A comparison of modelling options to assess annual variation in susceptibility of generic Escherichia coli isolates to ceftiofur, ampicillin and nalidixic acid from retail chicken meat in Canada.
Statistical modelling of antimicrobial resistance (AMR) data is an important aspect of AMR surveillance programs; however, minimum inhibitory concentration (MIC) data can be challenging to model. The conventional approach is to dichotomize data using established breakpoints, then use logistic regression modelling for analysis. A disadvantage of this approach is a loss of information created by dichotomizing the data. The objectives of the study were to compare the performance and results of different regression models for the analysis of annual variation in susceptibility of generic Escherichia coli (E. coli) isolates to ceftiofur, ampicillin and nalidixic acid from retail chicken meat surveillance samples. E. coli susceptibility data for the three antimicrobials from retail chicken samples from 2007 to 2014 were obtained from the Canadian Integrated Program for Antimicrobial Resistance Surveillance (CIPARS). Annual variation in susceptibility for each antimicrobial was evaluated using multivariable linear, tobit, logistic, multinomial, ordinal and complementary log-log regression models (clog-log). MIC (log2), censored MIC (log2), resistant/susceptible, and categorized MIC (3 or 4 categories) data were used as outcome variables for the appropriate statistical models. Year and region were modelled as categorical predictor variables. Random intercepts were included in the ceftiofur and ampicillin models to account for clustering by retail establishment. The model assumptions evaluated for the mixed models included homoscedasticity and normality of residuals (linear and tobit), homoscedasticity and normality of best linear unbiased predictions (all models), proportional odds (ordinal), and proportional hazards (clog-log). Fixed effects models were used for the nalidixic acid models. The model assumptions evaluated for the fixed effects models included homoscedasticity and normality of residuals (linear and tobit), goodness-of-fit test (logistic and multinomial), proportional odds (ordinal), and proportional hazards (clog-log).Only logistic and multinomial models met model assumptions. Significant annual variation in susceptibility to all three antimicrobials was identified by the multinomial regression models, whereas the logistic regression models only identified significant annual variation in susceptibility to ceftiofur. The multinomial regression model consistently identified additional significant annual variation in susceptibility compared to the logistic regression model. The multinomial modelling approach was able to identify differences between MIC categories within susceptible MIC values, which were below the breakpoint (R) detection level. Given the convention of dichotomizing susceptibility data, the logistic regression approach is likely to remain the standard method of analysis for AMR surveillance data; however, the results of this study demonstrate that multinomial regression should be considered for the analysis of AMR surveillance data.


[Clinical and laboratory features compared between JAK2 exon12 and JAK2 V617F mutated polycythemia vera].
Objective: To compare clinical and laboratory features between JAK2 exon12 and JAK2 V617F mutated polycythemia vera (PV) . Method: We collected data from 570 consecutive newly-diagnosed subjects with PV and JAK2 mutation, and compared clinical and laboratory features between patients with JAK2 exon12 and JAK2 V617F mutation. Results: 543 (95.3%) subjects harboured JAK2 V617F mutation (JAK2 V617F cohort) , 24 (4.2%) harboured JAK2 exon12 mutations (JAK2 exon12 cohort) , and 3 (0.5%) harboured JAK2 exon12 and JAK2 V617F mutations. The mutations in JAK2 exon12 including deletion (n=10, 37.0%) , deletion accompanied insertion (n=10, 37.0%) , and missense mutations (n=7, 25.9%) . Comparing with JAK2 V617F cohort, subjects in JAK2 exon12 cohort were younger [median age 50 (20-73) years versus 59 (25-91) years, P=0.040], had higher RBC counts [8.19 (5.88-10.94) ×10(12)/L versus 7.14 (4.11-10.64) ×10(12)/L, P<0.001] and hematocrit [64.1% (53.7-79.0%) versus 59.6% (47.2%-77.1%) , P=0.001], but lower WBC counts [8.29 (3.2-18.99) ×10(9)/L versus 12.91 (3.24-38.3) ×10(9)/L, P<0.001], platelet counts [313 (83-1433) ×10(9)/L versus 470 (61-2169) ×10(9)/L, P<0.001] and epoetin [0.70 (0.06-3.27) versus 1.14 (0.01-10.16) IU/L, P=0.002] levels. We reviewed bone marrow histology at diagnosis in 20 subjects with each type of mutation matched for age and sex. Subjects with JAK2 exon12 mutations had fewer loose megakaryocyte cluster (40% versus 80%, P=0.022) compared with subjects with JAK2 V617F. The median follow-ups were 30 months (range 4-83) and 37 months (range 1-84) for cohorts with JAK2 V617F and JAK2 exon12, respectively. There was no difference in overall survival (P=0.422) and thrombosis-free survival (P=0.900) . Conclusions: Compared with patients with JAK2 V617F mutation, patients with JAK2 exon12 mutation were younger, and had more obvious erythrocytosis and less loose cluster of megakaryocytes.


In vitro fertilization-intracytoplasmic sperm injection split: an insemination method to prevent fertilization failure.
To determine whether the performance of intracytoplasmic sperm injection (ICSI) in cases of unexplained infertility and of borderline semen parameters can prevent fertilization failure. Prospective cohort study. Hospital-based assisted reproductive technology program. Sixty couples with unexplained infertility (group 1) and 50 couples with borderline semen (group 2). Conventional IVF and ICSI were performed on sibling oocyte cumulus complexes. Rate of fertilization according to patient diagnosis. The fertilization rate per oocyte cumulus complex in couples with unexplained infertility (group 1) was significantly higher with ICSI (65.3%) compared with IVF insemination (48.1%). Fertilization rates per OCC in couples with borderline semen (group 2) were not significantly different between ICSI (58.1%) and IVF (56.7%). In group 1, failure of fertilization after IVF insemination occurred in 10 of the 60 couples (16.7%) and in none with ICSI. In group 2, 2 of 50 couples (4.0%) failed fertilization by IVF, and 1 (2.0%) failed with ICSI. No couple in group 2 failed both IVF insemination and ICSI. In couples with unexplained infertility, a higher fertilization rate was achieved through ICSI compared with conventional IVF. No such benefit could be demonstrated for couples with borderline semen parameters. The use of ICSI rescued 12 of 110 cycles (10.9%) where IVF failed. Adoption of the ICSI-IVF insemination split in cases of unexplained infertility may help eliminate fertilization failures.


Characterizations of irofulven cytotoxicity in combination with cisplatin and oxaliplatin in human colon, breast, and ovarian cancer cells.
This study assessed the cytotoxic effects of irofulven in combination with oxaliplatin and cisplatin in a panel of human cancer cell lines. Growth inhibition studies were performed using the human HT29 colon cancer cell line, irofulven-resistant derivative HT29/IF2, breast cancer cell line MCF7, and ovarian cancer line CAOV3. Irofulven-oxaliplatin combinations were compared with irofulven-cisplatin combinations in the same cell lines using similar experimental settings. Cells were exposed for 1 h to irofulven and then for 24 h to oxaliplatin or cisplatin and vice versa. Single agent irofulven displayed cytotoxic effects against human colon HT29 cells, human breast cancer cell lines including MCF7, SKBR3, and ZR-75-1, and human ovarian cancer cell lines CAOV3, OVCAR3, and IGROV1, with OVCAR3 being the most sensitive cancer cell line (IC50: 2.4 microM). In all tested cell lines the oxaliplatin-irofulven combination led to clear evidence of synergistic activity. In HT29 and HT29/IF2, the sequence oxaliplatin followed by irofulven appears to be the most effective whereas in MCF7 cells, irofulven given prior to or simultaneously with oxaliplatin is more effective than the other schedule. The combination displays additive activity toward CAOV3 ovarian cells when irofulven was administered prior to or simultaneously with oxaliplatin and partially synergistic when oxaliplatin was followed by irofulven. In most of the cell lines, the sequence oxaliplatin followed by irofulven appears to be the most effective as compared to other schedules. A combination of irofulven with cisplatin has the same efficacy as with oxaliplatin for the same cell lines. Cell cycle studies show that irofulven increases the proportion of cells in the S phase. Cisplatin-irofulven and oxaliplatin-irofulven combinations block cells in G1/S and potently induce apoptosis. Irofulven displays synergistic antiproliferative and pro-apoptotic effects when combined with oxaliplatin over a broad range of concentrations in human colon and breast cancer cells. Acquired resistance to irofulven has limited impact on the effects of cisplatin-irofulven and oxaliplatin-irofulven combinations. Based on these data, irofulven-oxaliplatin and cisplatin-irofulven combinations will be further explored in clinical trials, favoring the use schedules of oxaliplatin given prior to irofulven in patients with cancer.


