Gastrin-releasing peptide receptor antagonist or N-acetylcysteine combined with omeprazol protect against mitochondrial complex II inhibition in a rat model of gastritis.
The pathophysiology of gastritis involves an imbalance between gastric acid attack and mucosal defence. In addition, the gastric mucosal injury results in adenosine triphosphate (ATP) depletion leading to mitochondrial dysfunction. Several studies have shown the association of mitochondrial disorders with gastrointestinal dysfunction. In the present study, we investigated the activity of mitochondrial respiratory chain complexes activity in the stomach of rats with gastritis induced by indomethacin (IDM) and treated with omeprazole (OM), N-acetylcysteine (NAC) and the gastrin-releasing peptide receptor (GRPR) antagonist RC-3095. Adult male Wistar rats were pre-treated for 7 days with OM, NAC, RC-3095, combination of OM plus RC-3095, OM plus NAC and water (control). The animals were then submitted to fasting for 24 hr; IDM was administered. The rats were killed 6 hr later, and the stomachs were used for evaluation of macroscopic damage and respiratory chain activity. Our results showed that complex I and IV activities were not affected by administration of IDM. On the other hand, complex II and III activities were inhibited. In addition, OM plus RC-3095 and OM plus NAC did not reverse complex II activity inhibition. However, the complex III activity inhibition was reversed only with the combined use of OM plus RC-3095 and OM plus NAC. Our results are in agreement with previous studies indicating mitochondrial dysfunction in the pathophysiology of gastrointestinal tract disease and we suggest that GRPR antagonism might be a novel therapeutic strategy in gastritis.


Pharmacological evidence for systemic and peripheral antinociceptive activities of pioglitazone in the rat formalin test: Role of PPARγ and nitric oxide.
Nitric oxide (NO) is involved in numerous physiological processes of the central and peripheral nervous system. This study aimed to evaluate the involvement of PPARγ and NO pathway in the systemic and peripheral antinociceptive effect pioglitazone (Pio) using formalin test in rats. After allocation, rats were injected with 2.5% formalin solution and the flinching behaviors were recorded for 5min (phase 1) and 15-60min (phase 2). Pioglitazone was administered intraperitoneally (i.p.) at doses (10-50mg/kg) and intraplantarly (i.pl.) at doses (10-30μg/paw) 60 and 20min before test, respectively. To investigate the mechanism involved, rats were given GW-9662 (a PPARγ antagonist), L-NAME (NO synthase inhibitor), L-arginine (NO precursor), or l-NAME+GW-9662 along with pioglitazone. Results showed that both of i.p. and i.pl. routes of pioglitazone administration produced antinociception in both phases of formalin-induced pain. Antinociception caused by i.p. and i.pl. pioglitazone was blocked by GW-9662 at doses 2mg/kg (i.p.) and 3μg/paw (i.pl.) in both phases of the test, respectively. The antinociceptive effects of i.p. and i.pl. pioglitazone were significantly reduced by l-arginine, but were augmented by l-NAME in second phase of test. However, pre-treatment with GW-9662 inhibited the enhanced antinociceptive effect of l-NAME on pioglitazone in second phase of formalin test during i.p. and i.pl. administration. Furthermore, the antinociceptive effect of systemic pioglitazone was antagonized by i.pl. administration of GW-9662 (3μg/paw). Our data suggest that local and systemic antinociceptive activity of pioglitazone is mediated partly through PPARγ in collaboration with NO pathway. Moreover, the cumulative results suggest a close link of interaction between PPARγ and NO.


The Myxobacterium Myxococcus xanthus Can Sense and Respond to the Quorum Signals Secreted by Potential Prey Organisms.
The myxobacterium Myxococcus xanthus is a predatory member of the soil microfauna, able to consume bacteria (Gram-negative, Gram-positive), archaea, and fungi. Many potential prey of M. xanthus communicate amongst themselves using acyl homoserine lactones (AHLs) as quorum signals. M. xanthus cannot itself produce AHLs, but could potentially benefit by responding to exogenous AHLs produced during signaling between proximal prey. Four AHLs of different side chain length were tested and all found to delay sporulation of M. xanthus vegetative cells, and to stimulate germination of myxospores, increasing the proportion of predatory vegetative cells in the population. The predatory activity and expansion rates of M. xanthus colonies were also found to be stimulated by AHLs. Thermally inactivated AHLs had no effect on M. xanthus cells, and the response to AHLs depended (non-linearly) on the length of AHL side chain, suggesting that the effect of AHLs was mediated by specific signaling within M. xanthus, rather than being a consequence of the chemical or physical properties of AHLs. Therefore, it seems that the presence of xenic quorum signaling molecules enhances the predatory activity of M. xanthus. AHLs increase the proportion of the population capable of predation, and stimulate the motility and predatory activity of vegetative cells. We therefore propose that in the wild, M. xanthus uses AHLs as markers of nearby prey, potentially eavesdropping on the conversations between prey organisms.


Unusual location in the left ventricular outflow tract and atypical symptoms of cardiac papillary fibroelastoma.
Cardiac papillary fibroelastoma, though potentially fatal, are rare benign tumours. Therefore, high index of suspicion is needed in order to identify these lesions and to limit complications at surgery or during long-term oral anticoagulation if the patient is not a surgical candidate. We present a case report of unusual location and presentation, highlighting the pathological findings. A 55-year-old white male, without risk factors for ischaemic cardiomyopathy, presented several episodes of chest pain. Nine years previously, the patient had had a convulsive attack without any organic neurological finding and was treated with different anticonvulsive drugs for five years. Echocardiography showed a mobile mass in the left ventricular outflow tract. The patient underwent surgical excision of the mass, which was later identified as cardiac papillary fibroelastoma.


Enterovirus type 71-immunized chicken egg yolk immunoglobulin has cross antiviral activity against coxsackievirus A16 in vitro.
To exploit a cross passive immunotherapy for enterovirus-induced hand-foot-and-mouth disease (HFMD), the cross antiviral activity of a neutralizing antibody against enterovirus 71 (EV71) and coxsackievirus A16 (CVA16) was investigated in vitro. White Leghorn specific-pathogen-free chickens were immunized with EV71 antigens and a specific isolated immunoglobulin (IgY) was prepared from the chicken egg yolk. IgY was further purified and characterized by SDS-PAGE, ELISA, western blotting and bidirectional immune agar diffusion testing. The antiviral activity and dose-response of the IgY were determined by assessing the cytopathic effect in rhabdomyosarcoma (RD) cells in vitro. It was indicated that the levels of IgY were increased at day 7, peaked at week 7 and were maintained at a higher level for 4 weeks following immunization when compared with the negative control. The results of western blotting and bidirectional immune agar diffusion testing revealed that the IgY had cross-binding properties in EV71 and CVA16 strains through targeting the envelope proteins (VP0, VP1 and VP3) of EV71 and CVA16. Neutralization assay results indicated that the infectivity of EV71 and CVA16 strains in RD cells was cross-blocked by IgY in a dose-dependent manner. To conclude, these findings indicate that IgY has cross antiviral activity against EV71 and CVA16 in vitro, and could potentially be developed as a passive immunotherapy for EV71- and CVA16-induced HFMD.


Inula sesquiterpenoids: structural diversity, cytotoxicity and anti-tumor activity.
The plants of the genus Inula (Asteraceae) are widely distributed throughout Europe, Africa and Asia, and many of these plants have long been used in folk medicine. This genus is a rich source of sesquiterpenoids, which exhibit a wide range of biological activities. Recently, a series of bioactive sesquiterpenoid dimers, with unusual carbon skeletons, have been reported and these have gathered considerable interest. This article systematically reviews sesquiterpenoids isolated from the genus Inula that have appeared in literature up to August 2013, critically highlighting their anti-tumoral activities and relevant mechanistic insights. The authors also discuss the initial structure-activity relationships for the cytotoxic and anti-tumoral activities of the Inula sesquiterpenoids. Finally, the authors discuss the challenges and potential applications of these sesquiterpenoids in the future. Cytotoxic and anti-tumor activities of Inula sesquiterpenoids have been extensively studied since the 1970s. One promising compound, Japonicone A, a dimeric sesquiterpene lactone from traditional herb Inula japonica, has displayed potent in vitro and in vivo anti-tumor activity against Burkitt's lymphoma. Additionally, acetylbritannilactone is thought to be capable of suppressing the abnormal vascular smooth muscle cell proliferation, with the induction of apoptosis in vivo and in vitro. In this regard, it may be worthwhile further investigating acetylbritannilactone in patients with vascular restenosis. Furthermore, given the anti-inflammatory property of britanin, clinical studies on chronic bronchitis and asthma, using the ethanol extract of I. japonica, are currently underway in South Korea. However, despite demonstrating good therapeutic effects, additional pharmacological and toxicological studies are still needed.


Reproducibility of ambulatory blood pressure and assessing treatment withdrawal in hypertension trial.
Ambulatory blood pressure monitoring (ABPM), like casual blood pressure (BP), is imperfectly reproducible between visits. The reproducibility of ABPM is less than the reproducibility predicted from a simple model of random variation of BP. This suggests either increased technical error in the technique, an element of increased biologic variability, or both. In addition, ABP shows a between-day variation (add about 6 to 7 mm Hg diastolic, similar in magnitude to what is observed with casual BP) which cannot be obviated by the average of many within-day measurements. The reliability of ABPM, although conventionally judged excellent at about RI = 0.75, is insufficient to avoid misclassification errors and regression to the mean when BP cutpoints are employed. About 40% of patients apparently failing treatment withdrawal at a threshold of +2 SD, or about 95 mm Hg diastolic ABP, will be false-positive failures when categorized by a single ABP. Despite the inconvenience, obtaining an average of two or more ABP measurements on different days may be cost-saving to a clinical trial because of the improved reproducibility; other costs may exceed $1000 per entrant.


KAP1, a novel substrate for PIKK family members, colocalizes with numerous damage response factors at DNA lesions.
The DNA damage response requires a coordinated nucleo-cytoplasmic cascade of events, which ultimately converge on damaged DNA packaged in chromatin. Few connections between the proteins that remodel chromatin and the proteins that mediate this damage response have been shown. We have investigated the DNA damage-induced phosphorylation of the KRAB-ZFP-associated protein 1 (KAP1), the dedicated corepressor for Krüppel-associated box (KRAB) zinc finger protein (ZFP) proteins. We show that KAP1 is rapidly phosphorylated following DNA damage by members of the phosphatidylinositol-3 kinase-like family of kinases. This phosphorylation occurs at a single amino acid residue that is conserved from mice to humans and is located adjacent to the bromodomain, suggesting that it may regulate chromatin recognition by that module. Phosphorylated KAP1 rapidly localizes to sites of DNA strand breaks in the nucleus in response to ionizing radiation. This discovery provides a novel link between chromatin-mediated transcriptional repression and the recognition/repair of DNA, which must be accomplished by the cellular DNA damage response.


