The New Biomarker for Cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma (CESC) Based on Public Database Mining.
To reconstruct the ceRNA biological network of cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) and to select an appropriate mRNA as a biomarker that could be used for CESC early diagnosis and prognosis evaluation. We downloaded CESC data from the TCGA public database, and statistical analysis was conducted with the R software to find out differential expressed genes encoding for lncRNAs, miRNAs, and mRNAs. The differentially expressed mRNAs (DEmRNAs) screened in the ceRNA network were analyzed for survival to find the mRNAs with significantly linked to the survival prognosis. These mRNAs were searched in the Pathological Atlas to identify the final appropriate mRNAs. Differential expression analysis revealed 773 lncRNAs, 94 miRNAs, and 2466 mRNAs. Survival analysis of DEmRNAs in the ceRNA network indicated that ADGRF4, ANXA8L1, HCAR3, IRF6, and PDE2A (P < 0.05) were negatively correlated with survival time. Verification of these six DEmRNAs in the Pathology Atlas indicated that PDE2A was a possible biomarker for CESC patients. PDE2A might be a biomarker for early diagnosis and prognosis evaluation of CESC patients, but due to the lack of available data, further studies may be needed for confirmation.


Life Experience of Chinese Pediatric Medulloblastoma Survivors: A Qualitative Study.
BACKGROUND: With the improvement of technology and the advancement of medical treatment in recent decades, more and more pediatric medulloblastoma survivors reintegrate to the community. This study aimed to examine the experiences of pediatric medulloblastoma survivors. METHODS: A qualitative research was conducted. Twenty Chinese pediatric medulloblastoma survivors were interviewed. Interviews were recorded and transcribed. Colaizzi's analysis method was used to analyze data. RESULTS: There were 4 themes in this study: physical health issues, community reintegration challenges, overcoming psychological pressure, and multiple unmet needs. CONCLUSION: Pediatric medulloblastoma survivors face challenges in the physical, psychological, and social aspects of their health, along with multiple unmet healthcare needs. Nurses should comprehensively assess the survivor's needs from admission, plan for discharge, and provide regular follow-up care after discharge. Furthermore, nurses should collaborate with caregivers, clinicians, and schoolteachers to develop programs aimed at enhancing the quality of life for survivors. It is also important to explore the survival experiences of individuals in different regions.


Torturing personification of chronic pain among torture survivors.
Consistent with the human tendency to anthropomorphize objects, events, and situations, individuals might ascribe human characteristics to physical symptoms and illnesses. This manuscript presents an examination of chronic pain personification in torture survivors. Specifically, it was hypothesized that torture survivors personify chronic pain as a torturing sensation. It was further hypothesized that PTSD mediates the effect of past torture on torturing pain personification. Fifty-nine Israeli ex-prisoners of war (ex-POWs), who experienced severe torture in captivity, and 44 matched controls completed self-administered questionnaires at 18, 30, and 35years post captivity. Whereas ex-POWs exhibit higher torturing personification than controls, no differences were found in concrete description of chronic pain. PTSD trajectories were implicated in different levels of torturing personification. Finally, sequential mediation analysis revealed that PTSD at T2 and T3 mediated the association between torture and torturing personification. The findings suggest that trauma shapes the way individuals relate to and experience their bodily sensations.


Spontaneous Renal Artery Dissection Resulting in Renal Infarction: A Case Report and Review of the Literature.
Spontaneous renal artery dissection is a rare disease and an uncommon cause of renal infarction. The patient was a man who presented to the emergency room with sudden-onset right flank pain. Computed tomography revealed right renal infarction; thus, anticoagulation was initiated. Renal angiography revealed luminal narrowing of the segmental artery to the superior pole of right kidney without a dissection flap or false lumen. We stopped anticoagulation due to a lack of evidence of thrombi or luminal narrowing of the dissected vessels. When patients present with acute flank pain, it is important to suspect renal infarction and to perform a correct diagnostic workup, even when the patient shows normal urinalysis results and a normal LDH value.


Rifampicin inhibits alpha-synuclein fibrillation and disaggregates fibrils.
The aggregation of alpha-synuclein in dopaminergic neurons of the substantia nigra is a critical step in the pathogenesis of Parkinson's disease. We show that the antibiotic rifampicin inhibited alpha-synuclein fibrillation and disaggregated existing fibrils in a concentration-dependent manner. Size-exclusion chromatography data indicated that rifampicin stabilized alpha-synuclein as both a monomer and soluble oligomers comprised of partially folded alpha-synuclein. Experiments using aged samples of rifampicin indicated that the most active species in inhibiting fibrillation and disaggregating fibrils is an oxidation product of rifampicin, which was confirmed in experiments under anaerobic conditions. These results indicate that rifampicin-mediated inhibition of alpha-synuclein fibrillation and disaggregation of fibrils involves preferential stabilization of monomeric and soluble oligomeric forms, and that rifampicin potentially may have therapeutic application for Parkinson's disease.


Intracavernous calcitonin gene-related peptide plus prostaglandin E1: possible alternative to penile implants in selected patients.
The implantation of a penile prosthesis is still the ultima ratio for patients with erectile dysfunction who fail other treatment options such as pharmacotherapy and penile venous surgery. Despite mostly favorable results regarding restoration of erectile capacity, penile allografts are often not accepted for various reasons. Therefore, pharmacotesting with a mixture of calcitonin gene-related peptide and prostaglandin E1 (CGRP/PGE1) was offered to different selected patients populations: 28 patients with erectile dysfunction and venous leakage who failed penile venous surgery, 28 patients with erectile dysfunction and venous leakage (who refused penile venous surgery) and 12 patients without venous leakage, but poor response to maximum doses of papaverine/phentolamine, received 5 micrograms CGRP plus 10 micrograms PGE1. Erections sufficient for intercourse were noted in 19/28 (67.9%), 20/28 (71.4%) and 11/12 (91.7%) patients, respectively. Our data show that a combination of CGRP and PGE1 may be an alternative to penile implants in selected patients.


[Pelvic organ prolapse, a hidden epidemic of the 21st century.]
Pelvic organ prolapse (POP) is a common condition in menopausal and postmenopausal women. POP is a chronic, slowly progressive disease that leads to physical and psycho-emotional discomfort, brings physical and moral suffering to the patient and reduces the quality of life. Among the factors contributing to the development of this pathology, there is a history of obstetric trauma, obesity, heavy physical labor, as well as genetically determined connective tissue dysplasia. Conservative methods of treating POP are known, but the low frequency of their use is due to low efficiency and late diagnosis of this pathology. The main method of treatment is surgical. Currently, more than 500 methods of surgical correction of POP in women have been described. However, the relapse rate reaches 38%. The introduction of mesh implants also did not solve this problem due to the development of implant-associated complications. Thus, it is currently relevant to further study the causes of pelvic organ prolapse, taking into account the genetic, phenotypic and clinical-anamnestic risk factors of the patient, as well as to develop a personalized approach to choosing the optimal method of surgical treatment in each individual case.


DNA methylation of KIFC1 gene in determination of histological diagnosis, prognosis and metastasis of lung cancer.
One of the main features of cancer, especially lung cancer (LC), is abnormal cell division. Abnormal expression of kinesin family member C1 (KIFC1/HSET), which is involved in mitotic cell division and ensures equatorial alignment of chromosomes during division, is observed in both premalignant and malignant lesions. There are no studies in the literature addressing the role of KIFC1 in the diagnosis and follow-up of LC. In this study, we investigated the epigenetic role of KIFC1 in the diagnosis, stage, and prognosis of various histological subtypes diagnosed with LC. The expression and methylation status of the KIFC1 gene were examined after DNA/RNA isolation in tumor, conjugate normal tissue, and blood samples from 39 patients diagnosed with LC and in blood samples from 39 healthy controls. Changes in KIFC1 gene expression were examined by the Quantitative Real Time-PCR (qRT-PCR) method after cDNA synthesis following RNA isolation. The Methylation-Specific PCR (MSP) method was used to determine the methylation status of the KIFC1 gene. In this study, the expression/methylation profiles of the KIFC1 gene and the clinical and pathological characteristics of the patients were analyzed by statistical methods. Hypomethylation was detected in 95.8% of the 62.1% of patients' tissues with increased KIFC1 gene expression. The expression level of the KIFC1 gene was found to be increased 3.2-fold in the tumor tissues of the patients compared with the conjugated normal tissues and 2.4-fold in the serum of the patients compared with the healthy serum. Statistical comparison of patients' clinical parameters and methylation and expression results revealed statistical significance between KIFC1 expression and metastasis, tumor stage and tumor grade. In conclusion, the increase in the expression level of the KIFC1 gene is higher in patients diagnosed with LC than in the healthy population, and therefore, the increase in the expression level of the KIFC1 gene due to hypomethylation can be used as a screening biomarker in LC. It can also be considered that the methylation profile of the KIFC1 gene may be a potential biomarker for determining the subtype of squamous cell carcinoma in LC. The results of the study need to be analyzed and continued with a larger number of patients.


Carcinogenetic process in gallbladder mucosa with pancreaticobiliary maljunction (Review).
Pancreaticobiliary maljunction (PBM) is a congenital anomaly with a high incidence of biliary tract carcinoma. Pathological findings strongly suggest that there is a hyperplasia-dysplasia-carcinoma sequence in carcinogenesis of PBM. A molecular biological analysis revealed high incidence of cellular proliferation activating factors such as TGF-alpha, COX-2 from the hyperplasia stage. In addition, cellular proliferative activity including BrdU, AgNOR, PCNA, and Ki-67 was significantly higher in regular gallbladder mucosa without PBM. Furthermore, a high incidence of K-ras gene mutation could be seen in hyperplasia (13-63%) and microsatellite instability could be observed in 60% of all cases in dysplasia. In cancerous lesions, a high rate of overexpression of cyclin D1, beta-catenin, p53, as well as p53 gene mutation has been recognized. These results suggest that a multistep carcinogenetic process contributes to the carcinogenesis of PBM, similar to that of other cancers. In addition, after preventive operation with resection of the extrahepatic bile duct is performed, carcinogenesis in the remnant biliary tract or pancreatic duct is rarely found. Whether the carcinogenesis is a result of the accumulation of genetic alteration from shortly after birth, or a result of regurgitation of gastrointestinal juice due to hepaticoenterostomy, remains unknown. Since a high frequency of COX-2 is positive in PBM, COX-2 inhibitors such as NSAIDs may play an important role in preventing carcinogenesis.