A naturally occurring gene encoding the major surface antigen precursor p190 of Plasmodium falciparum lacks tripeptide repeats.
Plasmodium falciparum merozoites have variable surface proteins that are processed from a 190-kd precursor protein (p190). The gene encoding p190 exists in two allelic forms and cross-over events occurring mainly near the 5' end, combined with isolate-specific tripeptide repeats, contribute to its antigen diversity. We have sequenced a large portion of the p190 gene from the parasite isolate RO-33 (Ghana). Remarkably, the typical N-terminal tripeptide repeat structure is lacking. Apart from mutations in the variable parts, the gene appears identical to the MAD-20 allele (Papua, New Guinea). Southern blot analysis detects p190 genes similar to RO-33 in other parasite isolates independent of their geographical origin. The lack of p190 repeats in RO-33 eliminates the possibility that they are involved in host cell recognition or integration and restricts their function to immune escape.


Development and validation of a random forest model to predict functional outcome in patients with intracerebral hemorrhage.
To develop and validate a machine learning (ML)-based model to predict functional outcome in Chinese patients with intracerebral hemorrhage (ICH). This retrospective cohort study enrolled patients with ICH between November 2017 and November 2020. The follow-up period ended in February 2021. The study population was divided into training and testing sets with a ratio of 7:3. All variables were included in the least absolute shrinkage and selection operator (LASSO) regression for feature selection. The selected variables were incorporated into the random forest algorithm to construct the prediction model. The predictive performance of the model was evaluated via the area under the curve (AUC), accuracy, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and calibration curve. A total of 412 ICH patients were included, with 288 in the training set, and 124 in the testing set. Twelve attributes were selected: neurological deterioration, Glasgow Coma Scale (GCS) score at 24 h, baseline GCS score, time from onset to the emergency room, blood glucose, diastolic blood pressure (DBP) change in 24 h, hematoma volume change in 24 h, systemic immune-inflammatory index (SII), systolic blood pressure (SBP) change in 24 h, serum creatinine, serum sodium, and age. In the testing set, the accuracy, AUC, sensitivity, specificity, PPV, and NPV of the model were 0.895, 0.964, 0.872, 0.906, 0.810, and 0.939, respectively. The calibration curves showed a good calibration capability of the model. This developed random forest model performed well in predicting 3-month poor functional outcome for Chinese ICH patients.


[Transvenous electrode implantation into the left heart auricle via vena saphena magna].
A new simple variant of the transvernous implantation of atrial electrodes for the pacemaker therapy is reported. It consist in the fact that via the V. saphena magna under fluorography a hook electrode is shifted into the right auricular appendix by means of a slightly bent conducting wire and is anchored by leading out the hooks.


Pulmonary and systemic hemodynamic effects of delta9-tetrahydrocannabinol in conscious and morphine--chloralose-anesthetized dogs: anesthetic influence on drug action.
Pulmonary and systemic hemodynamic effects of delta 9-tetrahydrocannabinol (delta 9-THC) in conscious dogs and in those anesthetized with morphine (3 mg/kg, i.m.) plus alpha-chloralose (100 mg/kg i.v.) were evaluated in this study. A decrease in the heart rate, cardiac output (PBF) and a concomitant increase in the pulmonary arterial pressure (PAP), pulmonary vascular resistance (PVR) and right ventricular stroke work (RVSW) observed in conscious animals following the administration of delta 9-THC were qualitatively similar to the effects reported in dogs anesthetized with sodium pentobarbital; however, unlike in the pentobarbital group, hypotensive effects to THC were not evident in the consious animals. In contrast, the effect of delta 9-THC in morphine--chloralose dogs were different; in this group delta 9-THC administration resulted in increases in the heart rate the PBF, and significant reductions in PAR, PVR and RVSW. Further, a decrease in the arterial blood pressure noted following THC administration was closely associated with a reduction in the total peripheral resistance in the morphine--chloralose group. The results of this study indicated that the pulmonary effects of THC in dogs may be related to its actions on the heart rate and differ qualitatively as well as quantitatively depending on the anesthetic used.


A new perspective on lysogeny: prophages as active regulatory switches of bacteria.
Unlike lytic phages, temperate phages that enter lysogeny maintain a long-term association with their bacterial host. In this context, mutually beneficial interactions can evolve that support efficient reproduction of both phages and bacteria. Temperate phages are integrated into the bacterial chromosome as large DNA insertions that can disrupt gene expression, and they may pose a fitness burden on the cell. However, they have also been shown to benefit their bacterial hosts by providing new functions in a bacterium-phage symbiotic interaction termed lysogenic conversion. In this Opinion article, we discuss another type of bacterium-phage interaction, active lysogeny, in which phages or phage-like elements are integrated into the bacterial chromosome within critical genes or operons and serve as switches that regulate bacterial genes via genome excision.


Single-center phase 2 study of PD-1 inhibitor combined with DNA hypomethylation agent + CAG regimen in patients with relapsed/refractory acute myeloid leukemia.
Anti-PD-1 monotherapy had limited clinical efficacy in relapsed/refractory (r/r) AML patients with higher PD-1 and PD-L1 expression. Hence, we investigated the efficacy and safety of PD-1 inhibitor with DNA hypomethylating agent (HMA) + CAG regimen in patients who had failed prior AML therapy. In this phase 2, single-arm study, r/r AML patients received azacitidine or decitabine plus CAG regimen with tislelizumab. Primary endpoints were efficacy (objective response rate [ORR]) and safety. Secondary endpoints included overall survival (OS), event-free survival (EFS) and duration of response (DOR). Statistical analyses were performed using Stata 14.0 and SPSS 20.0 software where P < 0.05 denoted significance. Twenty-seven patients were enrolled patients and completed 1 cycle, and 14 (51.9%) and 4 (14.8%) patients completed 2 and 3 cycles, respectively. ORR was 63% (14: complete remission [CR]/CR with incomplete hematologic recovery [CRi], 3: partial remission (PR), 10: no response [NR]). Median OS (mOS) and EFS were 9.7 and 9.2 months, respectively. With a median follow-up of 8.2 months (1.1-26.9), the mOS was not reached in responders (CR/CRi/PR) while it was 2.4 months (0.0-5.4) in nonresponders (P = 0.002). Grade 2-3 immune-related adverse events (irAEs) were observed in 4 (14.8%) patients and 3 nonresponders died of lung infection after treatment. Tislelizumab + HMA + CAG regimen showed improved outcomes in r/r AML patients with lower pretherapy leukemia burden. irAEs were mild and low-grade and higher pretherapy bone marrow CD4+ CD127+ PD-1+ T cells might serve as a predictor of treatment response.ClinicalTrials.gov identifier NCT04541277.


Allelotype influence at glutathione S-transferase M1 locus on breast cancer susceptibility.
The influence of polymorphisms of the glutathione S-transferase gene GSTM1 in breast cancer susceptibility has been assessed in this study. Previous studies correlated the absence of the GSTM1 protein with an increased risk of developing some cancers, especially lung or bladder cancers, in heavy smokers. In this study, we determined GSTM1 polymorphisms in a population of 437 female controls from the west of France and 361 community breast cancer patients. Three distinct alleles of this gene exist: GSTM1*A, GSTM1*B and GSTM1*0 (deleted allele). Null subjects (GSTM1 null) are homozygous for this deletion. The comparative analysis of GSTM1 allelotypes in our two populations did not demonstrate a statistically significant difference in distribution (P = 0.22), although the null genotype was more frequent in cancer patients. However, breast cancer risk was increased in null subjects > or = 50 years of age compared with non-null subjects [odds ratio = 1.99 (1.19-3.32), P = 0.009], but not in null subjects < 50 years of age compared with non-null subjects (P = 0.86). Our results suggest that the GSTM1 null genotype may play a role in post-menopausal breast cancer development. They also point to a putative protective role of the A allele in the older female control group, especially in hemizygous subjects [odds ratio = 0.42 (0.23-0.77), P = 0.03].


Radiation therapy in the management of desmoid tumors.
To evaluate the outcome of patients with extra-mesenteric desmoid tumors treated with radiation therapy, with or without surgery. The outcome for 75 patients receiving radiation for desmoid tumor with or without complete gross resection between 1965 and 1994 was retrospectively reviewed utilizing univariate and multivariate statistical methods. With a median follow-up of 7.5 years, the overall freedom from relapse was 78% and 75% at 5 and 10 years, respectively. Of the total, 23 patients received radiation for gross disease because it was not resectable. Of these 23 patients, 7 sustained local recurrence, yielding a 31% actuarial relapse rate at 5 years. Radiation dose was the only significant determinant of disease control in this group. A dose of 50 Gy was associated with a 60% relapse rate, whereas higher doses yielded a 23% relapse rate (p < 0.05). The other 52 patients received radiation in conjunction with gross total resection of tumor. The 5- and 10-year relapse rates were 18% and 23%, respectively. No factor correlated significantly with disease outcome. There was no evidence that radiation doses exceeding 50 Gy improved outcome. Positive resection margins were not significantly deleterious in this group of irradiated patients. For all 75 patients, there was no evidence that radiation margins exceeding 5 cm beyond the tumor or surgical field improved local-regional control. Ultimately, 72 of the 75 patients were rendered disease-free, but 3 required extensive surgery (amputation, hemipelvectomy) to achieve this status. Significant radiation complications were seen in 13 patients. Radiation dose correlated with the incidence of complications. Doses of 56 Gy or less produced a 5% 15-year complication rate, compared to a 30% incidence with higher doses (p < 0.05). Radiation is an effective modality for desmoid tumors, either alone or as an adjuvant to resection. For patients with negative resection margins, postoperative radiation is not recommended. Patients with positive margins should almost always receive 50 Gy of postoperative radiation. Unresectable tumors should be irradiated to a dose of approximately 56 Gy, with a 75% expectation of local control.