Flow cytometric detection of minimal residual disease in acute lymphoblastic leukemia.
Assessment of minimal residual disease (MRD) during the first months of therapy gives information on the timely response to treatment, and proves to be a powerful and independent indicator of treatment outcome in patients with acute lymphoblastic leukemia (ALL). Immunological evaluation by flow cytometry (FCM) is one of the most attractive approaches to this. The present review summarizes the historical development of this approach over the last 20 years, and shows that current methodology is based on the existence of leukemia-associated patterns of derangement in antigen expression with respect to normal differentiation or location of occurrence. Recent clinical studies are summarized which proved that FCM is applicable to more than 90% of patients with ALL and gives prognostic information comparable to polymerase chain-reaction (PCR)-based technology. Ongoing efforts based on parallel application of both technologies are explained which are designed to clarify which approach bears the best cost-relevance ratio in order to be broadly used in the future for risk assessment and tailoring of treatment modalities. Concluding perspectives relate to further technical developments like usage of peripheral blood (PB) instead of bone marrow (BM), absolute quantification, or strategic placement of investigative time-points, which may allow to simplify the MRD approach and thus augment it's economic efficiency.


Nerve growth factor suppresses the tumoral phenotype of human prolactinomas.
We summarize here our data showing that various phenotypical characteristics distinguish prolactinoma cell lines obtained from responder and nonresponder patients, as defined by their responses to bromocriptine administration. Nonresponder cell lines have a higher degree of malignancy than responder cells and do not express D2 receptors for dopamine. Both cell lines express NGF receptors. Exposure of the most malignant nonresponder cell lines to NGF, both in vitro and when transplanted in vivo in nude mice, results in their differentiation into the responder phenotype reexpressing D2 receptors. Sequential administration of NGF and bromocriptine thus may be a promising therapy for patients refractory to bromocriptine.


Efficacy and Safety of Adding Olanzapine to the Standard Preventive Regimen for Chemotherapy-induced Nausea and Vomiting in Children: A Randomized Double-blind Controlled Trial.
This study aimed to assess the additive value of olanzapine to a combination of ondansetron and dexamethasone to prevent chemotherapy-induced nausea and vomiting (CINV) in pediatric patients. A total of 40 patients between 4 to 18 years of age were enrolled in this randomized clinical trial. Both groups received a combination of ondansetron and dexamethasone, and 0.14 mg/kg olanzapine or matched placebo were administered for olanzapine and control groups, respectively. The primary end points were complete response and lack of nausea as far as three days after chemotherapy evaluated by the Common Terminology Criteria for Adverse Effects (CTCAE) v5.0 and the Multinational Association of Supportive Care in Cancer (MASCC) Anti-emesis Tool (MAT). Side effects of olanzapine were also analyzed. In patients receiving the standard regimen of ondansetron and dexamethasone, nausea was observed in 10.5% and 21% of patients according to MAT and CTCAE scales, respectively. In the olanzapine group, 37.5% (MAT scale) and 31.3% (CTCAE scale) of patients developed nausea. Complete response was observed in 84% (MAT scale) and 94.7% (CTCAE scale) of patients in the placebo group receiving ondansetron and dexamethasone. In comparison, it was observed in 87.5% (MAT scale) and 81.25% (CTCAE scale) for patients allocated to the olanzapine group. Neither acute nor delayed CINV was statistically different between placebo and olanzapine groups. The frequency of adverse effects was higher in the olanzapine group. Adding olanzapine to the standard regimen of CINV prophylaxis was only unhelpful in pediatric patients receiving moderately emetogenic chemotherapy but also associated with a higher rate of minor side effects.


Single-Nucleotide Variants and Epimutations Induce Proteasome Inhibitor Resistance in Multiple Myeloma.
Proteasome inhibitors (PI) are the backbone of various treatment regimens in multiple myeloma. We recently described the first in-patient point mutations affecting the 20S subunit PSMB5 underlying PI resistance. Notably, in vivo, the incidence of mutations in PSMB5 and other proteasome encoding genes is too low to explain the development of resistance in most of the affected patients. Thus, additional genetic and epigenetic alterations need to be explored. We performed DNA methylation profiling by Deep Bisulfite Sequencing in PSMB5, PSMC2, PSMC5, PSMC6, PSMD1, and PSMD5, a subset of proteasome subunits that have hitherto been associated with PI resistance, recruited from our own previous research, the literature, or a meta-analysis on the frequency of somatic mutations. Methylation was followed up on gene expression level and by dual-luciferase reporter assay. The KMS11 cell line served as a model to functionally test the impact of demethylating agents. We identified PSMD5 promoter hypermethylation and subsequent epigenetic gene silencing in 24% of PI refractory patients. Hypermethylation correlated with decreased expression and the regulatory impact of this region was functionally confirmed. In contrast, patients with newly diagnosed multiple myeloma, along with peripheral blood mononuclear cells and CD138+ plasma cells from healthy donors, generally show unmethylated profiles. Under the selective pressure of PI treatment, multiple myeloma cells acquire methylation of the PSMD5 promoter silencing the PSMD5 gene expression. PSMD5 acts as a key orchestrator of proteasome assembly and its downregulation was described to increase the cell's proteolytic capacity. PSMD5 hypermethylation, therefore, represents a novel mechanism of PI tolerance in multiple myeloma.


Effects of Laser Acupuncture and Dietary Intervention on Key Obesity Parameters.
Objectives: The scope of obesity includes quality of life (QoL); emotions; and financial burdens on individuals, families, and society. Obesity contributes to many diseases, such as coronary heart disease, type 2 diabetes, stroke, osteoarthritis, and cancer. Dietary modifications, lifestyle interventions, pharmacologic agents, and surgical interventions are some ways to address obesity; yet, safer, more-effective options are needed. Laser acupuncture can significantly lower body mass index (BMI) by reducing abdominal and visceral adipose tissue content and regulating lipid metabolism. This study investigated the effects of laser acupuncture + diet modification on fasting blood-glucose level, insulin level, waist:hip ratio, QoL scoring, high-density lipoprotein (HDL) level, triglycerides, BMI, and appetite scoring in obese patients. Materials and Methods: The patients (N = 38) were divided randomly into 2 groups: (1) laser acupuncture + dietary intervention (n = 19) and (2) sham laser acupuncture + dietary intervention (n = 19). Both groups had the same dietary intervention and laser acupuncture sessions, 3 times/week for 4 weeks. All parameters were assessed before and after the interventions. Results: There were statistically significant differences in waist:hip ratio (P = 0.000), QoL scores (P = 0.000), BMI (P = 0.000), and appetite scores (P = 0.000) between the 2 groups after the interventions. There were no differences in levels of blood glucose (P = 0.543), insulin (P = 1.00), HDL (P = 0.208), and triglycerides (P = 0.413) between the 2 groups after the interventions. Conclusions: Combining laser acupuncture and a dietary intervention has good effects on waist:hip ratio, QoL scores, BMI, and appetite scores in obese patients.


The concepts of representation and information in explanatory theories of human behavior.
Focusing in experimental study of human behavior, this article discusses the concepts of information and mental representation aiming the integration of their biological, computational, and semantic aspects. Assuming that the objective of any communication process is ultimately to modify the receiver's state, the term correlational information is proposed as a measure of how changes occurring in external world correlate with changes occurring inside an individual. Mental representations are conceptualized as a special case of information processing in which correlational information is received, recorded, but also modified by a complex emergent process of associating new elements. In humans, the acquisition of information and creation of mental representations occurs in a two-step process. First, a sufficiently complex brain structure is necessary to establishing internal states capable to co-vary with external events. Second, the validity or meaning of these representations must be gradually achieved by confronting them with the environment. This contextualization can be considered as part of the process of ascribing meaning to information and representations. The hypothesis introduced here is that the sophisticated psychological constructs classically associated with the concept of mental representation are essentially of the same nature of simple interactive behaviors. The capacity of generating elaborated mental phenomena like beliefs and desires emerges gradually during evolution and, in a given individual, by learning and social interaction.


Complete cartilage-ring tracheal stenosis associated with anomalous left pulmonary artery: the ring-sling complex.
The persistent high mortality in infants with pulmonary artery "sling" (retrotracheal anomalous left pulmonary artery) is primarily due to the coexistence in such patients of long-segment tracheal stenosis due to complete cartilage rings. Five such patients are reported. Airway studies (by filtered high-kV radiography, bronchography, and/or CT) showed low carina, horizontal equal-length right and left mainstem bronchi, and long-segment tracheal stenosis. The length of the stenosis far exceeded the contact with the pulmonary sling. The suggested term "ring-sling complex" for such patients correctly places emphasis on detection of the tracheal malformation, which currently has no satisfactory surgical treatment.


Molecular changes in Entamoeba histolytica in response to bacteria.
Entamoeba histolytica, the protozoan parasite, is the causative agent of amoebiasis. The degree of virulence, as inferred from invasiveness, of potentially pathogenic strains may be regulated by both host and parasite factors that determine the gut environment. One such factor that plays an important role is the bacterial flora in the gut. Previous studies have clearly shown that bacterial flora is an important determinant of virulence in E. histolytica. However, the exact nature of changes induced in E. histolytica in response to bacteria and their role in virulence is not clear. In this study the levels of a number of molecules potentially important in virulence mechanisms were determined in E. histolytica cells grown with and without normal human bacterial flora, using enzyme-linked immunosorbent assay. Significant changes were observed only after the E. histolytica cells had been adapted to grow with bacterial flora for a number of generations, and not in short term culture.


Troglitazone: current therapeutic role in type 2 diabetes mellitus.
To describe the role of troglitazone in the treatment of non-insulin-dependent diabetes mellitus. The potential mechanisms of action of the thiazolidinediones are outlined, and studies that have been conducted in animals and in humans are reviewed. Although the precise mode of action of troglitazone, a thiazolidinedione, is unknown, this agent is an insulin sensitizer that has been shown to decrease fasting insulin, fasting plasma glucose, and blood pressure levels in humans. The effect of troglitazone is progressively greater over time; in several studies, the maximal action occurred as long as 12 weeks after initiation of treatment. The usual daily dose is 200 to 600 mg, and no dosage adjustment is necessary in patients with renal insufficiency. Adverse events, including fluid retention and hepatic dysfunction, may limit the utility of troglitazone in some clinical situations. Both in monotherapy and in combination with sulfonylureas, insulin, or metformin, troglitazone has proved to be an effective agent for the treatment of type 2 diabetes mellitus.


