Effectiveness of aripiprazole, olanzapine, quetiapine, and risperidone augmentation treatment for major depressive disorder: a nationwide population-based study.
Previous studies suggested that antidepressants augmented with second-generation antipsychotics (SGAs), including aripiprazole, olanzapine, quetiapine, and risperidone, resulted in better treatment response or higher rates of remission in patients with major depressive disorder (MDD). However, population-based study on SGA augmentation for patients with MDD remains limited. The purpose of this study was to investigate the effectiveness of SGA augmentation for treatment of MDD using the National Health Insurance Research Database in Taiwan. The subjects were patients with MDD (ICD-9-CM code: 296.2 and 296.3) who were initially admitted to psychiatric inpatient settings for the first time between January 1, 1996, and December 31, 2007, and could be tracked until December 31, 2011. To assess the treatment effect of SGA augmentation, 993 MDD patients who received aripiprazole, olanzapine, quetiapine, or risperidone augmentation treatment for 8 weeks or more were included in this 1-year mirror-image study. Outcome measures included length of psychiatric hospitalization and number of psychiatric admissions and emergency room (ER) visits. After patients received SGA augmentation treatment, key psychiatric service use (including length of psychiatric hospitalization [P < .0001], number of psychiatric admissions [P < .0001], and ER visits [P = .0006]) due to MDD diagnosis was significantly reduced. Subgrouping analysis for each SGA drug also showed significant reduction in number of psychiatric admissions for MDD patients who received aripiprazole (P < .0001), olanzapine (P = .003), quetiapine (P < .0001), and risperidone (P < .0001). The study provides support that aripiprazole, olanzapine, quetiapine, and risperidone augmentation therapy could be effective in reducing psychiatric service utilization among MDD patients.


Diagnostic Techniques in Autoimmune Blistering Diseases.
Autoimmune blistering diseases (AIBD) comprise a heterogeneous group of uncommon disorders of the skin and mucous membranes, characterised by antibodies targeting structural proteins within epithelial tissue and the underlying basement membrane. There can be significant overlap in clinical presentation of these diseases and accurate diagnosis relies on the detection and characterisation of relevant autoantibodies. Immunofluorescence provides the gold-standard diagnostic tool for these diseases, identifying both tissue-bound autoantibodies in biopsy material using direct immunofluorescence and circulating antibodies in serum through indirect immunofluorescence. Following advances in the identification and subsequent characterisation of numerous antigenic targets in these diseases, the development of antigen-specific tests, in particular, enzyme-linked immunosorbent assays on serum specimens, has provided a third key tool to not only identify, but also quantify AIBD autoantibodies. This quantification has proven particularly useful in monitoring disease activity and informing clinical management decisions. Accurate diagnosis of these diseases is important since optimal treatment strategies differ between them and, prognostically, some diagnoses are associated with an increased risk of malignancy. This review outlines the molecular pathology underlying the major AIBD and describes how the three principal techniques can be used in combination, to provide best practice for diagnosis and treatment monitoring.


Effects of insulin and guanosine 5'-[gamma-thio]triphosphate on fatty acid synthesis and lipolysis within electropermeabilized fat-cells.
1. Exposure to electric fields ('electroporation') has been used to investigate the mechanism of the action of insulin on the regulation of fatty acid synthesis and lipolysis in isolated rat fat-cells. 2. Exposure of the cells to electric fields (six pulses at 2 or 3 kV/cm) permitted the uptake of a number of low-Mr molecules normally excluded from cells, including sucrose (Mr 342), EDTA (Mr 394) and propidium iodide (Mr 668). At least 90% of the cells were found to be permeable to these species. 3. Insulin stimulated the synthesis of fatty acids in electroporated (2 kV/cm) cells to a similar extent (0.68 +/- 0.19 to 6.7 +/- 0.7 micrograms-atoms of glucose carbon/h per g, or 3.3 +/- 0.6 to 11.2 +/- 1.6 micrograms-atoms of H2O hydrogen/h per g) to that observed in non-electroporated cells. Guanosine 5'-[gamma-thio]triphosphate (GTP[S]; 0.5 mM) also stimulated fatty acid synthesis (2-fold) and flux of glucose carbon into triacylglycerol glycerol (3-fold) in these cells, but had no effect on these parameters in non-electroporated cells. 4. Lipolysis in the electroporated cells was stimulated by isoprenaline and also by GTP[S], but only the effects of isoprenaline were inhibited by insulin. 5. Exposure to a higher field strength (3 kV/cm) gave results qualitatively similar to those described above, although the effects of insulin and isoprenaline were diminished. 6. These studies provide evidence against a role for changes in Ca2+, and probably also Na+, K+ or Mg2+, in insulin action on fat-cells, but may support a role for GTP-binding proteins.


Characterization of cis-regulatory elements of the vascular endothelial growth inhibitor gene promoter.
VEGI (vascular endothelial growth inhibitor), a member of the tumour necrosis factor superfamily, has been reported to inhibit endothelial cell proliferation, angiogenesis and tumour growth. We identified and cloned approx. 2.2 kb of the VEGI promoter from mouse cerebral endothelial cells. The promoter contained an atypical TATA-box-binding protein sequence TAAAAAA residing at -32/-26 relative to the transcription initiation site (+1), 83 bp upstream from the ATG start codon. To investigate critical sequences in the VEGI promoter, a series of deleted and truncated segments were constructed from a 2300 bp promoter construct (-2201/+96) linked to a luciferase reporter gene. Transient transfection of cerebral microvascular cells (bEND.3) and rat C6 glioma cells demonstrated that a 1700 bp deletion from the -2201 to -501 did not significantly affect promoter activity; however, a truncated construct (-501/+96) lacking the region between -312 and -57 resulted in nearly 90% loss of promoter activity. A consensus NF-kappaB (nuclear factor kappaB) and several SP1 (specificity protein-1)-binding sequences were identified within the deleted segment. Supershift analysis revealed that NF-kappaB subunits, p50 and p65, interacted with the VEGI promoter. Exposure of cerebral endothermic cells to the pro-inflammatory cytokine, tumour necrosis factor-alpha, increased VEGI mRNA levels and DNA-binding activities, whereas an NF-kappaB inhibitor attenuated this increase. In addition, p65 overexpression enhanced, whereas p50 overexpression decreased, the luciferase activity. Furthermore, mutation of the NF-kappaB DNA binding site blocked this p65- and tumour necrosis factor-alpha-induced luciferase activity. These findings suggest that the transcription factor NF-kappaB plays an important role in the regulation of VEGI expression.


Risk of resistance and the metabolic resistance mechanism of Laodelphax striatellus (Fallén) to cyantraniliprole.
Cyantraniliprole is a highly effective diamide insecticide used to control of Laodelphax striatellus (Fallén). This study aimed to assess the insecticide resistance risk of L. striatellus and its metabolic resistance mechanisms. After 25 continuous generations of selection, the resistance of L. striatellus to cyantraniliprole increased by 17.14-fold. The realistic heritability of resistance was 0.0751. After successive rearing for five generations without exposure to insecticides, the resistance ratio for the resistant strain of L. striatellus decreased by 3.47-fold, and the average resistance decline rate per generation was 0.0266. Cyantraniliprole-resistant strains did not exhibit cross-resistance to triflumezopyrim, pymetrozine, flonicamid, sulfoxaflor, dinotefuran, clothianidin, thiamethoxam, nitenpyram, or imidacloprid. Compared to those of the sensitive strain, the 2nd, 3rd, and 4th instars, nymphal stage durations, total preoviposition period, and average generation time of the resistant strain were markedly reduced. Furthermore, the activity of cytochrome P450 monooxygenase (P450) and carboxylesterase (CarE) were markedly increased. The upregulation of CYP419A1v2 expression was most evident among the P450 genes, with a 6.10-fold increase relative to that in the sensitive strain. The CarE gene LsCarE5 was significantly upregulated by 1.94-fold compared with that in the sensitive strain. With the continuous use of cyantraniliprole, L. striatellus may develop resistance to this insecticide. This resistance may be related to the increase in metabolic enzyme activities regulated by the overexpression of P450 and CarE genes.


Aerobic bacterial microbiota of the conjunctiva in diabetic patients with normal and altered glycated hemoglobin levels in two regions in Brazil.
To study the aerobic bacterial microbiota of the conjunctiva in diabetic patients with regard to the management of diabetes, assessed using glycated hemoglobin levels. A cross-sectional study was conducted using conjunctival smears of diabetic patients from both sexes and with different ages, residing in two different Brazilian cities (Sorocaba and Rio Branco). A control group of non-diabetic patients was also included. The diabetic patients were considered to have controlled diabetes when their glycated hemoglobin level was ≤7% and blood glucose level was ≤126 mg/dL. Patients with non-controlled diabetes were those with glycated hemoglobin levels >7% and blood glucose levels >126 mg/dL. The samples obtained were inoculated in Brain-Heart Infusion broth and in culture media for aerobic bacteria (blood and chocolate agars); bacterial growth was evaluated in a microbiology laboratory. A total of 120 eyes of 120 patients were included in the present study. The percentage of cultures in which bacterial growth was observed was greater in diabetic patients, although the difference was not statistically significant (p=0.103). There was a greater trend toward bacterial growth in the conjunctiva of diabetic patients with altered fasting blood glucose. There was no difference in the frequency of bacterial growth on the conjunctiva between diabetic patients with normal or altered glycated hemoglobin levels. In Sorocaba, conjunctival bacterial growth was similar to that observed in Rio Branco. The microorganism most frequently detected in the present study was Staphylococcus epidermidis, followed by Staphylococcus aureus, Proteus mirabilis, and Escherichia coli. There was no difference between diabetic patients with normal or altered glycated hemoglobin levels. The microorganisms found were similar to those found in studies investigating the conjunctival bacterial flora of diabetic and non-diabetic patients.


