Hormonal control of H-type alpha(1-2)fucosyltransferase messenger ribonucleic acid in the mouse uterus.
The H epitope, an alpha(1-2)fucosylated carbohydrate structure, has been implicated in initial attachment of the murine blastocyst to luminal uterine epithelial cells in vitro. In this study, the expression of the H-type alpha(1-2)fucosyltransferase (FUT1) gene was examined in endometrium of mice. Northern blotting of luminal epithelial RNA identified a single 6.2-kilobase transcript. In situ hybridization studies showed a signal for FUT1 mRNA on Days 1-3 of pregnancy in glands and luminal epithelium. The signal diminished by Day 4 and could not be detected on Day 5 of pregnancy. The in situ signal in endometrial epithelia was highest at estrus and metestrus and was absent at diestrus. Estrogen treatment after ovariectomy gave strong FUT1 mRNA expression in epithelia, but with progesterone, progesterone + estrogen, or vehicle, no message could be detected. A semiquantitative reverse transcription-polymerase chain reaction (PCR) analysis of FUT1 mRNA from luminal epithelium generated large amounts of PCR product on Day 1 of pregnancy; this diminished on Days 2, 3, and 4, and the product was barely detectable on Day 5. A kinetic analysis of FUT1 activity on Day 1 of pregnancy suggested a single enzyme with a Michaelis-Menten constant (Km) of 0.29 mM towards phenyl-beta-D-galactoside and of 1.75 mM towards Galbeta(1-3)GalNAc. These results suggest that expression of the H epitope is regulated at the level of FUT1 transcription and that transcription is stimulated by estrogen in the endometrial epithelium.


Tracking the sources of nitrate in groundwater using coupled nitrogen and boron isotopes: a synthesis.
Nitrate (NO3) is one of the world's major pollutants of drinking water resources. Although recent European Directives have reduced input from intensive agriculture, NO3 levels in groundwater are approaching the drinking water limit of 50 mg L(-1) almost everywhere. Determining the sources of groundwater contamination is an important first step toward improving its quality by emission control. It is with this aim that we review here the benefit of using a coupled isotopic approach (delta15N and delta11B), in addition to conventional hydrogeological analyses, to trace the origin of NO3 in water. The studied watersheds include both fractured bedrock and alluvial (subsurface and deep) hydrogeological contexts. The joint use of nitrogen and boron isotope systematics in each context deciphers the origin of NO3 in the groundwater and allows a semi-quantification of the contributions of the respective pollution sources (mineral fertilizers, wastewater, and animal manure).


Relative sensitivity of parkin and other cysteine-containing enzymes to stress-induced solubility alterations.
Loss of parkin function is a predominant cause of familial Parkinsonism. Emerging evidence also suggests that parkin expression variability may confer a risk for sporadic Parkinson disease. We have recently demonstrated that a wide variety of Parkinson disease-linked stressors, including dopamine (DA), induce parkin solubility alterations and promote its aggregation within the cell, a phenomenon that may underlie the progressive susceptibility of the brain to degeneration. The vulnerability of parkin to stress-induced modification is likely due to its abundance of cysteine residues. Here, we performed a comprehensive mutational analysis and demonstrate that Cys residues residing both within and outside of the RING-IBR (in between RING fingers)-RING domain of parkin are important in maintaining its solubility. The majority of these Cys residues are highly conserved in parkin across different species and potentially fulfil important structural roles. Further, we found that both parkin and HHARI (human homologue of Drosophila ariadne), another RING-IBR-RING-type ubiquitin ligase, are comparably more susceptible to solubility alterations induced by oxidative and nitrosative stress when compared with other non-RING-IBR-RING Cys-containing enzymes. However, parkin appears to be uniquely sensitive to DA-mediated stress, the specificity of which is likely due to DA modification of 2 Cys residues on parkin (Cys-268 and Cys-323) that are distinct from other RING-IBR-RING members.


Modulation of interferon-specific gene expression by albumin-interferon-alpha in interferon-alpha-experienced patients with chronic hepatitis C.
Albumin-interferon-alpha (alb-IFN) is a novel recombinant protein derived from IFN-alpha2b genetically fused to human albumin. The resulting single polypeptide combines in one molecule the antiviral properties of IFN-alpha with the long serum half-life of albumin. IFN-mediated biological responses stem from the engagement of IFN-alpha with its target receptor and subsequent modulation of IFN-specific gene (ISG) expression. To evaluate the pharmacodynamics of alb-IFN during the Phase I/II study conducted in patients with chronic hepatitis C (CHC) who had previously failed IFN-alpha-containing regimens, ISG induction was evaluated in peripheral blood and compared with antiviral response. Whole blood was obtained at day 0, day 7 and day 28 from 21 patients enrolled in the higher dose (500-900 microg) alb-IFN cohort, who received two injections on day 0 and day 14. Taqman real-time PCR was used to assess candidate ISG expression. There was sustained induction on day 7 and day 28 of the ISG's OAS1, IRF-7, IFI44 and IFI27. Although all patients showed a molecular response to alb-IFN, individual variability in pretreatment gene expression levels and fold of modulation during treatment was observed. At day 28, induction of OAS1, IFI44 and IRF7 showed pairwise correlation in individual patients (P < 0.05). Moreover, the induction of expression at day 28, and pretreatment levels of OAS1 and IFI44 correlated with hepatitis C virus RNA reduction at day 28 (P < 0.05). In conclusion, alb-IFN demonstrated robust induction of ISG that was consistent with the response associated with an IFN-alpha.


Medulloblastomas and primitive neuroectodermal tumors rarely contain polyomavirus DNA sequences.
To address the hypothesis that medulloblastoma or supratentorial primitive neuroectodermal tumor (sPNET) can arise through infection by polyomaviruses, we examined genomic DNA isolated from 15 primary medulloblastoma and 5 sPNET biopsy specimens and from 2 medulloblastoma cell lines for the presence of DNA sequences from the polyomaviruses simian virus 40 (SV40), JC virus, and BK virus. These polyomaviruses have oncogenic potential in animals, and their DNA sequences have been detected in other surveys of various solid tumors, including childhood brain tumors. The tumor DNA samples were analyzed by Southern blot hybridization of polymerase chain reaction products that employed probes designed to detect specific polyomavirus sequences. Neither JC virus nor BK virus DNA sequences were detected in any of the specimens. None of the primary medulloblastoma or sPNET specimens contained SV40 sequences. However, SV40 DNA coding and noncoding sequences were detected in the D283-Med (medulloblastoma) cell line. Immunocytochemical studies of D283-Med revealed nuclear expression of SV40 large T antigen. In contrast to childhood ependymomas and choroid plexus tumors, medulloblastomas and sPNETs infrequently express evidence of polyomavirus infection.


Can Whipple's disease be transmitted by gastroscopes?
To determine whether disinfection protocols currently used for gastroscopes are effective against cultures of Tropheryma whipplei. The bactericidal activity of 2% glutaraldehyde and two peracetic acids on the Twist-Marseille strain of T. whipplei grown in cell monolayers was determined. Two patients who were diagnosed as having Whipple's disease 3 years after they had had intestinal biopsies. The disinfectants reduced bacteria by approximately 2 log to 3 log10 after 5 to 60 minutes of contact. The bactericidal activity of a disinfectant is usually considered significant if it causes a 5 log10 or greater reduction in viable bacterial titers. Disinfecting gastroscopes with 2% glutaraldehyde or peracetic acids for 20 minutes may be insufficient to prevent transmission of T. whipplei on the instruments or stop false-positive results on polymerase chain reaction.


Comparison of mesiodistal tooth widths in Caucasian, African and Japanese individuals with Brazilian ancestry and normal occlusion.
To observe the presence of sexual dimorphism and compare the mesiodistal width of the teeth in Caucasian, African and Japanese individuals with Brazilian ancestry not orthodontically treated and with normal occlusion. One hundred pairs of dental casts were used. It was measured, from first molar to first molar in both arches, the teeth's mesiodistal widths, using a digital caliper. For the statistical analysis of results Kolmogorov-Smirnov, t test, ANOVA and Tukey's test (p < 0.05) were used. Sexual dimorphism occurred on the three evaluated groups, and the highest mesiodistal widths were found in males. There was statistically significant difference between racial groups in all evaluated teeth in males. However, in females, this same difference was found only on upper lateral incisor and first molar; and lower lateral incisor, canine, first premolar and first molar. Most of mesiodistal measures present particular characteristics in relation to gender, with higher values for males, and to race, with a tendency for African to present greater mesiodistal distance of the teeth, followed by Japanese and Caucasians, respectively, important for the correct diagnosis and orthodontic planning.


The comparative antimalarial properties of weak base and neutral synthetic ozonides.
Thirty-three N-acyl 1,2,4-dispiro trioxolanes (secondary ozonides) were synthesized. For these ozonides, weak base functional groups were not required for high antimalarial potency against Plasmodium falciparum in vitro, but were necessary for high antimalarial efficacy in Plasmodium berghei-infected mice. A wide range of LogP/D(pH)(7.4) values were tolerated, although more lipophilic ozonides tended to be less metabolically stable.


Could ionizing radiation forestall cauliflower ear?
Repeated trauma to the ear very often results in "cauliflower ear." Many methods have been suggested to prevent an injured ear from demonstrating a cauliflowerlike deformity. The principles of treatment are evacuation of the hematoma, control of the reaccumulation of fluid, and maintenance of the cartilage contour. The authors studied the effect of ionizing radiation on deformed rabbit ears induced by repeated trauma. Twenty ears (10 rabbits) were used in the experiment. The animals were divided into four groups (control, preradiation, low dose, and high dose). Hematoma was produced by pounding the lateral side of the auricle 10 times with a 50-g weight at a height of 15 cm. The thickness of the injured and uninjured sites was measured, and histological analysis was performed for each group. The thickness of the ears of the irradiated groups was significantly less than the control group. The authors think that radiation treatment of repeatedly injured ears could prevent ear deformity, and could possibly be an adjunctive form of management of cauliflower ear in addition to hematoma evacuation and compression therapy.