IL-17-receptor-associated adaptor Act1 directly stabilizes mRNAs to mediate IL-17 inflammatory signaling.
Mechanisms that degrade inflammatory mRNAs are well known; however, stabilizing mechanisms are poorly understood. Here, we show that Act1, an interleukin-17 (IL-17)-receptor-complex adaptor, binds and stabilizes mRNAs encoding key inflammatory proteins. The Act1 SEFIR domain binds a stem-loop structure, the SEFIR-binding element (SBE), in the 3' untranslated region (UTR) of Cxcl1 mRNA, encoding an inflammatory chemokine. mRNA-bound Act1 directs formation of three compartmentally distinct RNA-protein complexes (RNPs) that regulate three disparate events in inflammatory-mRNA metabolism: preventing mRNA decay in the nucleus, inhibiting mRNA decapping in P bodies and promoting translation. SBE RNA aptamers decreased IL-17-mediated mRNA stabilization in vitro, IL-17-induced skin inflammation and airway inflammation in a mouse asthma model, thus providing a therapeutic strategy for autoimmune diseases. These results reveal a network in which Act1 assembles RNPs on the 3' UTRs of select mRNAs and consequently controls receptor-mediated mRNA stabilization and translation during inflammation.


Metformin - its potential anti-cancer and anti-aging effects.
The generally accepted mechanism of metformin's effect is stimulation of adenosine monophosphate (AMP)-activated protein kinase (AMPK). AMPK is directly activated by an increase in AMP:ATP ratio in metabolic stress conditions including hypoxia and glucose deprivation. Lately, many novel pathways, besides AMPK induction, have been revealed, which can explain some of metformin's beneficial effects. It may help to identify new targets for treatment of diabetes and metabolic syndrome. Moreover, metformin is now attracting the attention of researchers in fields other than diabetes, as it has been shown to have anti-cancer, immunoregulatory and anti-aging effects. The aim of this review is to describe the potential anti-cancer and anti-aging properties of metformin and discuss the possible underlying mechanisms.


Nail Ultrasound in Psoriasis and Psoriatic Arthritis-A Narrative Review.
Ultrasonography has advantages for assessing psoriatic arthritis (PsA) due to its ability to evaluate several targets, including joints, entheses, and tendons, but also skin and nails. Although ultrasound is widely used in PsA, nail ultrasound, despite its potential as a non-invasive method for the early detection of inflammation in the nail apparatus, has low applicability in medical practice, as probes with a higher frequency are needed compared with the frequency of probes usually used. In the present article, we have narratively evaluated the studies published in the last 5 years (19 February 2018-18 February 2023) on nail ultrasound value in the diagnosis and monitoring of PsA. The studies published during this period share common measurement parameters, such as the OMERACT definition of enthesis published in 2018. We included original articles published in PubMed and Web of Science using the following search terms in all possible combinations: psoriatic arthritis, psoriasis, ultrasound, and nail. Articles were declared relevant if they presented data on nail morphology, power Doppler evaluation and nearby structure evaluation, while focusing on digitorum extensor enthesitis. In most of the studies, common morphological parameters were generally increased in patients with psoriasis or PsA and were demonstrated to change with medication. The thickness of the extensor tendon was greater in patients with PsA and psoriasis versus controls and it was correlated with nail clinical changes, especially the presence of onycholysis. The presence of PD showed large variability in healthy individuals. The link between enthesitis and nail involvement is still a subject of controversy, taking into account the latest histological findings. The use of ultrasound in the evaluation of nail and DIP enthesitis remains a challenge and an area of research in the coming years.


Biologically active metabolite(s) from haemolymph of red-headed centipede Scolopendra subspinipes possess broad spectrum antibacterial activity.
The discovery of novel antimicrobials from animal species under pollution is an area untapped. Chinese red-headed centipede is one of the hardiest arthropod species commonly known for its therapeutic value in traditional Chinese medicine. Here we determined the antibacterial activity of haemolymph and tissue extracts of red-headed centipede, Scolopendra subspinipes against a panel of Gram-positive and Gram-negative bacteria. Lysates exhibited potent antibacterial activities against a broad range of bacteria tested. Chemical characterization of biologically active molecules was determined via liquid chromatography mass spectrometric analysis. From crude haemolymph extract, 12 compounds were identified including: (1) L-Homotyrosine, (2) 8-Acetoxy-4-acoren-3-one, (3) N-Undecylbenzenesulfonic acid, (4) 2-Dodecylbenzenesulfonic acid, (5) 3H-1,2-Dithiole-3-thione, (6) Acetylenedicarboxylate, (7) Albuterol, (8) Tetradecylamine, (9) Curcumenol, (10) 3-Butylidene-7-hydroxyphthalide, (11) Oleoyl Ethanolamide and (12) Docosanedioic acid. Antimicrobial activities of the identified compounds were reported against Gram-positive and Gram-negative bacteria, fungi, viruses and parasites, that possibly explain centipede's survival in harsh and polluted environments. Further research in characterization, molecular mechanism of action and in vivo testing of active molecules is needed for the development of novel antibacterials.


Molecular Subtyping of Pancreatic Cancer: Translating Genomics and Transcriptomics into the Clinic.
Pancreatic cancer remains one of the most lethal malignancies, and insights into both personalized diagnosis and intervention of this disease are urgently needed. The rapid development of sequencing technologies has enabled the successive completion of a series of genetic and epigenetic sequencing studies of pancreatic cancer. The mutational landscape of pancreatic cancer is generally portrayed in terms of somatic mutations, structural variations, epigenetic alterations and the core signaling pathways. In recent years, four significant molecular subtype classifications of pancreatic cancer have been proposed based on the expression of transcription factors and downstream targets or the distribution of structural rearrangements. Increasing researches focus on the identification of somatic mutations and other genetic aberrations that drive pancreatic cancer has led to a new era of precision medicine based on molecular subtyping. However, few known molecular classifications are used to guide clinical strategies. Specific scientific, regulatory and ethical challenges must be overcome before genomic and transcriptomic discoveries can be translated into the clinic.


Primary percutaneous coronary intervention in 'early' latecomers with ST-segment elevation acute myocardial infarction: the role of the infarct-related artery status.
A high proportion of patients with ST-segment elevation myocardial infarction (STEMI) are evaluated more than 12 h after symptom onset. In this setting, current guidelines suggest that mechanical reperfusion should be considered for patients with clinical and/or electrocardiographic evidence of ongoing ischaemia, re-infarction, cardiogenic shock, haemodynamic instability, or documented ejection fraction less than 40% and serious ventricular arrhythmias. Moreover, some adjunctive aspects like the stuttering course of acute myocardial infarction, the chance of an existing coronary collateral circulation, the ischaemic preconditioning and the infarct-related artery patency should be taken into consideration for patients with STEMI presenting from 12 to 72 h after symptom onset. These patients are known as 'early' latecomers. The aim of the present review is to summarize the current knowledge of the pathophysiology related to this topic and to suggest some new indications for primary percutaneous coronary intervention in 'early' latecomers.


[Insulin treatment of adults with type 1 diabetes].
Whereas insulin treatment of type 1 diabetes formerly was limited by the availability of one or a few types of insulin with suboptimal pharmacokinetic properties, insulin analogues with more fitting physiological action profiles have now been developed and ultimately near-physiological insulin treatment can be delivered with insulin pumps. Adjustments of insulin dosing can be rationally based on dosing algorithms. This requires frequent glucose measurements and knowledge about dietary carbohydrate content. Today, the treatment and its complexity are individualized according to needs and wishes of the patient.


The Italian national telemedicine programme.
The Italian national telemedicine programme included a broad range of research projects, but they all served the common purpose of bringing about improvements in health-care management and performance. The programme consisted of seven projects, each of which had specific research and training objectives, and a three-year duration. The systems developed in the course of the programme were not experimental prototypes:they were intended to be pre-commercial systems. The functional and clinical merits of the products and systems developed were evaluated, and their costs and benefits measured with reference to those already in use. The seven projects were completed in 1999. The Italian Ministry of Universities, Research and Technology granted research funds totalling 50,000,000 Euros for the whole programme. While the results of the research were promising, successful projects alone are not sufficient to reduce costs in health-care. Indeed, far more money can be saved simply by encouraging the uptake on a larger scale of many technologies and practices that already exist.


Tunneling resonances and coherence in an optical lattice.
The center-of-mass quantization of atoms trapped in a gray optical lattice is observed to manifest itself in the steady-state properties of the atoms. Modulations in the lifetime and macroscopic magnetization as a function of an applied B field are attributed to quantum mechanical tunneling resonances and are shown to exist only under conditions which afford spatial coherence of the trapped atoms over several lattice wells and coherence times that exceed the tunneling period.


Double primary hepatic cancer (sarcomatoid carcinoma and hepatocellular carcinoma): A case report.
Primary liver sarcomatoid carcinoma (SC) is a rare and aggressive tumor exhibiting rapid growth and a high recurrence rate following resection. To date, there have been no reports of primary liver SC occurring simultaneously with hepatocellular carcinoma (HCC). This is the case report of a 54-year-old man with liver cirrhosis due to hepatitis B virus (HBV) infection and alcoholic hepatitis. The abdominal computed tomography and magnetic resonance imaging revealed two distinct hepatic masses in a background of hepatic cirrhosis and esophageal varices. Following a clinical diagnosis of two HCCs, a right hepatic lobectomy was performed. Grossly, two distinct lesions were identified: the larger mass was gray to white and well-demarcated, sized 2.5×2.0 cm, located in S5-6, whereas the other was a gray to whitish nodule, sized 1.3×1.0 cm, located in S8. The microscopic analysis revealed that the larger mass was a primary liver SC, which was immunoreactive for cytokeratin (CK) and vimentin (VMT) and negative for hepatocyte-specific antigen (HSA). The other nodule was histologically diagnosed as HCC, which was positive for HSA and CK and negative for HSA, VMT, CK7 and CK19. There was no transition or intermingling lesion between the two tumors. To the best of our knowledge, this is the first case report of double primary liver cancer comprising an SC and a HCC.


