Are routine duodenal and antral biopsies useful in the management of "functional" dyspepsia? A diagnostic and therapeutic study.
Fifty-three patients with previously uninvestigated chronic dyspepsia symptoms in the absence of gastrointestinal or extra-gastrointestinal disease (functional dyspepsia) underwent antral and duodenal mucosal biopsies to detect the role of such samplings in the presence of normal endoscopic findings. Patients were enrolled in a randomized, placebo-controlled, double-blind trial, receiving either eradicating treatment (colloidal bismuth subcitrate plus metronidazole) or placebo if they had Helicobacter pylori-associated gastritis (20 patients), or cisapride or placebo if they had normal antral mucosa (28 cases). Unsuspected celiac sprue was found in one patient. Eradicating treatment ameliorated histological gastritis (p = 0.01). However, owing to great placebo efficacy, symptom remission rates following a 1-month wash-out period in both treatment groups were no higher than that in controls. Independent of the initial randomization, an extremely low symptom recurrence rate was observed during a drug-free follow-up study equivalent to the mean duration of symptoms before enrollment. We conclude that in functional dyspepsia, bulbar and antral biopsies are not useful in clinical management, equivalent symptom relief can be achieved in patients randomly assigned to both drugs and placebos, and such improvement can be long lasting in the absence of any maintenance treatment. We believe the prevalence of unsuspected villous atrophy and the therapeutic role of investigation-based reassurance deserve further assessment.


Probabilistic Mental Models with Continuous Predictors.
Gigerenzer and his colleagues have sought to develop psychologically plausible models of human judgment. Their models are classified as ones of bounded rationality based on a principle of one-reason decision making. The models associated with the theory of Probabilistic Mental Models (PMM) have been developed for tasks in which all predictors are binary. This article extends PMM to the case of continuous predictors. The current model employs the limitation on the number of categories people use in making absolute judgments along a single perceptual dimension (7 +/- 2; Miller, 1956). The algorithm transforms each continuous predictor to be consistent with this limitation, then implements a step-down one-reason decision procedure similar to previous PMM models. Like previous PMM models, the 7 +/- 2 model predicts binary judgments as well as a multiple-regression model. However, the model does not successfully predict the probability judgments of individual participants, which is also true of all other models in the literature. Copyright 2000 Academic Press.


2-Methoxy-7-Acetonyljuglone Isolated from Reynoutria japonica Increases the Activity of Nuclear Factor Erythroid 2-Related Factor-2 through Inhibition of Ubiquitin Degradation in HeLa Cells.
The nuclear factor erythroid-derived 2-related factor 2 (NRF2) is a key transcription factor for the activation of genes responsible for oxidative stress and drug detoxification. Thus, it is important to identify NRF2 activators, which can be used to protect the cells from oxidative damage. Here, we investigated the effect of juglone derivatives isolated from Reynoutria japonica on the activity of NRF2 in HeLa cells. We demonstrated that among the juglone derivatives, 2-methoxy-7-acetonyljuglone (MA) strongly stimulated the antioxidant response element (ARE)-luciferase activity in a dose-dependent manner. In addition, MA significantly increased the nuclear localization of NRF2 and, consequently, increased the expression of NRF2 target genes, including heme oxygenase-1(HO-1), NAD(P)H: quinine oxidoreductase-1 (NQO-1), and glutamate-cysteine ligase catalytic (GCLC). To gain insights into the NRF2 signaling mechanism by MA, we measured the activities of RAC-alpha serine/threonine-protein kinase (AKT) and mitogen-activated protein (MAP) kinase family proteins, including extracellular signal-regulated kinase (ERK) and p38. Our results showed that MA induced NRF2 activity through p38 and AKT signaling. Subsequently, we found that MA significantly enhanced NRF2 stability by inhibiting ubiquitin-dependent proteasomal degradation. Thus, MA might protect cells by enhancing the activity and stability of NRF2 through inhibition of the proteasomal degradation pathway.


[Prediction of preeclampsia:new hypotheses, new approaches].
Preeclampsia is a multisystem disorder affecting 5.8% of primigravidas. It is a progressive disease with a very variable mode of presentation and rate of progression. Of all the features of the syndrome, hypertension and pregnancy-induced proteinuria are the classic clinical manifestations. This disease causes severe complications of the mother and the fetus. Neither are factors available for prediction, nor are there strategies for prevention and therapy of this disease. The accumulated evidence strongly suggests that failure or incomplete trophoblastic invasion (end of first, beginning of second trimester) of the spiral arteries, resulting in narrowed spiral arteries and subsequent endothelial damage, is responsible for the occurrence of this disease (third trimester). The reason for trophoblastic failure is not known. After clinical symptoms have occurred, only symptomatic therapeutic options are available. In this paper, we discuss potential ways to find specific and sensitive predictive parameters according to the current knowledge of the pathophysiology of this pregnancy-induced severe disorder.


Thrombocytopenic purpura and cardiomyopathy in pregnancy reversed by combined plasma exchange and infusion.
Thrombocytopenia and hemolytic anemia have been seen with thrombotic thrombocytopenic purpura (TTP), HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets), and hemolytic uremic syndrome (HUS). Differentiating between TTP, HUS, and HELLP syndrome is often difficult. Coexistence of TTP and HELLP is possible. Cardiomyopathy occurring in pregnancy can be idiopathic or associated with TTP. We describe a previously healthy woman who developed thrombocytopenia and hemolysis at 34 wk gestation. The patient underwent delivery after transfusion with platelets and RBCs. The suspicion of TTP was raised, and plasma exchange was begun by the third hospital day. On the seventh day of treatment, the patient developed shortness of breath, and an echocardiogram showed global hypokinesis with an ejection fraction of 25%. Plasma infusion, one unit q 4 h, was initiated in addition to the daily plasma exchange. The patient improved and her ejection fraction normalized. Plasma exchange and infusion and corticosteroids were gradually tapered off. von Willebrand factor (vWF) protease activity in the plasma upon transfer was completely deficient with the presence of inhibitor. This case illustrates that vWF protease assay and detection of inhibitor can be used for the diagnosis of TTP during pregnancy; and a severe cardiomyopathy in TTP can be reversed rapidly with combined plasma exchange and infusion.


Nitrate-Alkaline Pulp from Non-Wood Plants.
Because there is a lack of wood resources in many countries, this work focused on pulp and paper production from the waste and agricultural residues of non-wood plants. The work aimed to pulp the nitrate-alkaline of black mustard (Brassica Nigra L.) and camelina (Camelina Sativa L.). The black mustard and the camelina were selected due to the expanding planted areas of these crops in the Czech Republic. To characterize the chemical composition of black mustard and camelina, cellulose, lignin, ash, and extractives were determined. Raw alpha-cellulose, beta-cellulose, and gamma-cellulose were also measured. The results showed that the content of lignin in non-wood plants is lower than that in softwoods. The cooked pulp was characterized by the delignification degree-Kappa number. Additionally, handsheet papers were made for selected samples of pulp. The handsheet papers were characterized by tensile index, breaking length, and smoothness and compared with commonly available papers.


Nurses leadership in research and policy in Nigeria: A myth or reality?
This study evaluates nurses' leadership in research and policy formulation in southern Nigeria. In Africa and particularly in low- and middle-income countries, expected health information from nurse's leaders is sometimes not available, thereby hindering the attainment of sustainable health. This qualitative study used 12 high-ranking nurses leader from primary, secondary and tertiary health care systems in Cross River State, Nigeria. In-depth interview and focus group discussion were used to generate and validate collected data. There was marginal leadership in research and policy formulation. The hindering factors were mainly individual and institutional barriers. Nurses effective leadership in research and policy have not yet been actualized. Suggested remedies include mentoring of the mentee in research, provision of designated grants for nursing research, acceptance of nurses as policy formulators rather than implementers among others. The small sample size informs the need for further study throughout the region. Nurses have the capability to exercise influence directly or indirectly on health care goals. Dereliction in research and policy formulation could hinder the attainment of desired health care reforms due to absence of innovation in nursing practice and management.


Reinforcement of colonic anastomoses with a collagenous double-layer matrix extracted from porcine dermis.
Anastomotic leakage is a major factor for morbidity in colorectal surgery. Anastomotic reinforcement with biological or synthetic materials has been claimed to be useful in preventing anastomotic leakage. We evaluated a non-cross-linked collagenous matrix Bio-Gide (BG) for sealing colonic anastomoses in a rodent model. The animals were investigated for 4, 30 and 90 days. Macroscopic examination, histological examination and measurement of bursting pressure were performed. The anastomotic stricture rate was evaluated by radiographic contrast enema. Microscopically anastomoses sealed by BG showed impaired anastomotic healing. Blood vessel ingrowth and collagen deposition were decreased without reaching significance after 4 days. The anastomotic bursting pressure was significantly decreased (p = 0.0454) in the early phase of healing. Anastomotic neovascularization was significantly decreased compared to the control group after 30 (p = 0.0058) and 90 days (p = 0.0275). Although no difference in anastomotic stricture rate was evident, the rate of intra-abdominal adhesions was significantly increased after 30 (p = 0.0124) and 90 days (p = 0.0281). BG failed to improve colonic anastomotic healing. Early anastomotic healing was impaired if anastomoses were reinforced with BG. BG did not affect the anastomotic stricture rate for up to 3 months; nevertheless, intra-abdominal adhesions were increased.


Transcriptional regulation of immediate-early gene response by THOC5, a member of mRNA export complex, contributes to the M-CSF-induced macrophage differentiation.
Hematopoiesis and commitment to a restricted lineage are guided by a timely expressed set of cytokine receptors and their downstream transcription factors. A member of the mRNA export complex, THOC5 (suppressors of the transcriptional defects of hpr1 delta by overexpression complex 5) is a substrate for several tyrosine kinases such as macrophage colony-stimulating factor (M-CSF) receptor and various leukemogenic tyrosine kinases, such as Bcr-Abl, or NPM-ALK. THOC5 tyrosine phosphorylation is elevated in stem cells from patients with chronic myeloid leukemia, suggesting that THOC5 may be involved in leukemia development. THOC5 is also an essential element in the maintenance of hematopoiesis in adult mice. In this report, we show that THOC5 is located in the nuclear speckles, and that it is translocated from the nucleus to cytoplasm during M-CSF-induced bone marrow-derived macrophage differentiation. Furthermore, we have identified THOC5 target genes by trancriptome analysis, using tamoxifen-inducible THOC5 knockout macrophages. Although only 99 genes were downregulated in THOC5-depleted macrophages, half of the genes are involved in differentiation and/or migration. These include well-known regulators of myeloid differentiation inhibitor of DNA binding (Id)1, Id3, Smad family member 6 (Smad6) and Homeobox (Hox)A1. In addition, a subset of M-CSF-inducible genes, such as Ets family mRNAs are THOC5 target mRNAs. Upon depletion of THOC5, unspliced v-ets erythroblastosis virus E26 oncogene homolog (Ets1) mRNA was accumulated in the nucleus. Furthermore, THOC5 was recruited to chromatin where Ets1 was transcribed and bound to unspliced and spliced Ets1 transcripts, indicating that THOC5 has a role in processing/export of M-CSF-inducible genes. In conclusion, regulation of immediate-early gene response by THOC5, a member of mRNA export complex contributes to the M-CSF-induced macrophage differentiation.


