Anatomic investigation of lumbar transforaminal fenestration approach and its clinical application in far lateral disc herniation.
Treating lumbar disease at the intervertebal foramina is controversial because we lack an approach providing sufficient exposure and preserving spinal stability. The primary objective of this study was to investigate the feasibility of the transforaminal fenestration (TFF) approach for treating lumbar disease involving the intervertebal foramina.In the anatomic study of 30 adult cadaveric lumbar spine specimens, the TFF approach was used from L1 to S1. The scope of resection was measured manually and on 3D CT images. 3D CT images of the lumbar spine of 31 adult patients were collected, and the scope of resection needed during the TFF approach was defined and measured from L1 to S1. In total, 30 patients (14 men) with lumbar FLDH underwent microendoscopic discectomy (MED) via the TFF approach. The results were evaluated with visual analog scale (VAS), Oswestry Disability Index (ODI), Short Form-36 survey (SF-36), and the MacNab scale.In cadavers, the TFF approach provided sufficient exposure to the posterolateral aspect of the disc and the exiting nerve root at all segments. At L1 to L4, a relatively small part of the isthmus and facet joint was resected; at L4 to S1, a relatively large part of the isthmus and facet joint was resected, so luniform fenestration was needed to preserve a more inferior articular process and continuity of the isthmus. Treatment with MED via the TFF approach was successful in the 30 patients with significantly relieved of symptom after operation. In total, 24 patients were followed for a mean of 24 months. The VAS, ODI, SF-36 physical component, and mental component summary scores at the final follow-up improved significantly compared with preoperative data (P < .05), and excellent results were obtained in 19 patients and good results in 6 according to the Macnab scale.The TFF approach can provide sufficient exposure to the lumbar intervertebal foramina with preservation of stability and can be used effectively with MED to treat lumbar FLDH.


Excessive hyaluronan production promotes acquisition of cancer stem cell signatures through the coordinated regulation of Twist and the transforming growth factor β (TGF-β)-Snail signaling axis.
The cancer stem cell (CSC) model suggests that a small subpopulation of cancer cells possesses the ability to self-renew and give rise to malignant progeny that drive cancer progression. Recent reports have also proposed the existence of certain extra- or intracellular signals that allow cancer progenitors to dynamically revert to a stem cell state. However, the mechanisms underlying cancer cell plasticity and CSC expansion are not entirely clear. Our previous studies using a hyaluronan synthase 2 (Has2) transgenic mouse model demonstrated that hyaluronan overproduction caused rapid development of aggressive breast carcinoma at a high incidence. Thus, we hypothesize that hyaluronan overproduction may accelerate cancer progression by expanding CSC subpopulations during cancer development. Primary cancer cells were established from mammary tumors developed in the transgenic mice and subjected to the Hoechst 33342 dye exclusion assay to sort side population (SP) from non-side population (non-SP) cells. Flow cytometric analysis demonstrated the enrichment of CD44(high)/CD24(low) CSC-like cells in the SP fraction of hyaluronan-overproducing cancer cells. This subpopulation exhibited several characteristics that were similar to CSCs, including cancer-initiating and mammosphere-forming abilities. Excess hyaluronan production drove the epithelial-to-mesenchymal transition process defined as the loss of epithelial phenotypes, up-regulation of transforming growth factor β (TGF-β), and induction of the epithelial-to-mesenchymal transition-related transcriptional factors Snail and Twist. Inhibition of TGF-β-Snail signaling or silencing of Twist expression abrogated the entrance into a stem cell state. Taken together, our findings suggest that hyaluronan overproduction allows plastic cancer cell populations to revert to stem cell states via Twist and the TGF-β-Snail signaling axis.


Misoprostol for termination of second trimester pregnancy in a scarred uterus.
To investigate whether Misoprostol for mid-trimester pregnancy interruption in women with a scarred uterus has any adverse effects compared with those without a scar. During 5-year period from 2000-2004 at Queen Alia Military Hospital, Royal Medical Services, Amman, Jordan, a consecutive series of 520 women of 15-28 weeks of gestation who underwent termination of pregnancy were studied. Sixty-three patients had undergone at least previous one cesarean section and 457 served as control. Termination was undertaken using Misoprostol 400 ug vaginally as a starting dose followed by 200 ug vaginally every 6 hours, complications for each group were recorded. The induction to abortion time was not significantly different in both groups (p=0.16); the median dosage was almost the same (p=0.31). The rate of incomplete abortion was significantly higher in the study group than control 82% versus 60% and 11.5% versus 6.1% for bleeding of more than 500 cc, while the rate of other complications was almost the same. In the second trimester termination of pregnancy, the use of Misoprostol in women with previous single or multiple cesarean sections was not associated with excess complications.


TRPV1 receptor in expression of opioid-induced hyperalgesia.
Opiates are currently the mainstay for treatment of moderate to severe pain. However, prolonged administration of opiates has been reported to elicit hyperalgesia in animals, and examples of opiate-induced hyperalgesia have been reported in humans as well. Despite the potential clinical significance of such opiate-induced actions, the mechanisms of opiate-induced hypersensitivity remain unknown. The transient receptor potential vanilloid1 (TRPV1) receptor, a molecular sensor of noxious heat, acts as an integrator of multiple forms of noxious stimuli and plays an important role in the development of inflammation-induced hyperalgesia. Because animals treated with opiates show thermal hyperalgesia, we examined the possible role of TRPV1 receptors in the development of morphine-induced hyperalgesia using TRPV1 wild-type (WT) and knock-out (KO) mice and with administration of a TRPV1 antagonist in mice and rats. Administration of morphine by subcutaneous implantation of morphine pellets elicited both thermal and tactile hypersensitivity in TRPV1 WT mice but not in TRPV1 KO mice. Moreover, oral administration of a TRPV1 antagonist reversed both thermal and tactile hypersensitivity induced by sustained morphine administration in mice and rats. Immunohistochemical analyses indicate that sustained morphine administration modestly increases TRPV1 labeling in the dorsal root ganglia. In addition, sustained morphine increased flinching and plasma extravasation after peripheral stimulation with capsaicin, suggesting an increase in TRPV1 receptor function in the periphery in morphine-treated animals. Collectively, our data indicate that the TRPV1 receptor is an essential peripheral mechanism in expression of morphine-induced hyperalgesia. Opioid-induced hyperalgesia possibly limits the usefulness of opioids, emphasizing the value of alternative methods of pain control. We demonstrate that TRPV1 channels play an important role in peripheral mechanisms of opioid-induced hyperalgesia. Such information may lead to the discovery of analgesics lacking such adaptations and improving treatment of chronic pain.


The PedsQL in pediatric cancer pain: a prospective longitudinal analysis of pain and emotional distress.
The objective of this prospective study was to investigate the cross-sectional and longitudinal associations between pain and emotional distress in children and adolescents with cancer as measured by the Pediatric Quality of Life Inventory (PedsQL) Emotional Functioning and Pain Scales. The PedsQL 1.0 Generic Core Scales are multidimensional scales developed as the generic core measure to be integrated with the PedsQL Disease-Specific Modules. The PedsQL 1.0 Cancer Module was designed to measure pediatric cancer-specific health-related quality of life. The PedsQL Generic Core Scales, Emotional Functioning Scale and Cancer Module Pain Scale, were administered to 69 children and 59 adolescents and their parents at Time 1 and Time 2, which was 6 months on average after Time 1. Prospective hierarchical multiple regression analyses supported a longitudinal predictive model with Time 1 pain predicting Time 2 pain and Time 1 emotional distress predicting Time 2 emotional distress, respectively. Time 1 emotional distress did not predict Time 2 pain, and Time 1 pain did not predict Time 2 emotional distress. The results demonstrate that pediatric cancer pain and emotional distress, although associated cross-sectionally, are differentially predictive in prospective longitudinal analyses. These results suggest that both pain and emotional distress should be targeted for treatment interventions concurrently to enhance long-term health-related quality of life of the pediatric patient with cancer.


Magnesium deficiency in alcoholism.
Significant magnesium deficiency occurs in chronic alcoholism. The evidence depends on a number of related lines of evidence: hypomagnesemia, a number of clinical symptoms in common with patients with nonalcoholic causes of magnesium deficiency, induction of magnesium excretion by alcohol ingestion (167-260% of control values), positive magnesium balance on alcohol withdrawal (average 1.15 meq/kg), decreased exchangeable magnesium (28Mg, mean deficit 1.12 meq/kg), a mean deficit of 11.4 meq/kg of fat-free dry weight of muscle of alcoholic patients, and hypocalcemia responsive only to magnesium therapy. When alcohol is withdrawn, free fatty acids rise sharply and plasma magnesium falls. Respiratory alkalosis occurs abruptly also on alcohol withdrawal. The alkalosis and rise of free fatty acids with concomitant fall of magnesium produces an acute instability of the internal milieu and could result in acute symptoms. There also are a number of nutritional deficiencies which need to be cared for, but magnesium, thiamine, and other B vitamins need to be administered immediately. Potassium and phosphorus should be supplied when they are low.


True abdominal epilepsy is clonic jerking of the abdominal musculature.
Abdominal epilepsy (AE) has long been reported as a rare phenomenon in children with various episodic gastrointestinal sensory and painful symptoms suspected to be due to epileptic seizures. Originally, AE was diagnosed when abdominal sensory or painful symptoms were associated with pain, temporal lobe origin, an epileptiform or paroxysmal EEG pattern, and a clinical response to antiseizure medication. AE has also been associated with non-epileptic etiologies such as migraine. Reports of abdominal epilepsy based on an abnormal EEG or clinical response to antiseizure medication without diagnosis confirmation by video-EEG are at best speculative, and at worst, misdiagnoses. We describe three adult patients with focal aware motor seizures manifesting as recurrent, isolated prolonged painless rhythmic clonic jerking of the abdominal musculature including epilepsia partialis continua. All patients had a contralateral structural lesion on high-resolution brain MRI in the abdominal region of the motor homunculus. Standard EEG was unrevealing and only after extra EEG electrodes and video-EEG monitoring was the ictal origin confirmed. Historically, AE has been described as a disorder involving subjective sensory symptoms including vague abdominal pain, instead of epileptic motor signs of abdominal clonic jerking. We recommend replacing the use of vague terms such as AE with International League Against Epilepsy terminology along with diagnostic confirmation validated by video-EEG monitoring. [Published with video sequence].


