


Analytical purification of a 60-kDa target protein of artemisinin detected in Trypanosoma brucei brucei.
Here we describe the isolation and purity determination of Trypanosoma brucei (T. b.) brucei candidate target proteins of artemisinin. The candidate target proteins were detected and purified from their biological source (T. b. brucei lysate) using the diazirine-free biotinylated probe 5 for an affinity binding to a streptavidin-tagged resin and, subsequently, the labeled target proteins were purified by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). We herein showed the electrophoresis gel and the immunoblotting film containing the 60-kDa trypanosomal candidate target protein of artemisinin as a single band, which was visualized on-gel by the reverse-staining method and on a Western blotting film by enhanced chemiluminescence. The data provided in this article are related to the original research article "Biotinylated probes of artemisinin with labeling affinity toward Trypanosoma brucei brucei target proteins", by Konziase (Anal. Biochem., vol. 482, 2015, pp. 25-31. http://dx.doi.org/10.1016/j.ab.2015.04.020).


A complex case of necrobiotic xanthogranuloma with IgG-kappa paraproteinemia: Disease regression achieved with melphalan and prednisone combination therapy.
Necrobiotic xanthogranuloma (NXG) is a rare dermatosis that is often associated with monoclonal paraproteinemia and hematological malignancies. We report the rare case of an 84-year-old gentleman with extensive truncal NXG and IgG-kappa paraproteinemia who achieved significant disease regression following six cycles of combination melphalan/prednisone therapy.


The effects of total and partial callosal agenesis on the development of morphological brain asymmetries in the BALB/cCF mouse.
The corpus callosum fails to develop in some mice of the BALB/cCF strain. We report here a study on cerebral morphological asymmetry in males of this particular strain in order to test the hypothesis that the normal development of the corpus callosum is responsible for the establishment of brain asymmetries. In 46 animals the dorsal area and the weight of each hemisphere were measured. In order to identify the animals with callosal defects and check for size anomalies of the anterior commissure, the hemispheres were cut into sagittal sections and stained with cresyl violet. Measures of sagittal area of the anterior commissure did not support the hypothesis that this commissure is enlarged when the corpus callosum is reduced or absent. In normal animals, the mean difference between left and right dorsal cortical areas showed a significant directional asymmetry, the left being consistently greater than the right. A similar pattern was found for weight. In mice with callosal defects there were no significant differences, either between the dorsal areas or between the weights of the hemispheres. However, data on the absolute values of the hemispheric differences indicated the presence of a nondirectional asymmetry not only in normal animals, but also in mice with callosal defects. Therefore, our data suggest that the ontogenesis of the corpus callosum plays a role in directing the development of cerebral asymmetries.


Human immunodeficiency virus-1 Nef suppresses Hsp70-mediated Tat activation.
The human immunodeficiency virus type 1 (HIV-1) long terminal repeat (LTR) contains binding sites for several host transcription factors that contribute to HIV-1 gene expression. Although previous reports have indicated that HIV-1 Nef positively or negatively regulates HIV-1 gene expression, the precise molecular mechanisms by which this occurs remain largely unknown. In this study, we report that Nef suppressed LTR-driven transcription only in the presence of HIV-1 Tat, which was localized to the cytoplasm and degraded by the proteasome. However, the depletion of Hsp70 was found to reduce the suppressive effect of Nef on HIV-1 gene expression. These results suggest that Nef suppresses Hsp70-mediated HIV-1 Tat activation.


Effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and several of its analogues on the dopaminergic nigrostriatal pathway in mice.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a recently discovered neurotoxin, caused extensive losses of dopamine and its major metabolites after its administration to male Swiss-Webster mice. In contrast, under identical conditions, several MPTP analogues, even those with relatively minor structural changes, were without toxicity. These include compounds with a 1-ethyl and 1-propyl substituent rather than the 1-methyl, the compound lacking the double bond in the tetrahydropyridine ring, as well as the compound with no phenyl substituent. It follows that each part of the MPTP molecule is important in determining its neurotoxic activity.