Combination gene therapy of IL-12 and allogeneic MHC class I gene via stimulating NK cytolytic activity.
In this study, we tested whether expressing an allogeneic MHC class I gene and/or a cytokine gene in tumor cells could induce anti-tumor immunity. We compared the potential therapeutic benefit of introducing IL-12 or H-2Kb alone and in combination into CT26 tumor cells. Whereas IL-12 expression in CT26 cells delayed the formation of tumors, the expression of class I molecules alone was apparently insufficient to reduce tumorigenicity. The combined expression of IL-12 and H-2Kb, however, more efficiently reduced tumor growth than did either genes alone. Histological examination of tumors expressing IL-12 and H-2Kb showed a non-specific inflammatory reaction, such as a necrosis, and an increased tissue infiltrate of immune effectors. These results suggest that the combined expression of IL-12 and H-2Kb in tumor cells has potential therapeutic benefit.


Relationship between Sensory Attributes and Chemical Composition of Different Mango Cultivars.
The present study investigated the relationship between the chemical composition and sensory quality of different mango ( Mangifera indica L.) cultivars by multivariate statistical analysis. The results showed that the high hedonic rating of mangoes was due in part to its flavor profile such as fruity, pineapple, and coconut with sweetness. High hedonic liking and positive flavors of mangoes could be responsible for the volatile compounds including fruity esters, 1-octanol, ( E, Z)-2,6-nonadienal, and γ-octalactone with high contents of sugars. On the other hand, turpentine-like and green flavors of mangoes are attributed to the relatively low hedonic liking of mangoes, which correlated with high contents of amino acids and terpenes. These findings demonstrated that interaction between individual chemical compounds within mangoes could be responsible for the specific sensory qualities of mango cultivars and provided insight into a paradigm for the selection and development of new and more desirable mango cultivars in the future.


Pilot Study on Folate Bioavailability from a Camembert Cheese Reveals Contradictory Findings to Recent Results from a Human Short-term Study.
Different dietary sources of folate have differing bioavailabilities, which may affect their nutritional "value." In order to examine if these differences also occur within the same food products, a short-term human pilot study was undertaken as a follow-up study to a previously published human trial to evaluate the relative native folate bioavailabilities from low-fat Camembert cheese compared to pteroylmonoglutamic acid as the reference dose. Two healthy human subjects received the test foods in a randomized cross-over design separated by a 14-day equilibrium phase. Folate body pools were saturated with a pteroylmonoglutamic acid supplement before the first testing and between the testings. Folates in test foods and blood plasma were analyzed by stable isotope dilution assays. The biokinetic parameters C max, t max, and area under the curve (AUC) were determined in plasma within the interval of 0-12 h. When comparing the ratio estimates of AUC and C max for the different Camembert cheeses, a higher bioavailability was found for the low-fat Camembert assessed in the present study (≥64%) compared to a different brand in our previous investigation (8.8%). It is suggested that these differences may arise from the different folate distribution in the soft dough and firm rind as well as differing individual folate vitamer proportions. The results clearly underline the importance of the food matrix, even within the same type of food product, in terms of folate bioavailability. Moreover, our findings add to the increasing number of studies questioning the general assumption of 50% bioavailability as the rationale behind the definition of folate equivalents. However, more research is needed to better understand the interactions between individual folate vitamers and other food components and the potential impact on folate bioavailability and metabolism.


Normal brain activation in schizophrenia patients during associative emotional learning.
Emotional deficits are among the core features of schizophrenia and both associative emotional learning and the related ability to verbalize emotions can be reduced. We investigated whether schizophrenia patients demonstrated impaired function of limbic and prefrontal areas during associative emotional learning. Patients and controls filled out an alexithymia questionnaire and performed an associative emotional learning task with positive, negative and neutral picture-word pairs during fMRI scanning. After scanning, they indicated for each pair whether they remembered it. We conducted standard GLM analysis and Independent Component Analysis (ICA). Both the GLM results and task-related ICA components were compared between groups. The alexithymia questionnaire indicated more cognitive-emotional processing difficulties in patients than controls, but equal experienced intensity of affective states. Patients remembered less picture-word pairs, irrespective of valence. GLM analysis showed significant visual, temporal, amygdalar/hippocampal, and prefrontal activation in all subjects. ICA identified a network of brain areas similar to GLM, mainly in response to negative stimuli. Neither analysis showed differences between patients and controls during learning. Although in previous studies schizophrenia patients showed abnormalities in both memory and emotion processing, neural circuits involved in cross-modal associative emotional learning may remain intact to a certain degree, which may have potential consequences for treatment.


Reduced expression of SRY-box containing gene 17 correlates with an unfavorable melanoma patient survival.
SRY-box containing gene 17 (Sox17), a transcription factor, is considered as an antagonist to canonical Wnt/β‑catenin signaling in several types of malignant tumors. As the influence of Sox17 in the pathogenesis of human melanoma is still unknown, the investigation of Sox17 expression in melanoma is warranted and its prognostic value is of great interest. In the present study, Sox17 expression was examined in 525 cases of melanocytic lesions (33 common acquired nevi, 59 dysplastic nevi, 291 primary melanomas and 142 metastatic melanomas) at different stages by tissue microarray. The correlation of Sox17 expression with melanoma progression and its prognostic value in melanoma patients were examined. We also analyzed the correlation between Sox17 and cyclin-dependent kinase inhibitor p27 expression in 374 melanoma samples. The results showed that Sox17 expression was significantly decreased in primary and metastatic melanoma compared to common acquired nevi and dysplastic nevi (P=2.4x10-17). Furthermore, Sox17 expression was inversely correlated with American Joint Committee on Cancer stage (P=4.6x10-15), thickness (P=0.00004) and ulceration (P=0.03). Notably, reduced Sox17 expression was correlated with a poorer overall and disease-specific 5- and 10-year survival of the patients. Multivariate Cox regression analyses indicated that Sox17 is an independent prognostic marker for melanoma patients. Moreover, we found a significant positive correlation between Sox17 and p27 expression in melanoma biopsies; their concomitant expression was closely correlated with the survival of melanoma patients. Taken together, decreased Sox17 expression is correlated with melanoma progression, an unfavorable survival of melanoma patients and is an independent molecular prognostic factor for melanoma.


Long-term haemodynamic and antiarrhythmic benefits of DDIR versus DDI pacing mode in sick sinus syndrome and chronotropic incompetence.
The aim of this Italian multicentre study was to evaluate the haemodynamic and antiarrhythmic effects of DDIR versus DDI pacing mode in sick sinus syndrome with chronotropic incompetence. Seventy-nine patients were implanted with a dual chamber rate-responsive pacemaker (Medtronic 7075) and centrally randomised to DDI or DDIR pacing mode. After six months, the pacing modality was crossed over. Follow-up included clinical data, rest ECG, echocardiography, Holter monitoring and exercise testing in DDIR. a) Haemodynamic effects. Comparing postimplant exercise testing in DDIR mode with preimplant tests, peak heart rate increased from 96 +/- 17 to 115 +/- 17 bpm (+20%, p < 0.0001), total work capacity from 7.0 +/- 3.5 to 8.8 +/- 4.3 minutes (+26%, p < 0.0001), peak oxygen uptake from 1238 +/- 406 to 1453 +/- 423 ml/min (+17%, p < 0.001) and oxygen uptake at anaerobic threshold from 977 +/- 343 to 1222 +/- 415 ml/min (+25%, p < 0.001). These benefits persisted unchanged during one-year follow-up. b) Antiarrhythmic effects. After six months, paroxysmal atrial fibrillation recurrence significantly decreased in the whole population: group I (DDI) 20.7 vs 48.3%, p < 0.02; group II (DDIR) 21.2 vs 36.4%, p < 0.05; group I + II (DDI + DDIR) 21.0 vs 41.9%, p < 0.001. After one year no significant differences were found between DDI and DDIR. Group I: DDI 23.8 vs DDIR 28.6%, ns; group II: DDI 22.7 vs DDIR 18.2%, ns. DDIR vs DDI significantly improves short- and long-term haemodynamic performance. Dual chamber pacing shows a significant reduction of paroxysmal atrial fibrillation recurrence, regardless of rate responsiveness.