Relationship between periodontal disease and lung cancer: A systematic review and meta-analysis.
Periodontal disease (PD), as a chronic bacterial infection, might cause cardiovascular and some other systemic diseases, with recent studies reporting that it exhibits some connection with lung cancer. While studies have shown that poor oral health might increase the risk of lung cancer, the veracity of these reports is questionable. Therefore, this meta-analysis was undertaken to investigate the association between PD and the risk of lung cancer. A search was run in PubMed, EMBASE, MEDLINE, CENTRAL, and ClinicalTrials.gov databases up to January 1, 2020. Cohort and case-control studies investigating the correlation between PD and lung cancer were included. Eligibility assessment and data extraction were conducted independently, and a meta-analysis was performed to synthesize the data. The association between PD, edentulism, and lung cancer was measured by the adjusted hazard ratios (HRs) or odds ratios (ORs) and their 95% confidence intervals (CIs) provided in articles. We employed appropriate effect model in terms of I2 (a fixed-effect model for PD and a random-effect model for edentulism) to obtain summary effect estimates. Statistical heterogeneity was investigated by chi-square test and I2 statistics. Newcastle-Ottawa Scale (NOS) was used to assess the quality of their method. Six cohort studies (eight references) and two case-control studies, assessed as high-quality, involving 167 256 participants, were included in the review. The summary estimates based on adjusted data showed an association between PD and a significant risk of lung cancer both in cohort studies (HR = 1.40, 95% CI = 1.25-1.58; I2 = 8.7%) and case-control studies (OR = 1.51, 95% CI = 1.16-1.98; I2 = 36.5%). Similar features were found in the sensitivity analysis and subgroups for six cohort studies, of male only (HR = 1.36, 95% CI = 1.15-2.60), setting the lung cancer incidence as endpoint (HR = 1.39, 95% CI = 1.24-1.57; I2 = 23.9%), and adjusting alcohol for multifactorial HR (HR = 1.38, 95% CI = 1.21-1.57; I2 = 39.9%). The summary HR for edentulism was 1.93 (95% CI = 1.05-3.57; I2 = 55.3%). No obvious publication bias was detected. This systematic review and meta-analysis demonstrated a significant association between PD and the incidence of lung cancer. Further observational studies are required by using standardized measurements to assess the periodontal status and by eliminating confounding factors, such as alcohol and diabetes, to verify such a relationship.


Extraction of rules from artificial neural networks for nonlinear regression.
Neural networks (NNs) have been successfully applied to solve a variety of application problems including classification and function approximation. They are especially useful as function approximators because they do not require prior knowledge of the input data distribution and they have been shown to be universal approximators. In many applications, it is desirable to extract knowledge that can explain how Me problems are solved by the networks. Most existing approaches have focused on extracting symbolic rules for classification. Few methods have been devised to extract rules from trained NNs for regression. This article presents an approach for extracting rules from trained NNs for regression. Each rule in the extracted rule set corresponds to a subregion of the input space and a linear function involving the relevant input attributes of the data approximates the network output for all data samples in this subregion. Extensive experimental results on 32 benchmark data sets demonstrate the effectiveness of the proposed approach in generating accurate regression rules.


A Minigenome Study of Hazara Nairovirus Genomic Promoters.
Hazara nairovirus (HAZV) is a trisegmented RNA virus most closely related to Crimean-Congo hemorrhagic fever virus (CCHFV) in the order Bunyavirales The terminal roughly 20 nucleotides (nt) of its genome ends are highly complementary, similar to those of other segmented negative-strand RNA viruses (sNSV), and act as promoters for RNA synthesis. These promoters contain two elements: the extreme termini of both strands (promoter element 1 [PE1]) are conserved and virus specific and are found bound to separate sites on the polymerase surface in crystal structures of promoter-polymerase complexes. The following sequences (PE2) are segment specific, with the potential to form double-stranded RNA (dsRNA), and the latter aspect is also important for promoter activity. Nairovirus genome promoters differ from those of peribunyaviruses and arenaviruses in that they contain a short single-stranded region between the two regions of complementarity. Using a HAZV minigenome system, we found the single-stranded nature of this region, as well as the potential of the following sequence to form dsRNA, is essential for reporter gene expression. Most unexpectedly, the sequence of the PE2 dsRNA appears to be equally important for promoter activity. These differences in sNSV PE2 promoter elements are discussed in light of our current understanding of the initiation of RNA synthesis.IMPORTANCE A minigenome system for HAZV, closely related to CCHFV, was used to study its genome replication. HAZV genome ends, like those of other sNSV, such as peribunyaviruses and arenaviruses, are highly complementary and serve as promoters for genome synthesis. These promoters are composed of two elements: the extreme termini of both 3' and 5' strands that are initially bound to separate sites on the polymerase surface in a sequence-specific fashion and the following sequences with the potential to anneal but whose sequence is not important. Nairovirus promoters differ from the other sNSV cited in that they contain a short single-stranded RNA (ssRNA) region between the two elements. The single-stranded nature of this region is an essential element of the promoter, whereas its sequence is unimportant. The sequence of the following complementary region is unexpectedly also important, a possible rare example of sequence-specific dsRNA recognition.


Single screw fixation in stable and unstable slipped upper femoral epiphysis.
The aim of this single centre retrospective study was to assess the outcome of patients after the fixation of slipped upper femoral epiphysis (SUFE) using a single cannulated screw. Thirty-eight slips, 28 stable and 10 unstable were treated with single in-situ screw fixation. The minimum follow-up was 1 year. The overall adverse outcome in terms of avascular necrosis (AVN), chondrolysis and revision surgery for slip progression was 18%, which was considered satisfactory. Slip progression of more than 10° was higher in the unstable when compared with the stable group but not statistically significant. Two out of the nine satisfactorily fixed unstable slips required revision surgery as opposed to none in the stable group. The incidence of AVN in the unstable group was 20%. There were no cases of AVN in the stable group. The adverse outcome in terms of AVN, chondrolysis and revision surgery for slip progression was significantly higher in the unstable group. In our study, results of single screw fixation for SUFE were found to be satisfactory as shown by earlier studies with the unstable SUFEs as expected having a poorer outcome when compared with the stable SUFEs.


The use of cannabinoids as anticancer agents.
It is well-established that cannabinoids exert palliative effects on some cancer-associated symptoms. In addition evidences obtained during the last fifteen years support that these compounds can reduce tumor growth in animal models of cancer. Cannabinoids have been shown to activate an ER-stress related pathway that leads to the stimulation of autophagy-mediated cancer cell death. In addition, cannabinoids inhibit tumor angiogenesis and decrease cancer cell migration. The mechanisms of resistance to cannabinoid anticancer action as well as the possible strategies to develop cannabinoid-based combinational therapies to fight cancer have also started to be explored. In this review we will summarize these observations (that have already helped to set the bases for the development of the first clinical studies to investigate the potential clinical benefit of using cannabinoids in anticancer therapies) and will discuss the possible future avenues of research in this area.


Maternal depressive symptoms linked to reduced fecal Immunoglobulin A concentrations in infants.
Secretory Immunoglobulin A (sIgA) plays a critical role to infant gut mucosal immunity. Delayed IgA production is associated with greater risk of allergic disease. Murine models of stressful events during pregnancy and infancy show alterations in gut immunity and microbial composition in offspring, but little is known about the stress-microbiome-immunity pathways in humans. We investigated differences in infant fecal sIgA concentrations according to the presence of maternal depressive symptoms during and after pregnancy. A subsample of 403 term infants from the Canadian Healthy Infant Longitudinal Development (CHILD) cohort were studied. Their mothers completed the Center of Epidemiologic Studies Depression Scale when enrolled prenatally and again postpartum. Quantified by Immundiagnostik sIgA ELISA kit, sIgA from infant stool was compared across maternal depressive symptom categories using Mann-Whitney U-tests and logistic regression models that controlled for various covariates. Twelve percent of women reported clinically significant depressive symptoms only prenatally, 8.7% had only postpartum symptoms and 9.2% had symptoms both pre and postnatally. Infants born to mothers with pre and postnatal symptoms had significantly lower median sIgA concentrations than those in the reference group (4.4 mg/g feces vs. 6.3 mg/g feces; p = 0.033). The odds for sIgA concentrations in the lowest quartile was threefold higher (95% CI: 1.25-7.55) when mothers had pre and postnatal symptoms, after controlling for breastfeeding status, infant age, antibiotics exposure and other covariates. Postnatal symptoms were not associated with fecal sIgA, independently of breastfeeding status. Infants born to mothers with depressive symptoms appear to have lower fecal sIgA concentrations, predisposing them to higher risk for allergic disease.


Prognostic Gene Expression Signature in Patients With Distinct Glioma Grades.
Glioma is the most common type of primary brain tumor in adults. Patients with the most malignant form have an overall survival time of <16 months. Although considerable progress has been made in defining the adapted therapeutic strategies, measures to counteract tumor escape have not kept pace, due to the developed resistance of malignant glioma. In fact, identifying the nature and role of distinct tumor-infiltrating immune cells in glioma patients would decipher potential mechanisms behind therapy failure. We integrated into our study glioma transcriptomic datasets from the Cancer Genome Atlas (TCGA) cohort (154 GBM and 516 LGG patients). LM22 immune signature was built using CIBERSORT. Hierarchical clustering and UMAP dimensional reduction algorithms were applied to identify clusters among glioma patients either in an unsupervised or supervised way. Furthermore, differential gene expression (DGE) has been performed to unravel the top expressed genes among the identified clusters. Besides, we used the least absolute shrinkage and selection operator (LASSO) and Cox regression algorithm to set up the most valuable prognostic factor. Our study revealed, following gene enrichment analysis, the presence of two distinct groups of patients. The first group, defined as cluster 1, was characterized by the presence of immune cells known to exert efficient antitumoral immune response and was associated with better patient survival, whereas the second group, cluster 2, which exhibited a poor survival, was enriched with cells and molecules, known to set an immunosuppressive pro-tumoral microenvironment. Interestingly, we revealed that gene expression signatures were also consistent with each immune cluster function. A strong presence of activated NK cells was revealed in cluster 1. In contrast, potent immunosuppressive components such as regulatory T cells, neutrophils, and M0/M1/M2 macrophages were detected in cluster 2, where, in addition, inhibitory immune checkpoints, such as PD-1, CTLA-4, and TIM-3, were also significantly upregulated. Finally, Cox regression analysis further corroborated that tumor-infiltrating cells from cluster 2 exerted a significant impact on patient prognosis. Our work brings to light the tight implication of immune components on glioma patient prognosis. This would contribute to potentially developing better immune-based therapeutic approaches.