Orexin (hypocretin)-like immunoreactivity in the cat hypothalamus: a light and electron microscopic study.
Orexin-A-like immunoreactive (OrA-ir) neurons and terminals in the cat hypothalamus were examined using immunohistochemical techniques. OrA-ir neurons were found principally in the lateral hypothalamic area (LHA) at the level of the tuberal cinereum and in the dorsal and posterior hypothalamic areas. In the LHA the majority of the neurons were located dorsal and lateral to the fornix; a small number of OrA-ir neurons were also present in other regions of the hypothalamus. OrA-ir fibers with varicose terminals were detected in almost all hypothalamic regions. The high density of fibers was located in the suprachiasmatic nucleus, the infundibular nucleus (INF), the tuberomamillary nucleus (TM) and the supra- and pre-mamillary nuclei. Ultrastructural analysis revealed that OrA-ir neurons in the LHA receive abundant input from non-immunoreactive terminals. These terminals, which contained many small, clear, round vesicles with a few large, dense core vesicles, made asymmetrical synaptic contacts with OrA-ir dendrites, indicating that the activity of orexin neurons is under excitatory control. On the other hand, the terminals of OrA-ir neurons also made asymmetrical synaptic contact with dendrites in the LHA, the INF and the TM. The dendrites in the LHA were both non-immunoreactive and OrA-ir; conversely, the dendrites in the INF and the TM were non-immunoreactive. In these regions, OrA-ir terminals contained many small, clear, round vesicles with few large, dense core vesicles, suggesting that orexinergic neurons also provide excitatory input to other neurons in these regions.


Iron-responsive element of Divalent metal transporter 1 (Dmt1) controls Notch-mediated cell fates.
Notch receptor activation is regulated by the intramembrane protease γ-secretase, which cleaves and liberates the Notch intracellular domain (Nicd) that regulates gene transcription. While γ-secretase cleavage is necessary, we demonstrate it is insufficient for Notch activation and requires vesicular trafficking. Here, we report Divalent metal transporter 1 (Dmt1, Slc11A2) as a novel and essential regulator of Notch signalling. Dmt1-deficient cells are defective in Notch signalling and have perturbed endolysosomal trafficking and function. Dmt1 encodes for two isoforms, with and without an iron response element (ire). We show that isoform-specific silencing of Dmt1-ire and Dmt1+ire has opposite consequences on Notch-dependent cell fates in cell lines and intestinal organoids. Loss of Dmt1-ire suppresses Notch activation and promotes differentiation, whereas loss of Dmt1+ire causes Notch activation and maintains stem-progenitor cell fates. Dmt1 isoform expression correlates with Notch and Wnt signalling in Apc-deficient intestinal organoids and human colorectal cancers. Consistently, Dmt1-ire silencing induces Notch-dependent differentiation in colorectal cancer cells. These data identify Dmt1 isoforms as binary switches controlling Notch cell fate decisions in normal and tumour cells.


Expression of snail in epidermal keratinocytes promotes cutaneous inflammation and hyperplasia conducive to tumor formation.
Although metastasis is the most lethal consequence of tumor progression, comparatively little is known regarding the molecular machinery governing this process. In many carcinomas, there is a robust correlation between the expression of the transcription factor Snail and a poor prognosis, but the contribution of this protein to the metastatic process remains unresolved. Interestingly, the prolonged expression of Snail in epidermal keratinocytes is sufficient to recapitulate early features of metastasis. However, it does so without inducing a complete epithelial-mesenchymal transition (EMT), a developmental phenomenon mediated by Snail that is extensively invoked as the mechanism fueling tumorigenesis. Instead, we found that the local invasiveness of keratinocytes is the consequence of the recruitment and activity of macrophages. Moreover, keratinocyte proliferation is the product of an IL-17/IL-6/Stat3 signaling module initiated by activated resident γδT cells in the transgenic skin. Together, these phenotypes prime the transgenic skin for the formation and metastasis of tumors in response to chemically induced carcinogenesis. Thus, the contribution of Snail to the progression of carcinomas is largely through the creation of a hyperproliferative and inflammatory niche that facilitates tumor development and dissemination.


Paratesticular rhabdomyosarcoma mimicking complicated epididymal cyst.
Paratesticular rhabdomyosarcoma (RMS) is a rare nongerm cell intrascrotal malignant tumor in children and young adult/teens resulting from the mesenchymal tissues of the tunica vaginalis, epididymis, spermatic cord, and testis. RMS accounts for approximately 7% of all genitourinary tract RMSs and 12% of all pediatric scrotal neoplasms. Patients usually present with a painless unilateral scrotal mass. We report a 16-year-old boy with a paratesticular RMS mimicking epididymal cyst. To our knowledge, this is the first case reported in the literature presenting as an epididymal cyst.


[Axillary Lymph Node Dissection and Chemotherapy were Useful for Occult Cancer - Report of a Case].
We report a case of occult cancer. In this case, axillaryly mph node dissection and chemotherapywere useful treatments. The patient was a 71-year-old woman who had left axillaryly mph node swelling. Mammographyshowed the swollen axillary lymph nodes, but there was no lesion in either breast. Ultrasonographyalso showed the swollen axillaryly mph nodes, but there was no malignant lesion in her breasts. CT showed swollen axillaryand mediastinal lymph nodes. We checked her entire body, but could not find a malignant lesion, so we diagnosed an occult cancer. She underwent axillary lymph node dissection. The pathological diagnosis from the resected surgical specimen was metastatic carcinoma, negative for ER and PgR, and negative for HER2/neu protein expression. She was given TC chemotherapyand her CEA value decreased. After 8 cycles of TC chemotherapy, she was well without metastasis.


An improved method for growing neurons: Comparison with standard protocols.
Since different culturing parameters - such as media composition or cell density - lead to different experimental results, it is important to define the protocol used for neuronal cultures. The vital role of astrocytes in maintaining homeostasis of neurons - both in vivo and in vitro - is well established: the majority of improved culturing conditions for primary dissociated neuronal cultures rely on astrocytes. Our culturing protocol is based on a novel serum-free preparation of astrocyte - conditioned medium (ACM). We compared the proposed ACM culturing method with other two commonly used methods Neurobasal/B27- and FBS- based media. We performed morphometric characterization by immunocytochemistry and functional analysis by calcium imaging for all three culture methods at 1, 7, 14 and 60days in vitro (DIV). ACM-based cultures gave the best results for all tested criteria, i.e. growth cone's size and shape, neuronal outgrowth and branching, network activity and synchronization, maturation and long-term survival. The differences were more pronounced when compared with FBS-based medium. Neurobasal/B27 cultures were comparable to ACM for young cultures (DIV1), but not for culturing times longer than DIV7. ACM-based cultures showed more robust neuronal outgrowth at DIV1. At DIV7 and 60, the activity of neuronal network grown in ACM had a more vigorous spontaneous electrical activity and a higher degree of synchronization. We propose our ACM-based culture protocol as an improved and more suitable method for both short- and long-term neuronal cultures.


Retinoblastoma binding protein 2 (RBP2) promotes HIF-1α-VEGF-induced angiogenesis of non-small cell lung cancer via the Akt pathway.
Pathological angiogenesis plays an essential role in tumor aggressiveness and leads to unfavorable prognosis. The aim of this study is to detect the potential role of Retinoblastoma binding protein 2 (RBP2) in the tumor angiogenesis of non-small cell lung cancer (NSCLC). Immunohistochemical staining was used to detect the expression of RBP2, hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF) and CD34. Two pairs of siRNA sequences and pcDNA3-HA-RBP2 were used to down-regulate and up-regulate RBP2 expression in H1975 and SK-MES-1 cells. An endothelial cell tube formation assay, VEGF enzyme-linked immunosorbent assay, real-time PCR and western blotting were performed to detect the potential mechanisms mediated by RBP2 in tumor angiogenesis. Of the 102 stage I NSCLC specimens analyzed, high RBP2 protein expression is closely associated with tumor size (P = 0.030), high HIF-1α expression (P = 0.028), high VEGF expression (P = 0.048), increased tumor angiogenesis (P = 0.033) and poor prognosis (P = 0.037); high MVD was associated with high HIF-1α expression (P = 0.034), high VEGF expression (P = 0.001) and poor prognosis (P = 0.040). Multivariate analysis indicated that RBP2 had an independent influence on the survival of patients with stage I NSCLC (P = 0.044). By modulating the expression of RBP2, our findings suggested that RBP2 protein depletion decreased HUVECs tube formation by down-regulating VEGF in a conditioned medium. RBP2 stimulated the up-regulation of VEGF, which was dependent on HIF-1α, and activated the HIF-1α via phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. Moreover, VEGF increased the activation of Akt regulated by RBP2. The RBP2 protein may stimulate HIF-1α expression via the activation of the PI3K/Akt signaling pathway under normoxia and then stimulate VEGF expression. These findings indicate that RBP2 may play a critical role in tumor angiogenesis and serve as an attractive therapeutic target against tumor aggressiveness for early-stage NSCLC patients.


Secondary surgical treatment of the masculinized external genitalia of patients with virilizing adrenal hyperplasia.
Among 84 patients with virilizing adrenal hyperplasia operated on for deformed genitalia and followed for 7 to 22 years (mean 12 9/12 yr), 25 (30%) required secondary operations. For the most part, the secondary procedures were to provide a vaginal orifice adequate for coitus. The difficulties were due either to failure to adequately exteriorize the orifice at the first operation or to contraction of the outlet due to scar formation. Simple operative procedures to correct these difficulties are described.


Developing a scoring tool to estimate the risk of deterioration for normotensive patients with acute pulmonary embolism on admission.
It is important to identify deterioration in normotensive patients with acute pulmonary embolism (PE). This study aimed to develop a tool for predicting deterioration among normotensive patients with acute PE on admission. Clinical, laboratory, and computed tomography parameters were retrospectively collected for normotensive patients with acute PE who were treated at a Chinese center from January 2011 to May 2020 on admission into the hospital. The endpoint of the deterioration was any adverse outcome within 30 days. Eligible patients were randomized 2:1 to derivation and validation cohorts, and a nomogram was developed and validated by the aforementioned cohorts, respectively. The areas under the curves (AUCs) with 95% confidence intervals (CIs) were calculated. A risk-scoring tool for predicting deterioration was applied as a web-based calculator. The 845 eligible patients (420 men, 425 women) had an average age of 60.05 ± 15.43 years. Adverse outcomes were identified for 81 patients (9.6%). The nomogram for adverse outcomes included heart rate, systolic pressure, N-terminal-pro brain natriuretic peptide, and ventricle/atrial diameter ratios at 4-chamber view, which provided AUC values of 0.925 in the derivation cohort (95% CI 0.900-0.946, p < 0.001) and 0.900 in the validation cohort (95% CI 0.883-0.948, p < 0.001). A risk-scoring tool was published as a web-based calculator ( https://gaoyzcmu.shinyapps.io/APE9AD/ ). We developed a web-based scoring tool that may help predict deterioration in normotensive patients with acute PE.