Acute effects of zatebradine on cardiac conduction and repolarization.
Zatebradine, a potent bradycardic agent, is believed to act selectively at the sinoatrial node. The selectivity of such a property relative to various electrophysiologic classes of action is not well defined. To characterize the electrophysiologic properties of zatebradine, the corrected sinus node recovery time, sinoatrial conduction time, conduction intervals, atrial effective refractory period and monophasic action potential duration in the ventricle were measured before and after incremental doses of zatebradine (0.1-1.5 mg/kg) in 15 anesthetized dogs. The electrophysiologic effects of zatebradine developed immediately after a single i.v. bolus dose, reaching steady-steady-state at 15 minutes with the maximum effect evident at 0.75 mg/kg. The IC(50) was 0.23 mg/kg. There was no significant effect on the sinus node recovery time. The PR interval on the electrocardiogram was significantly increased when the dose was higher than 0.25 mg/kg. The duration of the P wave and the PA interval were not changed. Zatebridine greatly increased the AH (from 135 to 178 milliseconds) without changing the HH and HV intervals in His bundle recordings. The EC(50) of this effect was 0.58 mg/kg. The QRS interval was not changed. The QTc was significantly increased from 0.43 to 0.56 s(1/2) (P < 0.05). The action potential duration was significantly increased by high dose zatebradine (> 0.5 mg/kg), the EC(50) for this effect was 0.76 mg/kg. The atrium effective refractory period was significantly increased (31%) with an EC(50) 0.69 mg/kg. These results indicate that zatebradine selectively inhibits sinus node automaticity at low doses. The inhibition of the AV nodal conduction and the lengthening of the refractory period and repolarization in the atria and the ventricles occur at higher dose.


Fatigue in older cancer patients: etiology, assessment, and treatment.
Cancer-related fatigue (CRF) is one of the most common and debilitating symptoms experienced by elderly cancer patients and by cancer survivors. However, this has not translated into an increase in clinical trials for assessment and therapy of CRF in this population. The early recognition and formal assessment of this symptom is important in order to be able to treat it, before it negatively impacts the patient's quality of life. All reversible causes like anemia, depression, anxiety, and hypothyroidism should be ruled out and treated appropriately. CRF can be treated with pharmacologic and nonpharmacologic measures and possibly a combination of both measures. Pharmacologic measures that have been studied in cancer patients with fatigue include hematopoeitics, antidepressants, donepezil, modafinil, methylphenidate, and other agents. Exercise programs continue to be the most popular and widely studied nonpharmacologic intervention for CRF. Psychosocial interventions, energy conservation measures, and improvement of sleep also can lead to less fatigue in cancer patients. However, there continues to be a need for randomized controlled trials (RCTs) evaluating CRF specifically in elderly patients with cancer. This review provides a brief overview of CRF in elderly cancer patients and highlights the areas of required research in this patient population.


Expression of Melittin in Fusion with GST in Escherichia coli and Its Purification as a Pure Peptide with Good Bacteriostatic Efficacy.
The expression and purification of melittin (MET) in microbials are difficult because of its antibacterial activities. In this work, MET was fused with a glutathione-S-transferase (GST) tag and expressed in Escherichia coli to overcome its lethality to host cells. The fusion protein GST-MET was highly expressed and then purified by glutathione sepharose high-performance affinity chromatography, digested with prescission protease, and further purified by Superdex Peptide 10/300 GL chromatography. Finally, 3.5 mg/L recombinant melittin (rMET) with a purity of >90% was obtained; its antibacterial activities against Gram-positive Bacillus pumilus and Staphylococcus pasteuri were similar to those of commercial MET. A circular dichroism spectroscopic assay showed that the rMET peptide secondary structure was similar to those of the commercial form. To our knowledge, this is the report of the preparation of active pure rMET with no tags. The successful expression and purification of rMET will enable large-scale, industrial biosynthesis of MET.


Bacillus velezensis CC09: A Potential 'Vaccine' for Controlling Wheat Diseases.
Biocontrol bacteria that can act like a "vaccine", stimulating plant resistance to pathogenic diseases, are still not fully elucidated. In this study, an endophytic bacterium, Bacillus velezensis CC09, labeled with green fluorescent protein, was tested for its colonization, migration, and expression of genes encoding iturin A synthetase within wheat tissues and organs as well as for protective effects against wheat take-all and spot blotch diseases. The results showed that strain CC09 not only formed biofilm on the root surface but was also widely distributed in almost every tissue, including the epidermis, cortex, and xylem vessels, and even migrated to stems and leaves, resulting in 66.67% disease-control efficacy (DCE) of take-all and 21.64% DCE of spot blotch. Moreover, the gene cluster encoding iturin A synthase under the control of the pitu promoter is expressed in B. velezensis CC09 in wheat tissues, which indicates that iturin A might contribute to the in-vivo antifungal activity and leads to the disease control. All these data suggested that strain CC09 can act like a 'vaccine' in the control of wheat diseases, with a single treatment inoculated on roots through multiple mechanisms.


LGN input to simple cells and contrast-invariant orientation tuning: an analysis.
We develop a new analysis of the lateral geniculate nucleus (LGN) input to a cortical simple cell, demonstrating that this input is the sum of two terms, a linear term and a nonlinear term. In response to a drifting grating, the linear term represents the temporal modulation of input, and the nonlinear term represents the mean input. The nonlinear term, which grows with stimulus contrast, has been neglected in many previous models of simple cell response. We then analyze two scenarios by which contrast-invariance of orientation tuning may arise. In the first scenario, at larger contrasts, the nonlinear part of the LGN input, in combination with strong push-pull inhibition, counteracts the nonlinear effects of cortical spike threshold, giving the result that orientation tuning scales with contrast. In the second scenario, at low contrasts, the nonlinear component of LGN input is negligible, and noise smooths the nonlinearity of spike threshold so that the input-output function approximates a power-law function. These scenarios can be combined to yield contrast-invariant tuning over the full range of stimulus contrast. The model clarifies the contribution of LGN nonlinearities to the orientation tuning of simple cells and demonstrates how these nonlinearities may impact different models of contrast-invariant tuning.


The environmentally impacts of digital health.
Digital health interventions are widely celebrated due to their low-cost nature and ability to provide tailored person-centred care in communities worldwide. As coronavirus disease-19 has rapidly accelerated their growth and reach, interest in global ethical questions surrounding digital health is growing. However, the global environmental implications of digital health have been overlooked. This commentary draws attention to the environmental impacts of digital health devices and communication networks, as well as the data produced by digital health activities. Unless serious attention is paid to greening digital health practices, the rise of digital health will significantly contribute to environmental change, and thus create outcomes of ill-health.


Accumulation of 131Iodine in the nasolacrimal sac/duct after radioiodine therapy for papillary thyroid cancer.
SPECT/CT is a powerful tool for assessing unexpected concentrations of radioiodine resulting from benign uptake in organs with sodium-iodide symporter (NIS) expression. We report a case of accumulation of 131Iodine in the nasolacrimal sac/duct after radioiodine therapy for papillary thyroid cancer. A whole-body scan was taken 3 days after the administration of 5.5 GBq of 131Iodine. SPECT/CT images localized the focal tracer uptake in the nasolacrimal sac/duct likely due to nasolacrimal duct obstruction secondary to prior radioiodine or iodine therapies. Hybrid SPECT/CT allows precise anatomical localization and help differentiate benign mimics of disease, which can alter patient management.


Evolving role of tissue factor and its pathway inhibitor.
To review the experimental and clinical evidence of the emerging role of tissue factor in intravascular thrombosis and to examine evidence supporting the potential use of tissue factor pathway inhibitor as an antithrombotic therapeutic agent. A PubMed search was conducted encompassing articles in the English language relating to tissue factor and tissue factor pathway inhibitor in intravascular coagulation. Tissue factor, a membrane-bound procoagulant glycoprotein, is the initiator of the extrinsic clotting cascade, which is the predominant coagulation pathway in vivo. The traditional view localizes tissue factor to extravascular sites, where it remains sequestered from circulating factor VII until vascular integrity is disrupted or until tissue factor expression is induced in endothelial cells or monocytes. This perspective has been challenged since the discovery of tissue factor antigen in plasma, on circulating microparticles, and on leukocytes in whole blood. Recently, the apparent role of tissue factor has expanded with the demonstration that this molecule also functions as a signaling receptor. Recombinant tissue factor pathway inhibitor, an analogue of the physiologic inhibitor of tissue factor, is a potent inhibitor of thrombus formation in experimental models. In summary, the tissue factor pathway initiates thrombosis in vivo. In addition to its classic tissue-bound distribution, recently discovered blood-borne tissue factor may have an important procoagulant function. Despite showing promise in early human studies, a recently completed phase 3 trial of recombinant tissue factor pathway inhibitor in severe sepsis failed to show a reduction in the primary end point of 28-day all-cause mortality. Tissue factor pathway inhibitor, however, remains a plausible therapeutic agent in other conditions of increased thrombogenicity, such as acute coronary syndromes, and further studies to examine this potential are warranted.


Evoked potentials in head injury and states of increased intracranial pressure.
Recent clinical studies have addressed the utility of sensory evoked potentials (auditory, somatosensory, and visual) in head injury. The clinical significance of evoked potentials in head trauma, states of increased intracranial pressure, and post-traumatic syndrome is discussed. Emphasis is placed on up-to-date studies discussing evoked potential correlation with clinical findings, lesion localization, intracranial pressure, brain herniation, and prognosis.


Acceptance and Change as Dialectic of Recovery: Examples of Storytelling, Fairy Tale and Psychopharmacotherapy as Therapeutic Modalities.
"Narative medicine" promotes theraputic healing and recovery using fairy tales and traditional folk stories. Individuals are capable of shaping their lives through various narrative strategies and re-authoring alternative stories that are concerned with different aspects of acceptance and change. Psychotherapy through the eyes of stories and fairy tales can have two perspectives. Firstly, fairy tale acts like a weft around which the very story/script of the patient is formed, which in itself becomes the basis for interpreting the occurrence of a mental disorder. The second perspective is the perspective of healing or getting out of a "fairytale" story/script by changing an incoherent life narrative into an alternative coherent narrative (reframing). The aim of this pilot case studies approach was to use a narrative approach based on stories and fairy tales in order to promote psychological growth, meaning in life, resilience, self-realization and improved well-being and highlight the dialectic of recovery, an interplay of acceptance and change (reframing). With properly applied personalized narrative psychopharmacotherapy, the patient is capable of changing their beliefs in order to reach a new meaning of life, and thus to facilitate the lowering of symptomatology, its dissaperance and possibly even a cure, whatever that may mean for an individual. Considering its promising results, clinical implications and possible further applications are discussed.