National action plan of the Islamic Republic of Iran for combating antimicrobial resistance during 2016 - 2021.
Background: Antimicrobial resistance (AMR) is one of the most important threats to health worldwide. Therefore, the World Health Organization (WHO) have invited countries around the world to work together to inhibit AMR, and all the member states are expected to prepare a national plan for tackling AMR by 2017. This project was aimed to prepare the National Action Plan of the Islamic Republic of Iran for combating antimicrobial resistance (NAP-IRIAMR) during 2016 to 2021. Methods: In this article, the literature and available documents were reviewed to identify key stakeholders. Moreover, interviews, brain storming sessions, and meetings with key stakeholders were held to determine NAP-IRIAMR objectives, strategies, policies, and indicators for monitoring and evaluation. To reach consensus and make a conclusion, participants' views and comments were analyzed using Delphi method and expert panel. Results: In this national action plan for combating AMR, 13 key stakeholders were identified and 5 objectives were set: (1) raising public awareness and increasing trainings on AMR, (2) continuous monitoring of AMR, (3) preventing the spread of microorganisms resistant to antimicrobials, (4) promoting the rational use of antimicrobials, (5) promoting research and development in the field of AMR. Conclusion: The NAP-IRIAMR was prepared for the years 2016- 2021. Intersectoral cooperation is needed to combat AMR. It is expected that implementing the NAP-IRIAMR and reaching the determined goals will help overcome the problems related to AMR.


Exploitation of unique properties of zeolites in the development of gas sensors.
The unique properties of microporous zeolites, including ion-exchange properties, adsorption, molecular sieving, catalysis, conductivity have been exploited in improving the performance of gas sensors. Zeolites have been employed as physical and chemical filters to improve the sensitivity and selectivity of gas sensors. In addition, direct interaction of gas molecules with the extraframework cations in the nanoconfined space of zeolites has been explored as a basis for developing new impedance-type gas/vapor sensors. In this review, we summarize how these properties of zeolites have been used to develop new sensing paradigms. There is a considerable breadth of transduction processes that have been used for zeolite incorporated sensors, including frequency measurements, optical and the entire gamut of electrochemical measurements. It is clear from the published literature that zeolites provide a route to enhance sensor performance, and it is expected that commercial manifestation of some of the approaches discussed here will take place. The future of zeolite-based sensors will continue to exploit its unique properties and use of other microporous frameworks, including metal organic frameworks. Zeolite composites with electronic materials, including metals will lead to new paradigms in sensing. Use of nano-sized zeolite crystals and zeolite membranes will enhance sensor properties and make possible new routes of miniaturized sensors.


Expression and characterization of SUMO-conjugated metal-responsive transcription factor 1: SIM-dependent cross-interaction and distinct DNA binding activity.
Metal-responsive transcription factor 1 (MTF-1) regulates a variety of genes involving in metal homeostasis and oxidative stress. We have shown that MTF-1 can be conjugated by small ubiquitin-like modifier (SUMO) and forms complexes with cellular factor(s) in a SUMO-interacting motif (SIM)-dependent manner. To investigate whether the interaction of MTF-1 and its SUMO conjugate occurs, we expressed and isolated MTF-1 and sumoylated MTF-1 (S-MTF-1) for functional studies. Various conditions were examined to optimize the expressions of MTF-1 and S-MTF-1. Results from affinity column chromatography demonstrated that the unmodified MTF-1 consistently co-eluted with the S-MTF-1. Mutations at the SIM did not reduce the level of MTF-1 sumoylation but the sumoylated product can then be purified to homogeneity. The presence of MTF-1 cross-interaction was further supported by in vitro pull-down assays. The ability of the purified proteins in binding metal-responsive element (MRE) was assessed with electrophoretic mobility shift assay. Noticeably, MTF-1 required the presence of cell extracts to render the binding activity. However, S-MTF-1 binds MRE in void of other cellular factors. The same characteristic was found for MTF-1 with SUMO fusion at the carboxyl terminus. These results indicate that the presence of SUMO moiety allows the protein to interact directly with MRE.


Cycling of auxin-binding protein through the plant cell: pathways in auxin signal transduction.
The auxin receptor literature contains a glaring discrepancy that invites explanation. While some physiological experiments suggest that active auxin receptors are sited inside the cell, others point to action at the cell surface. Furthermore, although the major auxin-binding protein (ABP) of maize (Zea mays) coleoptiles is found in the lumen of the endoplasmic reticulum (ER), exogenous ABP can mediate auxin-dependent changes in the plasma membrane potential of protoplasts. How can an ER protein mediate changes in cell potential? To resolve this dilemma, I propose that ABP cycles through the cell. In response to auxin, ABP is released from the ER and follows a secretory pathway to the cell surface. After secretion, ABP would bind sites on the cell surface and become subject to endocytosis, cycling back to the ER. Elevated auxin would accelerate the cycling of ABP between the ER and the cell surface. If cell wall precursors interacted with ABP during their progression through the secretory pathway, this would provide a mechanism for regulating cell wall synthesis. At the cell surface ABP would regulate an enzyme responsible for maintaining membrane potential. Both of these responses are components of auxin-regulated growth. This hypothesis does not exclude other mechanisms of signal transduction, particularly in gene regulation.


Outcomes and complications of Titanium elastic nailing for forearm bones fracture in children: our experience in a district general hospital in the United Kingdom.
Intramedullary Titanium elastic nailing (TENS) is successfully used for irreducible and displaced forearm bone fractures in children. The purpose of this study was to report the potential complications and functional outcomes associated with paediatric forearm fractures treated with TENS nails. We retrospectively reviewed 65 children with displaced forearm bone fractures treated by TENS nailing with a mean follow-up of 5.84 months (4-12). Data detailing patient demographics, fracture characteristics, associated fractures, injury surgery interval, grade of the operating surgeon, methods of fixation, time to union, the timing of removal of the nail, and complications were collected and analysed. The mean age in our study was 9.13 years. 92% had fractures of both radius and ulna, 83.3% had fixation of both bones, and 16.7% had single bone fixation only. Open reduction was required in 38.5% of cases. The average time to fracture union was 10.34 weeks (6-20). The average time of implant removal was 20.12 weeks (9-32). We observed an overall complication rate of 41.5%. We noted a higher (56% vs 32.5%, p=0.059) complication rate in open reduction cases. According to the Price criteria, we had excellent to good results in over 98% of patients despite a slightly higher complication rate. Titanium elastic nailing is a safe, reliable method of internal fixation for irreducible or unstable fractures of both bones of the forearm in children. Open reduction of fracture was associated with higher complications. Despite higher overall complications, we noted excellent functional results in most cases.


Optical Biopsy of the Upper GI Tract Using Fluorescence Lifetime and Spectra.
Screening and surveillance for gastrointestinal (GI) cancers by endoscope guided biopsy is invasive, time consuming, and has the potential for sampling error. Tissue endogenous fluorescence spectra contain biochemical and physiological information, which may enable real-time, objective diagnosis. We first briefly reviewed optical biopsy modalities for GI cancer diagnosis with a focus on fluorescence-based techniques. In an ex vivo pilot clinical study, we measured fluorescence spectra and lifetime on fresh biopsy specimens obtained during routine upper GI screening procedures. Our results demonstrated the feasibility of rapid acquisition of time-resolved fluorescence (TRF) spectra from fresh GI mucosal specimens. We also identified spectroscopic signatures that can differentiate between normal mucosal samples obtained from the esophagus, stomach, and duodenum.


Ligand-independent activation of the androgen receptor by insulin-like growth factor-I and the role of the MAPK pathway in skeletal muscle cells.
In this study, the roles of the p38 MAPK, ERK1/2 and JNK signaling pathway in IGF-I-induced AR induction and activation were examined. C2C12 cells were treated with IGF-I in the absence or presence of various inhibitors of p38 MAPK (SB203580), ERK1/2 (PD98059), and JNK (SP600125). Inhibition of the MAPK pathway with SB203580, PD98059, or SP600125 significantly decreased IGF-I-induced AR phosphorylation and total AR protein expression. IGF-I-induced nuclear fraction of total AR and phosphorylated AR were significantly inhibited by SB203580, PD98059, or SP600125. Furthermore, IGF-I-induced AR mRNA and skeletal alpha-actin mRNA were blocked by those inhibitors in dose-dependent manner. Confocal images showed that IGF-I-induced AR nuclear translocation from cytosol was significantly blocked by SB203580, PD98059, or SP600125, suggesting that the MAPK pathway regulates IGF-I-induced AR nuclear localization in skeletal muscle cells. The present results suggest that the MAPK pathways are required for the ligand-independent activation of AR by IGF-I in C2C12 skeletal muscle cells.


Multicenter validation of the liver graft assessment following transplantation (L-GrAFT) score for assessment of early allograft dysfunction.
Early allograft dysfunction (EAD) following liver transplantation (LT) negatively impacts graft and patient outcomes. Previously we reported that the liver graft assessment following transplantation (L-GrAFT7) risk score was superior to binary EAD or the model for early allograft function (MEAF) score for estimating 3-month graft failure-free survival in a single-center derivation cohort. Herein, we sought to externally validate L-GrAFT7, and compare its prognostic performance to EAD and MEAF. Accuracies of L-GrAFT7, EAD, and MEAF were compared in a 3-center US validation cohort (n = 3,201), and a Consortium for Organ Preservation in Europe (COPE) normothermic machine perfusion (NMP) trial cohort (n = 222); characteristics were compared to assess generalizability. Compared to the derivation cohort, patients in the validation and NMP trial cohort had lower recipient median MELD scores; were less likely to require pretransplant hospitalization, renal replacement therapy or mechanical ventilation; and had superior 1-year overall (90% and 95% vs. 84%) and graft failure-free (88% and 93% vs. 81%) survival, with a lower incidence of 3-month graft failure (7.4% and 4.0% vs. 11.1%; p <0.001 for all comparisons). Despite significant differences in cohort characteristics, L-GrAFT7 maintained an excellent validation AUROC of 0.78, significantly superior to binary EAD (AUROC 0.68, p = 0.001) and MEAF scores (AUROC 0.72, p <0.001). In post hoc analysis of the COPE NMP trial, the highest tertile of L-GrAFT7 was significantly associated with time to liver allograft (hazard ratio [HR] 2.17, p = 0.016), Clavien ≥IIIB (HR 2.60, p = 0.034) and ≥IVa (HR 4.99, p = 0.011) complications; post-LT length of hospitalization (p = 0.002); and renal replacement therapy (odds ratio 3.62, p = 0.016). We have validated the L-GrAFT7 risk score as a generalizable, highly accurate, individualized risk assessment of 3-month liver allograft failure that is superior to existing scores. L-GrAFT7 may standardize grading of early hepatic allograft function and serve as a clinical endpoint in translational studies (www.lgraft.com). Early allograft dysfunction negatively affects outcomes following liver transplantation. In independent multicenter US and European cohorts totaling 3,423 patients undergoing liver transplantation, the liver graft assessment following transplantation (L-GrAFT) risk score is validated as a superior measure of early allograft function that accurately discriminates 3-month graft failure-free survival and post-liver transplantation complications.


