Bacterial production of methylglyoxal: a survival strategy or death by misadventure?
The production of MG (methylglyoxal) in bacterial cells must be maintained in balance with the capacity for detoxification and protection against this electrophile. Excessive production of MG leads to cell death. Survival of exposure to MG is best understood in the Gram-negative bacteria. The major mechanism of protection is the spontaneous reaction of MG with GSH to form hemithiolacetal, followed by detoxification by the glyoxalase system leading to the production of D-lactate. The KefB and KefC glutathione-gated K(+) efflux systems are integrated with the activity of the glyoxalase system to regulate the cytoplasmic pH in response to exposure to electrophiles. Bacteria only produce MG when an imbalance occurs in metabolism. Operation of the MG bypass enables cells to adapt, such that balance is restored to metabolism. Excessive production of MG is an adaptive ploy, which, if it fails, has fatal consequences. On this basis one might define MG-induced loss of life as "death by misadventure" rather than suicide!


Post-infectious irritable bowel syndrome.
Irritable bowel syndrome (IBS) affects 8% to 22% of the general population. Although patients describe an insidious onset of symptoms, including abdominal pain relieved with bowel movements, excessive intestinal gas, variable bowel habits, and abdominal bloating, a subgroup of individuals describe the onset of IBS symptoms following an episode of acute gastroenteritis, known as post-infectious IBS (PI-IBS). Several studies have demonstrated the development of IBS following infection. Risk factors for the development of PI-IBS are female sex and longer duration of initial illness. Although the underlying mechanism of PI-IBS is unclear, ongoing inflammation is clearly a factor in the pathogenesis. The underlying inflammatory process results in increased enterochromaffin cells, T-lymphocytes, intestinal permeability, colonic transit time, and a variety of immunologic abnormalities. PI-IBS patients tend to have a better prognosis than do those with idiopathic IBS, with resolution of symptoms within 5 to 6 years. Treatment is similar to that of idiopathic IBS.


Import of Agrobacterium T-DNA into plant nuclei: two distinct functions of VirD2 and VirE2 proteins.
To study the mechanism of nuclear import of T-DNA, complexes consisting of the virulence proteins VirD2 and VirE2 as well as single-stranded DNA (ssDNA) were tested for import into plant nuclei in vitro. Import of these complexes was fast and efficient and could be inhibited by a competitor, a nuclear localization signal (NLS) coupled to BSA. For import of short ssDNA, VirD2 was sufficient, whereas import of long ssDNA additionally required VirE2. A VirD2 mutant lacking its C-terminal NLS was unable to mediate import of the T-DNA complexes into nuclei. Although free VirE2 molecules were imported into nuclei, once bound to ssDNA they were not imported, implying that when complexed to DNA, the NLSs of VirE2 are not exposed and thus do not function. RecA, another ssDNA binding protein, could substitute for VirE2 in the nuclear import of T-DNA but not in earlier events of T-DNA transfer to plant cells. We propose that VirD2 directs the T-DNA complex to the nuclear pore, whereas both proteins mediate its passage through the pore. Therefore, by binding to ssDNA, VirE2 may shape the T-DNA complex such that it is accepted for translocation into the nucleus.


Preliminary fsLIBS study on bone tumors.
The aim of this study is to evaluate the capability of femtosecond Laser Induced Breakdown Spectroscopy (fsLIBS) to discriminate between normal and cancerous bone, with implications to femtosecond laser surgery procedures. The main advantage of using femtosecond lasers for surgery is that the same laser that is being used to ablate can also be used for a feedback system to prevent ablation of certain tissues. For bone tumor removal, this technique has the potential to reduce the number of repeat surgeries that currently must be performed due to incomplete removal of the tumor mass. In this paper, we performed fsLIBS on primary bone tumor, secondary tumor in bone, and normal bone. These tissues were excised from consenting patients and processed through the UC Davis Cancer Center Biorepository. For comparison, each tumor sample had a matched normal bone sample. fsLIBS was performed to characterize the spectral signatures of each tissue type. A minimum of 20 spectra were acquired for each sample. We did not detect significant differences between the fsLIBS spectra of secondary bone tumors and their matched normal bone samples, likely due to the heterogeneous nature of secondary bone tumors, with normal and cancerous tissue intermingling. However, we did observe an increase in the fsLIBS magnesium peak intensity relative to the calcium peak intensity for the primary bone tumor samples compared to the normal bone samples. These results show the potential of using femtosecond lasers for both ablation and a real-time feedback control system for treatment of primary bone tumors.


Cell-free transcription directed by the 422 adipose P2 gene promoter: activation by the CCAAT/enhancer binding protein.
Previous investigations have shown that CCAAT/enhancer binding protein (C/EBP) can function as a trans-activator of the promoters of several adipocyte-specific genes--i.e., the 422 adipose P2 (422/aP2), stearoyl-CoA desaturase 1 (SCD1), and glucose transporter 4 (GLUT4) genes, in 3T3-L1 mouse preadipocytes. We now describe a cell-free system prepared from nuclei of 3T3-L1 cells that carries out transcription directed by these promoters. To measure transcript formation, we employed a polymerase chain reaction-assisted analysis. Nuclear extract from 3T3-L1 adipocytes that express C/EBP supports a higher rate of transcription of chimeric 422(aP2) promoter-chloramphenicol acetyltransferase (CAT) reporter gene constructs than nuclear extract from preadipocytes that lack C/EBP. A competitor oligonucleotide containing the C/EBP binding site sequence and antibodies raised against C/EBP inhibit transcription directed by the 422(aP2) promoter. The factor limiting transcription by nuclear extract from preadipocytes appears to be C/EBP, since recombinant C/EBP (rC/EBP) markedly activates transcription of the 422(aP2) promoter-CAT gene with preadipocyte extract but not with adipocyte extract. rC/EBP also activates cell-free transcription of SCD1 promoter-CAT and GLUT4 promoter-CAT chimeric genes. Point mutations within the C/EBP binding site in the 422(aP2) promoter markedly decrease transcription activated by rC/EBP. Consistent with activation by cAMP of the 422(aP2) promoter in intact preadipocytes, cAMP-dependent protein kinase activates transcription through this promoter with the cell-free system, this effect being independent of C/EBP. Thus, regulation of transcription directed by the 422(aP2) promoter in the cell-free system resembles that which occurs in intact 3T3-L1 cells.


Mixed epithelial and stromal tumor of the kidney.
We describe the clinicopathologic features of 12 patients with a distinctive tumor of the kidney characterized by a mixture of epithelial and stromal elements that form solid and cystic growth patterns. Similar tumors were reported previously in the literature under various names, including adult mesoblastic nephroma. All but one of the patients were women. The only man had a long history of treatment with lupron and diethylstilbesterol. Seven of the women had histories of long-term oral estrogen use of whom six had undergone total abdominal hysterectomy and bilateral salpingo-oophorectomy several years prior, and the seventh patient had been using oral contraceptives for many years. Another woman had this operation but did not receive any hormone therapy. Ages ranged from 31 to 71 years (mean, 56 yrs). Six patients presented with symptoms, including pain and infections attributable to mass effect, and in six the tumor was detected incidentally. Grossly, the tumors were well-circumscribed (mean size, 6 cm; range, 3-12 cm) and consisted of solid and cystic components, most often in equal proportions but in variable distribution. Microscopically, the spindle cell component ranged in appearance from scar-like fibrous tissue to leiomyoma-like interlacing fascicles; usually there was a mixture of both. More cellular foci reminiscent of ovarian stroma or solitary fibrous tumor were also present. No blastema was present. Epithelial elements (composed of clusters of tubules with variable lining) were scattered amidst the spindle cells, and focally transformed into large cysts lined by cells with abundant pink cytoplasm and a hobnail appearance. Immature epithelial elements typical of Wilms' tumor were not present. Muscle markers (desmin and smooth muscle actin) were positive diffusely and strongly in the spindle cells of all tumors, whereas HMB-45 and CD34 were absent. Estrogen receptors were detected in the nuclei of spindle cells in seven tumors and progesterone receptors in three. The distinctive clinicopathologic characteristics of these lesions warrant their classification as a separate category of kidney tumor. We suggest the descriptive term "mixed epithelial and stromal tumor" for this group until its nature and relationship to other kidney lesions are further clarified. Its preponderance in females with a history of long-term estrogen replacement and the history of long-term sex-steroid use in the only male patient, combined with the frequent content of estrogen and progesterone receptors in the spindle cells, suggest that the hormonal milieu plays a role in the evolution of these tumors. The clinical and pathologic parallels with mucinous cystic tumors of pancreas and liver raise the possibility of a common pathogenetic mechanism that may be linked to the periductal fetal mesenchyme. We think this entity is a benign composite neoplasm in which stroma and epithelium are both integral neoplastic components.


Hypertension and primary myocardial disease in congestive cardiac failure.
This study has tried to use end diastolic diameter the index of chamber dilatation to discriminate between hypertensive heart failure and diluted cardiomyopathy as both conditions are known to overlap in cases of congestive cardiac failure. The sensitivity, specificity and positive predictive value was 66.7%, 68% and 66.7% respectively. This means that alone, end diastolic diameter is not a very acute discriminator in cases where an overlap as shown in the figure occurs. It is therefore necessary to use all discriminatory indices in combination to get better accuracy.


Injectable Thermosensitive Formulation Based on Polyurethane Hydrogel/Mesoporous Glasses for Sustained Co-Delivery of Functional Ions and Drugs.
Mini-invasively injectable hydrogels are widely attracting interest as smart tools for the co-delivery of therapeutic agents targeting different aspects of tissue/organ healing (e.g., neo-angiogenesis, inflammation). In this work, copper-substituted bioactive mesoporous glasses (Cu-MBGs) were prepared as nano- and micro-particles and successfully loaded with ibuprofen through an incipient wetness method (loaded ibuprofen approx. 10% w/w). Injectable hybrid formulations were then developed by dispersing ibuprofen-loaded Cu-MBGs within thermosensitive hydrogels based on a custom-made amphiphilic polyurethane. This procedure showed almost no effects on the gelation potential (gelation at 37 °C within 3-5 min). Cu2+ and ibuprofen were co-released over time in a sustained manner with a significantly lower burst release compared to MBG particles alone (burst release reduction approx. 85% and 65% for ibuprofen and Cu2+, respectively). Additionally, released Cu2+ species triggered polyurethane chemical degradation, thus enabling a possible tuning of gel residence time at the pathological site. The overall results suggest that hybrid injectable thermosensitive gels could be successfully designed for the simultaneous localized co-delivery of multiple therapeutics.