Depletion of calcium stores contributes to progesterone-induced attenuation of calcium signaling of G protein-coupled receptors.
Progesterone non-genomically attenuates the calcium signaling of the human oxytocin receptor and several other Galpha(q) protein-coupled receptors. High progesterone concentrations are found in the endometrium during pregnancy opposing the responsiveness of the underlying myometrium to labor-inducing hormones. Here, we demonstrate that within minutes, progesterone inhibits oxytocin- and bradykinin-induced contractions of rat uteri, calcium responses induced by platelet-activating factor in the human endometrial cell line MFE-280, and oxytocin-induced calcium signals in PHM1-31 immortalized pregnant human myometrial cells. Using human embryonic kidney (HEK293) cells as model system, we analyzed the molecular mechanisms underlying these effects. Our data indicate that progesterone rapidly depletes intracellular calcium stores. The resulting desensitization of the cells might contribute to the quiescence of the uterus during pregnancy.


Dehydrogenation of benzene on liquid Al100(+).
The reactions of benzene on Al100(+) have been investigated as a function of cluster temperature (300-1100 K) and relative kinetic energy (1-14 eV) by low-energy ion-beam methods and mass spectrometry. Benzene chemisorbs on both solid and liquid aluminum clusters to generate Al100C6D6(+). A series of Al(100-n)(+) (n = 1, 2, 3, ...) products was also observed. As the cluster temperature was raised above the melting temperature of Al100(+), the Al100C6D6(+) product dehydrogenates to form Al100C6D4(+), Al100C6D2(+), and Al100C6(+). The degree of dehydrogenation was measured as a function of temperature. Very little Al100C6D2(+) was observed, suggesting that the losses of the second and third D2 molecules are coordinated.


Activin receptor-like kinase 3: a critical modulator of development and function of mineralized tissues.
Mineralized tissues, such as teeth and bones, pose significant challenges for repair due to their hardness, low permeability, and limited blood flow compared to soft tissues. Bone morphogenetic proteins (BMPs) have been identified as playing a crucial role in mineralized tissue formation and repair. However, the application of large amounts of exogenous BMPs may cause side effects such as inflammation. Therefore, it is necessary to identify a more precise molecular target downstream of the ligands. Activin receptor-like kinase 3 (ALK3), a key transmembrane receptor, serves as a vital gateway for the transmission of BMP signals, triggering cellular responses. Recent research has yielded new insights into the regulatory roles of ALK3 in mineralized tissues. Experimental knockout or mutation of ALK3 has been shown to result in skeletal dysmorphisms and failure of tooth formation, eruption, and orthodontic tooth movement. This review summarizes the roles of ALK3 in mineralized tissue regulation and elucidates how ALK3-mediated signaling influences the physiology and pathology of teeth and bones. Additionally, this review provides a reference for recommended basic research and potential future treatment strategies for the repair and regeneration of mineralized tissues.


Diffuse Jejunal Lipomatosis and Associated Complications.
Small intestinal lipomatosis is a rare condition with a poorly understood epidemiology and pathophysiology. Cases of small intestinal lipomatosis have been documented in multiple countries over the last century, yet little has been published regarding the natural history of this disease. Therapeutic options are largely surgical and based on limited evidence. We report a unique case of diffuse jejunal lipomatosis in a 62-year-old man with complications of small bowel obstruction, small bowel volvulus, jejunal diverticulosis, pneumatosis intestinalis, malnutrition, small intestinal bacterial overgrowth, and intestinal dysmotility developing over a 12-year period.


Psychosocial issues in reproductive genetic testing and pregnancy loss.
This paper considers the psychosocial experience of women undergoing reproductive genetic testing, with attention to the impact of pregnancy loss after testing. New directions for research are called for to provide more in-depth understanding of the meaning of these experiences for women and their male partners.


Sarcomas with combined features of liposarcoma and leiomyosarcoma. Study of two cases of an unusual soft-tissue tumor showing dual lineage differentiation.
Two cases are described of a soft-tissue sarcoma characterized histologically by the intimate admixture of areas displaying the features of liposarcoma and leiomyosarcoma. Both cases occurred in men, 70 and 77 years of age. The lesions were located in the left scrotum and abdominal cavity, respectively. Histologically, the lipomatous component in both cases consisted predominantly of well-differentiated liposarcoma with myxoid areas. The smooth-muscle component was characterized by intersecting fascicles of spindle cells displaying nuclear atypicality and scattered mitotic figures; the spindle cells in these areas were strongly immunoreactive with actin and desmin antibodies. The above tumors must be distinguished from angiomyolipoma, spindle-cell lipoma, myolipoma of soft tissue, and more importantly, from "dedifferentiated" liposarcoma. The development of dual lineage differentiation within adipose tissue tumors as exemplified by these two cases may be more prevalent than has been generally recognized, and may require the application of immunohistochemical markers for specific identification of the spindle-cell component.


Up-to-Date Information on Rheumatoid Arthritis-Associated Interstitial Lung Disease.
Pulmonary involvement is common in rheumatoid arthritis (RA) and affects all the components of the lung. Interstitial lung disease (ILD) is the most predominant pulmonary manifestation and has been identified as the main cause of morbidity and mortality in RA. Clinically significant RA-ILD occurs in approximately 10% of RA patients. Several risk factors, such as old age, male gender, and smoking, have been reported to date. Histologically, the proportion of the usual interstitial pneumonia (UIP) pattern is higher in RA-ILD than in ILD associated with other connective tissue diseases, and RA-ILD also shows nonspecific interstitial pneumonia and organizing pneumonia patterns. High-resolution computed tomography scans are highly predictive of the histological UIP pattern with a specificity of 96%-100%. Acute exacerbation, which is the acute deterioration of the respiratory status characterized by newly developed bilateral infiltrates with unknown etiologies, has been reported in RA-ILD. Although acute exacerbation of RA-ILD has high mortality, similar to that of idiopathic pulmonary fibrosis, its incidence is lower in RA-ILD than in idiopathic pulmonary fibrosis. A consensus treatment has not yet been established. Current therapeutic regimens typically include corticosteroids with or without cytotoxic agents. Recent large longitudinal studies reported that the prognosis of RA-ILD was poor with a median survival of 2.6-3.0 years. Furthermore, histological and/or radiological patterns, such as UIP or non-UIP, have significant prognostic implications. RA-ILD patients with histological or radiological UIP patterns have poorer prognoses than those with non-UIP patterns. This review assessed the characteristics of RA-ILD by overviewing recent studies in the field and focused on the clinical significance of histological and/or radiological patterns in RA-ILD.


Insight into the molecular genetics of myopia.
Myopia is the most common cause of visual impairment worldwide. Genetic and environmental factors contribute to the development of myopia. Studies on the molecular genetics of myopia are well established and have implicated the important role of genetic factors. With linkage analysis, association studies, sequencing analysis, and experimental myopia studies, many of the loci and genes associated with myopia have been identified. Thus far, there has been no systemic review of the loci and genes related to non-syndromic and syndromic myopia based on the different approaches. Such a systemic review of the molecular genetics of myopia will provide clues to identify additional plausible genes for myopia and help us to understand the molecular mechanisms underlying myopia. This paper reviews recent genetic studies on myopia, summarizes all possible reported genes and loci related to myopia, and suggests implications for future studies on the molecular genetics of myopia.


Revision of Lissoporcellana streptochiroides (Johnson, 1970) (Crustacea: Decapoda: Anomura: Porcellanidae), with description of a new species of Lissoporcellana Haig, 1978 from Beibu Bay, South China Sea.
A new porcellanid crab, Lissoporcellana demani n. sp. is described based on material from the Beibu Bay in the northern South China Sea. The new species can be distinguished from other congeners by the shape of rostrum, form of fixed finger of smaller cheliped and armature of lateral margins of carapace. The poorly known species L. streptochiroides (Johnson, 1970), which resembles L. demani n. sp. in carapace shape, is redescribed on the basis of examination of the syntypes from Singapore and transferred to Pisidia Leach, 1820.


Preferential import of queuosine-modified tRNAs into Trypanosoma brucei mitochondrion is critical for organellar protein synthesis.
Transfer RNAs (tRNAs) are key players in protein synthesis. To be fully active, tRNAs undergo extensive post-transcriptional modifications, including queuosine (Q), a hypermodified 7-deaza-guanosine present in the anticodon of several tRNAs in bacteria and eukarya. Here, molecular and biochemical approaches revealed that in the protozoan parasite Trypanosoma brucei, Q-containing tRNAs have a preference for the U-ending codons for asparagine, aspartate, tyrosine and histidine, analogous to what has been described in other systems. However, since a lack of tRNA genes in T. brucei mitochondria makes it essential to import a complete set from the cytoplasm, we surprisingly found that Q-modified tRNAs are preferentially imported over their unmodified counterparts. In turn, their absence from mitochondria has a pronounced effect on organellar translation and affects function. Although Q modification in T. brucei is globally important for codon selection, it is more so for mitochondrial protein synthesis. These results provide a unique example of the combined regulatory effect of codon usage and wobble modifications on protein synthesis; all driven by tRNA intracellular transport dynamics.


Mapping Geospatial Gaps in Early Identification of Children With Autism Spectrum Disorder.
Despite the known developmental benefits of early intervention for autism spectrum disorder (ASD), diagnosis before age 5 years is often not achieved. Research suggests that lack of health insurance and living in rural areas and areas of severe provider shortages contribute significantly to these delays. The purpose of this project was to conduct a geospatial evaluation of potential gaps in early ASD diagnosis of uninsured children in Virginia. A secondary purpose was to show the use of geospatial analysis by pediatric nurse practitioners for policy advocacy. We mapped data from a statewide provider of ASD evaluative services associated with the Virginia Department of Health and found several communities with high numbers of uninsured children where children may not be receiving early diagnostic services. Pediatric nurse practitioners can help address community-level gaps in early identification of ASD for uninsured young children living in rural areas by conducting outreach programs to providers and families within rural communities and concurrently partnering with nurse-scientists to develop visually impactful geospatial analyses to educate legislators and further advocate for policy positions.