Intramuscular Stimulation of Muscle Afferents Attains Prolonged Tremor Reduction in Essential Tremor Patients.
This study proposes and clinically tests intramuscular electrical stimulation below motor threshold to achieve prolonged reduction of wrist flexion/extension tremor in Essential Tremor (ET) patients. The developed system consisted of an intramuscular thin-film electrode structure that included both stimulation and electromyography (EMG) recording electrodes, and a control algorithm for the timing of intramuscular stimulation based on EMG (closed-loop stimulation). Data were recorded from nine ET patients with wrist flexion/extension tremor recruited from the Gregorio Marañón Hospital (Madrid, Spain). Patients participated in two experimental sessions comprising: 1) sensory stimulation of wrist flexors/extensors via thin-film multichannel intramuscular electrodes; and 2) surface stimulation of the nerves innervating the same target muscles. For each session, four of these patients underwent random 60-s trials of two stimulation strategies for each target muscle: 1) selective and adaptive timely stimulation (SATS) - based on EMG of the antagonist muscle; and 2) continuous stimulation (CON) of target muscles. Two patients underwent SATS stimulation trials alone while the other three underwent CON stimulation trials alone in each session. Kinematics of wrist, elbow, and shoulder, together with clinical scales, were used to assess tremor before, right after, and 24 h after each session. Intramuscular SATS achieved, on average, 32% acute (during stimulation) tremor reduction on each trial, while continuous stimulation augmented tremorgenic activity. Furthermore, tremor reduction was significantly higher using intramuscular than surface stimulation. Prolonged reduction of tremor amplitude (24 h after the experiment) was observed in four patients. These results showed acute and prolonged (24 h) tremor reduction using a minimally invasive neurostimulation technology based on SATS of primary sensory afferents of wrist muscles. This strategy might open the possibility of an alternative therapeutic approach for ET patients.


The Effects of General Practitioners' Use of Argumentation to Support Their Treatment Advice: Results of an Experimental Study Using Video-Vignettes.
In recent years, general practice consultation has often been characterized as an argumentative activity. It has been argued that, guided by the ethical and legal principle of informed consent and the ideal standards of participatory and evidence-based medicine, doctors should provide argumentative support for their recommendations in order to encourage patients to actively take part in the treatment decision-making discussion. Thus far, however, it has remained unclear what causal effect general practitioners' provision of argumentation may have on consultation outcomes, such as patients' perceptions of their doctors' decision-making style and credibility, their acceptance and recall of the medical advice, and subsequently their intention to adhere to the advice. In this study, therefore, the effect of general practitioners' argumentative support for their treatment recommendations is studied experimentally using scripted video-vignettes. Moreover, rather than focusing merely on the presence of argumentation, the role of the pragma-dialectical reasonableness of general practitioners' argumentation is also taken into account.


Protection of renal tubular cells by antioxidants: current knowledge and new trends.
Acute renal damage mainly develops following toxic or ischemic insults and is defined as acute. These damages have largely been attributed to oxidative stress. Recently much attention has been directed toward decreased renal tubular cell regeneration during tubular cell injury. Antioxidants have recently been the focus of researchers and scientists for prevention and treatment of various oxidative stress-related conditions, including renal toxicities. Although free radicals are known to contribute in kidney injury and abundant researches, particularly laboratory trials, have shown the beneficial effects of antioxidants against these complications, long term clinical trials do not uniformly confirm this matter, especially for single antioxidant consumption such as vitamin C. The aim of this paper is to discuss the possible explanation of this matter.


Elevated luteinizing hormone receptor signaling or selenium treatment leads to comparable changes in adrenal cortex histology and androgen-AR/ZIP9 signaling.
The importance and regulation of adrenal androgen production and signaling are not completely understood and are scarcely studied. In addition, there is still a search for appropriate animal models and experimental systems for the investigation of adrenal physiology and disease. Therefore, the main objective of the study was to evaluate the effect of luteinizing hormone (LH) signaling and selenium (Se2+) exposure on androgen adrenal signaling via canonical androgen receptor (AR), and membrane androgen receptor acting as zinc transporter (zinc- and iron-like protein 9; ZIP9). For herein evaluations, adrenals isolated from transgenic mice with elevated LH receptor signaling (KiLHRD582G) and adrenals obtained from rabbits used for ex vivo adenal cortex culture and exposure to Se2+ were utilized. Tissues were assessed for morphological, morphometric, and Western blot analyses and testosterone and zinc level measurements.Comparison of adrenal cortex histology and morphometric analysis in KiLHRD582G mice and Se2+-treated rabbits revealed cell hypertrophy. No changes in the expression of proliferating cell nuclear antigen (PCNA) were found. In addition, AR expression was decreased (p < 0.001) in both KiLHRD582G mouse and Se2+-treated rabbit adrenal cortex while expression of ZIP9 showed diverse changes. Its expression was increased (P < 0.001) in KiLHRD582G mice and decreased (P < 0.001) in Se2+-treated rabbits but only at the dose 10 ug/100 mg/ tissue. Moreover, increased testosterone levels (P < 0.05) and zinc levels were detected in the adrenal cortex of KiLHRD582G mice whereas in rabbit adrenal cortex treated with Se2+, the effect was the opposite (P < 0.001).


Behavioral weight-loss treatment plus motivational interviewing versus attention control: lessons learned from a randomized controlled trial.
Studies evaluating the benefit of adding motivational interviewing (MI) to behavioral weight-loss programs (BWLPs) have yielded mixed findings. The aims of this randomized controlled trial were to: (1) assess the efficacy of adding MI to a BWLP on weight loss and adherence among 135 individuals with overweight and obesity (77.8% female; mean BMI = 33.6 kg/m2) enrolled in a 12-week BWLP and (2) explore levels of importance, confidence, and readiness for change ratings. Participants, who were randomized to receive two MI sessions or two attention control sessions, were assessed at baseline, the end of the BWLP, and 6 months post BWLP. Both groups decreased their weight from baseline to the end of the BWLP; however, there was no weight change in either group when measured between baseline and 6 months post BWLP. We observed no group differences in importance, confidence, and readiness for change after each session. We highlight some important lessons learned from the present trial that can be applied to MI + BWLP research. Participants may not have benefited from MI because they were already highly motivated to change, which highlights the importance of pretreatment assessment. Findings also suggest that treatment monitoring may help to enhance MI + BWLP efficacy by guiding a stepped-care approach that identifies individuals for whom additional MI sessions are needed, and when. A focus on refining elements of treatment remains an important direction. ClinicalTrials.gov, Identifier: NCT02649634 . Retrospectively registered on 5 January 2016.


Ontology development for a pharmacogenetics knowledge base.
Research directed toward discovering how genetic factors influence a patient's response to drugs requires coordination of data produced from laboratory experiments, computational methods, and clinical studies. A public repository of pharmacogenetic data should accelerate progress in the field of pharmacogenetics by organizing and disseminating public datasets. We are developing a pharmacogenetics knowledge base (PharmGKB) to support the storage and retrieval of both experimental data and conceptual knowledge. PharmGKB is an Internet-based resource that integrates complex biological, pharmacological, and clinical data in such a way that researchers can submit their data and users can retrieve information to investigate genotype-phenotype correlations. Successful management of the names, meaning, and organization of concepts used within the system is crucial. We have selected a frame-based knowledge-representation system for development of an ontology of concepts and relationships that represent the domain and that permit storage of experimental data. Preliminary experience shows that the ontology we have developed for gene-sequence data allows us to accept, store, and query data submissions.


Heterologous complementation of a pyrF deletion in Caldicellulosiruptor hydrothermalis generates a new host for the analysis of biomass deconstruction.
Members of the thermophilic, anaerobic Gram-positive bacterial genus Caldicellulosiruptor grow optimally at 65 to 78°C and degrade lignocellulosic biomass without conventional pretreatment. Decomposition of complex cell wall polysaccharides is a major bottleneck in the conversion of plant biomass to biofuels and chemicals, and conventional biomass pretreatment includes exposure to high temperatures, acids, or bases as well as enzymatic digestion. Members of this genus contain a variety of glycosyl hydrolases, pectinases, and xylanases, but the contribution of these individual enzymes to biomass deconstruction is largely unknown. C. hydrothermalis is of special interest because it is the least cellulolytic of all the Caldicellulosiruptor species so far characterized, making it an ideal naïve system to study key cellulolytic enzymes from these bacteria. To develop methods for genetic manipulation of C. hydrothermalis, we selected a spontaneous deletion of pyrF, a gene in the pyrimidine biosynthetic pathway, resulting in a strain that was a uracil auxotroph resistant to 5-fluoroorotic acid (5-FOA). This strain allowed the selection of prototrophic transformants with either replicating or non-replicating plasmids containing the wild-type pyrF gene. Counter-selection of the pyrF wild-type allele on non-replicating vectors allowed the construction of chromosomal deletions. To eliminate integration of the non-replicating plasmid at the pyrF locus in the C. hydrothermalis chromosome, we used the non-homologous Clostridium thermocellum wild-type pyrF allele to complement the C. hydrothermalis pyrF deletion. The autonomously replicating shuttle vector was maintained at 25 to 115 copies per chromosome. Deletion of the ChyI restriction enzyme in C. hydrothermalis increased the transformation efficiency by an order of magnitude and demonstrated the ability to construct deletions and insertions in the genome of this new host. The use of C. hydrothermalis as a host for homologous and heterologous expression of enzymes important for biomass deconstruction will enable the identification of enzymes that contribute to the special ability of these bacteria to degrade complex lignocellulosic substrates as well as facilitate the construction of strains to improve and extend their substrate utilization capabilities.