Breakpoint characterization of the ret/PTC oncogene in human papillary thyroid carcinoma.
The ret/PTC oncogene, rearranged form of the ret proto-oncogene (c-ret), has been detected specifically in a minority of papillary thyroid carcinomas. Three forms of the ret/PTC oncogene have been identified; the two most common forms, ret/PTC-1 and ret/PTC-3, both result from a paracentric inversion, of the long arm of chromosome 10. In this study, we have successfully amplified the chimeric introns resulting from these inversions, ranging from 1.4 to 10 kb, from four of five tumors known to contain the ret/PTC-1 oncogene (where c-ret rearranges with the H4 gene), and from 1/1 tumors containing the ret/PTC-3 oncogene (where c-ret rearranges with the ele1 gene). We localized the breakpoints within the chimeric introns using nested PCR, and determined the exact nucleotide sequence at the breakpoint for each tumor. Our results indicate that the breakpoints in c-ret occur at sites distributed across intron 11, where breaks in H4 intron 1 appear more frequently at the 5'- end of the intron. Interestingly, in all tumors that we investigated, the breakpoints occurred at sits of two or three nucleotide matches between the contributing germline sequences. In summary, we describe a simple, convenient way to investigate the ret/PTC breakpoints, and have revealed several common features of the breakpoints which warrant further investigations.


m6 A-mediated regulation of PBX1-GCH1 axis promotes gastric cancer proliferation and metastasis by elevating tetrahydrobiopterin levels.
Methyltransferase 3 (METTL3)-mediated N6-methyladenosine (m6 A) RNA modification has been demonstrated to be a potential factor in promoting gastric cancer (GC). METTL3 regulates a series of signaling pathways by modifying various mRNAs. This study aimed to identify novel METTL3-mediated signaling pathways and explored possible targets for use in the clinical setting of gastric cancer. To investigate the proliferation and metastatic capacity of GC cell lines with METTL3 knockdown, a xenograft, lung metastasis, and popliteal lymph node metastasis model was used. The m6 A-modified RNA immunoprecipitation (Me-RIP) sequence was utilized to explore the target mRNAs of METTL3. Cell counting kit 8 and transwell assays were performed to investigate the promoting function of pre-B cell leukemia homeobox 1 (PBX1) and GTP cyclohydrolase 1 (GCH1). Western blotting and chromatin immunoprecipitation were employed to confirm the involvement of the METTL3-PBX1-GCH1 axis. ELISA and liquid chromatography-mass spectrometry were used to explore the biological function of tetrahydrobiopterin (BH4 ). Knockdown of METTL3 suppressed xenograft tumor growth and lung/lymph node metastasis in vivo. Mechanistically, we found that METTL3 combined with and stabilized PBX1 mRNAs. Chromatin immunoprecipitation (ChIP) and further experiments suggested that PBX1 acted as a transcription factor inducing GCH1 expression. Moreover, the METTL3-PBX1-GCH1 axis increased BH4 levels in GC cells, thereby promoting tumor progression. This study suggested that METTL3 enzymes promote tumor growth and lung/lymph node metastasis via METTL3-PBX1-GCH1 axis increasing BH4 levels in GC.


Cochlear implant in a patient with mondini's deformity of the cochlea: pilot patient in Pakistan.
Autosomal-recessive genes account for about 80% of the patients of non-syndromic deafness, and a major portion of those lead to cochlear pathology. Given the strong cultural practice of consanguineous marriages and the lack of awareness regarding screening modalities, a high prevalence of hereditary pre-lingual deafness is seen in Pakistan. Considering the situation, cochlear implant surgery was introduced by Aga Khan University Hospital (AKUH), Karachi, Pakistan, in 2003. Recently we decided to expand the profile and services available and conducted the first ever cochlear implant on an anatomically-challenged cochlea. The case report relates to the experience of our pilot patient who was suffering from Mondini's deformity.


Indigenous health in a global frame: from community development to human rights.
This essay explores the shift from 'human rights' to community development' in the framing of Koori (or Indigenous) health policy research at the University of Melbourne in the 1990s. It provides an overview of the recent history of rights-based discourses in international health, contrasting cosmopolitan claims of rights with older civic reference points for health intervention: such as 'citizenship' and 'community development.' In particular it considers the relations of the conjunction 'health and human rights' to the global emergence during the past twenty years of nongovernmental organisations and their challenge to the power of the nation-state. This account draws heavily on the author's observation of the institutionalisation of rights discourses in health research programs at Melbourne and Harvard, vantage points that provide at best a partial perspective, but one that may nonetheless reveal some salient historical features.


Toxicity and activity of purified trichosanthin.
Trichosanthin was purified from fresh Chinese root tubers of Trichosanthes kirilowii and evaluated for anti-HIV activity. Trichosanthin inhibited syncytium formation between infected H9 cells and uninfected Sup-T1 cells from 0.5 to 4 micrograms/ml. Trichosanthin also inhibited HIV replication in H9 and CEM-SS cells at 1 microgram/ml, but was toxic for MT-4 cells (HTLV-I-positive), at doses greater than 0.25 microgram/ml. This new purification procedure confirms the anti-HIV activity of trichosanthin on some cell lines in different biological assays.


Dye-Assembled Upconversion Nanocomposite for Luminescence Ratiometric in Vivo Bioimaging of Copper Ions.
Overdose of Cu2+ is associated with multiple diseases, such as Wilson disease, Parkinson disease, and Alzheimer disease. Therefore, detections of Cu2+ in vivo and in vitro are meaningful. Near-infrared fluorescent probes are commonly applied for the detection of Cu2+ in real time. With mono detection signal provided, these probes are not persuasive when applied to complicated biological environments, such as cells and animals. In this report, we conjugated the organic fluorescent probe CYDAC16 with the UCNPs (lanthanide-doped upconversion nanoparticles) to develop a ratiometric luminescent probe for Cu2+. The composite material UCNPs-CYDAC16 provides a ratiometric signal based on an upconversion luminescence 660 and 800 nm. With good sensitivity and selectivity for Cu2+, it works well in vivo and in vitro for the detection of Cu2+. We believe it is promising in further biological applications.


Purification of cysteine-containing synthetic peptides via selective binding of the alpha-amino group to immobilised Cu2+ and Ni2+ ions.
Peptides containing a cysteine residue but lacking histidine and tryptophan were synthesised by the solid-phase method. Their retention behaviour on Cu2+ - and Ni2+ -loaded immobilised metal ion affinity chromatography (IMAC) supports at pH 5-11 was studied and compared with that observed for the corresponding compounds without the free alpha-amino group and/or the thiol function. Unexpectedly, it was found that neither a cysteine side-chain nor a cysteine disulphide affects the retention of the peptides. A free alpha-amino group is required for binding; no retention is observed in its absence. At pH 9 substantial amounts of metal ions were transferred from the chromatographic support to an alpha-amino-protected cysteine-containing peptide. However, at pH 7 no such transfer occurred. Therefore, the lack of retention observed for peptides with a blocked alpha-amino function over the entire pH range is not solely caused by metal ion scavenging by the thiol group. Partial dimerisation may occur upon chromatography; the dimers formed are retained strongly due to the presence of two free alpha-amino groups. It seems that IMAC on a Cu2+ - or Ni2+ -loaded support can be used for the purification of cysteine-containing peptides synthesised by the solid-phase method. Inclusion of a capping protocol in the synthesis ensures that a free alpha-amino group, which can be used as an affinity handle, will be present only on the target peptide.


Inhibitory action of somatostatin on meiotic maturation of cultured porcine follicular ova.
To investigate the physiological importance of somatotrophin release-inhibiting factor (SRIF), effects in vitro of synthetic SRIF 14 on germinal vesicle breakdown (GVB) of cultured porcine follicular ova were studied. The proportion of ova with GVB decreased gradually and significantly with increasing concentrations of SRIF 14 in the range from 6 X 10(-12) to 6 X 10(-7) M during a 22 h period of culture. The inhibitory effect was apparent for the period between 14 and 22 h in the course of culture but was reversed by a concomitant addition of anti-SRIF to the medium. Neither synthetic oxytocin, vasoactive intestinal polypeptide nor substance P exerted any inhibitory or stimulatory action on GVB. These results suggest a limited but definite inhibitory action of SRIF on GVB of porcine ova.


Outcomes of a health informatics technology-supported behavioral activation training for care managers in a collaborative care program.
Health informatics-supported strategies for training and ongoing support may aid the delivery of evidence-based psychotherapies. The objective of this study was to describe the development, implementation, and practice outcomes of a scalable health informatics-supported training program for behavioral activation for patients who screened positive for posttraumatic stress disorder and/or bipolar disorder. We trained 34 care managers in 12 rural health centers. They used a registry checklist to document the delivery of 10 behavioral activation skills for 4,632 sessions with 455 patients. Care managers received performance feedback based on registry data. Using encounter-level data reported by care managers, we described the implementation outcomes of patient reach and care manager skill adoption. We used cross-classified multilevel modeling to explore variation in skill delivery accounting for patient characteristics, provider characteristics, and change over time. Care managers engaged 88% of patients in behavioral activation and completed a minimum course for 57%. The average patient received 5.9 skills during treatment, with substantial variation driven more by providers (63%) than patients (29%). Care managers significantly increased the range of skills offered to patients over time. The registry-based checklist was a feasible training and support tool for community-based providers to deliver behavioral activation. Providers received data-driven performance feedback and demonstrated skill improvement over time, promoting sustainment. Future research will examine patient-level outcomes. Results underscore the potential public health impact of a simple registry-based skills checklist coupled with a scalable remote training program for evidence-based psychotherapy. (PsycInfo Database Record (c) 2021 APA, all rights reserved).


[Characteristic clinical features of pyelonephritis caused by Enterococcus faecalis].
A clinical study was performed in 13 cases of refractory Enterococcus faecalis pyelonephritis that were detected in the Department of Urology, Hiratsuka Municipal Hospital, from April 1975 to March 1995. The characteristic features were that pyelonephritis was commonly seen in females, and clinical symptoms (low-grade intermittent fever, low back pain, general malaise, etc.) were continuously refractory. Bacteriuria or polymicrobial infections were often found, and bacterial count was often as high as 10(2)-10(4)/ml. Nevertheless we considered that E. faecalis caused of refractory pyelonephritis must not have week adherence and pathogenesis to the kidney, owing to the clinical symptoms and the basic subjects. Furthermore this infection was difficult to cure completely with antimicrobials having activity against E. faecalis, and long-term treatment was needed. Therefore, we recommend that treatment for refractory E. faecalis pyelonephritis be carefully selected according to clinical symptoms and the bacterial density of this strain.


Post-acquisition filtering of salt cluster artefacts for LC-MS based human metabolomic studies.
Liquid chromatography-high resolution mass spectrometry (LC-MS) has emerged as one of the most widely used platforms for untargeted metabolomics due to its unparalleled sensitivity and metabolite coverage. Despite its prevalence of use, the proportion of true metabolites identified in a given experiment compared to background contaminants and ionization-generated artefacts remains poorly understood. Salt clusters are well documented artefacts of electrospray ionization MS, recognized by their characteristically high mass defects (for this work simply generalized as the decimal numbers after the nominal mass). Exploiting this property, we developed a method to identify and remove salt clusters from LC-MS-based human metabolomics data using mass defect filtering. By comparing the complete set of endogenous metabolites in the human metabolome database to actual plasma, urine and stool samples, we demonstrate that up to 28.5 % of detected features are likely salt clusters. These clusters occur irrespective of ionization mode, column type, sweep gas and sample type, but can be easily removed post-acquisition using a set of R functions presented here. Our mass defect filter removes unwanted noise from LC-MS metabolomics datasets, while retaining true metabolites, and requires only a list of m/z and retention time values. Reducing the number of features prior to statistical analyses will result in more accurate multivariate modeling and differential feature selection, as well as decreased reporting of unknowns that often constitute the largest proportion of human metabolomics data.