Quinazoline derivatives as anticancer drugs: a patent review (2011 - present).
Quinazoline is one of the most studied moieties in medicinal chemistry due to the wide range of biological properties such as the anticancer, antibacterial, anti-inflammatory, antimalarial and antihypertensive activities. During the past decades, several patents and articles have been published in international peer-reviewed literature regarding the discovery and development of original and promising quinazoline derivatives for cancer treatment. Although quinazolines are well known to inhibit EGFR, there is also a large panel of other therapeutic protein targets. This review summarized the new patents and articles published about quinazoline derivatives as anticancer drugs since 2011. Since 2011, a lot of quinazoline compounds have shown EGFR inhibition. Unlike the first-generation EGFR inhibitors, they inhibit both wild-type and mutated EGFR. In recent years, a number of studies on quinazoline synthesis have been reported and used by several medicinal chemistry groups for better and easier development of new derivatives. Therefore, several patents have been approved for the use of quinazoline compounds as inhibitors of other kinases, histone deacetylase, Nox and some metabolic pathways. Because of the large number of proteins targeted, some high structural diversity is observed in patented quinazoline compounds. Due to the vast applications of quinazoline derivatives, development of novel quinazoline compounds as anticancer drugs remains a promising field.


Old drugs, old problems: where do we stand in prediction of rheumatoid arthritis responsiveness to methotrexate and other synthetic DMARDs?
Methotrexate (MTX) is the central drug in the management of rheumatoid arthritis (RA) and other immune mediated inflammatory diseases. It is widely used either in monotherapy or in association with other synthetic and biologic disease modifying anti-rheumatic drugs (DMARDs). Although comprehensive clinical experience exists for MTX and synthetic DMARDs, to date it has not been possible to preview correctly whether or not a patient will respond to treatment with these drugs. Predicting response to MTX and other DMARDs would allow the selection of patients based on their likelihood of response, thus enabling individualized therapy and avoiding unnecessary adverse effects and elevated costs. However, studies analyzing this issue have struggled to obtain consistent, replicable results and no factor has yet been recognized to individually distinguish responders from nonresponders at treatment start. Variables possibly influencing drug effectiveness may be disease-, patient- or treatment-related, clinical or biological (genetic and nongenetic). In this review we summarize current evidence on predictors of response to MTX and other synthetic DMARDs, discuss possible causes for the heterogeneity observed and address its translation into daily clinical practice.


Examination of the relationship between peak linear and angular accelerations to brain deformation metrics in hockey helmet impacts.
Ice hockey is a contact sport which has a high incidence of brain injury. The current methods of evaluating protective devices use peak resultant linear acceleration as their pass/fail criteria, which are not fully representative of brain injuries as a whole. The purpose of this study was to examine how the linear and angular acceleration loading curves from a helmeted impact influence currently used brain deformation injury metrics. A helmeted Hybrid III headform was impacted in five centric and non-centric impact sites to elicit linear and angular acceleration responses. These responses were examined through the use of a brain model. The results indicated that when the helmet is examined using peak resultant linear acceleration alone, they are similar and protective, but when a 3D brain deformation response is used to examine the helmets, there are risks of brain injury with lower linear accelerations which would pass standard certifications for safety.


Core Warming of Coronavirus Disease 2019 Patients Undergoing Mechanical Ventilation: A Pilot Study.
Fever is a recognized protective factor in patients with sepsis, and growing data suggest beneficial effects on outcomes in sepsis with elevated temperature, with a recent pilot randomized controlled trial (RCT) showing lower mortality by warming afebrile sepsis patients in the intensive care unit (ICU). The objective of this prospective single-site RCT was to determine if core warming improves respiratory physiology of mechanically ventilated patients with coronavirus disease 2019 (COVID-19), allowing earlier weaning from ventilation, and greater overall survival. A total of 19 patients with mean age of 60.5 (±12.5) years, 37% female, mean weight 95.1 (±18.6) kg, and mean body mass index 34.5 (±5.9) kg/m2 with COVID-19 requiring mechanical ventilation were enrolled from September 2020 to February 2022. Patients were randomized 1:1 to standard of care or to receive core warming for 72 hours through an esophageal heat exchanger commonly utilized in critical care and surgical patients. The maximum target temperature was 39.8°C. A total of 10 patients received usual care and 9 patients received esophageal core warming. After 72 hours of warming, the ratio of arterial oxygen partial pressure to fractional inspired oxygen (PaO2/FiO2) ratios were 197 (±32) and 134 (±13.4), cycle thresholds were 30.8 (±6.4) and 31.4 (±3.2), ICU mortalities were 40% and 44%, 30-day mortalities were 30% and 22%, and mean 30-day ventilator-free days were 11.9 (±12.6) and 6.8 (±10.2) for standard of care and warmed patients, respectively (p = NS). This pilot study suggests that core warming of patients with COVID-19 undergoing mechanical ventilation is feasible and appears safe. Optimizing time to achieve febrile-range temperature may require a multimodal temperature management strategy to further evaluate effects on outcome. ClinicalTrials.gov Identifier: NCT04494867.


Genetic organization of Pasteurella multocida cap Loci and development of a multiplex capsular PCR typing system.
Current serotyping methods classify Pasteurella multocida into five capsular serogroups (serogroups A, B, D, E, and F) and 16 somatic serotypes (serotypes 1 to 16). In the present study, we have developed a multiplex PCR assay as a rapid alternative to the conventional capsular serotyping system. The serogroup-specific primers used in this assay were designed following identification, sequence determination, and analysis of the capsular biosynthetic loci of each capsular serogroup. The entire capsular biosynthetic loci of P. multocida A:1 (X-73) and B:2 (M1404) have been cloned and sequenced previously (J. Y. Chung, Y. M. Zhang, and B. Adler, FEMS Microbiol. Lett. 166:289-296, 1998; J. D. Boyce, J. Y. Chung, and B. Adler, Vet. Microbiol. 72:121-134, 2000). Nucleotide sequence analysis of the biosynthetic region (region 2) from each of the remaining three serogroups, serogroups D, E, and F, identified serogroup-specific regions and gave an indication of the capsular polysaccharide composition. The multiplex capsular PCR assay was highly specific, and its results, with the exception of those for some serogroup F strains, correlated well with conventional serotyping results. Sequence analysis of the strains that gave conflicting results confirmed the validity of the multiplex PCR and indicated that these strains were in fact capsular serogroup A. The multiplex PCR will clarify the distinction between closely related serogroups A and F and constitutes a rapid assay for the definitive classification of P. multocida capsular types.


Studies on the assembly of cytochrome oxidase in isolated rat hepatocytes.
1. The assembly of rat liver cytochrome oxidase was studied in isolated hepatocytes and isolated liver mitochondria labelled with L-[35S]methionine. 2. Labelled subunits II and III appeared in the immunoabsorbed holoenzyme within minutes after the initiation of a pulse label. In contrast, labelled subunit I appeared in immunoabsorbed holoenzyme only after a subsequent 2 h chase or after an additional 2 h of labelling. Subunit I was heavily labelled, however, in intact mitochondria after 10 min. 3. A similar pattern of labelling was observed in holo-cytochrome oxidase which was chemically isolated by a small scale procedure adapted for this purpose. The appearance of subunit I in the holoenzyme was delayed for 1.5-2 h after a 60 min pulse with labelled methionine. 4. Incubation of hepatocytes for 4 h in the presence of cycloheximide had no effect on the labelling pattern described above. 5. Methods were developed in which newly translated, presumably unassembled, subunits of cytochrome oxidase could be separated from the holoenzyme by fractionation in Triton X-114. Short-term pulse experiments indicate that subunits II and III are associated with the holoenzyme fraction immediately after their completion, whereas subunit I is not. 6. The data are consistent with a model in which cytochrome oxidase assembly is viewed as an ordered and sequential event.


Effects of anticoagulation provider continuity on time in therapeutic range for warfarin patients.
Anticoagulation (AC) clinics use the percentage of time in the therapeutic INR range (%TTR) to characterize the quality of management for patients treated with warfarin. In order to guide policy and procedure changes, the purpose of this quality improvement (QI) study was to characterize the AC patient population at The Johns Hopkins Hospital (JHH). We set out to investigate the impact of AC clinic provider continuity on the quality of anticoagulation management. This QI study is a retrospective chart review of 525 warfarin patients managed by pharmacists in the Hematology AC Management Clinic at JHH from June 28, 2013 to November 1, 2014. We recorded patient demographic and clinical characteristics and the quality of AC management using %TTR, and compared these parameters between patients with (Group A) and without a primary AC (Group B). Group A patients had a significantly higher %TTR than Group B patients (53.2 vs. 46.5 %, p = 0.008). In conclusion, we found that patients with a primary AC clinic provider had a higher %TTR than patients with multiple providers. If confirmed prospectively, this approach to warfarin management could represent one technique for AC clinics to optimize patient management and clinical outcomes.


Pain Pressure Threshold in the Region of the Sacroiliac Joint in Patients Diagnosed with Sacroiliac Joint Pain.
Although the prevalence of sacroiliac joint (SIJ) pain is relatively high (15 - 30%), there is no unambiguous reference standard to diagnose SIJ pain. Pressure tenderness in the SIJ region is used for diagnostic purposes, but the clinimetric properties of this procedure remain to be determined. The aim of this study is to determine the reliability of pain pressure threshold (PPT) measurements in the SIJ region and the difference in PPTs in the SIJ region between healthy volunteers and PPTs in patients with SIJ pain. Prospective cohort study. Outpatient pain clinic VU University Medical Center. Forty-one healthy volunteers and 31 patients diagnosed with SIJ pain were included. PPTs were obtained from 5 measurement points in the region of the SIJ with a pressure pain algometer using a standardized protocol. The inter-rater reliability of this method was calculated by means of the Intraclass Correlation Coefficients (ICC) of individual assessment performed by 2 individual raters of SIJs of healthy volunteers on both sides. PPTs of healthy volunteers were compared to those of the affected side in patients with SIJ pain. PPT measurement showed moderate to good inter-rater reliability (ICC 0.6 - 0.82).The median PPTs of 5 points was comparable for both sides in healthy volunteers (right: 8.5 kg/cm2 [IQR 6.0 - 10.0]; left 8.3 kg/cm2 (5.8 - 10.0]). Median PPTs for the affected sides of patients with SIJ pain were significantly lower compared to the same side of healthy volunteers (right: 2.4 kg/cm2 [IQR 2.2 - 3.2, n = 15]; left: 2.5 kg/cm2 [2.3 - 3.2, n = 16]; P < 0.001 for both sides). Only the SIJ on one side of was measured in patients with SIJ pain, where both sides would be desirable. Pressure pain algometry appears to be a reliable method to establish differences in PPTs between healthy volunteers and patients with SIJ pain. The diagnostic accuracy of this test should be investigated further.