Development of neural receptors for serotonin in the murine bowel.
During the ontogeny of the enteric nervous system, the varicosities of mature neurons contact dividing neural precursors, which persist in the developing murine gut for several weeks postnatally. This phenomenon has led to the hypothesis that the release of transmitter from mature neurons may influence the subsequent development of uncommitted neuroblasts. In order to test this hypothesis, it is necessary to know the timing of the expression of postsynaptic receptors for enteric neurotransmitters. Since serotoninergic neurons are among the earliest of enteric neurons to develop (appearing on day E12 of development in the mouse), the ontogeny of enteric neural serotonin receptors (5-HTR) was studied. These receptors have previously been characterized in adult guinea pigs and rabbits. In the current experiments, 5-HTR were identified in the adult murine bowel; their properties were compared with the 5-HTR of guinea pig and rabbits; their ontogeny was followed throughout the length of the developing mouse gut; and the properties of 5-HTR in the developing murine bowel were compared with those of the mature gut. The 5-HTR were assayed by measuring the binding of 3H-serotonin (3H-5-HT) to isolated enteric membranes by rapid filtration, and to frozen sections of bowel by radioautography. A single saturable, high affinity 3H-5-HT binding site was found in membranes from the adult mouse gut (KD = 3.9 +/- 0.5 nM; Bmax = 1.6 +/- 0.3 pmoles/mg protein). Binding of 3H-5-HT at this site was not antagonized by compounds known to be antagonists at receptors for other neurotransmitters or at the 5-HT1 or 5-HT2 class of CNS 5-HTR. Hydroxylation of the indole ring of analogues of serotonin was required for affinity at the enteric 3H-5-HT binding site. Binding of 3H-5-HT was inhibited by N-acetyl-5-hydroxytryptophyl-5-hydroxytryptophan dipeptide, a compound that has been demonstrated to antagonize those responses of myenteric neurons to serotonin that resemble slow excitatory postsynaptic potentials, but not by ICS 205-930 (Sandoz), a serotonin antagonist that does not block these responses. All of these properties of adult murine 3H-5-HT binding sites are virtually identical of those of guinea pigs and rabbits, which have previously been shown to be 5-HTR; therefore, murine enteric 3H-5-HT binding sites are probably 5-HTR as well.(ABSTRACT TRUNCATED AT 400 WORDS)


Complete Genome Sequences of Three Listeria monocytogenes Strains from Microgreens Obtained with MinION and MiSeq Sequencing.
Listeria monocytogenes is a Gram-positive, rod-shaped, non-spore-forming bacterium which is an important foodborne bacterial pathogen for human worldwide with 20-30% mortality. Here, we report circular complete genome sequences of three Listeria monocytogenes strains isolated from the samples of microgreens in Canada.


Blood-brain barrier dysfunction, status epilepticus, seizures, and epilepsy: a puzzle of a chicken and egg?
Status epilepticus is often associated with endothelial dysfunction and increased vessels permeability. We discuss here the direct role of blood-brain barrier (BBB) dysfunction in epileptogenesis and brain damage. On the cellular level, astrocytes respond early to the efflux of serum proteins in the presence of dysfunctional BBB, with activation of the innate immune system and disturbed homeostasis of extracellular potassium and glutamate. In turn, there is enhanced excitability of neurons and altered network connectivity. Transforming growth factor beta (TGF-β) signaling appears to be a potential new target for the prevention of epileptogenesis and secondary damage following status epilepticus.


Tissue factor-dependent coagulation is preferentially up-regulated within arterial branching areas in a baboon model of Escherichia coli sepsis.
Endothelium plays a critical role in the pathobiology of sepsis by integrating systemic host responses and local rheological stimuli. We studied the differential expression and activation of tissue factor (TF)-dependent coagulation on linear versus branched arterial segments in a baboon sepsis model. Animals were injected intravenously with lethal doses of Escherichia coli or saline and sacrificed after 2 to 8 hours. Whole-mount arterial segments were stained for TF, TF-pathway inhibitor (TFPI), factor VII (FVII), and markers for endothelial cells (ECs), leukocytes, and platelets, followed by confocal microscopy and image analysis. In septic animals, TF localized preferentially at branches, EC surface, leukocytes, and platelet aggregates and accumulated in large amounts in the subendothelial space. FVII strongly co-localized with TF on ECs and leukocytes but less so with subendothelial TF. TFPI co-localized with TF and FVII on endothelium and leukocytes but not in the subendothelial space. Focal TF increases correlated with fibrin deposition and increased endothelial permeability to plasma proteins. Biochemical analysis confirmed that aortas of septic baboons expressed more TF mRNA and protein than controls. Branched segments contained higher TF protein levels and coagulant activity than equivalent linear areas. These data suggest that site-dependent endothelial heterogeneity and rheological factors contribute to focal procoagulant responses to E. coli.