Peripheral doses from pediatric IMRT.
Peripheral dose (PD) data exist for conventional fields (> or = 10 cm) and intensity-modulated radiotherapy (IMRT) delivery to standard adult-sized phantoms. Pediatric peripheral dose reports are limited to conventional therapy and are model based. Our goal was to ascertain whether data acquired from full phantom studies and/or pediatric models, with IMRT treatment times, could predict Organ at Risk (OAR) dose for pediatric IMRT. As monitor units (MUs) are greater for IMRT, it is expected IMRT PD will be higher; potentially compounded by decreased patient size (absorption). Baseline slab phantom peripheral dose measurements were conducted for very small field sizes (from 2 to 10 cm). Data were collected at distances ranging from 5 to 72 cm away from the field edges. Collimation was either with the collimating jaws or the multileaf collimator (MLC) oriented either perpendicular or along the peripheral dose measurement plane. For the clinical tests, five patients with intracranial or base of skull lesions were chosen. IMRT and conventional three-dimensional (3D) plans for the same patient/target/dose (180 cGy), were optimized without limitation to the number of fields or wedge use. Six MV, 120-leaf MLC Varian axial beams were used. A phantom mimicking a 3-year-old was configured per Center for Disease Control data. Micro (0.125 cc) and cylindrical (0.6 cc) ionization chambers were appropriated for the thyroid, breast, ovaries, and testes. The PD was recorded by electrometers set to the 10(-10) scale. Each system set was uniquely calibrated. For the slab phantom studies, close peripheral points were found to have a higher dose for low energy and larger field size and when MLC was not deployed. For points more distant from the field edge, the PD was higher for high-energy beams. MLC orientation was found to be inconsequential for the small fields tested. The thyroid dose was lower for IMRT delivery than that predicted for conventional (ratio of IMRT/conventional ranged from 0.47-0.94) doses approximately [0.4-1.8 cGy]/[0.9-2.9 cGy]/fraction, respectively. Prior phantom reports are for fields 10 cm or greater, while pediatric central nervous system fields range from 4 to 7 cm, and effectively much smaller for IMRT (2-6 cm). Peripheral dose in close proximity (< 10 cm from the field edge) is dominated by internal scatter; therefore, field-size differences overwhelm phantom size affects and increased MU. Distant peripheral dose, dominated by head leakage, was higher than predicted, even when accounting for MUs (approximtely factor of 3) likely due to the pediatric phantom size. The ratio of the testes dose ranged from 3.3-5.3 for IMRT/conventional. PD to OAR for pediatric IMRT cannot be predicted from large-field full phantom studies. For regional OAR, doses are likely lower than predicted by existing "large field" data, while the distant PD is higher.


Supramolecular Paradigm for Capture and Co-Precipitation of Gold(III) Coordination Complexes.
A new supramolecular paradigm is presented for reliable capture and co-precipitation of haloauric acids (HAuX4 ) from organic solvents or water. Two classes of acyclic organic compounds act as complementary receptors (tectons) by forming two sets of directional non-covalent interactions, (a) hydrogen bonding between amide (or amidinium) NH residues and the electronegative X ligands on the AuX4 - , and (b) electrostatic stacking of the electron deficient Au center against the face of an aromatic surface. X-ray diffraction analysis of four co-crystal structures reveals the additional common feature of proton bridged carbonyls as a new and predictable supramolecular design element that creates one-dimensional polymers linked by very short hydrogen bonds (CO⋅⋅⋅OC distance <2.5 Å). Two other co-crystal structures show that the amidinium-π⋅⋅⋅XAu interaction will reliably engage AuX4 - with high directionality. These acyclic compounds are very attractive as co-precipitation agents within new "green" gold recovery processes. They also have high potential as tectons for controlled self-assembly or co-crystal engineering of haloaurate composites. More generally, the supramolecular paradigm will facilitate the design of next-generation receptors or tectons with high affinity for precious metal square planar coordination complexes for use in advanced materials, nanotechnology, or medicine.


The role of the upper airway in contributing to respiratory responses during experimental seizures in piglets.
Recent data demonstrating stimulation of respiration during seizures are at odds with the frequent clinical finding of respiratory impairment in patients with generalized seizures. To determine the role of the upper airway in contributing to these clinical observations, a study was performed in 12 weanling piglets. An arterial catheter and epidural electrodes were placed in ketamine-anesthetized piglets. In intact piglets, all airflow was measured through a snug-fitting nasal mask whereas pressure was measured with a subglottic catheter. Tracheostomized piglets had airflow and pressure measured at the trachea. Seizures were induced with i.v. injections of pentylenetetrazol. Peak inspiratory flow resistance was calculated by averaging three epochs of five to seven consecutive breaths. Epochs of greater than 20 s in duration with a tidal volume of < 10 mL were termed apnea. Apnea was considered central when airway pressure was > -2 cm H2O and obstructive when < -10 cm H2O. After 20 min of untreated seizures, intact piglets had significant respiratory and metabolic acidosis, whereas tracheostomized piglets had significant increases in Ve and mild metabolic acidosis. Apnea and obstruction were observed frequently in intact piglets. Resistance was unchanged during seizures in tracheostomized piglets, whereas a nearly 4-fold increase in inspiratory resistance was observed in intact piglets. We conclude that upper airway patency and resistances are important determinants of respiratory responses during generalized seizures in piglets.


Determination of the cleavage specificity of Streptomyces griseus protease B in the presence of guanidinium chloride.
Streptomyces griseus protease B (SGPB), a Pronase enzyme, has been shown to be stable and active in the presence of 6.0 M guanidinium chloride (Siegel, S. et al. (1972) J. Biol. Chem. 247, 4155-4159). In order to determine the cleavage specificity of this unusual enzyme under denaturing conditions, 12 peptides of known amino acid sequence were hydrolyzed by SGPB in the absence and presence of 6.0 M guanidinium chloride. The new N-terminal amino acids produced by the action of SGPB were dansylated and quantitatively identified by reverse phase HPLC. The results indicate that SGPB retained its cleavage specificity for phenylalanyl, tyrosyl, tryptophanyl, and leucyl peptide bonds in the presence of 6.0 M guanidinium chloride. Of these peptide bonds, SGPB exhibited a greater cleavage preference for phenylalanyl and tryptophanyl bonds, which was relatively unaffected by the presence of the denaturant. The SGPB-catalyzed cleavages of the leucyl peptide bonds examined (Leu-Met, Leu-Arg, Leu-Val, Leu-Thr, and Leu-Ile) were substantially decreased under denaturing conditions, while Leu-Gly bond cleavage by SGPB was virtually unaffected by denaturant. The demonstrated predictability of the catalytic preference of this unusual protease for phenylalanyl, tyrosyl, tryptophanyl, and leucyl-glycine peptide bonds under denaturing conditions enhances its utility in the site-specific proteolysis of insoluble or otherwise proteolysis-resistant polypeptide substrates.


Understanding diagnostic testing for periodontal diseases.
Probability computations are used to characterize new periodontal diagnostic tests and are an integral facet of risk assessment for periodontal diseases. However, misinterpretation of these data can result in confusion and erroneous conclusions regarding the relationship of test results to the presence or absence of disease in a subject, or to episodes of periodontal destruction at specific sites. This paper was written to provide clinicians with a primer to help in understanding calculations used to evaluate diagnostic tests and risk assessment.


Yes It Can: On the Functional Abilities of the Human Unconscious.
Understanding the division of labor between conscious processes and unconscious ones is central to our understanding of the human mind. This article proposes a simple "Yes It Can" (or YIC) principle: It argues that unconscious processes can perform the same fundamental, high-level functions that conscious processes can perform. The author presents considerations of evolutionary pressures and of the availability of mental resources that render YIC a reasonable hypothesis. Evidence is then reviewed from various subfields of the cognitive sciences, which shows that functions that were traditionally thought of as requiring consciousness can occur nonconsciously. On the basis of these data and arguments, it is proposed that an answer to the question "What is it that consciousness does?" would not be in the form of "Consciousness is necessary for F," where F is a fundamental, high-level cognitive function. In Marr's (1982) terms, the argument is that computationally conscious and unconscious processes are very similar. Yet differences in how these processes kick in and in the ways in which they play out (Marr's algorithmic-representational level) are likely to have interesting implications for human cognition, motivation, and emotion.


Expression of the nerve growth factor gene is controlled by the microtubule network.
Colchicine, nocodazol, and vinblastine, three microtubule-disrupting drugs, were shown to increase the levels of both nerve growth factor (NGF) mRNA and cell-secreted NGF protein in L929 cells, with levels of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) or amyloid precursor protein (APP) mRNAs remaining unaffected. Northern blot analysis demonstrated that colchicine also increased NGF mRNA levels in rat primary astrocytes and mouse skin fibroblasts. The specificity of the effects observed was assessed by the fact that the microtubule-stabilizing agent Taxotere, a semisynthetic compound structurally related to taxol, suppressed the effects of colchicine, whereas lumicolchicine, a colchicine derivative that has no action on the microtubule network, had no influence on NGF expression. Likewise, the disruption of the microfilament network by cytochalasin B did not increase NGF mRNA levels in L929 cells. Furthermore, the increase in NGF gene expression observed following microtubule disruption depended on a cascade of events involving at least one protein kinase, which is not down-regulated by phorbol ester, and on a pertussis toxin sensitive step. These results support the concept that tubulin and/or the microtubule cytoskeleton play an active role in the regulation of the NGF gene.


Cyclooxygenase-2 protects germ cells against spermatogenesis disturbance in experimental cryptorchidism model mice.
The role of cyclooxygenases (COX) in the male reproductive organ remains unclear. However, there are some reports suggesting that COX-2 might have an effect on spermatogenesis or steroidogenesis. In this study, we examined whether COX-2 was induced in impaired testes, and we also investigated the possible role of COX in the testes using experimental cryptorchidism model mice. Five-week-old male mice underwent an operation to induce unilateral cryptorchidism via an abdominal incision and suturing of the left testes to the lateral abdominal wall, and they were then divided into 3 groups: 1) experimental cryptorchidism plus SC560 (selective COX-1 inhibitor) administration; 2) experimental cryptorchidism plus NS398 (selective COX-2 inhibitor) administration; 3) and experimental cryptorchidism alone. The expression levels of COX-1 and COX-2 were determined by immunohistologic staining and quantitative reverse transcription-polymerase chain reaction (RT-PCR). The influence of COX inhibitors on the testes was assessed by measuring the concentration of serum testosterone and evaluating the seminiferous tubules according to the Johnsen score. Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling (TUNEL) staining was also performed to detect apoptosis in the testes. Immunohistologic staining and RT-PCR revealed that the expression of COX-2 was increased in the experimental cryptorchid testes (groups 1-3). The concentration of serum testosterone was significantly lower in group 2 at 5 weeks after surgery than in the other groups. The Johnsen score of the cryptorchid testes in group 2 was significantly lower than those in other groups at 5 weeks after surgery. TUNEL staining revealed that the number of apoptotic cells was significantly increased in group 2 compared with the other groups. However, the COX-1 inhibitor did not appear to affect spermatogenesis in the experimental cryptorchid testes. These results suggest that the COX-2 inhibitor provoked testicular damage in experimental cryptorchidism by inducing germ cell apoptosis. The expression of COX-2 might be induced to protect germ cells from heat stress caused by experimental cryptorchidism.