Time trend in the prevalence of adult asthma in Japan: findings from population-based surveys in Fujieda City in 1985, 1999, and 2006.
The burden of asthma is recognized as an important public health problem worldwide. In most countries, the prevalence of asthma has been reported to increase in the last few decades. However, more recent epidemiological studies have shown that the prevalence of asthma has been flat or even decreasing after the 1990 s in some developed countries. The recent time trend in the prevalence of adult asthma in Japan is unknown. Population-based surveys were conducted three times in the same region, in 1985, 1999, and 2006, at Fujieda City, Shizuoka, Japan, and the results were reported previously. We compared the results of these surveys to reveal the time trend in the prevalence of adult asthma. Although the questionnaires used in these surveys were not exactly the same, the time trend was assessed by comparing the responses to relevant questions between questionnaires. The prevalences of wheeze following a common cold and dyspneal feeling at night increased significantly from 1985 to 1999 (4.2% to 7.6%, and 3.2% to 5.3%, respectively). The prevalences of lifetime asthma and current asthma also significantly increased from 1999 to 2006 (5.1% to 6.7%, and 1.5% to 3.4%, respectively). The prevalences of asthma among adults in Fujieda City consistently increased from 1985 to 2006. There was no evidence that the prevalences were in plateau or decreasing. These findings suggest that more efforts are required to stop the increase in the burden of this disease in Japan.


A prospective, randomized comparison of computed tomography with conventional diagnostic methods in the evaluation of penetrating injuries to the back and flank.
We prospectively compared computed tomography with conventional diagnostic methods in the evaluation of penetrating injuries to the back and flank in 85 patients. Immediate laparotomy was performed in 24 patients because of physical findings, and these patients were not randomized. Nine unnecessary operations were performed in this group, and these nine patients had significantly higher hospital costs than patients in either randomized group. In the randomized patients, there were only three true-positive and three false-positive findings. Both computed tomographic evaluation (31 patients) and conventional evaluation (30 patients) were highly accurate and specific for injuries that required operation. Evaluation with computed tomography required a longer time to make a hospital disposition but required fewer diagnostic tests. Computed tomography can be useful in the assessment of penetrating injuries to the back and flank.


The new Spanish curriculum: reasons for change.
To summarize it can be stated that: The dependence of dental science on medicine in Spain has not been in any way advantageous to the profession, the practice of dentistry or the oral health of the population. Today's teaching must change if Spain is to face up to the enormous challenges of the future, including new trends in demand, the right to health and the decrease of the professional's standard of living. In future it will be necessary to include new curricular parameters, such as the organization of work, prevention and behavioural sciences, etc., with the objective of being able to provide the population with improved and more accessible services. It is necessary to reflect upon the position as regards technology, so as to be able to optimize its utilization at each appropriate level and avoid excessive dependence on industry. The new curriculum has been based on an increased amount of teaching of the basic and medical sciences, an earlier integration of the students into the clinic, a closer relationship with the community, and finally, a more integrated approach to, and methodology in, all clinical work. In Spain, both the State and the universities have made an enormous effort to bring the teaching of dental science up to date by seeking its equivalence and harmony with that of the EEC. This effort, owing to the special circumstances within Spain, has made the acceptance and extension of a profound philosophical, academic and professional change necessary.


Intraluminal irradiation for the palliation of lung cancer with the high dose rate micro-Selectron.
Fifty patients with inoperable, symptomatic endobronchial carcinoma were treated by a single exposure of intraluminal radiotherapy. A high dose rate afterloading system (the micro-Selectron-HDR) was used to minimise radiation exposure for staff. Haemoptysis was relieved in 24 of 28 patients, breathlessness in 21 of 33 patients, and cough in nine of 18 patients. Radiological collapse resolved in 11 of 24 patients. Treatment was given on an outpatient basis and was well tolerated. Intraluminal radiotherapy appears to offer an effective alternative to conventional fractionated external beam radiotherapy.


Efficacy and toxicity of particle radiotherapy in WHO grade II and grade III meningiomas: a systematic review.
OBJECTIVEAdjuvant radiotherapy has become a common addition to the management of high-grade meningiomas, as immediate treatment with radiation following resection has been associated with significantly improved outcomes. Recent investigations into particle therapy have expanded into the management of high-risk meningiomas. Here, the authors systematically review studies on the efficacy and utility of particle-based radiotherapy in the management of high-grade meningioma.METHODSA literature search was developed by first defining the population, intervention, comparison, outcomes, and study design (PICOS). A search strategy was designed for each of three electronic databases: PubMed, Embase, and Scopus. Data extraction was conducted in accordance with the PRISMA guidelines. Outcomes of interest included local disease control, overall survival, and toxicity, which were compared with historical data on photon-based therapies.RESULTSEleven retrospective studies including 240 patients with atypical (WHO grade II) and anaplastic (WHO grade III) meningioma undergoing particle radiation therapy were identified. Five of the 11 studies included in this systematic review focused specifically on WHO grade II and III meningiomas; the others also included WHO grade I meningioma. Across all of the studies, the median follow-up ranged from 6 to 145 months. Local control rates for high-grade meningiomas ranged from 46.7% to 86% by the last follow-up or at 5 years. Overall survival rates ranged from 0% to 100% with better prognoses for atypical than for malignant meningiomas. Radiation necrosis was the most common adverse effect of treatment, occurring in 3.9% of specified cases.CONCLUSIONSDespite the lack of randomized prospective trials, this review of existing retrospective studies suggests that particle therapy, whether an adjuvant or a stand-alone treatment, confers survival benefit with a relatively low risk for severe treatment-derived toxicity compared to standard photon-based therapy. However, additional controlled studies are needed.


A retrospective study of skeletal and disease-free survival benefits of zoledronic acid therapy in patients with multiple myeloma treated with novel agents.
The large majority of patients with multiple myeloma develop bone lesions and typically receive bisphosphonates to maintain bone health and prevent/delay skeletal-related events. Recent clinical data show that the newer-generation bisphosphonate, zoledronic acid, may confer a survival benefit when combined with antimyeloma therapy. However, clinical data describing the combination of zoledronic acid with newer antimyeloma regimens are limited. This retrospective study analyzed efficacy and safety outcomes in patients with multiple myeloma receiving first- and second-line treatment with bortezomib, lenalidomide, or thalidomide, with or without zoledronic acid. Records data from 94 patients with Durie-Salmon stage 3A/B multiple myeloma were collated. Most patients (~80%) had bone lesions at study entry. Almost all patients received zoledronic acid at some time during their treatment. Adding zoledronic acid was associated with a numerical, but statistically nonsignificant, benefit in the 1-year progression-free survival rate in both the first- and second-line setting. A similar benefit was observed on the 2-year skeletal-related event rate. Notably, combining zoledronic acid with newer antimyeloma agents was feasible, tolerable, and did not affect the duration of antimyeloma treatment. Three cases of osteonecrosis of the jaw were reported; there were no reports of acute renal failure. This retrospective analysis suggests that extended treatment with zoledronic acid in combination with bortezomib, lenalidomide, or thalidomide is safe and tolerable in patients receiving these therapies as first- or second-line treatment. The addition of zoledronic acid may improve both myeloma and skeletal-related outcomes.


Comparison of Powerlifting Performance in Trained Men Using Traditional and Flexible Daily Undulating Periodization.
Colquhoun, RJ, Gai, CM, Walters, J, Brannon, AR, Kilpatrick, MW, D'Agostino, DP, and Campbell, WI. Comparison of powerlifting performance in trained men using traditional and flexible daily undulating periodization. J Strength Cond Res 31(2): 283-291, 2017-Daily undulating periodization (DUP) is a growing trend, both in practice and in the scientific literature. A new form of DUP, flexible daily undulating periodization (FDUP), allows for athletes to have some autonomy by choosing the order of their training. The purpose of this study was to compare an FDUP model to a traditional model of DUP on powerlifting performance in resistance-trained men. Twenty-five resistance-trained men were randomly assigned to one of 2 groups: FDUP (N = 14) or DUP (N = 11). All participants possessed a minimum of 6 months of resistance training experience and were required to squat, bench press, and deadlift 125, 100, and 150% of their body mass, respectively. Dependent variables assessed at baseline and after the 9-week training program included bench press 1 repetition maximum (1RM), squat 1RM, deadlift 1RM, powerlifting total, Wilks Coefficient, fat mass, and fat-free mass (FFM). Dependent variables assessed during each individual training session were motivation to train, Session Rating of Perceived Exertion (Session RPE), and satisfaction with training session. After the 9-week training program, no significant differences in intensity or volume were found between groups. Both groups significantly improved bench press 1RM (FDUP: +6.5 kg; DUP: +8.8 kg), squat 1RM (FDUP: +15.6 kg; DUP: +18.0 kg), deadlift 1RM (FDUP: +14.8 kg; DUP: +13.6 kg), powerlifting total (FDUP: +36.8 kg; DUP: +40.4 kg), and Wilks Coefficient (FDUP: +24.8; DUP: +26.0) over the course of study (p = <0.001 for each variable). There was also a significant increase in FFM (FDUP: +0.8 kg; DUP: +0.8 kg) for both groups (p = 0.003). There were no differences in motivation to train, session RPE, or satisfaction with training session measurements between groups (p = 0.369-0.702, respectively). In conclusion, FDUP seems to offer similar resistance training adaptations when compared with a traditional DUP in resistance-trained men.


