A structural map of oncomiR-1 at single-nucleotide resolution.
The miR-17-92a cluster, also known as 'oncomiR-1', is an RNA transcript that plays a pivotal regulatory role in cellular processes, including the cell cycle, proliferation and apoptosis. Its dysregulation underlies the development of several cancers. Oncomir-1 comprises six constituent miRNAs, each processed with different efficiencies as a function of both developmental time and tissue type. The structural mechanisms that regulate such differential processing are unknown, and this has impeded our understanding of the dysregulation of oncomiR-1 in pathophysiology. By probing the sensitivity of each nucleotide in oncomiR-1 to reactive small molecules, we present a secondary structural map of this RNA at single-nucleotide resolution. The secondary structure and solvent accessible regions of oncomiR-1 reveal that most of its primary microRNA domains are suboptimal substrates for Drosha-DGCR8, and therefore resistant to microprocessing. The structure indicates that the binding of trans-acting factors is required to remodel the tertiary organization and unmask cryptic primary microRNA domains to facilitate their processing into pre-microRNAs.


Cyclin H is targeted to the nucleus by C-terminal nuclear localization sequences.
Cdk-activating kinase (CAK) is a trimeric complex consisting of cdk7, cyclin H, and MAT1, which activates the cell-cycle-regulating cdks through T loop phosphorylation. In addition, other substrates of the CAK complex have been identified when CAK is assembled with the TFIIH core proteins, thereby regulating transcription and nucleotide excision repair. Little is known about the regulation of the CAK complex through cyclin H. In this study we further analyzed cyclin H regulation and identified two basic clusters in the C terminus of the protein as putative nuclear localization sequences (NLSs). Fusion constructs of full-length and truncated cyclin H sequences demonstrated the functionality of the NLSs. A peptide-binding assay revealed that at least one NLS interacts with the nuclear import receptors importin alpha/beta. Phosphorylation in the vicinity of the NLSs by cyclin C/cdk8 or protein kinase CK2, however, does not influence the nuclear translocation of cyclin H.


Audio Visual Integration with Competing Sources in the Framework of Audio Visual Speech Scene Analysis.
We introduce "Audio-Visual Speech Scene Analysis" (AVSSA) as an extension of the two-stage Auditory Scene Analysis model towards audiovisual scenes made of mixtures of speakers. AVSSA assumes that a coherence index between the auditory and the visual input is computed prior to audiovisual fusion, enabling to determine whether the sensory inputs should be bound together. Previous experiments on the modulation of the McGurk effect by audiovisual coherent vs. incoherent contexts presented before the McGurk target have provided experimental evidence supporting AVSSA. Indeed, incoherent contexts appear to decrease the McGurk effect, suggesting that they produce lower audiovisual coherence hence less audiovisual fusion. The present experiments extend the AVSSA paradigm by creating contexts made of competing audiovisual sources and measuring their effect on McGurk targets. The competing audiovisual sources have respectively a high and a low audiovisual coherence (that is, large vs. small audiovisual comodulations in time). The first experiment involves contexts made of two auditory sources and one video source associated to either the first or the second audio source. It appears that the McGurk effect is smaller after the context made of the visual source associated to the auditory source with less audiovisual coherence. In the second experiment with the same stimuli, the participants are asked to attend to either one or the other source. The data show that the modulation of fusion depends on the attentional focus. Altogether, these two experiments shed light on audiovisual binding, the AVSSA process and the role of attention.


Mutation of Arg191 in FtsZ Impairs Cytokinetic Abscission of Bacillus subtilis Cells.
FtsZ monomers assemble to form a dynamic Z-ring at the midcell position in bacteria that coordinates bacterial cell division. Antibacterial agents plumbagin and SB-RA-2001 were found to bind to FtsZ and to inhibit Z-ring formation in bacteria. Docking analysis indicated similar binding regions for these two inhibitors on FtsZ, and residue R191 was involved in the binding interaction with both compounds. In this work, the importance of R191 in FtsZ assembly and in bacterial cell division was analyzed. R191A-FtsZ exhibited significantly poorer polymerization ability. Further, the mutant FtsZ could poison the assembly of wild-type FtsZ (WT-FtsZ). The expression of R191A-FtsZ in Bacillus subtilis strain PL2084 perturbed Z-ring formation and produced filamentous cells, indicating that the mutation hindered the division of these cells. The results suggested that the R191A mutation is a dominant negative mutation of FtsZ. Molecular dynamics simulations of R191A-FtsZ and WT-FtsZ revealed a kink in helices H5 and H7 in the active site of R191A-FtsZ compared to that of WT-FtsZ, which is required for FtsZ assembly. The findings suggested that R191 is an important residue for FtsZ assembly, which can be targeted for the design of FtsZ inhibitors.


Rotational laxity after anterior cruciate ligament injury by kinematic evaluation of clinical tests.
Despite the numerous studies on anterior cruciate ligament biomechanics and clinical tests, some disagreements still exist in the literature on the role of ACL in restraining rotations and which kinematic test after ACL injuries is the most suitable to evaluate this instability. This work analyses the capability of passive clinical and stress tests to detect an ACL state quantifying rotational instability. The study was conducted on animal knees with a new protocol. We found that an internal-external stress test can give a useful indication on the ACL state when used to estimate the side to side differences while varus-valgus laxity and secondary motions in standard kinematic tests did not seem to be affected by ACL injury. The kinematic protocol performed could be used intra-operatively to quantify rotations, allowing a more accurate evaluation of knee instability to guide surgical reconstruction and improve its final outcome.


Efficacy of sorafenib combined with radiofrequency ablation in renal cancer and its effects on immunity and inflammation in patients.
This study aimed to compare the efficacy of laparoscopic and conventional left hemicolectomy for treating colon cancer and their effects on stress response and quality of life of patients. 92 patients with colon cancer were selected. Forty three patients in the study group were treated with laparoscopic left hemicolectomy, and 49 patients in the control group were treated with conventional left hemicolectomy. The surgery, postoperative recovery, intraoperative and postoperative complications were compared between the two groups. The enzyme-linked immunosorbent assay (ELISA) was used to detect the levels of IL1β and IL-6. The quality of life of patients after surgery was analyzed by the Functional Assessment of Cancer Therapy-Lung (FACT-L). The operation time and intraoperative blood loss of the study group were statistically lower than those of the control group (p<0.05). The postoperative exhaust time and hospitalization time of the study group were statistically shorter than those of the control group (p<0.05). Serum IL-1β and IL-6 levels in the study group were significantly lower than those in the control group (p<0.05). In the two groups, the overall scores of quality of life after surgery were significantly lower than those before surgery (p<0.05). After surgery, the overall score of quality of life in the study group was significantly higher than that in the control group (p<0.05). The laparoscopic left hemicolectomy with surgical approaches on the surgical plane has high safety and marked efficacy.


Effect of education and feedback on thyroid function testing strategies of primary care clinicians.
We examined the effect of an educational memorandum incorporating simple guidelines for thyroid function testing on test utilization in a primary care health maintenance organization practice. We then compared the effectiveness of a reminder alone or combined with individual test ordering feedback at maintaining an effect. The subjects were 17 physicians and 13 physician assistants and nurse practitioners separated into two similar study groups with little clinical interaction. Both groups responded to the education with increased compliance (from 36% to greater than 67%) with the recommended testing strategy. The group subsequently receiving only a reminder showed a further increase in compliance from 68% to 81% at 6 months and 79% at 12 months. The group receiving a reminder and feedback showed no subsequent change in testing pattern (65% compliance before the reminder-feedback and 64% at both subsequent measurements). The effect of the educational intervention was greater on nurse practitioners and physician assistants than physicians (absolute increase in compliance, 63% vs 28%). We conclude that education can be an effective tool for modifying clinician testing patterns to conform to simple clinical guidelines. Further study of the effect of education and other strategies on compliance with more complex guidelines is needed.


Development of a new screening method for the detection of antibiotic residues in muscle tissues using liquid chromatography and high resolution mass spectrometry with a LC-LTQ-Orbitrap instrument.
A liquid chromatography-high resolution mass spectrometry (LC-HRMS) method was developed for screening meat for a wide range of antibiotics used in veterinary medicine. Full-scan mode under high resolution mass spectral conditions using an LTQ-Orbitrap mass spectrometer with resolving power 60,000 full width at half maximum (FWHM) was applied for analysis of the samples. Samples were prepared using two extraction protocols prior to LC-HRMS analysis. The scope of the method focuses on screening the following main families of antibacterial veterinary drugs: penicillins, cephalosporins, sulfonamides, macrolides, tetracyclines, aminoglucosides and quinolones. Compounds were successfully identified in spiked samples from their accurate mass and LC retention times from the acquired full-scan chromatogram. Automated data processing using ToxId software allowed rapid treatment of the data. Analyses of muscle tissues from real samples collected from antibiotic-treated animals was carried out using the above methodology and antibiotic residues were identified unambiguously. Further analysis of the data for real samples allowed the identification of the targeted antibiotic residues but also non-targeted compounds, such as some of their metabolites.


Subcellular localisation, protein interactions, and RNA binding of Potato mop-top virus triple gene block proteins.
Subcellular localisation, protein interactions, and RNA binding of the triple gene block proteins (TGBp) of Potato mop-top virus (PMTV) were studied. The 13-kDa (TGBp2) and 21-kDa (TGBp3) proteins with or without green fluorescent protein fused to their N-terminus, and the 51-kDa protein (TGBp1) were expressed individually from a recombinant Tobacco mosaic virus (TMV) vector. Fluorescent images and Western immunoblotting experiments of recombinant TMV-infected Nicotiana benthamiana cells suggested that TGBp2 and TGBp3 were associated with cellular endomembranes and that TGBp3 was associated with the cell wall, possibly located close to plasmodesmata. In Western blots, TGBp1 was detected in fractions containing the cell wall and those enriched for organelles and membranous structures. Self-interactions were demonstrated with all three proteins in yeast two-hybrid experiments, and a heterologous interaction was found between TGBp2 and TGBp3. No additional heterologous interactions were discovered between the different TGBp and none were detected in an in vitro binding assay. TGBp1 and TGBp2 but not TGBp3 were shown to bind ssRNA in a sequence nonspecific manner. The results support the model where TGBp2 and TGBp3 facilitate delivery and localisation of the ribonucleoprotein complex to the plasmodesmata. However, the process is facilitated by RNA-protein rather than protein:protein interactions between the TGBp1 in complex with viral RNA and membrane-localised TGBp2.