Waterless live transport degrades the flesh quality of Litopenaeus vannamei by disturbing neuroendocrine response: based on physiology and metabolomics.
Shrimp is one of the most popular marine foods consumed throughout the world and its freshness is a crucial indicator for consumers. However, the flesh quality degradation of shrimp during waterless live transport has been observed and the underlying mechanism remains unknown. The present study aimed to clarify the biochemistry mechanisms of flesh degradation with integration of quality evaluation, metabolic profiling and histopathological analysis. The flesh quality indicators such as water holding capacity, protein and lipid contents, amino acid composition and myofiber components degraded with the prolongation of combined stress. In addition, the metabolites including gamma-aminobutyric acid, Val-Ala, Trh and derivatives of carnitine, phosphocholine and prostaglandin all reduced significantly under combined stress (P < 0.05). Furthermore, Kyoto Encyclopedia of Genes and Genomes (https://www.genome.jp/kegg) analysis revealed the enrichment of neuroactive ligand-receptor interaction and estrogen signaling pathways, indicating the involvement of neuroendocrine in stress response. Moreover, architecture impairment in hepatopancreas tissue verified the accumulation of metabolic disturbance. Taken together, the findings of the present study indicate that neuroendocrine system mediates the flesh degradation of L. vannamei during waterless transport by disturbing the biochemical metabolic pathways and inducing architecture impairment of myofibril components. © 2022 Society of Chemical Industry.


Intra-Atrial Conduction Delay Revealed by Multisite Incremental Atrial Pacing is an Independent Marker of Remodeling in Human Atrial Fibrillation.
This study sought to characterize direction-dependent and coupling interval-dependent changes in left atrial conduction and electrogram morphology in uniformly classified patients with paroxysmal atrial fibrillation (AF) and normal bipolar voltage mapping. Although AF classifications are based on arrhythmia duration, the clinical course, and treatment response vary between patients within these groups. Electrophysiological mechanisms responsible for this variability are incompletely described. Intracardiac contact mapping during incremental atrial pacing was used to characterize atrial conduction, activation dispersion, and electrogram morphology in 15 consecutive paroxysmal AF patients undergoing first-time pulmonary vein isolation. Outcome measures were vulnerability to AF induction at electrophysiology study and 2-year follow-up for arrhythmia recurrence. Conduction delay showed a bimodal distribution, occurring at either long (high right atrium pacing: 326 ± 13 ms; coronary sinus pacing: 319 ± 16 ms) or short (high right atrium pacing: 275 ± 11 ms; coronary sinus pacing: 271 ± 11 ms) extrastimulus coupling intervals. Arrhythmia recurrence was found only in patients with conduction delay at long extrastimulus coupling intervals, and patients with inducible AF were characterized by increased activation dispersion (activation dispersion time: 168 ± 29 ms vs. 136 ± 11 ms). Electrogram voltage and duration varied throughout the left atrium, between patients, and with pacing site but were not correlated with AF vulnerability or arrhythmia recurrence. Within the single clinical entity of paroxysmal AF, incremental atrial pacing identified a spectrum of activation patterns correlating with AF vulnerability and arrhythmia recurrence. In contrast, electrogram morphology (characterized by electrogram voltage and duration) was highly variable and not associated with AF vulnerability or recurrence. An improved understanding of the electrical phenotype in AF could lead to improved mechanistic classifications.


Low-grade gastric adenomas/dysplasias: phenotypic expression, DNA ploidy pattern, and LOH at microsatellites linked to the APC gene.
The adenoma-adenocarcinoma sequence in the colon is generally accepted. Regarding the stomach, however, opinions about tumorigenesis are different. We analyzed the phenotypes, DNA ploidy patterns, and microsatellite regions linked to adenomatous polyposis coli (APC) gene on chromosome 5q of low-grade gastric adenomas/dysplasias, Vienna Category 3, to investigate whether these lesions have the potential to become adenocarcinomas. Phenotypes were determined by immunohistochemical staining with monoclonal antibodies MUC2, MUC5AC, MUC6, CD10, and Cdx2. DNA ploidy patterns were determined by static cytofluorometry. Microsatellite analyses were performed using Genescan on genetic analyzer ABI PRISM 310. None of the 15 cases showed coexisting high-grade adenomas/dysplasias or adenocarcinoma. Eighty percent of the cases had the complete intestinal phenotype, and the remainder showed slight MUC6 positivity for the intestinal phenotype. All cases were positive for Cdx2 and showed diploid DNA. In addition, 46.7% of the cases exhibited loss of heterozygosity (LOH) of chromosome 5q. Except for one case, 5q-LOH was detected at a single locus in cases with the complete intestinal phenotype. According to previous studies, most gastric adenocarcinomas have the gastric phenotype and no 5q-LOH. These results suggest that low-grade gastric adenomas/dysplasias, Vienna category 3, seldom progress to gastric adenocarcinomas of the differentiated type.


Aspirin--relieved asthma.
It is widely known that there might occur three different responses to the administration of ASA or NSAID to patients with bronchial asthma-bronchoconstriction, bronchodilatation or lack of bronchopulmonary action. Nevertheless, the beneficial effect of SAID has been confirmed in patients who are both nonallergic and cortico-dependent asthmatics. Our hypothesis is that in these specific cases the arachidonic acid metabolism is diverted towards cyclo-oxygenase products and that this metabolic diversion leads to an increased production of bronchoconstriction prostaglandins. The administration of NSAID inhibits the cyclo-oxygenase suppressing the enhanced basal production of these bronchoconstrictors and relieving the bronchospasm. The suspected abnormality in arachidonic acid metabolism would be restricted to the respiratory system.


Levodopa Responsiveness in Adult-onset Lower Limb Dystonia is Associated with the Development of Parkinson's Disease.
Adult-onset primary lower limb dystonia (AOPLLD) has been reported as an early sign of Parkinson's disease (PD) or Parkinson-plus syndrome in case series. No prior systematic analysis has assessed clinical clues predicting later development of PD or Parkinson-plus syndrome. We identified patients with AOPLLD from medical records. We excluded patients who had not been diagnosed by a neurologist, and who had a pre-existing diagnosis of PD, psychogenic, or secondary dystonia. Records were subdivided into those who later developed PD or Parkinson-plus disorders and those who did not. The following clinical characteristics were compared between the two groups: dystonia onset age, type of dystonia, levodopa response, anticholinergic response, and family history of Parkinsonism or tremor. Twenty-two AOPLLD patients were identified: 77% female; the median dystonia onset age was 53 years. Eight (37%) developed Parkinson's disease; 2 (9%) developed corticobasal syndrome. Twelve patients (54%) did not develop Parkinsonism after a median follow-up period of 1.5 years. There was a significant difference in leg dystonia levodopa response between the two groups (p = 0.02). In patients with AOPLLD, leg dystonia with levodopa response is associated with the future development of PD.


Use of very long-distance NOEs in a fully deuterated protein: an approach for rapid protein fold determination.
The high sensitivity of modern NMR instrumentation, in combination with full deuteration, enabled the measurement of long-range NOEs between amide protons in a fully deuterated protein corresponding to distances up to 8A. These are beyond the limit normally observed in protonated samples. Such long-distance NOEs could be observed using long mixing times, which became possible due to reduced spin diffusion and T1 relaxation of the amide protons in the fully deuterated sample. This information was used in combination with secondary structure restraints derived from secondary chemical shifts for structure calculations. With these backbone amide proton NOEs only, a unique fold could be obtained with positional root mean square deviations from the average of 1.30 and 2.25 A for backbone and heavy atoms, respectively. Despite the low density of restraints, no mirror image problems were observed. Addition of sidechain NOE information increased the precision of the ensemble and in particular of the core packing. The structures obtained in this way were close to the published crystal structure. NOE completeness analysis revealed that the cumulative completeness is still more than 80% for an 8.0 A cut-off distance.