[Treatment modalities in central retinal vein occlusion].
Central retinal vein occlusion (CRVO) remains one of the most common retinal vascular disorders that may lead to blindness. The etiology is unknown, however, predisposing factors such as hypertension, diabetes, atherosclerosis and hypercoagulable states have all been described. Local ophthalmic illnesses such as open angle glaucoma, ocular trauma and orbital infections have also been suggested as causative. CRVO can be subdivided into two clinical types, ischemic and non-ischemic. The non-ischemic type comprises the milder form of the disease with partial venous obstruction and good visual outcome. Ischemic CRVO is the severe form and is associated with visual loss, because of nearly total retinal vein obstruction and poor perfusion to retina. In addition, patients with ischemic CRVO may end up with additional complications such as neovascular glaucoma that may lead to blindness. Over 90% of CRVO occurs in patients > 65 years. The presenting symptom is a sudden painless mono-ocular decrease in visual acuity which could result from macular edema, ischemia, or intraocular bleeding. Ophthalmoscopic examination reveals macular edema, retinal bleeding (more peripheral), tortuous vein dilatation and swollen disc. Current treatment modalities include systemic use of anticoagulation drugs, local treatments including laser, intravitreal injection of anti-vascular endothelial growth factor and surgery (vitrectomy). This review presents the current therapeutic modalities in CRVO.


Ltbetar signaling does not regulate Aire-dependent transcripts in medullary thymic epithelial cells.
Thymic medullary epithelial cells (mTECs) play a major role in central tolerance induction by expressing tissue-specific Ags (TSAs). The expression of a subset of TSAs in mTECs is under the control of Aire (autoimmune regulator). Humans defective for AIRE develop a syndrome characterized by autoimmune disease in several endocrine glands. Aire has been proposed to be regulated by lymphotoxin beta receptor (Ltbetar) signaling and there is evidence that, additionally, Aire-independent transcripts may be regulated by this pathway. Given the potential clinical importance of Aire regulation in mTECs for the control of autoimmunity, we investigated the relation between Ltbetar signaling and TSA expression by whole genome transcriptome analysis. In this study, we show that the absence of Ltbetar has no effect on the expression of Aire and Aire-dependent TSAs. Also, the lack of Ltbetar signaling does not disturb regulatory T cells or the distribution of dendritic cells in the thymus. However, mTECs in Ltbetar-deficient mice show an aberrant distribution within the thymic medulla with disruption of their three-dimensional architecture. This is predicted to impair the interaction between mTECs and thymocytes as shown by the reduced surface uptake of MHCII by mature thymocytes in Ltbetar-deficient mice. We propose that the physiological medullary architecture ensures negative-selection by supporting lympho-epithelial interaction through a large epithelial cell surface distributed evenly across the medulla.


Peripapillary retinal nerve fibre layer thickness in highly myopic Caucasians as measured by Stratus optical coherence tomography.
To assess peripapillary retinal nerve fibre layer (RNFL) thickness distribution in a group of non-glaucomatous Caucasian subjects with a high degree of myopia and to evaluate the relationship between RNFL thickness, both global and sectoral, and other variables including axial length and optic disc size. 31 eyes of 31 healthy Caucasian subjects with spherical equivalent >or=-6 dioptres (D) were recruited from a community optometric practice. RNFL thickness was measured using the Stratus optical coherence tomography (OCT) Fast RNFL 3.4 mm scan protocol. Optic disc area was measured using the Heidelberg Retinal Tomograph II and axial length using the IOL Master. Associations between RNFL measurements and axial length, spherical equivalent and optic disc area were evaluated by linear regression analysis. The sample had a mean age of 48.1 years, mean spherical equivalent of -7.7 D, and mean axial length of 26.5 mm. The mean (SD) RNFL thickness was 81.4 (13.7) microm. In comparison with the Status OCT normative database, the distribution of RNFL thickness was substantially lower in the study group. The greatest disparity was around 7 clock hours centred on the nasal meridian in which 26/31 (83.9%) had one or more clock hours in which RNFL thickness was below normal at the 5% probability level in comparison with the Stratus normative database. No statistically significant associations between mean RNFL thickness and age (p = 0.12), gender (p = 0.76), spherical equivalent (p = 0.80), cup:disc area ratio (p = 0.88), optic disc area (p = 0.14) or axial length (p = 0.18) were identified in this group. However, RNFL thickness from vertical quadrants and in particular the superior sector correlated strongly with axial length, age and optic disc area. The Stratus OCT normative database may be misleading in highly myopic eyes from Caucasians resulting in a substantial proportion of false positive errors. Particular caution is needed when the RNFL appears to be below the normative database normal limit at the upper or lower poles or on the nasal side of the disc. Stratified normal databases are required for accurate diagnosis of conditions resulting in nerve fibre loss such as chronic glaucoma.


High-level expression of a mitochondrial enzyme, ornithine transcarbamylase from rat liver, in a baculovirus expression system.
The mitochondrial enzyme, ornithine transcarbamylase (OTC) from rat liver was expressed in Spodoptera frugiperda (Sf) insect cells using a baculovirus vector. When insect cells were infected with recombinant Autographica californica nuclear polyhedrosis virus (AcNPV) containing a cDNA encoding the precursor form of OTC (pOTC) inserted into the polyhedrin gene, they expressed catalytically active enzyme at levels of approximately 2.5 micrograms/10(6) cells. About 25% of the active enzyme was a novel, partially processed product of pOTC containing four extra amino acids at the amino terminus of OTC. The most abundant protein found in mitochondria from infected insect cells was the normal processing intermediate iOTC, which contains 8 extra amino acids at the amino terminus of OTC. Whereas this species, present at 20 micrograms/10(6) cells, was not active and did not bind the transition-state analog inhibitor of OTC, delta-PALO, the novel processing product did bind and was affinity-purified, along with mature OTC, on a PALO-affinity column. The OTC expressed in insect cells was located in the same compartment of the mitochondrion as in rat liver. The incomplete processing occurred in vitro in both noninfected and infected insect cells. The high level of expression of iOTC using the baculoviral expression system provides a means of overproducing an obligatory intermediate in the mitochondrial import process.


Method for spectroradiometric temperature measurements in two phase flows. 1: Theory.
The problem of applying spectroradiometric temperature measurement techniques to hot gases containing scattering particles is considered. A temperature measurement procedure is developed. This procedure is shown to yield a significant advantage over previous techniques while requiring only minimal knowledge of the exact nature of the scattering particles.


Case Report: Massive epistaxis from juvenile angiofibroma in an adolescent with severe haemophilia A.
Epistaxis may be profuse in individuals with normal bleeding parameters, but in an individual with haemophilia, it may be life-threatening. It is even more dangerous when epistaxis is caused by an undetected concomitant juvenile angiofibroma, and only one such case has been reported in the English literature. We report another case, of an 18-year-old Filipino adolescent with severe haemophilia A who was referred for repeated massive epistaxis. The epistaxis had been attributed to his haemophilia and managed with nasal packing, multiple blood transfusions and Factor VIII administration. After two years of unsuccessful management, nasal endoscopy was performed for the first time, revealing an intranasal mass. Imaging showed a right intranasal vascular tumour supplied mainly by the right sphenopalatine artery. He subsequently underwent preoperative embolization and endoscopic excision of the tumour with Factor VIII transfused pre-, intra-, and post-operatively, and recombinant Factor VII added post-operatively. Final histopathology was consistent with juvenile angiofibroma. There has been no nasal obstruction or recurrence of epistaxis seven years since the surgery. Clinicians should be more meticulous in assessing epistaxis in any patient with a bleeding disorder and investigate more subtle symptoms such as nasal obstruction. Verification of the source by direct visualization and ancillary diagnostic techniques (such as imaging) when indicated should be the standard of care for all patients presenting with epistaxis, whether or not a concomitant bleeding disorder exists. A high index of suspicion for juvenile angiofibroma should be maintained in adolescent males with epistaxis and nasal obstruction.


Stimulation of erythroblast formation in suspension cultures of murine marrow by a factor in normal mouse serum, and its relationship to erythropoietin.
Addition of normal mouse serum to liquid suspension cultures of murine marrow cells resulted in dose-related increases in the number of heme-synthesizing erythroid cells. Removal of late normoblasts and reticulocytes by differential immune lysis prior to culture greatly enhanced the difference in heme synthesis between cultures with or without added mouse serum, permitting detection of as little as 1 microliter/l.5 ml of medium. Cell counts on these cultures indicated that the mouse serum factor actually stimulated formation of late normoblasts through proliferation and maturation of their precursors. The effect required either the presence of Ep in the medium, or the presence in the to be cultured cell suspensions of proerythroblasts which had been induced by or had contact with Ep prior to collection of the marrow.


New insights into riboswitch regulation mechanisms.
Riboswitches are genetic elements located in non-coding regions of some messenger RNAs (mRNAs) that are present in all three domains of life. The binding of ligands to riboswitches induces conformational changes in the mRNA molecule, resulting in modulation of gene transcription, or RNA splicing, translation or stability. This mechanism of regulation is particularly widespread in bacteria and allows a direct response to various metabolic changes. A large number of riboswitches have been discovered in the last few years, suggesting the existence of a huge diversity of regulatory ligands and genetic mechanisms of regulation. This review focuses on recent discoveries in riboswitch regulatory mechanisms as well as current outstanding challenges.


Mechanical and assembly units of viral capsids identified via quasi-rigid domain decomposition.
Key steps in a viral life-cycle, such as self-assembly of a protective protein container or in some cases also subsequent maturation events, are governed by the interplay of physico-chemical mechanisms involving various spatial and temporal scales. These salient aspects of a viral life cycle are hence well described and rationalised from a mesoscopic perspective. Accordingly, various experimental and computational efforts have been directed towards identifying the fundamental building blocks that are instrumental for the mechanical response, or constitute the assembly units, of a few specific viral shells. Motivated by these earlier studies we introduce and apply a general and efficient computational scheme for identifying the stable domains of a given viral capsid. The method is based on elastic network models and quasi-rigid domain decomposition. It is first applied to a heterogeneous set of well-characterized viruses (CCMV, MS2, STNV, STMV) for which the known mechanical or assembly domains are correctly identified. The validated method is next applied to other viral particles such as L-A, Pariacoto and polyoma viruses, whose fundamental functional domains are still unknown or debated and for which we formulate verifiable predictions. The numerical code implementing the domain decomposition strategy is made freely available.


Revisiting Masculine and Feminine Grammatical Gender in Spanish: Linguistic, Psycholinguistic, and Neurolinguistic Evidence.
Research on grammatical gender processing has generally assumed that grammatical gender can be treated as a uniform construct, resulting in a body of literature in which different gender classes are collapsed into single analysis. The present work reviews linguistic, psycholinguistic, and neurolinguistic research on grammatical gender from different methodologies and across different profiles of Spanish speakers. Specifically, we examine distributional asymmetries between masculine and feminine grammatical gender, the resulting biases in gender assignment, and the consequences of these assignment strategies on gender expectancy and processing. We discuss the implications of the findings for the design of future gender processing studies and, more broadly, for our understanding of the potential differences in the processing reflexes of grammatical gender classes within and across languages.