Could exemestane affect insulin-like growth factors, interleukin 6 and bone metabolism in postmenopausal advanced breast cancer patients after failure on aminoglutethimide, anastrozole or letrozole?
Postmenopausal hormone-sensitive breast cancer is currently treated with either antioestrogens or aromatase inhibitors (AIs), due to the clinical efficacy and safety of these drugs. Today's challenge is the sequential use of AIs with different structure and no cross-resistance to improve the therapeutic outcome. The present study describes the biological action of the steroidal structure (SS)-AI exemestane (EXE), in patients progressing on aminoglutethimide (AG) or other non-steroidal structure (NSS)-AIs (letrozole or anastrozole). Thirteen patients were evaluated for serum insulin-like growth factor (IGF) components [total IGF-1, IGF-2 and IGF binding protein (IGFBP)-3], interleukin (IL)-6 system [IL-6 and soluble IL-6 receptor (sIL-6-R)] and bone metabolism markers [bone gla protein/osteocalcin (BGP), bone-specific isoform of alkaline phosphatase (BAP) and carboxy-telopeptide of type I procollagen (ICTP)]. IGF system components show a trend to increase both in patients progressing on AG and in patients progressing on other NSS-AIs. Such an increase depends on the wash-out length from the previous treatment and is strictly linked to the circulating oestrogen levels. Serum IL-6 and sIL-6-R are mainly related to the patients' clinical outcome. Bone formation (BGP and BAP) and bone resorption (ICTP) markers seem to be at equilibrium with oestrogen levels when starting EXE and do not appear to be uncoupled over treatment. The observed variations seem to be mainly linked to the circulating oestrogen levels rather than directly to the way of action of the AI employed.


The genetic heterogeneity of hereditary transthyretin amyloidosis in a sample of the Brazilian population.
To present the genetic heterogeneity of a sample of the Brazilian population with transthyretin (TTR) mutations. This cohort study was descriptive and retrospective, and enrolled patients with peripheral neuropathy of unknown cause that were found to have a mutation in the TTR gene during the process of etiological investigation, between July 1997 to January 2016. Over the study period, 129 point mutations were identified in 448 tested patients, of whom 128 were of Brazilian origin. The TTR Val30Met mutation was identified in 116 patients (90.6%); while 7 (4.7%) patients had a pathogenic non-TTR mutation and 7 (4.7%) carried non-pathogenic mutations (4.7%). The four non-TTRMet30 pathogenic mutations were TTR Aps38Tyr; TTR Ile107Val; TTR Val71Ala; and TTR Val122Ile. In the non-pathogenic group, we only found two mutations, including TTR Gly6Ser and TTR Thr119Thr. Our study depicts a scenario of greater genetic heterogeneity among Brazilian hereditary transthyretin amyloidosis (hATTR) patients with familial amyloidotic polyneuropathy (FAP). We expect that this number will grow fast over a short period of time, due to increasing availability of genetic tests, increasing knowledge of the disease and the multivariate origin of our population.


Was the black death in India and China?
Firsthand accounts of the Black Death in Europe and the Middle East and many subsequent historians have assumed that the pandemic originated in Asia and ravaged China and India before reaching the West. One reason for this conviction among modern historians is that the plague in the nineteenth century originated and did its worst damage in these countries. But a close examination of the sources on the Delhi Sultanate and the Yuan Dynasty provides no evidence of any serious epidemic in fourteenth-century India and no specific evidence of plague among the many troubles that afflicted fourteenth-century China.


[The serotonin syndrome: why should cardiologists be aware and scared of it].
The serotonin syndrome (SS) represents a life-threatening adverse drug reaction, caused by serotonin overload in the central and peripheral nervous system, producing autonomic instability, neuromuscular and cardiovascular abnormalities, and cognitive alterations. The incidence of SS has been growing over the last few years, as a consequence of population aging and the steadily increasing use of pro-serotoninergic agents in clinical practice, in the presence of various comorbidities, mainly cardiovascular. Cardiologists often use combination therapies including serotoninergic agents, and should therefore consider the risk of serotoninergic adverse events caused by inappropriate drug interactions. SS is often difficult to diagnose and may be life-threatening if not adequately managed. Considering the several published case reports of overdose or not recommended associations, a greater awareness by clinicians about the potential risks associated with inappropriate use of these drugs is needed, as well as better information on the clinical features and therapeutic approaches to SS.


[Evaluation of the effect of certain pharmacologic agents on the activity of the "punishment" system].
The influence of serotonin-, cholin- and GABAergic drugs on the "punishment" system has been investigated on albino rats. Fluoxetine (20 mg/kg) and citalopram (20 mg/kg) prolonged the latency of escape (EL) from central aversive brain stimulation, while thresholds of pose shifts (PS) and movement initiation (MI) under stimulation of the same medial hypothalamus sites remained unchanged. Muscimol (2 mg/kg) and physostigmine (0,5 mg/kg) + methylatropine (1 mg/kg) increased both EL and threshold of PS and MI. In a conflict situation all the drugs either failed to produce a disinhibitory effect or even enhanced behaviour suppression; at the same time, however, the manifestations of emotional tension (emotional, reactivity, defecation) decreased. It is suggested that activation of serotonin-, cholin- and GABAergic processes decreases the functioning of both perceptive and emotional components of the punishment system.


Postoperative analgesia after peripheral nerve block for podiatric surgery: clinical efficacy and chemical stability of lidocaine alone versus lidocaine plus ketorolac.
The purpose of this study was to determine whether the addition of ketorolac tromethamine to local anesthesia for ankle block alters the quality or duration of analgesia after podiatric surgery. The second aim was to determine the chemical stability of ketorolac tromethamine when added to local anesthetic solutions. The study design was double-blinded, placebo-controlled, and randomized. Seventy-nine American Society of Anesthesiologists (ASA) class I or II patients scheduled for bunionectomy or hammer toe repair, or both were randomized to 1 of 4 groups. Group L received plain 1.73% lidocaine for their ankle block. Group K received 1.73% lidocaine with ketorolac (4 mg/mL) added to the local solution. Group Kiv received 1.73% plain lidocaine for ankle block and 20 mg of ketorolac intravenously. Group E received 1.73% lidocaine with .67% ethanol added. The final concentration of lidocaine for all groups was 1.73%. The block performed in each patient was a 5-point ankle block. Beginning at 1 hour after the completion of the block and every 30 minutes thereafter, visual analogue scale (VAS) and verbal pain scores were recorded. The time from performance of the block to the initial pain and time to the first oral pain medication intake were also recorded. The time and amount of postoperative oral analgesics in the first 9 hours after the block were recorded. Adverse events were also recorded for each group. There were significantly lower overall VAS and verbal pain scores for group K compared with groups E and L and group Kiv compared with group E. Group K also had a significantly longer time to the first reported pain and first oral pain medications than groups E and L, but not with Group Kiv. The same group had significantly fewer average doses of pain medications postoperatively than Groups E and L. Group E had significantly shorter times to first report of pain and first pain medications and higher mean dose of postoperative oral analgesics than group K and Group Kiv. There were no untoward side effects reported from any group. Chemical analysis by gas chromatography (GC) and capillary electrophoresis (CE) showed no significant change in composition of the solutions when ketorolac was mixed with lidocaine and/or bupivacaine and stored at 37 degrees C for 1 week. The addition of ketorolac to lidocaine for ankle block contributed to longer duration and better quality analgesia after foot surgery compared with plain 1.73% lidocaine or 1.73% lidocaine plus intravenous ketorolac. The ethanol vehicle is unlikely responsible for the analgesic effects of ketorolac. Ketorolac retains its chemical stability when placed in local solutions of lidocaine or bupivacaine.


Evaluation of anti-diabetic drugs by using silkworm, Bombyx mori.
Since diabetes patients are increasing in the world, establishment of a novel method for development of anti-diabetic drugs is desired. In this review, we describe recent results of our studies regarding diabetic model using silkworms for evaluation of anti-diabetic drugs for patients of both type I and type II diabetes. The use of the evaluation systems using silkworms is expected to contribute to reduction in cost and in the number of mammals sacrificed for screening of anti-diabetic drugs.


[Calibration of examiners for dental caries epidemiologic studies].
The aim of this study was describe a training and calibration exercise for dental caries and to discuss the use of validity and reliability statistical tests. Eight dentists examined seventeen 12 year-old schoolchildren using World Health Organization (1997) criteria. Data analysis included calculation of the DMF-T index, the percent agreement, and the kappa scores on a tooth-by-tooth basis. Inter-examiner agreement was tested against a gold standard examiner. Scores for measures of agreement calculated on a tooth-by-tooth basis were lower than those calculated for the whole mouth. The training and calibration exercise is a crucial step in cross-sectional epidemiological surveys, and the kappa test calculated on a tooth-by-tooth basis is the appropriate measurement to test agreement between examiners for dental caries.


Serum albumin and risk of venous thromboembolism.
The incidence of venous thromboembolism (VTE) is increased in patients with albuminuria. However, whether a low serum albumin concentration is associated with increased risk of VTE has been a matter of controversy. We determined the association of serum albumin with VTE incidence in two large, prospective, population-based cohorts: the Atherosclerosis Risk in Communities (ARIC) Study (n = 15,300) and the Cardiovascular Health Study (CHS) (n = 5,400). Validated VTE occurrence (n = 462 in ARIC and n = 174 in CHS) was ascertained during follow-up. In both studies, after adjustment for age, sex, race, use of hormone replacement therapy, estimated glomerular filtration rate, history of cancer, and diabetes, serum albumin tended to be associated inversely with VTE. The adjusted hazard ratio per standard deviation lower albumin was 1.18 (95% confidence interval [CI] = 1.08, 1.31) in ARIC and 1.10 (95% CI = 0.94, 1.29) in CHS. The hazard ratio for albumin below (vs. above) the fifth percentile was 1.28 (95% CI = 0.90, 1.84) in ARIC and 1.80 (95% CI = 1.11, 2.93) in CHS. In conclusion, low serum albumin was a modest marker of increased VTE risk. The observed association likely does not reflect cause and effect, but rather that low serum albumin reflects a hyperinflammatory or hypercoagulable state. Whether this association has clinical relevance warrants further study.


Intracerebral hemorrhage secondary to ventriculoperitoneal shunt insertion--four case reports.
Four patients presented with intracerebral hemorrhage secondary to ventriculoperitoneal (VP) shunt insertion. VP shunt insertion was performed for idiopathic normal-pressure hydrocephalus (Case 1), hydrocephalus after cerebellar hemorrhage (Case 2), and subarachnoid hemorrhage followed by meningitis (Cases 3 and 4). Cerebral hemorrhage was confirmed 4 hours (Case 1), 2 days (Case 2), 7 days (Case 3), and 13 days (Case 4) after the operation. Cases 1 and 2 required intraoperative hemostasis for bleeding from the cortical vein. The 7 previous and our 4 patients were divided according to early (within 2 days after shunt placement, n = 6, Group 1) and delayed (5-13 days post-shunting, n = 5, Group 2) hemorrhage. Bleeding was attributable to venous occlusion due to intraoperative manipulation in Group 1, and to the vulnerability of brain tissue induced by a primary brain disease in Group 2.