Consideration of Sex, Gender, or Age on Outcomes of Digital Technologies for Treatment and Monitoring of Chronic Obstructive Pulmonary Disease: Overview of Systematic Reviews.
Several systematic reviews have addressed digital technology use for treatment and monitoring of chronic obstructive pulmonary disease (COPD). This study aimed to assess if systematic reviews considered the effects of sex, gender, or age on the outcomes of digital technologies for treatment and monitoring of COPD through an overview of such systematic reviews. The objectives of this overview were to (1) describe the definitions of sex or gender used in reviews; (2) determine whether the consideration of sex, gender, or age was planned in reviews; (3) determine whether sex, gender, or age was reported in review results; (4) determine whether sex, gender, or age was incorporated in implications for clinical practice in reviews; and (5) create an evidence map for development of individualized clinical recommendations for COPD based on sex, gender, or age diversity. MEDLINE, the Cochrane Library, Epistemonikos, Web of Science, and the bibliographies of the included systematic reviews were searched to June 2022. Inclusion was based on the PICOS framework: (1) population (COPD), (2) intervention (any digital technology), (3) comparison (any), (4) outcome (any), and (5) study type (systematic review). Studies were independently selected by 2 authors based on title and abstract and full-text screening. Data were extracted by 1 author and checked by another author. Data items included systematic review characteristics; PICOS criteria; and variables related to sex, gender, or age. Systematic reviews were appraised using A Measurement Tool to Assess Systematic Reviews, version 2 (AMSTAR 2). Data were synthesized using descriptive statistics. Of 1439 records, 30 systematic reviews published between 2010 and 2022 were included in this overview. The confidence in the results of 25 of the 30 (83%) reviews was critically low according to AMSTAR 2. The reviews focused on user outcomes that potentially depend on sex, gender, or age, such as efficacy or effectiveness (25/30, 83%) and acceptance, satisfaction, or adherence (3/30, 10%) to digital technologies for COPD. Reviews reported sex or gender (19/30 systematic reviews) or age (25/30 systematic reviews) among primary study characteristics. However, only 1 of 30 reviews included age in a subgroup analysis, and 3 of 30 reviews identified the effects of sex, gender, or age as evidence gaps. This overview shows that the effects of sex, gender, or age were rarely considered in 30 systematic reviews of digital technologies for COPD treatment and monitoring. Furthermore, systematic reviews did not incorporate sex, gender, nor age in their implications for clinical practice. We recommend that future systematic reviews should (1) evaluate the effects of sex, gender, or age on the outcomes of digital technologies for treatment and monitoring of COPD and (2) better adhere to reporting guidelines to improve the confidence in review results. PROSPERO CRD42022322924; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=322924. RR2-10.2196/40538.


ATPase Inhibitory Factor 1-A Novel Marker of Cellular Fitness and Exercise Capacity?
ATPase inhibitory factor 1 is a myokine inhibiting the hydrolytic activity of mitochondrial adenosine triphosphate synthase and ecto-F1-ATPase on the surface of many cells. IF1 affects ATP metabolism in mitochondria and the extracellular space and upregulates glucose uptake in myocytes; these processes are essential in physical activity. It is unknown whether the IF1 serum concentration is associated with exercise capacity. This study explored the association between resting IF1 serum concentration and exercise capacity indices in healthy people. IF1 serum concentration was measured in samples collected at rest in 97 healthy amateur cyclists. Exercise capacity was assessed on a bike ergometer at the successive stages of the progressive cardiopulmonary exercise test (CPET). IF1 serum concentration was negatively and significantly correlated with oxygen consumption, oxygen pulse, and load at various CPET stages. A better exercise capacity was associated with lower circulating IF1. IF1 may reflect better cellular/mitochondrial energetic fitness, but there is uncertainty regarding how IF1 is released into the intravascular space. We speculate that lower IF1 concentration may reflect a better cellular/mitochondrial integrity, as this protein is bound more strongly with ATPases in mitochondria and cellular surfaces in people with higher exercise capacity.


Testing a digital system that ranks the risk of unplanned intensive care unit admission in all ward patients: protocol for a prospective observational cohort study.
Traditional early warning scores (EWSs) use vital sign derangements to detect clinical deterioration in patients treated on hospital wards. Combining vital signs with demographics and laboratory results improves EWS performance. We have developed the Hospital Alerting Via Electronic Noticeboard (HAVEN) system. HAVEN uses vital signs, as well as demographic, comorbidity and laboratory data from the electronic patient record, to quantify and rank the risk of unplanned admission to an intensive care unit (ICU) within 24 hours for all ward patients. The primary aim of this study is to find additional variables, potentially missed during development, which may improve HAVEN performance. These variables will be sought in the medical record of patients misclassified by the HAVEN risk score during testing. This will be a prospective, observational, cohort study conducted at the John Radcliffe Hospital, part of the Oxford University Hospitals NHS Foundation Trust in the UK. Each day during the study periods, we will document all highly ranked patients (ie, those with the highest risk for unplanned ICU admission) identified by the HAVEN system. After 48 hours, we will review the progress of the identified patients. Patients who were subsequently admitted to the ICU will be removed from the study (as they will have been correctly classified by HAVEN). Highly ranked patients not admitted to ICU will undergo a structured medical notes review. Additionally, at the end of the study periods, all patients who had an unplanned ICU admission but whom HAVEN failed to rank highly will have a structured medical notes review. The review will identify candidate variables, likely associated with unplanned ICU admission, not included in the HAVEN risk score. Approval has been granted for gathering the data used in this study from the South Central Oxford C Research Ethics Committee (16/SC/0264, 13 June 2016) and the Confidentiality Advisory Group (16/CAG/0066). Our study will use a clinical expert conducting a structured medical notes review to identify variables, associated with unplanned ICU admission, not included in the development of the HAVEN risk score. These variables will then be added to the risk score and evaluated for potential performance gain. To the best of our knowledge, this is the first study of this type. We anticipate that documenting the HAVEN development methods will assist other research groups developing similar technology. ISRCTN12518261.


The presence of pacemaker HCN channels identifies theta rhythmic GABAergic neurons in the medial septum.
The medial septum (MS) is an indispensable component of the subcortical network which synchronizes the hippocampus at theta frequency during specific stages of information processing. GABAergic neurons exhibiting highly regular firing coupled to the hippocampal theta rhythm are thought to form the core of the MS rhythm-generating network. In recent studies the hyperpolarization-activated, cyclic nucleotide-gated non-selective cation (HCN) channel was shown to participate in theta synchronization of the medial septum. Here, we tested the hypothesis that HCN channel expression correlates with theta modulated firing behaviour of MS neurons by a combined anatomical and electrophysiological approach. HCN-expressing neurons represented a subpopulation of GABAergic cells in the MS partly overlapping with parvalbumin (PV)-containing neurons. Rhythmic firing in the theta frequency range was characteristic of all HCN-expressing neurons. In contrast, only a minority of HCN-negative cells displayed theta related activity. All HCN cells had tight phase coupling to hippocampal theta waves. As a group, PV-expressing HCN neurons had a marked bimodal phase distribution, whereas PV-immunonegative HCN neurons did not show group-level phase preference despite significant individual phase coupling. Microiontophoretic blockade of HCN channels resulted in the reduction of discharge frequency, but theta rhythmic firing was perturbed only in a few cases. Our data imply that HCN-expressing GABAergic neurons provide rhythmic drive in all phases of the hippocampal theta activity. In most MS theta cells rhythm genesis is apparently determined by interactions at the level of the network rather than by the pacemaking property of HCN channels alone.


Outpatient Management of Patients with Immune Thrombocytopenia (ITP) by Hematologists 1995-2014.
The aim of this study was to evaluate the treatment reality for outpatients with immune thrombocytopenia (ITP) managed by hematologists in routine care. All patients with ITP diagnosed between 06/1995 and 12/2014 in a community-based oncology group practice in Germany were retrospectively analyzed. 422 patients with a median age of 55 years (range 7-91 years) were evaluated. 57% were female and 43% male. Only 198 (47%) patients needed therapy. First-line therapy (n = 198) consisted of steroids in 81%, intravenous immunoglobulins (IVIG) in 12%, and IVIG plus steroids in 6%. Patients received a median of 2 (range 1-10) lines of therapy. The most frequently used treatment modalities were steroids in 93%, IVIG in 55%, splenectomy in 21%, and other immunosuppressive agents (OISA) in 23% of patients. Rituximab and thrombopoietin receptor agonists (TRAs) were used in 10% and 6% only. 9 (2%) patients needed hospitalization due to bleeding complications. 72% of patients achieved a durable remission after their last line of therapy. 1 (0.2%) patient died due to bleeding complications. The treatment modalities most frequently used are steroids, immunoglobulins, splenectomy, and OISA. Rituximab and TRAs are only used infrequently. 72% of ITP patients achieve durable remissions. The rate of hospital admissions due to bleeding complications and the ITP-related mortality are low. The majority of ITP patients can be safely managed by hematologists on an outpatient basis.


Effect of radiation and ibuprofen on normoxic renal carcinoma cells overexpressing hypoxia-inducible factors by loss of von Hippel-Lindau tumor suppressor gene function.
Tumor hypoxia is a major limiting factor for radiation therapy. Hypoxia-inducible factors (HIFs) are overexpressed in several human cancers and are considered prognostic markers and potential targets for cancer therapy. The purpose of the present study was to investigate the impact of HIFs on radiosensitivity. Renal clear cell carcinoma (RCC) cell lines overexpressing HIFs under normoxic conditions because of inactivation of von Hippel-Lindau tumor suppressor gene function (VHL-ve) and their matched pairs in which overexpression of HIFs was abolished by expression of functional VHL (VHL+ve) were irradiated. Radiosensitivity was determined by clonogenic assay. HIF and VHL protein levels were evaluated by Western blot analysis. RCC cells were also treated with ibuprofen, a radiosensitizer and HIF inhibitor in prostate cancer cells. The effect of ibuprofen on radiosensitization and HIF and VHL proteins was compared in RCC matched-pair cell lines. The data showed only small differences in the radiosensitivity between the cells overexpressing HIFs and cells with basal HIF levels. The dose-modifying factors for C2, 786-0, and A498 RCC cells were 1.14, 1.14 and 1.15, respectively. Radiation did not alter HIF or VHL protein levels. Ibuprofen inhibited HIFs in VHL+ve cells expressing basal levels of HIFs. In VHL-ve cells overexpressing HIFs, the inhibition was very modest. Ibuprofen radiosensitized C2 RCC cells to the same extent irrespective of their HIF status. Overexpression of HIFs in RCC cells harboring VHL mutations has only a modest effect on the radiosensitivity. Radiosensitization by ibuprofen appears to be independent of HIF status.