Overexpressed in colorectal carcinoma gene (OCC-1) upregulation and APPL2 gene downregulation in breast cancer specimens.
Breast cancer is the most common cancer type and the second cause of cancer death in women. Different mechanisms are contributed to the initiation and progression of the breast cancer. OCC-1 and APPL2 neighboring genes located in 12q.23.3 human chromosome region are related to colorectal cancer. Here, we intended to investigate OCC-1 newly reported transcript variants and APPL2 gene expression alteration in breast cancer specimens and investigate OCC-1 variants overexpression effect on APPL2 and on cell cycle status. Rt-qPCR analysis indicated that the expression level of OCC-1A/B and OCC-1D (not OCC-1C) transcript variants has been increased while, APPL2 gene expression level has been decreased in breast cancer specimen, compared to their normal pairs. Therefore, a negative correlation of expression is evident between APPL2 and OCC-1 genes in breast cancer specimen. Unlike OCC-1A/B which encodes a small protein, OCC-1D noncoding RNA overexpression lead to APPL2 downregulation in MCF7 cells. Consistently, OCC-1D overexpression resulted in increased sub-G1 cell population in MCF7 cells, detected by flow cytometry. Altogether, these results suggest that OCC1-D variant have an inhibitory effect on APPL2 expression and may regulate the cell cycle status.


Quantitative assessment of vasospasm by Doppler spectrum analysis in patients with primary Raynaud's phenomenon.
The aim of the study was to investigate whether increased peripheral resistance which is supposed to exist in patients with primary Raynaud's phenomenon, can be quantified by using parameters of Doppler spectra of flow in the ulnar and radial arteries. A group of 24 patients with this abnormality were compared with a matched group of 24 normal subjects. Doppler spectra were analysed according to the methods of Fronek, Gosling and by Fast Fourier Transform analysis. The Doppler spectra obtained from patients at room temperature were very different from those in normal subjects, showing characteristic wave-forms with multiple oscillations in 92% of the patients. All three analysing techniques demonstrated significant differences between the two groups, which can be attributed to increased peripheral vascular resistance in the patient group. The results of this study emphasize the value of analysis of Doppler spectra obtained from ulnar and radial arteries in the assessment of peripheral vascular resistance in vasospastic disease.


The effect of dietary fish oil on muscle and adipose tissue lipoprotein lipase.
The activity of lipoprotein lipase (LPL) in the adipose tissue and skeletal muscle of rats fed glucose- or fructose-based diets containing fish oil, corn oil or tallow was examined. In addition, heart LPL activity was measured in rats fed a glucose-based diet containing either corn oil or fish oil. Adipose tissue LPL activity was unaffected by dietary fat. In both heart and skeletal muscle, LPL activity was higher in rats fed the fish oil diet. These results suggest that increased removal of triglyceride by muscle may contribute to the blood triglyceride lowering effect of dietary fish oil.


Ultrasound-guided peripheral deep vein cannulation to perform automated red cell exchange-A pilot study in a single centre.
Securing adequate vascular access is essential for a successful apheresis procedure. In most, peripheral access is preferred but it is not always technically possible. Ultrasound-Guided Peripheral Vascular Access (USG-PIVA) is a well-documented technique in the setting of Emergency departments. However, limited data exists reporting its use in the context of automated red cell exchanges (a-RCEx). To assess the effectiveness and feasibility of USG-PIVA to undertake successful a-RCEx. Data was collected prospectively from patients with sickle cell disease and difficult venous access, undergoing a-RCEx at a single centre. The USG-PIVA technique was attempted and data relating to each attempt was collected and analysed. Between April 2014 and July 2015 84 USG-PIVA procedures were performed on 38 patients. 71 USG-PIVA (85%) were successful, 13 (15%) were unsuccessful. Veins successfully cannulated: in the upper arm, basilic (22), brachial (33) and cephalic (2) veins; in the antecubital fossa, basilic (3) and median cubital (7) and in the lower arm, cephalic (2) and radial (2). Cannulas used: Introcan Safety® Braun 22 g (1), 20 g (9) and 18 g (61). Inlet flow rates achieved: 30-60 ml/min (mean 45 ml/min). Depth of veins cannulated: 2-12 mm (mean 5 mm). two complications were observed-one cannula displacement and one nerve injury. No arterial punctures occurred. Central Venous Catheters avoided (49). The US-PIVA method offers an effective alternative to Central Venous Access in patients requiring a-RCEx procedures who lack visual or palpable peripheral access, with minimal complications seen in this series. J. Clin. Apheresis 31:501-506, 2016. © 2015 Wiley Periodicals, Inc.


Glucosteroid (GS)-dependent immunomodulation of immunoglobulin biosynthesis in vitro. I. GS stimulate spontaneous immunoglobulin synthesis.
Glucosteroids (GS) enhance spontaneous differentiation of human B lymphocytes to Ig containing plasma cells. The use of the reverse plasque-forming cell (PFC) assay made it possible to subdivide normal donors into GS-responder and non-responder inhibitable group. Peripheral blood B cells appear to be especially prone to GS-dependent enhancement of differentiation. While B cells derived from lymphoid organs retain their susceptibility to GS, they are less sensitive inasmuch enhancement of Ig synthesis is concerned.


Inhalational mold toxicity: fact or fiction? A clinical review of 50 cases.
Three well-accepted mechanisms of mold-induced disease exist: allergy, infection, and oral toxicosis. Epidemiologic studies suggest a fourth category described as a transient aeroirritation effect. Toxic mold syndrome or inhalational toxicity continues to cause public concern despite a lack of scientific evidence that supports its existence. To conduct a retrospective review of 50 cases of purported mold-induced toxic effects and identify unrecognized conditions that could explain presenting symptoms; to characterize a subgroup with a symptom complex suggestive of an aeroirritation-mediated mechanism and compare this group to other diagnostic categories, such as sick building syndrome and idiopathic chemical intolerance; and to discuss the evolution of toxic mold syndrome from a clinical perspective. Eighty-two consecutive medical evaluations were analyzed of which 50 met inclusion criteria. These cases were critically reviewed and underwent data extraction of 23 variables, including demographic data, patient symptoms, laboratory, imaging, and pulmonary function test results, and an evaluation of medical diagnoses supported by medical record review, examination, and/or test results. Upper respiratory tract, lower respiratory tract, systemic, and neurocognitive symptoms were reported in 80%, 94%, 74%, and 84% of patients, respectively. Thirty patients had evidence of non-mold-related conditions that explained their presenting complaints. Two patients had evidence of allergy to mold allergens, whereas 1 patient exhibited mold-induced psychosis best described as toxic agoraphobia. Seventeen patients displayed a symptom complex that could be postulated to be caused by a transient mold-induced aeroirritation. The clinical presentation of patients with perceived mold-induced toxic effects is characterized by a disparate constellation of symptoms. Close scrutiny revealed a number of preexisting diagnoses that could plausibly explain presenting symptoms. The pathogenesis of aeroirritation implies completely transient symptoms linked to exposures at the incriminated site. Toxic mold syndrome represents the furtive evolution of aeroirritation from a transient to permanent symptom complex in patients with a psychogenic predisposition. In this respect, the core symptoms of toxic mold syndrome and their gradual transition to chronic symptoms related to nonspecific environmental fragrances and irritants appear to mimic what has been observed with other pseudodiagnostic categories, such as sick building syndrome and idiopathic chemical intolerance.


Bacterial Sexually Transmitted Infection Incidence Among Southern Men Who Have Sex With Men With Human Immunodeficiency Virus in the Treatment as Prevention Era, 2014-2019.
In this retrospective analysis of men who have sex with men with human immunodeficiency virus (HIV) in the South from 2014 through 2019, incident bacterial sexually transmitted infections (STIs) increased regardless of virologic control. Clinicians should prioritize STI screening and management in primary HIV care.


Big deal. Can United HealthCare make a silk purse out of a sow's ear?
On the surface, United HealthCare Corp.'s purchase of The MetraHealth Cos. two months ago looks like a great deal. But United's grand strategy is fraught with obstacles, and the move seems sure to heat up the competition and consolidation taking place in health care coverage.


Proteins that bind A-type lamins: integrating isolated clues.
What do such diverse molecules as DNA, actin, retinoblastoma protein and protein kinase Calpha all have in common? They and additional partners bind 'A-type' lamins, which form stable filaments in animal cell nuclei. Mutations in A-type lamins cause a bewildering range of tissue-specific diseases, termed 'laminopathies', including Emery-Dreifuss muscular dystrophy and the devastating Hutchinson-Gilford progeria syndrome, which mimics premature aging. Considered individually and collectively, partners for A-type lamins form four loose groups: architectural partners, chromatin partners, gene-regulatory partners and signaling partners. We describe 16 partners in detail, summarize their binding sites in A-type lamins, and sketch portraits of ternary complexes and functional pathways that might depend on lamins in vivo. On the basis of our limited current knowledge, we propose lamin-associated complexes with multiple components relevant to nuclear structure (e.g. emerin, nesprin 1alpha, actin) or signaling and gene regulation (e.g. LAP2alpha, retinoblastoma, E2F-DP heterodimers, genes) as 'food for thought'. Testing these ideas will deepen our understanding of nuclear function and human disease.