Activation of the proapoptotic Bcl-2 protein Bax by a small molecule induces tumor cell apoptosis.
The proapoptotic Bcl-2 protein Bax by itself is sufficient to initiate apoptosis in almost all apoptotic paradigms. Thus, compounds that can facilitate disruptive Bax insertion into mitochondrial membranes have potential as cancer therapeutics. In our study, we have identified small-molecule compounds predicted to associate with the Bax hydrophobic groove by a virtual-screen approach. Among these, one lead compound (compound 106) promotes Bax-dependent but not Bak-dependent apoptosis. Importantly, this compound alters Bax protein stability in vitro and promotes the insertion of Bax into mitochondria, leading to Bax-dependent permeabilization of the mitochondrial outer membrane. Furthermore, as a single agent, compound 106 inhibits the growth of transplanted tumors, probably by inducing apoptosis in tumors. Our study has revealed a compound that activates Bax and induces Bax-dependent apoptosis, which may lead to the development of new therapeutic agents for cancer.


Video-assisted thoracic surgery lobectomy: report of CALGB 39802--a prospective, multi-institution feasibility study.
To evaluate the technical feasibility and safety of video-assisted thoracic surgery (VATS) lobectomy for small lung cancers. The Cancer and Leukemia Group B 39802 trial was a prospective, multi-institutional study designed to elucidate the technical feasibility of VATS in early non-small-cell lung cancer (NSCLC) using a standard definition for VATS lobectomy (one 4- to 8-cm access and two 0.5-cm port incisions) that mandated videoscopic guidance and a traditional hilar dissection without rib spreading. Between 1998 and 2001, 128 patients with peripheral lung nodules < or = 3 cm in size with suspected NSCLC were prospectively registered for VATS lobectomy. One hundred twenty-seven patients (66 males and 61 females; median age, 66 years; range, 37 to 86 years), with a performance status of 0 (74%) or 1 (26%), underwent surgery. Patients with lymph nodes more than 1 cm by computed tomography scan underwent mediastinal lymph node sampling to rule out N2 disease. One hundred eleven patients (87%) had stage I lung cancer, and 96 (86.5%) of these 111 patients underwent successful VATS lobectomies. The median procedure length was 130 minutes (range, 47 to 428 minutes), and median chest tube duration was 3 days (range, 1 to 14 days). Fifty-eight (60%) of 97 patients underwent diagnostic biopsy at lobectomy. Within 30 days, three (2.7%) of 111 patient deaths occurred, none of which were directly related to VATS technique; seven (7.4%) of 95 patients had grade 3 or greater complications, with only one case of bleeding. A standardized approach to VATS lobectomy as specifically defined with avoidance of rib spreading is feasible.


NOD2 silencing promotes cell apoptosis and inhibits drug resistance in chronic lymphocytic leukemia by inhibiting the NF-κB signaling pathway.
Recent years have witnessed increasing studies on the effect of epigenetic silencing of genes in the progression of chronic lymphocytic leukemia (CLL). This study investigates whether the nucleotide binding oligomerization domain containing 2 (NOD2) participates in the cell apoptosis and drug resistance of CLL cells. Cells were treated with adriamycin (ADR), etoposide, aclacinomycin and daunorubicin. After treatment, drug resistance and cell proliferation were examined to detect the inhibitory effect of ADR on cell proliferation; flow cytometry to identify ADR accumulation, the cell cycle distribution and apoptosis after transfection, and rhodamine 123 accumulation and efflux tests to assess P-glycoprotein (P-gp) function. NOD2 silencing or inhibition of the nuclear factor kappa-B (NF-κB) signaling pathway suppressed the multidrug resistance level in CLL, the inhibition rate, and cell proliferation caused by ADR at concentrations of approximately 0.25-1.5 μmol/L. Greater accumulation of ADR was observed in the CLL-AAT cell line than in the CLL-AAT/A02 cell line, but NOD2 silencing or inhibition of the NF-κB signaling pathway further increased the accumulation of ADR drugs in the CLL-AAT cell line and inhibited the drug efflux pump function of P-gp. Additionally, NOD2 silencing or NF-κB signaling pathway inhibition increased the apoptotic rate. The results of this study indicate that NOD2 promotes cell apoptosis and reduces the drug resistance of CLL by inhibiting the NF-κB signaling pathway.


Molecular Mapping of Flowering Time Major Genes and QTLs in Chickpea (Cicer arietinum L.).
Flowering time is an important trait for adaptation and productivity of chickpea in the arid and the semi-arid environments. This study was conducted for molecular mapping of genes/quantitative trait loci (QTLs) controlling flowering time in chickpea using F2 populations derived from four crosses (ICCV 96029 × CDC Frontier, ICC 5810 × CDC Frontier, BGD 132 × CDC Frontier and ICC 16641 × CDC Frontier). Genetic studies revealed monogenic control of flowering time in the crosses ICCV 96029 × CDC Frontier, BGD 132 × CDC Frontier and ICC 16641 × CDC Frontier, while digenic control with complementary gene action in ICC 5810 × CDC Frontier. The intraspecific genetic maps developed from these crosses consisted 75, 75, 68 and 67 markers spanning 248.8 cM, 331.4 cM, 311.1 cM and 385.1 cM, respectively. A consensus map spanning 363.8 cM with 109 loci was constructed by integrating four genetic maps. Major QTLs corresponding to flowering time genes efl-1 from ICCV 96029, efl-3 from BGD 132 and efl-4 from ICC 16641 were mapped on CaLG04, CaLG08 and CaLG06, respectively. The QTLs and linked markers identified in this study can be used in marker-assisted breeding for developing early maturing chickpea.


Substance P receptor-like immunoreactive neurons in the caudal spinal trigeminal nucleus send axons to the gelatinosus thalamic nucleus in the rat.
By means of substance P receptor (SPR) immunofluorescence histochemistry combined with Fluoro-Gold (FG) fluorescent retrograde labeling, SPR-like immunoreactive neurons in the caudal spinal trigeminal nucleus of the rat were observed to send their axons to the gelatinosus thalamic nucleus with a clear ipsilateral dominance. FG/SPR double-labeled neurons were distributed mainly in the ventral part of lamina I at the rostral level of the caudal spinal trigeminal nucleus. The percentages of FG/SPR-LI neurons in the total number of SPR-LI neurons and FG-labeled neurons are 10.5% and 31.1%, respectively. The present results suggest that trigemino-gelatinosus thalamic projection neurons with SPR-LI in the caudal spinal trigeminal nucleus might receive SP-containing, nociceptive primary afferent fibers from the orofacial region and transmit nociception to the gelatinosus thalamic nucleus.


Targeting signaling pathways in acute lymphoblastic leukemia: new insights.
The genetics of acute lymphoblastic leukemia are becoming well understood and the incidence of individual chromosomal abnormalities varies considerably with age. Cytogenetics provide reliable risk stratification for treatment: high hyperdiploidy and ETV6-RUNX1 are good risk, whereas BCR-ABL1, MLL rearrangements, and hypodiploidy are poor risk. Nevertheless, some patients within the good- and intermediate-risk groups will unpredictably relapse. With advancing technologies in array-based approaches (single nucleotide polymorphism arrays) and next-generation sequencing to study the genome, increasing numbers of new genetic changes are being discovered. These include deletions of B-cell differentiation and cell cycle control genes, as well as mutations of genes in key signaling pathways. Their associations and interactions with established cytogenetic subgroups and with each other are becoming elucidated. Whether they have a link to outcome is the most important factor for refinement of risk factors in relation to clinical trials. For several newly identified abnormalities, including intrachromosomal amplification of chromosome 21 (iAMP21), that are associated with a poor prognosis with standard therapy, appropriately modified treatment has significantly improved outcome. After the successful use of tyrosine kinase inhibitors in the treatment of BCR-ABL1-positive acute lymphoblastic leukemia, patients with alternative ABL1 translocations and rearrangements involving PDGFRB may benefit from treatment with tyrosine kinase inhibitors. Other aberrations, for example, CRLF2 overexpression and JAK2 mutations, are also providing potential novel therapeutic targets with the prospect of reduced toxicity.


Pharmacists' Confidence in Managing Patients with Inflammatory Bowel Disease.
Background and aim: Managing patients with a chronic condition such as inflammatory bowel disease (IBD), requires a multidiscipline approach. The pharmacist might be the first point of contact for patients with initial symptoms or relapsing flares, yet there is no available literature on the role of pharmacists in IBD management. We conducted a survey to explore pharmacists' confidence in and potential barriers to managing IBD and assess the impact of IBD education on their confidence in IBD management. Methods: Surveys assessing confidence levels in managing IBD, additional learning opportunities about IBD and barriers to their learning of IBD management were provided to pharmacists for completion before and after attending an IBD-specific education session at a national conference. Results: Of the 195 attendees, 125 participants completed the survey (64%). Most respondents reported a low to mid-range level of confidence with managing IBD. Specifically, they were only slightly confident in decision making on patient care, addressing patient needs and providing additional support for IBD patients; and somewhat confident with understanding, management and providing relevant information on IBD. Whist the education session improved pharmacists perceived level of confidence, most respondents indicated a need to learn more about IBD. Areas of additional learning included science, drug therapy, treatments (includes non-pharmacological options as well) and guidelines. A majority of pharmacists identified time constraints as a key barrier to learning. Conclusion: Pharmacists lack sufficient confidence about managing inflammatory bowel disease. These data indicate support within the pharmacy profession to play a more active role in the management of IBD.


(M4H3X)2B2O2: hydrometal complexes (M = Ni, Mg) containing double tetracoordinate planar nonmetal centers (X = C, N).
Geometrical optimizations and electronic structural analyses of the -O(2)B(2)- bridged hydrometal complexes (M(4)H(3)C)(2)B(2)O(2) and (M(4)H(3)N)(2)B(2)O(2)(2+) (M = Ni, Mg) containing double tetracoordinate planar nonmetals (TPN) have been performed using the density functional theory at the B3LYP/6-311+G(d,p) level. Theoretical evidence of the possibility of double TPN centers coexisting in one planar molecule is presented.