Comparison of bacteria isolated from emergency department patients versus hospitalized patients.
The frequencies and corresponding susceptibilities of bacteria isolated from patients in the emergency department (ED) were compared with those from hospitalized patients. A microbiology laboratory report of all positive bacterial cultures obtained in the ED, regardless of the source (e.g., blood, urine, sputum), was obtained. In the case of duplicate cultures, only the first isolate cultured from a single patient was included. Colonization-site cultures (e.g., nasal swabs) and culture reports identified by the laboratory as contaminant organisms were excluded from the evaluation. Antimicrobial susceptibility results were then compiled into a standardized ED-specific antibiogram. Antimicrobial susceptibilities for each pathogen in the ED antibiogram were compared with those in the hospitalwide antibiogram. If there was a difference of ≥5% between the susceptibility of a single antimicrobial agent, chi-square tests were conducted, and unadjusted odds ratios were calculated. Pathogens with fewer than 30 isolates were excluded from the susceptibility comparison. A total of 3140 cultures were evaluated (1417 from the ED, 1723 from the hospital). The frequencies of pathogens isolated in the ED and hospitalwide were similar, with the exception of Escherichia coli, which were more commonly isolated in ED patients, and Enterococcus species and Pseudomonas aeruginosa, which were more common in hospitalized patients. Significant differences in susceptibility profiles were identified for Staphylococcus aureus, coagulase-negative Staphylococcus, Enterococcus faecalis, E. coli, Klebsiella pneumoniae, and P. aeruginosa. Significant differences in the frequencies of bacteria isolated and corresponding susceptibilities were found in cultures obtained in ED patients compared with those obtained in hospitalized patients.


[Methodological problems of the impact of G-loads on the functional status and occupation health of the pilot].
The paper deals with the methodological aspects and conceptual models of the impact of g-loads on the functional status and occupational health of high-maneuvering plane pilots in the context of the effective dose conception. Quantitative approaches to evaluating the influence of this factor are considered by taking into account a risk for specific abnormalities and its combination with other factors and conditions of a pilot's work. Practical aspects of the application of the approaches developed to enhance the safety of flights and the promotion of flying personnel's health are also considered and promising avenues of further studies are outlined.


Individual versus group cognitive-behavioral treatment for obsessive-compulsive disorder: a controlled pilot study.
This study sought to examine the effectiveness of group and individual cognitive-behavioral treatment (CBT) and to compare the results with those of a wait-list control group among a sample of patients with obsessive-compulsive disorder (OCD). Fifty-seven individuals diagnosed with OCD were evaluated pre- and posttreatment with the Yale-Brown Obsessive Compulsive Scale and the Hamilton Rating Scales for Anxiety and Depression. Both group and individual CBT obtained statistically significant reductions in anxiety and depressive symptoms. Patients in individual treatment achieved a statistically significant reduction in OCD symptoms compared with those in group treatment, but their dropout rate was twice as high. Patients with symmetry and order rituals presented less improvement in anxiety symptoms than those with other rituals. Associated general symptoms were lower in patients receiving either mode of CBT compared with wait-list participants. The authors found that individual treatment is more effective in reducing obsessive-compulsive symptoms than group treatment.


Pdx1 expression in Irs2-deficient mouse beta-cells is regulated in a strain-dependent manner.
We previously demonstrated that Irs2-/- mice develop diabetes due to beta-cell growth failure and insulin resistance; however, glucose-induced insulin secretion was increased in islets isolated from Irs2-/- mice. Pdx-1, a transcription factor important for maintenance of the beta-cell function, was recently reported to be severely reduced in Irs2-/- murine beta-cells. We report herein that Pdx-1 expression, including the amount of Pdx-1 localized in the nucleus, is not down-regulated in our Irs2-/- murine beta-cells with a C57BL/6 background. We have also demonstrated the expression of upstream genes of Pdx-1, such as HNF3beta and HNF1alpha, as well as its downstream genes, including insulin, Glut2, and Nkx6.1, to be well preserved. We have further demonstrated Pdx-1 expression to also be preserved in beta-cells of 30-week-old diabetic Irs2-/- mice. In addition, surprisingly, even in Irs2-/- mice on a high fat diet with markedly elevated blood glucose, exceeding 400 mg/dl, Pdx-1 expression was not reduced. Furthermore, we found Pdx-1 to be markedly decreased in certain severely diabetic Irs2-/- mice with a mixed C57BL/6J x 129Sv background. We conclude that 1) Pdx-1 expression in Irs2-/- mice is regulated in a strain-dependent manner, 2) Irs2-/- mice develop diabetes associated with beta-cell growth failure even when Pdx1 expression is preserved, and 3) Pdx-1 expression is preserved in severely hyperglycemic Irs2-/- mice with a C57BL/6 background on a high fat diet.


Gastrointestinal motility following thoracic surgery: the effect of thoracic epidural analgesia. A randomised controlled trial.
Impairment of gastrointestinal (GI) motility is an undesirable but inevitable consequence of surgery. This prospective randomised controlled study tested the hypothesis that postoperative thoracic epidural analgesia (TEA) with ropivacaine or a combination of ropivacaine and morphine accelerates postoperative GI function and shortens the duration of postoperative ileus following major thoracic surgery compared to intravenous (IV) morphine. Thirty patients scheduled for major thoracic surgery were randomised to three groups. All patients had bowel motility assessments 1 week preoperatively. All patients received general anaesthesia. Group Ep-R received TEA with ropivacaine; group Ep-RM received TEA with ropivacaine and morphine and group IV-M received IV morphine via patient controlled analgesia pump (PCA). Bowel motility was assessed by clinical examination in addition to oro-ceacal transit time (OCTT) on the first and third postoperative days and colonic transit time (CTT). Overall the OCTT demonstrated a 2.5-fold decrease in bowel motility on the first postoperative day. The OCTT test revealed statistically significant differences between all groups (Ep-R vs Ep-RM, p = 0.43/Ep-R vs IV-M, p = 0.039 / Ep-RM vs IV-M, p < 0.001). Also, very significant differences were found in the OCCT test between days (Ep-R vs Ep-RM, p < 0.001/Ep-R vs IV-M, p < 0.001 / Ep-RM vs IV-M, p = 0.014). There were no significant differences in the CTT test or the clinical signs between groups. However, 70% of the patients in the Ep-R group and 80% in the Ep-RM group defecated by the third day compared to only 10% in the IV-M group, (p = 0.004). Objective tests demonstrated the delayed motility of the whole GI system postoperatively following thoracic surgery. They also demonstrated that continuous epidural analgesia with or without morphine improved GI motility in comparison to intravenous morphine. These differences were more pronounced on the third postoperative day. ISRCTN number: 11953159 , retrospectively registered on 20/03/2017.


Clinical significance of total nucleated cell count in bone marrow of patients with acute lymphoblastic leukemia who underwent allogeneic hematopoietic stem cell transplantation.
The clinical implications of recipient bone marrow nucleated cell count (NCC) prior to allogeneic hematopoietic stem cell transplantation (allo-HSCT) remain unknown. We conducted a multicenter retrospective study to evaluate the clinical significance of bone marrow NCC prior to allo-HSCT in patients with acute lymphoblastic leukemia. Patients who were in remission and underwent the initial allo-HSCT were included and stratified into high- and low-NCC groups using an NCC of 10 × 104/µL as the cut-off. The 3-year overall survival (OS), non-relapse mortality (NRM), and relapse rates for the high- and low-NCC groups were 51.2 vs. 84.5% (p < 0.001), 27.5 vs. 6.5% (p < 0.001), and 31.1 vs. 24.4% (p = 0.322), respectively. The high-NCC group had significantly poorer OS and higher NRM when compared with the low-NCC group. In summary, high recipient bone marrow NCC is associated with higher NRM and lower OS following allo-HSCT.


Diagnostic accuracy of mammography, clinical examination, US, and MR imaging in preoperative assessment of breast cancer.
To prospectively assess accuracy of mammography, clinical examination, ultrasonography (US), and magnetic resonance (MR) imaging in preoperative assessment of local extent of breast cancer. Institutional review board approval and informed patient consent were obtained. Results of bilateral mammography, US, and contrast-enhanced MR imaging were analyzed from 111 consecutive women with known or suspected invasive breast cancer. Results were correlated with histopathologic findings. Analysis included 177 malignant foci in 121 cancerous breasts, of which 89 (50%) foci were palpable. Median size of 139 invasive foci was 18 mm (range, 2-107 mm). Mammographic sensitivity decreased from 100% in fatty breasts to 45% in extremely dense breasts. Mammographic sensitivity was highest for invasive ductal carcinoma (IDC) in 89 of 110 (81%) cases versus 10 of 29 (34%) cases of invasive lobular carcinoma (ILC) (P < .001) and 21 of 38 (55%) cases of ductal carcinoma in situ (DCIS) (P < .01). US showed higher sensitivity than did mammography for IDC, depicting 104 of 110 (94%) cases, and for ILC, depicting 25 of 29 (86%) cases (P < .01 for each). US showed higher sensitivity for invasive cancer than DCIS (18 of 38 [47%], P < .001). MR showed higher sensitivity than did mammography for all tumor types (P < .01) and higher sensitivity than did US for DCIS (P < .001), depicting 105 of 110 (95%) cases of IDC, 28 of 29 (96%) cases of ILC, and 34 of 38 (89%) cases of DCIS. In anticipation of conservation or no surgery after mammography and clinical examination in 96 breasts, additional tumor (which altered surgical approach) was present in 30. Additional tumor was depicted in 17 of 96 (18%) breasts at US and in 29 of 96 (30%) at MR, though extent was now overestimated in 12 of 96 (12%) at US and 20 of 96 (21%) at MR imaging. After combined mammography, clinical examination, and US, MR depicted additional tumor in another 12 of 96 (12%) breasts and led to overestimation of extent in another six (6%); US showed no detection benefit after MR imaging. Bilateral cancer was present in 10 of 111 (9%) patients; contralateral tumor was depicted mammographically in six and with both US and MR in an additional three. One contralateral cancer was demonstrated only clinically. In nonfatty breasts, US and MR imaging were more sensitive than mammography for invasive cancer, but both MR imaging and US involved risk of overestimation of tumor extent. Combined mammography, clinical examination, and MR imaging were more sensitive than any other individual test or combination of tests.


Surface morphology of Al0.3Ga0.7N/Al2O3-high electron mobility transistor structure.
We present surface properties of buffer films (AIN and GaN) and Al0.3Gao.zN/Al2O3-High Electron Mobility Transistor (HEMT) structures with/without AIN interlayer grown on High Temperature (HT)-AIN buffer/Al2O3 substrate and Al2O3 substrate. We have found that the GaN surface morphology is step-flow in character and the density of dislocations was about 10(8)-10(9) cm(-2). The AFM measurements also exhibited that the presence of atomic steps with large lateral step dimension and the surface of samples was smooth. The lateral step sizes are in the range of 100-250 nm. The typical rms values of HEMT structures were found as 0.27, 0.30, and 0.70 nm. HT-AIN buffer layer can have a significant impact on the surface morphology of Al0.3Ga0.7N/Al2O3-HEMT structures.