Preparation and coating of finely dispersed drugs 4. Loratadine and danazol.
The preparation of colloidal particles of different morphologies, including spheres, of two drugs, loratadine and danazol, is described. In principle these particles were obtained by precipitation when nonsolvents (water or aqueous surfactant solutions) were added to ethanol solutions of the drug. In addition, procedures were developed that made it possible to use the drug particles thus obtained as cores to be then coated with either silica or aluminum (hydrous) oxide layers. The presence of these inorganic shells was confirmed by electron microscopy, energy dispersive spectroscopy, and electrophoresis.


Biochemical and functional characterization of human tissue-type plasminogen activator variants with mutagenized kringle domains.
The cDNA encoding full-length human tissue-type plasminogen activator (t-PA) and five variant cDNAs, constructed by in vitro site-directed mutagenesis, were cloned and expressed in Chinese hamster ovary cells. The variant cDNAs were designed to increase the fibrin affinity of t-PA by mutagenesis in the kringle domains of specific amino acids which are assumed to constitute the lysine-binding site. These amino acids were replaced with the corresponding amino acids present in kringle 1 of plasminogen, which has a high affinity for lysine analogues. The mutants included: rt-PA-Arg125 with a Pro125----Arg mutation; rt-PA-Arg164,Tyr165 with Ser164,Ser165----Arg,Tyr; rt-PA-Arg125,Arg164,Tyr165 with Pro125,Ser164,Ser165----Arg,Arg,Tyr; rt-PA-Arg213 with Val213----Arg; and rt-PA-Arg252 with Thr252----Arg. Compared to wild-type recombinant t-PA (rt-PA), the catalytic efficiency for plasminogen activation was enhanced 4-fold for rt-PA-Arg125, and 3-fold for rt-PA-Arg252 while stimulation of plasminogen activation by CNBr-digested fibrinogen was comparable to wild-type rt-PA for rt-PA-Arg125 and 2-fold enhanced for rt-PA-Arg252. All rt-PA moieties showed a similar concentration-dependent and nearly quantitative binding to fibrin as well as to lysine-Sepharose and induced a similar time- and concentration-dependent lysis of a 125I-fibrin-labeled plasma clot immersed in human plasma. Equieffective concentrations (causing 50% clot lysis in 2 h) were 0.17 micrograms/ml for rt-PA-Arg125, and 0.31 micrograms/ml for rt-PA-Arg252 as compared to 0.55 micrograms/ml for rt-PA. The initial plasma half-life following intravenous bolus injection of 0.25 mg/kg in hamsters was 1.2-2.6 min, not significantly different from wild-type rt-PA (2.4 min). Continuous infusion over 60 min in hamsters with a 125I-fibrin-labeled pulmonary embolus produced 50% clot lysis over background with a dose of 0.9-1.8 mg/kg, which is not markedly superior to wild-type rt-PA (2.1 mg/kg). It is concluded that these variants, designed to mimic the high affinity fibrin-binding site of plasminogen, are not endowed with a markedly improved thrombolytic potency.


Reproducibility of standardized uptake value measurements determined by 18F-FDG PET in malignant tumors.
18F-FDG PET is increasingly being used to monitor the early response of malignant tumors to chemotherapy. Understanding the reproducibility of standardized uptake values (SUVs) is an important prerequisite in estimating what constitutes a significant change. Twenty-six patients were studied on 2 separate occasions (mean interval +/- SD, 3 +/- 2 d; range, 1-5 d). A static PET/CT scan was performed 94 +/- 9 min after the intravenous injection of 383 +/- 15 MBq of 18F-FDG. Mean and maximum SUVs (SUVmean and SUVmax, respectively) were determined for regions of interest drawn around the tumor on the first study and for the same regions of interest transferred to the second study. SUVmean in tumors ranged from 1.49 to 17.48 and SUVmax ranged from 2.99 to 24.09. The correlation between SUVmean determined on the 2 separate visits was 0.99; the mean difference between the 2 measurements was 0.01 +/- 0.27 SUV. The 95% confidence limits for the measurements were +/-0.53. For SUVmax, the mean difference was -0.05 +/- 1.14 SUV. Our study demonstrates that repeated measurements of SUVmean performed a few days apart are highly reproducible. A decrease of 0.5 in the SUV is statistically significant.


Remediation of arsenic contaminated soils by iron-oxide application, evaluated in terms of plant productivity, arsenic and phytotoxic metal uptake.
Four iron-bearing additives, selected for known or potential ability to adsorb anions, were evaluated for their effectiveness in attenuation of arsenic (As) in three soils with different sources of contamination (canal dredgings, coal fly ash deposits, and low-level alkali waste). Amendments used were lime, goethite (alpha-FeOOH) (crystallised iron oxide) and three iron-bearing additives, iron grit and iron (II) and (III) sulphates plus lime, which result in 'de novo' iron oxide formation in soils. Each was applied to the test soils at a rate of 1% w/w. A series of plant growth trials were conducted on the equilibrated, amended soils using spinach (Spinacia oleracea) and tomato (Lycopersicon esculentum) as test crops. These were grown in the contaminated soils for a period of three months in controlled glasshouse conditions. Evaluation of the potential of the amendments as immobilising agents was determined by plant growth (biomass) and elemental accumulation in plant tissues, indicating the bioavailability of As and other heavy metals following amendment. Goethite produced the most promising results in terms of reduction of plant shoot As content. It was concluded that, whilst Fe-oxides may be used as effective in situ amendments to attenuate As in soils by reducing its bioavailability, their effects on plant growth require careful consideration. In addition, soil-plant transfer of As was not completely halted by any amendment.


The possibilities of uncemented glenoid component--a finite element study.
(1) Determine the initial stress distributions within an uncemented implanted glenoid during elevation of the arm and to investigate whether failure is caused by stresses generated within this implant-bone structure. (2) Compare stress patterns between the uncemented design and two basic models of cemented prostheses. The uncemented component consists of a polyethylene cup with a metal-backing. All material interfaces were assumed to be fully bonded. Cemented glenoid components have been frequently vulnerable to failure within itself and at the cement-bone interface. A 3-D finite element analysis of an uncemented design is required to investigate whether clinical observations on failure can be better explained with a stress analysis. A 3-D finite element submodel an uncemented prosthesis was generated using CT-scan data and realistic loading conditions (humeral abduction, 30-180 degrees ). The submodelling approach was based on an overall solution of a complete scapula acted upon by all muscles, ligaments and joint reaction forces. High Von Mises stresses (20-70 MPa) were generated in the metal-backing during abduction. Stresses were reduced in the polyethylene cup by 17-20% as compared to the cemented designs. Stresses in the underlying bone were substantially lower than to the natural glenoid. Stress-shielding can be observed in the trabecular bone underlying the prosthesis. The implant-bone interface is secure against interface failure at moderate loads, although the implant-bone (metal-bone) interface around the superior edge of the prosthesis is subject to high stresses (normal: 11.85 MPa, shear: 6.67 MPa) as compared to the cemented prosthesis. Whereas, the cement-bone interface, appears more likely to fail either at locations adjacent to the keel or at locations around the superior edge of the cemented design. The uncemented design therefore appeared to be a reasonable alternative to fixation with cement. Results of this study strongly agree with clinical and radiographic findings. Although indications of stress-shielding and separation of modular parts of the prosthesis were apparent, the implant-bone interface seems less likely to fail as compared to cemented designs. Once initial fixation of the implant is achieved, the uncemented design appears to have better prospects than cemented ones.


Cloning and partial characterization of the promoter for the human p55 tumor necrosis factor (TNF) receptor.
An 809-bp region at the 5' flank of the human p55 tumor necrosis factor receptor (TNF-R)-encoding gene was found to be active in driving expression of the cat reporter gene, indicating that it contains a functional promoter. Deletion analysis showed that the promoter activity is present in the region between nucleotides (nt) -385 and -207; the sequence upstream from this region (nt -809 to -385) has an inhibitory effect. The promoter for the p55 TNF-R resembles housekeeping-type promoters in that it drives transcription from multiple start points (tsp) and lacks canonical TATA and CAAT box motifs. The cluster of tsp lies in a region which is particularly C+T rich. In this region, upstream from and near to the furthest upstream tsp, two closely located TCC repeat motifs were identified. These motifs also appear twice in the promoter for the epidermal growth factor receptor, where they were shown to be essential for promoter activity. The human p55 TNF-R promoter shows an overall resemblance, yet also some marked dissimilarities, to the recently described promoter for the mouse p55 TNF-R.