Phosphorylation- and Skp1-independent in vitro ubiquitination of E2F1 by multiple ROC-cullin ligases.
Ubiquitin-dependent proteolysis plays a critical role in the control of many cellular processes and is mediated by a cascade of enzymes involving ubiquitin activating (El), conjugating (E2), and ligating (E3) activities. Cullin 1/CDC53 functions as an E3 ligase by interacting with RING finger protein ROC1 and recruiting phosphorylated substrate. We report here that E2F1 transcription factor can be ubiquitinated in vitro and in vivo by multiple ROC-cullin ligases. In vitro, E2F1 can be ubiquitinated by E2/Ubc5 but not by E2/CDC34, is dependent on catalytically active ROC1, and is protected by the Rb protein. In contrast to substrates of the SKP1-Cullin 1-F box (SCF) complexes, in vitro ubiquitination of E2F1 by CUL1-ROC1 ligase does not require E2F1 phosphorylation, is not stimulated by overexpression of F box protein SKP2, and is not affected by immunodepletion of SKP1 or mutations in CUL1 disrupting SKPI binding. These results suggest a novel, SKP1-independent mechanism for targeting E2F1 ubiquitination.


[Anatomy, biomechanics, and physiopathology of the rotator cuff].
Rotator cuff disease is the most common cause of shoulder pain and dysfunction in adults. Despite the significant amount of pain and disability related to rotator cuff pathology, there is insufficient information to guide the clinician in planning therapeutic interventions. In this article, we reviewed the anatomy, biomechanics, and pathophysiology of the rotator cuff in an attempt to cover recent literature thereof. A consensus is now emerging that the etiology of rotator cuff disease is multifactorial, including extrinsic and intrinsic factors. Further investigations are needed to clarify the mechanisms and the pathogenesis of rotator cuff disease, as well as the effectiveness of various treatment modalities.


Anthropogenic alteration of nutrient supply increases the global freshwater carbon sink.
Lakes have a disproportionate effect on the global carbon (C) cycle relative to their area, mediating C transfer from land to atmosphere, and burying organic-C in their sediments. The magnitude and temporal variability of C burial is, however, poorly constrained, and the degree to which humans have influenced lake C cycling through landscape alteration has not been systematically assessed. Here, we report global and biome specific trajectories of lake C sequestration based on 516 lakes and show that some lake C burial rates (i.e., those in tropical forest and grassland biomes) have quadrupled over the last 100 years. Global lake C-sequestration (~0.12 Pg year-1) has increased by ~72 Tg year-1 since 1900, offsetting 20% of annual CO2 freshwater emissions rising to ~30% if reservoirs are included and contributing to the residual continental C sink. Nutrient availability explains ~70% of the observed increase, while rising temperatures have a minimal effect.


A Sensory 3D Map of the Odor Description Space Derived from a Comparison of Numeric Odor Profile Databases.
Many authors have proposed different schemes of odor classification, which are useful to aid the complex task of describing smells. However, reaching a consensus on a particular classification seems difficult because our psychophysical space of odor description is a continuum and is not clustered into well-defined categories. An alternative approach is to describe the perceptual space of odors as a low-dimensional coordinate system. This idea was first proposed by Crocker and Henderson in 1927, who suggested using numeric profiles based on 4 dimensions: "fragrant," "acid," "burnt," and "caprylic." In the present work, the odor profiles of 144 aroma chemicals were compared by means of statistical regression with comparable numeric odor profiles obtained from 2 databases, enabling a plausible interpretation of the 4 dimensions. Based on the results and taking into account comparable 2D sensory maps of odor descriptors from the literature, a 3D sensory map (odor cube) has been drawn up to improve understanding of the similarities and dissimilarities of the odor descriptors most frequently used in fragrance chemistry.


The change of lung capacity in elderly women caused by life span.
[Purpose] Although lung capacity in the elderly is affected by age, little research has been performed studying decreasing lung capacity in relation to increasing life expectancy. The aim of this study was to examine the effects of increased life span on the lung capacity of women. [Subjects and Methods] The subjects of this study were 55 healthy elderly women over 60 years of age who were living in Busan. Subjects were classified in the following age categories: 60s, 70s and 80s. For the pulmonary function test, a spirometry (Pony FX, COSMED Inc., Italy) was used. The item for measurement of pulmonary function in elderly women was maximum-effort expiratory spirogram (MES). The pulmonary function test was performed 3 times, and its mean value was used for analysis. [Results] Among items of maximum-effort expiratory spirogram, a significant difference according to age was demonstrated in forced vital capacity, forced expiratory volume in 1 second, peak expiratory flow, maximum expiratory flow 75%, maximum expiratory flow 50%, and inspiratory capacity. [Conclusion] According to this study, lung capacity decreases remarkably as age increases. In conclusion, a continuous exercise program beginning at an early age is essential to prevent decrease in lung capacity as age progresses.


Multilocus Phylogeny of the Afrotropical Freshwater Crab Fauna Reveals Historical Drainage Connectivity and Transoceanic Dispersal Since the Eocene.
Phylogenetic reconstruction, divergence time estimations and ancestral range estimation were undertaken for 66% of the Afrotropical freshwater crab fauna (Potamonautidae) based on four partial DNA loci (12S rRNA, 16S rRNA, cytochrome oxidase one [COI], and histone 3). The present study represents the most comprehensive taxonomic sampling of any freshwater crab family globally, and explores the impact of paleodrainage interconnectivity on cladogenesis among freshwater crabs. Phylogenetic analyses of the total evidence data using maximum-likelihood (ML), maximum parsimony (MP), and Bayesian inference (BI) produced a robust statistically well-supported tree topology that reaffirmed the monophyly of the Afrotropical freshwater crab fauna. The estimated divergence times suggest that the Afrotropical Potamonautidae diverged during the Eocene. Cladogenesis within and among several genera occurred predominantly during the Miocene, which was associated with major tectonic and climatic ameliorations throughout the region. Paleodrainage connectivity was observed with specimens from the Nilo-Sudan and East African coast proving to be sister to specimens from the Upper Guinea Forests in West Africa. In addition, we observed strong sister taxon affinity between specimens from East Africa and the Congo basin, including specimens from Lake Tanganyika, while the southern African fauna was retrieved as sister to the Angolan taxa. Within the East African clade we observed two independent transoceanic dispersal events, one to the Seychelles Archipelago and a second to Madagascar, while we observe a single transoceanic dispersal event from West Africa to São Tomé. The ancestral area estimation suggested a West African/East African ancestral range for the family with multiple dispersal events between southern Africa and East Africa, and between East Africa and Central Africa The taxonomic implications of our results are discussed in light of the widespread paraphyly evident among a number of genera.


Inhibition of glycolysis and respiration of sarcoma-180 cells by echitamine chloride.
Malignant tumors are known to exhibit high rates of glycolytic activity leading to high production of lactic acid. Hence, neoplastic cells have elevated activity of enzymes responsible for glycolysis. Echitamine chloride, an indole alkaloid extracted from the bark of Alstonia scholaris, has been reported to have a highly promising anticancer activity against fibrosarcoma in rats. In the present study, the effect of echitamine chloride on energy metabolism of S-180 cells is investigated to have a better understanding on the mode of action of echitamine chloride. The effect of echitamine chloride on the mitochondrial and cellular respiration of S-180 cells was studied. Also, the effects on glucose utilization, pyruvate utilization and lactate formation were studied on whole S-180 cells and S-180 cell-free homogenate. The levels of glycolytic enzymes such as hexokinase and lactate dehydrogenase were estimated in which particular emphasis has been laid on hexokinase which occurs both in cytosolic and particulate forms in neoplastic cells. Hence the differential effect of echitamine chloride on the levels of total, cytosolic and particulate hexokinase has been investigated. In conclusion, echitamine chloride affects both cellular and mitochondrial respiration, leading to reduction of the cellular energy pool and thereby resulting in the loss of viability of S-180 cells.


Quantitative proteomics identification of phosphoglycerate mutase 1 as a novel therapeutic target in hepatocellular carcinoma.
Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide with poor prognosis due to resistance to conventional chemotherapy and limited efficacy of radiotherapy. There is an urgent need to develop novel biomarkers for early diagnosis, as well as to identify new drug targets for therapeutic interventions. 54 paired HCC samples and 21 normal liver tissues were obtained from West China Hospital of Sichuan University. Informed consent was obtained from all the patients or their relatives prior to analysis, and the project was approved by the Institutional Ethics Committee of Sichuan University. Stable Isotope Labeling with Amino Acids in Cell Culture (SILAC)-based proteomics was employed to profile the differentially expressed proteins between a HepG2 human hepatoma cell line and an immortal hepatic cell line L02. Validation of PGAM1 expression was performed by semi-quantitative RT-PCR, immunoblot and immunohistochemistry using clinical samples. shRNA expressing plasmids specifically targeting PGAM1 were designed and constructed by GenePharma Corporation (Shanghai, China), and were utilized to silence expression of PGAM1 in vitro and in vivo. Cell proliferation was measured by a combination of colony formation assay and Ki67 staining. Apoptosis was examined by flow cytometry and TUNEL assay. A total of 63 dysregulated proteins were identified, including 51 up-regulated proteins, and 12 down-regulated proteins (over 2-fold, p < 0.01). Phosphoglycerate mutase 1 (PGAM1) was found markedly upregulated. Clinico-pathological analysis indicated that overexpression of PGAM1 was associated with 66.7% HCC, and strongly correlated with poor differentiation and decreased survival rates (p < 0.01). shRNAs-mediated repression of PGAM1 expression resulted in significant inhibition in liver cancer cell growth both in vitro and in vivo. Our studies suggested that PGAM1 plays an important role in hepatocarcinogenesis, and should be a potential diagnostic biomarker, as well as an attractive therapeutic target for hepatocellular carcinoma.