Differential activation of PKC delta in the substantia nigra of rats following striatal or nigral 6-hydroxydopamine lesions.
Parkinsonian neurodegeneration is associated with heightened levels of oxidative stress and the activation of apoptotic pathways. In an in vitro cellular model, we reported that 6-hydroxydopamine (6-OHDA) induces apoptotic cell death via the induction of mitochondrial dysfunction, the activation of caspase 3 and the consequent proteolytic activation of the redox-sensitive kinase, protein kinase C (PKC)delta, in PC12 cells. Here we have investigated the involvement of PKCdelta in 6-OHDA-induced cell death in vivo. The nigrostriatal pathway of rats was lesioned by unilateral infusion of 6-OHDA into either the striatum or substantia nigra pars compacta (SNpc). Infusion into the SNpc resulted in rapid loss of tyrosine hydroxylase (TH)-positive cells (87% decrease after 4 days), consistent with a necrotic-like mode of cell death. In contrast, striatal infusion initiated a slower, progressive decline in TH immunoreactivity (25% decrease in the SNpc after 4 days); cell appearance was characteristic of apoptosis. This is consistent with a transient increase in active caspase 3 immunoreactivity at 4 days post-infusion, and a concomitant proteolytic activation of PKCdelta in the SNpc of striatal-lesioned rats. Cleavage of PKCdelta did not occur in the striatum or cerebellum of lesioned animals, or in the SNpc of sham-operated controls. No increase in caspase 3 immunoreactivity or proteolytic activation of PKCdelta was detected in nigral-lesioned rats. These results suggest that after 6-OHDA infusion into the striatum, retrograde neurotoxicity induces caspase 3-dependent PKCdelta proteolytic activation in the cell bodies of the SNpc, implicating this kinase in the neurodegenerative process.


Enhanced causal effect of ecosystem photosynthesis on respiration during heatwaves.
Because of global warming, Earth's ecosystems have been experiencing more frequent and severe heatwaves. Heatwaves are expected to tip terrestrial carbon sequestration by elevating ecosystem respiration and suppressing gross primary productivity (GPP). Here, using the convergent cross-mapping technique, this study detected positive bidirectional causal effects between GPP and respiration in two unprecedented European heatwaves. Heatwaves enhanced the causal effect strength of GPP on respiration rather than respiration on GPP across 40 site-years of observations. Further analyses and global simulations revealed spatial heterogeneity in the heatwave response of the causal link strength between GPP and respiration, which was jointly driven by the local climate and vegetation properties. However, the causal effect strength of GPP on respiration showed considerable uncertainties in CMIP6 models. This study reveals an enhanced causal link strength between GPP and respiration during heatwaves, shedding light on improving projections for terrestrial carbon sink dynamics under future climate extremes.


Simulation of the resonance Raman spectra for 5-halogenated (F, Cl, and Br) uracils.
The resonance Raman spectra of the 5-halogenated (F, Cl, and Br) uracils are simulated via the Herzberg-Teller (HT) short-time dynamics formalism. The gradient of the S1 excited state is computed at the CAMB3LYP/aug-cc-pVTZ level of theory in the conductor-like polarizable continuum model for water (C-PCM, H2O), based on the equilibrium geometry determined using PBE0/aug-cc-pVTZ in H2O (C-PCM). The simulated resonance Raman spectra show good agreement with the experimental spectra in terms of both peak positions and intensities. The differences between the resonance Raman spectra of the three 5-halogenated uracils, caused by the effect of halogen substitution, are examined in terms of ground-state normal-mode eigenvectors and excited-state Cartesian gradients, according to the HT formalism. The differences in the normal-mode eigenvectors and excited-state Cartesian gradients between 5-fluorouracil and 5-chlorouracil are used to interpret the dissimilarity between their resonance Raman spectra. Meanwhile, the similarity between the spectra of 5-chlorouracil and 5-bromouracil is explained by the correspondence between their normal modes and excited-state gradients.


Consistency of financial interest disclosures in the biomedical literature: the case of coronary stents.
Disclosure of authors' financial interests has been proposed as a strategy for protecting the integrity of the biomedical literature. We examined whether authors' financial interests were disclosed consistently in articles on coronary stents published in 2006. We searched PubMed for English-language articles published in 2006 that provided evidence or guidance regarding the use of coronary artery stents. We recorded article characteristics, including information about authors' financial disclosures. The main outcome measures were the prevalence, nature, and consistency of financial disclosures. There were 746 articles, 2985 authors, and 135 journals in the database. Eighty-three percent of the articles did not contain disclosure statements for any author (including declarations of no interests). Only 6% of authors had an article with a disclosure statement. In comparisons between articles by the same author, the types of disagreement were as follows: no disclosure statements vs declarations of no interests (64%); specific disclosures vs no disclosure statements (34%); and specific disclosures vs declarations of no interests (2%). Among the 75 authors who disclosed at least 1 relationship with an organization, there were 2 cases (3%) in which the organization was disclosed in every article the author wrote. In the rare instances when financial interests were disclosed, they were not disclosed consistently, suggesting that there are problems with transparency in an area of the literature that has important implications for patient care. Our findings suggest that the inconsistencies we observed are due to both the policies of journals and the behavior of some authors.


Exploring the interaction mechanism of chlorogenic acid and myoglobin: Insights from structure and molecular dynamics simulation.
This study focused on non-covalent complex of myoglobin-chlorogenic acid (Mb-CA) and the changes in conformation, oxidation, and microstructure induced by varying concentrations of CA (10-40 μmol/g Mb). Employing molecular docking and dynamics simulations, further insights into the interaction between Mb and CA were obtained. The findings revealed that different CA concentrations enhanced Mb's thermal stability, while diminishing particle size, solubility, and relative content of metmyoglobin (MetMb%). The optimal interaction occurred at 40 μmol/g Mb. Furthermore, CA exhibited static quenching of Mb, with thermodynamic analysis confirming a 1:1 complex formation. These insights deepen our understanding of interaction between Mb and CA, providing valuable clarity.


XDS.
The usage and control of recent modifications of the program package XDS for the processing of rotation images are described in the context of previous versions. New features include automatic determination of spot size and reflecting range and recognition and assignment of crystal symmetry. Moreover, the limitations of earlier package versions on the number of correction/scaling factors and the representation of pixel contents have been removed. Large program parts have been restructured for parallel processing so that the quality and completeness of collected data can be assessed soon after measurement.


N-Glycans on the extracellular domain of the Notch1 receptor control Jagged-1 induced Notch signalling and myogenic differentiation of S100β resident vascular stem cells.
Notch signalling, critical for development and postnatal homeostasis of the vascular system, is highly regulated by several mechanisms including glycosylation. While the importance of O-linked glycosylation is widely accepted, the structure and function of N-glycans has yet to be defined. Here, we take advantage of lectin binding assays in combination with pharmacological, molecular, and site-directed mutagenetic approaches to study N-glycosylation of the Notch1 receptor. We find that several key oligosaccharides containing bisecting or core fucosylated structures decorate the receptor, control expression and receptor trafficking, and dictate Jagged-1 activation of Notch target genes and myogenic differentiation of multipotent S100β vascular stem cells. N-glycans at asparagine (N) 1241 and 1587 protect the receptor from accelerated degradation, while the oligosaccharide at N888 directly affects signal transduction. Conversely, N-linked glycans at N959, N1179, N1489 do not impact canonical signalling but inhibit differentiation. Our work highlights a novel functional role for N-glycans in controlling Notch1 signalling and differentiation of vascular stem cells. A sweet development in Notch regulation of vascular smooth muscle cell differentiation.


Demonstration of prominent actin filaments in the root columella.
The distribution of actin filaments within the gravity-sensing columella cells of plant roots remains poorly understood, with studies over numerous years providing inconsistent descriptions of actin organization in these cells. This uncertainty in actin organization, and thus in actin's role in graviperception and gravisignaling, has led us to investigate actin arrangements in the columella cells of Zea mays L., Medicago truncatula Gaertn., Linum usitatissiilium L. and Nicotianla benthamiana Domin. Actin organization was examined using a combination of optimized immunofluorescence techniques, and an improved fluorochrome-conjugated phalloidin labeling method reliant on 3-maleimidobenzoyl-N-hydroxy-succinimide ester (MBS) cross-linking combined with glycerol permeabilization. Confocal microscopy of root sections labeled with anti-actin antibodies revealed patterns suggestive of actin throughout the columella region. These patterns included short and fragmented actin bundles, fluorescent rings around amyloplasts and intense fluorescence originating from the nucleus. Additionally, confocal microscopy of MBS-stabilized and Alexa Fluor-phalloidin-labeled root sections revealed a previously undetected state of actin organization in the columella. Discrete actin structures surrounded the amyloplasts and prominent actin cables radiated from the nuclear surface toward the cell periphery. Furthermore, the cortex of the columella cells contained fine actin bundles (or single filaments) that had a predominant transverse orientation. We also used confocal microscopy of plant roots expressing endoplasmic reticulum (ER)-targeted green fluorescent protein to demonstrate rapid ER movements within the columella cells, suggesting that the imaged actin network is functional. The successful identification of discrete actin structures in the root columella cells forms the perception and signaling.


Longitudinal pathways from marital hostility to child anger during toddlerhood: genetic susceptibility and indirect effects via harsh parenting.
We examined direct and indirect pathways from marital hostility to toddler anger/frustration via harsh parenting and parental depressive symptoms, with an additional focus on the moderating role of genetic influences as inferred from birth parent anger/frustration. Participants were 361 linked triads of birth mothers, adoptive parents, and adopted children who were 9 (T1) and 18 (T2) months old across the study period. Results indicated an indirect effect from T1 marital hostility to T2 toddler anger/frustration via T2 parental harsh discipline. Results also indicated that the association between marital hostility and toddler anger was moderated by birth mother anger/frustration. For children whose birth mothers reported high levels of anger/frustration, adoptive parents' marital hostility at T1 predicted toddler anger/frustration at T2. This relation did not hold for children whose birth mothers reported low levels of anger/frustration. The results suggest that children whose birth mothers report elevated frustration might inherit an emotional lability that makes them more sensitive to the effects of marital hostility.