How do hedgerow characteristics alter the dispersal of Pseudocercospora fijiensis propagules?
Hedgerows represent an agroecological lever for pest management. To date, few studies have shown that they can be used as a lever for the control of aerial fungal diseases, especially as a barrier to dispersal. On banana production, the main disease is black leaf streak disease (BLSD), which is a fungal disease caused by Pseudocercospora fijiensis. This pathogen disperses through two types of spores: ascospore and conidia. The aim of this study was to observe and to quantify the effect of hedgerows on BLSD dispersal. Trap plants were placed at the same distance to an artificial source of inoculum with a hedgerow on one side. Lesions were counted to establish the daily lesion density of each trap plant. The combination of hedgerow characteristics such as height, width, and optical porosity were used to evaluate its potential capacity to intercept spores. When ascospores were used as a source of inoculum, the lesion density on traps plant decreased up to 50% between the hedgerow with the lowest interception capacities and the one with the highest interception capacities. For conidia, hedgerow height and side of the trap plants (with or without hedgerow between them and the source) were not significant, but low porosity of the hedgerow reduced the lesion density. On the contrary, for ascospore, the hedgerow effect was anisotropic; the trap plants on hedgerow side had less lesions. Our study is the first experimental proof of the effect of hedgerows on P. fijiensis dispersion, both on conidia and ascospore. We showed that hedgerow characteristics impact the capacity of interception of the hedgerow. © 2023 Society of Chemical Industry.


Epidemiology of hepatitis B virus in Africa, its genotypes and clinical associations of genotypes.
Of approximately 360 million people in the world chronically infected with hepatitis B virus (HBV), 65 million reside in Africa. Thus, Africa, with 12% of the world's population, carries approximately 18% of the global burden of HBV infection, with hepatocellular carcinoma and cirrhosis accounting for 2% of the continent's annual deaths. Despite HBV being endemic or hyperendemic in Africa, there is a paucity of data on the genotypes and their distribution. Genotype A is found mainly in southern, eastern and central Africa. Most African genotype A strains belong to subgenotype A1, with subgenotype A3 found in western Africa. Genotype D prevails in northern countries and genotype E in western and central Africa. Ithas become increasingly evident that heterogeneity in the global distribution of HBV genotypes may be responsible for differences in the clinical outcomes of HBV infections and the response to antiviral treatment and vaccination. A limited number of studies have been published relating genotypes to clinical outcomes in African countries. Because observations from other regions of the world can not be extrapolated from one locale to another, the HBV strains circulating in Africa should be studied and related to clinical outcomes.


Upper Respiratory Infections and Airway Adverse Events in Pediatric Procedural Sedation.
Upper respiratory infections (URIs) are associated with airway adverse events (AAEs) during general anesthesia. There have been no large studies examining the relationship between URIs and AAEs during pediatric procedural sedation. We hypothesized that there would be a relationship between URI status and AAEs in pediatric procedural sedation. We examined prospectively collected data from the Pediatric Sedation Research Consortium database. Specific questions regarding URI status were added to the database to facilitate our analysis. Characteristics of patients, procedure types, adjunctive medications, adverse events, and airway interventions (AIs) were reported. We performed bivariate analysis of adverse events and URI status, then used a multivariable logistic regression model to assess the relationship between URI status and adverse events. We examined the secondary outcome of AI similarly. Of the 105 728 sedations entered into the Pediatric Sedation Research Consortium database during the study period, we were able to use 83 491 for analysis. Controlling for multiple patient, drug, and procedure characteristics, recent and current URI were associated with increased frequency of AAEs. In general, the frequency of AAEs and AIs increased from recent URI, to current URI-clear secretions to current URI-thick secretions. We did not find a relationship between URI status and non-AAEs. URI status is associated with a statistically significant increase in frequency of AAEs and AI during pediatric procedural sedation for the population sedated by our consortium. Although URI status merits consideration in determining potential risk for sedation, rates of some AAEs and AIs remained low regardless of URI status.


Direct observation of spin correlations in an artificial triangular lattice Ising spin system with grazing-incidence small-angle neutron scattering.
The triangular lattice with Ising magnetic moments is an archetypical example of geometric frustration. In the case of dipolar-coupled out-of-plane moments, the geometric frustration results in a disordered classical spin-liquid state at higher temperatures while the system is predicted to transition to an anti-ferromagnetic stripe ground state at low temperatures. In this work we fabricate artificial triangular Ising spin systems without and with uniaxial in-plane compression to tune the nature and temperature of the correlations. We probe the energy scale and nature of magnetic correlations by grazing-incidence small-angle neutron scattering. In particular, we apply a newly-developed empirical structure-factor model to describe the measured short-range correlated spin-liquid state, and find good agreement with theoretical predictions. We demonstrate that grazing-incidence neutron scattering on our high-quality samples, in conjunction with detailed modeling of the scattering using the Distorted Wave Born Approximation, can be used to experimentally quantify the spin-liquid-like correlations in highly-frustrated artificial spin systems.


Intimate Partner Violence Perpetration, Victimization, and Overlap Among Serious Juvenile Offenders: Trajectories of Emerging Adulthood.
This study uses group-based trajectory analysis and data from the Pathways to Desistance Study to examine the prevalence and patterns of intimate partner victimization, offending, and overlap among justice-involved adolescents (i.e., general offenders) who reported dating (n = 909); regression analysis was further utilized to assess predictors of intimate partner violence (IPV) group membership. Findings revealed that 40% of adjudicated youth reported IPV as a victim, an offender, or as both a victim and an offender during emerging adulthood. Findings also indicated that there was significant overlap between victimization and offending, and 5% of the sample was assigned to both the high-rate perpetration and victimization trajectory groups. Maternal hostility, alcohol use, and witnessing violence predicted higher rate perpetration and victimization overlap group membership compared with very-low-rate perpetration/victimization group membership. Implications for informing policy and future research are discussed.


Clinical outcomes of Epstein-Barr virus (EBV)-associated metastatic and locally advanced unresectable gastric cancers (GCs) in patients receiving first-line fluoropyrimidine and platinum (FP) doublet chemotherapy.
Epstein-Barr virus-associated gastric cancer (EBVaGC) is a distinct molecular subgroup showing excellent outcomes after surgery for localized disease. Prominent immune cell infiltration in EBVaGC reflects the immunogenicity of Epstein-Barr virus (EBV) and, as suggested by some investigators, responsiveness to immune checkpoint inhibitors in the palliative setting. However, few data are available on the prevalence, clinical characteristics, and prognosis of EBVaGC patients receiving palliative cytotoxic chemotherapy. In this retrospective study, we identified 1061 patients with metastatic, recurrent, or locally advanced unresectable gastric cancer (GC) who started first-line fluoropyrimidine/platinum (FP) doublet chemotherapy with or without trastuzumab from January 2015 to August 2018. For 766 patients with available tumor tissue, the presence of EBV in cancer cells was evaluated by EBV-encoded RNA in situ hybridization and correlated with clinical characteristics and treatment outcomes. Among the patients evaluated (n = 766), 40 (5.0%) were EBV-positive. EBVaGC was associated with male sex (p = 0.009) and lower neutrophil-lymphocyte ratio (NLR < 2.46, p = 0.03). Efficacy of first-line FP chemotherapy, in terms of response rate ad progression-free survival (PFS), did not differ between EBVaGC and EBV-negative GC (overall response rate: 53.8% vs. 51.8%, p = 0.99; median PFS: 6.4 vs. 6.7 months, p = 0.90). However, overall survival tended to be better with EBVaGC than EBV-negative GC (16.4 vs. 14.0 months, p = 0.07). EBVaGC accounted for 5% of metastatic/unresectable GCs. While EBVaGC was not associated with better response to or PFS following first-line cytotoxic chemotherapy, it showed a trend toward better overall survival.


Preoperative magnetic resonance enterography in predicting findings and optimizing surgical approach in Crohn's disease.
Many Crohn's disease patients require surgery. Intraoperative detection of new lesions may lead to change in planned surgery. This study aimed to determine whether magnetic resonance enterography can optimize surgical planning and guide decision making in Crohn's disease. Seventy-five patients with complicated Crohn's disease were enrolled and underwent preoperative magnetic resonance enterography. Analysis included imaging accuracy and change in surgical strategy due to discordance with imaging findings. Surgery was performed laparoscopically in 39/75 patients (52 %), with conversion to open surgery required in six (15 %). Concordance between observers was excellent (kappa value >0.8). Magnetic resonance enterography accuracy for stenosis, abscess, and fistula were all above 85 % in per-patient analysis. In 68/75 cases (90.7 %) surgery was correctly predicted. Conversely, in 7/75 cases (three false-positives and four false-negatives) surgical strategy (type of resection or strictureplasty, n = 5) and/or surgical approach (conversion from laparoscopy to open surgery, n = 2) changed due to discordance with magnetic resonance enterography findings. Surgical strategy and approach are correctly predicted by magnetic resonance enterography in the majority of patients with complicated Crohn's disease.


Agreement between clinician and patient ratings of adaptive functioning and developmental history.
Psychiatric researchers rely heavily on patient report data for clinical research. However, patient reports are prone to defensive and self-presentation biases. Recent research using practice networks has relied on clinician reports, and both forensic and personality disorder researchers have recently turned to quantified data from clinically expert observers as well. However, critics have raised legitimate concerns about the reliability and validity of data from clinician informants. The aim of this study was to assess the validity and diagnostic efficiency of clinician reports of their patients' adaptive functioning and developmental histories, using patient reports as the comparative standard traditionally used in psychiatric research. Eighty-four clinicians and their patients completed a clinical data form designed to assess a range of patient functioning, clinical history, and developmental relationship variables used in multiple clinician report studies. The authors correlated clinician and patient reports across a number of clinically relevant adaptive functioning variables and calculated diagnostic efficiency statistics for a range of clinical history variables, including suicide attempts, hospitalizations, arrests, interpersonal conflicts affecting employment, and childhood physical and sexual abuse. Across variables, patient-therapist correlations (0.40-0.66) and overall correct classification statistics (0.74-0.96) were high. The data demonstrate that clinicians' judgments about their patients' functioning and histories agree with patients' self-reports and that in areas of discrepancy, clinicians tend to make appropriately conservative judgments in the absence of clear data. These findings suggest that quantified clinical judgment provides a vast untapped potential for large-sample research on psychopathology and treatment.


[A contribution to institutionalized health evaluation: a proposal for self-evaluation].
In the context of measures to institutionalize the evaluation of primary health care in Brazil, the Ministry of Health proposed a formative and normative evaluation of the implementation of the project entitled Technical Capacity-Building of State Health Departments for Monitoring and Evaluation, as part of the National Policy for the Evaluation of Primary Care. One of the objectives was to develop a self-evaluation model using the rapid evaluation method (REM). This article presents the stages concluded to date in the self-evaluation model, together with the theoretical references. The final self-evaluation proposal was based on a theoretical evaluation model developed for formative evaluation and included the principal actions proposed for State health management, with all the tested indicators, thus increasing the internal validity and consistency. The final perspective is that this instrument, used with a participatory approach as provided in the proposal, helps assess the extent to which the project's objectives and actions are achieved, while identifying situations that can interfere in different contexts.