Dynamic prediction of transition to psychosis using joint modelling.
Considerable research has been conducted seeking risk factors and constructing prediction models for transition to psychosis in individuals at ultra-high risk (UHR). Nearly all such research has only employed baseline predictors, i.e. data collected at the baseline time point, even though longitudinal data on relevant measures such as psychopathology have often been collected at various time points. Dynamic prediction, which is the updating of prediction at a post-baseline assessment using baseline and longitudinal data accumulated up to that assessment, has not been utilized in the UHR context. This study explored the use of dynamic prediction and determined if it could enhance the prediction of frank psychosis onset in UHR individuals. An emerging statistical methodology called joint modelling was used to implement the dynamic prediction. Data from the NEURAPRO study (n = 304 UHR individuals), an intervention study with transition to psychosis study as the primary outcome, were used to investigate dynamic predictors. Compared with the conventional approach of using only baseline predictors, dynamic prediction using joint modelling showed significantly better sensitivity, specificity and likelihood ratios. As dynamic prediction can provide an up-to-date prediction for each individual at each new assessment post entry, it can be a useful tool to help clinicians adjust their prognostic judgements based on the unfolding clinical symptomatology of the patients. This study has shown that a dynamic approach to psychosis prediction using joint modelling has the potential to aid clinicians in making decisions about the provision of timely and personalized treatment to patients concerned.


Neutrophil gelatinase-associated lipocalin in adult septic patients with and without acute kidney injury.
To study the impact of inflammation/sepsis on the concentrations of neutrophil gelatinase-associated lipocalin (NGAL) in plasma and urine in adult intensive care unit (ICU) patients and to estimate the predictive properties of NGAL in plasma and urine for early detection of acute kidney injury (AKI) in patients with septic shock. Sixty-five patients admitted to the general ICU at the Karolinska University Hospital Solna, Sweden, with normal plasma creatinine were assessed for eligibility. Twenty-seven patients with systemic inflammatory response syndrome (SIRS), severe sepsis, or septic shock without AKI and 18 patients with septic shock and concomitant AKI were included in the final analysis. Plasma and urine were analyzed twice daily for plasma NGAL (pNGAL), C-reactive protein (CRP), procalcitonin, myeloperoxidase, plasma cystatin C, plasma creatinine, urine NGAL (uNGAL), urine cystatin C, and urine alpha1-microglobulin. Of the 45 patients, 40 had elevated peak levels of pNGAL. Peak levels of pNGAL were not significantly different between septic shock patients with and without AKI. Peak levels of uNGAL were below the upper reference limit in all but four patients without AKI. uNGAL was a good predictor (area under ROC 0.86) whereas pNGAL was a poor predictor (area under ROC 0.67) for AKI within the next 12 h in patients with septic shock. pNGAL is raised in patients with SIRS, severe sepsis, and septic shock and should be used with caution as a marker of AKI in ICU patients with septic shock. uNGAL is more useful in predicting AKI as the levels are not elevated in septic patients without AKI.


Magnesium-Organic Framework-Loaded Bisphosphonate-Functionalized Gel Scaffolds for Enhanced Bone Regeneration.
The development of magnesium-derived biomaterials is one of the most promising research in bone tissue engineering, and related strategies have been extensively used for tendon, skull, cartilage, and bone regeneration. Also, alendronate, a well-recognized drug for osteoporosis treatment, has recently attracted a great deal of attention for bone repair. However, rapid corrosion in vivo of Mg2+ and low systemic bioavailability of alendronate are the main limitations hampering their full exploitation. In this work, by means of physical and chemical cross-linking conjugating magnesium-metal-organic frameworks (Mg-MOFs) and bone-targeting alendronate to biocompatible gelatin scaffolds, a facile method is developed for the preparation of organic/inorganic nanocomposite gel scaffolds. The results affirmed that the nanocomposite gel scaffolds possessed excellent biocompatibility, continuous slow release of Mg2+ and alendronate, strong bone affinity, and bone regeneration. It is noteworthy that the continuous slow release of Mg2+ and alendronate could induce the macrophage switch to the M2 phenotype and promote osteogenic differentiation in the early stage, resulting in improved bone regeneration during implanting the scaffolds into the distal femoral. In summary, Mg-MOFs-loaded alendronate-modified gelatin gel scaffolds have been developed, exhibiting great potential for bone regenerative.


Is residents' progress on individualized learning plans related to the type of learning goal set?
To determine the types of learning goals residents select for their individualized learning plans (ILPs) and the relationship between goal type and progress toward achieving that goal. Pediatric and combined pediatric residents at 46 U.S. training programs completed a Web-based survey on ILPs in 2008-2009, describing their most important learning goal and the goals on which they made the most and least progress. Using iterative inductive review, responses were categorized into seven types (six corresponding with the Accreditation Council for Graduate Medical Education general competencies). Descriptive statistics and regression models were used to assess the relationship between goal type and progress made. Of 1,739 eligible residents, 992 (57%) completed the survey; 668 (38%) had previously completed an ILP and described their learning goals. Residents were more likely to report medical knowledge (MK) (53.7%) and patient care (PC) (25.9%) goals as most important and less likely to report professionalism (1.5%) and systems-based practice (SBP) (1.0%) goals as most important. Compared with progress on MK goals, residents reported significantly greater progress on PC (odds ratio [OR]: 2.20; 95% confidence interval [CI]: 1.57-3.09) and practice-based learning and improvement teaching (OR: 2.99; 95% CI: 1.59-5.63) goals and less progress on SBP goals (OR: 0.16; 95% CI: 0.05-0.56). Residents most commonly identified MK and PC learning goals as the most important. Residents made more progress on goals related to everyday tasks, such as PC and teaching, compared with goals less integrated in everyday training, such as SBP.


[Early postoperative complications in patients with Moyamoya disease--a comparison of inhaled anesthesia with total intravenous anesthesia (TIVA)].
Moyamoya disease is a rare neurovascular disorder that requires special anesthetic managements during revascularization procedures. We have investigated the incidence of early postoperative complications under inhaled anesthesia in comparison with total intravenous anesthesia (TIVA) retrospectively. Seventy-two patients undergoing revascularization procedures were divided into two groups, one with inhaled anesthesia (n = 23) and the other with TIVA (n = 49). Surgical procedures were performed under normocapnia, proper body temperature, and all patients were prevented from anemia by homologous transfusion. To avoid the variance in anesthetic managements, 39 patients under 15 years of age were picked up and divided in the same way as above. Early postoperative complications including transient ischemic attack and cerebral infarction during the first 2 weeks after operation were investigated. In all patients, early postoperative complications occurred in 48% of inhaled anesthesia group and in 49% of TIVA group. In patients under 15, these complications occurred in 44% and in 57%, respectively. There was no significant difference in the incidence of complications between the two anesthetic groups. Several previous studies reported the excellence of TIVA for revascularization procedure on the basis of regional blood flow because inhaled anesthesia may provoke intracerebral steal in moyamoya disease. Our investigation in this study revealed that both anesthetic methods have no significant difference in postoperative complications during the first 2 weeks after operation. Thus further study should be needed to verify the safety of inhalation anesthetics in patients with moyamoya disease.


Effect of ionophore A23187 on the membrane permeability in mouse fibroblasts.
Addition of the divalent cation ionophore A23187 to transformed mouse fibroblasts (3T6) resulted in an increase in the cell membrane permeability to normally impermeant solutes (e.g., nucleotides). The membrane permeability was assessed by following the efflux of prelabeled adenine nucleotides, the influx of p-nitrophenyl phosphate in cells attached to plastic dishes and reconstitution of intracellular protein synthesis in the presence of exogenously added normally impermeant factors required for macromolecular synthesis. The permeability change of 3T6 cells was found to be dependent on the specific presence of external calcium ion. The permeabilization was found to occur preferably in alkaline pH and specific to certain transformed cells. It is preceded by rapid efflux of K+, influx of Na+ and partial hydrolysis of cellular nucleotides in 3T6 cells. Similar ion fluxes were previously found to precede cell permeabilization by electrogenic ionophores for monovalent ions and by exogenous ATP. Our data suggest that a calcium dependent process caused the K+ release and excess Na+ entry, causing dissipation of the membrane potential and subsequent formation of aqueous channels.


Regional pelvic hyperthermia as an adjunct to chemotherapy (oxaliplatin, folinic acid, 5-fluorouracil) in pre-irradiated patients with locally recurrent rectal cancer: a pilot study.
The aim of this study was to evaluate the feasibility and toxicity of a novel hyperthermic chemotherapy approach for patients with locally recurrent adenocarcinoma of the rectum. All patients were pre-irradiated (> or = 45 Gy) and had histologically proven pelvic recurrence. Hyperthermic chemotherapy was applied according to a modified 'OFF'-schedule with weekly infusions of 43 mg/m2 of oxaliplatin (i.v., 120 min), 500 mg/m2 of folinic acid (i.v., 120 min) and 2.6 g/m2 of continuous infusional 5-fluorouracil (24 h) for 6 consecutive weeks. Oxaliplatin was started in parallel to pelvic radiofrequency hyperthermia that was provided by the BSD 2000-system. A total of 67 applications were administered to nine patients and were well tolerated. A total of 55/67 (82%) chemotherapy courses were applied without dose-reduction. In 62/67 (93%) hyperthermia sessions, a treatment time of > 60 min was maintained. Tolerated power levels were on average 600 W and, thus, slightly lower than those described in curative pelvic hyperthermia schedules. Eight out of 10 episodes of severe (WHO III degrees) toxicity represented typical side-effects of the chemotherapy given (nausea n = 4, diarrhoea n = 3, neuropathy n = 1). Two severe adverse events were firstly attributable to hyperthermia (haematuria, n = 1; deterioration of a decubital ulcer, n = 1). No patient suffered WHO-disease progression during the treatment period. Two patients achieved a partial remission. It is concluded that hyperthermic chemotherapy with oxaliplatin, folinic acid and 5-FU is feasible on an outpatient basis. Overall toxicity was moderate, although hyperthermia may add side-effects to this approach. Results, moreover, suggest a relevant palliative effect in patients with pre-irradiated pelvic recurrence of rectal cancer.