[Immunochemical similarity of GTP-binding proteins of various systems].
It was found that antibodies specifically raised against GTP-binding proteins of bovine retina photoreceptor membranes block the inhibiting effect of estradiol on phosphodiesterase from human and rat uterus cytosol and prevent the combined effect of catecholamines and guanylyl-5'-imidodiphosphate on rat skeletal muscle adenylate cyclase. Using double radial immunodiffusion, it was demonstrated that the antibodies form a precipitating complex with purified tubulin from bovine brain as well as with retinal preparations obtained from the visual organs of ox, pig, rat, frog, some fish species and one reptile species. No appearance of a precipitation band was observed, when retinal preparations of invertebrates (squid, octopus) were used as antigens. The antibodies interacted with the alpha- and beta-subunits of GTP-binding proteins of bovine retinal photoreceptor membranes.


Rapid commitment to negative selection of a thymocyte line independent of CD4 co-engagement.
Biochemical and genetic investigations of thymocyte negative selection will be facilitated by the availability of cultured cell lines representing immature thymocytes, but to date thymocyte lines have demonstrated resistance to Ag receptor-mediated death. It is shown here that a CD4+CD8+ TCR alpha beta+ cell line with a TCR of known Ag and class II MHC specificity (cytochrome c with I-Ek) undergoes Ag dose-dependent apoptotic death in a manner consistent with negative selection of normal thymocytes. In contrast to superantigen-induced selection, apoptosis in this model is unaffected by blocking co-engagement of CD4 and the TCR. At high Ag doses, a significant fraction of thymocytes becomes committed to apoptosis within 2 h of contact with antigen-pulsed APCs, while increased interaction times increase the probability of death. Longer contact periods are required at lower Ag doses. These kinetics of commitment to apoptosis suggest that, in normal negative selection, a thymocyte clone may be deleted after any of several encounters with MHC-bearing cells during progress through the thymus. They also suggest why negative selection predominates when a specific peptide is competent both to delete and to select positively.


Validation of radial artery-based uncalibrated pulse contour method (PulsioFlex) in critically ill patients: A observational study.
Because of their simplicity, uncalibrated pulse contour (UPC) methods have been introduced into clinical practice in critical care but are often validated with a femoral arterial waveform. We aimed to test the accuracy of cardiac index (CI) measurements and trending ability from a radial artery with one UPC. An observational study. Tertiary care mixed-surgical ICU. Data were obtained from April 2015 to July 2016. We studied 20 critically ill mechanically ventilated patients monitored by UPC (PulsioFlex; Pulsion Medical Systems SE, Feldkirchen, Germany). We used transpulmonary thermodilution (PiCCO2) as a reference. Bland-Altman-analyses with percentage errors were calculated to assess the accuracy of CI values from radial pulse contour analysis (CIRAD), autocalibration (CIAC) and femoral pulse contour analysis (CIFEM). All were compared with a reference (CITD) at 4-h intervals for 24 h. Trending ability was assessed by polar-plots and four-quadrant-plots. CI is given in l min m. Bland-Altman-analyses: for CIRAD, the mean bias was -0.1 with limits of agreement (LOA) of -2.9 to 2.7 and a percentage error of 70%; for CIAC, the mean bias was 0 with LOA -2.8 to 2.7 and a percentage error of 70%; for CIFEM, the mean bias was 0 with LOA -1.2 to 1.2 and a percentage error of 30%, respectively. Polar plots for trending: for CIRAD, the angular bias was 12° with radial LOA of 39°, a polar concordance rate of 73% and a concordance rate of 67% in the four-quadrant-plot; for CIAC, the angular bias was 4° with radial LOA of 41°, polar concordance rate of 79% and a concordance rate of 74% in the four quadrant plot; for CIFEM, the angular bias was -2° with radial LOA of 50°, polar concordance rate of 74% and a concordance rate of 81%. In critically ill patients, the PulsioFlex system connected to a radial arterial catheter is inaccurate for CI measurements and does not track changes in CI adequately. We therefore recommend using validated thermodilution techniques for monitoring in the critical care setting.


Progenitor cell transplantation for chronic myelogenous leukemia.
Chronic myelogenous leukemia (CML), a myeloproliferative disorder characterized by the clonal proliferation of a hematopoietic stem cell, is a malignancy for which allogeneic bone marrow transplantation (BMT), when available, constitutes a mainstay of treatment. Several clinical considerations, especially the patient's age, influence the availability and likely outcome of BMT for patients with CML. Recent advances in nontransplant treatments for CML, notably interferon-alpha, have made the decision about the implementation and timing of BMT in CML more complex. Areas of active investigation include transplantation from a matched unrelated donor (MUD) and autologous BMT.


Npro of classical swine fever virus enhances HMGB1 acetylation and its degradation by lysosomes to evade from HMGB1-mediated antiviral immunity.
Classical swine fever virus (CSFV) can dampen the host innate immunity by destabilizing IRF3 upon its binding with viral Npro. High mobility group box 1 (HMGB1), a non-histone nuclear protein, has diverse functions, including inflammation, innate immunity, etc., which are closely related to its cellular localization. We investigated potential mutual interactions between CSFV and HMGB1 and their effects on virus replication. We found that HMGB1 at the protein level, but not at mRNA level, was markedly reduced in CSFV-infected or Npro-expressing IPEC-J2 cells. HMGB1 in the nuclear compartment is anti-CSFV by promoting IFN-mediated innate immune response, as evidenced by overexpression of nuclear or cytoplasmic dominant HMGB1 mutant in IPEC-J2 cells stimulated with poly(I:C). However, CSFV Npro upregulates HMGB1 acetylation, a modification that promotes HMGB1 translocation into the cytoplasmic compartment where it is degraded by lysosomes. Ethyl pyruvate could downregulate HMGB1 acetylation and prevent Npro-mediated HMGB1 reduction. Inhibition of deacetylase HDAC1 with MS275 or by RNA silencing could promote Npro-mediated HMGB1 degradation. Taken together, our study elucidates the mechanism with which HMGB1 in the nuclei initiates antiviral innate immune response to suppress CSFV replication and elaborates the pathway by which CSFV uses its Npro to evade from HMGB1-mediated antiviral immunity through upregulating HMGB1 acetylation with subsequent translocation into cytoplasm for lysosomal degradation.


Total Extraction as a Treatment for Anaemia in a Patient of Glanzmann's Thrombasthenia with Chronic Gingival Bleed: Case Report.
Glanzmann's Thrombasthenia (GT) is a rare autosomal recessive bleeding disorder affecting the megakaryocyte lineage and is characterized by lack of platelet aggregation on stimulation. The molecular basis is linked to quantitative and qualitative abnormalities of αIIbβ3 integrin. Most of the patients with severe Glanzmann's thrombasthenia have spontaneous gum bleeding and persistent low haemoglobin levels. Often these patients are addressed with local haemostatic measures and platelet coverage. We report a case of a severe Glanzmann's thrombasthenia with chronic gingivitis and associated spontaneous gum bleed with chronic low haemoglobin levels, managed subsequently with total dental extraction under appropriate platelet and recombinant factor VIIa coverage. Further follow up of the patient substantiated the treatment protocol with increased and stable haemoglobin levels, thus emphasizing the need for total dental extraction in patients with severe Glanzmann's with chronic spontaneous gum bleed, as a definitive treatment option, which has not been reported so far in the literature.


Bisphenol-A exposure and risk of breast and prostate cancer in the Spanish European Prospective Investigation into Cancer and Nutrition study.
Bisphenol A (BPA) is an endocrine disruptor that it is present in numerous products of daily use. The aim of this study was to assess the potential association of serum BPA concentrations and the risk of incident breast and prostate cancer in a sub-cohort of the Spanish European Prospective Investigation into Cancer and Nutrition (EPIC). We designed a case-cohort study within the EPIC-Spain cohort. Study population consisted on 4812 participants from 4 EPIC-Spain centers (547 breast cancer cases, 575 prostate cancer cases and 3690 sub-cohort participants). BPA exposure was assessed by means of chemical analyses of serum samples collected at recruitment. Borgan II weighted Cox regression was used to estimate hazard ratios. Median follow-up time in our study was 16.9 years. BPA geometric mean serum values of cases and sub-cohort were 1.12 ng/ml vs 1.10 ng/ml respectively for breast cancer and 1.33 ng/ml vs 1.29 ng/ml respectively for prostate cancer. When categorizing BPA into tertiles, a 40% increase in risk of prostate cancer for tertile 1 (p = 0.022), 37% increase for tertile 2 (p = 0.034) and 31% increase for tertile 3 (p = 0.072) was observed with respect to values bellow the limit of detection. No significant association was observed between BPA levels and breast cancer risk. We found a similar percentage of detection of BPA among cases and sub-cohort from our population, and no association with breast cancer risk was observed. However, we found a higher risk of prostate cancer for the increase in serum BPA levels. Further investigation is needed to understand the influence of BPA in prostate cancer risk.


Vitamin D receptor phosphorylation in transfected ROS 17/2.8 cells is localized to the N-terminal region of the hormone-binding domain.
The human 1,25-dihydroxyvitamin D3 receptor (hVDR) has been recently shown to be phosphorylated in vitro by casein kinase-II. Most of the residues phosphorylated by this enzyme were shown to reside between Asn160 and Asp232, a region near the N-terminal boundary of the hormone-binding domain. We report here that the hVDR is also phosphorylated in vivo after transfection into ROS 17/2.8 cells. In addition to testing full-length hVDR, we analyzed several internally deleted hVDR mutants. The expression and phosphorylation of full-length and mutated hVDRs were monitored in transfected cells by metabolic labeling with either [35S]methionine or [32P]orthophosphate, followed by immunopurification using monoclonal anti-VDR antibody linked to agarose beads. Transfected hVDR is distinguishable from the endogenous rat VDR when the immunoprecipitated proteins are resolved on sodium dodecyl sulfate-polyacrylamide gels. Significant phosphorylation of transfected full-length hVDR was observed in ROS 17/2.8 cells, and it was less dependent on the presence of 1,25-dihydroxyvitamin D3 than that of the endogenous rat receptor. Most importantly, the region of in vivo phosphorylation, as defined by internal deletion mutants, resides between Met197 and Val234. Therefore, we have localized the major site of phosphorylation of hVDR to residues in the N-terminal region of the hormone-binding domain. The boundaries of this region fall within the amino acid segment defined for phosphorylation of hVDR by casein kinase-II in vitro, suggesting that VDR is an in vivo substrate for casein kinase-II or a related protein kinase.