XMeis3 is necessary for mesodermal Hox gene expression and function.
Hox transcription factors provide positional information during patterning of the anteroposterior axis. Hox transcription factors can co-operatively bind with PBC-class co-factors, enhancing specificity and affinity for their appropriate binding sites. The nuclear localisation of these co-factors is regulated by the Meis-class of homeodomain proteins. During development of the zebrafish hindbrain, Meis3 has previously been shown to synergise with Hoxb1 in the autoregulation of Hoxb1. In Xenopus XMeis3 posteriorises the embryo upon ectopic expression. Recently, an early temporally collinear expression sequence of Hox genes was detected in Xenopus gastrula mesoderm (see intro. P3). There is evidence that this sequence sets up the embryo's later axial Hox expression pattern by time-space translation. We investigated whether XMeis3 is involved in regulation of this early mesodermal Hox gene expression. Here, we present evidence that XMeis3 is necessary for expression of Hoxd1, Hoxb4 and Hoxc6 in mesoderm during gastrulation. In addition, we show that XMeis3 function is necessary for the progression of gastrulation. Finally, we present evidence for synergy between XMeis3 and Hoxd1 in Hoxd1 autoregulation in mesoderm during gastrulation.


Toward determining amyloid fibril structures using experimental constraints from Raman spectroscopy.
We present structural models for three different amyloid fibril polymorphs prepared from amylin20-29 (sequence SNNFGAILSS) and amyloid-β25-35 (Aβ25-35) (sequence GSNKGAIIGLM) peptides. These models are based on the amide C=O bond and Ramachandran ψ-dihedral angle data from Raman spectroscopy, which were used as structural constraints to guide molecular dynamics (MD) simulations. The resulting structural models indicate that the basic structural motif of amylin20-29 and Aβ25-35 fibrils is extended β-strands. Our data indicate that amylin20-29 forms both antiparallel and parallel β-sheet fibril polymorphs, while Aβ25-35 forms a parallel β-sheet fibril structure. Overall, our work lays the foundation for using Raman spectroscopy in conjunction with MD simulations to determine detailed molecular-level structural models of amyloid fibrils in a manner that complements gold-standard techniques, such as solid-state nuclear magnetic resonance and cryogenic electron microscopy.


Effects of melatonin on the Harderian gland of lipopolysaccharide-treated rats: morphological observations.
Melatonin is a free radical scavenger and antioxidant. This indol is reported to efficiently scavenge both hydroxyl and peroxyl radicals and it also reduces both in vitro and in vivo tissue damage due to oxidants which generate oxygen toxic radicals. Lipopolysaccharide (LPS) administration induces oxidative damage in various tissues mainly due to its ability to increase reactive oxygen species. In the present work, we studied the morphological changes and lipid peroxidation in the Harderian gland after LPS administration and the effects of melatonin in preventing the induced changes. Hyperchromasia, vesicular degeneration, necrosis and infiltration with macrophages, monocytes and neutrophils were observed in the LPS-treated group (10 mg/kg, intraperitonally [i.p.]). Also, a typical structure of the glandular acini of the gland exhibited diffuse damage. In the LPS rats treated with melatonin (10 mg/kg, i.p.), a diminished number of infiltrative cells was seen, and cloudy swelling was reduced, as was nuclear hyperchromasia. Neither necrosis nor vesicular degeneration were noted in the melatonin-treated rats, and in general, glandular structure was preserved. Lipid peroxidation products increased significantly within six hours after LPS administration, and melatonin treatment decreased the LPS-dependent lipid peroxidation products. These data together suggest that melatonin protects the Harderian gland against LPS toxicity in terms of morphological damage.


Potential therapeutic targets for steroid-resistant asthma.
Glucocorticoids are the mainstay of asthma management and effectively treat acute exacerbations of asthma. However, a small subset of asthmatics, usually with severe asthma, respond poorly even to systemic administration of high-dose glucocorticoids and this condition is termed "steroid-resistant asthma". This cohort, although small, accounts for approximately 50% of total health care cost for asthma. New investigations into the mechanisms of glucocorticoid action have broadened and deepened our understanding of glucocorticoid resistance. Here we review the importance and characteristics of steroid resistant asthma, the mechanisms that mediate the function of glucocorticoids and that lead to the development of this disease and potential therapies to reverse resistance to treatment. Cellular and molecular factors, receptors and complex signalling pathways have all been implicated. Indeed, based on molecular biological studies, excessive activation of intracellular transcription factors, impaired histone deacetylase, and epigenetic (such as miR-18 and miR-124a) as well as other factors (e.g. vitamin D, P-glycoprotein 170, and macrophage migration inhibitory factor and T helper 17 cells and factors related to innate immunity (such as IFN-gamma and LPS)) may result in glucocorticoid resistance. A thorough understanding of the pathogenesis of steroid resistant asthma will help to develop more efficacious agents for the treatment of the disease.


Accepting risk in the acceleration of drug development for rare cancers.
Rare cancers collectively contribute a disproportionate fraction of the total burden of cancer. The oncology community is increasingly facing small numbers of patients with each cancer subtype, requiring cooperation and collaboration to complete multicentre trials that advance knowledge and patient care. At the same time, new insights into the biology of rare cancers have led to an explosion in knowledge and development of targeted agents. These insights and techniques are set to revolutionise the care of patients with cancer. However, drug development strategies and the availability of new agents for rare cancers are at risk of stalling owing to the ever-increasing complexity and costs of clinical trials. Finding solutions to these problems is imperative to the future of cancer care. We propose that a greater degree of risk sharing is needed than is currently accepted to enable the use of new methods with confidence, and to keep pace with scientific advancement.


Small, Dynamic Clusters of Tir-Intimin Seed Actin Polymerization.
The understanding of actin pedestal formation by enteropathogenic Escherichia coli (EPEC) relies mainly on static ensemble information obtained from cell lysates. Here, the dynamic nature of signaling components on the subsecond timescale, which resemble phase condensates, is demonstrated. Unlike in vitro phase condensates, transfected intimin receptor (Tir) and downstream component form clusters 200 nm in diameter that are spaced ≈500 nm on average, indicating cellular regulation. On supported lipid bilayers with diffusive intimin, Tir-expressing fibroblasts formed Tir-intimin clusters even without Tir tyrosines, although Tir tyrosine phosphorylation is necessary for actin polymerization from clusters. Single-molecule tracking showed that Tir is diffusive in the clusters and exchanges with Tir in the plasma membrane. Further, Nck and N-WASP bind to the clusters and exchange with cytoplasmic molecules. Tir has a similar cluster lifetime to Nck, but longer than that of N-WASP. Actin polymerization from the clusters requires N-WASP binding, involved Arp2/3 activation, and stabilized N-WASP clusters. These dynamic properties are distinct from larger in vitro systems and do not depend significantly upon crosslinking. Thus, Tir-intimin clusters in the plasma membrane are limited in size by exchange and enhance signaling needed for actin polymerization that enables strong and stable bacterial attachment to host cells.


EV20‑sss‑vc/MMAF, an HER‑3 targeting antibody‑drug conjugate displays antitumor activity in liver cancer.
Liver cancer (LC) is an aggressive disease with a markedly poor prognosis. Therapeutic options are limited, and, until recently the only FDA‑approved agent for first‑line treatment of patients with LC was the multi‑kinase inhibitor sorafenib, which exhibits limited activity and an increased overall survival (OS) of only 3 months over placebo. Therefore, the development of alternative therapeutic molecules for the treatment of LC is an urgent medical need. Antibody‑drug conjugates (ADCs) are an emerging class of novel anticancer agents, which have been developed recently for the treatment of malignant conditions, including LC, and are being studied in preclinical and clinical settings. Our group has recently generated an ADC [EV20/monomethyl auristatin F (MMAF)] by coupling the HER3 targeting antibody (EV20) to MMAF via a non‑cleavable maleimidocaproyl linker. This ADC was revealed to possess potent therapeutic activity in melanoma and breast carcinoma. In the present study, using western blot and flow cytometric analysis, it was reported that HER‑3 receptor was highly expressed in LC and activated by its ligand NRG‑1β in a panel of LC cell lines, thus indicating that this receptor may serve as a suitable target for ADC therapy. A novel ADC [EV20‑sss‑valine‑citrulline (vc)/MMAF] was generated, in which the cytotoxic payload MMAF was site‑specifically coupled to an engineered variant of EV20 via a vc cleavable linker. Cytotoxicity assays were performed to investigate in vitro antitumor activity of EV20‑sss‑vc/MMAF and it was compared to EV20/MMAF, which revealed only modest activity in LC.EV20‑sss‑vc/MMAF exhibited a significant cell killing activity in several LC cell lines. Additionally, in vivo xenograft experiments revealed that EV20‑sss‑vc/MMAF inhibited growth of LC tumors. The present data indicated that EV20‑sss‑vc/MMAF is a worthy candidate for the treatment of HER‑3 positive LC.


Defective ATP breakdown activity related to an ENTPD1 gene mutation demonstrated using 31P NMR spectroscopy.
The ecto-nucleoside triphosphate diphosphohydrolase-1 (E-NTPDase-1, CD39) enzyme is responsible for the breakdown of extracellular ATP to ADP and then to AMP by a two-step process. Defective CD39 activity has been described in a variety of medical conditions including malignancy and rheumatic diseases and has been proved to be of major diagnostic and clinical importance. Here we show for the first time that a 31P NMR spectroscopy methodology enables the quantification of these two steps in a single blood sample. We have applied this assay to determine the E-NTPDase activity on human mononuclear cells taken from two siblings affected by a stop-codon mutation in the ENTPD1 gene, their obligatory heterozygous parents, and healthy volunteers. The affected subjects presented low ATP breakdown activity, mainly expressed as low AMP production.


Static and Fatigue Behavior Investigation of Artificial Notched Steel Reinforcement.
Pitting corrosion is one of the most common forms of localized corrosion. Corrosion pit results in a stress concentration and fatigue cracks usually initiate and propagate from these corrosion pits. Aging structures may fracture when the fatigue crack reaches a critical size. This paper experimentally simulates the effects of pitting morphologies on the static and fatigue behavior of steel bars. Four artificial notch shapes are considered: radial ellipse, axial ellipse, triangle and length-variable triangle. Each shape notch includes six sizes to simulate a variety of pitting corrosion morphologies. The stress-strain curves of steel bars with different notch shape and depth are obtained based on static tensile testing, and the stress concentration coefficients for various conditions are determined. It was determined that the triangular notch has the highest stress concentration coefficient, followed by length-variable triangle, radial ellipse and axial ellipse shaped notches. Subsequently, the effects of notch depth and notch aspect ratios on the fatigue life under three stress levels are investigated by fatigue testing, and the equations for stress range-fatigue life-notch depth are obtained. Several conclusions are drawn based on the proposed study. The established relationships provide an experimental reference for evaluating the fatigue life of concrete bridges.