A novel luminescent Pb(ii) - organic framework exhibiting a rapid and selective detection of trace amounts of NACs and Fe3+ with excellent recyclability.
A novel three-dimensional metal organic framework, Pb3O2L (1) (H2L = 4-(1H-tetrazol-5-yl)phenol), with a unique 3D network structure exhibits excellent luminescence and good stability in water and other organic solvents. 1 can act as a promising dual functional sensor for the detection and recognition of nitroaromatic explosives (NACs) and Fe3+ ions via fluorescence quenching with high selectivity and sensitivity in an aqueous phase. Importantly, 1 as a fluorescent sensor of Fe3+ can be simply and quickly regenerated, which represents a rare example of a reported luminescent sensor of Fe3+ ions. Furthermore, the visible colour changes in the detection process make them easy to distinguish by the naked eyes, and luminescent test plates broaden its potential application in detection of Fe3+ ions. Experimental and theoretical calculations indicate that the luminescence quenching can be attributed to an electron and resonance energy transfer between the MOF and analytes. The present study contributes to the development of MOF materials research, specifically in their application as biological and environmental fluorescent sensors.


Clonal Diversity in Multi Drug Resistant (MDR) Enterococci Isolated from Fecal Normal Flora.
Enterococci are Gram positive and catalase- negative cocci that are found in the gastrointestinal tract of mammals and birds, and are readily isolated from soil, surface and waters. The aim of this study was to discriminate between Enterococcus isolates based on repetitive element sequence based -PCR (Rep-PCR) with the BOXA2R primer and their antibiotics profile. Enterococci isolates were obtained from 180 fecal samples. The isolates were identified by biochemical reaction and specific identification was confirmed by PCR with species specific primers. All isolates were subjected to Rep typing and antimicrobial susceptibility tests. Rep-PCR analysis of 180 isolates revealed 93 REP types with forty-five single types (ST1 to ST45) and forty-eight common types (CT1 to 48). Antibiotic susceptibility tests exhibited that 53 (29.4%), 43 (23.8%), 11 (6.1%) and 9 (5%) were resistant to erythromycin, tetracycline, gentamicin and ciprofloxacin respectively but among the isolates, sixteen were multi drug resistant (MDR). These MDR isolates showed 11 Rep types with seven single types and four common types. In addition, 81.2% of MDR isolates were from male subjects and the average age of these persons was more than fifty years. This study showed that 56.2% of MDR isolates were homogeneous with 95 % similarity, and high rate of resistance to tetracycline and erythromycin (81.2%) were observed in these isolates. The concern about these normal flora isolates are the pathogenic potential of these bacteria through the horizontal transfer of antibiotic resistance and virulence genes.


Long-term renal survival of γ3-heavy chain deposition disease: a case report.
Monoclonal immunoglobulin deposition disease (MIDD) is characterized by the non-amyloid deposition of monoclonal immunoglobulin fragments in the basement membranes. Heavy chain deposition disease (HCDD) is a type of MIDD. HCDD is an extremely rare disease, and only three cases have been reported in Japan up to the present. The prognosis of HCDD is very poor, and optimal treatment has not been established. Only a few cases of HCDD with favorable long-term renal prognosis have been reported to date. The authors describe a 61-year-old woman who presented with massive proteinuria, progressive kidney impairment, and hypocomplementemia. Kidney biopsy was performed for a precise diagnosis. On light microscopy, glomerules were lobulated and presented with nodular sclerosing glomerulopathy with membranoproliferative glomerulonephritis-like features. Immunofluorescence studies were positive for IgG, C3, and C1q within the mesangial nodules and in a linear distribution along the capillary walls without associated deposition of light chains. Staining for IgG showed the presence of linear deposits along tubular basement membranes. The analysis of the IgG subclass stain demonstrated intense positivity for IgG3 only. Electron microscopy revealed non-organized electron-dense deposits in the expanded mesangial area and inner aspect of the glomerular basement membranes. In accordance with the histological findings, we diagnosed γ3-HCDD. There was no evidence of plasma cell dyscrasia as a result of bone marrow aspiration. Serum and urine monoclonal proteins were not detected by immunoelectrophoresis and immunofixation electrophoresis. The serum free light chain ratio was within normal range. At first, prednisolone was administrated at a dose of 40 mg/day. However, a therapeutic effect was not observed. Urinary protein was not decreased and renal function further deteriorated. Therefore, melphalan plus prednisolone (MP) therapy was initiated. After 4 courses of MP therapy, the clinical parameters, including proteinuria, serum creatinine, albumin, and complement level (C3 and C4) were ameliorated. To date, the patient has been followed for 28 months, and long-term renal survival has been observed. In this case, hematologic disease such as multiple myeloma was not detected; however, MP therapy was effective. Recently, the novel concept of monoclonal gammopathy of renal significance (MGRS) has been reported. MIDD, which includes HCDD, is one category of MGRS. In MGRS, aggressive chemotherapy may induce favorable renal outcomes.


[Possibilities of prognostication of suppurative-inflammatory complications of surgical treatment of patients with nonrecurrent postoperative ventral hernia].
On the basis of the data of a retrospective investigation of 541 patients with nonrecurrent noncomplicated postoperative ventral hernia the criteria of prognosis of pyo-inflammatory complications in the operative wound after liquidation of the abdominal wall defect became more exact and quantitated. It was established that 18 criteria can be used for prognosis, 14 of them--before operation. During the operative procedure it can be possible to make the prognosis more exact with the intraoperative findings taken into account. Among them of special significance are 4 prognostic criteria: multichamber hernial sac, commissural process in the abdominal cavity, the fact of separation of the commissures and possible perforation of the hollow organ. The efficiency of the program was 80%. The approbation of the program has shown that prognosis of the development of pyo-inflammatory complications must be made on the basis of both the preoperative and intraoperative criteria. It allows to reliably reduce the amount of postoperative pyo-inflammatory complications from 8.6% (retrospective data) to 5.2% (prospective data).


Response time effectiveness: comparison of response time and survival in an urban emergency medical services system.
Emergency medical services (EMS) administrators seek methods to enhance system performance. One component scrutinized is the response time (RT) interval between call receipt and arrival on scene. While reducing RTs may improve survival, this remains speculative and unreported. To determine the effect of current RTs on survival in an urban EMS system. The study was conducted in a metropolitan county (population 620,000). The EMS system is a single-tier, paramedic service and provides all service requests. The 90% fractile RT specifications required for county compliance include 10:59 minutes for emergency life-threatening calls (priority I) and 12:59 minutes for emergency non-life-threatening calls (priority II). All emergency responses resulting in a priority I or priority II transport to a Level 1 trauma center emergency department over a six-month period were evaluated to determine the relation between specified and arbitrarily assigned RTs and survival. Five thousand, four hundred twenty-four transports were reviewed. Of these, 71 patients did not survive (1.31%; 95% CI = 1.04% to 1.67%). No significant difference in median RTs between survivors (6.4 min) and nonsurvivors (6.8 min) was noted (p = 0.10). Further, there was no significant difference between observed and expected deaths (p = 0.14). However, mortality risk was 1.58% for patients whose RT exceeded 5 minutes, and 0.51% for those whose RT was under 5 minutes (p = 0.002). The mortality risk curve was generally flat over RT intervals exceeding 5 minutes. In this observational study, emergency calls where RTs were less than 5 minutes were associated with improved survival when compared with calls where RTs exceeded 5 minutes. While variables other than time may be associated with this improved survival, there is little evidence in these data to suggest that changing this system's response time specifications to times less than current, but greater than 5 minutes, would have any beneficial effect on survival.


Formation of gizzard erosion-inducing substance in heated casein-histidine mixture.
Formation of a toxic substance inducing gizzard erosion (GE) was examined by using mainly a casein-histidine mixture as a simple model of fish meal. When a casein-histidine mixture was heated at 135 degrees C for three or five hours or at 160 degrees C for one hour, it induced severe GE. Changes in pH of histidine solution seemed to have little effect on the production of the toxic substance. Addition of a heated mixture of 30 mg of histidine and 150 g of casein (per kg of diet) failed to induce GE. A mixture of 750 mg of histidine and 150 g of casein was enough to produce a maximal toxicity. A heated mixture of histidine and isolated soybean protein, ovalbumin or gluten induced severe GE. A heated mixture of gelatin and histidine had a somewhat milder toxicity. On the other hand, zein and yeast treated in the same way showed only a slight toxicity. Two kinds of pre-treatment of casein before the addition of histidine were proved to be ineffective to inhibit the formation of the toxic substance. The toxicity of heated casein-histamine was rather lower than that of heated casein-histidine. Studies were also made on releasing of the toxic substance from heated casein-histidine into the soluble fraction by acidic hydrolysis and precipitation of this substance at acidic pH.


Idiopathic Parkinson's disease combined with multiple system atrophy. A clinicopathological report.
The clinical and postmortem findings of a patient with Lewy body pathology combined with multiple-system atrophy are described. When alive the patient was diagnosed as having Parkinson's disease. Pathological examination found evidence of striatonigral and olivopontocerebellar degeneration, together with Lewy bodies at a number of sites characteristic for idiopathic Parkinson's disease. Taken together, the clinical history and histological findings support the coexistence of two disease processes.


Do Neighborhoods Matter? A Systematic Review of Modifiable Risk Factors for Obesity among Low Socio-Economic Status Black and Hispanic Children.
Childhood obesity increases the risk of obesity and harmful comorbidities later in life. It is influenced by characteristics of a child's neighborhood, particularly among underserved groups. Our objective was to systematically review the evidence relating neighborhood environment and obesity risk among urban, low socioeconomic status (SES) Black and Hispanic children. We included studies published from 1993 through early 2017 from PubMed, SCOPUS, Web of Science, and Sociological Abstracts databases investigating relationships between empirically measured neighborhood characteristics and obesity risk factors in the populations of interest. Databases were last searched on May 8, 2018. Initial analysis took place during 2014 and was completed during 2017. We extracted data on study population, design, and associations between neighborhood characteristics and obesity risk factors. We identified 2011 unique studies; 24 were included. Few studies demonstrated consistent patterns of association. Most neighborhood characteristics were not examined across multiple studies. BMI may be related to living in a lower-income neighborhood or convenience store access. This review found that the body of evidence relating neighborhood exposures and obesity risk factors among urban, low SES Black (also commonly referred to in the literature as "non-Hispanic Black" or African American) and Hispanic children is limited. Given the high risk of obesity and cardiovascular disease among these populations throughout the life course, research on neighborhood determinants of obesity should specifically include these populations, ensuring adequate power and methodological rigor to detect differences.