Recent transmission of tuberculosis involving retired patients.
The reported incidence of tuberculosis (TB) in three different regions of Rio Grande do Sul State in Brazil varies considerably. We used IS6110-RFLP and spoligotyping methods to genotype Mycobacterium tuberculosis isolates obtained from 268 patients between 1998 and 2000 in order to assess the levels of recent transmission of TB in the three regions. The degree of clustering of the strain types did not differ among the three regions; neither did other characteristics such as demographic features, underlying medical conditions, or the proportion of resistant TB. As reported previously, male patients were at greater risk of developing TB and our data suggest that part of this may be related to the higher rates of recent transmission among them (P<0.05). In addition, we found that retired patients were almost 3 times more likely to be infected with cluster-pattern strains than patients reporting any other occupation (P<0.05), and more than 3 times more likely than non-retired patients in the same age group (P<0.05) to be infected with cluster-pattern strains. We conclude that recent transmission is not a major factor contributing to the differences in TB incidence in the three regions of Rio Grande do Sul. The reason for the suggested high proportion of recent transmission TB cases among the retired people needs further studies.


Antibiotic resistome in a landfill leachate treatment plant and effluent-receiving river.
Landfills leachate contained diverse antibiotic resistance genes (ARGs). Treated landfill leachate effluent could enter into the downstream environments, leading to the dissemination of ARGs, which might pose a health risk to public. Here, we used high-throughput qPCR to characterize the resistome and 16S rRNA-based Illumina sequencing to analyze the bacterial community in a leachate treatment plant and the river near the landfill. A total of 91 ARGs and 5 mobile genetic elements were detected. Leachate treatment process significantly changed the profiles of resistome and bacterial community structures. Similar bacterial community structure and ARG profiles were detected between effluent and downstream river, which were both dominated by multidrug and beta-lactams resistance genes and harbored higher ARG relative abundance than that in upstream river. In particular, seven ARGs were detected both in effluent and downstream river samples but not detected in upstream river, including genes encoding resistance to vancomycin (vanXD and vanSB) and carbapenem (cphA and blaGES), which implied the effects of the effluent on its receiving river. This study highlights the risk of discharge of processed landfill leachate in dissemination of antibiotic resistance determinants to the environments, and suggests an urgent need for surveillance of ARGs and development of techniques to mitigate the risk.


Haplotype and minimum-chimerism consensus determination using short sequence data.
Assembling haplotypes given sequence data derived from a single individual is a well studied problem, but only recently has haplotype assembly been considered for population-sampled data. We discuss a software tool called Hapler, which is designed specifically for low-diversity, low-coverage data such as ecological samples derived from natural populations. Because such data may contain error as well as ambiguous haplotype information, we developed methods that increase confidence in these assemblies. Hapler also reconstructs full consensus sequences while minimizing and identifying possible chimeric points. Experiments on simulated data indicate that Hapler is effective at assembling haplotypes from gene-sized alignments of short reads. Further, in our tests Hapler-generated consensus sequences are less chimeric than the alternative consensus approaches of majority vote and viral quasispecies estimation regardless of error rate, read length, or population haplotype bias. The analysis of genetically diverse sequence data is increasingly common, particularly in the field of ecoinformatics where transcriptome sequencing of natural populations is a cost effective alternative to genome sequencing. For such studies, it is important to consider and identify haplotype diversity. Hapler provides robust haplotype information and identifies possible phasing errors in consensus sequences, providing valuable information for population studies and downstream usage of resulting assemblies.


An investigation of the pharmacokinetic profile of propofol ('Diprivan') after administration for induction and maintenance of anaesthesia by repeat bolus doses in patients having spinal anaesthetic block.
In 12 premedicated patients, spinal anaesthesia was established with 0.5% bupivacaine. General anaesthesia was then induced using 2.5 mg/kg propofol given over 20s, and maintained by the administration of repeated bolus doses of 1 mg/kg propofol given 3 min after induction and at intervals of 6 min thereafter. Anaesthesia was successfully induced and maintained by this technique and recovery from anaesthesia in most patients was rapid. Blood samples were collected 2 and 6 min after each dose and at recovery in order to determine the concentrations of propofol. Pharmacokinetic data were fully evaluated in 5 patients whose dosing and sampling regimen did not differ from the methods described above. Propofol blood concentrations declined rapidly between the 2 and 6 min samples, indicating rapid distribution of propofol from blood into tissues. In 3 of the 5 patients slight accumulation of propofol occurred although there was no consistent trend. There was a wide inter-individual variability in propofol concentrations on waking.


EPR determination of the oxidation-reduction potentials of the hemes in cytochrome c3 from Desulfovibrio vulgaris.
EPR spectroscopy in conjunction with oxidation-reduction potentiometry has been used to determine the half-reduction potentials of the four hemes of cytochrome c3. As predicted, the four hemes of cytochrome c3 have different mid-point potentials. The Em values are: Heme I,--284 mV; Heme II,--310 mV; Heme III,--324 mV and Heme IV,--319 mV. The n-values in each case was near one.