Notifications of hospital events to outpatient clinicians using health information exchange: a post-implementation survey.
The trend towards hospitalist medicine can lead to disjointed patient care. Outpatient clinicians may be unaware of patients' encounters with a disparate healthcare system. Electronic notifications to outpatient clinicians of patients' emergency department (ED) visits and inpatient admissions and discharges using health information exchange can inform outpatient clinicians of patients' hospital-based events. Assess outpatient clinicians' impressions of a new, secure messaging-based, patient event notification system. Twenty outpatient clinicians receiving notifications of hospital-based events were recruited and 14 agreed to participate. Using a semi-structured interview, clinicians were asked about their use of notifications and the impact on their practices. Nine of 14 interviewed clinicians (64%) thought that without notifications, they would have heard about fewer than 10% of ED visits before the patient's next visit. Nine clinicians (64%) thought that without notifications, they would have heard about fewer than 25% of inpatient admissions and discharges before the patient's next visit. Six clinicians (43%) reported that they call the inpatient team more often because of notifications. Eight users (57%) thought that notifications improved patient safety by increasing their awareness of the patients' clinical events and their medication changes. Key themes identified were the importance of workflow integration and a desire for more clinical information in notifications. The notification system is perceived by clinicians to be of value. These findings should instigate further message-oriented use of health information exchange and point to refinements that can lead to even greater benefits.


Cessation of oral anticoagulation in relation to mortality and the risk of thrombotic events in patients with atrial fibrillation.
Bleeding risk (often perceived, rather than actual) is a common reason for cessation of oral anticoagulation with Vitamin K antagonists (VKA). We investigate clinical outcomes in a consecutive population of VKA naïve atrial fibrillation (AF) patients, who initiated VKA therapy in our clinic. We included consecutive VKA-naïve patients with non valvular AF, initiated on VKA therapy in our anticoagulation outpatient clinic in 2009. During follow-up, adverse events [thrombotic/vascular events (stroke, acute coronary syndrome, acute heart failure and cardiac death), major bleeding and death], and VKA cessation were recorded. At the end of the follow-up, we determined time within therapeutic range (TTR), using a linear approximation (Rosendaal method). We studied 529 patients (49% male, median age 76), median follow-up 835 days (IQR 719-954). During this period 114 patients stopped VKA treatment. 63 patients suffered a thrombotic/cardiovascular event (5.17%/year, 27 thrombotic/ischaemic strokes), 51 major bleeding (4.19%/year) and 48 died (3.94%/year). Median TTR was 54% (34-57). On multivariate analysis (adjusted by CHA₂DS₂-VASc score), VKA cessation was associated with death [Hazard Ratio (HR) 3.43; p<0.001], stroke [4.21; p=0.001] and thrombotic/cardiovascular events [2.72; p<0.001]. Independent risk factors for major bleeding were age [1.08; p<0.001], previous stroke [1.85; p=0.049], and TTR [0.97; p=0.001], but not VKA cessation. In conclusion, in AF patients AF, VKA cessation is independently associated with mortality stroke and cardiovascular events. Specifically, VKA cessation independently increased the risk of stroke, even after adjusting for CHA₂DS₂-VASc score. TTR was an independent risk factor for major bleeding following initiation of VKA therapy.


Insulin and insulin-like growth factor 1 antagonize the stimulation of ob gene expression by dexamethasone in cultured rat adipose tissue.
The ob gene, specifically expressed in fat cells, encodes leptin, a hormone that induces satiety and increases energy expenditure. In this study, we investigated the interactions between glucocorticoids and insulin on ob gene expression in cultured explants of rat adipose tissue. Only low levels of ob mRNA were detected when adipose tissue from fasted rats was cultured for 12-24 h in minimal essential medium. However, the addition of dexamethasone to the medium increased ob gene expression in a concentration-dependent manner (EC50 10 nM). With 1 microM dexamethasone, ob mRNA levels were similar to those in fresh fat pads from fed rats, reaching a maximum after 12 h. The effect of dexamethasone was blocked by actinomycin D, which indicates an action on transcription. This effect was increased when a minimum amount of fuel (glucose or a mixture of lactate and pyruvate) was supplied in the medium. Unlike dexamethasone, insulin, even when combined with high glucose concentrations, did not induce ob expression, although it strongly increased the accumulation of mRNA species for fatty acid synthase (FAS), the insulin-sensitive glucose transporter GLUT4 and the gamma isoform of peroxisome proliferator-activated receptor (PPARgamma). Unexpectedly, insulin dose-dependently inhibited dexamethasone-induced ob mRNA accumulation. This effect was observed at low concentrations of insulin (IC50 1 nM) and was delayed in onset, beginning after 6-9 h of culture. It was mimicked by insulin-like growth factor 1 (IGF-1) (100 nM). The inhibition by insulin was only detectable when fuels were present and/or when a critical level of ob expression was reached. As this inhibitory effect was reversed by cycloheximide, this suggests that it required ongoing protein synthesis. In conclusion, unlike dexamethasone, insulin had no direct stimulatory effect on ob gene expression. On the other hand, insulin (and IGF-1) even inhibited the dexamethasone-induced accumulation of ob mRNA. The underlying mechanism involved ongoing synthesis of an inhibitory protein by insulin, which is in keeping with its delayed effect. Moreover, the expression of genes for FAS, GLUT4 and PPARgamma may be inversely related to that of ob.


Rare occurrence of hand-foot syndrome due to paclitaxel: A rare case report.
Hand-foot syndrome (HFS) is a relatively frequent adverse reaction to certain anticancer drugs. HFS is a type of dermatitis which has been most commonly described with 5-fluorouracil and capecitabine. However, HFS with paclitaxel is rare and has been reported sparingly in the literature. A 52-year-old male patient with recurrent carcinoma of the buccal mucosa was started on palliative chemotherapy regimen, injection paclitaxel (175 mg/m2) in combination with injection carboplatin. On post-chemotherapy day 13, the patient started developing pain, dysesthesia followed by bullae formation, and desquamation over palms and soles. Clinically, the patient had Grade 3 HFS characterized by symmetrical, tender skin lesions over the dorsal aspect of palms, and soles with desquamation necessitating interruption of treatment. Therefore, this case has been presented to be cognizant with this rare form of side effect with one of the most commonly used drug in oncology.


Mitochondria-Targeted Therapeutics for Alzheimer's Disease: The Good, the Bad, the Potential.
Significance: Alzheimer's disease (AD) is the leading cause of dementia. Thus far, 99.6% of clinical trials, including those targeting energy metabolism, have failed to exert disease-modifying efficacy. Altered mitochondrial function and disruption to the brain bioenergetic system have long-been documented as early events during the pathological progression of AD. Recent Advances: While therapeutic approaches that directly promote mitochondrial bioenergetic machinery or eliminate reactive oxygen species have exhibited limited translatability, emerging strategies targeting nonenergetic aspects of mitochondria provide novel therapeutic targets with the potential to modify AD risk and progression. Growing evidence also reveals a critical link between mitochondrial phenotype and neuroinflammation via metabolic reprogramming of glial cells. Critical Issues: Herein, we summarize major classes of mitochondrion-centered AD therapeutic strategies. In addition, the discrepancy in their efficacy when translated from preclinical models to clinical trials is addressed. Key factors that differentiate the responsiveness to bioenergetic interventions, including sex, apolipoprotein E genotype, and cellular diversity in the brain, are discussed. Future Directions: We propose that the future development of mitochondria-targeted AD therapeutics should consider the interactions between bioenergetics and other disease mechanisms, which may require cell-type-specific targeting to distinguish neurons and non-neuronal cells. Moreover, a successful strategy will likely include stratification by metabolic phenotype, which varies by sex and genetic risk profile and dynamically changes throughout the course of disease. As the network of mitochondrial integration expands across intracellular and systems level biology, assessment of intended, the good, versus unintended consequences, the bad, will be required to reach the potential of mitochondrial therapeutics.


The importance of perceptual experience in the esthetic appreciation of the body.
Several studies suggest that sociocultural models conveying extreme thinness as the widespread ideal of beauty exert an important influence on the perceptual and emotional representation of body image. The psychological mechanisms underlying such environmental influences, however, are unclear. Here, we utilized a perceptual adaptation paradigm to investigate how perceptual experience modulates body esthetic appreciation. We found that the liking judgments of round bodies increased or decreased after brief exposure to round or thin bodies, respectively. No change occurred in the liking judgments of thin bodies. The results suggest that perceptual experience may shape our esthetic appreciation to favor more familiar round body figures. Importantly, individuals with more deficits in interoceptive awareness were less prone to increase their liking ratings of round bodies after exposure, suggesting a specific risk factor for the susceptibility to the influence of the extreme thin vs. round body ideals of beauty portrayed by the media.


Characterization of Antimicrobial Agent Loaded Eudragit RS Solvent Exchange-Induced In Situ Forming Gels for Periodontitis Treatment.
Eudragit RS (ERS), a quaternary polyacrylate positively charged polymer, exhibits a very low permeability and swells in aqueous media independently of pH without dissolving. Owing to its high solubility in N-methyl pyrrolidone (NMP), it was interesting to apply as polymer matrix for solvent-exchanged in situ forming gel. The aim of this research was to prepare in situ forming gels from ERS to deliver the antimicrobial agents (doxycycline hyclate, metronidazole, and benzoyl peroxide) for periodontitis treatment. They were evaluated for viscosity and rheology, gel formation, syringeability, drug release, and antimicrobial activities. The solvent exchange between NMP and an external aqueous simulated gingival crevicular fluid stimulated the dissolved ERS transforming into the opaque rigid gel. Antimicrobial agent loaded ERS systems exhibited Newtonian flow with acceptable syringeability. The higher-loaded ERS promoted the more prolongation of drug release because of the retardation of water diffusion into the precipitated matrix. Antimicrobial activities against Staphylococcus aureus, Escherichia coli, Candida albicans, Streptococcus mutans, and Porphyromonas gingivalis depended on type of drugs and test microorganisms. Doxycycline hyclate loaded ERS systems showed these activities greater than the others; however, all of them could inhibit all test microorganisms. Thus, the solvent exchange-induced in situ forming gels comprising ERS-antimicrobial drugs exhibited potential use as localized delivery systems for periodontitis treatment.