Giant placental chorioangioma followed by circulatory failure of the newborn and infantile hemangioma: Case report.
Placental chorioangioma (CA) is a benign placental tumor. No specific treatment is required for asymptomatic cases. We report a female infant born to a mother with giant placental CA. However fetal growth was normal and, fetal hydrops was not detected by ultrasound examination until delivery, she had hydrops, subgaleal hematoma, thrombocytopenia, hemolytic anemia, respiratory distress and circulatory failure after birth. She was successfully treated without any neurological sequelae. At 2 months of age, infantile hemangioma appeared in her lower lip. The present case suggested that giant placental CA might cause postnatal problems and be associated with the development of infantile hemangioma.


National Health Preparedness and Response Centers: Revisiting the Increasingly Critical Need to Expand Cooperative Emergency Response Capabilities in the United States.
In 1999, a robust National Health Preparedness and Response Center was conceptualized and piloted, but never fully operationalized. This study revisits the expansive, coordinated efforts invested in this concept, considered an overdue remedy for persistent shortfalls in medical Chemical, Biological, Radiological, Nuclear, and High Yield Explosives training, proficiency, and preparation. The concept defined a robust mission for longstanding, proven programs for prepositioning equipment and associated training of personnel. This study explores the reasons that ended military and governmental support, attendant funding, and operations of the created Joint/Interagency Civil Support Center, which ceased on September 30, 2006. Unfortunately, the concept remains relevant. Major gaps in disaster medical response capabilities have been recognized for decades. Experts from the Institute of Medicine, United States Northern Command, and multiple academic centers and professional organizations have identified these shortcomings, but the national response posture remains disjointed, under-resourced, and based upon obsolete planning premises. Given increasing threats, the authors recommend revisiting the collaboration of military, civilian, academic, and governmental resources that once established the Joint/Interagency Civil Support Center as a multidisciplinary and trans-disciplinary model for a new National Health Preparedness and Response Center coordinated framework for enhanced resilience and operational response capabilities on a national level.


c-Myc regulates self-renewal in bronchoalveolar stem cells.
Bronchoalveolar stem cells (BASCs) located in the bronchoalveolar duct junction are thought to regenerate both bronchiolar and alveolar epithelium during homeostatic turnover and in response to injury. The mechanisms directing self-renewal in BASCs are poorly understood. BASCs (Sca-1(+), CD34(+), CD31(-) and, CD45(-)) were isolated from adult mouse lung using FACS, and their capacity for self-renewal and differentiation were demonstrated by immunostaining. A transcription factor network of 53 genes required for pluripotency in embryonic stem cells was assessed in BASCs, Kras-initiated lung tumor tissue, and lung organogenesis by real-time PCR. c-Myc was knocked down in BASCs by infection with c-Myc shRNA lentivirus. Comprehensive miRNA and mRNA profiling for BASCs was performed, and significant miRNAs and mRNAs potentially regulated by c-Myc were identified. We explored a c-Myc regulatory network in BASCs using a number of statistical and computational approaches through two different strategies; 1) c-Myc/Max binding sites within individual gene promoters, and 2) miRNA-regulated target genes. c-Myc expression was upregulated in BASCs and downregulated over the time course of lung organogenesis in vivo. The depletion of c-Myc in BASCs resulted in decreased proliferation and cell death. Multiple mRNAs and miRNAs were dynamically regulated in c-Myc depleted BASCs. Among a total of 250 dynamically regulated genes in c-Myc depleted BASCs, 57 genes were identified as potential targets of miRNAs through miRBase and TargetScan-based computational mapping. A further 88 genes were identified as potential downstream targets through their c-Myc binding motif. c-Myc plays a critical role in maintaining the self-renewal capacity of lung bronchoalveolar stem cells through a combination of miRNA and transcription factor regulatory networks.


If only....: failed, missed and absent error recovery opportunities in medication errors.
Systematic analysis of error recovery can provide hospitals with important information to help them improve their ability to detect and correct errors. Because errors will always crop up and 100% safety can never be achieved, hospitals should be able to prevent patient harm by timely and effective error recovery. In this study, failed, missed and absent recovery opportunities were identified in 52 medication errors which all resulted in severe patient harm or patient death. For all identified recovery opportunities, the underlying failure factors were identified and classified according to the Eindhoven classification model. Those failure factors represent negative influences on error recovery. The number of recovery opportunities per error ranged from 0 to 11; on average, 2.4 recovery opportunities were identified. Of 127 identified recovery opportunities, 94 (74%) were planned and 33 (26%) were unplanned or ad hoc. Most failure factors underlying the planned recovery opportunities were organisational failure factors; most failure factors underlying the unplanned recovery opportunities were human failure factors. From this study, it can be concluded that actual accidents can be used as an alternative data source to near misses for the analysis and understanding of error recovery. By using both sources, hospitals can enhance their resilience by reinforcing the positive influences on error recovery as well as reducing the negative ones. Together with traditional error reduction methodologies, which only concentrate on eliminating failure factors, hospitals thus have numerous opportunities to improve patient safety.


Five Piconewtons: The Difference between Osteogenic and Adipogenic Fate Choice in Human Mesenchymal Stem Cells.
The ability of mesenchymal stem cells to sense nanoscale variations in extracellular matrix (ECM) compositions in their local microenvironment is crucial to their survival and their fate; however, the underlying molecular mechanisms defining how such fates are temporally modulated remain poorly understood. In this work, we have utilized self-assembled block copolymer surfaces to present nanodomains of an adhesive peptide found in many ECM proteins at different lateral spacings (from 30 to 60 nm) and studied the temporal response (2 h to 14 days) of human mesenchymal stem cells (hMSCs) using a panel of real-time localization and activity biosensors. Our findings revealed that within the first 4 to 24 h postadhesion and spreading, hMSCs on smaller nanodomain spacings recruit more activated FAK and Src proteins to produce larger, longer-lived, and increased numbers of focal adhesions (FAs). The adhesions formed on smaller nanospacings rapidly recruit higher amounts of nonmuscle myosin IIA and vinculin and experience tension forces (by >5 pN/FA) significantly higher than those observed on larger nanodomain spacings. The transmission of higher levels of tension into the cytoskeleton at short times was accompanied by higher Rac1, cytosolic β-catenin, and nuclear localization of YAP/TAZ and RUNX2, which together biased the commitment of hMSCs to an osteogenic fate. This investigation provides mechanistic insights to confirm that smaller lateral spacings of adhesive nanodomains alter hMSC mechanosensing and biases mechanotransduction at short times via differential coupling of FAK/Src/Rac1/myosin IIA/YAP/TAZ signaling pathways to support longer-term changes in stem cell differentiation and state.


Eosinophilia and Ulcerative Colitis Associated with Eosinophilic Myocarditis.
Reactive eosinophilia is associated with inflammatory bowel disease, but its association with eosinophilic myocarditis is rare. We report a case of a 42-year-old man who presented with hypovolemic shock secondary to diarrhea and recently diagnosed nonischemic cardiomyopathy (left ventricular ejection fraction, 0.29). Laboratory evaluation revealed marked peripheral eosinophilia. Cardiac magnetic resonance imaging showed evidence of subacute-to-chronic myocarditis, and endomyocardial biopsy results were consistent with eosinophilic myocarditis. Colonic biopsy specimens revealed ulcerative colitis and no eosinophils. Hematologic evaluation was negative for an alternative cause of eosinophilia. The patient was given corticosteroids; his diarrhea resolved, but there was no short-term improvement in his ejection fraction, so an implantable cardioverter-defibrillator was placed. Follow-up at one year showed that the patient's left ventricular ejection fraction had improved to 0.42.


Retropharyngeal space infection.
Retropharyngeal space infections are relatively rare since the widespread use of modern antibiotics. In children, retropharyngeal space infections usually occur following an upper respiratory tract infection, while in adults they are usually caused by trauma, foreign bodies or extension from adjacent spaces. The authors reviewed 12 patients with retropharyngeal space infection between July 1996 and June 2002. Age, sex, duration of symptoms and hospitalization time, clinical presentation, etiology, underlying disease, bacteriology, treatment and complications were analyzed. Widening of the prevertebral soft tissue as seen on a plain film of the lateral neck was the most important diagnostic tool. Fever was the most common symptom (91.6%) and showed a high prevalence in adult populations (66.6%). Half of the cases were caused by ingestion of a foreign body. Nine cases underwent surgical drainage which was positive in eight cases (88.8%). Staph. aureus, K. pneumoniae and Enterobacter species were the predominant pathogens. Early diagnosis and appropriate use of antibiotics lessened morbidity. Only two cases had postoperative complications and both recovered.


Moorfields AMD database report 2: fellow eye involvement with neovascular age-related macular degeneration.
Neovascular age-related macular degeneration (nAMD) is frequently bilateral, and previous reports on 'fellow eyes' have assumed sequential treatment after a period of treatment of the first eye only. The aim of our study was to analyse baseline characteristics and visual acuity (VA) outcomes of fellow eye involvement with nAMD, specifically differentiating between sequential and non-sequential (due to macular scarring in the first eye) antivascular endothelial growth factor treatment and timelines for fellow eye involvement. Retrospective, electronic medical record database study of the Moorfields AMD database of 6265 patients/120 286 single entries with data extracted between 21 October 2008 and 9 August 2018. The data set for analysis consisted of 1180 sequential, 807 non-sequential and 3410 unilateral eyes. Mean VA (ETDRS letters±SD) of sequentially treated fellow eyes at baseline was significantly higher (63±13), VA gain over 2 years lower (0.37±14) and proportion of eyes with good VA (≥70 letters) higher (46%) than the respective first eyes (baseline VA 54±16, VA gain at 2 years 5.6±15, percentage of eyes with good VA 39%). Non-sequential fellow eyes showed baseline characteristics and VA outcomes similar to first eyes. Fellow eye involvement rate was 32% at 2 years, and median time interval to fellow eye involvement was 71 (IQR: 27-147) weeks. This report shows that sequentially treated nAMD fellow eyes have better baseline and final VA than non-sequentially treated eyes after 2 years of treatment. Sequentially treated eyes also had a greater proportion with good VA after 2 years.