Repurposing approved drugs for cancer therapy.
Many drugs approved for other indications can control the growth of tumor cells and limit adverse events (AE). Literature searches with keywords 'repurposing and cancer' books, websites: https://clinicaltrials.gov/, for drug structures: https://pubchem.ncbi.nlm.nih.gov/. Introducing approved drugs, such as those developed to treat diabetes (Metformin) or inflammation (Thalidomide), identified to have cytostatic activity, can enhance chemotherapy or even replace more cytotoxic drugs. Also, anti-inflammatory compounds, cytokines and inhibitors of proteolysis can be used to control the side effects of chemo- and immuno-therapies or as second-line treatments for tumors resistant to kinase inhibitors (KI). Drugs specifically developed for cancer therapy, such as interferons (IFN), the tyrosine KI abivertinib TKI (tyrosine kinase inhibitor) and interleukin-6 (IL-6) receptor inhibitors, may help control symptoms of Covid-19. Better knowledge of mechanisms of drug activities is essential for repurposing. Chemotherapies induce ER stress and enhance mutation rates and chromosome alterations, leading to resistance that cannot always be related to mutations in the target gene. Metformin, thalidomide and cytokines (IFN, tumor necrosis factor (TNF), interleukin-2 (IL-2) and others) have pleiomorphic activities, some of which can enhance tumorigenesis. The small and fragile patient pools available for clinical trials can cloud the data on the usefulness of cotreatments. Better understanding of drug metabolism and mechanisms should aid in repurposing drugs for primary, adjuvant and adjunct treatments. Optimizing drug combinations, reducing cytotoxicity of chemotherapeutics and controlling associated inflammation.


A high-throughput semi-automated bone segmentation workflow for murine hindpaw micro-CT datasets.
Micro-computed tomography (μCT) is a valuable imaging modality for longitudinal quantification of bone volumes to identify disease or treatment effects for a broad range of conditions that affect bone health. Complex structures, such as the hindpaw with up to 31 distinct bones in mice, have considerable analytic potential, but quantification is often limited to a single bone volume metric due to the intensive effort of manual segmentation. Herein, we introduce a high-throughput, user-friendly, and semi-automated method for segmentation of murine hindpaw μCT datasets. In vivo μCT was performed on male (n = 4; 2-8-months) and female (n = 4; 2-5-months) C57BL/6 mice longitudinally each month. Additional 9.5-month-old male C57BL/6 hindpaws (n = 6 hindpaws) were imaged by ex vivo μCT to investigate the effects of resolution and integration time on analysis outcomes. The DICOMs were exported to Amira software for the watershed-based segmentation, and watershed markers were generated automatically at approximately 80% accuracy before user correction. The semi-automated segmentation method utilizes the original data, binary mask, and bone-specific markers that expand to the full volume of the bone using watershed algorithms. Compared to the conventional manual segmentation using Scanco software, the semi-automated approach produced similar raw bone volumes. The semi-automated segmentation also demonstrated a significant reduction in segmentation time for both experienced and novice users compared to standard manual segmentation. ICCs between experienced and novice users were >0.9 (excellent reliability) for all but 4 bones. The described semi-automated segmentation approach provides remarkable reliability and throughput advantages. Adoption of the semi-automated segmentation approach will provide standardization and reliability of bone volume measures across experienced and novice users and between institutions. The application of this model provides a considerable strategic advantage to accelerate various research opportunities in pre-clinical bone and joint analysis towards clinical translation.


Patterns and harms of pharmaceutical drug use among ecstasy users in Australia.
There has been a significant incursion of prescription drugs in to the club scene worldwide. The concomitant use of ecstasy and pharmaceutical drugs is associated with potentially serious health-related harms. This has ramifications for people who deliberately combine pharmaceutical drugs with ecstasy to achieve a specific effect and for people legitimately using pharmaceutical drugs for a health condition who may incidentally use ecstasy. This exploratory study had the broad aim to investigate the patterns and harms of concomitant use of pharmaceutical drugs and ecstasy, and to explore participants' experiences when visiting a General Practitioner (GP). In-depth interviews were conducted with 30 ecstasy/pharmaceutical drug users. Users reported deliberately combining stimulants (dexamphetamine, methylphenidate (e.g. Ritalin), antidepressants and sildenafil (e.g. Viagra) for non-medical purposes with ecstasy. A wide range of effects were reported. Several clear relationships emerged between the use of pharmaceutical drugs and ecstasy, and the distinctions between these in terms of motivations for use and consequences are discussed. The attitudes of GPs were professional and non-judgemental and there was little reluctance among participants to disclose illicit drug use. Screening for illicit drug use was limited. Findings have important implications for clubbers in regard to harm reduction strategies and highlight a number of areas for future research.


Influence of substrate stiffness on the phenotype of heart cells.
Adult cardiomyocytes (CM) retain little capacity to regenerate, which motivates efforts to engineer heart tissues that can emulate the functional and mechanical properties of native myocardium. Although the effects of matrix stiffness on individual CM have been explored, less attention was devoted to studies at the monolayer and the tissue level. The purpose of this study was to characterize the influence of substrate mechanical stiffness on the heart cell phenotype and functional properties. Neonatal rat heart cells were seeded onto collagen-coated polyacrylamide (PA) substrates with Young's moduli of 3, 22, 50, and 144 kPa. Collagen-coated glass coverslips without PA represented surfaces with effectively "infinite" stiffness. The local elastic modulus of native neonatal rat heart tissue was measured to range from 4.0 to 11.4 kPa (mean value of 6.8 kPa) and for native adult rat heart tissue from 11.9 to 46.2 kPa (mean value of 25.6 kPa), motivating our choice of the above PA gel stiffness. Overall, by 120 h of cultivation, the lowest stiffness PA substrates (3 kPa) exhibited the lowest excitation threshold (ET; 3.5 +/- 0.3 V/cm), increased troponin I staining (52% positively stained area) but reduced cell density, force of contraction (0.18 +/- 0.1 mN/mm(2)), and cell elongation (aspect ratio = 1.3-1.4). Higher stiffness (144 kPa) PA substrates exhibited reduced troponin I staining (30% positively stained area), increased fibroblast density (70% positively stained area), and poor electrical excitability. Intermediate stiffness PA substrates of stiffness comparable to the native adult rat myocardium (22-50 kPa) were found to be optimal for heart cell morphology and function, with superior elongation (aspect ratio > 4.3), reasonable ET (ranging from 3.95 +/- 0.8 to 4.4 +/- 0.7 V/cm), high contractile force development (ranging from 0.52 +/- 0.2 to 1.60 +/- 0.6 mN/mm(2)), and well-developed striations, all consistent with a differentiated phenotype.


Riboswitch-mediated control of gene expression in eukaryotes.
The discovery of metabolite-sensing RNA domains with gene regulatory functions, so-called riboswitches, has greatly expanded our view of the structural and functional complexity of RNA. Hitherto, more than 20 distinct riboswitch classes have been identified, which respond to a variety of small molecules and perform sophisticated gene regulatory tasks. Riboswitches are typically positioned in the 5' untranslated region of bacterial mRNAs, where they control gene expression by transcriptional or translational attenuation. However, the recent investigation of additional riboswitch classes has revealed a more complex repertoire of regulatory mechanisms. This also includes splicing control in filamentous fungi, green algae and higher plants by thiamin pyrophosphate-binding riboswitches, the only class of metabolite-sensing RNAs identified in eukaryotes so far. All eukaryotic riboswitches characterized to date modulate, in a first step, splicing, but the downstream processes under control vary fundamentally among different species further highlighting the versatility of this gene regulatory mechanism.


Microscopic peliosis of pancreatic islets in a woman with MEN-1 syndrome.
We report herein a case of histologically identified peliosis of pancreatic islets in the surgically removed portion of the pancreas of a 30-year-old woman with multiple endocrine neoplasm, type 1 (MEN-1) syndrome. In addition to microscopic peliosis, the pancreas contained multiple endocrine tumors producing insulin, glucagon, somatostatin, and growth hormone-releasing factor and showed evidence of widespread nesidioblastosis. It is uncertain whether peliosis of pancreatic islets and MEN-1 syndrome were coincidental or whether the two diseases were causally related. Since hormonal factors can result in hepatic peliosis, it is tempting to speculate that the endocrine imbalance secondary to MEN-1 syndrome might have played a role in the genesis of peliosis in this case. Although no direct proof of vascular damage was encountered, it is conceivable that escape of red blood cells from the circulation and their accumulation in tissue spaces was due to abnormal islet blood flow and increased capillary permeability.


Use of technology to facilitate a prospective surveillance program for breast cancer-related lymphedema at the Massachusetts General Hospital.
Breast cancer-related lymphedema (BCRL) is a negative sequela of breast cancer (BC) caused by trauma to the lymphatic system during surgery or radiation to the axillary lymph nodes. BCRL affects approximately one in five patients treated for BC, and patients are at a lifelong risk for BCRL after treatment. Early diagnosis of BCRL may prevent its progression and reduce negative effects on quality of life, necessitating comprehensive prospective screening. This paper provides an overview of technology that may be used as part of a BCRL screening program, including objective measures such as perometry, bioimpedance spectroscopy, tissue tonometry, and three-dimensional optical imaging. Furthermore, this paper comprehensively reviews the technology incorporated into the established prospective screening program at Massachusetts General Hospital. Our prospective screening program consists of longitudinal measurements via perometry, symptoms assessment, and clinical examination by a certified lymphedema therapist (CLT) as needed. Discussion about use of perometry within the screening program and incorporation of arm volume measurements into equations to determine change over time and accurate diagnosis is included [relative volume change (RVC) and weight-adjusted change (WAC) equations]. Use of technology throughout the program is discussed, including a HIPPA-compliant online research database, the patient's electronic medical record, and incorporation of BCRL-related symptoms [BC and lymphedema symptom experience index (BCLE-SEI) survey]. Ultimately, both subjective and objective data are used to inform BCRL diagnosis and treatment by the CLT. In conclusion, the role of technology in facilitating BCRL screening is indispensable, and the continued development of objective assessment methods that are not only reliable and valid, but also cost-effective and portable will help establish BCRL screening as the standard of care for patients treated for BC.