Self-Regulation Phenomenon Emerged During Prolonged Fatigue Driving: An EEG Connectivity Study.
Driving fatigue is a common experience for most drivers and can reduce human cognition and judgment abilities. Previous studies have exhibited a phenomenon of the non-monotonically varying indicators (both behavioral and neurophysiological) for driving fatigue evaluation but paid little attention to this phenomenon. Herein, we propose a hypothesis that the non-monotonically varying phenomenon is caused by the self-regulation of brain activity, which is defined as the fatigue self-regulation (FSR) phenomenon. In this study, a 90-min simulated driving task was performed on 26 healthy university students. EEG data and reaction time (RT) were synchronously recorded during the whole task. To identify the FSR phenomenon, a data-driven criterion was proposed based on clustering analysis of individual behavioral data and the FSR group was determined as having non-monotonic increase trend of RT and the drops of RT during prolonged driving were more than two levels among the total five levels. The subjects were then divided into two groups: the FSR group and the non-FSR group. Quantitative comparative analysis showed significant differences in behavioral performance, functional connectivity, network characteristics, and classification performance between the FSR and non-FSR groups. Specifically, the behavioral performance exhibited apparent non-monotonic development trend: increasing-decreasing-increasing. Moreover, network characteristics presented similar self-regulated development trends. Our study provides a new insight for revealing the complex neural mechanisms of driving fatigue, which may promote the development of practical techniques for automatic detection method and mitigation strategy.


Current status of robotics in female urology and gynecology.
Currently, there has been limited reporting and research in the female urology and gynecological literature concerning the use of robotics. To date, robotics have been utilized only for the treatment of three benign gynecologic conditions: benign hysterectomy; repair of vesicovaginal fistula; and sacrocolpopexy which is a treatment for posthysterectomy vaginal vault prolapse. We describe a novel minimally invasive technique of vaginal vault prolapse repair and present our initial experience. The surgical technique involves placement of five laparoscopic ports: three for the daVinci robot and two for the assistant. A polypropylene mesh is then attached to the sacral promontory and to the vaginal apex using Gortex sutures. Thirty-one patients underwent a robotic-assisted laparoscopic sacrocolpopexy at our institution in the past 24 months for severe symptomatic vaginal vault prolapse. Complications were limited to mild port site infections in two patients, which resolved with oral antibiotic therapy. While our early experience utilizing robotic repairs in female urology and gynecology is encouraging, long-term data are needed to confirm these findings and establish longevity of the repair.


Phenotyping for drought tolerance in grain crops: when is it useful to breeders?
Breeding for drought tolerance in grain crops is not a generic issue. Periods of drought vary in length, timing and intensity and different traits are important with different types of drought. The search for generic drought tolerance using single-gene transformations has been disappointing. It has typically concentrated on survival of plants suffering from severe water stress, which is rarely an important trait in crops. More promising approaches that target complex traits tailored to specific requirements at the different main stages of the life of a crop, during: establishment, vegetative development, floral development and grain growth are outlined. The challenge is to devise inexpensive and effective ways of identifying promising phenotypes with the aim of aligning them with genomic information to identify molecular markers useful to breeders. Controlled environments offer the stability to search for attractive phenotypes or genotypes in a specific type of drought. The recent availability of robots for measuring large number of plants means that large numbers of genotypes can be readily phenotyped. However, controlled environments differ greatly from those in the field. Devising pot experiments that cater for important yield-determining processes in the field is difficult, especially when water is limiting. Thus, breeders are unlikely to take much notice of research in controlled environments unless the worth of specific traits has been demonstrated in the field. An essential link in translating laboratory research to the field is the development of novel genotypes that incorporate gene(s) expressing a promising trait into breeding lines that are adapted to target field environments. Only if the novel genotypes perform well in the field are they likely to gain the interest of breeders. High throughput phenotyping will play a pivotal role in this process.


Facile oxidative addition of N-C and N-H bonds to monovalent rhodium and iridium.
An investigation of room-temperature oxidative addition of N-C and N-H bonds to RhI and IrI in solution and in the solid state is presented. The rigid, product-adapted framework of the pincer bis(ortho-phosphinoaryl)amine (PNP) ligand may contribute to the ease of the N-C and N-H cleavage. The migration of Me from N of the coordinated amine moiety to Rh proceeds with near-zero entropy of activation in solution. In the solid state, this transformation is a crystal-to-crystal reaction, transforming only one of the two independent molecules of (PN(Me)P)RhCl into (PNP)Rh(Me)Cl.


Postoperative pelvic gas collections simulating pelvic abscess.
Extraperitoneal gas collections are routinely found in pelvic soft tissues following abdominal hysterectomy. These collections have the typical appearance of extraperitoneal gas but should not be confused with pelvic infection or bowel injury. Similar collections are not routinely found following vaginal hysterectomy.


Nanotechnology and the Nanodermatology Society.
Nanotechnology is a rapidly developing discipline with enormous promise for consumers and patients. Currently, it is entering an inflection point in its growth phase--both in the number and diversity of products developed or soon to be available for society and medicine. It is no surprise that a vast number of patents have been issued for nanotechnology in the cosmetics arena as a means of enhancing topical delivery of a broad range of over-the-counter products. In fact, the skin is the first point of contact for a whole host of nanomaterials, ranging from topical preparations, articles of clothing and household products, to sporting goods and industrial manufactured goods. Very little is known about the safety aspects of the nano-engineered materials that are being released in the environment, as well as those in consumer and healthcare products.


Bladder exstrophy: Comparison of anatomical bladder neck repair with innervation preserving sphincteroplasty versus Young-Dees-Leadbetter bladder neck reconstruction.
To evaluate the outcome of innervation preserving sphincteroplasty along with anatomical bladder neck reconstruction (IPS-ABNR) compared to classic Young-Dees-Leadbetter (YDL) bladder neck reconstruction in exstrophy with insufficient bladder capacity requiring detubularized-ileocystoplasty. Sixteen male patients of exstrophy bladder who required ileocystoplasty from 2004 to 2010 were randomized into group A (n = 7) and group B (n = 9). After detubularized-ileocystoplasty with Mitrofanoff stoma and ureteric reimplantation in all, group A received YDL bladder neck repair while group B received IPS-ABNR repair through a midline scrotoperineal approach. Outcome measurement included operative and postoperative problems, continence, and upper tract status. In group A, two had incompetent bladder neck with gross incontinence, while four had a dry interval of more than 3 h without the ability of voiding per urethra. In group B, seven patients had dry interval of more than 3 h with an ability of urethral voiding and midstream holding in five. Exstrophy patients requiring augmentation cystoplasty and repaired with IPS-ABNR can achieve dynamic bladder outlet resistance with adequate leak point pressure and ability to void voluntarily with midstream holding capability. The children had the satisfaction of voiding per urethra with ability to stop in midstream similar to that in normal children.


Both Prediabetes and Type 2 Diabetes Are Associated With Lower Heart Rate Variability: The Maastricht Study.
Low heart rate variability (HRV), a marker for cardiac autonomic dysfunction, is a known feature of type 2 diabetes, but it remains incompletely understood whether this also applies to prediabetes or across the whole glycemic spectrum. Therefore, we investigated the association among prediabetes, type 2 diabetes, and measures of glycemia and HRV. In the population-based Maastricht Study (n = 2,107; mean ± SD age 59 ± 8 years; 52% men; normal glucose metabolism [n = 1,226], prediabetes [n = 331], and type 2 diabetes [n = 550, oversampled]), we determined 24-h electrocardiogram-derived HRV in time and frequency domains (individual z-scores, based upon seven and six variables, respectively). We used linear regression with adjustments for age, sex, and major cardiovascular risk factors. After adjustments, both time and frequency domain HRV were lower in prediabetes and type 2 diabetes as compared with normal glucose metabolism (standardized β [95% CI] for time domain: -0.15 [-0.27; -0.03] and -0.34 [-0.46; -0.22], respectively, P for trend <0.001; for frequency domain: -0.14 [-0.26; -0.02] and -0.31 [-0.43; -0.19], respectively, P for trend <0.001). In addition, 1-SD higher glycated hemoglobin, fasting plasma glucose, and 2-h postload glucose were associated with lower HRV in both domains (time domain: -0.16 [-0.21; -0.12], -0.16 [-0.21; -0.12], and -0.15 [-0.20; -0.10], respectively; frequency domain: -0.14 [-0.19; -0.10], -0.14 [-0.18; -0.09], and -0.13 [-0.18; -0.08], respectively). Both prediabetes and type 2 diabetes were independently associated with lower HRV. This is further substantiated by independent continuous associations between measures of hyperglycemia and lower HRV. These data strongly suggest that cardiac autonomic dysfunction is already present in prediabetes.


Roles of innate lymphoid cells (ILCs) in allergic diseases: The 10-year anniversary for ILC2s.
In the 12 years since the discovery of innate lymphoid cells (ILCs), our knowledge of their immunobiology has expanded rapidly. Group 2 ILCs (ILC2s) respond rapidly to allergen exposure and environmental insults in mucosal organs, producing type 2 cytokines. Early studies showed that epithelium-derived cytokines activate ILC2s, resulting in eosinophilia, mucus hypersecretion, and remodeling of mucosal tissues. We now know that ILC2s are regulated by other cytokines, eicosanoids, and neuropeptides as well, and interact with both immune and stromal cells. Furthermore, ILC2s exhibit plasticity by adjusting their functions depending on their tissue environment and may consist of several heterogeneous subpopulations. Clinical studies show that ILC2s are involved in asthma, allergic rhinitis, chronic rhinosinusitis, food allergy, and eosinophilic esophagitis. However, much remains unknown about the immunologic mechanisms involved. Beneficial functions of ILCs in maintenance or restoration of tissue well-being and human health also need to be clarified. As our understanding of the crucial functions ILCs play in both homeostasis and disease pathology expands, we are poised to make tremendous strides in diagnostic and therapeutic options for patients with allergic diseases. This review summarizes discoveries in immunobiology of ILCs and their roles in allergic diseases in the past 5 years, discusses controversies and gaps in our knowledge, and suggests future research directions.


[Prevalence of Lyme borreliosis in The Netherlands].
In the autumn of 1989 a seroepidemiological study was carried out among 440 owners of hunting dogs and 1052 blood donors from different regions in the Netherlands. To detect IgG antibodies to Borrelia burgdorferi an enzyme-linked immunosorbent assay was performed. The prevalence of antibodies to B. burgdorferi in owners of hunting dogs was 15%, which was significantly higher than in blood donors (9%). In both groups the prevalence of seropositivity increased with age. There was no difference between men and women. The prevalence of antibodies to B. burgdorferi in blood donors from different regions varied significantly, ranging from 2% to 17%. Only 3% of the owners of hunting dogs could recall having had symptoms most likely to be due to Lyme borreliosis. Of the 68 seropositive hunters 64 (94%) were asymptomatic. The results of this study indicate that in the Netherlands asymptomatic infections with B. burgdorferi are common in individuals highly exposed to ticks and that there is considerable variation in the prevalence of seropositivity in the general population. Hence caution is called for in the clinical interpretation of IgG test results.