Another use of the mobile device: warm-up for laparoscopic surgery.
An important facet of laparoscopic surgery is its psychomotor component. As this aspect of surgery gains attention, lessons from other psychomotor-intense fields such as athletics have led to an investigation of the benefits of "warming up" prior to entering the operating room. Practical implementation of established methods of warm-up is hampered by a reliance on special equipment and instrumentations that are not readily available. In light of emerging evidence of translatability between video-game play and operative performance, we sought to find if laparoscopic task performance improved after warming up on a mobile device balance game. Laparoscopic novices were randomized into either the intervention group (n = 20) or the control group (n = 20). The intervention group played a mobile device balance game for 10 min while the control group did no warm-up whatsoever. Assessment was performed using two tasks on the ProMIS laparoscopic simulation system: "object positioning" (where small beads are transferred between four cups) and "tissue manipulation" (where pieces of plastic are stretched over pegs). Metrics measured were time to task completion, path length, smoothness, hand dominance, and errors. The intervention group made fewer errors: object positioning task 0.20 versus 0.70, P = 0.01, tissue manipulation task 0.15 versus 0.55, P = 0.05, total errors 0.35 versus 1.25, P = 0.002. The two groups performed similarly on the other metrics. Warm-up using a mobile device balance game decreases errors on basic tasks performed on a laparoscopic surgery simulator, suggesting a practical way to warm-up prior to cases in the operating room.


Clinical characteristics of veterans prescribed high doses of opioid medications for chronic non-cancer pain.
Little is known about patients prescribed high doses of opioids to treat chronic non-cancer pain, though these patients may be at higher risk for medication-related complications. We describe the prevalence of high-dose opioid use and associated demographic and clinical characteristics among veterans treated in a VA regional healthcare network. Veterans with chronic non-cancer pain prescribed high doses of opioids (≥ 180 mg/day morphine equivalent; n=478) for 90+ consecutive days were compared to two groups with chronic pain: Traditional-dose (5-179 mg/day; n=500) or no opioid (n=500). High-dose opioid use occurred in 2.4% of all chronic pain patients and in 8.2% of all chronic pain patients prescribed opioids long-term. The average dose in the high-dose group was 324.9 (SD=285.1)mg/day. The only significant demographic difference among groups was race (p=0.03) with black veterans less likely to receive high doses. High-dose patients were more likely to have four or more pain diagnoses and the highest rates of medical, psychiatric, and substance use disorders. After controlling for demographic factors and VA facility, neuropathy, low back pain, and nicotine dependence diagnoses were associated with increased likelihood of high-dose prescriptions. High-dose patients frequently did not receive care consistent with treatment guidelines: there was frequent use of short-acting opioids, urine drug screens were administered to only 25.7% of patients in the prior year, and 32.0% received concurrent benzodiazepine prescriptions, which may increase risk for overdose and death. Further study is needed to identify better predictors of high-dose usage, as well as the efficacy and safety of such dosing.


Non-degree allopathic practitioners as first contact points for acute illness episodes: insights from a qualitative study in rural northern India.
In 2005, the Indian government launched the National Rural Health Mission (NRHM) to improve the quality of and access to rural public health care. Despite these efforts, recent evidence shows that the rural poor continue to primarily consult private non-degree allopathic practitioners (NDAPs) for acute illness episodes. To examine this phenomenon, we explore the rural poor's perception and utilization of the rural health care system and the role and accessibility of NDAPs therein. Our study is based on qualitative data from focus group discussions conducted in three rural districts in Bihar and Uttar Pradesh, two high-focus states of the NRHM in northern India, in 2009/2010. Our study population consists of female micro-credit self-help group members and their male household heads. We apply a directed content analysis and use a theoretical framework to differentiate between physical, financial and cultural access to care. Our study population distinguishes between "home treatment" (informal self-care), "local treatment" (formally unqualified care) and "outside treatment" (formally qualified care). Because of their proximity, flexible payment options and familiarity with patients' belief systems, among other things, local NDAPs are physically, financially and culturally accessible. They are usually the first contact points for patients before turning to qualified practitioners, and treat minor illnesses, provide first relief, refer patients to other providers and administer formally prescribed treatments. Our findings are similar for all three study sites and reinforce recent findings from southern and eastern India. The poor's understanding and utilization of the rural health system deviates from governmental ideas. Because of their embeddedness in the community, private NDAPs are the most accessible medical providers and first contact points for acute illness episodes. Thus, they de-facto fulfill the role envisaged by the Indian government for accredited social health activists introduced as part of the NRHM. We conclude that instead of trying to replace NDAPs with public initiatives, the Indian government should regulate, qualify and integrate them as part of the existing public health care system. This way, we argue, India can improve the rural poor's access to formally qualified practitioners.


Automated fault diagnosis in nonlinear multivariable systems using a learning methodology.
The paper presents a robust fault diagnosis scheme for detecting and approximating state and output faults occurring in a class of nonlinear multiinput-multioutput dynamical systems. Changes in the system dynamics due to a fault are modeled as nonlinear functions of the control input and measured output variables. Both state and output faults can be modeled as slowly developing (incipient) or abrupt, with each component of the state/output fault vector being represented by a separate time profile. The robust fault diagnosis scheme utilizes on-line approximators and adaptive nonlinear filtering techniques to obtain estimates of the fault functions. Robustness with respect to modeling uncertainties, fault sensitivity and stability properties of the learning scheme are rigorously derived and the theoretical results are illustrated by a simulation example of a fourth-order satellite model.


Prevention and Control of Seasonal Influenza with Vaccines: Recommendations of the Advisory Committee on Immunization Practices, United States, 2021-22 Influenza Season.
This report updates the 2020-21 recommendations of the Advisory Committee on Immunization Practices (ACIP) regarding the use of seasonal influenza vaccines in the United States (MMWR Recomm Rep 2020;69[No. RR-8]). Routine annual influenza vaccination is recommended for all persons aged ≥6 months who do not have contraindications. For each recipient, a licensed and age-appropriate vaccine should be used. ACIP makes no preferential recommendation for a specific vaccine when more than one licensed, recommended, and age-appropriate vaccine is available. During the 2021-22 influenza season, the following types of vaccines are expected to be available: inactivated influenza vaccines (IIV4s), recombinant influenza vaccine (RIV4), and live attenuated influenza vaccine (LAIV4).The 2021-22 influenza season is expected to coincide with continued circulation of SARS-CoV-2, the virus that causes COVID-19. Influenza vaccination of persons aged ≥6 months to reduce prevalence of illness caused by influenza will reduce symptoms that might be confused with those of COVID-19. Prevention of and reduction in the severity of influenza illness and reduction of outpatient visits, hospitalizations, and intensive care unit admissions through influenza vaccination also could alleviate stress on the U.S. health care system. Guidance for vaccine planning during the pandemic is available at https://www.cdc.gov/vaccines/pandemic-guidance/index.html. Recommendations for the use of COVID-19 vaccines are available at https://www.cdc.gov/vaccines/hcp/acip-recs/vacc-specific/covid-19.html, and additional clinical guidance is available at https://www.cdc.gov/vaccines/covid-19/clinical-considerations/covid-19-vaccines-us.html.Updates described in this report reflect discussions during public meetings of ACIP that were held on October 28, 2020; February 25, 2021; and June 24, 2021. Primary updates to this report include the following six items. First, all seasonal influenza vaccines available in the United States for the 2021-22 season are expected to be quadrivalent. Second, the composition of 2021-22 U.S. influenza vaccines includes updates to the influenza A(H1N1)pdm09 and influenza A(H3N2) components. U.S.-licensed influenza vaccines will contain hemagglutinin derived from an influenza A/Victoria/2570/2019 (H1N1)pdm09-like virus (for egg-based vaccines) or an influenza A/Wisconsin/588/2019 (H1N1)pdm09-like virus (for cell culture-based and recombinant vaccines), an influenza A/Cambodia/e0826360/2020 (H3N2)-like virus, an influenza B/Washington/02/2019 (Victoria lineage)-like virus, and an influenza B/Phuket/3073/2013 (Yamagata lineage)-like virus. Third, the approved age indication for the cell culture-based inactivated influenza vaccine, Flucelvax Quadrivalent (ccIIV4), has been expanded from ages ≥4 years to ages ≥2 years. Fourth, discussion of administration of influenza vaccines with other vaccines includes considerations for coadministration of influenza vaccines and COVID-19 vaccines. Providers should also consult current ACIP COVID-19 vaccine recommendations and CDC guidance concerning coadministration of these vaccines with influenza vaccines. Vaccines that are given at the same time should be administered in separate anatomic sites. Fifth, guidance concerning timing of influenza vaccination now states that vaccination soon after vaccine becomes available can be considered for pregnant women in the third trimester. As previously recommended, children who need 2 doses (children aged 6 months through 8 years who have never received influenza vaccine or who have not previously received a lifetime total of ≥2 doses) should receive their first dose as soon as possible after vaccine becomes available to allow the second dose (which must be administered ≥4 weeks later) to be received by the end of October. For nonpregnant adults, vaccination in July and August should be avoided unless there is concern that later vaccination might not be possible. Sixth, contraindications and precautions to the use of ccIIV4 and RIV4 have been modified, specifically with regard to persons with a history of severe allergic reaction (e.g., anaphylaxis) to an influenza vaccine. A history of a severe allergic reaction to a previous dose of any egg-based IIV, LAIV, or RIV of any valency is a precaution to use of ccIIV4. A history of a severe allergic reaction to a previous dose of any egg-based IIV, ccIIV, or LAIV of any valency is a precaution to use of RIV4. Use of ccIIV4 and RIV4 in such instances should occur in an inpatient or outpatient medical setting under supervision of a provider who can recognize and manage a severe allergic reaction; providers can also consider consulting with an allergist to help identify the vaccine component responsible for the reaction. For ccIIV4, history of a severe allergic reaction (e.g., anaphylaxis) to any ccIIV of any valency or any component of ccIIV4 is a contraindication to future use of ccIIV4. For RIV4, history of a severe allergic reaction (e.g., anaphylaxis) to any RIV of any valency or any component of RIV4 is a contraindication to future use of RIV4. This report focuses on recommendations for the use of vaccines for the prevention and control of seasonal influenza during the 2021-22 influenza season in the United States. A brief summary of the recommendations and a link to the most recent Background Document containing additional information are available at https://www.cdc.gov/vaccines/hcp/acip-recs/vacc-specific/flu.html. These recommendations apply to U.S.-licensed influenza vaccines used according to Food and Drug Administration-licensed indications. Updates and other information are available from CDC's influenza website (https://www.cdc.gov/flu); vaccination and health care providers should check this site periodically for additional information.