Laminotomy with continuous irrigation in patients with pyogenic spondylitis in thoracic and lumbar spine.
Pyogenic spondylitis often results in acute neurological deterioration requiring adequate surgical intervention and appropriate antibiotic treatment. The purpose of this study was to conduct an analysis of the clinical effect of continuous irrigation via laminotomy in a series of patients with pyogenic spondylitis in thoracic and lumbar spine. The authors conducted a retrospective investigation of 31 consecutive patients with pyogenic thoracic and lumbar spondylitis who underwent continuous irrigation through laminotomy from 2004 to 2008. The study included 22 men and 9 women, ranging in age from 38 to 78 years (mean 58.1 years). The average follow-up duration was 13.4 months (range, 8-34 months). We performed debridement and abscess removal after simple laminotomy, and then washed out epidural and disc space using a continuous irrigation system. Broad spectrum antibiotics were administered empirically and changed according to the subsequent culture result. Clinical outcomes were based on the low back outcome scale (LBOS), visual analogue scale (VAS) score, and Frankel grade at the last follow-up. Radiological assessment involved plain radiographs, including functional views. Common predisposing factors included local injection for pain therapy, diabetes mellitus, chronic renal failure, and liver cirrhosis. Causative microorganisms were identified in 22 cases (70.9%) : Staphylococcus aureus and Streptococcus spp. were the main organisms. After surgery, LBOS, VAS score, and Frankel grade showed significant improvement in most patients. Spinal stability was maintained during the follow-up period, making secondary reconstructive surgery unnecessary for all patients, except one. Simple laminotomy with continuous irrigation by insertion of a catheter into intervertebral disc space or epidural space was minimally invasive and effective in the treatment of pyogenic spondylitis. This procedure could be a beneficial treatment option in patients with thoracolumbar spondylitis combined with minimal or moderate destructive change of vertebrae.


Letting the story unfold: a case study of client-centered therapy for childhood traumatic grief.
There has been increasing interest in the newly identified condition of childhood traumatic grief (CTG) since the 2001 attack on the World Trade Center. The case presented here is one of an adolescent girl who was diagnosed with CTG following the death of her father, a firefighter killed in the line of duty on September 11, 2001. Literature on CTG, its treatment, and adolescent development will be discussed. The application of client-centered treatment to CTG will be highlighted by the case description and diagnostic findings prior to, during, and following treatment.


Treatment-resistant Obsessive-compulsive Disorder in Young People: Assessment and Treatment Strategies.
Cognitive behaviour therapy (CBT) and selective serotonin reuptake inhibitors have both been established as effective interventions for paediatric obsessive-compulsive disorder (OCD), with CBT being the recommended first-line treatment in most cases. While the majority of young people respond well to these treatments, a significant proportion remain symptomatic. Although the research on treatment-resistant OCD remains limited, increasing empirical attention is being paid to predictors of treatment outcome in young people with OCD, and efforts are being made to identify the factors that hinder recovery. This article outlines potential barriers in treatment and highlights strategies for optimising outcome, with particular focus on cognitive behavioural techniques.


High-throughput sequencing of circRNAs reveals novel insights into mechanisms of nigericin in pancreatic cancer.
Our previous study had proved that nigericin could reduce colorectal cancer cell proliferation in dose- and time-dependent manners by targeting Wnt/β-catenin signaling. To better elucidate its potential anti-cancer mechanism, two pancreatic cancer (PC) cell lines were exposed to increasing concentrations of nigericin for different time periods, and the high-throughput sequencing was performed to explore the circRNA expression profiles after nigericin exposure on pancreatic cancer (PC) cells. In this study, a total of 183 common differentially expressed circRNAs were identified, and the reliability and validity of the sequencing data were verified by the PCR analysis. According to the parental genes of circRNAs, the GO analysis was performed to predict the most enriched terms in the biological process, cellular components and molecular functions. The KEGG analysis and pathway-pathway network exhibited the potential signal pathways and their regulatory relationships. Meanwhile, a potential competing endogenous RNA (ceRNA) mechanism through a circRNA-miRNA-mRNA network was applied to annotate potential functions of these common differentially expressed circRNAs, and these predicted miRNAs or mRNAs might be involved in nigericin damage. By the bioinformatics method, our data will facilitate the understanding of nigericin in PC cells, and provide new insight into the molecular mechanism of nigericin toward cancer cells. This is the first report that discusses the potential functions of nigericin in cancers through the bioinformatics method. Our data will facilitate the understanding of nigericin-mediated anti-cancer mechanisms in PC.


Fullerene C70 characterization by 13C NMR and the importance of the solvent and dynamics in spectral simulations.
The nuclear magnetic resonance (NMR) spectroscopy combined with theoretical calculations is an important tool for fullerene identification. However, the accuracy of available theoretical methods is often not adequate. Therefore, in this work, different computational aspects needed to simulate realistically chemical shifts in the C70 molecule are investigated by density functional theory (DFT) calculations. The importance of the functional choice, basis set, solvent, and molecular motions was assessed. The solvent was simulated using the implicit conductor-like polarized continuum model. The molecular motions were included via anharmonic corrections and averaging of snapshots obtained from classical and first-principles molecular dynamics (MD) simulations. Comparison to experiment revealed that density functional calculations typically overestimate the (13)C NMR chemical shifts. Hybrid functionals, such as BHandH and BHandHLYP, and long-range corrected functionals, such as wB97xd and CAM-B3LYP, give the best results. While the solvent has a minor effect (chemical shift changes by ~1 ppm), the vibrational and dynamical effects are surprisingly large, causing changes up to 9 ppm. Consideration of the latter was also necessary to explain the observed temperature dependence. While the dynamical corrections for MD performed in vacuum were overestimated, inclusion of the solvent in simulations provided more realistic results. The study thus points out the importance of an appropriate solvent model and a complex approach to the modelling, balancing the static, dynamic and environmental factors.


Migration of bovine bronchial epithelial cells to extracellular matrix components.
Migration of epithelial cells is an important feature of wound healing. Components of extracellular matrix stimulate migration of other cells, and we hypothesized that basement membrane components, laminin and type IV collagen, stimulate migration of bovine bronchial epithelial cells (BBEC). BBEC cultured for 3 days were used in migration assays using the blindwell chamber technique. BBEC migrated in a concentration-dependent manner to laminin, type IV collagen, and fibronectin. "Checkerboard" analysis demonstrated that the migration was directional for each of the components studied. We also evaluated the stimulatory activity of fibronectin fragments. A fragment containing the RGDS peptide was stimulatory of migration while other fragments were much less so, suggesting a role for RGDS-sensitive, integrin-mediated mechanisms. In order to evaluate whether bound or soluble matrix components were required to direct cell migration, we performed haptotaxis assays with precoated filters in the migration chambers. Fibronectin-precoated filters demonstrated significant stimulation of migration, suggesting that some of the migration in our original assays with fibronectin present in the lower chambers could be termed haptotactic. laminin- and type IV collagen-precoated filters were less active. When insulin was used as a chemoattractant, the fibronectin-precoated filters were more facilitatory of migration than the other matrix coatings. In summary, BBEC can chemotactically migrate to extracellular matrix components. Thus, the composition of the provisional matrix that forms at sites of epithelial injury may play an important role in the repair processes that occur after injury to the bronchial epithelium.


Thyrotoxicosis, unstable angina and normal coronary angiogram.
It is well known that thyrotoxicosis may elicit acute myocardial ischemia even in patients with angiographically normal coronary vessels. The involved mechanisms are not clearly defined although some hypothesis have been suggested. We report a case of a 54-year-old woman affected by Graves' disease with thyrotoxicosis which was referred to our Institute because of unstable angina. During hospitalization a two dimensional echocardiogram, performed during chest discomfort, showed left ventricular apical akinesis and impaired global systolic function. A subsequent coronary angiography revealed normal epicardial vessels. She was successfully treated with high-dose methimazole and propranolol and a repeat echocardiogram evaluation showed normalization of left ventricular systolic function. Six months later, because of the appearance of paroxysmal atrial fibrillation, the patient underwent total thyroidectomy and a substitutive therapy with L-T4 (100 micrograms/die) was started. The authors review the possible mechanisms involved in the pathogenesis of myocardial ischemia during thyrotoxicosis.


Disposition of flavonoids via enteric recycling: structural effects and lack of correlations between in vitro and in situ metabolic properties.
The purpose of this study is to determine the importance of coupling of efflux transporters and metabolic enzymes in the intestinal disposition of six isoflavones (genistein, daidzein, formononetin, glycitein, biochanin A, and prunetin), and to determine how isoflavone structural differences affect the intestinal disposition. A rat intestinal perfusion model was used, together with rat intestinal and liver microsomes. In the intestinal perfusion model, significant absorption and excretion differences were found between isoflavones and their respective glucuronides (p <0.05), with prunetin being the most rapidly absorbed and formononetin glucuronides being the most excreted in the small intestine. In contrast, glucuronides were excreted very little in the colon. In an attempt to account for the differences, we measured the glucuronidation rates of six isoflavones in microsomes prepared from rat intestine and liver. Using multiple regression analysis, intrinsic clearance (CL(int)) and other enzyme kinetic parameters (V(max) and K(m)) were determined using appropriate kinetic models based on Akaike's information criterion. The kinetic parameters were dependent on the isoflavone used and the types of microsomes. To determine how metabolite excretion rates are controlled, we plotted excretion rates versus calculated microsomal rates (at 10 microM), CL(int) values, K(m) values, or V(max) values, and the results indicated that excretion rates were not controlled by any of the kinetic parameters. In conclusion, coupling of intestinal metabolic enzymes and efflux transporters affects the intestinal disposition of isoflavones, and structural differences of isoflavones, such as having methoxyl groups, significantly influenced their intestinal disposition.


[Gender related salivation features].
The aim of the study was to assess gender related salivation features. One hundred and seventy-five patients were enrolled in the study (115 females and 60 males aged from 18 to 75 years). The study results showed xerostomia to be more common in females and it's subjective symptoms are more prominent partly because of gender-related psychological reasons. Xylitol-based paste and spray were successfully used for symptoms relief.