Sensitivity to violence measured by ratings of severity increases after nonviolence training.
It was hypothesized that training in nonviolence would increase participants' sensitivity to violence because such training emphasizes both the harm and the avoidability of many kinds of violence. This research built upon earlier studies, which had proposed that ratings of the severity of violent behaviors (e.g., murder, bullying, cursing) can be interpreted as measuring sensitivity to violence. Two quasi-experiments examined changes in ratings of severity obtained before and after nonviolence training. In Study 1, 28 college-age traffic offenders who received nonviolence training judged stimulus behaviors ranging from life-threatening physical harm to verbal disrespect as more violent after their training. An untrained comparison group did not show this change. In Study 2, 30 student teachers who received instruction in nonviolence also rated behaviors as more violent after training; an untrained comparison group did not. Results are interpreted as showing increased sensitivity to violence following exposure to nonviolence.


[Pleural effusion: criteria for distinguishing between transudates and exudates].
The first step in the diagnostic study of a pleural effusion is to classify as a transudate or exudate. Light's criteria (pleural fluid/serum proteines > 0.5; lactatedehydrogenase [LDH] > 2/3 of the upper normal limit in serum; pleural fluid/serum LDH > 0.6) usually used, incorrectly classify some cases, especially transudates. For this reason, different alternative criteria has been proposed: pleural fluid cholesterol, pleural fluid/serum cholesterol ratio, pleural fluid/serum bilirubin ratio, and serum/pleura albumin ratio. Althought the first results suggested better results that those obtained with the Light's criteria, after the analysis of the different studys we conclude that a method to diferentiate perfectly transudates and exudates is not yet available.


GLE2, a Saccharomyces cerevisiae homologue of the Schizosaccharomyces pombe export factor RAE1, is required for nuclear pore complex structure and function.
To identify and characterize novel factors required for nuclear transport, a genetic screen was conducted in the yeast Saccharomyces cerevisiae. Mutations that were lethal in combination with a null allele of the gene encoding the nucleoporin Nup100p were isolated using a colony-sectoring assay. Three complementation groups of gle (for GLFG lethal) mutants were identified. In this report, the characterization of GLE2 is detailed. GLE2 encodes a 40.5-kDa polypeptide with striking similarity to that of Schizosaccharomyces pombe RAE1. In indirect immunofluorescence and nuclear pore complex fractionation experiments, Gle2p was associated with nuclear pore complexes. Mutated alleles of GLE2 displayed blockage of polyadenylated RNA export; however, nuclear protein import was not apparently diminished. Immunofluorescence and thin-section electron microscopic analysis revealed that the nuclear pore complex and nuclear envelope structure was grossly perturbed in gle2 mutants. Because the clusters of herniated pore complexes appeared subsequent to the export block, the structural perturbations were likely indirect consequences of the export phenotype. Interestingly, a two-hybrid interaction was detected between Gle2p and Srp1p, the nuclear localization signal receptor, as well as Rip1p, a nuclear export signal-interacting protein. We propose that Gle2p has a novel role in mediating nuclear transport.


Epithelial cell apoptosis facilitates Entamoeba histolytica infection in the gut.
Entamoeba histolytica is the protozoan parasite that causes amebic colitis. The parasite triggers apoptosis on contact with host cells; however, the biological significance of this event during intestinal infection is unclear. We examined the role of apoptosis in a mouse model of intestinal amebiasis. Histopathology revealed that abundant epithelial cell apoptosis occurred in the vicinity of amoeba in histological specimens. Epithelial cell apoptosis occurred rapidly on co-culture with amoeba in vitro as measured by annexin positivity, DNA degradation, and mitochondrial dysfunction. Administration of the pan caspase inhibitor ZVAD decreased the rate and severity of amebic infection in CBA mice by all measures (cecal culture positivity, parasite enzyme-linked immunosorbent assay, and histological scores). Similarly, caspase 3 knockout mice on the resistant C57BL/6 background exhibited even lower cecal parasite antigen burden and culture positive rates than wild type mice. The permissive effect of apoptosis on infection could be tracked to the epithelium, in that transgenic mice that overexpressed Bcl-2 in epithelial cells were more resistant to infection as measured by cecal parasite enzyme-linked immunosorbent assay and histological scores. We concluded that epithelial cell apoptosis in the intestine facilitates amebic infection in this mouse model. The parasite's strategy for inducing apoptosis may point to key virulence factors, and therapeutic maneuvers to diminish epithelial apoptosis may be useful in amebic colitis.


Dehydroevodiamine attenuates beta-amyloid peptide-induced amnesia in mice.
Dehydroevodiamine has been reported to have anticholinesterase activity and an anti-amnesic effect. This study examined the effects of dehydroevodiamine on scopolamine- and beta-amyloid peptide-(25--35)-induced amnesia in mice, using a step-through passive avoidance test. Similarly to the cholinesterase inhibitor, physostigmine (0.03--0.3 mg/kg, i.p.), dehydroevodiamine (0.75--12.0 mg/kg, i.p.) administered 30 min before the training trial, immediately after the training trial, and 30 min before the retention test significantly improved scopolamine- and beta-amyloid peptide-(25--35)-induced amnesia. In beta-amyloid peptide-(25--35)-induced amnesia, the rank order of anti-amnesic potency in these three administration schedules for dehydroevodiamine was different from that for physostigmine. Furthermore, dehydroevodiamine was more potent to improve beta-amyloid peptide-(25--35)-induced amnesia than scopolamine-induced amnesia when administered before the training trial. These results suggested that dehydroevodiamine may have an action other than that of an anticholinesterase and may be a novel and effective ligand for improvement of beta-amyloid type amnesia.


Early pH Changes in Musculoskeletal Tissues upon Injury-Aerobic Catabolic Pathway Activity Linked to Inter-Individual Differences in Local pH.
Local pH is stated to acidify after bone fracture. However, the time course and degree of acidification remain unknown. Whether the acidification pattern within a fracture hematoma is applicable to adjacent muscle hematoma or is exclusive to this regenerative tissue has not been studied to date. Thus, in this study, we aimed to unravel the extent and pattern of acidification in vivo during the early phase post musculoskeletal injury. Local pH changes after fracture and muscle trauma were measured simultaneously in two pre-clinical animal models (sheep/rats) immediately after and up to 48 h post injury. The rat fracture hematoma was further analyzed histologically and metabolomically. In vivo pH measurements in bone and muscle hematoma revealed a local acidification in both animal models, yielding mean pH values in rats of 6.69 and 6.89, with pronounced intra- and inter-individual differences. The metabolomic analysis of the hematomas indicated a link between reduction in tricarboxylic acid cycle activity and pH, thus, metabolic activity within the injured tissues could be causative for the different pH values. The significant acidification within the early musculoskeletal hematoma could enable the employment of the pH for novel, sought-after treatments that allow for spatially and temporally controlled drug release.


Assessing consumer responses to potential reduced-exposure tobacco products: a review of tobacco industry and independent research methods.
Internal tobacco industry documents and the mainstream literature are reviewed to identify methods and measures for evaluating tobacco consumer response. The review aims to outline areas in which established methods exist, identify gaps in current methods for assessing consumer response, and consider how these methods might be applied to evaluate potentially reduced exposure tobacco products and new products. Internal industry research reviewed included published articles, manuscript drafts, presentations, protocols, and instruments relating to consumer response measures were identified and analyzed. Peer-reviewed research was identified using PubMed and Scopus. Industry research on consumer response focuses on product development and marketing. To develop and refine new products, the tobacco industry has developed notable strategies for assessing consumers' sensory and subjective responses to product design characteristics. Independent research is often conducted to gauge the likelihood of future product adoption by measuring consumers' risk perceptions, responses to product, and product acceptability. A model that conceptualizes consumer response as comprising the separate, but interacting, domains of product perceptions and response to product is outlined. Industry and independent research supports the dual domain model and provides a wide range of methods for assessment of the construct components of consumer response. Further research is needed to validate consumer response constructs, determine the relationship between consumer response and tobacco user behavior, and improve reliability of consumer response measures. Scientifically rigorous consumer response assessment methods will provide a needed empirical basis for future regulation of potentially reduced-exposure tobacco products and new products, to counteract tobacco industry influence on consumers, and enhance the public health.


Cultural identity, explanatory style, and depression in Navajo adolescents.
This study investigated the interrelationships among cultural identity, explanatory style, and depression in Navajo adolescents. A total of 332 (197 female, 135 male) Navajo adolescents completed 7 self-report measures. These data were used to create, via structural equation modeling, a series of factor models and full structural models. Analyses indicated that current factor structures for explanatory style and depression are adequate for use with Navajo adolescents. Increased control and predictability and limited duration of stressful encounters were both predictive of decreased symptoms of depression. Higher levels of Navajo cultural identity had a modest effect in terms of reducing depression. Other factors, such as perceived discrimination and urban/reservation domicile, are important to study to provide an increased understanding of depression among Navajo adolescents.


Analysis of allergy alerts within a computerized prescriber-order-entry system.
Allergy alerts within a computerized prescriber-order-entry (CPOE) system were analyzed. A retrospective analysis was performed to evaluate inpatient CPOE orders that triggered an allergy alert for one month in November 2007. Data were extracted from a computer-generated report to identify the total number of prescription orders and the number of orders triggering an allergy alert during the study time frame. When overriding an allergy alert from the CPOE system, prescribers had to choose one of three rationales: the benefit outweighs the risk, the patient previously tolerated the medication, and the medication is therapeutically appropriate. Data collected included the number of allergy alerts, allergy alert overrides, override rationale, and patients' demographic information. Descriptive statistics were used to summarize the results. Allergy alerts were triggered on 643 (1.3%) of the 49,887 total orders entered during the month (95% confidence interval [CI], 1.2-1.4%). Alerts were triggered on a total of 289 patients, with a mean of 2 orders triggering alerts per patient. The median age was 65 years old. The median hospital stay for patients with an order triggering an alert was three days. Overall, 625 of 643 alerts (97%) were overridden for rationales as following: the patient previously tolerated the medication (49%), the benefit outweighed the risk (29%), and the medication was therapeutically appropriate (24%), and a free text explanation (8%). While a small portion of prescription orders generated through a CPOE system triggered an allergy alert, most of the allergy alerts were overridden by prescribers.


Electrical-driven transport of endohedral fullerene encapsulating a single water molecule.
Encapsulating a single water molecule inside an endohedral fullerene provides an opportunity for manipulating the H2O@C60 through the encapsulated polar H2O molecule. Using molecular dynamic simulations, we propose a strategy of electrical-driven transport of H2O@C60 inside a channel, underpinned by the unique behavior of a water molecule free from a hydrogen-bonding environment. When an external electrical field is applied along the channel's axial direction, steady-state transport of H2O@C60 can be reached. The transport direction and rate depend on the applied electrical intensity as well as the polar orientation of the encapsulated H2O molecule.