Isolated late metastasis from testicular seminoma presenting as a parotid gland mass: case report and review of the literature.
Parotid metastases from non-head-and-neck cancers are rare and may represent a diagnostic and therapeutic challenge. A late metastasis to the parotid gland from a seminoma is an unusual manifestation of disease. A 45-year-old man with a history of testicular seminoma 5 years earlier presented with a rapidly progressing parotid mass. Ultrasonography and computed tomography showed a space-occupying lesion at the angle of the right jaw. The mass was infiltrating into the parotid gland and into the parapharyngeal space. A primary parotid neoplasm was suspected, and panendoscopy combined with open biopsy was performed. Histology examination confirmed a seminoma metastatic to the parotid gland, and comparison with the primary tumour showed identical histology. The patient received chemotherapy for recurrent seminoma in accordance with the pei (cisplatin, etoposide, ifosfamide) protocol. After 4 courses of chemotherapy, salvage radical parotidectomy with removal of all suspicious residual tumour tissue was performed. This case illustrates the difficulties that may be encountered in the differential diagnosis of parotid gland masses and underlines the necessity for a detailed clinical history and for strong interdisciplinary collaboration between oncologists and pathologists to correctly diagnose cases with such unusual presentations.


Identification of eyeworm (Oxyspirura petrowi) and caecal worm (Aulonocephalus pennula) infection levels in Northern bobwhite quail (Colinus virginianus) of the Rolling Plains, TX using a mobile research laboratory: Implications for regional surveillance.
Over the last few decades, there has been a decline in Northern bobwhite quail (Colinus virginianus) throughout their native range. While there are various factors that may be influencing this decline, it is suggested that parasites should be taken into consideration as a potential contributor in the Rolling Plains Ecoregion. High prevalence of the eyeworm (Oxyspirura petrowi) and caecal worm (Aulonocephalus pennula) in bobwhite of this region, coupled with a continuous decline, creates a need to assess infection through alternative methods for regional surveillance. Previous studies have developed a qPCR method and mobile research laboratory as an option for nonlethal procedures. However, there is still a need for standardization of these techniques. Therefore, this study builds on previous protocols to develop an application that considers factors that may influence qPCR results. In this study, cloacal swabs are collected from bobwhite in three locations throughout the Rolling Plains and scaled based on amount of feces present on the swab. This data is compared to qPCR standards as a limit of quantification for both eyeworm and caecal worm to define parasitic infection levels. Binary logistic regressions confirm that the probability of detection increases for both eyeworm (Odds Ratio: 2.3738; 95% Confidence Interval: [1.7804, 3.1649]) and caecal worm (Odds Ratio: 2.8516; 95% Confidence Interval: [2.2235, 3.6570]) as swab score increases. Infection levels for eyeworm and caecal worm are based on the generated cycle threshold value averages of qPCR standards. Based on the results of this study, this method can be applied in the mobile research laboratory to quantitatively assess regional parasitic infection in bobwhite throughout the Rolling Plains.


Pharmacokinetics, Tissue Distribution and Excretion of Demethyleneberberine, a Metabolite of Berberine, in Rats and Mice.
Demethyleneberberine is an active component extracted from the Chinese herbal drug Cortex Phellodendri. It is also a metabolite of berberine in animals and humans. However, the pharmacokinetics, tissue distribution and excretion of demethyleneberberine have not been reported. The present study aimed to investigate the pharmacokinetic parameters of demethyleneberberine by applying high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS). After intragastric administration of demethyleneberberine in rats and mice, the pharmacokinetics, tissue distribution and excretion of demethyleneberberine were comparatively studied for the first time. The plasma concentration of demethyleneberberine reached its peak within 5 min after intragastric administration in both rats and mice. Furthermore, its bioavailability was comparable, ranging from 4.47% to 5.94%, higher than that of berberine. The total excretion of demethyleneberberine in the urine, feces and bile was 7.28~9.77%. These findings provide valuable insights into the pharmacological and clinical research on demethyleneberberine.


Prostacyclin: a potent antimetastatic agent.
Metastasis is the principal cause of failures to cure human cancers. Prostacyclin is a powerful antimetastatic agent against B16 amelanotic melanoma cells. This effect, which may result from the platelet antiaggregatory action of prostacyclin, is potentiated by a phosphodiesterase inhibitor. Inhibitors of prostacyclin synthesis increase metastasis. Prostacyclin and agents that may increase endogenous prostacyclin production or prolong its activity are suggested as new antimetastatic agents.


A strategy for synthesis of pathogenic human immunoglobulin free light chains in E. coli.
Monoclonal immunoglobulin light chains are normally synthesized in excess compared to the heavy chain partners and can be detected in serum and urine ("free" LC). Occasionally free LC are per se cause of organ toxicity, as in free LC-related disorders. In AL amyloidosis, the most common of these conditions, free LC with peculiar biophysical properties related to their primary structure damage target organs and organize in amyloid fibrils. Unlimited availability of well-characterized free LC is instrumental to investigate the toxic effect of these proteins and to study their interactions with targets. We present a straightforward strategy to obtain recombinant monoclonal free LC by using a bacterial system. These proteins, expressed as inclusion bodies, were subjected to solubilization and refolding procedures to recover them in native form. To minimize differences from the circulating natural LC, full-length recombinant LC were expressed, i.e. complete of variable and constant regions, with the original amino acid sequence along the entire protein, and with no purification tags. The strategy was exploited to generate free LC from three AL amyloidosis patients. After purification, recombinant proteins were biochemically characterized and compared to the natural Bence Jones protein isolated from one of the patients. Results showed that the recombinant free LC were properly folded and formed homodimers in solution, similar to the natural Bence Jones protein used for comparison. Furthermore, as proof of pathogenicity, recombinant proteins formed amyloid fibrils in vitro. We believe that the present strategy represents a valuable tool to speed research in free LC-related disorders.


Complete genome of Streptomyces hygroscopicus subsp. limoneus KCTC 1717 (=KCCM 11405), a soil bacterium producing validamycin and diverse secondary metabolites.
Streptomyces hygroscopicus subsp. limoneus is a Gram-positive, aerobic, aerial mycelial, spore-forming bacterium that was first isolated from a soil sample in Akashi City, Hyogo Prefecture, Japan. We here report the complete genome of S. hygroscopicus subsp. limoneus KCTC 1717 (=KCCM 11405=IFO 12704=ATCC 21432), which consists of 10,537,932 bp (G+C content of 71.96%) with two linear chromosomes, 8983 protein-coding genes, 67 tRNAs and 6 rRNA operons. Genes related to biosynthesis of validamycin, valienamine and diverse secondary metabolites were detected in this genome. Genomic data is thus expected to considerably improve our understanding of how industrially important aminocyclitols are biosynthesized by microbial cells.


Inaccuracies in ICD Coding for Obesity Would Be Expected to Bias Administrative Database Spine Studies Toward Overestimating the Impact of Obesity on Perioperative Adverse Outcomes.
Retrospective cohort study. To determine if International Classification of Diseases (ICD) coding for obesity is biased toward certain subgroups and how potential bias may influence the outcomes of database research in spine. There has been increased use of national databases using administrative data in the spine surgery literature. Past research demonstrates that sensitivity of ICD codes for obesity is poor, but it is unknown if such inaccuracies are systematically biased and if they may bias studies utilizing such data. Patients who underwent elective posterior lumbar fusion, 2013 to 2016, at a large academic hospital were identified. All ICD codes assigned to the encounter were obtained. Body mass index (BMI) was calculated based on height and weight. The sensitivity of ICD coding for obesity was calculated. Sensitivity was compared for subgroups defined by demographic, comorbidity, intraoperative, and postoperative factors. The association of obesity (as defined by BMI≥30 and ICD coding) with 30-day postoperative adverse events was tested with multivariate regression. The study included 796 patients. The overall sensitivity of ICD coding for obesity was 42.5%. The sensitivity of ICD coding for obesity was significantly higher in patients with greater BMI, diabetes, American Society of Anesthesiologists class≥III, increased length of stay, venous thromboembolism, any adverse event, and major adverse event. Multivariate analysis for determining outcomes of increased risk with obesity as defined by ICD coding included venous thromboembolism, major adverse events, and any adverse events. However, multivariate analysis for determining outcomes of increased risk with obesity defined by BMI did not yield any positive associations. ICD codes for obesity are more commonly assigned to patients with other comorbidities or postoperative complications. Further, use of such nonrandomly assigned ICD codes for obesity has the potential to skew studies to suggest greater associated adverse events than calculated BMI would demonstrate. 3.


Does flip-flop style footwear modify ankle biomechanics and foot loading patterns?
Flip-flops are an item of footwear, which are rubber and loosely secured across the dorsal fore-foot. These are popular in warm climates; however are widely criticised for being detrimental to foot health and potentially modifying walking gait. Contemporary alternatives exist including FitFlop, which has a wider strap positioned closer to the ankle and a thicker, ergonomic, multi-density midsole. Therefore the current study investigated gait modifications when wearing flip-flop style footwear compared to barefoot walking. Additionally walking in a flip-flop was compared to that FitFlop alternative. Testing was undertaken on 40 participants (20 male and 20 female, mean ± 1 SD age 35.2 ± 10.2 years, B.M.I 24.8 ± 4.7 kg.m(-2)). Kinematic, kinetic and electromyographic gait parameters were collected while participants walked through a 3D capture volume over a force plate with the lower limbs defined using retro-reflective markers. Ankle angle in swing, frontal plane motion in stance and force loading rates at initial contact were compared. Statistical analysis utilised ANOVA to compare differences between experimental conditions. The flip-flop footwear conditions altered gait parameters when compared to barefoot. Maximum ankle dorsiflexion in swing was greater in the flip-flop (7.6 ± 2.6°, p = 0.004) and FitFlop (8.5 ± 3.4°, p < 0.001) than barefoot (6.7 ± 2.6°). Significantly higher tibialis anterior activation was measured in terminal swing in FitFlop (32.6%, p < 0.001) and flip-flop (31.2%, p < 0.001) compared to barefoot. A faster heel velocity toward the floor was evident in the FitFlop (-.326 ± .068 m.s(-1), p < 0.001) and flip-flop (-.342 ± .074 m.s(-1), p < 0.001) compared to barefoot (-.170 ± .065 m.s(-1)). The FitFlop reduced frontal plane ankle peak eversion during stance (-3.5 ± 2.2°) compared to walking in the flip-flop (-4.4 ± 1.9°, p = 0.008) and barefoot (-4.3 ± 2.1°, p = 0.032). The FitFlop more effectively attenuated impact compared to the flip-flop, reducing the maximal instantaneous loading rate by 19% (p < 0.001). Modifications to the sagittal plane ankle angle, frontal plane motion and characteristics of initial contact observed in barefoot walking occur in flip-flop footwear. The FitFlop may reduce risks traditionally associated with flip-flop footwear by reducing loading rate at heel strike and frontal plane motion at the ankle during stance.