A review of in vitro and in vivo studies on the efficacy of herbal medicines for primary dysmenorrhea.
Purpose. Primary dysmenorrhea (PD) is a common gynecological complaint among adolescent girls and women of reproductive age. This study aims to review the findings of published articles on the in vitro and in vivo efficacy of herbal medicines for PD. Methods. In vitro and in vivo studies of herbal compounds, individual herbal extracts, or herbal formula decoctions published from their inception to April 2014 were included in this review. Results. A total of 18 studies involving herbal medicines exhibited their inhibitory effect on PD. The majority of in vitro studies investigated the inhibition of uterine contractions. In vivo studies suggest that herbal medicines exert a peripheral analgesic effect and a possible anti-inflammatory activity via the inhibition of prostaglandin (PG) synthesis. The mechanisms of herbal medicines for PD are associated with PG level reduction, suppression of cyclooxygenase-2 expression, superoxide dismutase activation and malondialdehyde reduction, nitric oxide, inducible nitric oxide synthase, and nuclear factor-kappa B reduction, stimulation of somatostatin receptor, intracellular Ca(2+) reduction, and recovery of phospholipid metabolism. Conclusions. Herbal medicines are thought to be promising sources for the development of effective therapeutic agents for PD. Further investigations on the appropriate herbal formula and their constituents are recommended.


The starfish egg mRNA responsible for meiosis reinitiation encodes cyclin.
During meiotic maturation and early embryonic cycles, the activity of maturation-promoting factor (MPF) cycles in exact correspondence with the mitotic cycles. For the appearance of MPF activity in starfish, protein synthesis is required except in the first meiotic cycle. In order to identify newly synthesized proteins involved in the regulation of MPF activity, we extracted poly(A)+ RNA from starfish eggs, and found that the egg poly(A)+ RNA induced germinal vesicle breakdown (GVBD) upon injection into immature oocytes of starfish and Xenopus. The molecular size of the poly(A)+ RNA responsible for GVBD was estimated to be approximately 22S by sucrose density gradient centrifugation. Since these characteristics of the starfish egg poly(A)+ RNA are similar to those of cyclin mRNAs from sea urchin and surf clam eggs, we synthesized a 50-mer antisense-cyclin oligonucleotide probe coding for a part of the sea urchin cyclin cDNA and used this to screen starfish RNA. The Northern blot analysis showed that the starfish egg RNA contained cyclin homologous transcripts. Incubation of the starfish egg poly(A)+ RNA and the antisense-cyclin oligonucleotide with RNase H completely destroyed its GVBD-inducing activity. These results indicated that starfish cyclin mRNA was the only poly(A)+ RNA responsible for GVBD. We constructed a starfish egg cDNA library to clone starfish cyclin cDNA. The longest cDNA clone containing 2190 base pairs was sequenced. The longest open reading frame consisted of 395 amino acid residues, and the predicted molecular size was 48 kDa. Comparison of the deduced amino acid sequences of starfish cyclin with known cyclins indicated that the starfish cyclin belongs to the B-type. Injection of synthetic mRNA of starfish cyclin caused GVBD in immature oocytes of starfish and Xenopus, while injection of synthetic mRNA of human CDC2 had no effect. The Northern blot analysis of starfish RNA extracted at various stages of the meiotic cycles suggested that the starfish cyclin transcript was stored in its polyadenylated form even in immature oocytes and was further polyadenylated at maturation.


Reliability of gait speed measured by a timed walking test in patients one year after stroke.
To assess the reliability of gait speed in late-stage stroke patients. Test-retest reliability of three timed walks to 10 metres repeated during two assessments one week apart. The patient's home. Twenty-two stroke patients with mobility problems more than one year after stroke. Gait speed measured in seconds taken to walk 10 metres. Intraclass correlations (ICCs) with 95% confidence interval (CI) and the Bland and Altman method for assessing agreement by calculating the mean difference between measurements (d); the 95% CI for d; the standard deviation of the difference (SDdiff); a reliability coefficient and the 95% limits of agreement. There was a trend for decreased times taken to walk 10 metres both within each assessment and between assessments. ICCs for within-assessment reliability were 0.95-0.99. The d (SDdiff) for the second and third walks for assessment 1 was -1.00 (2.63) seconds and for assessment 2 was -0.70 (1.58) seconds. The reliability coefficient was 5.26 for assessment 1 and 3.17 for assessment 2. ICCs for between-assessment reliability were 0.87-0.88. The d (SDdiff) for the comparison of the third walks at assessment 1 and assessment 2 was -0.90 (5.01) seconds. The reliability coefficient was 10.02 and the 95% limits of agreement were -10.92 to +9.12 seconds. Within-assessment gait speed measured at home is highly reliable. The between-assessment reliability of gait speed measurement is less reliable but comparable with other studies.


Replicating medication trend studies using ad hoc information extraction in a clinical data warehouse.
Medication trend studies show the changes of medication over the years and may be replicated using a clinical Data Warehouse (CDW). Even nowadays, a lot of the patient information, like medication data, in the EHR is stored in the format of free text. As the conventional approach of information extraction (IE) demands a high developmental effort, we used ad hoc IE instead. This technique queries information and extracts it on the fly from texts contained in the CDW. We present a generalizable approach of ad hoc IE for pharmacotherapy (medications and their daily dosage) presented in hospital discharge letters. We added import and query features to the CDW system, like error tolerant queries to deal with misspellings and proximity search for the extraction of the daily dosage. During the data integration process in the CDW, negated, historical and non-patient context data are filtered. For the replication studies, we used a drug list grouped by ATC (Anatomical Therapeutic Chemical Classification System) codes as input for queries to the CDW. We achieve an F1 score of 0.983 (precision 0.997, recall 0.970) for extracting medication from discharge letters and an F1 score of 0.974 (precision 0.977, recall 0.972) for extracting the dosage. We replicated three published medical trend studies for hypertension, atrial fibrillation and chronic kidney disease. Overall, 93% of the main findings could be replicated, 68% of sub-findings, and 75% of all findings. One study could be completely replicated with all main and sub-findings. A novel approach for ad hoc IE is presented. It is very suitable for basic medical texts like discharge letters and finding reports. Ad hoc IE is by definition more limited than conventional IE and does not claim to replace it, but it substantially exceeds the search capabilities of many CDWs and it is convenient to conduct replication studies fast and with high quality.


Preparation of La0.7Ca0.3-xSrxMnO₃ Manganites by Four Synthesis Methods and Their Influence on the Magnetic Properties and Relative Cooling Power.
Manganites of the family La0.7Ca0.3-xSrxMnO₃ were fabricated by four preparation methods: (a) the microwave-assisted sol-gel Pechini method; (b) sol-gel Pechini chemical synthesis; (c) solid-state reaction with a planetary mill; and (d) solid-state reaction with an attritor mill, in order to study the effect of the preparation route used on its magnetocaloric and magnetic properties. In addition, the manganites manufactured by the Pechini sol-gel method were compacted using Spark Plasma Sintering (SPS) to determine how the consolidation process influences its magnetocaloric properties. The Curie temperatures of manganites prepared by the different methods were determined in ~295 K, with the exception of those prepared by a solid-state reaction with an attritor mill which was 301 K, so there is no correlation between the particle size and the Curie temperature. All samples gave a positive slope in the Arrot plots, which implies that the samples underwent a second order Ferromagnetic (FM)⁻Paramagnetic (PM) phase transition. Pechini sol-gel manganite presents higher values of Relative Cooling Power (RCP) than the solid-state reaction manganite, because its entropy change curves are smaller, but wider, associated to the particle size obtained by the preparation method. The SPS technique proved to be easier and faster in producing consolidated solids for applications in active magnetic regenerative refrigeration compared with other compaction methods.


Minocycline reduces mechanical allodynia and depressive-like behaviour in type-1 diabetes mellitus in the rat.
A common and devastating complication of diabetes mellitus is painful diabetic neuropathy (PDN) that can be accompanied by emotional disorders such as depression. A few studies have suggested that minocycline that inhibits microglia may attenuate pain hypersensitivity in PDN. Moreover, a recent study reported that minocycline has an acute antidepressive-like effect in diabetic animals. Here we studied whether (i) prolonged minocycline treatment suppresses pain behaviour in PDN, (ii) the minocycline effect varies with submodality of pain, and (iii) the suppression of pain behaviour by prolonged minocycline treatment is associated with antidepressive-like effect. The experiments were performed in streptozotocin-induced rat model of type-1 diabetes. Pain behaviour was evoked by innocuous (monofilaments) and noxious (paw pressure) mechanical stimulation, innocuous cold (acetone drops) and noxious heat (radiant heat). Depression-like behaviour was assessed using forced swimming test. Minocycline treatment (daily 80mg/kg per os) of three-week duration started four weeks after induction of diabetes. Diabetes induced mechanical allodynia and hyperalgesia, cold allodynia, heat hypoalgesia, and depression-like behaviour. Minocycline treatment significantly attenuated mechanical allodynia and depression-like behaviour, while it failed to produce significant changes in mechanical hyperalgesia, cold allodynia or heat hypoalgesia. The results indicate that prolonged per oral treatment with minocycline has a sustained mechanical antiallodynic and antidepressive-like effect in PDN. These results support the proposal that minocycline might provide a treatment option for attenuating sensory and comorbid emotional symptoms in chronic PDN.


[Laboratory and clinical investigation of multifunctional dentifrices. Clinical study of a new triclosan-containing toothpaste].
The purpose of this work was to assess the in vitro antibacterial effectiveness of three dentifrices containing antimicrobial agents and to test the in vivo anti plaque and anti gingivitis effect of a toothpaste containing triclosan (CAOLA). The in vitro tests showed a marked antibacterial effect of both triclosan and chlorhexidine containing dentifrices. The randomized clinical trial presented good evidences that the triclosan had some but statistically non significant plaque and gingivitis reduction in patients even without previous mechanical cleaning. Nevertheless the triclosan dentifrice was effective in reducing the plaque and gingivitis scores in combination with initial mechanical debridement and oral hygienic instructions.


Enhancing Access to Diabetes Self-management Education in Primary Care.
The purpose of this continuous quality improvement project was to improve access to diabetes self-management education (DSME) and to evaluate the impact on glycemic and weight control by translating an academic medical center's DSME program, accredited per the Education Recognition Program (ERP) of the American Diabetes Association, into a program offered at primary care clinics (PCCs). Certified diabetes educators from the medical center trained PCC registered dietitian nutritionists, registered nurses, and social workers to provide DSME in their community-based clinic. Main outcomes of this retrospective, pretest/posttest, observational project were to evaluate enrollment in DSME classes and change in A1C and weight as patients underwent a combined intervention of diabetes education classes with or without consultation and support from a PCC registered dietitian nutritionist or registered nurse. PCC DSME was associated with increased enrollment in DSME classes and a significant reduction of A1C and weight at 3 and 6 months post-DSME. Greatest A1C and weight reductions were observed in patients with newly diagnosed diabetes. Reductions were also seen in patients with diabetes duration ≥10 years, participants taking insulin, and those with depression. PCC DSME availability increased access to group diabetes education and resulted in reduced A1C and weight for participants. This model was successful in translating an established academic accredited DSME-ERP into a PCC. Results have implications for increasing access to diabetes education programs and improving diabetes control for patients not located near major hospital-based DSME programs.