Organization of Valence-Encoding and Projection-Defined Neurons in the Basolateral Amygdala.
The basolateral amygdala (BLA) mediates associative learning for both fear and reward. Accumulating evidence supports the notion that different BLA projections distinctly alter motivated behavior, including projections to the nucleus accumbens (NAc), medial aspect of the central amygdala (CeM), and ventral hippocampus (vHPC). Although there is consensus regarding the existence of distinct subsets of BLA neurons encoding positive or negative valence, controversy remains regarding the anatomical arrangement of these populations. First, we map the location of more than 1,000 neurons distributed across the BLA and recorded during a Pavlovian discrimination task. Next, we determine the location of projection-defined neurons labeled with retrograde tracers and use CLARITY to reveal the axonal path in 3-dimensional space. Finally, we examine the local influence of each projection-defined populations within the BLA. Understanding the functional and topographical organization of circuits underlying valence assignment could reveal fundamental principles about emotional processing.


Observed parental needs during their child's hospitalization.
Hospitalization involves that parents are in an unfamiliar environment and their parental role changes. The purpose of this study was to study parental needs during the course of events when their child is hospitalized. Thirty-five parents of 24 children (aged 5 months to 18 years) were followed by observers during their child's hospitalization at a pediatric department in Sweden. Field notes were analyzed by manifest and latent coding. Nine themes characterizing parental needs were identified in the analysis. The themes consisted of the need for security, mediating security to the child, communication, control, pleasing staff, being a competent parent, the family, relief, and satisfying personal needs. The most prominent needs were the need for security and mediating security to the child.


The effect of vocabulary knowledge on novel word identification.
The study investigated the relationship between vocabulary knowledge and novel word reading. Fourth-grade students were assessed on standardized measures of word identification, decoding, and receptive vocabulary, as well as on an experimental word identification measure using words that students in the fourth grade are unlikely to have seen before in print. In the experimental measure, pairs of words were matched on printed frequency and orthographic pattern (with a variety of spelling patterns represented), but differed in terms of the frequency of expected oral exposure for children (i.e., higher vs. lower). Results showed that students' receptive vocabulary knowledge was significantly related to performance on both the standardized and experimental measures of word identification, even after accounting for the substantial amount of variance explained by decoding ability. Students performed better reading the words with higher expected oral frequencies on the experimental task than on those items with lower expected oral frequencies. The results point to the benefits, albeit modest, of oral word familiarity for reading words when they are first encountered in print and suggest that this top-down effect is not limited to exception words, as has been suggested, but has a wider scope.


Stronger induction of callose deposition in barley by Russian wheat aphid than bird cherry-oat aphid is not associated with differences in callose synthase or beta-1,3-glucanase transcript abundance.
The effects of infestation by the bird cherry-oat aphid (BCA), (Rhopalosiphum padi L) and the Russian wheat aphid (RWA) (Diuraphis noxia Mordvilko) on callose deposition and transcription of genes related to callose accumulation were investigated in barley (Hordeum vulgare L. cv. Clipper). The BCA, which gives no visible symptoms, induced very limited callose deposition, even after 14 days of infestation. In contrast, RWA, which causes chlorosis, white and yellow streaking and leaf rolling, induced callose accumulation already after 24 h in longitudinal leaf veins. The deposition was pronounced after 72 h, progressing during 7 and 14 days of infestation. In RWA-infested source leaves, callose was also induced in longitudinal veins basipetal to the aphid-infested tissue, whereas in sink leaves, more callose deposition was found above the feeding sites. Eight putative callose synthase genes were identified in a database search, of which seven were expressed in the leaves, but with similar transcript accumulation in control and aphid-infested tissue. Five out of 12 examined beta-1,3-glucanases were expressed in the leaves. All five were upregulated in RWA-infested tissue, but only two in BCA-infested tissue, and to a lesser extent than by RWA. The results suggest that callose accumulation may be partly responsible for the symptoms resulting from RWA infestation and that a callose-inducing signal may be transported in the phloem. Furthermore, it is concluded that the absence of callose deposition in BCA-infested leaves is not because of a stronger upregulation of callose-degrading beta-1,3-glucanases in this tissue, as compared to RWA-infested leaves.


Effects of endogenous formaldehyde in nasal tissues on inhaled formaldehyde dosimetry predictions in the rat, monkey, and human nasal passages.
Formaldehyde is a nasal carcinogen in rodents at high doses and is an endogenous compound that is present in all living cells. Due to its high solubility and reactivity, quantitative risk estimates for inhaled formaldehyde have relied on internal dose estimates in the upper respiratory tract. Dosimetry calculations are complicated by the presence of endogenous formaldehyde concentrations in the respiratory mucosa. Anatomically accurate computational fluid dynamics (CFD) models of the rat, monkey, and human nasal passages were used to simulate uptake of inhaled formaldehyde. An epithelial structure was implemented in the nasal CFD models to estimate formaldehyde absorption from air:tissue partitioning, species-specific metabolism, first-order clearance, DNA binding, and endogenous formaldehyde production. At an exposure concentration of 1 ppm, predicted formaldehyde nasal uptake was 99.4, 86.5, and 85.3% in the rat, monkey, and human, respectively. Endogenous formaldehyde in nasal tissues did not significantly affect wall mass flux or nasal uptake predictions at exposure concentrations > 500 ppb; however, reduced nasal uptake was predicted at lower exposure concentrations. At an exposure concentration of 1 ppb, predicted nasal uptake was 17.5 and 42.8% in the rat and monkey; net desorption of formaldehyde was predicted in the human model. The nonlinear behavior of formaldehyde nasal absorption will affect the dose-response analysis and subsequent risk estimates at low exposure concentrations. Updated surface area partitioning of nonsquamous epithelium and average flux values in regions where DNA-protein cross-links and cell proliferation rates were measured in rats and monkeys are reported for use in formaldehyde risk models of carcinogenesis.


A road from health care classifications and coding systems to biomedical ontology: the CEN categorial structure for terminologies of human anatomy: Catanat.
There is an increasing need for updated and harmonised health care classifications and coding systems to allow international comparisons and cooperation for instance for population based WHO indicators, Electronic Health Record safety, trans border migration of population, case mix and procedure payment. It is not feasible to propose a standardisation of the linguistic expressiveness of different health care professionals and of the citizens. Natural language expressions show inconsistencies and ambiguities as assessed by biomedical ontology driven tools. In order to build a road towards standardisation the European Standard Body CEN has stated that it was not possible to convince the different European member states using different national languages to agree on a reference clinical terminology as Snomed-CT or to standardise a detailed language independent biomedical ontology. It has developed since 1990 an approach named categorial structure as a step standardising only the terminologies model structure. The categorial structure for terminologies of human anatomy currently in the phase of final approval is presented as a methodology for bridging between classifications and coding systems and biomedical ontology on the way to semantic interoperability between different languages, legacies and goals.


Zinc Prevents the Development of Diabetic Cardiomyopathy in db/db Mice.
Diabetic cardiomyopathy (DCM) is highly prevalent in type 2 diabetes (T2DM) patients. Zinc is an important essential trace metal, whose deficiency is associated with various chronic ailments, including vascular diseases. We assessed T2DM B6.BKS(D)-Leprdb/J (db/db) mice fed for six months on a normal diet containing three zinc levels (deficient, adequate, and supplemented), to explore the role of zinc in DCM development and progression. Cardiac function, reflected by ejection fraction, was significantly decreased, along with increased left ventricle mass and heart weight to tibial length ratio, in db/db mice. As a molecular cardiac hypertrophy marker, atrial natriuretic peptide levels were also significantly increased. Cardiac dysfunction and hypertrophy were accompanied by significantly increased fibrotic (elevated collagen accumulation as well as transforming growth factor β and connective tissue growth factor levels) and inflammatory (enhanced expression of tumor necrosis factor alpha, interleukin-1β, caspase recruitment domain family member 9, and B-cell lymphoma/leukemia 10, and activated p38 mitogen-activated protein kinase) responses in the heart. All these diabetic effects were exacerbated by zinc deficiency, and not affected by zinc supplementation, respectively. Mechanistically, oxidative stress and damage, mirrored by the accumulation of 3-nitrotyrosine and 4-hydroxy-2-nonenal, was significantly increased along with significantly decreased expression of Nrf2 and its downstream antioxidants (NQO-1 and catalase). This was also exacerbated by zinc deficiency in the db/db mouse heart. These results suggested that zinc deficiency promotes the development and progression of DCM in T2DM db/db mice. The exacerbated effects by zinc deficiency on the heart of db/db mice may be related to further suppression of Nrf2 expression and function.


Geographic variation of the predictive values of genomic mutations associated with streptomycin resistance in Mycobacterium tuberculosis.
Specific mutations associated with resistance to streptomycin (SM) in Mycobacterium tuberculosis suggest themselves for its rapid prediction. However, as with any diagnostic test, their predictive values are dependent on their prevalences. In this report, SM resistance associated mutations in the rrs and rpsL genes of 25 SM resistant isolates from Germany and 25 SM resistant isolates from Sierra Leone were characterized and compared. Mutations in the rrs gene were infrequent in isolates from both localities (20% and 12%, respectively) and thus of limited predictive values. In contrast, rpsL mutations were found in 48% of the German isolates but only in 24% of the isolates from Sierra Leone. It is concluded that the predictive values of mutations in this gene may vary significantly with the origin of the samples under investigation.


Differential recovery of the electroretinogram, visually evoked cortical potential, and electrically evoked cortical potential following vitrectomy: implications for acute testing of an implanted retinal prosthesis.
To determine the extent to which electrophysiologic tests of the afferent visual pathway are affected by vitrectomy, the procedure was performed in 15 eyes of 11 adult Dutch-belted rabbits. An electroretinogram (ERG), visually evoked cortical potential (VECP), and electrically evoked cortical potential (EECP) were obtained preoperatively and sequentially after surgery. For electrical stimulations, biphasic impulses were delivered to the retina. Post-vitrectomy declines of 49, 25, and 41% from the median baseline amplitudes and increases of 13, 18, and 17% from the median baseline latency values were found for ERG, VECP, and EECP, respectively. At 90 min, 13 to 30% of eyes still had an amplitude more than 10% below baseline on at least one of the three tests, whereas 10 to 47% of eyes had an abnormal latency more than 10% above baseline on at least one of the three tests. Amplitudes were more likely than latencies to return to near baseline, but for eyes that remained subnormal, the decline was greater for amplitudes than latencies. Significant alterations in retinal function, manifested by declines in amplitudes and increases in latencies of the ERG, VECP, and EECP, persist in a large proportion of eyes up to 90 min post-vitrectomy.