A novel approach to production of Chlorella protothecoides oil-loaded nanoparticles via electrospraying method: Modeling of critical parameters for particle sizing.
Bioactive compounds in algae have chain rings that protect the tissue from chemical damage and disease symptoms. In addition, algal bioactive agents have the ability to stimulate the immune system, protective and therapeutic effects against many diseases, including various types of cancers, coronary heart disease, premature aging, and arthritis. These bioactive compounds also have antioxidant, anticoagulant, antiviral, and anti-inflammatory properties. It is very important to encapsulate these algal compounds for preserving bioactive properties. Two of the most efficient methods used for encapsulation are electrospraying and microemulsion techniques. Although electrospraying is a novel technique to produce nanoparticles in recent years, microemulsion is more conventional method compared with electrospraying. In this study, Chlorella protothecoides oil was encapsulated by using sodium alginate and chitosan biopolymers, and the effects of production parameters of electrospraying and microemulsion methods on the particle size and loading efficiency were investigated. Statistical modeling of critical parameters for particle sizing in microemulsion method and electrospraying technique, which is a novel approach to obtain microalgal oil-loaded nanoparticles, was also presented. It was seen that electrospraying is suitable for obtaining smaller nanoparticles (123.9-610 nm), homogeneous distribution, and higher oil loading efficiency (60%-77%) compared with microemulsion method (756.9-1128.2 nm and 57%-73%).


A microRNA signature for a BMP2-induced osteoblast lineage commitment program.
Bone morphogenetic proteins (BMPs) are potent morphogens that activate transcriptional programs for lineage determination. How BMP induction of a phenotype is coordinated with microRNAs (miRNAs) that inhibit biological pathways to control cell differentiation, remains unknown. Here, we show by profiling miRNAs during BMP2 induced osteogenesis of C2C12 mesenchymal cells, that 22 of 25 miRNAs which significantly changed in response to BMP2 are down-regulated. These miRNAs are each predicted to target components of multiple osteogenic pathways. We characterize two representative miRNAs and show that miR-133 directly targets Runx2, an early BMP response gene essential for bone formation, and miR-135 targets Smad5, a key transducer of the BMP2 osteogenic signal, controlled through their 3'UTR sequences. Both miRNAs functionally inhibit differentiation of osteoprogenitors by attenuating Runx2 and Smad5 pathways that synergistically contribute to bone formation. Although miR-133 is known to promote MEF-2-dependent myogenesis, we have identified a second complementary function to inhibit Runx2-mediated osteogenesis. Our key finding is that BMP2 controls bone cell determination by inducing miRNAs that target muscle genes but mainly by down-regulating multiple miRNAs that constitute an osteogenic program, thereby releasing from inhibition pathway components required for cell lineage commitment. Thus, our studies establish a mechanism for BMP morphogens to selectively induce a tissue-specific phenotype and suppress alternative lineages.


Post-menopausal osteoporosis. Has it been medicalized?
Millions of women will be prescribed hormone replacement therapy (HRT) and be told that it will prevent osteoporosis occurring, despite the fact that there is doubt about its long term usefulness. Preventive measures outlined in this article are much more preferable, but need to be directed towards the whole population, not just menopausal women. The prevention of osteoporosis is an important public health issue which needs to be addressed now, not in the next century. This article explores the issues that surround the medicalisation of post-menopausal osteoporosis.


Cerebellar foliation in rats. 1. Cortical changes preceding the formation of a fissure.
The cerebellar cortices of foetal rats were examined for structural changes occurring prior to the formation of fissures. Female rats were mated overnight and the first day on which a sperm-positive vaginal smear was found was designated as embryonic day 1 (E1). Birth of rats generally occurs on day E23. Foetuses from days E19 to 22 were fixed by perfusion followed by immersion, using a mixture of glutaraldehyde and paraformaldehyde, and their cerebella embedded in plastic. The cerebella of thirty-five foetuses were sectioned sagittally at intervals of 100 micron, and those of five were sectioned coronally. A continuous Purkinje cell layer was formed during the examination period by fusion of four transverse bands. The study revealed formation of pre-migratory granule cells in the EGL of foetal rats. The granule cells were orientated in the coronal plane and were seen only where Purkinje cells were present beneath the EGL. A local increase in pre-migratory granule cells and indentation of the Purkinje cell layer were early signs of foliation and occurred prior to the formation of a fissure. The subsequent deepening of the fissures was due to the outward expansion of lobules, and the bottom of the different fissures retained their spatial relationship. The findings show that the expansion of the cerebellar surface is tangential before and after the formation of a fisure. In order to indent the surface, the direction of the expansion must change temporarily. This reorientation of the expansion appears to be related to the cortical changes which have been described and marks the onset of foliation.


Therapeutic vaccination for HPV induced cervical cancers.
Cervical Cancer is the second leading cause of cancer-related deaths in women worldwide and is associated with Human Papillomavirus (HPV) infection, creating a unique opportunity to treat cervical cancer through anti-viral vaccination. Although a prophylactic vaccine may be available within a year, millions of women, already infected, will continue to suffer from HPV-related disease, emphasizing the need to develop therapeutic vaccination strategies. A majority of clinical trials examining therapeutic vaccination have shown limited efficacy due to examining patients with more advanced-stage cancer who tend to have decreased immune function. Current trends in clinical trials with therapeutic agents examine patients with pre-invasive lesions in order to prevent invasive cervical cancer. However, longer follow-up is necessary to correlate immune responses to lesion regression. Meanwhile, preclinical studies in this field include further exploration of peptide or protein vaccination, and the delivery of HPV antigens in DNA-based vaccines or in viral vectors. As long as pre-clinical studies continue to advance, the prospect of therapeutic vaccination to treat existing lesions seem good in the near future. Positive consequences of therapeutic vaccination would include less disfiguring treatment options and fewer instances of recurrent or progressive lesions leading to a reduction in cervical cancer incidence.


VLDP web server: a powerful geometric tool for analysing protein structures in their environment.
Protein structures are an ensemble of atoms determined experimentally mostly by X-ray crystallography or Nuclear Magnetic Resonance. Studying 3D protein structures is a key point for better understanding protein function at a molecular level. We propose a set of accurate tools, for analysing protein structures, based on the reliable method of Voronoi-Laguerre tessellations. The Voronoi Laguerre Delaunay Protein web server (VLDPws) computes the Laguerre tessellation on a whole given system first embedded in solvent. Through this fine description, VLDPws gives the following data: (i) Amino acid volumes evaluated with high precision, as confirmed by good correlations with experimental data. (ii) A novel definition of inter-residue contacts within the given protein. (iii) A measure of the residue exposure to solvent that significantly improves the standard notion of accessibility in some cases. At present, no equivalent web server is available. VLDPws provides output in two complementary forms: direct visualization of the Laguerre tessellation, mostly its polygonal molecular surfaces; files of volumes; and areas, contacts and similar data for each residue and each atom. These files are available for download for further analysis. VLDPws can be accessed at http://www.dsimb.inserm.fr/dsimb_tools/vldp.


'There is no choice apart from antibiotics…': Qualitative analysis of views on urinary infections in pregnancy and antimicrobial resistance.
Antimicrobial resistance (AMR) is a health risk as it can lead to life-threatening infections. There has been a rise in resistant urinary tract infections (UTIs) which is the most common infection in pregnancy. This can be challenging in pregnancy due to the additional need to safeguard foetal development. The study's aim was to explore views about AMR in women who experienced UTIs in pregnancy. Fifteen semi-structured interviews were conducted in the UK and analysed using thematic analysis. Results highlighted two themes: conceptualization of AMR and pregnancy as a deviation from the norm, with an overarching theme of 'self-efficacy'. Results show that participants were concerned about AMR but uncertain about the effect on society compared to individual's taking antibiotics and about completing antibiotic courses. Participants reported an unsparing use of antibiotics was justified in pregnancy, and behaviours like drinking adequate water were ineffective at preventing UTIs. In summary, women had low self-efficacy regards tackling AMR and managing their health. Misconceptions about how AMR affects society vs the individual translated into viewing it as a future problem to be tackled by the health-care sector. Consequently, AMR requires reconceptualization as a current problem requiring collective action. This research also indicates women endorse a biomedical model of UTIs in pregnancy which attributes resolving illness to interventions such as medicines, implying an automatic reliance on antibiotics. Subsequently, there is a need for self-efficacy by focusing on a behavioural model which emphasizes behaviours for infection prevention, thus reducing the need for antibiotics.


An evidence-based review of ixazomib citrate and its potential in the treatment of newly diagnosed multiple myeloma.
Proteasome inhibition represents one of the more important therapeutic targets in the treatment of multiple myeloma (MM), since by suppressing nuclear factor-κB activity, which promotes myelomagenesis, it makes plasma cells susceptible to proapoptotic signals. Bortezomib, the first proteasome inhibitor approved for MM therapy, has been shown to increase response rate and improve outcome in patients with relapsed/refractory disease and in the frontline setting, particularly when combined with immunomodulatory drugs and alkylating agents. Among second-generation proteasome inhibitors, ixazomib (MLN9708) is the first oral compound to be evaluated for the treatment of MM. Ixazomib has shown improved pharmacokinetic and pharmacodynamic parameters compared with bortezomib, in addition to similar efficacy in the control of myeloma growth and prevention of bone loss. Ixazomib was found to overcome bortezomib resistance and to trigger synergistic antimyeloma activity with dexamethasone, lenalidomide, and histone deacetylase inhibitors. Phase I/II studies using ixazomib weekly or twice weekly in relapsed/refractory MM patients suggested antitumor activity of the single agent, but more promising results have been obtained with the combination of ixazomib, lenalidomide, and dexamethasone in newly diagnosed MM. Ixazomib has also been used in systemic amyloidosis as a single agent, showing important activity in this difficult-to-treat plasma-cell dyscrasia. More frequent side effects observed during administration of ixazomib were thrombocytopenia, nausea, vomiting, diarrhea, fatigue, and rash, whereas severe peripheral neuropathy was rare. Here, we review the chemical characteristics of ixazomib, as well as its mechanism of action and results from preclinical and clinical trials.