Understanding attitudes and behaviors towards cell-free DNA-based noninvasive prenatal testing (NIPT): A survey of European health-care providers.
Cell-free DNA-based noninvasive prenatal testing (cfDNA) is a relatively new screening tool that analyzes cfDNA circulating in maternal plasma to screen for aneuploidies. Since its introduction, cfDNA has been rapidly adopted by health care providers (HCPs). This rapid adoption, as well as progressive developments in the technology, requires professional societies to continuously update their guidelines to indicate the broadening scope both in terms of test indications and patient populations for whom it has become the appropriate primary test. CfDNA testing, initially applied to high-risk patients, is now largely considered an option for all patients. For HCPs, the rapid introduction of cfDNA into clinical practice has come with the requirement to stay up-to-date and accurately informed. We performed a survey to understand the current practices and views of European HCPs on the use of cfDNA. European HCPs were surveyed on several topics such as familiarity with cfDNA-based noninvasive prenatal testing (NIPT), current usage, patient counseling, test menu expansion, and future perspectives. The results of this survey demonstrate increasing usage and awareness of cfDNA-based NIPT in five European countries (UK, France, Germany, Spain and Italy). Major barriers to implementation include cost and a lack of physician education on NIPT.


Conventional radiographs vs digitized radiographs: image quality assessment.
The aim of this study was to compare image quality characteristics of conventional radiographs and their digital counterparts. 100 conventional radiographs (E-speed) were used for the evaluation of density and contrast. The radiographs were made using a range of exposures under standardized conditions and were compared with digital images that resulted from scanning the above radiographs with a commercially available scanner. Resolution was evaluated with an experiment using 50 film packets and a resolution target exposed with different exposure times, using both the original radiographs and their scanned equivalents. The digitized radiographs appeared to be of higher density than the conventional ones. Moreover, they demonstrated a narrower density range. Resolution was similar for both types of images. Although there is an agreement with the literature that the digitized radiographs are of higher density, further investigation is required to detect the various factors that may have an effect on the quality of the digitized images.


Analysis of Heart Rate, Perception of Physical Effort and Performance of Individuals with Down Syndrome Submitted to a Protocol of Virtual Games for Home-Based Telerehabilitation.
Down syndrome (DS) is a genetic condition associated with impairments in several body systems, which may negatively influence the habit of practicing physical activities (PAs), increasing sedentary habits and the risk of comorbidities. Additionally, difficulty in accessing services, financial limitations and lack of interest may interfere with the practice of PAs. Considering the necessity of developing effective treatment alternatives, to increase the possibility of access and the interest of participants, we conducted a study using telerehabilitation with a virtual task to promote PA and analyze the motor performance of DS individuals. Our protocol consisted of 11 sessions of the virtual game called MoveHero. A total of 34 individuals with DS and 34 individuals with typical development participated in the study. Heart rate (HR) and rating of perceived effort (RPE) were collected at rest and during the game. Our results show that virtual reality presents a great possibility to promote PA and a way out of a sedentary lifestyle for DS individuals, considering the enhancement in HR and RPE found during the protocol for both groups. Moreover, our results show positive outcomes regarding motor performance, with significant improvement in the task with practice, demonstrating that individuals with DS are able to improve their motor proficiency with adequate stimuli in the virtual environment.


Daily Electrical Muscle Stimulation Enhances Functional Recovery Following Nerve Transection and Repair in Rats.
Incomplete recovery following surgical reconstruction of damaged peripheral nerves is common. Electrical muscle stimulation (EMS) to improve functional outcomes has not been effective in previous studies. To evaluate the efficacy of a new, clinically translatable EMS paradigm over a 3-month period following nerve transection and immediate repair. Rats were divided into 6 groups based on treatment (EMS or no treatment) and duration (1, 2, or 3 months). A tibial nerve transection injury was immediately repaired with 2 epineurial sutures. The right gastrocnemius muscle in all rats was implanted with intramuscular electrodes. In the EMS group, the muscle was electrically stimulated with 600 contractions per day, 5 days a week. Terminal measurements were made after 1, 2, or 3 months. Rats in the 3-month group were assessed weekly using skilled and overground locomotion tests. Neuromuscular junction reinnervation patterns were also examined. Muscles that received daily EMS had significantly greater numbers of reinnervated motor units with smaller average motor unit sizes. The majority of muscle endplates were reinnervated by a single axon arising from a nerve trunk with significantly fewer numbers of terminal sprouts in the EMS group, the numbers being small. Muscle mass and force were unchanged but EMS improved behavioral outcomes. Our results demonstrated that EMS using a moderate stimulation paradigm immediately following nerve transection and repair enhances electrophysiological and behavioral recovery.


Lumbar tuberculosis associated with membranous nephropathy and interstitial nephritis.
Tuberculosis is a common disease worldwide. However, it now is clear that tuberculosis can affect the kidney more insidiously. We describe a case of lumbar tuberculosis associated with simultaneous membranous nephropathy and interstitial nephritis, in which recovery of renal function occurred after treatment with steroids in addition to antituberculosis agents.


CuS nanoplates from ionic liquid precursors-Application in organic photovoltaic cells.
Hexagonal p-type semiconductor CuS nanoplates were synthesized via a hot injection method from bis(trimethylsilyl)sulfide and the ionic liquid precursor bis(N-dodecylpyridinium) tetrachloridocuprate(ii). The particles have a broad size distribution with diameters between 30 and 680 nm and well-developed crystal habits. The nanoplates were successfully incorporated into organic photovoltaic (OPV) cells as hole conduction materials. The power conversion efficiency of OPV cells fabricated with the nanoplates is 16% higher than that of a control device fabricated without the nanoplates.


Longitudinal quantification and visualization of intracerebral haemorrhage using multimodal magnetic resonance and diffusion tensor imaging.
To demonstrate a set of approaches using diffusion tensor imaging (DTI) tractography whereby pathology-affected white matter (WM) fibres in patients with intracerebral haemorrhage (ICH) can be selectively visualized. Using structural neuroimaging and DTI volumes acquired longitudinally from three representative patients with ICH, the spatial configuration of ICH-related trauma is delineated and the WM fibre bundles intersecting each ICH lesion are identified and visualized. Both the extent of ICH lesions as well as the proportion of WM fibres intersecting the ICH pathology are quantified and compared across subjects. This method successfully demonstrates longitudinal volumetric differences in ICH lesion load and differences across time in the percentage of fibres which intersect the primary injury. Because neurological conditions such as intracerebral haemorrhage (ICH) frequently exhibit pathology-related effects which lead to the exertion of mechanical pressure upon surrounding tissues and, thereby, to the deformation and/or displacement of WM fibres, DTI fibre tractography is highly suitable for assessing longitudinal changes in WM fibre integrity and mechanical displacement.


Clinical characteristics and impact of diabetes mellitus on outcomes in patients with nonvalvular atrial fibrillation.
Studies have shown that diabetes mellitus (DM) is a risk factor for cardiovascular disease, including atrial fibrillation (AF); however, the clinical characteristics and prognostic impact of DM in patients with nonvalvular AF have not been well understood in China. Included were 1644 consecutive patients with nonvalvular AF. Endpoints included all-cause mortality, cardiovascular mortality, stroke, major bleeding, and combined endpoint events (CEE) during a 1-year follow-up. The prevalence of DM was 16.8% in nonvalvular AF patients. Compared with non-diabetic AF patients, diabetic AF patients were older and tended to coexist with other cardiovascular diseases. Most patients with DM (93.5%) were eligible for anticoagulation, as determined by CHADS2 scores. However, only 11.2% of patients received anticoagulation. During a 1-year follow-up, the all-cause mortality and CEE rate in the DM group were significantly higher than those of the non-DM group, while the incidence of stroke was comparable. After multivariate adjustments, DM was still an independent risk factor for 1-year all-cause mortality [hazard ratio (HR)=1.558; 95% confidence interval (CI) 1.126-2.156; p=0.007], cardiovascular mortality (HR=1.615; 95% CI 1.052-2.479; p=0.028), and CEE (HR=1.523; 95% CI 1.098-2.112; p=0.012), yet not for stroke (HR=1.119; 95% CI 0.724-1.728; p=0.614). DM is a common morbidity coexisting with nonvalvular AF and is associated with an increased risk of 1-year all-cause mortality, cardiovascular mortality, and CEE. However, no increased risk of stroke was found during a 1-year follow-up in patients with AF and DM.


Horizontally Acquired Biosynthesis Genes Boost Coxiella burnetii's Physiology.
Coxiella burnetii, the etiologic agent of acute Q fever and chronic endocarditis, has a unique biphasic life cycle, which includes a metabolically active intracellular form that occupies a large lysosome-derived acidic vacuole. C. burnetii is the only bacterium known to thrive within such an hostile intracellular niche, and this ability is fundamental to its pathogenicity; however, very little is known about genes that facilitate Coxiella's intracellular growth. Recent studies indicate that C. burnetii evolved from a tick-associated ancestor and that the metabolic capabilities of C. burnetii are different from that of Coxiella-like bacteria found in ticks. Horizontally acquired genes that allow C. burnetii to infect and grow within mammalian cells likely facilitated the host shift; however, because of its obligate intracellular replication, C. burnetii would have lost most genes that have been rendered redundant due to the availability of metabolites within the host cell. Based on these observations, we reasoned that horizontally derived biosynthetic genes that have been retained in the reduced genome of C. burnetii are ideal candidates to begin to uncover its intracellular metabolic requirements. Our analyses identified a large number of putative foreign-origin genes in C. burnetii, including tRNAGlu2 that is potentially required for heme biosynthesis, and genes involved in the production of lipopolysaccharide-a virulence factor, and of critical metabolites such as fatty acids and biotin. In comparison to wild-type C. burnetii, a strain that lacks tRNAGlu2 exhibited reduced growth, indicating its importance to Coxiella's physiology. Additionally, by using chemical agents that block heme and biotin biosyntheses, we show that these pathways are promising targets for the development of new anti-Coxiella therapies.