Vertical head translation impairs dynamic visual acuity during near viewing.
Dynamic visual acuity is an important clinical tool for assessment of the rotational vestibulo-ocular reflex (rVOR). It is based on the fact that the normal rVOR stabilizes vision and maintains visual acuity during head rotation. The translational VOR (tVOR) generates eye movements during linear head motion. Studies in humans have shown that gaze stabilization during translation is incomplete and that there is a strong effect of the visual environment: eye velocity is much greater in the light than in the dark. In this study, we measured visual acuity during vertical translation in 11 subjects and asked whether a more complex visual background would enhance the response and improve acuity. During 2 Hz whole-body translation, tumbling-E optotypes (0.0-0.9 logMAR in steps of 0.1 logMAR, six trials of each size randomly ordered) were flashed on a screen that was 30 cm in front of the subject's eyes. The subject reported the optotype's orientation with a joystick. Based on a threshold of 75% trials correctly identified, the group dynamic acuity was 0.72 logMAR, compared to a static acuity of 0.0 logMAR. When the background was enhanced with a stationary dot pattern, dynamic acuity improved to 0.42 logMAR. Our findings show that vertical head translation degrades vision more than head rotation. This may limit the use of dynamic acuity as a clinical measure of otolith function.


Biopharmaceutical characterization of carbamazepine immediate release tablets. In vitro-in vivo comparison.
A growing concern for the biopharmaceutical characterization of pharmaceutical products increased the interest in the evaluation and identification of physicochemical properties of drugs and dosage forms that govern its biological performance. In vitro and in vivo characteristics of two carbamazepine (CAS 298-46-4) immediate release tablets were investigated and compared in order to establish level A in vitro-in vivo correlation. An in vivo study was conducted as a controlled, two-way, complete cross-over, single dose, pharmacokinetic trial in 18 subjects. The in vitro study was performed using various dissolution media in order to evaluate their potential influence on drug release and distinguish the set of experimental conditions relevant to the in vivo behavior of the investigated drug products. Beside significant differences among in vitro release profiles, the in vivo data indicated bioequivalence of the two formulations. Although a high level of correlation between in vivo and in vitro data was observed in some media, there was no single in vitro-in vivo correlation model applicable to both investigated products. The obtained results add to the existing debate on the rationale for the use of surfactants in drug release media and their in vivo relevance, emphasizing the importance of in vitro dissolution testing in addition to in vivo bioequivalence testing.


Topical ganciclovir treatment post-Descemet's stripping automated endothelial keratoplasty for patients with bullous keratopathy induced by cytomegalovirus.
To investigate the efficacy of topical ganciclovir (GCV) for preventing disease recurrence and improving the surgical outcome post-Descemet's stripping automated endothelial keratoplasty (DSAEK) in patients with cytomegalovirus (CMV) endotheliitis. This prospective, non-comparative case series study involved six eyes of six patients with endothelial decompensation due to CMV endotheliitis who underwent DSAEK, followed by a continuous, four to six times daily, topical administration of 0.5% GCV. Patient demographics, clinical history, and preoperative and postoperative examination (including any recurrence of CMV endotheliitis post-DSAEK), best corrected visual acuity (BCVA), intraocular pressure (IOP), graft survival rate and endothelial cell density (ECD) were examined. No recurrence of CMV endotheliitis was detected post-DSAEK. The mean follow-up period was 40 months (range, 12-60 months). The mean preoperative BCVA was 1.52±0.68 LogMAR (range, 0.52-2.40 LogMAR), yet it had significantly improved to 0.15±0.16 LogMAR (range: -0.08 to 0.30 LogMAR) by 1 year postoperative (P<0.01). In all patients, IOP was well controlled (10-20 mm Hg) postsurgery. The mean preoperative donor ECD was 2692±177 cells/mm2, and the mean postoperative ECD was 1974, 1771 and 1174 cells/mm2 for the ECD loss of 26%, 33% and 54% at 6, 12 and 36 months, respectively. No adverse effects were observed associated with the long-term topical administration of GCV. The continuous topical application of 0.5% GCV was found to be effective for preventing the recurrence of CMV endotheliitis, and it provided the optimal mid-term clinical outcomes post-DSAEK in patients with CMV endotheliitis. UMIN000026746.


Immunohistochemical and clinicopathologic features of estrogen receptor-negative, progesterone receptor-positive, HER-2 negative breast carcinomas.
Currently, there is an ongoing debate whether progesterone receptor positive and estrogen receptor negative breast carcinomas represent a true distinct subtype of tumor or a mere immunohistochemical artifact. In this study, we conducted an immunohistochemistry panel with the antibodies TFF1, EGFR, and CK5 to reclassify this phenotype in a luminal or basal-like subtype. Tumors estrogen receptor -/progesterone receptor +, Her-2 - from a large population of breast cancer patients were selected to be studied. Immunohistochemistry with the antibodies TFF1, EGFR, and CK5 was performed. Tumors showing positivity for TFF1, regardless of EGFR and CK5 results, were classified as luminal-like carcinomas. Those lesions that were negative for TFF1, but were positive for EGFR and/or CK5, were classified as basal-like triple-negative carcinomas. When the three markers were negative, tumors were classified as undetermined. Clinical pathologic characteristics of patients and tumor recurrence were evaluated. Out of 1188 breast carcinomas investigated, 30 cases (2.5%) presented the estrogen receptor -/progesterone receptor +/HER2- phenotype. Of them, 27 tumors (90%) were classified as basal-like triple-negative carcinomas, one as luminal-like (3.3%), and two as undetermined tumors (6.7%). The mean follow-up for the study group was 27.7 (2.7 to 50) months. Out of the 26 patients, 6 had cancer recurrence: 2 local and 4 systemic recurrences. The average time for recurrence was 17 (8 to 38) months. Estrogen receptor -/progesterone receptor +/tumors exhibit aggressive behavior, similar to triple-negative tumors. An appropriate categorization of these tumors should be made to improve their therapeutic management.


[Clinical importance of Acinetobacter calcoaceticus isolations from blood and venous catheters].
From 1980 to 1982 Acinetobacter calcoaceticus (A.c.) derived from blood cultures and venous catheters of 29 patients could be grown. 6 patients with clinical signs of Gram-negative septicemia had two or more blood cultures positive for A.c. Thus, the role of A.c. as the etiologically relevant pathogen seems to be evident. In 14 cases with clinical signs of septicemia but only one set of blood cultures positive for A.c. it is felt to be the causative agent since no other cause could be found. In 9 cases isolation of A.c. seems to be due to contamination - most likely from skin -, because neither evidence of septicemia nor relationship to the diseases present of A.c. existed.


Auditory- and Vestibular-Evoked Potentials Correlate with Motor and Non-Motor Features of Parkinson's Disease.
Degeneration of several brainstem nuclei has been long related to motor and non-motor symptoms (NMSs) of Parkinson's disease (PD). Nevertheless, due to technical issues, there are only a few studies that correlate that association. Brainstem auditory-evoked potential (BAEP) and vestibular-evoked myogenic potential (VEMP) responses represent a valuable tool for brainstem assessment. Here, we investigated the abnormalities of BAEPs, ocular VEMPs (oVEMPs), and cervical VEMPs (cVEMPs) in patients with PD and its correlation to the motor and NMSs. Fifteen patients diagnosed as idiopathic PD were evaluated by Unified Parkinson's Disease Rating Scale and its subscores, Hoehn and Yahr scale, Schwab and England scale, and Non-Motor Symptoms Scale. PD patients underwent pure-tone, speech audiometry, tympanometry, BAEP, oVEMPs, and cVEMPs, and compared to 15 age-matched control subjects. PD subjects showed abnormal BAEP wave morphology, prolonged absolute latencies of wave V and I-V interpeak latencies. Absent responses were the marked abnormality seen in oVEMP. Prolonged latencies with reduced amplitudes were seen in cVEMP responses. Rigidity and bradykinesia were correlated to the BAEP and cVEMP responses contralateral to the clinically more affected side. Contralateral and ipsilateral cVEMPs were significantly correlated to sleep (p = 0.03 and 0.001), perception (p = 0.03), memory/cognition (p = 0.025), and urinary scores (p = 0.03). The oVEMP responses showed significant correlations to cardiovascular (p = 0.01) and sexual dysfunctions (p = 0.013). PD is associated with BAEP and VEMP abnormalities that are correlated to the motor and some non-motor clinical characteristics. These abnormalities could be considered as potential electrophysiological biomarkers for brainstem dysfunction and its associated motor and non-motor features.


Quantification of amygdalin, prunasin, total cyanide and free cyanide in powdered loquat seeds.
Amygdalin, prunasin, total cyanide and free cyanide concentrations in 12 powdered loquat seeds were investigated. Loquat (Eriobotrya japonica) is a species of flowering plant in the family Rosaceae, and its fruit is quite popular in Japan. Amygdalin and prunasin were measured using LC-MS/MS. Total cyanide was measured by enzymatic treatment, steam distillation and colorimetric quantification using the pyridine-pyrazolone method. Free cyanide was measured without enzymatic treatment. The mean concentrations of amygdalin, prunasin, total cyanide and free cyanide in powdered loquat seeds were 5900, 760, 410 and 44 mg/kg, respectively. The range of each quantitative value was extensive. Seven out of twelve samples were at risk for exceeding the acute reference dose (ARfD) of cyanide.


Combinations of genotoxic tests for the evaluation of group 1 IARC carcinogens.
Many of the known human carcinogens are potent genotoxins that are efficiently detected as carcinogens in human populations but certain types of compounds such as immunosuppressants, sex hormones, etc. act via non-genotoxic mechanism. The absence of genotoxicity and the diversity of modes of action of non-genotoxic carcinogens make predicting their carcinogenic potential extremely challenging. There is evidence that combinations of different short-term tests provide a better and efficient prediction of human genotoxic and non-genotoxic carcinogens. The purpose of this study is to summarize the in vivo and in vitro comet assay (CMT) results of group 1 carcinogens selected from the International Agency for Research on Cancer and to discuss the utility of the comet assay along with other genotoxic assays such as Ames, in vivo micronucleus (MN), and in vivo chromosomal aberration (CA) test. Of the 62 agents for which valid genotoxic data were available, 38 of 61 (62.3%) were Ames test positive, 42 of 60 (70%) were in vivo MN test positive and 36 of 45 (80%) were positive for the in vivo CA test. Higher sensitivity was seen in in vivo CMT (90%) and in vitro CMT (86.9%) assay. Combination of two tests has greater sensitivity than individual tests: in vivo MN + in vivo CA (88.6%); in vivo MN + in vivo CMT (92.5%); and in vivo MN + in vitro CMT (95.6%). Combinations of in vivo or in vitro CMT with other tests provided better sensitivity. In vivo CMT in combination with in vivo CA provided the highest sensitivity (96.7%).