Caudate lobe amebic abscesses: percutaneous image-guided aspiration or drainage.
Amebic liver abscess is the most common type of liver abscess on a worldwide basis, with caudate lobe being a relatively uncommon location for its occurrence. Abscess in caudate lobe of liver is often considered a challenging location for image-guided percutaneous drainage due to its difficult-to-access location along with close relationship with major vessels at porta hepatis. This study aims to demonstrate safety and efficacy of percutaneous drainage for caudate lobe amebic abscess. In this retrospective study, hospital database was electronically searched for patients having caudate lobe amebic abscess that underwent percutaneous catheter drainage/needle aspiration (PCD/PNA) between January 2016 and January 2021. The etiology, risk factors, microbiology, complications, different approaches for PCD/PNA, and their outcome were studied and reported. Of 30 patients having caudate lobe amebic abscess treated with PCD/PNA, solitary caudate lobe abscess was seen in 29, whereas one patient had more than one abscesses in caudate lobe. Contained and free intraperitoneal rupture of the abscess were seen in 9 (30%) and one patient, respectively. Ten (32%) patients had associated vascular thrombosis, while 2 patients were found to have abscess-biliary communication. Twenty-six (86.7%) patients were treated with PCD, while remaining 4 (13.3%) with PNA. On Univariate analysis, factors such as volume, multilocularity, and contained rupture of the abscess were found to be significantly increasing the duration of percutaneous drainage (PCD), while only multilocularity (p value 0.007) continued to show statistical significance on Multivariate analysis. Venous thrombosis and duration of catheter drainage were the two factors found to have significant influence on the length of hospital stay on Univariate as well as Multivariate analysis (p value 0.05 and 0.001, respectively). The rates of catheter manipulation were also significantly higher in patients with abscess showing complex internal configuration (heteroechoic contents and/or multilocularity). Technical and clinical success rates of 100% and 96.7% were achieved through percutaneous interventions (PCD/PNA), despite the complex location of abscesses and associated complications, with no incidence of vascular injury. Liver abscess in caudate lobe can be accessed by different routes for percutaneous drainage, despite being surrounded by large vessels and its deep location, without major complications. Thus, PCD/PNA may be considered as a first-line therapy for the management of caudate lobe amebic abscesses in adjunct to medical therapy.


Short-chain fatty acid delivery: assessing exogenous administration of the microbiome metabolite acetate in mice.
Short-chain fatty acids (SCFAs) are fermentation by-products of gut microbes which have been linked to positive effects on host physiology; the most abundant SCFA is acetate. Exogenous administration of acetate alters host metabolism, immune function, and blood pressure, making it a biologic of interest. The effects of acetate have been attributed to activation of G-protein-coupled receptors and other proteins (i.e., HDACs), often occurring at locations distant from the gut such as the pancreas or the kidney. However, due to technical difficulties and costs, studies have often delivered exogenous acetate without determining if systemic plasma acetate levels are altered. Thus, it is unclear to what extent each method of acetate delivery may alter systemic plasma acetate levels. In this study, we aimed to determine if acetate is elevated after exogenous administration by drinking water (DW), oral gavage (OG), or intraperitoneal (IP) injection, and if so, over what timecourse, to best inform future studies. Using a commercially available kit, we demonstrated that sodium acetate delivered over 21 days in DW does not elicit a measurable change in systemic acetate over baseline. However, when acetate is delivered by OG or IP injection, there are rapid, reproducible, and dose-dependent changes in plasma acetate. These studies report, for the first time, the timecourse of changes in plasma acetate following acetate administration by three common methods, and thus inform the best practices for exogenous acetate delivery.


Workplace Romance Can Be Sexual Harassment: Time to Mandate Preventive and Protective Sensitivity Training.
Sensitivity training for workplace romance (WPR) and sexual harassment (SHM) across workplaces should be mandated because this knowledge may protect employees and employers by preventing workplace romanticism-sexism.


Microglia maintain the normal structure and function of the hippocampal astrocyte network.
Microglial control of activity-dependent plasticity and synaptic remodeling in neuronal networks has been the subject of intense research in the past several years. Although microglia-neuron interactions have been extensively studied, less is known about how microglia influence astrocyte-dependent control over neuronal structure and function. Here, we explored a role for microglia in regulating the structure and function of the astrocyte syncytium in mouse hippocampus. After depleting microglia using a CSF1R antagonist (PLX5622, Plexxikon), we observed severe disruption of astrocyte syncytial isopotentiality and dye coupling. A decrease in astrocyte-specific gap junction connexin (Cx) 30 and 43 expression, at least partially accounts for these microglia-dependent changes in astrocytes. Because neuronal function requires intact astrocyte coupling, we also evaluated the effects of microglia depletion on synaptic transmission in the hippocampus. Without microglia, the strength of synaptic transmission was reduced at baseline and after long-term potentiation (LTP). Conversely, priming microglia with systemic injections of lipopolysaccharide enhanced CA3-CA1 synaptic transmission. This microglia-induced scaling of synaptic transmission was associated with increased expression of post-synaptic scaffold proteins (Homer1) in CA1. However, astrocyte network function was not affected by microglia priming, indicating that microglia-dependent effects on astrocytes and neurons vary across functional states. Through manipulation of microglia in the brain, our results reveal the importance of microglia in homeostatic regulation of the astrocyte syncytium and scaling of synaptic transmission. These novel mechanisms uncover a new direction for future studies interrogating microglia function in various physiological and pathological contexts.


Erythrocyte cation transport and age: effects of digoxin and furosemide.
The uptake of rubidium 86 (86Rb) by human erythrocytes was measured at various ages. Effects of digoxin and furosemide on this process were examined and, in the case of digoxin, related to its numbers of specific cellular binding sites. There were no significant effects of age on absolute cellular Rb uptake, digoxin-sensitive Rb uptake, or numbers of cellular binding sites for digoxin, but the ability of digoxin to inhibit digoxin-sensitive 86Rb uptake increased with age. The ability of furosemide to inhibit digoxin-insensitive 86Rb uptake did not change with age. Results suggest a dynamic contribution to altered sensitivity to digoxin in elderly persons.


A comparison of the sealing properties of different retrograde techniques: an autoradiographic study.
Single-rooted teeth were instrumented and filled in vitro with a lateral condensation of gutta-percha with sealer. Following obturation, the tooth apices were treated by various retrograde procedures. The teeth were then coated with ethyl acetate, immersed in 45Ca solution, washed, and sectioned, and autoradiographs were used to compare the leakage of the various techniques. Statistical analysis indicated that lateral condensation produced a significantly better seal than any retrograde technique tested except retrofilling with Super EBA cement and that a significantly worse seal was obtained with amalgam retrofill when compared to all retrograde techniques except cold-burnished gutta-percha following apicoectomy. No significant difference existed between other group combinations.


Correlations between stochastic epidemics in two interacting populations.
It is increasingly apparent that heterogeneity in the interaction between individuals plays an important role in the dynamics, persistence, evolution and control of infectious diseases. In epidemic modelling two main forms of heterogeneity are commonly considered: spatial heterogeneity due to the segregation of populations and heterogeneity in risk at the same location. The transition from random-mixing to heterogeneous-mixing models is made by incorporating the interaction, or coupling, within and between subpopulations. However, such couplings are difficult to measure explicitly; instead, their action through the correlations between subpopulations is often all that can be observed. Here, using moment-closure methodology supported by stochastic simulation, we investigate how the coupling and resulting correlation are related. We focus on the simplest case of interactions, two identical coupled populations, and show that for a wide range of parameters the correlation between the prevalence of infection takes a relatively simple form. In particular, the correlation can be approximated by a logistic function of the between population coupling, with the free parameter determined analytically from the epidemiological parameters. These results suggest that detailed case-reporting data alone may be sufficient to infer the strength of between population interaction and hence lead to more accurate mathematical descriptions of infectious disease behaviour.


Studies on the mode of action of gonadotrophin-inhibiting material (anti-LH) isolated from human urine.
Gonadotrophin-inhibiting material (GIM) was able to inhibit the binding of 125I-hCG to rat Leydig cells, suggesting that its inhibiting properties are due to its ability to complete for the hCG binding sites on Leydig cells. Binding of fluorescein isothiocyanate-tagged GIM to Leydig cells was also seen. The effect of GIM on hCG-induced adenylate cyclase activation and testosterone production was also studied. It was found that there was a dose-dependent inhibition of both these effects.


Ruptured internal limiting membrane associated with blunt trauma revealed by indocyanine green staining.
Description of cases of traumatic macular hole that appeared concomitant with a ruptured internal limiting membrane (ILM) that was apparent during vitrectomy only after staining with indocyanine green (ICG). Vitrectomy with ILM peeling was performed on a 20-year-old man and a 13-year-old boy for treatment of traumatic macular holes. During vitrectomy, the ILM was found to be ruptured along the area of an identified macular hole only after ICG staining. After the vitrectomy, the macular holes were closed and visual acuity improved. However, visual field defect associated with apparent inner-layer retinal damage remained. Blunt trauma can cause severe inner-layer retinal damage with rupture of the ILM as well as frank macular hole formation and choroidal rupture.