A new approach method for characterizing inter-species toxicodynamic variability.
Inter-species differences in toxicodynamics are often a critical source of uncertainty in safety evaluations and typically dealt with using default adjustment factors. In vitro studies that use cells from different species demonstrated some success for estimating the relationships between life span and/or body weight and sensitivity to cytotoxicity; however, no apparent investigation evaluated the utility of these models for risk assessment. It was hypothesized that an in vitro model using dermal fibroblasts derived from diverse species and individuals might be utilized to inform the extent of inter-species and inter-individual variability in toxicodynamics. To test this hypothesis and characterize both inter-species and inter-individual variability in cytotoxicity, concentration-response cytotoxicity screening of 40 chemicals in primary dermal fibroblasts from 68 individuals of 54 diverse species was conducted. Chemicals examined included drugs, environmental pollutants, and food/flavor/fragrance agents; most of these were previously assessed either in vivo or in vitro for inter-species or inter-individual variation. Species included humans, the typical preclinical species and representatives from other orders of mammals and birds. Data demonstrated that both inter-species and inter-individual components of variability contribute to the observed differences in sensitivity to cell death. Further, it was found that the magnitude of the observed inter-species and inter-individual differences was chemical-dependent. This study contributes to the paradigm shift in risk assessment from reliance on in vivo toxicity testing to higher-throughput in vitro or alternative approaches, extending the strategy to replace use of default adjustment factors with experimental characterization of toxicodynamic inter-individual variability and to also address toxicodynamic inter-species variability.


Isolation and molecular characterization of a novel WIN1/SHN1 ethylene-responsive transcription factor TdSHN1 from durum wheat (Triticum turgidum. L. subsp. durum).
Over the last decade, APETALA2/Ethylene Responsive Factor (AP2/ERF) proteins have become the subject of intensive research activity due to their involvement in a variety of biological processes. This research led to the identification of AP2/ERF genes in many species; however, little is known about these genes in durum wheat, one of the most important cereal crops in the world. In this study, a new member of the AP2/ERF transcription factor family, designated TdSHN1, was isolated from durum wheat using thermal asymetric interlaced PCR (TAIL-PCR) method. Protein sequence analysis showed that TdSHN1 contained an AP2/ERF domain of 63 amino acids and a putative nuclear localization signal (NLS). Phylogenetic analysis showed that TdSHN1 belongs to a group Va protein in the ERF subfamily which contains the Arabidopsis ERF proteins (SHN1, SHN2, and SHN3). Expression of TdSHN1 was strongly induced by salt, drought, abscisic acid (ABA), and cold. In planta, TdSHN1 protein was able to activate the transcription of GUS reporter gene driven by the GCC box and DRE element sequences. In addition, TdSHN1 was targeted to the nucleus when transiently expressed in tobacco epidermal cells. In transgenic yeast, overexpression of TdSHN1 increased tolerance to multiple abiotic stresses. Taken together, the results showed that TdSHN1 encodes an abiotic stress-inducible, transcription factor which confers abiotic stress tolerance in yeast. TdSHN1 is therefore a promising candidate for improvement of biotic and abiotic stress tolerance in wheat as well as other crops.


Epidermal growth factor-mediated Rab25 pathway regulates integrin β1 trafficking in colon cancer.
Integrins play a critical role in carcinogenesis. Integrin β1 localization is regulated by the guanosine-5'-triphosphate hydrolase Rab25 and integrin β1 levels are elevated in the serum of colon cancer patients; thus, the present study examined the effects of epidermal growth factor (EGF) and Rab25 on integrin β1 localization in colon cancer cells. HCT116 human colon cancer cells were treated with increasing concentrations of EGF, and cell proliferation and protein expression were monitored by MTT and western blot analyses, respectively. Cell fractionation was performed to determine integrin β1 localization in the membrane and cytosol. Integrin β1 extracellular shedding was monitored by enzyme-linked immunosorbent assays (ELISAs) with culture supernatants from stimulated cells. HCT116 cells were transfected with Rab25-specific siRNA to determine the significance of Rab25 in integrin β1 trafficking in the presence of EGF. Total integrin β1 expression increased in response to EGF and subsequently decreased at 24 h post-stimulation. A similar decrease was observed in purified membrane fractions, whereas no changes were observed in cytosolic levels. ELISAs using media from stimulated cell cultures demonstrated increased integrin β1 levels corresponding to the decrease observed in membrane fractions, suggesting that EGF induces integrin receptor shedding. EGF stimulation in Rab25-knockdown cells resulted in integrin β1 accumulation in the membrane, suggesting that Rab25 promotes integrin endocytosis. Integrin β1 is shed from colon cancer cells in response to EGF stimulation in a Rab25-dependent manner. These results further the present understanding of the role of integrin β1 in colon cancer progression.


Nasopharyngeal carriage of Streptococcus pneumoniae among HIV-infected and -uninfected children <5 years of age before introduction of pneumococcal conjugate vaccine in Mozambique.
Nasopharyngeal carriage is a precursor for pneumococcal disease and can be useful for evaluating pneumococcal conjugate vaccine (PCV) impact. We studied pre-PCV pneumococcal carriage among HIV-infected and -uninfected children in Mozambique. Between October 2012 and March 2013, we enrolled HIV-infected children age <5 years presenting for routine care at seven HIV clinics in 3 sites, including Maputo (urban-south), Nampula (urban-north), and Manhiça (rural-south). We also enrolled a random sample of HIV-uninfected children <5 years old from a demographic surveillance site in Manhiça. A single nasopharyngeal swab was obtained and cultured following enrichment in Todd Hewitt broth with yeast extract and rabbit serum. Pneumococcal isolates were serotyped by Quellung reaction and multiplex polymerase chain reaction. Factors associated with pneumococcal carriage were examined using logistic regression. Overall pneumococcal carriage prevalence was 80.5% (585/727), with similar prevalences among HIV-infected (81.5%, 339/416) and HIV-uninfected (79.1%, 246/311) children, and across age strata. Among HIV-infected, after adjusting for recent antibiotic use and hospitalization, there was no significant association between study site and colonization: Maputo (74.8%, 92/123), Nampula (83.7%, 82/98), Manhiça (84.6%, 165/195). Among HIV-uninfected, report of having been born to an HIV-infected mother was not associated with colonization. Among 601 pneumococcal isolates from 585 children, serotypes 19F (13.5%), 23F (13.1%), 6A (9.2%), 6B (6.2%) and 19A (5.2%) were most common. The proportion of serotypes included in the 10- and 13-valent vaccines was 44.9% and 61.7%, respectively, with no significant differences by HIV status or age group. Overall 36.9% (n = 268) of children were colonized with a PCV10 serotype and 49.7% (n = 361) with a PCV13 serotype. Pneumococcal carriage was common, with little variation by geographic region, age, or HIV status. PCV10 was introduced in April 2013; ongoing carriage studies will examine the benefits of PCV10 among HIV-infected and-uninfected children.


Role of health education programmes within the Libyan community.
The effectiveness of existing Libyan health education programmes was evaluated in order to assess how the service may be improved. A representative sample of the general public completed a questionnaire on health knowledge, healthy behaviours and the impact of various health education media. The 872 participants ranked health education media by effectiveness, with television ranked highest and booklets and leaflets lowest. We recommend reorganization of the use of different health education media in future planning.


A novel Kluyveromyces marxianus strain with an inducible flocculation phenotype.
Flocculation is a very useful phenotype for industrial yeast strains, since it facilitates cell harvest and represents an easy way of cell immobilization in continuous fermentation processes. The present work represents the first time that an inducible flocculation phenotype has been generated in a non flocculent strain of Kluyveromyces marxianus. This was accomplished by expressing Saccharomyces cerevisiae FLO5 gene in K. marxianus CECT 11769 strain. The FLO 5 gene was placed under the control of an EPG promoter, not repressed by glucose and induced by anoxia. Our experimental approach successfully generated two novel K. marxianus flocculent phenotypes: one inducible and one constitutive. The constitutive phenotype originated from deletions in the FLO5 promoter region, indicating the existence of putative upstream repressor site involved in oxygen regulation of the EPG1 promoter. The novel strains here generated had a unique set of characteristics that provided an advantage, over the wild-type strain, for the industrial co-production of ethanol and polygalacturonase.


Effects of blood pressure lowering in the acute phase of total anterior circulation infarcts and other stroke subtypes.
Lowering of blood pressure (BP) in the acute phase of stroke is reported both to worsen and to improve the outcome. To investigate whether heterogeneity exists between stroke subtypes in the response to BP lowering, we analysed data from the Intravenous Nimodipine West European Stroke Trial (INWEST). INWEST enrolled acute ischaemic stroke patients within 24 h (n = 295) to the following groups: placebo (n = 100), 1 mg/h nimodipine (n = 101) or 2 mg/h nimodipine (n = 94). Patients were retrospectively classified as total anterior circulation infarct (TACI) (i.e. hemiparesis + hemianopia + dysphasia) and non-TACI (exclusion of any one of these). Main outcome measures were neurological (Orgogozo) and functional (Barthel) scores at day 21. 106 patients were labelled as TACI and 62 as non-TACI. No significant difference in BP was observed between the TACI and non-TACI subtypes at baseline, nor did the subtypes differ in BP course within the treatment groups. A higher proportion of non-TACI patients received postrandomisation antihypertensive agents in addition to the study drug compared with TACI patients (55% non-TACI vs. 26% TACI, p < 0.005). For TACI patients, there was no outcome difference between the placebo- and nimodipine-treated groups. For non-TACI patients, placebo had a significantly better neurological (p = 0.004) and functional (p = 0.04) outcome than the high-dose nimodipine group. In multivariate analysis for TACI patients, BP reduction and nimodipine treatment had no relation with outcome. Baseline stroke severity (p < 0.005) was the only significant predictor of the outcome at day 21. For non-TACI patients, diastolic BP (DBP) reduction (p = 0.03) and nimodipine treatment (p = 0.001) were related to neurological deterioration and nimodipine treatment (p = 0.01) to functional deterioration. Systolic BP reduction was associated with neurological (p < 0.005) and functional improvement (p = 0.01). Baseline stroke severity (p < 0.005) was related to both neurological and functional outcome. BP lowering and nimodipine treatment had no significant effect on outcome for TACI patients. For non-TACI patients, DBP lowering worsened the neurological outcome and high-dose nimodipine worsened both the neurological and functional outcome.