Investigation of variations in microbial diversity in anaerobic reactors treating landfill leachate.
A young landfill leachate containing elevated total ammonia concentrations frequently as high as 2,700 mg/l was anaerobically treated for 1,015 days in two different laboratory-scale anaerobic reactors configured as sludge blanket and hybrid bed. In this paper, the last 265 days of this long-term anaerobic treatability study are presented. Effects of high ammonia concentrations on reactor performances were correlated to the variations in microbial diversity by identifying the dominant microorganisms with FISH (fluorescent in-situ hybridization), cloning, DGGE (denaturing gradient gel electrophoresis) and morphological analysis. The results have indicated that the high ammonia landfill leachate can be treated successfully by using either an UASB or a hybrid bed reactor if temporary pH adjustments in the reactor influents are made when high ammonia concentrations are experienced. Consequently, COD removal efficiency is independent of microbial diversity and reactor configuration and it depends on the biodegradable portion of the leachate. Under this circumstance, stability of the reactors with low levels of acetate was supported by the abundance of Methanosaeta population. In both of the reactors, some populations of Methanobacteriaceae were also detected while other methanogenic species were virtually absent. However, after the termination of pH adjustment at Day 860, reactors immediately became unstable due to the sudden increase in free ammonia concentration up to 400 mg/l. COD removal efficiency decreased to 42% in the hybrid bed and to 48% in the UASB reactor. The durations of inhibitions were not long enough to severely deteriorate the massive Methanosaeta cells; therefore, many of them were again identified after two free ammonia inhibitions. However, subsequently, long filamentous morphologies of Methanosaeta cells shifted to shorter filaments and they lost their aggregating property.


Amplifying cancer treatment: advances in tumor immunotherapy and nanoparticle-based hyperthermia.
In the quest for cancer treatment modalities with greater effectiveness, the combination of tumor immunotherapy and nanoparticle-based hyperthermia has emerged as a promising frontier. The present article provides a comprehensive review of recent advances and cutting-edge research in this burgeoning field and examines how these two treatment strategies can be effectively integrated. Tumor immunotherapy, which harnesses the immune system to recognize and attack cancer cells, has shown considerable promise. Concurrently, nanoparticle-based hyperthermia, which utilizes nanotechnology to promote selective cell death by raising the temperature of tumor cells, has emerged as an innovative therapeutic approach. While both strategies have individually shown potential, combination of the two modalities may amplify anti-tumor responses, with improved outcomes and reduced side effects. Key studies illustrating the synergistic effects of these two approaches are highlighted, and current challenges and future prospects in the field are discussed. As we stand on the precipice of a new era in cancer treatment, this review underscores the importance of continued research and collaboration in bringing these innovative treatments from the bench to the bedside.


Shaping Rollable Display Devices: Effects of Gripping Condition, Device Thickness, and Hand Length on Bimanual Perceived Grip Comfort.
To examine the effects of the gripping condition, device thickness, and hand length on bimanual perceived grip comfort associated with unrolling hand-held rollable screens. Rollable displays can be rolled and unrolled to change screen size. Although diverse rollable display device concepts have been suggested, little is known regarding ergonomic forms for comfortable screen unrolling. Thirty young individuals (10 in each hand-length group) evaluated three rollable display device prototypes in three gripping conditions (no restriction on using side bezels, minimal use of side bezels, and restriction on the gripping type). Prototypes differed in their right-side thickness (2, 6, and 10 mm). Side bezel regions grasped during screen unrolling and corresponding bimanual grip comfort ratings were obtained. To improve perceived grip comfort and accommodate user-preferred gripping methods, rollable display devices should be 6 mm (preferably 10 mm) thick (vs. 2 mm) and have at least 20-mm-wide side bezels. Relative to device thickness, gripping conditions were more influential on grip comfort ratings. The "no restriction" condition improved grip comfort ratings and strengthened bimanual coupling in terms of grip comfort ratings. Contrary to current smartphone trends toward thinner and bezel-less designs, hand-held rollable display devices should be sufficiently thick and have sufficiently wide side bezels for screen unrolling. Hand-held rollable display devices should be 6- or preferably 10-mm thick (vs. 2 mm) and have at least 20-mm-wide side bezels to ensure higher perceived grip comfort during bilateral screen unrolling.


Algorithm for the management of ERCP-related perforations.
Perforation is a rare but serious adverse event of ERCP. There is no consensus to guide the clinician on the management of ERCP-related perforations, with particular controversy surrounding the immediate surgical management of postprocedurally detected duodenal perforation because of overextension of a sphincterotomy. Our aim was to assess patient outcomes using a predetermined algorithm based on managing ERCP-related duodenal perforations according to the mechanism of injury. A retrospective single-center study of all consecutive patients with Stapfer type I and II perforations between 2000 and 2014 were included. Our institutional algorithm since 2000 dictated that Stapfer type I perforations (duodenal wall perforation, endoscope related) should be managed surgically unless prohibited by underlying comorbidities and Stapfer type II perforations (periampullary, sphincterotomy related) managed nonsurgically unless a deterioration in clinical status necessitated surgery. Sixty-one patients (mean age, 51 years; 80% women) were analyzed with Stapfer type I perforations diagnosed in 7 (11%) and type II in 54 (89%). A postprocedural diagnosis of perforation was made in 55 patients (90%). Four patients (7%) had Stapfer type II perforations that failed medical management and required surgery. The mean length of stay (LOS) in the entire cohort was 9.6 days with a low mortality rate of 3%. Systemic inflammatory response syndrome was observed in 18 patients (33%) with Stapfer type II perforations and was not associated with the need for surgery. Concurrent post-ERCP pancreatitis was diagnosed in 26 patients (43%) and was associated with an increased LOS. Stapfer type II perforations have excellent outcomes when managed medically. We validate an algorithm for the management of ERCP-related perforations and propose that it should function as a guide.


Developmental changes in auditory temporal perception.
Infants, preschoolers, and adults were tested to determine the shortest time interval at which they would respond to the precedence effect--an auditory phenomenon produced by presenting the same sound through 2 loudspeakers with the input to 1 loudspeaker delayed relative to the other. The delayed sound is not localized at its source until time delays between onsets are lengthened beyond a critical limit, or threshold. Thresholds for the precedence effect were defined as the delay interval below which listeners respond only to the leading loudspeaker and above which they respond to both loudspeakers. Threshold estimates were determined for adults and preschoolers with an ascending and descending series, followed by a method of constant stimuli series. Infants were trained to respond to the delayed sound using a visually reinforced headturning procedure. For clicks, preschoolers' and adults' thresholds were around 12 msec, while 6-month-olds stopped responding to the delayed sound around 25 msec. A similar developmental difference in threshold was expressed between preschoolers and adults for a more complex sound, with younger subjects hearing the precedence effect over a longer time delay.


Molecular screening of insecticides with sigma glutathione S-transferases (GST) in cotton aphid Aphis gossypii using docking.
Glutathione S-transferases (GSTs) are one of the major families of detoxifying enzymes that detoxifies different chemical compounds including insecticides in different insect species. Among the GST subclasses, sigma GSTs are found to be the most abundant and conserved among different insect orders. These GSTs are found to play an important role in lipid peroxidation as well as detoxification. Cotton aphid, Aphis gossypii is the most damaging sucking pest with a wide range of hosts and vector of more than 50 plant viruses. Resistance to insecticides in A. gossypii is reported in India and in other countries. Glutathione S transferases (GSTs), an oxidative enzyme is understood to have a role in insecticide resistance and plant resistance breakdown. In relation to this, we have focused on the sigma 1 (GenBank Accession No: JN989964.1) and sigma 2 (GenBank Accession No: JN989965.1) GSTs of A. gossypii and their interaction with plant natural compounds and insecticides. Molecular screening of different insecticides (Chlorphinamidine, Mevinphos, Nitenpyrum, Piperonyl butoxide, Tetrachlorovinphos, Pyrethrins, Resmetrin, Pirimicarb and Dinotefuran) and known plant derived natural compounds (Catechin, Gossypol, Myrcene, Kaempferol, P-coumaric acid, Quercetin, Tannins, α-mangostin, Capsaicin, Cinnamic acid, Citronellal, Curcumin, Dicumarol, Ellagic acid, Eugenol, Geriniol, Isoeugenol, Juglone, Menadione, Methyl jasmonate, Morin, Myricetin, Myristicin, Piperine, Plumbagin, Tangitinin C, Thymol, Vanillin, Alpha pipene, α-terpineol Apigenin and β-Caryophyllene) with sigma 1 and sigma 2 GST protein models was completed using Maestro 9.3 (Schrodinger, USA). This exercise showed the binding of piperonyl butoxide with sigma 1 GST and tannin with sigma 2 GST for further consideration.


Voltammetric detection of lectin using sugar labeled with electroactive substance.
The voltammetric detection of soybean agglutinin (SBA) was investigated on the basis of an interaction between the lectin and a sugar. Because galactose and lactose combined with SBA, the sugars were labeled by a Schiff base with an electroactive daunomycin. After the labeled sugar and SBA were mixed, measurements were carried out by voltammetry. When SBA-sugar binding occurs, a part of daunomycin of the labeled sugar is taken to the binding sites. As a result, SBA is detected by a change in the peak current of daunomycin, and the SBA-sugar interaction is evaluated. The length of the alkyl chain between daunomycin and the sugar was also considered. The electrode response to the concentration of SBA was linear over the range of 0.04-0.8 microg min(-1). The merits of this procedure are the convenient preparation of labeled sugar and a rapid measurement without separation. On the other hand, the detection of sugar at the 10(-9) mol dm(-3) level was achieved by a competitive reaction to limited binding sites of the lectin between the sugar and the labeled sugar.


Early clinical applications for imaging at microscopic detail: microfocus computed tomography (micro-CT).
Microfocus CT (micro-CT) has traditionally been used in industry and preclinical studies, although it may find new applicability in the routine clinical setting. It can provide high-resolution three-dimensional digital imaging data sets to the same level of detail as microscopic examination without the need for tissue dissection. Micro-CT is already enabling non-invasive detailed internal assessment of various tissue specimens, particularly in breast imaging and early gestational fetal autopsy, not previously possible from more conventional modalities such as MRI or CT. In this review, we discuss the technical aspects behind micro-CT image acquisition, how early work with small animal studies have informed our knowledge of human disease and the imaging performed so far on human tissue specimens. We conclude with potential future clinical applications of this novel and emerging technique.