Suppressed prefrontal neuronal firing variability and impaired social representation in IRSp53-mutant mice.
Social deficit is a major feature of neuropsychiatric disorders, including autism spectrum disorders, schizophrenia, and attention-deficit/hyperactivity disorder, but its neural mechanisms remain unclear. Here, we examined neuronal discharge characteristics in the medial prefrontal cortex (mPFC) of IRSp53/Baiap2-mutant mice, which show social deficits, during social approach. We found a decrease in the proportion of IRSp53-mutant excitatory mPFC neurons encoding social information, but not that encoding non-social information. In addition, the firing activity of IRSp53-mutant neurons was less differential between social and non-social targets. IRSp53-mutant excitatory mPFC neurons displayed an increase in baseline neuronal firing, but decreases in the variability and dynamic range of firing as well as burst firing during social and non-social target approaches compared to wild-type controls. Treatment of memantine, an NMDA receptor antagonist that rescues social deficit in IRSp53-mutant mice, alleviates the reduced burst firing of IRSp53-mutant pyramidal mPFC neurons. These results suggest that suppressed neuronal activity dynamics and burst firing may underlie impaired cortical encoding of social information and social behaviors in IRSp53-mutant mice.


Non-coordinated histone synthesis with DNA replication and close temporal association of ribosomal proteins and rRNA syntheses in germinating Vicia faba embryos.
Syntheses of DNA, RNA and basic proteins during germination of Vicia faba seeds were examined. Incorporation of [3H]thymidine into DNA reached a maximum peak at approximately 34 h after beginning imbibition and the phase of DNA replication was preceded by active RNA synthesis. When Vicia embryos were labeled with [3H]lysine or E13H]arginine, these isotopes were incorporated into ribosomal proteins and histones. The incorporation studies indicated that the synthesis of ribosomal structural proteins is closely linked with rRNA synthesis and histone synthesis occurs during and also before the phase of DNA replication. Polyacrylamide gel electrophoresis of Vica histones indicated that some histones of Vicia embryos differ from corresponding calf thymus histones in their mobilities.


[Thyroid involvement in cystinosis].
Thyroid function was assessed in 15 children with cystinosis and it was abnormal in 12. Three of these children were clearly hypothyroid and in the other 9 there were abnormalities of TSH or in the response to TRF. Compensated hypothyroidism is frequent in cystinosis and may be one factor in the severe growth retardation in this condition. The preliminary results of replacement therapy support this hypothesis.


Role of the C-type lectins DC-SIGN and L-SIGN in Leishmania interaction with host phagocytes.
Leishmaniasis is a parasitic disease that courses with cutaneous or visceral clinical manifestations. The amastigote stage of the parasite infects phagocytes and modulates the effector function of the host cells. Our group has described that the interaction between Leishmania and immature monocyte-derived dendritic cells (DCs) takes place through dendritic cell-specific ICAM-3-grabbing nonintegrin (DC-SIGN), a C-type lectin that specifically recognizes fungal, viral and bacterial pathogens. The DC-SIGN-mediated recognition of Leishmania amastigotes does not induce DC maturation, and the DC-SIGN ligand/s on Leishmania parasites is/are still unknown. We have also found that the DC-SIGN-related molecule L-SIGN, specifically expressed in lymph node and liver sinusoidal endothelial cells, acts as a receptor for L. infantum, the parasite responsible for visceral leishmaniasis, but does not recognize L. pifanoi, which causes the cutaneous form of the disease. Therefore, DC-SIGN and L-SIGN differ in their ability to interact with Leishmania species responsible for either visceral or cutaneous leishmaniasis. A deeper knowledge of the parasite-C-type lectin interaction may be helpful for the design of new DC-based therapeutic vaccines against Leishmania infections.


Influence of general anaesthesia on slow waves of intracranial pressure.
Slow vasogenic intracranial pressure (ICP) waves are spontaneous ICP oscillations with a low frequency bandwidth of 0.3-4 cycles/min (B-waves). B-waves reflect dynamic oscillations in cerebral blood volume associated with autoregulatory cerebral vasodilation and vasoconstriction. This study quantifies the effects of general anaesthesia (GA) on the magnitude of B-waves compared to natural sleep and conscious state. The magnitude of B-waves was assessed in 4 groups of 30 patients each with clinical indications for ICP monitoring. Normal pressure hydrocephalus patients undergoing Cerebrospinal Fluid (CSF) infusion studies in the conscious state (GROUP A) and under GA (GROUP B), and hydrocephalus patients undergoing overnight ICP monitoring during physiological sleep (GROUP C) were compared to deeply sedated traumatic brain injury (TBI) patients with well-controlled ICP during the first night of Intensive Care Unit (ICU) stay (GROUP D). A total of 120 patients were included. During CSF infusion studies, the magnitude of slow waves was higher in conscious patients ( 0.23+/-0.10 mm Hg) when compared to anaesthetised patients ( 0.15+/-0.10 mm Hg; p = 0.011). Overnight magnitude of slow waves was higher in patients during natural sleep (GROUP C: 0.20+/-0.13 mm Hg) when compared to TBI patients under deep sedation (GROUP D: 0.11+/- 0.09 mm Hg; p = 0.002). GA and deep sedation are associated with a reduced magnitude of B-waves. ICP monitoring carried out under GA is affected by iatrogenic suppression of slow vasogenic waves of ICP. Accounting for the effects of anaesthesia on vasogenic waves may prevent the misidentification of potential shunt-responders as non-responders.


Lumbar laminectomy and fusion with routine local application of vancomycin powder: decreased infection rate in instrumented and non-instrumented cases.
Wound infections are one of the most common and potentially devastating complications of spinal surgery. Intra-wound application of vancomycin powder has been shown to lower the infection risk following posterior instrumented fusion, but little evidence supports use in other spinal operations. The goal of this study is to assess the efficacy of vancomycin powder for lumbar laminectomy and fusion, both instrumented and non-instrumented. All cases of lumbar laminectomy and posterior fusion (with or without pedicle screw fixation) by a single surgeon were reviewed from 2007 to 2011. Routine application of 1g vancomycin powder was started in August 2009. Baseline characteristics and operative data were compared between untreated patients and those who received vancomycin powder. Rates of wound infection were compared for all fusions, and then separately for instrumented and non-instrumented cases. 253 patients underwent lumbar laminectomy and fusion between 2007 and 2011. Baseline and operative variables were similar between untreated patients (n=97) and those who received vancomycin powder (n=156). Patients were followed for at least one year. The infection rate fell significantly following introduction of vancomycin powder (from 11% to 0%, p=0.000018). Subgroup analysis revealed significant infection reduction for both instrumented cases (from 12% to 0%, p=0.000806) and non-instrumented cases (from 10% to 0%, p=0.0496). No complications attributable to vancomycin powder were identified. Local vancomycin powder appears to lower the risk of wound infection following lumbar laminectomy and fusion, both instrumented and non-instrumented. Further studies are needed to optimize dosing of vancomycin powder, assess long-term safety and efficacy, and evaluate use in other spinal operations.


Mixture Compound Fertilizer and Super Absorbent Polymer Application Significantly Promoted Growth and Increased Nutrient Levels in Pinus massoniana Seedlings and Soil in Seriously Eroded Degradation Region of Southern China.
Pinus massoniana is the pioneer tree species in the red soil regions of southern China, however, the serious understory soil erosion and nutrient deficiency in that region are the main factors restricting the growth of P. massoniana. This field study examined the effects of compound fertilizer and super absorbent polymer (SAP) on the physiology, growth characteristics, biomass, soil nutrient, plant nutrient content, and nutrient uptake efficiency of 1-year-old P. massoniana seedlings for 2 years at Changting, Fujian in South China. One control (no fertilizer, CK) and fertilization treatments were established, namely, single compound fertilizer application (0.94, 1.89, and 3.56 g⋅plant-1) and mixture compound fertilizer and SAP application (0.94 + 1.01, 1.89 + 1.01, and 3.56 + 1.01 g⋅plant-1). Fertilization significantly improved the physiological performance, root collar diameter growth, height growth, biomass, and nutrient uptake of the seedlings. Compared with other fertilization treatments, the mixture compound fertilizer and SAP application significantly improved the seedling photosynthesis, which meant that the SAP had a significant effect on promoting photosynthesis. Under the mixture compound fertilizer and SAP application, the whole biomass of the seedlings was higher than that of all other treatments. Fertilization significantly increased the nitrogen (N), phosphorus (P), and potassium (K) content in the soils, leaves, stems, and roots of the seedlings, respectively. The P content was the main factor affecting growth characteristics and contributed to 58.03% of the total variation in seedling growth characteristics (P < 0.01). The N:P ratio of CK in the soils, leaves, and stems were higher than that of all the fertilization treatments, indicating that the severely eroded and degraded region had little P and required much of P. The principal component analysis indicated that the F2S (1.89 + 1.01 g) was the optimum fertilization amount and method in this experiment. These results provide a theoretical basis for the fertilization management of P. massoniana forests with severely eroded and degraded red soil regions.