Prevalence of sleep bruxism and awake bruxism in different chronotype profiles: Hypothesis of an association.
Sleep (SB) and awake bruxism (AB) recognize a multifactorial etiology and have a relationship with several psychological factors. Psychological disorders have recently been associated also with the chronotype, which is the propensity for an individual to be especially active at a particular time during a 24-h period. Based on the chronotype, the two extreme profiles are morningness and eveningness individuals. Due to the relationship that both the chronotype and bruxism have with psychological factors and the fact that performing tasks not compatible with chronotype can trigger stress, this review presents the hypothesis that the prevalence of SB and AB can differ with the various chronotype profiles. New perspectives for the study of bruxism etiology may emerge from investigations on the topic.


Review of the novelties from the 31st ECTRIMS Congress, 2015, presented at the 8th Post-ECTRIMS meeting.
Renowned national specialists in multiple sclerosis (MS) met, for the eighth year in a row, to give details of the latest novelties presented at the last ECTRIMS Congress 2015, which are included in this review. One of the highlights at this Congress was the new classification of the phenotypes of MS. Both the diagnostic criteria of the neuromyelitis optica spectrum and the problems involved in the differential diagnosis derived from the lack of definition of the radiological spectrum were reviewed. The microbiota comes to the fore as a possible factor determining the disease, together with extrinsic factors such as tobacco, salt ingestion or vitamin D deficiency. Advances made in immunomodulation are driving the progress being made in the treatment of MS. Ocrelizumab is the first treatment with positive results in the primarily progressive forms and tocilizumab, a drug product for rheumatoid arthritis, stands out as a potential candidate for the treatment of neuromyelitis optica. Certain antibiotics and vitamins could also play a role in the treatment of MS. In this edition of the Congress special attention was paid to personalised therapy. To date, 11 drugs have been approved for use in Europe. There is a need for therapeutic algorithms that help us to choose the best treatment for each patient. Likewise, we need to be able to identify, in the early stages of the disease, the risk of developing disability, so as to be able to design therapeutic strategies. To do so, molecular biomarkers and other predictive tools are required. The problems that still exist in software technology in magnetic resonance hinder its application in daily clinical practice.


Epitopes functional in neutralization of varicella-zoster virus.
By competition neutralization assay using monoclonal antibodies (MAbs) to varicella-zoster virus (VZV) glycoproteins (gps), we attempted to determine the topographical relationship of epitopes which are functional in VZV neutralization. MAbs against gpI interfered moderately to strongly with neutralization of MAbs against gpIII, and one antigenic domain with two distinct epitopes was identified on gpIII. Competition neutralization assays performed with MAbs to gpI revealed at least three distinct antigenic domains: the first contained two complement-dependent neutralizing epitopes; the second contained five complement-dependent neutralizing, overlapping epitopes and one nonneutralizing, nonoverlapping epitope; and the third contained one complement-enhanced neutralizing epitope. Competition neutralization assays performed with MAbs to gpIV showed one antigenic domain with two distinct epitopes which competed with nonneutralizing gpI MAbs. gpII did not interfere with neutralization of gpI, gpIII, or gpIV. Our data suggest that neutralizing and nonneutralizing MAbs can interfere with the action of viral neutralization either by inhibition or by enhancement. This report describes the epitope mapping of VZV gps by a functional biological assay.


Use of High-Protein and High-Dietary-Fibre Vegetable Processing Waste from Bell Pepper and Tomato for Pasta Fortification.
There is worldwide wastage of 1.3 billion tons of food annually. It is recommended that food waste should be reduced at every phase of production. By-products from food processing have high nutritional value so their use in new products is advisable. The aim of the study was to enrich the nutritional value of pasta using waste from the food industry. By-products from tomato processing (tomato waste-TW) and pepper (defatted pepper seeds-DPS, pepper placenta-PP) were used at a level of 10-30% to produce pasta. The farinographic characteristics, chemical composition, cooking quality, and colour of the pasta were studied. The results show a significant (p < 0.05), up to 27%, increase in the protein content of the TW30 samples, compared with the control (16.16% d.m. vs. 20.61% d.m.). The TDF content increased over five times in DPS30 and TW30 (27.99% d.m. and 25.44% d.m.). The amino acid composition of the pasta improved with the fortification but failed to achieve complete protein by FAO. The DPS30, PP20, PP30 and all TW samples can be considered high-protein products according to the EU definition (a minimum of 20% energy from protein). Vegetable waste can be a valuable additive for the improvement of the nutritional value of food.


Ovotesticular disorder of sex development with unusual karyotype: patient report.
Ovotesticular disorder of sex development (OT-DSD) (true hermaphroditism) is an anatomopathological diagnosis based on the findings of testicular and ovarian tissues in the same subject, in the same gonad (ovotestis), or in separate gonads. OT-DSD is a rare cause of sex ambiguity, and the most common karyotype is 46,XX; mosaics and chimeras are found only in 10%-20%. To report a case of an OT-DSD patient with a rare karyotype constitution. A 2-month-old child with male sex assignment was referred to our clinic for investigation of sex ambiguity. He was the second child of healthy unrelated parents; pregnancy and labor were uneventful. On physical examination, he had a 2.3-cm phallus and perineal hypospadias (Prader grade III); the right gonad was in the labioscrotal fold and the left was found in the inguinal channel. Karyotype was 46,XX/47,XXY/48,XXYY. Anatomopathological examination of gonads revealed right testis and left ovotestis. The male sex assignment was maintained; the child underwent left gonadectomy, removal of Mullerian structures and urethroplasty. A thorough revision of literature revealed a single case of OT-DSD with the same chromosome constitution. Gonadal biopsy is necessary to establish diagnosis in cases of sex chromosome mosaicism.


Practicing medicine in a new environment: what can we learn from the business managers?
Physicians, once only responsible for patient care, now are responsible for their organization's management. Although this paradigm shift occasioned much opposition, most aspects of this change are improving as the rules are reevaluated and reconsidered. Physician managers have difficult tasks for which medical school provides no preparation. Employees must be individually evaluated, so their unique talents can be properly exploited and appropriately compensated. Each person's weaknesses must be improved upon with delicacy, while his or her strengths are given greater and greater focus. This is especially true with regards to billing and coding because the financial health of all healthcare businesses requires organizational competence in this arena. It is vital to have an understanding of each staff member's skills, talents, and knowledge, and a proper deployment of each person into the appropriate job. The goal of any manager is a group of satisfied employees who enjoy their work and make appropriately recognized contributions.


Multi-terminology indexing for the assignment of MeSH descriptors to medical abstracts in French.
To facilitate information retrieval in the biomedical domain, a system for the automatic assignment of Medical Subject Headings to documents curated by an online quality-controlled health gateway was implemented. The French Multi-Terminology Indexer (F-MTI) implements a multiterminology approach using nine main medical terminologies in French and the mappings between them. This paper presents recent efforts to assess the added value of (a) integrating four new terminologies (Orphanet, ATC, drug names, MeSH supplementary concepts) into F-MTI's knowledge sources and (b) performing the automatic indexing on the titles and abstracts (vs. title only) of the online health resources. F-MTI was evaluated on a CISMeF corpus comprising 18,161 manually indexed resources. The performance of F-MTI including nine health terminologies on CISMeF resources with Title only was 27.9% precision and 19.7% recall, while the performance on CISMeF resources with Title and Abstract is 14.9 % precision (-13.0%) and 25.9% recall (+6.2%). In a few weeks, CISMeF will launch the indexing of resources based on title and abstract, using nine terminologies.


1.3E2, a variant of the B lymphoma 70Z/3, defective in activation of NF-kappa B and OTF-2.
The mouse B-cell cell lymphoma 70Z/3 is a convenient model system in which to study the regulation of immunoglobulin synthesis. Three transcriptional activators of kappa (kappa) light chain synthesis have been identified for these cells: bacterial lipopolysaccharide (LPS), interferon-gamma (IFN), and interleukin-1 (IL-1). The response of the kappa gene in 70Z/3 cells to LPS is mediated by increases in two transcription factors: NF-kappa B and OTF-2. In contrast, IFN has no effect on either of these factors in 70Z/3 cells. We have isolated by immunoselection an LPS- IFN+ variant of 70Z/3 called 1.3E2. We show here that LPS treatment of these cells causes no increase in nuclear localization of either NF-kappa B or OTF-2. Although they have normal levels of cytoplasmic NF-kappa B, it cannot be activated by LPS or by phorbol 12-myristate 13-acetate (PMA) treatment of the cells. These experiments expand the genetic dissection of the molecular pathways of activation of kappa transcription in 70Z/3 cells.


Heparin plus aspirin for unstable angina.
Adding heparin to aspirin in the treatment of people with unstable angina reduces the risk of myocardial infarction or death, research suggests. A meta-analysis was undertaken of six randomised trials which compared aspirin alone with aspirin plus heparin. The overall summary relative risk of myocardial infarction or death during randomised treatment was 0.67 in those treated with aspirin plus heparin compared with those treated with heparin alone. The risk for recurrent ischaemic pain was 0.68, 0.82 for infarction or death two to 12 weeks post-randomisation, 1.03 for revascularisation and 1.99 for major bleeding.


A Full-Coordinate Model of the Polymerase Domain of HIV-I Reverse Transcriptase and its Interaction With a Nucleic Acid Substrate.
Abstract We present a full-coordinate model of residues 1-319 of the polymerase domain of HIV-I reverse transcriptase. This model was constructed from the x-ray crystallographic structure of Jacobo-Molina et al. (Jacobo-Molina et al., P.N.A.S. USA 90, 6320-6324 (1993)) which is currently available to the degree of C- coordinates. The backbone and side-chain atoms were constructed using the MAXSPROUT suite of programs (L. Holm and C. Sander, Mol. Biol. 218, 183-194 (1991)) and refined through molecular modeling. A seven base pair A-form dsDNA was positioned in the nucleic acid binding cleft to represent the template-primer complex. The orientation of the template-primer complex in the nucleic acid binding cleft was guided by the positions of phosphorus atoms in the crystal structure. Two magnesium ions were placed in the active site in order to better understand the polymerization mechanism. The positions of metal ions in a number of structures guided the placement of ions in this study (L.S. Beese and T.A. Steitz, EMBO. J10, 25-33 (1991); T.A. Steitz and J.A. Steitz, P.N.A.S. USA 90, 6498-6502 (1993); D.L. Sloan et al., J. Biol. Chem. 250, 8913-8920 (1975); R.F. Setlik et al., J. Biomol. Str. Dyn. 10, 945-972 (1993)). The geometry of the active site allowed metal ions to be bound to Asp 110 and Asp 186 of the catalytic triad. However, due to spacial constraints, Asp 185 was found unable to bind to a metal ion. Due to its proximity to the attacking 3'OH group of the 3' terminal residue of the primer strand, it is proposed that this residue acts as a general base which abstracts a proton from the attacking group. Based on the locations of these metal ions with respect to the attacking group of the 3' end of the primer strand and to an incoming dTTP placed in the active site, we propose roles for the magnesium ions and discuss a mechanism through which chain elongation occurs. Also reported are the interactions between the polymerase domain and the template-primer complex observed in our model. These interactions are discussed in view of their possible roles in positioning the nucleic acid complex in the binding cleft and in regard to other structural and functional roles. The importance of these residues as observed in our model is compared to results from multiple sequence alignments and various mutational studies on HIV-I reverse transcriptase.