A 3-year follow-up study of preformed beta-quartz glass-ceramic insert restorations.
The purpose of this study was to evaluate the clinical performance of preformed beta-quartz glass-ceramic insert restorations. Nine Class I and 30 Class II beta-quartz glass-ceramic insert restorations were placed in 16 patients who were seen regularly by personnel at Umeå University Dental School. The California Dental Association criteria were used to evaluate the restorations at baseline, 6 months, and 1, 2, and 3 years after luting. The occurrence of postoperative sensitivity, the time taken to manufacture each restoration, and certain periodontal conditions were also evaluated. Sixty-nine percent of the restorations were rated satisfactory at the 3-year examination. During the follow-up period, 4 became loose and 7 were fractured or had flaking surfaces. Caries was registered in connection with 1 restoration. Excellent ratings were obtained for marginal integrity, anatomic form, surface, and color in 62%, 84%, 32%, and 44% of the restorations, respectively. There was no statistically significant difference in the occurrence of plaque and bleeding on probing in comparison with the controls. The mean overall time for placement was 38 minutes. The estimated survival rate (Kaplan-Meier) was 59% after 3.5 years. The quality of the beta-quartz glass-ceramic restorations in the present study was inferior to that presented in most earlier studies of ceramic or resin composite posterior restorations placed in patients treated at university clinics. Both the technique and the beta-quartz glass-ceramic inserts have to be evaluated in more long-term studies to assess the possibility of their serving as an alternative restorative technique.


TMPRSS2:ETV4 gene fusions define a third molecular subtype of prostate cancer.
Although common in hematologic and mesenchymal malignancies, recurrent gene fusions have not been well characterized in epithelial carcinomas. Recently, using a novel bioinformatic approach, we identified recurrent gene fusions between TMPRSS2 and the ETS family members ERG or ETV1 in the majority of prostate cancers. Here, we interrogated the expression of all ETS family members in prostate cancer profiling studies and identified marked overexpression of ETV4 in 2 of 98 cases. In one such case, we confirmed the overexpression of ETV4 using quantitative PCR, and by rapid amplification of cDNA ends, quantitative PCR, and fluorescence in situ hybridization, we show that the TMPRSS2 (21q22) and ETV4 (17q21) loci are fused in this case. This result defines a third molecular subtype of prostate cancer and supports the hypothesis that dysregulation of ETS family members through fusions with TMRPSS2 may be an initiating event in prostate cancer development.


PICs in motoneurons do not scale with the size of the animal: a possible mechanism for faster speed of muscle contraction in smaller species.
The majority of studies on the electrical properties of neurons are carried out in rodents, and in particular in mice. However, the minute size of this animal compared with humans potentially limits the relevance of the resulting insights. To be able to extrapolate results obtained in a small animal such as a rodent, one needs to have proper knowledge of the rules governing how electrical properties of neurons scale with the size of the animal. Generally speaking, electrical resistances of neurons increase as cell size decreases, and thus maintenance of equal depolarization across cells of different sizes requires the underlying currents to decrease in proportion to the size decrease. Thus it would generally be expected that voltage-sensitive currents are smaller in smaller animals. In this study, we used in vivo preparations to record electrical properties of spinal motoneurons in deeply anesthetized adult mice and cats. We found that PICs do not scale with size, but instead are constant in their amplitudes across these species. This constancy, coupled with the threefold differences in electrical resistances, means that PICs contribute a threefold larger depolarization in the mouse than in the cat. As a consequence, motoneuronal firing rate sharply increases as animal size decreases. These differences in firing rates are likely essential in allowing different species to control muscles with widely different contraction speeds (smaller animals have faster muscle fibers). Thus from our results we have identified a possible new mechanism for how electrical properties are tuned to match mechanical properties within the motor output system.NEW & NOTEWORTHY The small size of the mouse warrants concern over whether the properties of their neurons are a scaled version of those in larger animals or instead have unique features. Comparison of spinal motoneurons in mice to cats showed unique features. Firing rates in the mouse were much higher, in large part due to relatively larger persistent inward currents. These differences likely reflect adaptations for controlling much faster muscle fibers in mouse than cat.


Gynecological Disorders in Patients with Non-celiac Wheat Sensitivity.
Non-celiac wheat sensitivity (NCWS) most frequently presents clinically with irritable bowel syndrome (IBS)-like symptoms, although many extra-intestinal manifestations have also been attributed to it. No studies to date have evaluated the presence and frequency of gynecological symptoms in NCWS. To evaluate the frequency of gynecological disorders in patients with NCWS. Sixty-eight women with NCWS were included in the study. A questionnaire investigating gynecological symptoms and recurrent cystitis was administered, and patients reporting symptoms were then examined by specialists. Three control groups were selected: 52 patients with IBS not related to NCWS, 56 patients with celiac disease (CD), and 71 healthy controls. 59% of the patients with NCWS showed gynecological symptoms, a higher frequency than in healthy controls (P = 0.04), IBS controls (P = 0.01) and CD controls (P = 0.02). Menstrual cycle alterations were more frequent in patients with NCWS than in healthy controls (26.5% vs 11.3%; P = 0.03); the patients with NCWS suffered from recurrent vaginitis (16%) and dyspareunia (6%) significantly more frequently than healthy controls. Twenty-nine percent of patients with NCWS reported recurrent cystitis, a finding higher than in the control groups (vs healthy P = 0.0001, vs IBS P = 0.001, vs CD controls P = 0.04). Microbiological examinations were negative in most of the patients with NCWS and recurrent vaginitis or cystitis. During the 1-year follow-up, 46% of patients with menstrual disorders and 36% with recurrent vaginitis reported resolution of symptoms on a wheat-free diet. Patients with NCWS showed a significantly higher frequency of gynecological symptoms and recurrent cystitis than patients with IBS.


Selective release of calpain produced alphalI-spectrin (alpha-fodrin) breakdown products by acute neuronal cell death.
Activation of calpain results in the breakdown of alpha II spectrin (alpha-fodrin), a neuronal cytoskeleton protein, which has previously been detected in various in vitro and in vivo neuronal injury models. In this study, a 150 kDa spectrin breakdown product (SBDP150) was found to be released into the cell-conditioned media from SH-SY5Y cells treated with the calcium channel opener maitotoxin (MTX). SBDP150 release can be readily quantified on immunoblot using an SBDP150-specific polyclonal antibody. Increase of SBDP150 also correlated with cell death in a time-dependent manner. MDL28170, a selective calpain inhibitor, was the only protease inhibitor tested that significantly reduced MTX-induced SBDP150 release. The cell-conditioned media of cerebellar granule neurons challenged with excitotoxins (NMDA and kainate) also exhibited a significant increase of SBDP150 that was attenuated by pretreatment with an NMDA receptor antagonist, R(-)-3-(2-carbopiperazine-4-yl)-propyl-1-phosphonic acid (CPP), and MDL28170. In addition, hypoxic/hypoglycemic challenge of cerebrocortical cultures also resulted in SBDP150 liberation into the media. These results support the theory that an antibody-based detection of SBDP150 in the cell-conditioned media can be utilized to quantify injury to neural cells. Furthermore, SBDP150 may potentially be used as a surrogate biomarker for acute neuronal injury in clinical settings.


Hubble-bubble (water pipe) smoking: levels of nicotine and cotinine in plasma, saliva and urine.
The purpose of the present study was to assess the levels of nicotine and cotinine in biological fluids (plasma, saliva, and urine) following hubble-bubble (HB) smoking. Fourteen healthy male volunteers, aged 28 +/- 8 years, body weight of 82.7 +/- 13.53 kg, participated in the study. All volunteers were habitual HB smokers for 3.29 +/- 1.90 years who smoked at least 3 runs per week with an average of 20 g Mua'sel per run. Volunteers were requested to avoid smoking, at least 84 hours prior to the time of the study. After baseline samples were taken, volunteers started smoking 20 g of Mua'sel for a period of 45 minutes. Heparinized blood samples (5 or 10 ml each) were drawn for nicotine and cotinine analysis before, during and after the smoking period. Saliva samples were collected just before smoking (time 0) and at the end of smoking (45 min). Urine also was collected at time 0 and 24-hour urine collection was also taken to measure nicotine and cotinine excretion. Nicotine and cotinine were extracted from samples and assayed by gas chromatography. All data are presented as mean +/- SEM throughout the text, Tables and Figures unless indicated otherwise. Plasma nicotine levels rose from 1.11 +/- 0.62 ng/ml at baseline to a maximum of 60.31 +/- 7.58 ng/ml (p < 0.001) at the end of smoking (45 min). Plasma cotinine levels increased from 0.79 +/- 0.79 ng/ml at baseline to its highest concentration of 51.95 +/- 13.58 ng/ml (p < 0.001) 3 hours following the end of smoking. Saliva nicotine levels significantly rose from 1.05 +/- 0.72 to 624.74 +/- 149.3 ng/ml and also saliva cotinine levels significantly increased from 0.79 +/- 0.79 ng/ml to 283.49 +/- 75.04 ng/ml. Mean amounts of nicotine and cotinine excreted in urine during the 24-hour urine collection following smoking were equal to 73.59 +/- 18.28 and 249 +/- 54.78 microg, respectively. Following a single run of HB smoking, plasma, saliva and urinary nicotine and cotinine concentration increased to high values. This observation suggests that HB may not be an innocent habit, as people believe.