Assessing noninferiority: Evaluating efficacy of a new treatment without complete data.
The FDA released the final guidance on noninferiority trials in November 2016. In noninferiority trials, validity of the assessment of the efficacy of the test treatment depends on the control treatment's efficacy. Therefore, it is critically important that there be a reliable estimate of the control treatment effect-which is generally obtained from historical trials, and often assumed to hold in the current setting (the assay constancy assumption). Validating the constancy assumption requires clinical data, which are typically lacking. The guidance acknowledges that "lack of constancy can occur for many reasons." We clarify the objectives of noninferiority trials. We conclude that correction for bias, rather than assay constancy, is critical to conducting valid noninferiority trials. We propose that assay constancy not be assumed and discounting or thresholds be used to address concern about loss of historical efficacy. Examples are provided for illustration.


Understanding the adhesion mechanism of a mucin binding domain from Lactobacillus fermentum and its role in enteropathogen exclusion.
Lactobacillus species possesses surface exposed Mucin Binding Protein (MucBP) which plays a role in adhesion to gastrointestinal mucin. MucBP contains one or more mucin binding domain (MBD), the functionality of which has yet not been characterized thoroughly. Here, we have characterized a 93-amino acid MBD (MBD93) of MucBP (LAF_0673) from Lactobacillus fermentum. Multiple sequence alignment of L. fermentum MBD93 exhibited ∼60% sequence homology with MBDs from other Lactobacillus species. Further, we cloned, expressed and purified MBD93 from Escherichia coli as N-terminal histidine-tagged protein (6X His-MBD93). The purified MBD93 was able to bind to mucin and showed strong affinity towards the terminally expressed mucin glycans viz. N-acetylgalactosamine (GalNAc), N-acetylglucosamine (GlcNAc), Galactose (Gal), and Sialic acid (N-acetylneuraminic acid; Neu5Ac). In silico experiments further confirmed the interaction between homology modeled MBD93 to mucin glycans through hydrogen-bonding with its surface amino acid residues Ser57, Pro58, Ile60, Tyr63 and Ala65. We also have demonstrated that MBD93 was able to inhibit the adhesion of enteric pathogens, including E. coli, Salmonella Paratyphi A, Shigella sonnei and Proteus vulgaris to mucin. Our results suggested that L. fermentum MBD93 is a functionally sufficient unit to act as an adhesin and to protect from invading enteric pathogens.


The rat prolactin gene family locus: species-specific gene family expansion.
In the rat there is a large family of paralogous genes related to prolactin (PRL). Members of the PRL family are expressed in cell- and temporal-specific patterns in the anterior pituitary, uterus, and placenta. An overriding feature of the PRL family is its association with pregnancy. In this investigation, we used information derived from the public rat genome database as a tool for identifying new members of the rat PRL family. The entire rat PRL gene family locus spans approximately 1.7 megabases (Mb) on Chromosome 17. Genes possessed either 5- or 6-exon organization patterns. We provide information on three newly identified genes orthologous to previously identified members of the mouse PRL gene family [placental lactogen-Ialpha (PL-Ialpha), PL-Ibeta, and proliferin (PLF)] and a new member of the PRL family, termed PRL-like protein-P (PLP-P). Information is also presented on the existence of multiple PLP-M transcripts, which are generated by alternative splicing. Expansion of the PRL family has occurred independently in rodents versus the cow and does not exist in the human and dog. Elucidation of the rat PRL gene family locus provides tools for studying the genetics and biology of the rat PRL family and new insights into species-specific gene family expansion.


[Risk factors for 5-year recurrence of spontaneous symptomatic epileptic seizures in infants and young children].
To investigate the recurrence rate and risk factors of spontaneous symptomatic epileptic seizures after the first episode in infants and young children. The clinical data of infants and young children who experienced the first episode of spontaneous symptomatic epileptic seizures between April 2009 and April 2011 in Suzhou Children's Hospital were collected. Follow-up visits were performed once every 1-3 months, and the follow-up time was 1-60 months. The Kaplan-Meier method and Cox proportional hazards model were applied to calculate the recurrence rate of spontaneous symptomatic epileptic seizures and analyze the risk factors for seizure recurrence. Sixty-three children experiencing a first episode of spontaneous symptomatic epileptic seizures were enrolled. Within 5 years after the first episode, 43 children experienced the recurrence of spontaneous symptomatic epileptic seizures, with a 5-year cumulative recurrence rate of 69.4%. Among all recurrent cases, 86% experienced recurrence within 1 year after the first episode. The multivariate analysis with the Cox proportional hazards model showed that epileptiform discharges on electroencephalography were the independent risk factor for recurrence of spontaneous symptomatic epileptic seizures (HR=5.349, 95%CI: 2.375-12.048). The recurrence rate of spontaneous symptomatic epileptic seizures after the first episode is high in infants and young children. Epileptiform discharges on electroencephalography are the independent risk factor for the recurrence, and thus it is suggested to perform antiepileptic therapy for these children.


Ectopic lymphoid neogenesis and lymphoid chemokines in Sjogren's syndrome: at the interplay between chronic inflammation, autoimmunity and lymphomagenesis.
It has long been demonstrated that a subset of patients with Sjogren's syndrome (SS) develop ectopic lymphoid structures (ELS) in the salivary glands (SG). These structures are characterised by periductal clusters of T and B lymphocytes, development of high endothelial venules and differentiation of follicular dendritic cells (FDC) networks. Evidence in patients with and animal models of SS demonstrated that the formation and maintenance of ELS in the SG is critically dependent on the ectopic expression of lymphotoxins (LT) and lymphoid chemokines CXCL13, CCL19, CCL21 and CXCL12. Several cell types, including resident epithelial, stromal and endothelial cells as well as different subsets of infiltrating immune cells, have been shown to be capable of producing some of these factors during chronic inflammation in SS. In this review we focus on the cellular and molecular mechanisms regulating the formation of ELS in SS SG, with particular emphasis on the role of lymphoid chemokines. In addition, we summarise accumulating data in support of the notion that ELS in SS represent functional niches whereby autoreactive B cells undergo affinity maturation, clonal selection and differentiation into autoantibody producing cells, thus contributing to autoimmunity over and above secondary lymphoid organs. Furthermore, we review the emerging role of ELS and lymphoid chemokines in driving extranodal B cell lymphomagenesis in SS and we focus on recent evidence suggesting that ELS identify subsets of SS patients at increased risk of developing systemic manifestations and lymphoma.


[Role of epileptogenic lesions in the development of ictal and interictal epileptic disturbance].
The most common cause of focal epilepsies is the morphological brain abnormality, the epileptogenic lesion. Nowadays, by using MRI, the epileptogenic lesion can be demonstrated in vivo in more and more cases. Our knowledge regarding the clinical and pathophysiological features of epilepsy should be reevaluated in the highlight of the epileptogenic lesions demonstrated by MRI. The presence and the type of the epileptogenic lesion are important prognostic factors in the pharmacological and surgical treatments of epilepsy. Because the localization of the lesion is usually identical with the site of the seizure onset, the MRI investigation play an important role not only in identifying the epilepsy etiology but also in the non-invasive localization of the epileptic focus. Tumors, malformations of the cortical development, the hippocampal sclerosis, perinatal lesions, posttraumatic scars and the vascular malformations are the most important morphological abnormalities associated with epilepsy. Low-grade astrocytoma, pilocytic astrocytoma, oligodendroglioma, ganglioglioma, and the dysembrioplastic neuroepithelial tumors are the most common neoplasms associated with chronic epilepsy. Low grade astrocytomas or vascular malformations generate seizures due to chemical or mechanical effects of the lesion, the pacemaker area occurs obviously outside the lesion, in the adjacent brain tissue. Conversely, malformations of cortical development have intrinsic epileptogenicity. In them, the seizure onset zone is localized intralesional: the lesion generates seizures itself.


Necrotizing fasciitis of the head and neck: an analysis of 47 cases.
Necrotizing fasciitis is an overwhelming infection common to the perineum, abdominal wall, and extremities. It is a surgical emergency related to a high mortality rate that is more often seen in elderly and immunocompromised patients. Necrotizing fasciitis occurs uncommonly in the head and neck region. Over a 12-year period, 47 cases of necrotizing fasciitis of the head and neck region were collected at this hospital. The demographics, predisposing factors, clinical presentation and courses, management, complications, and outcomes were analyzed. The cases were divided into two groups: survivors and nonsurvivors. Statistical comparisons were made of the parameters age, gender, smoking or drinking habit, underlying medical problems, laboratory data, and treatments used. Forty-two patients (89.4 percent) had associated systemic disease; most of these patients had diabetes (72.3 percent). The clinical manifestations are nonspecific but are often typical for diagnosis. The necessity of computed tomographic scans is not conclusive in this study. Presentation of septic shock (p = 0.004) and association with underlying malignancy (p = 0.03) were the only statistically significant factors that led to a poor prognosis. The cornerstones of proper management include early diagnosis, aggressive surgical debridement, broad-spectrum antibiotics, and intensive supportive care.


Hyperglycemia in hospitalized patients receiving parental nutrition is associated with increased morbidity and mortality: a review.
Parenteral Nutrition (PN) is a valuable life saving intervention which can improve the nutritional status of hospitalized malnourished patients. PN is associated with complications including the development of hyperglycemia. This paper aims to provide a descriptive systematic review regarding the effects of PN-induced hyperglycemia in hospitalized patients, either in the intensive care unit or ward, while formulating and complementing existing guidelines on the administration of PN and glucose monitoring in hospitalized patients. Medline and Pubmed were searched for relevant articles describing complications arising from the development of hyperglycemia in patients receiving PN; four relevant studies were identified in the search. These articles had different glycemic targets and patient populations, and their protocols varied with regards to glycemic control. However, there was consistency regarding the association between hyperglycemia and mortality in patients receiving PN. These studies highlight the need for guidelines regarding monitoring and initiation of therapy in hyperglycemic patients. Unfortunately, all the currently available studies are retrospective in design; a large, prospective, randomized controlled trial regarding glycemic control in patients receiving PN is required for the development of standardized protocols.