Classification of Parkinson's disease using a region-of-interest- and resting-state functional magnetic resonance imaging-based radiomics approach.
To investigate the value of combining amplitude of low-frequency fluctuations-based radiomics and the support vector machine classifier method in distinguishing patients with Parkinson's disease from healthy controls. A total of 123 patients with Parkinson's disease and 90 healthy controls from three centers with functional and structural MRI images were included in this study. We extracted radiomics features using the Brainnetome 246 atlas from the mean amplitude of low-frequency fluctuations maps. Two-sample t-tests and recursive feature elimination combined with support vector machine method were applied for feature selection and dimensionality reduction. We used support vector machine classifier to construct model and identify the discriminative features. The automated anatomical labeling 90 atlas and fivefold cross-validation were used to evaluate the robustness and generalization of the classifier. We found our model obtained a high classification performance with an accuracy of 78.07%, and AUC, sensitivity, and specificity of 0.8597, 78.80%, and 76.08%, respectively. We detected 7 discriminative brain subregions. The fivefold cross-validation and automated anatomical labeling 90 atlas also got high classification accuracy, and we found Brainnetome 246 atlas achieved a higher classification performance than the automated anatomical labeling 90 atlas both with tenfold and fivefold cross-validation. Our findings may help the early diagnosis of Parkinson's disease and provide support for research on Parkinson's disease mechanisms and clinical evaluation.


Meniscal Root Repair Alone or Combined with Different Procedures After at Least 6 Months of Follow-Up: A Series of Cases.
To analyze clinical and functional outcomes of patients submitted to posterior meniscal root repair of the medial or lateral meniscus in different settings, with at least 6 months of follow-up. Retrospective multicentric study assessing epidemiological characteristics and clinical-functional results of 22 patients who underwent meniscal root reinsertion (MRR) by transtibial technique. This study addressed different settings: isolated medial root repair, medial root repair associated with high tibial osteotomy (HTO) and lateral root repair associated with anterior cruciate ligament (ACL) reconstruction. Twelve patients had an isolated tear of the posterior root of the medial meniscus and underwent MRR alone. Six patients had a varus axis >5°, undergoing MRR in addition to HTO in the same surgical procedure. Four patients underwent repair of the posterior root of the lateral meniscus associated with simultaneous reconstruction of the ACL. The main results of the study were observed in the improvement of the IKDC score from 27.7% preoperatively to 69.8% in the postoperative period (p < 0.0001) and the Lysholm score of 44.4 points preoperatively to 88.4 points in the postoperative period (p < 0.0001). Significant clinical and subjective improvements were also reported. Medial meniscal root repair, associated or not with valgus tibial osteotomy (when indicated) and lateral meniscal root repair associated with ACL reconstruction, improved clinical, functional, and subjective results of the patients presented in this case series in the short term.


Bone mesenchymal stem cells for gene transfer of NGF to the adult rat brain: rescue the NGFR p75 positive neurons from fimbria-fornix lesion-induced degeneration.
The study was to evaluate the therapeutic benefit of transplanted bone mesenchymal stem cells (BMSCs) transfected never growth factor (NGF) gene and GFP gene (as a reporter gene), in treating the rat with fimbria-fornix lesion. After transduction of NGF gene via recombinant retroviral vectors into the rat BMSCs, BMSCs were therefore transformed into the GFP-NGF positive BMSCs, nearly 100% of BMSCs expressed NGF, and then transplanted into basal forebrain of rat with fimbria-fornix lesion. After 2 weeks post-transplantation, the GFP-NGF positive BMSCs survive and fuse in vivo with astroglia or NGFR p75 positive neurons in the basal forebrain, no evidence of transdifferentiation was observed in this study. The number of NGFR p75 positive neurons in basal forebrain of NGF group was significantly higher than those of the void plasmid group (p < 0.05) or the PBS group (p < 0.01). These results indicate that the GFP-NGF positive BMSCs provide, by way of paracrine, NGF that effectively perform the functions of neuroprotection, which cell fusion may be also contribute to.


Signaling defense responses of upland rice to avirulent and virulent strains of Magnaporthe oryzae.
Rice blast (Magnaporthe oryzae) can cause large losses in crop yields, especially in upland rice systems. Avirulent strains of M. oryzae can induce resistance to subsequent attacks by virulent strains in plants. This study aimed to investigate the defense responses in upland rice challenged with a virulent strain of M. oryzae after acclimation with an avirulent strain. The avirulent strain decreased rice blast severity in the challenged plants. Induced resistance was characterized by a hypersensitive response and early accumulation of phenolic compounds. Scanning electron microscopy showed that M. oryzae conidia germinate and form appressoria, but do not colonize leaf tissues. The activities of pathogenesis-related proteins, total phenolic compounds, and salicylic acid (SA) were affected by acclimation to the avirulent strain. The activities of β-1,3-glucanase, phenylalanine ammonia-lyase, and peroxidase, as well as the SA levels explained most of the variability in the rice plant responses to M. oryzae. In addition, OsXa13, OsMAPKKK74, OsAOS2, OsACO7, and OsMAS1 expression was modulated depending on the virulence of the M. oryzae strains. This modulation in gene expression is critical for infection and some of these mechanisms are targeted by effectors, resulting in enhanced susceptibility and pathogen infection. These results have practical importance in plant-pathogen interaction studies to identify resistance-relevant mechanisms against M. oryzae in upland rice.