Prevalence of mouse mammary tumor virus (MMTV) in wild house mice (Mus musculis) in southeastern Australia.
We determined the prevalence of mouse mammary tumor virus (MMTV) in introduced, free-roaming, wild house mice (Mus musculus domesticus) [corrected] and compared envelope (env) and long terminal repeat (LTR) nucleotide sequences of viruses from wild mice and other sources. Mice were trapped on two occasions, in October (spring) and the following May (autumn) of 2003-2004 in the Mallee region of northwestern Victoria, Australia. Animals were assigned to three cohorts (subadult, young, and old adults) based on their body length. The DNA from salivary glands (62 of 62 mice) and mammary glands (19 of 32 female mice) was screened for the MMTV envelope (env) gene, and the long terminal repeat (LTR) region including the superantigen (SAg) sequence was amplified from a subset. Positive polymerase chain reaction (PCR) results for the MMTV env PCR were detected from salivary gland tissues from 60 of 62 (97%) mice and from mammary gland tissues from 19 of 19 (100%) female mice. All but two mice were positive for MMTV env across both sexes and the three cohorts. Similarity of the SAg carboxy-terminal nucleotide sequence between free-roaming wild house mice varied from 64% to 99%, although most of this variation was due to DNA sequences from two mice (M4 and M5). Phylogenetic analysis of the LTR region did not result in distinct grouping of sequences derived from mice when comparisons were made among sequences from mice in the US, Europe, and Australia, and MMTV-like virus (MMTV-LV) env sequences derived from human hosts. We report a high prevalence of the MMTV env sequence during a sampling period when peak mouse density was low. This indicates that MMTV is an enzootic virus in a population of wild, free-ranging mice in northwestern Victoria, in Australia. Phylogenetic analysis, based upon env and LTR sequence data, indicated minor variation among all isolates. This represents the first report on the prevalence of MMTV in mouse populations in Australia.


Cohort study: "Outcomes of kidney transplantation in patients with prosthetic heart valves".
The number of kidney transplant candidates with prosthetic heart valves (PHVs) is increasing. Yet, outcomes of kidney transplantation in these patients are still unclear. This is the first report of post-transplant outcomes in patients with PHVs at time of kidney transplantation. We conducted a matched cohort study among recipients from the multicentric and prospective DIVAT cohort to compare the outcomes in patients with left-sided PHVs at time of transplantation and a group of recipients without PHV matched according to age, dialysis time, initial disease, pretransplant DSA, diabetes, and cardiovascular events. Of 23 018 patients, 92 patients with PHVs were included and compared to 276 patients without PHV. Delayed graft function and postoperative bleeding occurred more frequently in patients with PHVs. Kidney graft survival was similar between groups. 5-year overall survival was 68.5% in patients with PHV vs. 87.9% in patients without PHV [HR, 2.72 (1.57-4.70), P = 0.0004]. Deaths from infection, endocarditis, and bleeding were more frequent in patients with PHV. Mechanical valves, but not bioprosthetic valves, were independent risk factors for mortality [HR, 2.89 (1.68-4.97), P = 0.0001]. Patients with PHV have high mortality rates after kidney transplantation. These data suggest that mechanical valves, but not biological valves, increase risks of post-transplant mortality.


Hemophagocytic syndrome associated with Kikuchi's disease.
A 13-yr-old female was admitted to our hospital with fever, seizure, and cervical lymphadenopathy. Laboratory data showed pancytopenia, elevation of serum transaminase, lactate dehydrogenase, triglyceride, and ferritin levels. Lymph node biopsy revealed features of Kikuchi's disease and there were signs of histiocytosis and hemophagocytic phenomenon in bone marrow. She recovered after treatment with intravenous immunoglobulin and corticosteroids therapy. Hemophagocytic syndrome can be associated with Kikuchi's disease especially in childhood and seems to have a less aggressive clinical course and better prognosis.


Spatial assessments in texture analysis: what the radiologist needs to know.
To date, studies investigating radiomics-based predictive models have tended to err on the side of data-driven or exploratory analysis of many thousands of extracted features. In particular, spatial assessments of texture have proven to be especially adept at assessing for features of intratumoral heterogeneity in oncologic imaging, which likewise may correspond with tumor biology and behavior. These spatial assessments can be generally classified as spatial filters, which detect areas of rapid change within the grayscale in order to enhance edges and/or textures within an image, or neighborhood-based methods, which quantify gray-level differences of neighboring pixels/voxels within a set distance. Given the high dimensionality of radiomics datasets, data dimensionality reduction methods have been proposed in an attempt to optimize model performance in machine learning studies; however, it should be noted that these approaches should only be applied to training data in order to avoid information leakage and model overfitting. While area under the curve of the receiver operating characteristic is perhaps the most commonly reported assessment of model performance, it is prone to overestimation when output classifications are unbalanced. In such cases, confusion matrices may be additionally reported, whereby diagnostic cut points for model predicted probability may hold more clinical significance to clinical colleagues with respect to related forms of diagnostic testing.


Economic benefits of safety-engineered sharp devices in Belgium - a budget impact model.
Measures to protect healthcare workers where there is risk of injury or infection from medical sharps became mandatory in the European Union (EU) from May 2013. Our research objective was to estimate the net budget impact of introducing safety-engineered devices (SEDs) for prevention of needlestick injuries (NSIs) in a Belgian hospital. A 5-year incidence-based budget impact model was developed from the hospital inpatient perspective, comparing costs and outcomes with SEDs and prior-used conventional (non-safety) devices. The model accounts for device acquisition costs and costs of NSI management in 4 areas of application where SEDs are currently used: blood collection, infusion, injection and diabetes insulin administration. Model input data were sourced from the Institut National d'Assurance Maladie-Invalidité, published studies, clinical guidelines and market research. Costs are discounted at 3%. For a 420-bed hospital, 100% substitution of conventional devices by SEDs is estimated to decrease the cumulative 5-year incidence of NSIs from 310 to 75, and those associated with exposure to blood-borne viral diseases from 60 to 15. Cost savings from managing fewer NSIs more than offset increased device acquisition costs, yielding estimated 5-year overall savings of €51,710. The direction of these results is robust to a range of sensitivity and model scenario analyses. The model was most sensitive to variation in the acquisition costs of SEDs, rates of NSI associated with conventional devices, and the acquisition costs of conventional devices. NSIs are a significant potential risk with the use of sharp devices. The incidence of NSIs and the costs associated with their management can be reduced through the adoption of safer work practices, including investment in SEDs. For a Belgian hospital, the budget impact model reports that the incremental acquisition costs of SEDs are offset by the savings from fewer NSIs. The availability of more robust data for NSI reduction rates, and broadening the scope of the model to include ancillary measures for hospital conversion to SED usage, outpatient and paramedic device use, and transmission of other blood-borne diseases, would strengthen the model.


Functional analysis of chromatin assembled in synthetic nuclei.
Numerous regulatory mechanisms contribute to the control of eukaryotic transcription. These controls are manifested through higher-order protein-DNA structure within the nucleus. In vitro assays have proven extremely useful in deciphering the potential regulatory roles of chromatin and nuclear structure in transcription. Embryonic egg extracts of Xenopus with their vast maternal stores and rapid cell-cycle oscillations can be exploited to recapitulate multiple layers of nuclear regulation. Incubation of cloned DNA templates in Xenopus egg extracts promotes a self-ordered assembly of physiologically spaced nucleosomes and synthetic nuclei structure formation. Interaction of membrane vesicles with chromatin leads to formation of a bilayer nuclear envelope encapsulating the DNA. These synthetic nuclei are functional organelles capable of active protein transport and a single round of semiconservative DNA synthesis. This system can be used to directly test the mechanisms by which trans-acting factors promote transcription on nucleosomal DNA, either during chromatin assembly or postassembly or in conjunction with remodeling machinery and/or DNA replication. The functional consequences of trans-acting factor interaction within synthetic nuclei are determined by a coupled in vitro transcription analysis. Immobilizing biotin end-labeled DNA templates on paramagnetic streptavidin beads greatly improves the flexibility of the system. The ease of chromatin-assembled template recovery allows the introduction of wash steps, buffer changes, and specific reaction optimization. These methods for reconstituting gene regulatory mechanisms in vitro are an attempt to strike a balance between biochemical accessibility and physiological relevance.


Glucocorticoid receptor mediates the gluconeogenic activity of the farnesoid X receptor in the fasting condition.
The glucocorticoid receptor (GR) is a master gene orchestrating the activation of gluconeogenic genes in the liver in response to food withdrawal. Mechanisms of GR regulation by other nuclear receptors, however, are poorly defined. Here, we report that the farnesoid X receptor (FXR), a bile acid sensor, activates gluconeogenic pathways in the liver and regulates GR expression and activity. FXR-null mice are hypoglycemic in the unfed state and exhibit both a reduced hepatic production of glucose in response to the pyruvate challenge and a decreased expression of two rate-limiting enzymes involved in gluconeogenesis, phosphoenolpyruvate carboxykinase (PEPCK), and glucose-6-phosphatase (G6Pase), along with blunted liver expression of GR. Treating wild-type mice with a semisynthetic FXR ligand (6E-CDCA) increases the liver expression of GR, PEPCK, and G6Pase. This effect was lost in fed animals, as well as in FXR(-/-) mice. The human and mouse GR promoters contain a conserved FXR-responsive element (an ER-8 sequence) whose activation by FXR ligation leads to GR transcription. GR silencing by siRNA in vitro or its pharmacological antagonism in vivo with mifepristone reverses the effect of FXR activation on expression of gluconeogenic genes. These findings demonstrate that an FXR-GR pathway regulates the activation of hepatic gluconeogenesis in the transition from the unfed to the fed state.


On the dark side of therapies with immunoglobulin concentrates: the adverse events.
Therapy by human immunoglobulin G (IgG) concentrates is a success story ongoing for decades with an ever increasing demand for this plasma product. The success of IgG concentrates on a clinical level is documented by the slowly increasing number of registered indication and the more rapid increase of the off-label uses, a topic dealt with in another contribution to this special issue of Frontiers in Immunology. A part of the success is the adverse event (AE) profile of IgG concentrates which is, even at life-long need for therapy, excellent. Transmission of pathogens in the last decade could be entirely controlled through the antecedent introduction by authorities of a regulatory network and installing quality standards by the plasma fractionation industry. The cornerstone of the regulatory network is current good manufacturing practice. Non-infectious AEs occur rarely and mainly are mild to moderate. However, in recent times, the increase in frequency of hemolytic and thrombotic AEs raised worrying questions on the possible background for these AEs. Below, we review elements of non-infectious AEs, and particularly focus on hemolysis and thrombosis. We discuss how the introduction of plasma fractionation by ion-exchange chromatography and polishing by immunoaffinity chromatographic steps might alter repertoire of specificities and influence AE profiles and efficacy of IgG concentrates.