Three factors underlying incorrect in silico predictions of essential metabolic genes.
The indispensability of certain genes in an organism is important for studies of microorganism physiology, antibiotic targeting, and the engineering of minimal genomes. Time and resource intensive genome-wide experimental screens can be conducted to determine which genes are likely essential. For metabolic genes, a reconstructed metabolic network can be used to predict which genes are likely essential. The success rate of these predictions is less than desirable, especially with regard to comprehensively locating essential genes. We show that genes that are falsely predicted to be non-essential (for growth) share three characteristics across multiple organisms and growth media. First, these genes are on average connected to fewer reactions in the network than correctly predicted essential genes, suggesting incomplete knowledge of the functions of these genes. Second, they are more likely to be blocked (their associated reactions are prohibited from carrying flux in the given condition) than other genes, implying incomplete knowledge of metabolism surrounding these genes. Third, they are connected to less overcoupled metabolites. The results presented herein indicate genes that cannot be correctly predicted as essential have commonalities in different organisms. These elucidated failure modes can be used to better understand the biology of individual organisms and to improve future predictions.


Contact Kinematics Correlates to Tibial Component Migration Following Single Radius Posterior Stabilized Knee Replacement.
Contact kinematics between total knee arthroplasty components is thought to affect implant migration; however, the interaction between kinematics and tibial component migration has not been thoroughly examined in a modern implant system. A total of 24 knees from 23 patients undergoing total knee arthroplasty with a single radius, posterior stabilized implant were examined. Patients underwent radiostereometric analysis at 2 and 6 weeks, 3 and 6 months, and 1 and 2 years to measure migration of the tibial component in all planes. At 1 year, patients also had standing radiostereometric analysis examinations acquired in 0°, 20°, 40°, and 60° of flexion, and the location of contact and magnitude of any condylar liftoff was measured for each flexion angle. Regression analysis was performed between kinematic variables and migration at 1 year. The average magnitude of maximum total point motion across all patients was 0.671 ± 0.270 mm at 1 year and 0.608 ± 0.359 mm at 2 years (P = .327). Four implants demonstrated continuous migration of >0.2 mm between the first and second year of implantation. There were correlations between the location of contact and tibial component anterior-posterior tilt, varus-valgus tilt, and anterior-posterior translation. The patients with continuous migration demonstrated atypical kinematics and condylar liftoff in some instances. Kinematics can influence tibial component migration, likely through alterations of force transmission. Abnormal kinematics may play a role in long-term implant loosening.


Self-reported tick exposure as an indicator of Lyme disease risk in an endemic region of Quebec, Canada.
Lyme disease (LD) and other tick-borne diseases are emerging across Canada. Spatial and temporal LD risk is typically estimated using acarological surveillance and reported human cases, the former not considering human behavior leading to tick exposure and the latter occurring after infection. The primary objective was to explore, at the census subdivision level (CSD), the associations of self-reported tick exposure, alternative risk indicators (predicted tick density, eTick submissions, public health risk level), and ecological variables (Ixodes scapularis habitat suitability index and cumulative degree days > 0 °C) with incidence proportion of LD. A secondary objective was to explore which of these predictor variables were associated with self-reported tick exposure at the CSD level. Self-reported tick exposure was measured in a cross-sectional populational health survey conducted in 2018, among 10,790 respondents living in 116 CSDs of the Estrie region, Quebec, Canada. The number of reported LD cases per CSD in 2018 was obtained from the public health department. Generalized linear mixed-effets models accounting for spatial autocorrelation were built to fulfill the objectives. Self-reported tick exposure ranged from 0.0 % to 61.5 % (median 8.9 %) and reported LD incidence rates ranged from 0 to 324 cases per 100,000 person-years, per CSD. A positive association was found between self-reported tick exposure and LD incidence proportion (ß = 0.08, CI = 0.04,0.11, p < 0.0001). The best-fit model included public health risk level (AIC: 144.2), followed by predicted tick density, ecological variables, self-reported tick exposure and eTick submissions (AIC: 158.4, 158.4, 160.4 and 170.1 respectively). Predicted tick density was the only significant predictor of self-reported tick exposure (ß = 0.83, CI = 0.16,1.50, p = 0.02). This proof-of-concept study explores self-reported tick exposure as a potential indicator of LD risk using populational survey data. This approach may offer a low-cost and simple tool for evaluating LD risk and deserves further evaluation.


Inferring efficiency of translation initiation and elongation from ribosome profiling.
One of the main goals of ribosome profiling is to quantify the rate of protein synthesis at the level of translation. Here, we develop a method for inferring translation elongation kinetics from ribosome profiling data using recent advances in mathematical modelling of mRNA translation. Our method distinguishes between the elongation rate intrinsic to the ribosome's stepping cycle and the actual elongation rate that takes into account ribosome interference. This distinction allows us to quantify the extent of ribosomal collisions along the transcript and identify individual codons where ribosomal collisions are likely. When examining ribosome profiling in yeast, we observe that translation initiation and elongation are close to their optima and traffic is minimized at the beginning of the transcript to favour ribosome recruitment. However, we find many individual sites of congestion along the mRNAs where the probability of ribosome interference can reach $50\%$. Our work provides new measures of translation initiation and elongation efficiencies, emphasizing the importance of rating these two stages of translation separately.


Syndecan-1 (CD138) expression in acute myeloblastic leukemia cells--an immuno electron microscopic study.
Syndecan-1 (CD138), an important transmembrane heparan sulfate proteoglycan is expressed in distinct stages of cell differentiation. Although its expression in acute lymphoblastic leukemia (ALL) cells is well known: its function or presence in acute myeloblastic leukemia (AML) cells is still largely unknown. The expression of syndecan-1 was studied in bone marrow biopsies of three patients with AML using electron microscopic immunocytochemistry. Positive expression of syndecan-1 was found in AML cells. These results suggest that syndecan-1 expression is not only a characteristic phenotypic marker for ALL, but is also expressed in AML cells.


Enhancement of antitumor immunity by CTLA-4 blockade.
One reason for the poor immunogenicity of many tumors may be that they cannot provide signals for CD28-mediated costimulation necessary to fully activate T cells. It has recently become apparent that CTLA-4, a second counterreceptor for the B7 family of costimulatory molecules, is a negative regulator of T cell activation. Here, in vivo administration of antibodies to CTLA-4 resulted in the rejection of tumors, including preestablished tumors. Furthermore, this rejection resulted in immunity to a secondary exposure to tumor cells. These results suggest that blockade of the inhibitory effects of CTLA-4 can allow for, and potentiate, effective immune responses against tumor cells.


[Clinico-experimental study of auditory-speech agnosia (case with anatomo-histologic verification)].
Under observation there was a female patient (a right-hander) who had three ischemic cerebral strokes within a year. After the first stroke she developed an amnestic-sensory aphasia, after the second an auditory and speech agnosia with a complete loss of the ability to understand the speech addressed to her, and after the third stroke she died. Macro- and microscopic examinations showed that the first stroke caused a destruction in the region of the left temporal lobe cortex involving a part of the Heschl convolution; the second stroke resulted in destruction of the right temporal lobe involving almost the whole Heschl convolution. Thus, it has been confirmed that the syndrome can develop only in case of a grave bitemporal damage. Comparative examinations of the speech and audition after the first and the second stroke have shown that in auditory and speech agnosia, the auditory discernment of phonemes, their combinations and the speech prosodic elements is pronouncedly deranged, the formation of conditioned reflexes to sounds of a supraliminal force is disturbed, the detection of short acoustic messages and acoustic filtration are hampered (mainly on the side contralateral to the affected one) the amusia gets more marked and the discernment of rhythms more difficult. All these disturbances are highly dynamic. A question on the role of defects of the right and the left hemispheres in the clinical picture of the auditory and speech agnosia is discussed.


Thrombocytopenia in preeclampsia and eclampsia.
1. The lack of a general agreement on the definition of PE makes the interpretation of laboratory findings in different series of these patients difficult. 2. Thrombocytopenia is the most common hemostatic abnormality in patients with PE and is caused by platelet consumption. 3. There is little concrete evidence that thrombin mediates the thrombocytopenia in most of these patients. 4. Immune mechanisms or severe vasospasm with resultant endothelial damage may contribute to the thrombocytopenia in some patients.


[Nutrition and physical exercise].
The principles of a good diet and proper nutrition are the same for people practising sports and for non-athletes. The main difference lies in the amount of energy that sportsmen and women need to carry out a more intense physical activity and to keep an appropriate weight to allow greater performance. The relationship between nutrition and physical exercise has often been shrouded in confusion and conjecture, so certain products or supplements turn into real myths through attempts to achieve better athletic results, despite the fact the information available on the true effect of a particular substance or food on athletic performance is, quite limited and disputed. This paper attempts to clarify the scientific information available on this subject.


Ultrasonographic evaluation of horses with thrombophlebitis of the jugular vein: 46 cases (1985-1988).
Medical records of 46 horses with jugular vein thrombophlebitis that were evaluated ultrasonographically were reviewed. The ultrasonographic appearance of the thrombus within the jugular vein was classified as noncavitating if it had uniform low to medium amplitude echoes, or as cavitating if it was heterogenous with anechoic to hypoechoic areas representing fluid or necrotic areas within the thrombus, and/or hyperechoic areas representing gas. Signs of pain on palpation of the affected vein (P less than 0.001), heat over the vein (P = 0.001), and swelling of the vein (P less than 0.05) were significantly associated with the ultrasonographic detection of a cavitating lesion. Ultrasonography also was useful for selecting a site for aspiration of a specimen for bacteriologic culturing and susceptibility testing.


Incorporating immune-checkpoint inhibitors into systemic therapy of NSCLC.
Despite current therapeutic options metastatic non- small-cell lung cancer (NSCLC) remains incurable. Targeted therapies have opened new opportunities for several molecular subtypes, but virtually all patients treated will ultimately develop progressive disease by treatment resistance. Recent clinical trials have shown that immune-checkpoint blockade can result in striking and durable responses in metastatic NSCLC. These impressive results are yet to be confirmed in following trials; nonetheless, NSCLC therapeutic strategies will most likely need to integrate immune-checkpoint inhibitors in the near future. Interestingly, conventional therapies are capable of modulating the immune system and can therefore interact directly or indirectly with immunotherapies. This suggests that some combinations might have synergistic activity and lead to improved efficacy. Conventional and targeted therapies can induce rapid tumor lysis, and immune-checkpoint blockade can then help to induce a sustained immune-mediated tumor control. Moreover, the distinctive toxicity profile associated with immune-checkpoint modulators makes them good candidates for combination strategies. Here we summarize the results of immune-checkpoints trials in NSCLC, and also report how current therapeutic options can modulate the immune system. We provide a rationale and identify potential challenges for immune-checkpoint blockade combinations with conventional therapeutics in NSCLC.