Phenotype and function of raphe projections to the suprachiasmatic nucleus.
The circadian clock, located in the suprachiasmatic nucleus (SCN), receives a major afferent from the median raphe nucleus (MRN). In the Syrian hamster, only about 50% of the cells giving rise to this afferent contain serotonin. There is mixed evidence as to whether the serotonergic portion of this projection is involved in non-photic phase shifting of circadian locomotor rhythms. In order to better characterize the non-serotonergic projections, we conducted retrograde tract tracing using the beta subunit of cholera toxin combined with multi-label immunohistochemistry. Similar to previous findings, almost half of the retrogradely labeled cells contained serotonin. Additionally, approximately 30% of the retrogradely labeled cells contained vesicular glutamate transporter 3 (VGLUT3), but not serotonin. Surprisingly, some dorsal raphe cholera toxin labeling was also noted, particularly in animals with central-SCN injections. To determine if the non-serotonergic projections were important for non-photic phase shifts elicited by MRN stimulation, the MRN was electrically stimulated in animals pretreated with SCN injection of either the serotonin neurotoxin 5,7-dihydroxytryptamine or vehicle control. Intact animals phase advanced to midday electrical stimulation of the raphe while lesioned animals did not. Together, these results show that although some of the non-serotonergic raphe projections to the SCN contain VGLUT3, it is the serotonergic raphe innervation of the SCN that is critical for non-photic phase shifting elicited by MRN stimulation.


Donnai-Barrow syndrome (DBS/FOAR) in a child with a homozygous LRP2 mutation due to complete chromosome 2 paternal isodisomy.
Donnai-Barrow syndrome [Faciooculoacousticorenal (FOAR) syndrome; DBS/FOAR] is a rare autosomal recessive disorder resulting from mutations in the LRP2 gene located on chromosome 2q31.1. We report a unique DBS/FOAR patient homozygous for a 4-bp LRP2 deletion secondary to paternal uniparental isodisomy for chromosome 2. The propositus inherited the mutation from his heterozygous carrier father, whereas the mother carried only wild-type LRP2 alleles. This is the first case of DBS/FOAR resulting from uniparental disomy (UPD) and the fourth published case of any paternal UPD 2 ascertained through unmasking of an autosomal recessive disorder. The absence of clinical symptoms above and beyond the classical phenotype in this and the other disorders suggests that paternal chromosome 2 is unlikely to contain imprinted genes notably affecting either growth or development. This report highlights the importance of parental genotyping in order to give accurate genetic counseling for autosomal recessive disorders.


Machine learning and experiments identifies SPINK1 as a candidate diagnostic and prognostic biomarker for hepatocellular carcinoma.
Machine learning techniques have been widely used in predicting disease prognosis, including cancer prognosis. One of the major challenges in cancer prognosis is to accurately classify cancer types and stages to optimize early screening and detection, and machine learning techniques have proven to be very useful in this regard. In this study, we aimed at identifying critical genes for diagnosis and outcomes of hepatocellular carcinoma (HCC) patients using machine learning. The HCC expression dataset was downloaded from GSE65372 datasets and TCGA datasets. Differentially expressed genes (DEGs) were identified between 39 HCC and 15 normal samples. For the purpose of locating potential biomarkers, the LASSO and the SVM-RFE assays were performed. The ssGSEA method was used to analyze the TCGA to determine whether there was an association between SPINK1 and tumor immune infiltrates. RT-PCR was applied to examine the expression of SPINK1 in HCC specimens and cells. A series of functional assays were applied to examine the function of SPINK1 knockdown on the proliferation of HCC cells. In this study, 103 DEGs were obtained. Based on LASSO and SVM-RFE analysis, we identified nine critical diagnostic genes, including C10orf113, SPINK1, CNTLN, NRG3, HIST1H2AI, GPRIN3, SCTR, C2orf40 and PITX1. Importantly, we confirmed SPINK1 as a prognostic gene in HCC. Multivariate analysis confirmed that SPINK1 was an independent prognostic factor for overall survivals of HCC patients. We also found that SPINK1 level was positively associated with Macrophages, B cells, TFH, T cells, Th2 cells, iDC, NK CD56bright cells, Th1 cells, aDC, while negatively associated with Tcm and Eosinophils. Finally, we demonstrated that SPINK1 expression was distinctly increased in HCC specimens and cells. Functionally, silence of SPINK1 distinctly suppressed the proliferation of HCC cells via regulating Wnt/β-catenin pathway. The evidence provided suggested that SPINK1 may possess oncogenic properties by inducing dysregulated immune infiltration in HCC. Additionally, SPINK1 was identified as a novel biomarker and therapeutic target for HCC.


Cerebellar interaction with the acoustic reflex.
The involvement of the cerebellar vermis in the acoustic reflex was analyzed in 12 cats, decerebrated or in pentobarbital anesthesia. Anatomical data suggested the existence of a connection of lobules VIII with the ventral cochlear nucleus. Single cell recording and evoked potential techniques demonstrated the existence of the acoustic projection to lobulus VIII. Electrical stimulation of this area changed the tension of the middle ear muscle and caused evoked potential responses in the caudal part of the ventral cochlear nucleus. Electrical stimulation of the motor nucleus of the facial nerve evoked a slow wave in the recording taken from the surrounding of the cochlear round window. A hypothesis is proposed which postulates the involvement of the acoustic reflex in space localization of acoustic stimuli and the action of cerebellar vermis in order to assure the stability and plasticity of the acoustic reflex arc.


The outcome of intraoral onlay block bone grafts on alveolar ridge augmentations: a systematic review.
The purpose of this study was to systematically review clinical studies examining the survival and success rates of implants placed with intraoral onlay autogenous bone grafts to answer the following question: do ridge augmentations procedures with intraoral onlay block bone grafts in conjunction with or prior to implant placement influence implant outcome when compared with a control group (guided bone regeneration, alveolar distraction, native bone or short dental implants.)? An electronic data banks and hand searching were used to find relevant articles on vertical and lateral augmentation procedures performed with intraoral onlay block bone grafts for dental implant therapy published up to October 2013. Publications in English, on human subjects, with a controlled study design -involving at least one group with defects treated with intraoral onlay block bone grafts, more than five patients and a minimum follow-up of 12 months after prosthetic loading were included. Two reviewers extracted the data. A total of 6 studies met the inclusion criteria: 4 studies on horizontal augmentation and 2 studies on vertical augmentation. Intraoperative complications were not reported. Most common postsurgical complications included mainly mucosal dehiscences (4 studies), bone graft or membrane exposures (3 studies), complete failures of block grafts (2 studies) and neurosensory alterations (4 studies). For lateral augmentation procedures, implant survival rates ranged from 96.9% to 100%, while for vertical augmentation they ranged from 89.5% to 100%. None article studied the soft tissues healing. Survival and success rates of implants placed in horizontally and vertically resorbed edentulous ridges reconstructed with block bone grafts are similar to those of implants placed in native bone, in distracted sites or with guided bone regeneration. More surgical challenges and morbidity arise from vertical augmentations, thus short implants may be a feasible option.


Single-cell RNA sequencing indicates cordycepin remodels the tumor immune microenvironment to enhance TIGIT blockade's anti-tumor effect in colon cancer.
Both preclinical and clinical studies have extensively proven the effectiveness of TIGIT inhibitors in tumor immunotherapy. However, it has been discovered that the presence of CD226 on tumor-infiltrating lymphocytes is crucial for the effectiveness of both anti-TIGIT therapy alone and when combined with anti-PD-1 therapy for tumors. In our investigation, we observed that cordycepin therapy significantly augmented the expression of the Cd226 gene. As a result, it was hypothesized that cordycepin therapy could enhance the effectiveness of anti-TIGIT therapy. By employing single-cell RNA sequencing analysis of immune cells in the MC38 tumor model, we discovered that cordycepin combined with anti-TIGIT therapy led to a significant increase in the proportion of NK cells within the tumor immune microenvironment. This increased NK cell activity and decreased the expression of inhibitory receptors and exhaustion marker genes. In the combination therapy group, CD8+ T cells had lower exhaustion state scores and increased cytotoxicity, indicating a better immune response. The combination therapy group increased DCs in the tumor immune microenvironment and promoted cellular interaction with CD4+ T cell and CD8+ T cell populations while decreasing Treg cell interactions. In conclusion, cordycepin with anti-TIGIT therapy in colon cancer could reshape the tumor immune microenvironment and have notable anticancer effects.


Majorana fermions in ferromagnetic chains on the surface of bulk spin-orbit coupled s-wave superconductors.
Majorana fermion (MF) excitations in solid state system have non-Abelian statistics which is essential for topological quantum computation. Previous proposals to realize MF, however, generally requires fine-tuning of parameters. Here we explore a platform which avoids the fine-tuning problem, namely a ferromagnetic chain deposited on the surface of a spin-orbit coupled s-wave superconductor. We show that it generically supports zero-energy topological MF excitations near the two ends of the chain with minimal fine-tuning. Depending on the strength of the ferromagnetic moment in the chain, the number of MFs at each end, n, can be either one or two, and should be revealed by a robust zero-bias peak (ZBP) of height 2 ne(2)/h in scanning tunneling microscopy (STM) measurements which would show strong (weak) signals at the ends (middle) of the chain. The role of an approximate chiral symmetry which gives an integer topological invariant to the system is discussed.


Active Middle Ear Implant in a Patient with Neurofibromatosis Type 1 and Multiple Calvarial Defects: A Case Report.
Bony abnormalities, including sphenoid dysplasia and calvarial defects, are well recognized in patients with neurofibromatosis type 1. However, having multiple calvarial defects is rare. We present a case of a 35-year-old Japanese male patient who was referred to our hospital because of hearing loss. He was diagnosed with neurofibromatosis type 1 during early childhood. Otoscopic examination revealed a protrusion from the anterior wall of the external auditory canal that obstructed the external auditory canal. Computed tomography findings revealed multiple defects and an uneven skull surface. Large bony defects of the anterior wall of the external auditory canal were also identified bilaterally. Conductive hearing loss was caused by temporomandibular joint herniation that was obstructing the external auditory canal in both ears. An active middle ear implant was implanted in the right ear. A floating mass transducer was placed into the round window niche using a round window coupler. The active middle ear implant improved postoperative audiometric thresholds to approximately 35 dB across all frequencies. No complications occurred for up to 30 months after the operation. An active middle ear implant is a feasible and valuable option for patients with neurofibromatosis type 1 and conductive hearing loss due to multiple skull defects that result in temporomandibular joint herniation.