Rapid detection and quantification of RNA of Ebola and Marburg viruses, Lassa virus, Crimean-Congo hemorrhagic fever virus, Rift Valley fever virus, dengue virus, and yellow fever virus by real-time reverse transcription-PCR.
Viral hemorrhagic fevers (VHFs) are acute infections with high case fatality rates. Important VHF agents are Ebola and Marburg viruses (MBGV/EBOV), Lassa virus (LASV), Crimean-Congo hemorrhagic fever virus (CCHFV), Rift Valley fever virus (RVFV), dengue virus (DENV), and yellow fever virus (YFV). VHFs are clinically difficult to diagnose and to distinguish; a rapid and reliable laboratory diagnosis is required in suspected cases. We have established six one-step, real-time reverse transcription-PCR assays for these pathogens based on the Superscript reverse transcriptase-Platinum Taq polymerase enzyme mixture. Novel primers and/or 5'-nuclease detection probes were designed for RVFV, DENV, YFV, and CCHFV by using the latest DNA database entries. PCR products were detected in real time on a LightCycler instrument by using 5'-nuclease technology (RVFV, DENV, and YFV) or SybrGreen dye intercalation (MBGV/EBOV, LASV, and CCHFV). The inhibitory effect of SybrGreen on reverse transcription was overcome by initial immobilization of the dye in the reaction capillaries. Universal cycling conditions for SybrGreen and 5'-nuclease probe detection were established. Thus, up to three assays could be performed in parallel, facilitating rapid testing for several pathogens. All assays were thoroughly optimized and validated in terms of analytical sensitivity by using in vitro-transcribed RNA. The >or=95% detection limits as determined by probit regression analysis ranged from 1,545 to 2,835 viral genome equivalents/ml of serum (8.6 to 16 RNA copies per assay). The suitability of the assays was exemplified by detection and quantification of viral RNA in serum samples of VHF patients.


Measuring vibrational motion from a moving platform using speckle field detection.
We investigate the ability of a holographic laser vibrometer to mitigate noise introduced when operating on a moving platform or when measuring a moving target. This motion introduces a fundamental limitation on the measurement sensitivity due to the time-varying speckle pattern produced as the illumination beam scans across the target surface. In addition, since existing systems record the phase of only a single speckle grain, speckle fading imposes a limit on the coherent processing interval and thus the frequency resolution of these measurements. In this work, we show that by measuring N speckle grains in parallel using holographic detection, we are able to provide a N1/2 improvement in the system sensitivity while simultaneously overcoming the limitations on the coherent processing interval imposed by speckle fading. The ability to perform sensitive vibrational measurements of a moving target or from a moving platform could dramatically increase the applications available to laser vibrometry.


Predictors of Opioid Prescribing for Non-Malignant Low Back Pain in an Italian Primary Care Setting.
This study explores which patient characteristics could affect the likelihood of starting low back pain (LBP) treatment with opioid analgesics vs. Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) in an Italian primary care setting. Through the computerized medical records of 65 General Practitioners, non-malignant LBP subjects who received the first pain intensity measurement and an NSAID or opioid prescription, during 2015-2016, were identified. Patients with an opioid prescription 1-year before the first pain intensity measurement were excluded. A multivariable logistic regression model was used to determine predictive factors of opioid prescribing. Results were reported as Odds Ratios (ORs) with a 95% confidence interval (CI), with p < 0.05 indicating statistical significance. A total of 505 individuals with LBP were included: of those, 72.7% received an NSAID prescription and 27.3% an opioid one (64% of subjects started with strong opioid). Compared to patients receiving an NSAID, those with opioid prescriptions were younger, reported the highest pain intensity (moderate pain OR = 2.42; 95% CI 1.48-3.96 and severe pain OR = 2.01; 95% CI 1.04-3.88) and were more likely to have asthma (OR 3.95; 95% CI 1.99-7.84). Despite clinical guidelines, a large proportion of LBP patients started with strong opioid therapy. Asthma, younger age and pain intensity were predictors of opioid prescribing when compared to NSAIDs for LBP treatment.


Patient preferences and satisfaction in a multispecialty infusion center.
Direct feedback from patients about their preferred modes of medication administration has been increasingly sought by providers to develop care programs that best match patient goals. Multispecialty infusion centers generally provide care to hematology-oncology (HO) and non-HO patients in one unit, with the same nursing staff. Our staff perceived that this was dissatisfying to our non-HO patients. We assessed patient satisfaction, as well as nursing and physician perceptions of patient preference/satisfaction with our infusion center, to determine whether a separate unit should be recommended when designing our new Cancer Institute Infusion Center. A seven-question Likert scale satisfaction survey for patients, and a separate survey to assess nurses' and physicians' perception of patient satisfaction, were developed. The survey was administered to non-HO patients receiving infusions, doctors prescribing infusions, and nurses administering infusions. Results of the survey were compared between groups to assess differences in responses. Responses were received from 52 non-HO patients, 18 physicians, and 13 nurses. Patients had more satisfaction, on all survey items, with the multispecialty infusion center than had been realized by physicians and nurses. Analysis demonstrated that patients were satisfied with care in a multispecialty infusion unit and were in favor of continuing their care in this combined center. Total scores of patient surveys were significantly different (P<0.001) from those of physicians and nurses, who had assumed patients would prefer to have their care in a non-HO infusion setting. Understanding patient preferences is an important step in deciding the structure of infusion centers. Based on these survey conclusions, a combined multispecialty infusion center has been continued at our institution, thus improving quality by including patients in decision-making affecting their care.


Alterations in pulmonary structure by elastase administration in a model of emphysema in mice is associated with functional disturbances.
Several experimental studies of pulmonary emphysema using animal models have been described in the literature. However, only a few of these studies have focused on the assessment of ergometric function as a non-invasive technique to validate the methodology used for induction of experimental emphysema. Additionally, functional assessments of emphysema are rarely correlated with morphological pulmonary abnormalities caused by induced emphysema. The present study aimed to evaluate the effects of elastase administered by tracheal puncture on pulmonary parenchyma and their corresponding functional impairment. This was evaluated by measuring exercise capacity in C57Bl/6 mice in order to establish a reproducible and safe methodology of inducing experimental emphysema. Thirty six mice underwent ergometric tests before and 28 days after elastase administration. Pancreatic porcine elastase solution was administered by tracheal puncture, which resulted in a significantly decreased exercise capacity, shown by a shorter distance run (-30.5%) and a lower mean velocity (-15%), as well as in failure to increase the elimination of carbon dioxide. The mean linear intercept increased significantly by 50% in tracheal elastase administration. In conclusion, application of elastase by tracheal function in C57Bl/6 induces emphysema, as validated by morphometric analyses, and resulted in a significantly lower exercise capacity, while resulting in a low mortality rate.


Cocaine addicted to cytoskeletal change and a fibrosis high.
Cocaine is one of the most widely abused illicit drugs due to its euphoric and addictive properties. Cocaine-mediated cognitive impairments are the result of dynamic cytoskeletal rearrangements involved in mediating structural and behavioural plasticity. Cytoskeletal changes initiated following cocaine abuse are regulated by the Rho family of GTPases with significant downstream activity in key actin binding proteins. Moreover, signalling via the endoplasmic reticulum chaperone protein, sigma-1 receptor has highlighted the possibility of cocaine regulated pathology in other organ systems. However, the question of whether upstream stimulation of such a high affinity binding receptor is directly involved in cocaine-mediated cytoskeletal changes at present remains unknown. In this review, we describe the functional role of key cytoskeletal regulators in response to cocaine-induced signalling cues. In addition, we ascertain the extent of whether global cytoskeletal modulators involved in cocaine-induced neurological stimulation can be used as a platform for future studies into elucidating its fibrotic potential within the hepatic microenvironment. A focus on aspects still poorly understood relating to the nonneuronal pathological impact of cocaine is discussed in the sphere of hepatic dysregulation. Lastly, we suggest that cocaine may mediate its pathological capacity via the sigma1 receptor in regulating hepatoxicity, hepatic stellate cells activity, cytoskeletal dynamics, and the transcriptional regulation of key hepato-fibrogenic modulators.


Protective effects of fucoidan against γ-radiation-induced damage of blood cells.
Fucoidan, a sulfated polysaccharide purified from brown algae including Fucus vesiculosus and Laminaria japonica, has a variety of biological activities, including antioxidant and antitumor activities. Here, we investigated the radioprotective effects of fucoidan on human monoblastic leukemia cell line U937. Further, animal tests were carried out using Balb/c mice in order to determine the radiation-induced changes in the counts of blood cells, including thrombocytes, erythrocytes, leukocytes and hematocrit. Cell viability was assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, wherein fucoidan (1, 10, and 100 μg/mL) was observed to improve recovery from damage caused by 8-Gy radiation in a dose dependent manner. The viability of U937 cells pre-treated with fucoidan also increased in a dose dependent manner. Furthermore, fucoidan at 100 mg/kg was found to protect against changes in the counts of blood cells as follows: on day 28 after irradiation, the thrombocyte count in the irradiated controls decreased to 45% compared with the non-irradiated controls, while that in the fucoidan-treated group was 60%. The hematocrit in the fucoidan-treated group recovered to 75% on day 28, while that in the irradiated control was 68%. The erythrocyte count in the irradiated controls consistently ranged from 64% to 67% throughout the experiment, but that in the fucoidan-treated group increased gradually, ranging from 75% to 80%. The mean number of survival days and 50-day actuarial survival rate increased dose dependently in the fucoidan-treated group. The mean number of survival days and the 50-day actuarial survival rate in this group was 16, 21, and 29 days and 12%, 20%, and 30% at fucoidan doses of 1, 10, and 100 mg/kg. The values of these parameters in the control group were 9 days and 0%, although the difference between the test and control groups was not statistically significant. Our results may prove valuable in the field of radioprotection.