Comparison of a modified 2-step insulin response test performed with porcine zinc insulin and an oral glucose test to detect hyperinsulinemic Icelandic horses.
Both, oral and intravenous (IV) testing protocols, are recommended and still used to detect insulin dysregulation (ID) in equids. However, IV tests mainly focus on peripheral insulin resistance (IR), while oral tests assess hyperinsulinemia (HI), which are different aspects of ID. The objective of this study was to describe if horses with HI also demonstrate IR and consequently can be detected by a modified 2-step insulin response test (2-step IRT) performed with a veterinary approved porcine zinc insulin (PZI). Twelve Icelandic horses were subjected to an OGT and 2-step IRT in a crossover study. Serum insulin concentrations during the OGT revealed that six horses were hyperinsulinemic (HI) while six were not (NON-HI). To describe the glucose response to IV injected PZI, the decline of plasma glucose concentration within the first 30 min was analyzed. Glucose reduction was similar in horses with and without HI during the 2-step IRT over time. Additionally, none of the horses reached a glucose reduction of ≥ 50% at 30 min. The results of the present study indicated that a comparable insulin mediated glucose uptake may be observed in horses with and without HI during a modified 2-step IRT. While six out of twelve horses were identified as HI by the OGT, all twelve horses were identified as IR by the modified 2-step IRT performed with PZI underlining the importance, but difficulty in choosing the right diagnostic tool in clinical settings to assess ID.


Added Diagnostic Utility of Clinical Metagenomics for the Diagnosis of Pneumonia in Immunocompromised Adults.
In the evaluation of community-acquired pneumonia, 30% to 60% of cases remain undiagnosed, despite extensive conventional microbiologic testing (CMT). Clinical metagenomics (CM) is an unbiased pathogen detection method that can increase diagnostic yield. Does adding clinical metagenomics to conventional microbiologic testing improve the diagnostic yield for pneumonia in immunocompromised adults? We performed a noninterventional prospective study of immunocompromised adults with pneumonia who underwent bronchoscopy and BAL over 2 years. CMT was performed per standard of care. A commercial CM test was performed on residual BAL fluid. Final microbiologic diagnoses were based on CMT vs CMT + CM. Final clinical diagnoses for CMT and CMT + CM were made based on laboratory results in conjunction with clinical and radiologic findings. Hypothetical impact of CMT + CM on management and antimicrobial stewardship was also assessed. A total of 30 immunocompromised adult patients (31 episodes of pneumonia) were included. Final microbiologic diagnoses were made in 11 cases (35%) with the use of CMT and in 18 cases (58%) with the use of CMT + CM. Bacterial pneumonia was diagnosed in five cases (16%) by CMT and in 13 cases (42%) by CMT + CM; fungal pneumonia was diagnosed in six cases (19%) by CMT and in seven cases (23%) by CMT + CM, and viral pneumonia was diagnosed in two cases (6%) by CMT and in five cases (16%) by CMT + CM. The hypothetical impact of CMT + CM on management was deemed probable in one case, possible in eight cases, and unlikely in two cases, whereas the impact on antimicrobial stewardship was possible in 13 cases and unlikely in seven cases. Final clinical diagnoses were made in 20 of 31 cases (65%) based on CMT and in 23 of 31 cases (74%) based on CMT + CM. CMT + CM increased diagnostic yield in immunocompromised adults with pneumonia from 35% to 58%, mostly by the detection of additional bacterial causes but was less useful for fungal pneumonia.