Student Perceptions and Acceptance of Mobile Technology in an Undergraduate Nursing Program.
Mobile technology allows healthcare students to access current evidence-based resources. The purpose of this study was to evaluate the student experience of implementing point-of-care (POC) smartphone applications in a first-semester undergraduate nursing program. Teaching methods included using case studies in the laboratory to familiarize students with the apps. At community screening sites, evidence-based guidelines were referenced when students discussed screening results with patients. Surveys were administered prior to implementing this innovation and after the students utilized the apps in direct patient interactions. Survey results were analyzed to evaluate student perceptions and acceptance of mobile technology. Students felt that healthcare smartphone apps were a helpful and convenient way to obtain evidence-based clinical information pertinent to direct care settings. Over 90% of students planned to continue using healthcare smartphone apps. In conclusion, healthcare smartphone apps are a way for students to become comfortable accessing evidence-based clinical resources. It is important to encourage students to use these resources early in the curriculum. Community screenings are an independent health promotion activity which assists in the attainment of health equity and fosters nursing leadership.


Detection of differentially expressed basal cell proteins by mass spectrometry.
The ability of cells to modulate interactions with each other and the substrate is essential for epithelial tissue remodeling during processes such as wound healing and tumor progression. However, despite strides made in the field of proteomics, proteins involved in adhesion have been difficult to study. Here, we report a method for the enrichment and analysis of proteins associated with the basal surface of the cell and its underlying matrix. The enrichment involves deroofing the cells with 20 mM ammonium hydroxide and the removal of cytosolic and organellar proteins by stringent water wash. Proteomic profiling was achieved by LC-FTMS, which allowed comparison of differentially expressed or shared proteins under different cell states. First, we analyzed and compared the basal cell components of mouse keratinocytes lacking the cell-cell junction molecule plakoglobin with their control counterparts. Changes in the molecules involved in motility and invasion were detected in plakoglobin-deficient cells, including decreased detection of fibronectin, integrin beta(4), and FAT tumor suppressor. Second, we assessed the differences in basal cell components between two human oral squamous cell carcinoma lines originating from different sites in the oral cavity (CAL33 and UM-SCC-1). The data show differences between the two lines in the type and abundance of proteins specific to cell adhesion, migration, and angiogenesis. Therefore, the method described here has the potential to serve as a platform to assess proteomic changes in basal cell components including extracellular and adhesion-specific proteins involved in wound healing, cancer, and chronic and acquired adhesion-related disorders.


Conditions for the evolution of soldier sperm classes.
There has been wide disagreement as to whether sperm competition among animals can produce a soldier class of sperm to fight against other males. Utilizing mathematical models, we analyze the appropriate conditions for the evolution and maintenance of a soldier sperm class. We conclude that: (1) soldier sperm evolve even if one soldier sperm can kill or block less than one competing sperm; (2) soldier sperm evolve faster when there is a large variance in the number of competing sperm; (3) soldier ratio increases until reproductive sperm are too scarce to fertilize all ova or a sperm intensely refuses to become a soldier; and (4) soldier sperm are more likely to be smaller than reproductive sperm. Our models suggest that the conditions for the evolution of a soldier sperm class are not stringent.


A study on the brain structures related to conditioned emotional response by means of [14C]2-deoxy-D-glucose method.
Brain structures activated during conditioned emotional response were studied by means of the [14C]2-deoxyglucose method. The experimental (CSE) animals were conditioned with paired 25 25-sec-long flicker sequences (CS) and 1-sec-long 150 V AC electric shocks (US), while the control (CSC) animals were given only 25 CS sequences. Average densities of a unit square (200 microns x 200 microns) of 47 nuclei or cortical areas in the left hemisphere were obtained from an autoradiogram and the optical density ratio (ODR), which is the relative optical density of each structure to that of the corpus callosum, was calculated. Comparison of ODRs of each structure from both groups revealed a significant increased uptake of [14C]2-deoxyglucose (P less than 0.05, Mann-Whitney U-test) in the caudal portion of area 10, area 2, area 18 and the hippocampal formation.


Evidence-based cutoffs for total and adjusted calcium: a major factor in detecting severe hypo- and hypercalcemia.
Severe hypo- and hypercalcemia are common and urgent treatment is recommended. Free calcium (fCa) is the gold standard but needs blood gas tests with challenging preanalytics. Total calcium (tCa) and calculated adjusted calcium (aCa) are readily available, but their interpretation is hampered by identical tCa and aCa cutoffs, laborious local aCa calculation and difficult comparability of calcium biomarkers. Laboratory results from University Medicine Leipzig were evaluated over a five-year period (236,274 patients). A local aCa equation was derived by linear least squares regression, the agreement between fCa, tCa and aCa assessed with Cohen's κ and decision thresholds derived by this indirect method. The local aCa equation was created from data of 9,756 patients, each with one paired measurement of tCa, fCa and albumin. Derived aCa cutoffs (1.95/3.15 mmol/L) differ markedly from derived tCa cutoffs (1.6/2.9 mmol/L) and severe hypo- and hypercalcemia can be more accurately assessed by aCa (κ=0.489, 0.812) than by tCa (κ=0.445, 0.744). Comparing our approach to standard care (tCa, literature cutoff), a total 3,250 of 3,680 (88.3 %) misclassified measurements were correctly classified when using aCa with evidence-based cutoffs. Optimized cutoffs for aCa and tCa hold great potential for improved patient care. Locally derived aCa equations differ mostly in the chosen mean normal calcium and provide minimal overall improvement, but entail a close examination of the used cutoffs before application.


Physicochemical properties of inclusion complexes of highly soluble β-cyclodextrins with highly hydrophobic testosterone propionate.
Hydroxypropyl-β-cyclodextrin (HP-β-CyD) and sulfobutyl ether-β-cyclodextrin (SBE-β-CyD) were used to generate hydrophilic complexes of the poorly water-soluble drug testosterone propionate (TP). The inclusion complexes were obtained by freeze-drying, and then analyzed at both liquid and solid states. Phase solubility studies, performed according to the type-AL solubility diagrams of TP in presence of both CyDs, suggested the formation of water-soluble complexes at 1:1 molar ratio. These results were confirmed by continuous variation method (Job's plot). Both CyDs increased water-solubility of TP 100-fold as compared to the native drug. The host-guest arrangement of CyD complexes in a water solution was further investigated by one- and two-dimensional NMR spectroscopy, highlighting the insertion of the tetracyclic ring of TP into the CyD cavity, and the interaction of the pending ester chain of drug with the primary hydroxyl groups of CyDs at the narrow end of the toroid structure. In solid phase, FTIR-ATR spectroscopy showed that the CO stretching mode of the TP vibrational spectrum changed if the complex between the drug and CyDs occurred. This change is temperature-dependent, and its evolution, accounted for by deconvolution procedures, provided the thermodynamic parameters explaining the mechanisms involved in the formation of inclusion complexes.


Effect of ethnomedicinal plants used in folklore medicine in Jordan as antibiotic resistant inhibitors on Escherichia coli.
Escherichia coli occurs naturally in the human gut; however, certain strains that can cause infections, are becoming resistant to antibiotics. Multidrug-resistant E. coli that produce extended-spectrum beta lactamases (ESBLs), such as the CTX-M enzymes, have emerged within the community setting as an important cause of urinary tract infections (UTIs) and bloodstream infections may be associated with these community-onsets. This is the first report testing the antibiotic resistance-modifying activity of nineteen Jordanian plants against multidrug-resistant E. coli. The susceptibility of bacterial isolates to antibiotics was tested by determining their minimum inhibitory concentrations (MICs) using a broth microdilution method. Nineteen Jordanian plant extracts (Capparis spinosa L., Artemisia herba-alba Asso, Echinops polyceras Boiss., Gundelia tournefortii L, Varthemia iphionoides Boiss. & Blanche, Eruca sativa Mill., Euphorbia macroclada L., Hypericum trequetrifolium Turra, Achillea santolina L., Mentha longifolia Host, Origanum syriacum L., Phlomis brachydo(Boiss.) Zohary, Teucrium polium L., Anagyris foetida L., Trigonella foenum-graecum L., Thea sinensis L., Hibiscus sabdariffa L., Lepidium sativum L., Pimpinella anisum L.) were combined with antibiotics, from different classes, and the inhibitory effect of the combinations was estimated. Methanolic extracts of the plant materials enhanced the inhibitory effects of chloramphenicol, neomycin, doxycycline, cephalexin and nalidixic acid against both the standard strain and to a lesser extent the resistant strain of E. coli. Two edible plant extracts (Gundelia tournefortii L. and Pimpinella anisum L.) generally enhanced activity against resistant strain. Some of the plant extracts like Origanum syriacum L.(Labiateae), Trigonella foenum- graecum L.(Leguminosae), Euphorbia macroclada (Euphorbiaceae) and Hibiscus sabdariffa (Malvaceae) did not enhance the activity of amoxicillin against both standard and resistant E. coli. On the other hand combinations of amoxicillin with other plant extracts used showed variable effect between standard and resistant strains. Plant extracts like Anagyris foetida (Leguminosae) and Lepidium sativum (Umbelliferae) reduced the activity of amoxicillin against the standard strain but enhanced the activity against resistant strains. Three edible plants; Gundelia tournefortii L. (Compositae) Eruca sativa Mill. (Cruciferae), and Origanum syriacum L. (Labiateae), enhanced activity of clarithromycin against the resistant E. coli strain. This study probably suggests possibility of concurrent use of these antibiotics and plant extracts in treating infections caused by E. coli or at least the concomitant administration may not impair the antimicrobial activity of these antibiotics.


Fractionation and reconstitution of factors required for accurate transcription of mammalian ribosomal RNA genes: identification of a species-dependent initiation factor.
Mouse and human cell extracts (S100) can support an accurate and efficient transcription initiation on homologous ribosomal RNA gene (rDNA) templates. The cell extracts were fractionated with the aid of a phosphocellulose column into four fractions (termed A, B, C and D), including one containing a major part of the RNA polymerase I activity. Various reconstitution experiments indicate that fraction D is an absolute requirement for the correct and efficient transcription initiation by RNA polymerase I on both mouse and human genes. Fraction B effectively suppresses random initiation on these templates. Fraction A appears to further enhance the transcription which takes place with fractions C and D. Although fractions A, B and C are interchangeable between mouse and human extracts, fraction D is not; i.e. initiation of transcription required the presence of a homologous fraction D for both templates. The factor(s) in fraction D, however, is not literally species-specific, since mouse D fraction is capable of supporting accurate transcription initiation on a rat rDNA template in the presence of all the other fractions from human cell extract under the conditions where human D fraction is unable to support it. We conclude from these experiments that a species-dependent factor in fraction D plays an important role in the initiation of rDNA transcription in each animal species.