Medial temporal lobe atrophy and white matter hyperintensities are associated with mild cognitive deficits in non-disabled elderly people: the LADIS study.
To assess the associations of medial temporal lobe atrophy (MTA) and white matter hyperintensities (WMH) with cognitive function in a large group of independently functioning elderly people. Data were drawn from the multicentre, multinational leukoaraiosis and disability (LADIS) project which is studying prospectively the role of WMH as an independent predictor of the transition to disability in non-disabled elderly people. In all, 639 participants were enrolled in the LADIS study. For the present analysis, data on 581 subjects were available. Cognitive function was assessed by the mini-mental state examination (MMSE). Visual ratings of WMH and MTA were undertaken on magnetic resonance images (MRI). The presence of either severe WMH or MTA was associated with a modest but non-significant increase in frequency of mild cognitive deficits (severe WMH: odds ratio (OR) = 1.9 (95% confidence interval (CI), 1.0 to 3.7); MTA present: OR = 1.5 (95% CI, 0.8 to 2.8)). However, subjects with the combination of MTA and severe WMH had a more than fourfold increase in frequency of mild cognitive deficits (OR = 4.1 (95% CI, 2.3 to 7.4)). Analysis of variance with post hoc Bonferroni t tests showed that subjects with both MTA and severe WMH performed worse on MMSE than those with either no MRI abnormality or a single MRI abnormality (p<0.05). These results provide further evidence for the combined involvement of both Alzheimer type pathology and vascular pathology in the earliest stages of cognitive decline and suggest an additive effect of WMH and MTA.


The transcription factor Leu3 shows differential binding behavior in response to changing leucine availability.
The main transcriptional regulator of leucine biosynthesis in the yeast Saccharomyces cerevisiae is the transcription factor Leu3. It has previously been reported that Leu3 always binds to its target genes, but requires activation to induce their expression. In a recent large-scale study of high-resolution transcription factor binding site identification, we showed that Leu3 has divergent binding sites in different cultivation conditions, thereby questioning the results of earlier studies. Here, we present a follow-up study using chromatin immunoprecipitation followed by sequencing (ChIP-seq) to investigate the influence of leucine supplementation on Leu3 binding activity and strength. With this new data set we are able to show that Leu3 exhibits changes in binding activity in response to changing levels of leucine availability.


IgM are associated to Sp alpha (CD5 antigen-like).
In 1993, we reported the presence of an IgM-associated peptide (M(r) 44 kDa; pI 5.45) in all immunoglobulin M (IgM) fractions purified from plasma/serum by various methods. This peptide was absent in Ig fractions of non-IgM isotypes. The N-terminal sequence was determined as being APPSGVRLVGGLH. To gain insight into the nature of this peptide, we further analyzed, using modern proteomic tools, the IgM-associated peptide isolated from cryoglobulins. Mass spectrometry revealed three peptides of different masses: 2203.13 (ELGCGAASGTPSGILYEPPAEK), 1564.83 (KPIWLSQMSCSGR), and 1544.77 (EATLQDCPSGPWGK). Theses sequences together with the already known N-terminal sequence allowed us to identity the IgM-associated peptide as Sp alpha (O43866 in TrEMBL database; CD5 antigen-like). Sp alpha is a member of the scavenger receptor cysteine-rich superfamily of proteins. This family includes the T-and B-cell antigens CD5 and CD6, and several of its members influence immune cell fate. Our finding may have important implications in the understanding of the homeostasis of IgM antibodies.


Keratinocyte transglutaminase 2 promotes CCR6+ γδT-cell recruitment by upregulating CCL20 in psoriatic inflammation.
Keratinocyte-derived cytokines and chemokines amplify psoriatic inflammation by recruiting IL-17-producing CCR6+ γδT-cells and neutrophils. The expression of these cytokines and chemokines mainly depends on NF-κB activity; however, the pathway that activates NF-κB in response to triggering factors is poorly defined. Here, we show that transglutaminase 2 (TG2), previously reported to elicit a TH17 response by increasing IL-6 expression in a mouse model of lung fibrosis, mediates the upregulation of cytokines and chemokines by activating NF-κB in imiquimod (IMQ)-treated keratinocytes. TG2-deficient mice exhibited reduced psoriatic inflammation in skin treated with IMQ but showed systemic immune responses similar to wild-type mice. Experiments in bone marrow (BM) chimeric mice revealed that TG2 is responsible for promoting psoriatic inflammation in non-BM-derived cells. In keratinocytes, IMQ treatment activated TG2, which in turn activated NF-κB signaling, leading to the upregulation of IL-6, CCL20, and CXCL8 and increased leukocyte migration, in vitro. Consequently, TG2-deficient mice showed markedly decreased CCR6+ γδT-cell and neutrophil infiltration in IMQ-treated skin. Moreover, TG2 levels were higher in psoriatic skin than in normal skin and correlated with IL-6, CXCL8, and CCL20 levels. Therefore, these results indicate that keratinocyte TG2 acts as a critical mediator in the amplification of psoriatic inflammation.


Assessing the effect of patient screening and isolation on curtailing Clostridium difficile infection in hospital settings.
Patient screening at the time of hospital admission is not recommended as a routine practice, but may be an important strategy for containment of Clostridium difficile infection (CDI) in hospital settings. We sought to investigate the effect of patient screening in the presence of asymptomatic carriers and in the context of imperfect patient isolation. We developed and parameterized a stochastic simulation model for the transmission dynamics of CDI in a hospital ward. We found that the transmission of CDI in the hospital, either through asymptomatic carriers or as a results of ineffective implementation of infection control practices, at the time of hospital admission. The results show that, for a sufficiently high reproduction number of CDI, the disease can persist within a hospital setting in the presence of in-ward transmission, even when there are no asymptomatically colonized patients at the time of hospital admission. Our findings have significant public health and clinical implications, especially in light of the emergence and community spread of hypervirulent CDI strains with enhanced transmission rates and toxin production. Rapid detection of colonized patients remains an important component of CDI control, especially in the context of asymptomatic transmission. Screening of in-hospital patients with potential exposure to colonized patients or contaminated environment and equipment can help reduce the rates of silent transmission of CDI through asymptomatic carriers.


Dehydrogenative cyclocondensation of aldehydes, alkynes, and dialkylsilanes.
The nickel-catalyzed coupling of aldehydes, alkynes, and dialkylsilanes results in an unusual dehydrogenative cyclocondensation process to afford five-membered silacyclic products. The process allows dialkylsilanes to serve as a silylene synthetic equivalent. A mechanistic pathway for the process involving the formation of an aldehyde/alkyne-derived nickel metallacycle followed by sequential sigma-bond metathesis processes involving the two Si-H bonds has been proposed.


Safety profiles of non-small cell lung cancer patients treated with pemetrexed plus carboplatin: a real-world retrospective, observational, cohort study.
Pemetrexed plus carboplatin (PCb) is a frequently used first-line treatment in advanced non-small cell lung cancer (NSCLC). This study examined the characteristics and safety profile of a NSCLC population treated with PCb area under the concentration-time curve 5 (PCb5) or 6 mg/mL•min (PCb6) under real-world conditions. A retrospective, observational, cohort study was conducted, utilizing data from the IMS Oncology US clinic-based, longitudinal, patient-level electronic medical records (EMR), including patients with NSCLC on PCb5 or PCb6 regimens initiated concomitantly on or after the diagnosis of lung cancer during 2004-2014. Patient characteristics and incidence of adverse events (AEs) were described for each cohort. Propensity scores were calculated based on baseline demographic and clinical factors. Propensity score stratification was used to further adjust for cohort differences. In total, 636 NSCLC patients receiving PCb5 (37% aged ≥70 years) and 184 patients receiving PCb6 (34% aged ≥70 years) who met the inclusion criteria were identified in the EMR. Patients with more comorbidities were more likely to have received PCb5. Overall incidence rates (IRs) per 100 person-years were similar for neutropenia in both cohorts, were numerically higher for anemia (IR = 43.6 vs 101.0) and thrombocytopenia (IR = 1.5 vs 17.9), and were numerically lower for nausea (IR = 14.4 vs 9.9) in the PCb6 vs PCb5 cohort. Within the PCb6 cohort, the IR per 100 person-years was higher for neutropenia for ≥70 year-old patients (IR = 41.1) compared to <70 year-old patients (IR = 14.5). After propensity score stratification, adjusted IRs showed similar patterns. Limitations included lack of power for AEs other than anemia, given the nature of EMR. Results from this real-world analysis add to existing evidence from randomized clinical trials about PCb safety profiles in the overall NSCLC population and in elderly patients. These results may guide physicians when making treatment decisions.


Molecular assembly of superquenchers in signaling molecular interactions.
We have designed a novel molecular assembly of quencher molecules to form superquenchers with excellent quenching efficiency. The superquencher can be engineered as desired by assembling different types and different numbers of quencher molecules. By labeling a superquencher to a molecular beacon, a 320-fold enhancement of fluorescent signal was achieved, compared to about 14-fold from a molecular beacon prepared with the same monomer quencher. Our molecular assembly approach can effectively improve the sensitivity of a variety of fluorescent assays and can be widely useful for molecular interaction studies.


Intramedullary Nailing Versus Plate Fixation for Humeral Shaft Fractures: A Systematic Review and Meta-Analysis.
The two techniques most utilized in the surgical treatment of humeral shaft fractures are open reduction internal fixation (ORIF) and intramedullary nailing (IMN). Although there have been multiple comparative clinical studies comparing outcomes for these two treatments, studies have not suggested one approach to be superior to the other. The purpose of this study is to perform a systematic literature review and meta-analysis of studies that evaluated the treatment of humeral shaft fractures with either ORIF or intramedullary nail. We conducted this meta-analysis utilizing stricter inclusion and broader exclusion criteria to examine these two common approaches. We examined those articles which have compared first-time, closed fractures of the humeral diaphysis in adults in fracture patterns that could be treated equivalently by intramedullary nail or plate fixation. The primary outcome of interest was nonunion, and studies that did not report nonunion rates were excluded. There were a total of 1,926 abstracts reviewed and a total of three articles were included in the final analysis after screening. There was no significant difference in the incidence of nonunion between plating (2/111, 1.8%) and nailing (4/104, 3.9%) (P>0.05). The mean difference in average time to union for plated fractures and nailed fractures was 1.11 weeks (95% CI 0.82 to 1.40) which was statistically significant (P<0.05). There was a significant difference in the incidence of radial nerve palsy (12/111, 10.8%) for plating compared to nailing (0/104, 0%) (P=0.0004). There was no difference in incidence of post-operative infection between the two groups intramedullary nailing (P>0.05). The results of this analysis demonstrate an increased risk of iatrogenic radial nerve injury, and a significantly shorter time to union when treating humeral shaft fractures with plating as compared to intramedullary nailing. There was no difference in the rates of nonunion or delayed union. Based on the evidence, both plating and nailing can achieve a similar treatment effect on humeral shaft fractures.