Relation of atrial fibrillation to glomerular filtration rate.
Although both atrial fibrillation (AF) and decreasing glomerular filtration rate (GFR) are strongly related to advanced age and share common associated vascular risk factors, few studies have explored the relation between AF and GFR. From residents (age >or=40 years) in Kurashiki City, a total of 41,417 subjects (median age 72 years; 13,956 men) were enrolled in the Kurashiki City Annual Medical Survey from May to December 2006. The estimated overall prevalence of AF was 1.6% (2.8% in the low-GFR tertile, 1.2% in the middle tertile, and 0.9% in the high tertile, p <0.001). After all subjects were categorized into age tertiles (age thresholds 68 and 76 years), AF was identified in 0.9% in the low-GFR tertile, 0.6% in the middle tertile, and 0.5% in the high tertile in the low-age tertile (p = 0.018); 2.6% in the low-GFR tertile, 1.2% in the middle tertile, and 1.1% in the high tertile in the middle-age tertile (p <0.001); and 3.9% in the low-GFR tertile, 2.4% in the middle tertile, and 1.7% in the high tertile in the high-age tertile (p <0.001). The odds ratio for AF adjusted for age, gender, vascular risk factors, cardiac disease, and hemoglobin was 1.91 (95% confidence interval 1.54 to 2.38, p <0.001) for the low-GFR tertile versus the high tertile and 1.12 (95% confidence interval 0.88 to 1.42, p = 0.364) for the middle-GFR tertile versus the high tertile. The prevalence of AF gradually increased with decreasing GFR. In conclusion, AF appears to be associated with decreasing GFR.


Association between adherence to the American Cancer Society Nutrition and Physical Activity Guidelines and stool frequency among colon cancer survivors: a cohort study.
We sought to determine whether adherence to the American Cancer Society (ACS) Nutrition and Physical Activity Guidelines was associated with better bowel function among colon cancer survivors. This prospective cohort study included patients surgically treated for stage I-IV colon cancer enrolled in the Lifestyle and Outcomes after Gastrointestinal Cancer (LOGIC) study between February 2017 and May 2021. Participants were assigned an ACS score (0-6 points) at enrollment. Stool frequency (SF) was assessed every 6 months using the EORTC QLQ-CR29. Higher SF is an indication of bowel function impairment. ACS score at enrollment was examined in relation to SF at enrollment and over a 3-year period. Secondarily, we examined associations between the ACS score components (body mass index, dietary factors, and physical activity) and SF. Multivariable models were adjusted for demographic and surgical characteristics. A total of 112 people with colon cancer (59% women, mean age 59.5 years) were included. Cross-sectionally, for every point increase in ACS score at enrollment, the odds of having frequent stools at enrollment decreased by 43% (CI 0.42-0.79; p < 0.01). Findings were similar when we examined SF as an ordinal variable and change in SF over a 3-year period. Lower consumption of red/processed meats and consuming a higher number of unique fruits and vegetables were associated with lower SF (better bowel function) at enrollment. Colon cancer survivors who more closely followed the ACS nutrition and physical activity guidelines had lower SF, an indication of better bowel function. Our findings highlight the value of interventions that support health behavior modification as part of survivorship care for long-term colon cancer survivors.


Endovascular stenting for nutcracker syndrome.
Nutcracker syndrome (NCS) is a rare pathology manifested by pain or hematuria in males and females alike. It can be easily overlooked, and should be considered in young men or women with symptoms of extended duration. We present a case of a 54-year-old female with chronic lower abdominal pain radiating to the left thigh of 4 years in duration. Computed tomography (CT) eventually revealed engorged left renal, gonadal, and uterine veins due to compression between the superior mesenteric artery (SMA) and the abdominal aorta, consistent with NCS. After a successful endovascular stenting and a 6-month period of antiplatelet and anticoagulant therapy, the patient returned to stable health. NCS, while rare, should be suspected in patients of both sexes with persistent pain or hematuria.


Proinflammatory role of the histamine H4 receptor in dextrane sodium sulfate-induced acute colitis.
Millions of people worldwide are suffering from inflammatory bowel disease (IBD), which severely affects patients' life qualities and even life expectancies. The cause of the ailment is unknown and a profound understanding of the underlying pathogenetic mechanisms is still lacking. The biogenic amine histamine is one of several inflammatory mediators, to which a pathogenetic role in IBD has been attributed. Out of the four known histamine receptors, the histamine H4 receptor (H4R) has been demonstrated to act proinflammatory in experimental models of several inflammatory diseases. In order to evaluate a potential involvement of H4R in IBD we investigated the effect of genetic or pharmacological blockade of H4R-signaling in the model of dextran sodium sulfate (DSS)-induced colitis in mice. We analysed severity and progression of clinical signs of colitis, as well as histopathologic alterations in the colons and systemic or local cytokine concentrations. Both genetic deficiency and pharmacological blockade of H4R with the selective antagonist JNJ7777120 improved clinical and histological signs of colitis and dampened the inflammatory cytokine response. Our results indicate a proinflammatory role of histamine via H4R in IBD, thus extending the current pathophysiological understanding of IBD and demonstrating the therapeutic potential of selective H4R-antagonists for patients suffering from IBD.


Localisation of nonspecific esterases in mouse lymphoid leukemia L 1210 cells.
It was found that diazo dye used for histochemical reaction of nonspecific esterases may influence on the localisation of the reaction product.