Methodology and Early Results of the First Surveillance Program on Prevention and Control of Antimicrobial Resistance in Isfahan, Iran: The IAS-I Study.
Isfahan Antibiotic Resistance Surveillance System-1 has been instituted in Isfahan, Iran to construct a project for surveillance of clinically significant bacteria, and to help raise a logic regional stewardship program for prevention and control of disseminating-resistant organisms. During March 2016 to March 2018, an antibiotic resistance surveillance system was designed and implemented by Isfahan Infectious Diseases and Tropical Medicine Research Center. The surveillance program was implemented in three general hospitals in Isfahan. In addition to the routine microbiology data, clinical data (differentiation between true infections and contamination, healthcare-associated infections (HCAI) and community-acquired infections (CAI), as well as determination of the infection site) were obtained and analyzed by WHONET software. During a 2-year period, from 7056 samples that revealed growth of bacteria, 3632 (51.5%) isolates were detected as contamination and 3424 (48.5%) true bacterial isolates were identified. Of these, about 32% of isolates were recognized as HCAI. Totally, the most recognized infections were urinary tract infection, bloodstream infection and skin and soft tissue infections. In patients with HCAIs, 70% of isolates were gram negative and in patients with CAIs 73% isolates were gram negative bacteria. The strength of the project is gathering enough clinical information in addition to microbiologic data, which would increase application of the results for empiric treatment and prevention of the infectious diseases in clinical settings.


Transfer of noncoding DNA drives regulatory rewiring in bacteria.
Understanding the mechanisms that generate variation is a common pursuit unifying the life sciences. Bacteria represent an especially striking puzzle, because closely related strains possess radically different metabolic and ecological capabilities. Differences in protein repertoire arising from gene transfer are currently considered the primary mechanism underlying phenotypic plasticity in bacteria. Although bacterial coding plasticity has been extensively studied in previous decades, little is known about the role that regulatory plasticity plays in bacterial evolution. Here, we show that bacterial genes can rapidly shift between multiple regulatory modes by acquiring functionally divergent nonhomologous promoter regions. Through analysis of 270,000 regulatory regions across 247 genomes, we demonstrate that regulatory "switching" to nonhomologous alternatives is ubiquitous, occurring across the bacterial domain. Using comparative transcriptomics, we show that at least 16% of the expression divergence between Escherichia coli strains can be explained by this regulatory switching. Further, using an oligonucleotide regulatory library, we establish that switching affects bacterial promoter architecture. We provide evidence that regulatory switching can occur through horizontal regulatory transfer, which allows regulatory regions to move across strains, and even genera, independently from the genes they regulate. Finally, by experimentally characterizing the fitness effect of a regulatory transfer on a pathogenic E. coli strain, we demonstrate that regulatory switching elicits important phenotypic consequences. Taken together, our findings expose previously unappreciated regulatory plasticity in bacteria and provide a gateway for understanding bacterial phenotypic variation and adaptation.


Giant Right Atrial Abscess in a Premature Infant With Fungal Endocarditis in a Developing Country.
Although infective endocarditis rarely appears during infancy, fungal infections remain a concern in the preterm neonatal population as the result of compromised immunity, prolonged hospitalization, and invasive procedures. The increased awareness of fungal colonization and improvements in medical therapy have not reduced the high mortality rate of mycotic infections in premature newborns, especially in developing countries, and there is no consensus on the surgical timing to treat neonatal fungal endocarditis. We present the case of a two-month-old boy with a history of three weeks of hospitalization for prematurity. After being discharged, the patient developed symptomatic candidemia resulting from a large right atrial abscess obstructing the tricuspid valve; despite antifungal therapy, urgent surgical resection was required.


Efficacy and safety of intermittent versus continuous dose apatinib plus docetaxel as second-line therapy in patients with advanced gastric cancer or gastroesophageal junction adenocarcinoma: a randomized controlled study.
Previous studies of the second-line treatment for advanced gastric cancer or gastroesophageal junction adenocarcinoma (GC/GEJAC) had reported that apatinib combined with chemotherapy improved the treatment outcomes. However, the benefits were sometimes limited due to the tolerance of continuous dose regimen. This randomized controlled study aimed to investigate the efficacy and safety of intermittent or continuous dose apatinib plus docetaxel as a second-line therapy in patients with advanced GC/GEJAC. Advanced GC/GEJAC patients who failed first-line chemotherapy were recruited (enrollment time: from September 15, 2017 to July 21, 2019), and randomly assigned to either the intermittent dose group (IG group) or the continuous dose group (CG group) (1:1 ratio) using the block randomization method. In the IG group, patients received apatinib 500 mg/d for 5 consecutive days then held for 2 days plus docetaxel 60 mg/m2 q3w, in a 3-week cycle. In the CG group, patients received apatinib 500 mg daily plus docetaxel 60 mg/m2 q3w, in a 3-week cycle. The progression free survival (PFS) was evaluated every two cycles and follow-ups were performed monthly. The primary endpoint was PFS, and the secondary endpoints were objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety. In total, 76 eligible patients were enrolled and randomly assigned (1:1 ratio). The IG group exhibited similar PFS compared to the CG group [median PFS: 3.88 (95% CI: 1.72-6.03) months vs. 3.98 (95% CI: 1.06-6.90) months, P=0.546] and OS [median OS: 9.00 (95% CI: 5.31-12.70) months vs. 9.40 (95% CI: 5.20-13.59) months, P=0.310]. ORR (21.1% vs. 18.4%, P=0.773) and DCR (60.5% vs. 60.5%, P=1.000) were of not statistically different between the IG and CG groups. As for safety, the IG group exhibited less frequent hypoproteinemia (31.6% vs. 55.3%, P=0.037) and lactate dehydrogenase increased (18.4% vs. 44.7%, P=0.014), while no differences in other adverse events were observed between the two groups. Intermittent dose apatinib plus docetaxel was equally effective and more tolerable than continuous dose apatinib plus docetaxel as a second-line therapy in patients with advanced GC/GEJAC. ClinicalTrials.gov NCT03334591.


A partnership model for the delivery of health education to rural and remote communities using multipoint videoconferencing.
Multipoint videoconferencing has been used by Women's Health Queensland Wide (WHQW) for the delivery of health education to the residents of regional, remote and rural Queensland communities. The educational programme was a partnership between WHQW and health professionals in the participating communities. Telephone interviews with the health professionals were used in a follow-up study. Fifty-one interviews were conducted in October and November 2002; these involved 43 of the 64 participating towns. The results suggested that the project contributed to improved social capital in the participating communities. In addition, it gave rise to unexpected but valuable outcomes for WHQW and, potentially, for the Queensland community. The project demonstrated that success in telehealth can be measured in terms of social and community effects, as well as clinical outcomes and cost-effectiveness.


Effects of pregnancy and protein-energy malnutrition on monooxygenase O-dealkylation activity in rat liver microsomes.
Xenobiotic metabolism is influenced by a variety of physiological and environmental factors including pregnancy and nutritional status of the individual. Pregnancy has generally been reported to cause a depression of hepatic monooxygenase activities. Low-protein diets and protein-energy malnutrition have also been associated with a reduced activity of monooxygenases in nonpregnant animals. We investigated the combined effects of pregnancy and protein-energy malnutrition on liver monooxygenase O-dealkylation activity. On pregnancy day 0 rats were assigned at random to a group fed ad libitum (well-nourished, WN) or to a malnourished group (MN) which received half of the WN food intake (12 g/day). WN and MN rats were killed on days 0 (nonpregnant), 11 or 20 of pregnancy and ethoxy- (EROD), methoxy- (MROD) and penthoxy- (PROD) resorufin O-dealkylation activities were measured in liver microsomes. Only minor changes in enzyme activities were observed on pregnancy day 11, but a clear-cut reduction of monooxygenase activities (pmol resorufin min-1 mg protein-1) was noted near term (day 0 vs 20, means +/- SD, Student t-test, P<0.05) in WN (EROD: 78.9 +/- 15.1 vs 54.6 +/- 10.2; MROD: 67.8 +/- 10.0 vs 40.9 +/- 7.2; PROD: 6.6 +/- 0. 9 vs 4.3 +/- 0.8) and in MN (EROD: 89.2 +/- 23.9 vs 46.9 +/- 15.0; MROD: 66.8 +/- 13.8 vs 27.9 +/- 4.4; PROD: 6.3 +/- 1.0 vs 4.1 +/- 0. 6) dams. On pregnancy day 20 MROD was lower in MN than in WN dams. Malnutrition did not increase the pregnancy-induced reduction of EROD and PROD activities. Thus, the present results suggest that the activities of liver monooxygenases are reduced in near-term pregnancy and that protein-energy malnutrition does not alter EROD or PROD in pregnant rats.


BRAF V600E-Negative Hairy Cell Leukaemia.
Since the initial report of the BRAF V600E mutation in hairy cell leukemia, numerous investigators have demonstrated the presence of this activating mutation in nearly all cases of this disease. A case of hairy cell leukemia is documented with a classical clinical, morphological, immunophenotypic, and cytochemical profile in which the BRAF V600E was not detected. The diagnostic and therapeutic implications are discussed.


Alcohol Use Disorder and Hepatitis C Prevention and Care in People Who Inject Drugs: The State of Play.
Safe and effective treatment with direct-acting antivirals (DAAs) has ushered in an era in which hepatitis C virus (HCV) elimination, as set out by the World Health Organization, is possible. However, alcohol use disorder (AUD) has the potential to reduce the benefits of prevention interventions and reduce access to and continuity of HCV care in at-risk populations, such as people who inject drugs (PWID). We review the literature on the consequences of AUD on the effectiveness of HCV prevention and the cascade of care in PWID and provide recommendations for future research in the field of alcohol use and HCV.


Associations of protein intake, sources and distribution on muscle strength in community-dwelling older adults living in Auckland, New Zealand.
Protein intake, sources and distribution impact on muscle protein synthesis and muscle mass in older adults. However, it is less clear whether dietary protein influences muscle strength. Data were obtained from the Researching Eating Activity and Cognitive Health (REACH) study, a cross-sectional study aimed at investigating dietary patterns, cognitive function and metabolic syndrome in older adults aged 65-74 years. Dietary intake was assessed using a 4-d food record and muscle strength using a handgrip strength dynamometer. After adjusting for confounders, in female older adults (n 212), total protein intake (β = 0⋅22, P < 0⋅01); protein from dairy and eggs (β = 0⋅21, P = 0⋅03) and plant food sources (β = 0⋅60, P < 0⋅01); and frequently consuming at least 0⋅4 g/kg BW per meal (β = 0⋅08, P < 0⋅01) were associated with higher BMI-adjusted muscle strength. However, protein from meat and fish intake and the coefficient of variance of protein intake were not related to BMI-muscle strength in female older adults. No statistically significant associations were observed in male participants (n = 113). There may be sex differences when investigating associations between protein intake and muscle strength in older adults. Further research is needed to investigate these sex differences.