Early detection of prostate cancer: is PSA a reliable option?
A close relationship exists between prostate volume and prostate-specific antigen (PSA). Clinical decisions must be determined based on the variability of PSA. Screening with the PSA assay has contributed to early detection of prostate cancer. Some important undetermined issues are the optimal cutoff values of PSA, the proportion of free to total PSA, and the clinical usefulness of complexed PSA. Current articles demonstrating novel markers (human kallikrein-2, BPSA, and pro PSA) and artificial neural networks are introduced.


Utilization of serum tryptase and immunoglobulin e assay in the postmortem diagnosis of anaphylaxis.
The postmortem diagnosis of anaphylaxis is difficult. Serum concentrations of tryptase (a mast cell product released during anaphylaxis) have been used after death as an indicator of possible antemortem anaphylaxis. However, studies have indicated that tryptase may be elevated with increasing postmortem interval (PMI), or in nonanaphylactic deaths with significant atherosclerosis or chest trauma. Serum total IgE has been used by some to confirm anaphylaxis when tryptase is elevated. Serum levels of tryptase from 57 decedents with varying PMI, all dying of presumed nonanaphylactic causes, were determined. In cases with elevated levels (>11.4 ng/mL), an assay of total serum IgE was also performed. Both tryptase and IgE demonstrated significant elevations with increasing PMI. Decedents were categorized according to presence of cardiovascular disease, chest trauma, or both; many demonstrated elevation of 1 or both markers, without statistically significant differences between categories. Postulated mechanisms for nonanaphylactic elevations of these markers are reviewed. The possible utility of allergen-specific IgE or allergen panels is discussed.


CT sialography, Part I: Introduction, technique, anatomy, and variants.
The value of sialography in the investigation of parotid disease has been controversial and limited in its scope. The marked advantage of CT's ability to demonstrate soft tissue detail has been noted. However, parotid parenchyma is inadequately displayed in the unenhanced or intravenously enhanced state. Further information about pathology is available if the CT study is performed utilizing a sialographic contrast medium. Our method of performing such studies is demonstrated. Detail of parotid parenchyma available by this modality is noted. Illustrations of normal anatomy and variants that may be mistaken for mass lesions are presented.


Mortality of workers manufacturing friction materials using asbestos.
A mortality (1942-80) study was carried out on 13460 workers of a factory producing friction materials. The only type of asbestos used was chrysotile, except during two well-defined periods before 1945 when crocidolite was used, and over 99% of the population was traced. Compared with national death rates there were no detectable excesses of deaths due to lung cancer, gastrointestinal cancer, or other cancers; 11 deaths were due to pleural mesothelioma. A case-control study was carried out on deaths due to mesothelioma; this showed that eight workers had been exposed to crocidolite and another was possibly exposed intermittently to crocidolite. The other two had been employed for most of their working lives outside the factory, and their mesotheliomas could not be definitely attributed to exposure to chrysotile. Limiting the study to cases and controls who had exposure to 5 fibres/ml of chrysotile asbestos it was found that five of the six cases compared with two of the 10 controls had also been exposed to crocidolite. The probability (1:36) of this occurring were there no association with crocidolite is most unlikely. A case-control study was also carried out on deaths due to lung cancer and gastrointestinal cancer to investigate the dose-response relationships between these tumours and exposure to chrysotile. Measured and estimated fibre concentrations were available for the different jobs over the period of the study. No dose-response relationships were observed, but the exposures were low with only 5% of men accumulating 100 fibre-years/ml. The experience at this factory over a 40-year period showed that chrysotile asbestos was processed with no detectable excess mortality.


Efficacy of a lutein-based dye (Phacodyne™) for visualizing anterior capsulorhexis during cataract surgery by phacoemulsification.
To evaluate the efficacy and safety of a novel lutein-based dye for the anterior capsulorhexis during phacoemulsification in cataract surgery in humans. Twenty-five eyes from 25 patients were operated by 25 different surgeons who performed continuous circular capsulorhexis (CCC) guided by a lutein-based dye (Phacodyne™) during cataract surgery by phacoemulsification. A questionnaire assessed the surgeon's opinion regarding the efficacy of the dye. Follow-up examinations were performed at 1, 7, and 30 days post-surgery. Eyes were evaluated by full ophthalmic examination, corneal topography/pachymetry, and corneal endothelial cell count. As revealed by the answers to the questionnaire, the dye facilitated the CCC procedure in all eyes. Baseline nuclear cataract classification (according to the Lens Opacities Classification System III; LOCS III) was 3.24 (± 1.12). Preoperative BCVA (logMAR) was 0.89 ± 0.59 and improved to 0.23 ± 0.22 on day 30 after surgery. The intraocular pressure (IOP) remained stable and the inflammatory reaction subsided in all cases within the first 7 days after surgery. The pre-operative values of corneal pachymetry and IOP were similar to those found on follow-up day 30. Loss in endothelial cell number was similar to earlier reports. Phacodyne™ was efficient when used for anterior capsulorhexis during cataract surgery by phacoemulsification and


Fc-receptors, Ia-antigens, and immunoglobulin on normal and activated mouse T lymphocytes.
Using antibody coated bovine erythrocytes we were unable to demonstrate Fc-receptors on either thymus cells or T cells prepared from lymph node cell suspensions by anti-Ig column filtration. However, if parental thymus or lymph node T cells were transferred to X-irradiated F1 hybrids, activated donor T cells recovered from the recipient's spleen (ATC-spleen) were shown to express Fc-receptors. Fc-receptors were also demonstrable on ATC-spleen prepared between strain combinations differing at the M-locus. In marked contrast, Fc-receptors were not detected on ATC recovered from thoracic duct lymph (T.TDL). This applied to (a) H-2-activated T.TDL derived from normal thymus cells, (b) H-2-activated T.TDL derived from thymus cells depleted of B cells, and (c) M-locus-activated T.TDL. Of these three populations, surface Ig (of B cell origin) was detected on a large proportion of the first but not on the second and third populations. Thus, the failure to detect Fc-receptors on any of these populations could not be attributed to blocking by adsorbed surface Ig. In addition, various T-cell populations were examined by a microcytotoxicity assay for the presence of cell surface Ia-antigens. 5--10% of the thymus cells, 20--30% of cortisone-resistant thymus cells, 60--70% of lymph node cells, and 60--80% of ATC-spleen and T.TDL showed Ia.


Central nervous system effects of intranasally administered insulin during euglycemia in men.
Insulin receptors have been detected in several structures of the brain, yet the biological significance of insulin acting on the brain remains rather unclear. In humans, direct central nervous effects of insulin are difficult to distinguish from alterations in neuronal functions because of insulin-induced decrease in blood glucose levels. Since several intranasally administered viruses, peptides, and hormones have been shown to penetrate directly from the nose to the brain, we tested whether insulin after intranasal administration likewise has access to the brain. After a 60-min baseline period, insulin (20 IU H-Insulin 100 Hoechst) or vehicle (2.7 mg/ml m-Cresol) was intranasally administered every 15 min to 18 healthy subjects according to a double-blind within-subject crossover design. Auditory-evoked potentials (AEP) indexing cortical sensory processing were recorded while the subjects performed a vigilance task (oddball paradigm) during the baseline phase and after 60 min of intranasal treatment with insulin or placebo. Blood glucose and serum insulin levels were not affected by intranasal insulin. Compared with placebo, intranasal administration of insulin reduced amplitudes of the N1 (P < 0.005) and P3 (P < 0.02) components of the AEP and increased P3 latency (P < 0.05). The reduction in P3 amplitude was most pronounced over the frontal recording site (2.42 +/- 1.00 vs. 4.92 +/- 0.79 microV, P < 0.0005). At this site, after insulin administration, a broad negative shift developed in the AEP between 280 and 500 ms poststimulus (area under the curve -166.0 +/- 183.8 vs. 270.8 +/- 138.7 microV x ms after placebo, P < 0.01). The results suggest that after intranasal administration, insulin directly enters the brain and exerts distinct influences on central nervous functions in humans.


Retroperitoneal injuries of the duodenum caused by blunt abdominal trauma.
Five patients with blunt retroperitoneal injury of the duodenum are presented. In three of them the trauma was caused by a traffic accident, the most common mechanism of such injuries. One patient died. The high index of suspicion is still the best indication for laparotomy in retroperitoneal injuries of the duodenum, because no typical finding or reliably diagnostic test could be demonstrated even in the present study. The proper treatment in less severe injuries of the retroperitoneal duodenum is evacuation of the hematoma or simple suture of the rupture with drainage and naso-gastric suction. Internal drainage as an afferent jejunostomy is sometimes necessary in the treatment of more severe injuries. Pancreatoduodenectomy is to be reserved for only the very severe duodenal injuries, where the head of the pancreas is badly crushed.


A bacterial factor induces changes in cysteine proteinase forms in the cellular slime mould Dictyostelium discoideum.
The electrophoretic pattern of cysteine proteinases in axenically grown myxamoebae of Dictyostelium discoideum can be altered by the addition of either Gram-negative (Klebsiella aerogenes, Escherichia coli) or Gram-positive (Micrococcus lysodeikticus, Bacillus subtilis) bacteria to the culture. No changes occurred, however, if either yeast or latex beads were used in place of bacteria. The changes involved the simultaneous loss of proteinases characteristic of the axenic cells (the A-forms) and the acquisition of those found in cells which have been grown on bacteria (the B-forms). Using K. aerogenes the conversion was complete within 4 h. Extracellular proteinase activity was unaffected during this period. After the D. discoideum cells had been lysed, no equivalent change in proteinase band pattern could be produced either by prolonged incubation of cell extracts or by treatment with proteinases. An identical conversion could be induced in cultures of myxamoebae by a factor, cysteine proteinase converting factor (CPCF), present in the 15,000 g supernatant of a sonicated suspension of K. aerogenes. CPCF was macromolecular, as demonstrated by both ultrafiltration and gel filtration, acid-precipitable, but was soluble in ethanol or alkali. Its activity was unaffected by treatment with trypsin. The results suggested that CPCF might be a component of the bacterial cell wall, and since its activity was affected by lysozyme treatment, peptidoglycan is implicated. The results can be interpreted in terms of a novel nutrient-dependent post-translational change which affected most of the cysteine proteinases present in D. discoideum myxamoebae.