A common interleukin-6 promoter polymorphism in patients with vulvar cancer.
Besides its important role in immune response and inflammatory processes the cytokine interleukin-6 (IL-6) is crucially involved in carcinogenesis. A common polymorphism within the gene encoding IL-6 (IL6) is known to alter IL-6 protein expression and has been associated with patients' prognosis in various malignancies. No data are available with respect to vulvar cancer. Therefore, we determined the prognostic potential of the common -174(G-->C) single nucleotide polymorphism in the promoter region of IL6 in a series of patients with this disease. The IL6 promoter polymorphism was investigated in 81 Caucasian patients with surgically treated squamous cell vulvar cancer using pyrosequencing. Results were correlated with clinical data. No association was ascertained between the IL6 promoter polymorphism and the investigated clinicopathologic parameters, ie, tumor stage, lymph node involvement, tumor grade, and patient's age at diagnosis. In an univariate analysis, lymph node involvement and patients' age at diagnosis were associated with patient prognosis. In a multivariate analysis, including tumor stage and lymph node involvement as established prognostic factors and the IL6 promoter polymorphism, lymph node involvement, and the presence of at least one mutant allele, but not tumor stage, were associated with increased disease-free and overall survival. Our data suggest that the IL6 -174(G-->C) promoter polymorphism might serve as an additional prognostic parameter in patients with vulvar cancer.


The Otolaryngology Match: A Bibliometric Analysis of 222 First-Year Residents.
Research has long been acknowledged as important to successfully matriculate into an otolaryngology residency position. The objective of this study is to perform a bibliometric analysis to quantify the importance of scholarly productivity in the otolaryngology match process. Retrospective database review. A list of all Accreditation Council for Graduate Medical Education-accredited otolaryngology residency programs were identified. Websites of programs were reviewed to identify first-year otolaryngology residents for the 2016 to 2017 academic year and compared to two previous academic years. Research output measures were collected. Residencies were tiered 1 to 5 by departmental research output. Two hundred twenty-two records of first-year otolaryngology residents starting residency in 2016 were identified. After adjusting for number of total publications, number of original research articles, number of review articles, number of case reports, number of first author publications, number of otolaryngology-related publications, highest journal impact factor, average journal impact factor, and years since publication, h-index and number of total publications were associated with increasing tier of matriculation based on research output (P < .0001). Only number of publications correlated with increasing h-index (B = 1.11). With regard to applicant trends, there has been an increase in scholarly productivity as measured across all research parameters in the past 3 years. Research is an important component of successfully matriculating into an otolaryngology residency program. The h-index is a reliable tool to quantify research output and predict the tier of matriculation with regard to institutional research output. There has been a steadily increasing level of scholarly output among applicants in the past 3 years. NA Laryngoscope, 129:1561-1566, 2019.


Sublingual administration of Lactobacillus paracasei KW3110 inhibits Th2-dependent allergic responses via upregulation of PD-L2 on dendritic cells.
Lactic acid bacteria have potential in immunomodulation therapy, but their clinical efficacy and underlying mechanisms are unclear. We aimed to clarify the anti-allergic immune responses induced by intragastric and sublingual administration of heat-killed Lactobacillus paracasei KW3110 and Lactobacillus acidophilus L-92. The KW3110 strain (but not the L-92 strain) enhanced ovalbumin (OVA)-induced expression of CCR-7 and PD-L2 in murine dendritic cells (DCs), and strongly inhibited IL-5 and IL-13 production in vitro in co-cultures with Th2-skewed CD4(+) T cells from DO11.10 transgenic mice. Sublingual administration of low-dose KW3110 (but not L-92) to OVA-sensitized mice selectively suppressed serum IgE production and Th2 cytokine expression in cervical lymph nodes, and significantly improved symptoms after OVA provocation in vivo. KW3110 probably accelerates DC migration into the regional lymph nodes and inhibits Th2 cytokine production through enhanced CCR-7 and PD-L2 expression. Thus, sublingual KW3110 administration may be effective in reducing allergic inflammation.


Josef Jadassohn (1863-1936), Felix Lewandowsky (1879-1921), and their syndrome.
Josef Jadassohn (1863-1936) and his assistant, Felix Lewandowsky (1879-1921), were eminent German dermatologists who had several dermatology conditions linked eponymously. One such condition is Jadassohn-Lewandowsky syndrome, which is a type of pachyonychia congenita - a disease that is characterized by severe thickening of the nail due to massive nail hyperkeratosis. This report describes Jadassohn-Lewandowsky syndrome and the men behind this disease.