Determinants of Primaquine and Carboxyprimaquine Exposures in Children and Adults with Plasmodium vivax Malaria.
Primaquine is the only widely available drug for radical cure of Plasmodium vivax malaria. There is uncertainty whether the pharmacokinetic properties of primaquine are altered significantly in childhood or not. Patients with uncomplicated P. vivax malaria and with normal glucose-6-phosphate dehydrogenase were randomized to receive either chloroquine (25 mg base/kg of body weight) or dihydroartemisinin-piperaquine (dihydroartemisinin at 7 mg/kg and piperaquine at 55 mg/kg) plus primaquine, given either as 0.5 mg base/kg/day for 14 days or 1 mg/kg/day for 7 days. Predose day 7 venous plasma concentrations of chloroquine, desethylchloroquine, piperaquine, primaquine, and carboxyprimaquine were measured. Methemoglobin levels were measured at frequent intervals. Day 7 primaquine and carboxyprimaquine concentrations were available for 641 patients. After adjustment for the milligram-per-kilogram primaquine daily dose, day of sampling, partner drug, and fever clearance, there was a significant nonlinear relationship between age and trough primaquine and carboxyprimaquine concentrations and daily methemoglobin levels. Compared to adults 30 years of age, children 5 years of age had trough primaquine concentrations that were 0.53 (95% confidence interval [CI], 0.39 to 0.73)-fold lower, trough carboxyprimaquine concentrations that were 0.45 (95% CI, 0.35 to 0.55)-fold lower, and day 7 methemoglobin levels that were 0.87 (95% CI, 0.58 to 1.27)-fold lower. Increasing plasma concentrations of piperaquine and chloroquine and poor metabolizer CYP 2D6 alleles were associated with higher day 7 primaquine and carboxyprimaquine plasma concentrations. Higher blood methemoglobin concentrations were associated with a lower risk of recurrence. Young children have lower primaquine and carboxyprimaquine exposures and lower levels of methemoglobinemia than adults. Young children may need higher weight-adjusted primaquine doses than adults. (This study has been registered at ClinicalTrials.gov under identifier NCT01640574.).


The effect of flow changes on the arterial system proximal to an arteriovenous fistula for hemodialysis.
Arterial remodeling in response to flow changes is controlled by the endothelium, sensing wall shear stress (SS) changes. The present study focuses on the remodeling capacities of the brachial (BA) and radial artery (RA) of 16 renal failure patients after arteriovenous fistula creation. Pre- and postoperatively at predetermined time-points, diameter, wall thickness and peak and mean SS were assessed. After arteriovenous fistula creation, acute increases in BA SS (p = 0.018) and lumen diameter (p = 0.028) were observed. The diameter further increased in the next year (p = 0.023), whereas BA SS remained unchanged. RA SS and diameter increased acutely (p = 0.005) and remained unaltered after 1 y. RA wall thickness tended to decrease acutely (p = 0.059) and increased steadily during 1 y (p = 0.008). BA and RA diameter acutely increased after an acute SS rise and remained augmented after 1 y. Also, the RA vessel wall thickness enlarged, indicating structural remodeling. After 1 y, however, these changes did not result in SS restoration.


Is phytoestrogen intake associated with decreased risk of prostate cancer? A systematic review of epidemiological studies based on 17,546 cases.
This study uses current epidemiological data to evaluate whether phytoestrogen intake is associated with a reduced risk of prostate cancer. We performed a random-effect meta-analysis of published data retrieved from PubMed, Web of Science, ProQuest, and CNKI, which was supplemented by a manual search of relevant references. Study quality was assessed using the Newcastle-Ottawa Scale (NOS). Subgroup analysis and meta-regression were performed to explore the source of heterogeneity. Sensitivity analysis was evaluated to assess the stability of the results. Egger's test and funnel plots were used to detect the existence of publication bias. We retrieved 507 papers, and 29 studies were ultimately confirmed as eligible. The meta-analysis showed that phytoestrogen intake was significantly associated with a reduced risk of prostate cancer, with an odds ratio (OR) of 0.77 (95% CI 0.66-0.88; I(2) = 77.6%). The food/nutritional sources that were significantly associated with a reduced risk of prostate cancer included soy and soy products, tofu, legumes, daidzein, and genistein. Subgroup analysis indicated that the associations were significant among Asians and Caucasians, but not among Africans. Meta-regression revealed that the pooled OR increased with the number of cases in the studies. The results might be affected by publication bias based on the Eggers' test (p = 0.011) and the asymmetry of the funnel plot. Phytoestrogen intake may reduce the risk of prostate cancer in Asians and Caucasians. Regular intake of food that is rich in phytoestrogens, such as soy/soy products or legumes, should be recommended.


Cationic poly-L-lysine dendrimers: pharmacokinetics, biodistribution, and evidence for metabolism and bioresorption after intravenous administration to rats.
Cationic poly-L-lysine 3H-dendrimers with either 16 or 32 surface amine groups (BHALys [Lys]4 [3H-Lys]8 [NH2]16 and BHALys [Lys]8 [3H-Lys]16 [NH2]32, generation 3 and 4, respectively) have been synthesized and their pharmacokinetics and biodistribution investigated after intravenous administration to rats. The species in plasma with which radiolabel was associated was also investigated by size exclusion chromatography (SEC). Rapid initial removal of radiolabel from plasma was evident for both dendrimers (t(1/2) < 5 min). Approximately 1 h postdose, however, radiolabel reappeared in plasma in the form of free lysine and larger (but nondendrimer) species that coeluted with albumin by SEC. Plasma and whole blood pharmacokinetics were similar, precluding interaction with blood components as a causative factor in either the rapid removal or reappearance of radioactivity in plasma. Administration of monomeric 3H L-lysine also resulted in the appearance in plasma of a radiolabeled macromolecular species that coeluted with albumin by SEC, suggesting that biodegradation of the dendrimer to L-lysine and subsequent bioresorption may explain the pharmacokinetic profiles. Capping the Lys8 dendrimer with D-lysine to form BHALys [Lys]4 [3H-Lys]8 [D-Lys]16 [NH2]32 resulted in similar, and very rapid, initial disappearance kinetics from plasma when compared to the L-lysine capped dendrimer. Since significant extravasation of these large hydrophilic molecules seems unlikely, this most likely reflects both elimination and extensive binding to vascular surfaces. Capping with "non-natural" D-lysine also appeared to render the dendrimer essentially inert to the biodegradation process. For the L-lysine capped dendrimers, radiolabel was widely distributed throughout the major organs, with no apparent selectivity for organs of the reticuloendothelial system. In contrast, a greater proportion of the administered radiolabel was recovered in the organs of the reticuloendothelial system for the D-lysine capped system, as might be expected for a nondegrading circulating foreign colloid. To our knowledge this is the first data to demonstrate the biodegradation/bioresorption of poly-L-lysine dendrimers and has significant implications for the utility of these systems as drugs or drug delivery systems.


High incidence of multi-drug resistance and heterogeneity of mobile genetic elements in Escherichia coli isolates from diseased ducks in Sichuan province of China.
Harmonious ecological environment is a major concern with rising feeding and consumption of ducks, as these waterfowl birds can promote the spread of antibiotic resistant genes (ARGs). Therefore, this study was conducted to know diversity of antimicrobial resistance (AMR), integrons, and mobile genetic elements (MGEs) in Escherichia coli (E. coli) isolated from intestinal contents or pericardial effusion of diseased ducks from 2018 to 2020 in Sichuan, China. The AMR phenotype was determined via disk diffusion test in 165 E. coli isolates. Further, the integrase genes of integron (intI1, intI2 and intI3 genes), gene cassettes (GCs) and MGEs were screened by PCR and sequencing. The results indicated 100% isolates were resistant to at least one antibiotic and 98.8% were multidrug-resistant strains. Highest AMR phenotype was recorded to rifampin (97.0%) followed by ampicillin (95.8%), chloramphenicol (89.7%), trimethoprim-sulfamethoxazole (84.2%), ciprofloxacin (83.0%), cefotaxime (80.0%), streptomycin (75.8%), doxycycline (49.7%), amikacin (10.3%), amoxicillin/clavulanic acid (3.6%), polymyxin B (1.2%) and ertapenem (0.6%). Further, class 1 and 2 integrons were found in 87.3% and 17.6% isolates, respectively. All isolates were negative for intI3 gene. The variable region of class 1 and 2 integrons contained total 13 different GCs, including arr-3+dfrA27, dfrA1+aadA1, dfrA17+aadA5, dfrA12, dfrA1+sat2+aadA1, dfrA12+aadA2, dfrA5, aadA2+ere(A)+dfrA32, aac(6')-Ib-cr, aadA22, aadA5, dfrA17, and dfrA27. Moreover, 13 MGEs in 69 different combinations were observed with predominance of IS26 followed by tnpA/Tn21, trbC, ISEcp1, merA, ISAba1, tnsA, tnsB, tnsC, IS1133, tnsD, ISCR3/14, and tnsE. Thus, the monitoring of integrons, MGEs and ARGs is important to understand the complex mechanism of AMR, which might help to introduce interventions for prevention and control of AMR in duck farms in China.


Identification and quantitation of phenolic compounds in faecal matrix by capillary gas chromatography and nano-electrospray mass spectrometry.
Very few relevant methods have been described for the detection and quantitation of phenolic compounds in faecal matrix. Extraction with conventional organic solvents such as chloroform/methanol (2:1, Folch reagent), methanol and ethanol (72%) showed high extraction efficiency for lipids and also gave good recovery of the major phenolic compounds present in the matrix. However, in comparison with a newly developed phosphate buffer method, the yield of minor phenolics was negligible when detected by these conventional methods. Conventional methods also lead to contamination of the ion source of the mass spectrometer and rapid deterioration of column performance mostly due to the high concentration of lipids. However, if the faecal matrix is initially extracted with phosphate buffer, and the extract acidified and re-extracted with diethyl ether, the range and yield of phenolic compounds are enhanced and the problem of lipid contamination is substantially alleviated. Following pilot studies and optimisation of the procedure, individual phenolic compounds (n = 29) were identified by nano-electrospray ionisation mass spectrometry (nano-ESI-MS), nano-ESI-tandem mass spectrometry (MS/MS) and gas chromatography/mass spectrometry (GC/EI-MS) and quantitated (n = 27) by GC/MS in subsets (n = 5) of faecal samples, collected during the European Agency for Cancer Prevention calcium/fibre intervention study from four European countries (Italy, Germany, Spain and Denmark). A range of phenolic compounds (mainly acids) was detected, dominated by phenylacetic, benzoic, phenylpropionic and m-hydroxyphenylpropionic acids, representing on average 9.91 (93%), 8.25 (92%), 9.45 (95%) and 11.05 (98%) mM in the Italian, German, Spanish and Danish samples, respectively. The new method should enable large epidemiologic, case-control and intervention studies on the relevance of phenolic antioxidants in the aetiology of colorectal cancer to be conducted in the future.