Health-beneficial effects of probiotics: Its mode of action.
It is now widely recognized that probiotics have health-beneficial effects on humans and animals. Probiotics should survive in the intestinal tract to exert beneficial effects on the host's health. To keep a sufficient level of probiotic bacteria in the gastrointestinal tract, a shorter interval between doses may be required. Although adherence to the intestinal epithelial cell and mucus is not a universal property of probiotics, high ability to adhere to the intestinal surface might strongly interfere with infection of pathogenic bacteria and regulate the immune system. The administration of probiotic Lactobacillus stimulated indigenous Lactobacilli and the production of short-chain fatty acids. This alteration of the intestinal environment should contribute to maintain the host's health. The immunomodulatory effects of probiotics are related to important parts of their beneficial effects. Probiotics may modulate the intestinal immune response through the stimulation of certain cytokine and IgA secretion in intestinal mucosa. The health-beneficial effects, in particular the immunomodulation effect, of probiotics depend on the strain used. Differences in indigenous intestinal microflora significantly alter the magnitude of the effects of a probiotic. Specific probiotic strains suitable for each animal species and their life stage as well as each individual should be found.


Scorpions from Mexico: From Species Diversity to Venom Complexity.
Scorpions are among the oldest terrestrial arthropods, which are distributed worldwide, except for Antarctica and some Pacific islands. Scorpion envenomation represents a public health problem in several parts of the world. Mexico harbors the highest diversity of scorpions in the world, including some of the world's medically important scorpion species. The systematics and diversity of Mexican scorpion fauna has not been revised in the past decade; and due to recent and exhaustive collection efforts as part of different ongoing major revisionary systematic projects, our understanding of this diversity has changed compared with previous assessments. Given the presence of several medically important scorpion species, the study of their venom in the country is also important. In the present contribution, the diversity of scorpion species in Mexico is revised and updated based on several new systematic contributions; 281 different species are recorded. Commentaries on recent venomic, ecological and behavioral studies of Mexican scorpions are also provided. A list containing the most important peptides identified from 16 different species is included. A graphical representation of the different types of components found in these venoms is also revised. A map with hotspots showing the current knowledge on scorpion distribution and areas explored in Mexico is also provided.


[Therapy of multiple myeloma. Results of sequential treatment with melphalan-prednisolone and the M2 protocol].
Melphalan and prednisolone were intermittently used for treatment of 101 patients with multiple myeloma. In case of progression, either initially or after remission or after a phase of stabilisation, treatment was changed to the M-2 protocol. By primary treatment, remission was obtained in 24 patients, a stable phase in 47 patients. The treatment of second choice which became necessary in a total of 46 patients led to remission in 5 patients (11%), 21 (46%) became stabilised and in 20 (43%) the disease progressed. The median survival time for all 101 patients was 40.5 months after commencement of treatment. In patients with remission it was clearly longer (67 months) than in those with stable disease (38.1 months) or in those with progression (16.8 months). The mean time of survival after commencement of treatment of second choice was 12.5 months. Compared to other studies the remission rates are slight, the time of survival, however, is very remarkable. The overall survival rates are equivalent to the results thus far obtained by more aggressive treatment schemes.


Language impairment and early social competence in preschoolers with autism spectrum disorders: a comparison of DSM-5 profiles.
Children with autism spectrum disorder (ASD) and structural language impairment (LI) may be at risk of more adverse social-developmental outcomes. We examined trajectories of early social competence (using the Vineland-II) in 330 children aged 2-4 years recently diagnosed with ASD, and compared 3 subgroups classified by: language impairment (ASD/LI); intellectual disability (ASD/ID) and ASD without LI or ID (ASD/alone). Children with ASD/LI were significantly more socially impaired at baseline than the ASD/alone subgroup, and less impaired than those with ASD/ID. Growth in social competence was significantly slower for the ASD/ID group. Many preschool-aged children with ASD/LI at time of diagnosis resembled "late talkers" who appeared to catch up linguistically. Children with ASD/ID were more severely impaired and continued to lag further behind.


Leptin concentrations are related to glycaemic control, but do not change with short-term oral antidiabetic therapy in female patients with type 2 diabetes mellitus.
This study evaluated the relation of leptin with glycaemic control and the effect of 14 days of diet, or diet combined with gliclazide, glipizide-GITS or metformin treatment, on leptin concentration in 51 female patients with type 2 diabetes mellitus. Leptin levels were similar both at baseline and after treatment in diabetic and control groups. Diabetic patients with basal fasting plasma glucose (FPG) < 10 mmol/l or with basal postprandial plasma glucose (PPPG) < 13.9 mmol/l had significantly higher leptin levels than diabetic patients with basal FPG > or = 10 mmol/l or with basal PPPG > or = 13.9 mmol/l (19.6+/-8.7 vs. 13.65+/-5.4 microg/l, p < 0.05; and 20.2+/-7.9 vs. 12.9+/-5.2 microg/l, p < 0.05, respectively). Mode of treatment did not influence leptin levels. Delta leptin showed a weak correlation with basal FPG (r = 0.346; p < 0.05), basal and post-treatment PPPG (r = 0.335, p < 0.05 and r = 0.325, p < 0.05, respectively) and a moderate correlation with post-treatment FPG (r = 0.391, p < 0.01). In conclusion, leptin level is not affected by the presence of type 2 diabetes mellitus and by short-term treatment with diet or oral antidiabetic drugs but is directly related to glycaemic control in female patients with type 2 diabetes mellitus.


[The contribution of presynaptic dopaminergic receptors to the mechanism of the reactivating influences of blockade of the GABA-benzodiazepine-ionophor complex].
The changes in reactivating efficiency of the GABA-benzodiazepine-ionophore complex blockade were examined in mice after preliminary activation or inhibition of dopamine autoreceptors by (+)3PPP (2 mg/kg) and haloperidol (0.01 mg/kg). The passive avoidance learning task and amnesia produced by detention of a mouse in the dangerous compartment were used. The pretest injections of bicuculline (1 mg/kg), picrotoxin (1 mg/kg), and flumazenil (10 mg/kg) recovered the passive avoidance response in mice injected with saline before training. Pretreatment with the dopamine autoreceptor agonist and antagonist prevented from the recovery of amnestic memory trace induced by blockade of GABA-benzodiazepine-ionophore complex components. The results imply the involvement of dopamine/GABA-dependent mechanism in the modulation of memory trace retrieval.


Learning to tie the knot: The acquisition of functional object representations by physical and observational experience.
Here we examined neural substrates for physically and observationally learning to construct novel objects, and characterized brain regions associated with each kind of learning using fMRI. Each participant was assigned a training partner, and for five consecutive days practiced tying one group of knots ("tied" condition) or watched their partner tie different knots ("watched" condition) while a third set of knots remained untrained. Functional MRI was obtained prior to and immediately following the week of training while participants performed a visual knot-matching task. After training, a portion of left superior parietal lobule demonstrated a training by scan session interaction. This means this parietal region responded selectively to knots that participants had physically learned to tie in the post-training scan session but not the pre-training scan session. A conjunction analysis on the post-training scan data showed right intraparietal sulcus and right dorsal premotor cortex to respond when viewing images of knots from the tied and watched conditions compared to knots that were untrained during the post-training scan session. This suggests that these brain areas track both physical and observational learning. Together, the data provide preliminary evidence of engagement of brain regions associated with hand-object interactions when viewing objects associated with physical experience, and with observational experience without concurrent physical practice.


Sex differences in excess and reservoir arterial blood pressures as markers of phenotype.
Excess pressure and reservoir pressure are related to various clinical outcomes in cardiovascular diseases, but whether there are sex differences in healthy individuals remains uncertain. We compared phenotypes of excess pressure and reservoir pressure between healthy men and women. Different features of noninvasively recorded radial and reconstructed aortic pressure waveforms were measured in 435 healthy adults (257 women, 59%). In addition to SBP and DBP, we compared values of maximal excess pressure and reservoir pressure (RPMAX), excess pressure and reservoir pressure time integrals, respectively, as well as relative contributions of excess pressure (EPREL) and reservoir pressure to total blood pressure time integral, respectively, between men and women divided in two age categories, below 51 (82 women and 66 men) and greater than or equal to 51 years old (175 women and 112 men), corresponding to average age of menopause for women and acceleration of vascular ageing for all. In both age categories, compared with men, women had significantly lower peripheral and aortic SBP and DBP. Analysis of covariance adjusted for BMI revealed that women who were greater than or equal to 51 years old had significantly higher excess pressure time integral, RPMAX, reservoir pressure time integral, EPREL, and relative contributions of reservoir pressure than men in the same age category. In the younger age category below 51 years old, EPREL and RPMAX were also significantly higher in women than men. Our study shows that healthy women have lower peripheral and aortic SBP and DBP compared with healthy men; however, their excess and reservoir pressures are higher, particularly after 51 years of age.


Convergent diversity-oriented side-chain macrocyclization scan for unprotected polypeptides.
Here we describe a general synthetic platform for side-chain macrocyclization of an unprotected peptide library based on the SNAr reaction between cysteine thiolates and a new generation of highly reactive perfluoroaromatic small molecule linkers. This strategy enabled us to simultaneously "scan" two cysteine residues positioned from i, i + 1 to i, i + 14 sites in a polypeptide, producing 98 macrocyclic products from reactions of 14 peptides with 7 linkers. A complementary reverse strategy was developed; cysteine residues within the polypeptide were first modified with non-bridging perfluoroaryl moieties and then commercially available dithiol linkers were used for macrocyclization. The highly convergent, site-independent, and modular nature of these two strategies coupled with the unique chemoselectivity of a SNAr transformation allows for the rapid diversity-oriented synthesis of hybrid macrocyclic peptide libraries with varied chemical and structural complexities.


Fragile states of mind: neuroticism, vulnerability and the long-term outcome of depression.
This paper considers the extent to which vulnerability to the outcome of major affective disorder is conferred through personality deviance. Results are based upon a 12 year longitudinal follow-up study of 80 patients with a primary depressive disorder, originally selected from a consecutive series seeking care at a hospital in Scotland. The study included detailed clinical course assessments in association with the formal application of diagnostic criteria. Assessments on recovery from the index episode included measures of self-confidence and of neuroticism. Experience of selected severe loss events over the study period was also determined. Limited self-confidence was strongly related, unlike neuroticism, to the subsequent first recurrence of affective disorder. Relationships between psychosocial, clinical and demographic factors and long-term outcome revealed psychosocial factors, in particular neuroticism and a lack of self-confidence, to have the greatest prognostic significance. These results reveal the heightened risk over the long-term of a poor outcome for depressive disorder consequent upon measures of personality deviance and of exposure to adversity. While giving only limited support to narrowly defined psychosocial models of depression, they clarify the risk gradients involved and through this may provide a firmer basis than hitherto for relapse prevention.