What are the best methods for rapid reviews of the research evidence? A systematic review of reviews and primary studies.
Rapid review methodology aims to facilitate faster conduct of systematic reviews to meet the needs of the decision-maker, while also maintaining quality and credibility. This systematic review aimed to determine the impact of different methodological shortcuts for undertaking rapid reviews on the risk of bias (RoB) of the results of the review. Review stages for which reviews and primary studies were sought included the preparation of a protocol, question formulation, inclusion criteria, searching, selection, data extraction, RoB assessment, synthesis, and reporting. We searched 11 electronic databases in April 2022, and conducted some supplementary searching. Reviewers worked in pairs to screen, select, extract data, and assess the RoB of included reviews and studies. We included 15 systematic reviews, 7 scoping reviews, and 65 primary studies. We found that several commonly used shortcuts in rapid reviews are likely to increase the RoB in the results. These include restrictions based on publication date, use of a single electronic database as a source of studies, and use of a single reviewer for screening titles and abstracts, selecting studies based on the full-text, and for extracting data. Authors of rapid reviews should be transparent in reporting their use of these shortcuts and acknowledge the possibility of them causing bias in the results. This review also highlights shortcuts that can save time without increasing the risk of bias. Further research is needed for both systematic and rapid reviews on faster methods for accurate data extraction and RoB assessment, and on development of more precise search strategies.


Azithromycin non-susceptible Shigella circulating in Israel, 2014-2016.
Shigella species remains a major diarrhoeagenic agent, affecting mostly children, with global high incidence and high mortality rate specially in developing areas. Although azithromycin is recommended for treatment of shigellosis, there are currently no CLSI susceptibility breakpoints, accordingly no routine antimicrobial susceptibility test is performed in the clinical laboratory. The purpose of this study was to estimate the prevalence, resistance profile and molecular epidemiology of azithromycin non-susceptible Shigella strains in Israel during a three year period. Shigella isolates (n = 1,170) referred to the National Reference Center during 2014-2016, were included in this study. Serotyping was performed by slide agglutination. Resistance genes, mph(A) and erm(B), were identified by PCR and the phenotype profile was determined by broth microdilution (BMD). Genetic relatedness was assessed by wgMLST. Decreased susceptibility to azithromycin (DSA) phenotype and genotype were detected in various Shigella species and serotypes related to diverse genetic backgrounds and antimicrobial profiles: 6% (26/423) of Shigella flexneri and 2% (16/747) of Shigella sonnei displayed DSA (MIC16 mg/L). Correlation of this phenotype with the presence of mph(A) and erm(B) genes was confirmed. All DSA-strains displayed resistance to ≥3 different antimicrobial classes. Among DSA-strains, 14% were resistant to quinolones and 5% displayed resistance to ceftriaxone. Most of these strains (32/42) were isolated from children in the southern and central regions of Israel. Clonality and significant relatedness was confirmed by PFGE and wgMLST. The presence of macrolide resistance genes among the different species and lineages reflects the transmissible nature of these genes. The emergence of DSA-Shigella reinforces the necessity to establish clinical breakpoints that would warrant routine testing, reporting and surveillance for this drug of choice.


A protein-based phylogenetic tree for gram-positive bacteria derived from hrcA, a unique heat-shock regulatory gene.
The dnaK operon from Bacillus subtilis and other Gram-positive bacteria with low G + C DNA content contains additional heat-shock genes, including hrcA. The hrcA gene encodes a transcription factor that negatively regulates heat-shock genes and is uniformly present in all Gram-positive bacteria studied to date. An hrcA homologue is also present in Synechocystis species, Leptospira interrogans, Chlamydia trachomatis, Caulobacter crescentus and Methanococcus jannaschii, organisms that diverged early on from the common ancestor of all Gram-positive bacteria and Proteobacteria, according to 16S rRNA phylogeny. A partial, protein-based phylogenetic tree, derived using amino acid sequence homology of hrcA proteins from Gram-positive bacteria, is presented here, and the results are compared with the phylogenetic trees generated from 16S rRNA, dnaK and dnaJ sequences. The location of the hrcA gene and the genome organization of the dnaK operon support the division of all Gram-positive bacteria into three major groups: one group contains high-G + C Gram-positive bacteria, and two others contain low-G + C Gram-positive bacteria. Among the Gram-positive bacteria with low G + C DNA content, the results indicate that there is a close phylogenetic relationship between Bacillus species and Clostridium species on the one hand and between Lactococcus lactis and Streptococcus mutans on the other. Streptomyces and Mycobacterium species also exhibited a close relationship. A hierarchical arrangement of Gram-positive bacteria based on HrcA sequences is proposed as an additional refinement of the phylogenetic relationships within this important bacterial group.


Bayesian unknown change-point models to investigate immediacy in single case designs.
Although immediacy is one of the necessary criteria to show strong evidence of a causal relation in single case designs (SCDs), no inferential statistical tool is currently used to demonstrate it. We propose a Bayesian unknown change-point model to investigate and quantify immediacy in SCD analysis. Unlike visual analysis that considers only 3-5 observations in consecutive phases to investigate immediacy, this model considers all data points. Immediacy is indicated when the posterior distribution of the unknown change-point is narrow around the true value of the change-point. This model can accommodate delayed effects. Monte Carlo simulation for a 2-phase design shows that the posterior standard deviations of the change-points decrease with increase in standardized mean difference between phases and decrease in test length. This method is illustrated with real data. (PsycINFO Database Record


S-box and T-box riboswitches and antisense RNA control a sulfur metabolic operon of Clostridium acetobutylicum.
The ubiGmccBA operon of Clostridium acetobutylicum is involved in methionine to cysteine conversion. We showed that its expression is controlled by a complex regulatory system combining several RNA-based mechanisms. Two functional convergent promoters associated with transcriptional antitermination systems, a cysteine-specific T-box and an S-box riboswitch, are located upstream of and downstream from the ubiG operon, respectively. Several antisense RNAs were synthesized from the downstream S-box-dependent promoter, resulting in modulation of the level of ubiG transcript and of MccB activity. In contrast, the upstream T-box system did not appear to play a major role in regulation, leaving antisense transcription as the major regulatory mechanism for the ubiG operon. The abundance of sense and antisense transcripts was inversely correlated with the sulfur source availability. Deletion of the downstream promoter region completely abolished the sulfur-dependent control of the ubiG operon, and the expression of antisense transcripts in trans did not restore the regulation of the operon. Our data revealed important insights into the molecular mechanism of cis-antisense-mediated regulation, a control system only rarely observed in prokaryotes. We proposed a regulatory model in which the antisense RNA controlled the expression of the ubiG operon in cis via transcriptional interference at the ubiG locus.


Surgical treatment of unilateral cleft lip and palate - own experience.
the aim of this paper is to present the final modification to a one-step operation of unilateral cleft lip and palate, together with a plaster-model representation of the shape of the palate in the 5th , 10th and 15th year of life of the patients treated at the Institute of Mother and Child. A modified one-step surgical technique for treating cleft lip and palate is presented. The study included 265 children and adolescents from the years 1980-2000. The paper also discusses the so-called critical points relating to the surgical technique which to a large extent makes it possible to avoid complications. In addition, the importance of conducting the treatment by a multidisciplinary team is emphasised. Based on many years of experience and my own research, I believe that the use of the one-step surgery method in children with cleft lip and palate, as well as conducting the treatment in a multidisciplinary team, quickly restores the correct anatomical conditions in the craniofacial area and enables further growth and development similar to normal physiological phenomena. The need for subsequent orthognathic procedures may largely be due to genetic factors.


Evolution of nutrient acquisition: when adaptation fills the gap between contrasting ecological theories.
Although plant strategies for acquiring nutrients have been widely studied from a functional point of view, their evolution is still not well understood. In this study, we investigate the evolutionary dynamics of these strategies and determine how they influence ecosystem properties. To do so, we use a simple nutrient-limited ecosystem model in which plant ability to take up nutrients is subject to adaptive dynamics. We postulate the existence of a trade-off between this ability and mortality. We show that contrasting strategies are possible as evolutionary outcomes, depending on the shape of the trade-off and, when nitrogen is considered as the limiting nutrient, on the intensity of symbiotic fixation. Our model enables us to bridge these evolutionary outcomes to classical ecological theories such as Hardin's tragedy of the commons and Tilman's rule of R*. Evolution does not systematically maximize plant biomass or primary productivity. On the other hand, each evolutionary outcome leads to a decrease in the availability of the limiting mineral nutrient, supporting the work of Tilman on competition between plants for a single resource. Our model shows that evolution can be used to link different classical ecological results and that adaptation may influence ecosystem properties in contrasted ways.


Enabling Self-management of a Chronic Condition through Patient-centered Coaching: A Case of an mHealth Diabetes Prevention Program for Older Adults.
Patient-centered communication (PCC) by healthcare professionals can contribute to enacting and facilitating patients' self-management of chronic health conditions. This study investigates the emerging patterns of PCC that occur in an mHealth-based diabetes prevention program for older adults. The analysis of user-coach communication data during the 16-week period of the program revealed four PCC strategies employed by coaches: (a) triggering reflections on users' routinized habits, (b) jointly determining a measurable health goal, (c) facilitating self-evaluations on recent behavior change, and (d) tailoring programs to adapt to users' lifestyle and health status. To advance these strategies, coaches utilized various mHealth features that helped them (a) engage in data-driven coaching, (b) increase situational awareness of users' health conditions and routines, (c) provide continuous support to users through regular and spontaneous in-app chats, and (d) foster user autonomy and engagement. The findings extend implications for developing technology-enabled healthcare practice to enhance self-management of chronic illness.


Acute interstitial nephritis. A case characterized by increase in serum IgG, IgM, and IgE concentrations. Eosinophilia, and IgE deposition in renal tubules.
A case of acute interstitial nephritis with a distinct immunopathologic pattern was seen. The relevant findings included elevated levels of serum IgG, IgM, and IgE; persistent eosinophilia; prominent granular and electron-dense depositions of IgE and C3 in renal tubules, as demonstrated by direct immunofluorescent and electron microscopic procedures; persistent failure to demonstrate anti-basement membrane antibodies (both glomerular and tubular); and hypocomplementemia. The findings in our case suggest a type of acute interstitial nephritis with a somewhat different clinical outlook. In this respect, serial assays of complement components and IgE in serum and kidney tissue and determinations of circulating anti-basement membrane antibodies (both glomerular and tubular) may be of particular importance.