Human Cytomegalovirus MicroRNAs miR-US5-1 and miR-UL112-3p Block Proinflammatory Cytokine Production in Response to NF-κB-Activating Factors through Direct Downregulation of IKKα and IKKβ.
Emerging evidence indicates that human cytomegalovirus (HCMV) manipulates host cell signaling pathways using both proteins and noncoding RNAs. Several studies have shown that HCMV induces NF-κB signaling early in infection, resulting in the induction of antiviral proinflammatory cytokines with a subsequent reduction of these cytokines late in infection. The mechanism for late cytokine reduction is unknown. In this study, we show that HCMV microRNAs (miRNAs) miR-US5-1 and miR-UL112-3p target the IκB kinase (IKK) complex components IKKα and IKKβ to limit production of proinflammatory cytokines in response to interleukin 1β (IL-1β) and tumor necrosis factor alpha (TNF-α). Transfection of miR-UL112-3p and miR-US5-1 mimics reduced endogenous IKKα and IKKβ protein levels, and site-directed mutagenesis of the 3' untranslated regions (UTRs) identified the binding sites for each miRNA. Infection with mutant viruses lacking these miRNAs resulted in increased levels of IKKα and IKKβ proteins, an impaired ability to control NF-κB signaling at late times of lytic infection, and increased production of proinflammatory cytokines compared to wild-type virus in cell types relevant to HCMV infection in vivo These phenotypes were rescued by preexpression of miR-US5-1 and miR-UL112-3p in infected cells or by a miR-US5-1/miR-UL112-3p double mutant virus that expresses short hairpin RNAs (shRNAs) targeting IKKα and IKKβ, demonstrating the gene specificity of the miRNAs. These observations describe a mechanism through which HCMV miRNAs expressed late in the infectious cycle downregulate proinflammatory cytokine production to create a cellular proviral environment.IMPORTANCE Human cytomegalovirus (HCMV) is a significant cause of morbidity and mortality in transplant recipients and causes hearing loss and mental retardation when acquired congenitally. Initial events during HCMV infection result in the activation of NF-κB signaling, which culminates in the production of IL-6, CCL5, and TNF-α. Several viruses have developed mechanisms to block the antiviral effects of these cytokines. We show here that two HCMV miRNAs, miR-US5-1 and miR-UL112-3p, specifically downregulate IKKα and IKKβ signaling factors necessary to propagate NF-κB signaling and subsequent IL-6, CCL5, and TNF-α production. Regulation of these proinflammatory cytokines during lytic infection and during latency is critical to viral survival in the host.


Focus on occupational therapists' paradigms.
The primary aim of this study was to identify and characterize the perceptions of seven experienced occupational therapists' about their profession, in particular with respect to a 'world view' and a 'field of action view'. The secondary aim was to determine whether there were similarities among the respondents' personal paradigms that could constitute a potential, local ideology for the group. The study has an explorative design based on Törnebohm's theory of paradigms. Qualitative data were collected on three occasions during the autumn of 1996, using audio- and video-taped, thematic discussions, involving focus groups. The data were analysed qualitatively within the two paradigm components, 'world view' and 'field of action view'. The results show several unifying factors, and dissimilarities were limited to specifications within these unifying factors, with respect to the respondents' notions. The unifying factors could be described as a potential, local ideology for the group.


A case of secondary pulmonary hypertension due to microscopic pulmonary tumor cell embolism from gallbladder carcinoma.
We describe a case of subacute cor pulmonale caused by tumor embolism from a gallbladder carcinoma in a 63-year-old woman. The patient was admitted to hospital with increasing dyspnea. Physical examination and echocardiography showed signs of pulmonary hypertension. She died of circulatory failure. At autopsy microscopic studies revealed tumor embolism in the pulmonary vessels and subsequent lesions causing the lethal pulmonary hypertension. This is the first case report of pulmonary hypertension caused by embolism from a gallbladder carcinoma in the literature worldwide.


Primary malignant melanoma of the lung: A case report.
Malignant melanoma involving the respiratory tract is nearly always metastatic from a cutaneous lesion. Primary malignant melanoma of the lung (PMML) is very rare. We herein report the case of a 61-year-old female patient with PMML who presented with a small nodule in the lower lobe of the left lung on chest computed tomography. As an intraoperative diagnosis of malignant melanoma was made, left lower lobectomy with systematic lymph node dissection were performed. Pathologically, there were no lymph node or intrapulmonary metastases. Lesions other than the pulmonary nodule were not detected throughout the comprehensive postoperative examination of all organs. Thus, the patient was followed up regularly as an outpatient. However, 1 year after the operation, multiple organ metastases developed. The patient's condition rapidly deteriorated and she succumbed to the disease 15 months after the operation, despite intensive chemo-immunotherapy.


[Antidepressant Effects of Repetitive Transcranial Magnetic Stimulation from a Perspective of Neural Network Dynamics].
The neurobiological mechanisms that regulate the therapeutic effects of repetitive transcranial magnetic stimulation (rTMS) remain unknown to date. An optimized rTMS protocol has not been established, partly due to the wide variability in its aftereffects among individuals who have undergone the treatment. Responder rates to rTMS for treating major depression have been reported to be modest (30 to 40 percent). Thus, optimization and personalization of an rTMS protocol is required for better treatment outcomes. To this end, it is necessary to identify brain biomarkers for predicting responsiveness to rTMS treatment and the aftereffects and for personalizing rTMS. In this review, we introduced potential biomarkers of rTMS response for treating major depression by employing two modalities of resting-state functional magnetic resonance imaging (fMRI) and electroencephalogram (EEG) from a perspective of neural network dynamics.


Assessment of the ITMIG Statement on the WHO Histological Classification and of the Eighth TNM Staging of Thymic Epithelial Tumors of a Series of 188 Thymic Epithelial Tumors.
Thymic epithelial tumors (TETs) are rare intrathoracic malignancies that are categorized histologically according to the WHO classification, which was recently updated in 2015 on the basis of a consensus statement of the International Thymic Malignancy Interest Group (ITMIG); at the same time, the standard Masaoka-Koga staging system is scheduled to be replaced by the eighth edition of the TNM staging classification by the American Joint Committee on Cancer/Union for International Cancer Control consortium. Our objectives were to analyze the feasibility of assessing ITMIG consensus major and minor morphological and immunohistochemical criteria and the eighth edition of the TNM staging classification in a routine practice setting. This is a single-center study conducted at the Louis-Pradel Hospital of Lyon University, one of the largest centers for TETs in France. Overall, a large surgical series of 188 TETs diagnosed in 181 patients between 2000 and 2014 at our center were analyzed. There were 89 men (49%) and 92 women (51%); 57 patients (31%) presented with myasthenia gravis at time of diagnosis. According to the WHO classification, there were nine type A thymomas (5%), 67 type AB thymomas (36%), 19 type B1 thymomas (10%), 46 type B2 thymomas (24%), 27 type B3 thymomas (14%), and 20 thymic carcinomas (11%). ITMIG consensus major criteria were identified in 100% of type A, AB, B1, and B2 thymomas. After restaging according to the eighth edition of the TNM staging classification, there were 127 stage I (84%), three stage II (2%), 17 stage IIIa (11%), no stage IIIb, two stage IVa (1%), and three stage IVb (2%) thymomas. Significant correlation between histological type and stage at diagnosis was maintained after restaging according the TNM classification. Comprehensive analysis of our well-characterized surgical series of 188 TETs indicates the feasibility and the diagnostic value of the ITMIG consensus statement on WHO histological classification and highlights the major switch in staging when the eighth edition of the TNM staging classification is applied.


Ficus deltoidea Leaf Alters Oxidative Stress, Protein Homeostasis and Ubiquitin-Proteasome Pathways in Fatty Acid-Induced Cell Line.
Ficus deltoidea (mistletoe fig) is a shrub well known among locals in Malaysia primarily for its treatment of toothaches, colds and wounds. The aim of this study is to determine the potential of leaves, sourced from three different varieties of F. deltoidea, to exhibit antioxidant activity, a reduction of lipid concentration, and protein expression in steatosis-induced liver cell lines. The leaves of three F. deltoidea varieties, namely Ficus deltoidea var. angustifolia, Ficus deltoidea var. trengganuensis and Ficus deltoidea var. kunstleri, were subjected to water extraction. The resulting crude extracts were fractionated using water and ethyl acetate. Palmitic acid was used to induce lipid accumulation (steatosis) in human liver (WRL68) cells, before all the samples were tested for their lipid-reducing activity. Several proteomic approaches were incorporated. The changes in protein expression were determined using 2-dimensional gel electrophoresis separation, whereas identification of our protein spots of interest was carried out via matrix-assisted laser desorption/ionization time-of-flight. Ficus deltoidea var. kunstleri alone demonstrated the ability to reduce lipids at the highest tested concentration (200 µg/mL) and was, therefore, used for subsequent experiments. Treatment with Ficus deltoidea var. kunstleri was found to restore redox status by increasing superoxide dismutase and glutathione peroxidase amounts and decreasing malondialdehyde formation. Six proteins were successfully identified; these were heat shock protein beta-1 (HSPB1), proteasome subunit alpha type 1 (PSMA1), glutathione S-transferase omega 1 (GSTO1), peroxiredoxin-1 (PRDX1), histone H2B (HIST1H2BD) and ubiquitin c-terminal hydrolase L3 (UCHL3). Through bioinformatics analysis, it was found that these proteins were significantly involved in specific pathways such as oxidative stress (PRDX1 and GSTO1), protein homeostasis (HSPB1) and degradation (UCHL3 and PSMA1). F. deltoidea pretreatment was shown to reduce lipid accumulation, thus improving the redox status and protein homeostasis. This suggests the role of F. deltoidea as a preventive mechanism in non-alcohol fatty liver disease.