Group-combined P-values with applications to genetic association studies.
In large-scale genetic association studies with tens of hundreds of single nucleotide polymorphisms (SNPs) genotyped, the traditional statistical framework of logistic regression using maximum likelihood estimator (MLE) to infer the odds ratios of SNPs may not work appropriately. This is because a large number of odds ratios need to be estimated, and the MLEs may be not stable when some of the SNPs are in high linkage disequilibrium. Under this situation, the P-value combination procedures seem to provide good alternatives as they are constructed on the basis of single-marker analysis. The commonly used P-value combination methods (such as the Fisher's combined test, the truncated product method, the truncated tail strength and the adaptive rank truncated product) may lose power when the significance level varies across SNPs. To tackle this problem, a group combined P-value method (GCP) is proposed, where the P-values are divided into multiple groups and then are combined at the group level. With this strategy, the significance values are integrated at different levels, and the power is improved. Simulation shows that the GCP can effectively control the type I error rates and have additional power over the existing methods-the power increase can be as high as over 50% under some situations. The proposed GCP method is applied to data from the Genetic Analysis Workshop 16. Among all the methods, only the GCP and ARTP can give the significance to identify a genomic region covering gene DSC3 being associated with rheumatoid arthritis, but the GCP provides smaller P-value. http://www.statsci.amss.ac.cn/yjscy/yjy/lqz/201510/t20151027_313273.html firstname.lastname@example.com Supplementary data are available at Bioinformatics online.


Histomorphometric analysis of intramyocardial vessels in primary and senile amyloidosis: epicardium versus endocardium.
The literature is unclear as to the frequency and degree of vascular involvement among the various types of cardiac amyloidosis, specifically the senile type. We analyzed the intramyocardial vascular involvement, both qualitatively and quantitatively, in 18 patients with autopsy-proven cardiac amyloidosis [11 with primary amyloidosis (AL) and 7 with senile systemic amyloidosis (SSA)]. AL patients (10/11) showed focally transmural vascular involvement by amyloid with thickening of the wall and impingement on the lumens. In SSA patients (6/7), the amyloid deposition was concentrated largely in the adventitia and external media. Histomorphometric analysis revealed that all patients with AL, SSA, and heart failure without amyloidosis had greater luminal areas than normal controls. In addition, the median of the ratio of subendocardial to subepicardial vascular luminal areas was 0.59 in AL patients, 1.17 in SSA patients, 0.94 in heart failure without amyloidosis patients, and 0.89 in normal controls (P=.034). This study shows that the degree of vascular involvement and wall thickening with subsequent impingement on the lumen is much greater in AL than in SSA. All patients with heart failure, with and without amyloidosis, displayed greater luminal areas than normal controls. Moreover, a twofold dilatation of the vessels in the subepicardium compared to those in the subendocardium was noted only in patients with AL. This may be due to transmural vascular involvement by amyloid in these patients, which concomitantly decreases the transmural ventricular perfusion pressure, leading to compensatory expansion of the subepicardial vessels.


Strategies in case of positive in vivo results in genotoxicity testing.
At the 2009 International Workshop on Genotoxicity Testing in Basel, an expert group gathered to provide guidance on suitable follow-up tests to describe risk when basic in vivo genotoxicity tests have yielded positive results. The working group agreed that non-linear dose-response curves occur in vivo with at least some DNA-reactive agents. Quantitative risk assessment in such cases requires the use of (1) adequate data, i.e., the use of all available data for the selection of reliable in vivo models to be used for quantitative risk assessment, (2) appropriate mathematical models and statistical analysis for characterizing the dose-response relationships and allowing the use of quantitative and dose-response information in the interpretation of results, (3) mode of action (MOA) information for the evaluation and analysis of risk, and (4) reliable assessments of the internal dose across species for deriving acceptable margins of exposure and risk levels. Hence, the elucidation of MOA and understanding of the mechanism underlying the dose-response curve are important components of risk assessment. The group agreed on the need for (i) the development of in vivo assays, especially multi-endpoint, multi-species assays, with emphasis on those applicable to humans, and (ii) consensus about the most appropriate mathematical models and statistical analyses for defining non-linear dose-responses and exposure levels associated with acceptable risk.


Whatever happened to reversion?
The idea of 'reversion' or 'atavism' has a peculiar history. For many authors in the late-nineteenth and early-twentieth centuries - including Darwin, Galton, Pearson, Weismann, and Spencer, among others - reversion was one of the central phenomena which a theory of heredity ought to explain. By only a few decades later, however, Fisher and others could look back upon reversion as a historical curiosity, a non-problem, or even an impediment to clear theorizing. I explore various reasons that reversion might have appeared to be a central problem for this first group of figures, focusing on their commitment to a variety of conceptual features of evolutionary theory; discuss why reversion might have then ceased to be an interesting phenomenon; and, finally, close with some more general thoughts about the death of scientific problems.