Neutrophil-to-lymphocyte ratio predicts metachronous liver metastasis of pancreatic neuroendocrine tumors.
Pancreatic neuroendocrine tumors (PNETs) are clinically malignant, having metastatic potential. Histological tumor grade is an accepted indicator of malignant potential, but noninvasive prognostic markers have not yet been identified. This study assessed whether the preoperative neutrophil-to-lymphocyte ratio (NLR) could predict clinical outcomes of PNET patients. Fifty-eight patients who underwent curative resection for PNETs between 2001 and 2015 were retrospectively evaluated. The correlations between the preoperative NLR and clinicopathological parameters, including patient baseline clinical characteristics, tumor progression, and postoperative oncological outcome were evaluated. A high preoperative NLR was significantly associated with large tumor size (P = 0.0015) and high tumor grade (P < 0.0001). Overall survival and relapse-free survival of patients with a high NLR (≥2.4) were significantly shorter than those of patients with a low NLR (<2.4, P = 0.0481 and P < 0.0001, respectively). Multivariate analysis revealed that NLR ≥2.4 and tumor size ≥2 cm were independent predictors of postoperative recurrence (hazard ratio 6.012, P = 0.0035 and 6.760, P = 0.0049, respectively). Interestingly, a high NLR independently predicted postoperative liver, but not lymph node, metastasis. In this patient series, a high NLR (≥2.4) was a noninvasive marker that independently predicted postoperative liver metastasis in patients with PNETs, and thereby could be clinically useful.


Breastfeeding, ovulatory years, and risk of multiple sclerosis.
To determine whether women who breastfeed their infants longer or have fewer ovulatory years are at lower risk of developing multiple sclerosis (MS). We recruited women with newly diagnosed MS or its precursor, clinically isolated syndrome (CIS) (n = 397), and matched controls (n = 433) into the MS Sunshine Study from the membership of Kaiser Permanente Southern California. A structured in-person questionnaire was administered to collect the behavioral (pregnancies, breastfeeding, hormonal contraceptive use) and biological (age at menarche and menopause, amenorrhea) factors to make up ovulatory years. Among women who had live births, a cumulative duration of breastfeeding for ≥15 months was associated with a reduced risk of MS/CIS (adjusted odds ratio [OR] 0.47, 95% confidence interval [CI] 0.28-0.77; p = 0.003 compared to 0-4 months of breastfeeding). Being ≥15 years of age at menarche was also associated with a lower risk of MS/CIS (adjusted OR 0.56, 95% CI 0.33-0.96; p = 0.035). Total ovulatory years and the remaining factors that determine it, including gravidity, parity, episodes of amenorrhea, and hormonal contraceptive use, as well as age at first birth, showed no significant association with the risk of MS/CIS. Mothers who breastfeed longer may be at lower subsequent risk of developing multiple sclerosis. This is consistent with the other known maternal health benefits of breastfeeding and with our previous observation that women with MS who breastfeed exclusively are at lower risk of postpartum relapses.


Technical feasibility and clinical success of direct "free hand" EUS-guided gastroenterostomy in patients with gastric outlet obstruction.
Background and study aims Endoscopic ultrasound-guided gastroenterostomy (EUS-GE) with lumen-apposing metal stents (LAMS) appears to be a promising intervention in management of gastroduodenal out obstruction (GOO), particularly for patients for whom surgery is high risk or in a palliative setting. This study aimed to evaluate the technical feasibility, procedure-associated adverse events (AEs), and clinical outcome of direct "free hand" EUS-GE. Patients and methods This retrospective two-center study included patients who underwent direct "free hand" EUS-GE (April 2017 to March 2021) investigating technical success (correctly placed LAMS), clinical outcome (successful oral nutrition), and management of procedure-associated AEs. "Free hand" was defined as the use of the electrocautery enhanced stent delivery system alone without additional guidewire-assistance for EUS-GE creation. Results Forty-five patients (58 % women/42 % men; mean age 65 years) with malignant (n = 39), benign (n = 4) or unclear (n = 2) GOO underwent direct "free hand" EUS-GE. The technical success rate was 98 % (44/45). Of the patients, 95% (42/44) had less vomiting and increased ability to tolerate oral food intake after the intervention. In one patient, a second EUS-GE was necessary to achieve sufficient clinical improvement. Procedure-associated AEs were observed in 24 % (11/45) of cases including stent misplacement (n = 7), leakage (n = 1), development of a gastrojejunocolic fistula (n = 1), and bleeding (n = 2), which could be all managed endoscopically. Conclusions Direct EUS-GE has a favorable risk-benefit profile for patients with GOO, showing high technical success rates, manageable AEs, and rapid symptom relief.


A Cross-Sectional Study of Pain Among U.S. College Music Students and Faculty.
Studies over recent decades have demonstrated significant performance-related pain among professional musicians. However, there have been no largescale studies to evaluate pain among college musicians. The aim of this study was to determine the prevalence and anatomical locations of performance-related pain among students and faculty at the college level and learn what musicians do when they have pain. Cross-sectional data were collected using an online survey distributed to colleges across the United States. Data were analyzed using REDCap electronic data capture tools and Microsoft Excel. We received 1,007 survey responses and found that 67% of musicians at colleges experienced performance-related pain. The highest prevalence of pain was in woodwind musicians, with 83% reporting performance-related pain. The most common locations of pain were upper back (27%), lower back (26%), and fingers of the right hand (25%). Many student musicians with pain seek help from their teacher, but almost as many do not seek help at all. Less than 25% see a medical professional. Most musicians at colleges experience performance-related pain in a variety of anatomical locations depending upon instrument/voice. Performing arts health organizations can increase awareness of treatment options for musicians suffering from performance-related pain, which may lead to improved quality of life and increased career longevity for college musicians.


Energy-Efficient and Robust In-Network Inference in Wireless Sensor Networks.
Distributed in-network inference plays a significant role in large-scale wireless sensor networks (WSNs) in various applications for distributed detection and estimation. While belief propagation (BP) holds great potential for forming a powerful underlying mechanism for such distributed in-network inferences in WSNs, one major challenge is how to systematically improve the energy efficiency of BP-based in-network inference in WSNs. In this paper, we first propose a systematic and rigorous data-driven approach to building information models for WSN applications upon which BP-based in-network inference can be effectively and efficiently performed. We then present a wavelet-based BP framework for multiresolution inference, with respect to our WSN information modeling, to further reduce WSNs' energy. We empirically evaluate our proposed WSN information modeling and wavelet-based BP framework/multiresolution inference using real-world sensor network data. The results demonstrate the merits of our proposed approaches.


Eo: a history of a mutation.
Eighteen mouse t haplotype-carrying strains were found not to express cell-surface E molecules controlled by class II genes of the H-2 complex (= Eo strains). Northern and Southern blot analysis of these and other, non-t strains that also fail to express the E molecule, has revealed two kinds of defect. Three strains (CRO437, tw2, and presumably to) were found to transcribe the E alpha gene, but they were not able to convert the message into a functional protein. All other Eo strains fail to transcribe the E alpha gene because of a deletion encompassing the promoter region, the RNA initiation site, and the first exon. The length of the deletion is approximately 650 +/- 50 bp. These two defects closely resemble those found previously in standard inbred strains carrying the H-2f, H-2q (failure of E mRNA to be expressed functionally), H-2b, and H-2s (deletion of a part of the E alpha gene) haplotypes. In particular, the location and length of the E alpha deletion appear to be the same in the strains carrying this mutation. The E alpha deletion is in linkage disequilibrium with certain alleles at other H-2 loci in some of the strains. These observations, combined with the growing evidence that H-2 haplotypes associated with t chromosomes derive from a single ancestral haplotype, suggest that the E alpha deletion is an old mutation and that it has been disseminated in mouse populations by the t chromosomes.


Endoscopic closure of a refractory gastrocutaneous fistula using a novel over-the-scope Padlock clip following de-epithelialisation of the fistula tract.
Persistent gastrocutaneous fistula (GCF) is a difficult to manage complication following gastrostomy tube removal, with leakage resulting in distressing sequelae including cutaneous injury, infection and dehydration. Many such patients are high-risk for invasive surgery and, to date, endoscopic closure techniques, including clipping systems, have limitations. We present the case of a 62-year-old woman with persistently leaking GCF 6 months postgastrostomy tube removal, despite maximal antisecretory therapy and postpyloric feeding, and describe failed attempted endoscopic closure with conventional clips. Treatment options were discussed and informed consent was given for an attempt at endoscopic closure using a novel radial closure device ('Padlock clip') combined with surgical de-epithelialisation, with the understanding that this device has never previously been used in this setting. At follow-up 2 weeks postprocedure, the patient was asymptomatic with complete healing of the GCF. This approach has advantages over other endoscopic closure techniques and can be considered as an alternative approach to GCF closure.


Carotid endarterectomy based on duplex scanning without preoperative arteriography.
Between July 1985 and September 1987, 25 patients underwent 26 carotid endarterectomies based on an abnormal duplex scan (B-mode ultrasonography and pulsed-Doppler sound spectral analysis) indicative of severe stenosis or ulceration. Arteriography was not performed because of severe unstable angina requiring coronary artery bypass grafting (23 patients) or patient preference (two). Twelve patients were symptomatic, and 13 were asymptomatic but had severe (greater than or equal to 75%) bilateral or unilateral carotid artery stenosis. Operative and pathological analyses confirmed the duplex-scan findings in all 25 cases. All 25 patients survived the operation. One patient had a transient ipsilateral neurological deficit, and one had a permanent contralateral neurological deficit. Five patients died of ventricular arrhythmias within 30 days of operation. Duplex scanning is an accurate method for determining the presence of clinically and hemodynamically significant carotid arterial occlusive disease. Duplex scanning also serves as an alternative method for evaluating patients for whom carotid arteriography may be associated with significant risk.


Identification and characterization of a novel human collectin CL-K1.
Collectins are a family of C-type lectins with two characteristic structures, collagen like domains and carbohydrate recognition domains. They recognize carbohydrate antigens on microorganisms and act as host-defense. Here we report the cloning and characterization of a novel collectin CL-K1. RT-PCR analyses showed CL-K1 mRNA is present in all organs. The deduced amino acid sequence and the data from immunostaining of CL-K1 cDNA expressing CHO cells revealed that CL-K1 is expressed as a secreted protein. CL-K1 is found in blood by immunoblotting and partial amino acid analyses. CL-K1 showed Ca(2+)-dependent sugar binding activity of fucose and weakly mannose but not N-acetyl-galactosamine, N-acetyl-glucosamine, or maltose, though mannose-binding lectin (MBL) containing similar amino acid motif. CL-K1 can recognize specially several bacterial saccharides due to specific sugar-binding character. Elucidation of the role of two ancestor collectins of CL-K1 and CL-L1 could lead to see the biological function of collectin family.