Phototherapy for neonatal jaundice: optimal wavelengths of light.
Phototherapy results in transformation of bilirubin to more water-soluble isomers. The efficacy of monochromatic visible light from 350 to 550 nm in the fastest photoisomerization reaction was quantitated by high-pressure liquid chromatography. The most effective wavelengths in vitro (i.e., leading to greater than 25% photoisomer) were in the blue spectrum from approximately 390 to 470 nm. Green light (530 nm) was not only ineffective for production of photoisomer, but capable of reversing the reaction. The results indicate that any clinically useful phototherapy unit must include the blue portion of the visible spectrum, and suggest that the effectiveness of phototherapy may be increased by elimination of green light.


Ochratoxin A exposure causes meiotic failure and oocyte deterioration in mice.
Ochratoxin A (OTA) is a mycotoxin produced by fungi and occurs naturally in various foodstuffs and some animal-derived products. This mycotoxin can cause deleterious effects on kidney, liver, central nervous, and immune system. However, potential mechanisms regarding how OTA disrupts the mammalian oocyte quality have not been clearly defined. In this study, we proved that OTA weakened oocyte quality by impairing oocyte meiotic maturation. We found that female mice treated with 1 mg/kg body weight OTA by intraperitoneal (IP) injection for 7 days displayed ovarian dysfunction and decreased offspring number. We also found that OTA treatment at 7.5 μM for 16 h decreased the rate of first polar body extrusion by disrupting spindle and chromosome alignment. In addition, OTA caused oxidative stress by inducing the accumulation of reactive oxygen species and consumption of antioxidants during meiosis, consequently resulting in oocytes apoptosis. Mitochondrial damage and insufficient energy supply were also observed in OTA-pretreated oocytes, which led to the meiotic failure of oocyte. Moreover, the epigenetic modifications were also affected, showing with altered 5 mC, 5hmC, H3K9ac, and H3K9me3 levels in mice oocytes. In summary, these results showed that OTA could decrease oocyte maturation and fertility by inducing oxidative stress and epigenetic changes.


Developing Professional Identity in Undergraduate Pharmacy Students: A Role for Self-Determination Theory.
Professional identity development, seen as essential in the transition from student to professional, needs to be owned by the universities in order to ensure a workforce appropriately prepared to provide global health care in the future. The development of professional identity involves a focus on who the student is becoming, as well as what they know or can do, and requires authentic learning experiences such as practice exposure and interaction with pharmacist role models. This article examines conceptual frameworks aligned with professional identity development and will explore the role for self-determination theory (SDT) in pharmacy professional education. SDT explains the concepts of competence, relatedness and autonomy and the part they play in producing highly motivated individuals, leading to the development of one's sense of self. Providing support for students in these three critical areas may, in accordance with the tenets of SDT, have the potential to increase motivation levels and their sense of professional identity.


Maintenance on extended-release naltrexone is associated with reduced injection opioid use among justice-involved persons with opioid use disorder.
Opioid use disorder (OUD) and injection drug use (IDU) place justice-involved individuals at increased risk for acquiring or transmitting HIV or hepatitis C virus (HCV). Methadone and buprenorphine have been associated with reduced opioid IDU; however, the effect of extended-release naltrexone (XR-NTX) on this behavior is incompletely studied. This study examined injection opioid use and shared injection equipment behavior from a completed double-blind placebo-controlled trial of XR-NTX among 88 justice-involved participants with HIV and OUD. Changes in participants' self-reported daily injection opioid use and shared injection equipment was evaluated pre-incarceration, during incarceration, and monthly post-release for 6 months. The study also assessed differences in time to first opioid injection post-release. The research team performed intention to treat and "as treated" (high treatment versus low treatment) analyses. Fifty-eight of 88 participants (69.5 %) endorsed IDU and 26 (29.5 %) reported sharing injection equipment in the 30 days pre-incarceration; 2 participants (2.2 %) reported IDU during incarceration; 19 (21.6 %) reported IDU one month post-release from prison or jail. Fifty-four (61.4 %) participants had an HIV RNA below 200 copies/mL and 62 (70.5 %) were baseline HCV antibody positive. The 6-month follow-up rate was 49.5 % and 50.5 % for those who received XR-NTX and placebo, respectively, which was not significantly different (p = 0.822). Participants in the XR-NTX and placebo groups had similar low mean opioid injection use post-release and time to first injection opioid use in the Intention-to-treat analysis. In the as-treated analysis, participants in the high treatment group had significantly lower mean proportion of days injecting opioids (13.8 % high treatment versus 22.8 % low treatment, p = 0.02) by month 1, which persisted up to 5 months post-release (0 % high treatment vs 24.3 % low treatment, p < 0.001) and experienced a longer time to first opioid injection post-release (143.8 days high treatment vs 67.4 days low treatment, p < 0.001). Injection opioid use was low during incarceration and remained low post-release in this justice-involved population. Retention on XR-NTX was associated with reduced intravenous opioid use, which has important implications for reducing transmission of HIV and HCV.


Low-frequency sheath instability in a non-Maxwellian plasma with energetic ions.
Spontaneous low-frequency oscillations have been observed in the circuit of a positively biased electrode when the ambient nonuniform plasma is irradiated by a microwave pulse of short duration, which is approximately equal to the ion-plasma period. The instability with its characteristic frequency below the ion-plasma frequency is driven by an accelerated ion component interacting with the sheath of the electrode. A qualitative model of the instability is suggested.


Changes in mouse mammary epithelial cell size during mammary gland development.
The average volume and size distribution of mouse mammary epithelial cells (MMEC) at different stages of functional activity of the mammary gland have been estimated. During early pregnancy, the mean MMEC volume begins to enlarge, resulting in a 21-fold cell volume increase by late lactation (Day 18). Progressive increases in mean MMEC volume during late pregnancy and throughout lactation result from the appearance and progressive hypertrophy of secretory alveolar cells. Involution of the mammary tissue brings about a precipitous decrease both in the average MMED volume and in the distribution of cell sizes established during the later phases of lactation. The progressive hypertrophy of cells particularly throughout the lactational period appear to correlate with previously reported changes in the metabolic activities of the mammary gland.


Stabilization of HIF-2α impacts pancreas growth.
Hypoxia inducible factors (HIFs) are critical regulators of the response to oxygen deficiency by activating target genes involved in a variety of biological functions. HIFs have been implicated in the pathophysiology of numerous pathologies including cancer. Patients with mutations in the von Hippel-Lindau (VHL) gene, an essential regulator of HIF activity, develop tumors in several organs including the pancreas. Previous functional studies of HIF activation in the pancreas have used Vhlh (the murine homolog of VHL) deficient mice. However, the role of each specific HIF transcription factors in the pancreas has not been thoroughly examined. We derived mice that constitutively express a normoxia-stable form of HIF2α in the pancreas. Activation of HIF2α in the pancreas severely impairs postnatal exocrine pancreas. Mice with pancreas-specific activation of HIF2α develop histological features reminiscent of pancreatitis including loss of acinar cells, ductal dilation and fibrosis. Moreover, we provide evidence that signaling pathways important for acinar cell homeostasis are altered in HIF2α-overexpressing pancreata.


Qualitative and quantitative analyses of stroke dynamics and microfluidics of phacoemulsification probes operating in different modes.
To compare phacoemulsification (phaco) tip movement, microfluidic dynamics, and tip-to-load interaction between longitudinal, torsional, and elliptical ultrasound (US) modalities. Phacodynamics Laboratory, Clínica Oftalmológica, Pasteur, Santiago, Chile. Experimental study. All experiments were performed using a fluid-filled optical test chamber and phaco tips that were US power activated. Tip movement was evaluated using stroke tracing and stroboscopy imaging techniques. Qualitative and quantitative assessments of microfluidic behavior were performed using bead seeding and high-speed shadowgraphy imaging combined with particle-image velocimetry and vector analysis. Material load interaction was measured using a rubber sphere that represented lens material. Longitudinal and torsional US tips showed precise forward-and-backward and side-to-side (lateral) movement, respectively. Elliptical US tips scribed a 2-dimensional ellipsoid path that slightly changed in shape and orientation plane at higher powers. Longitudinal and lateral components of tip motion were evident in elliptical mode. Regular fluid flow was observed with longitudinal mode (forward-directed flow away from the aspiration port) and torsional mode (steady backflow into the aspiration port). In elliptical mode, bead repulsion, erratic bursts of acoustic streaming, oblique backflow, and areas of multidirectional flow were observed. The longitudinal mode caused the material load to bounce against the tip, whereas the torsional mode maintained a consistent load attraction. In elliptical mode, the material load rotated slightly and bounced away from the tip in irregular intervals when attraction was achieved. Tip movement, microfluidic behavior, and material load interaction were related within but varied across US modalities. The elliptical mode showed a movement pattern with longitudinal and lateral components and irregular microfluidic behaviors. Dr. Zacharias received research funding from Alcon Laboratories, Inc. He has no financial or proprietary interest in any material or method mentioned.


Transpupillary thermotherapy (TTT) with short duration laser exposures induce heat shock protein (HSP) hyperexpression on choroidoretinal layers.
To assess a choroidal heat shock protein hyperexpression after transpupillary thermotherapy (TTT) performed with exposures shorter than 60 seconds. Nine male pigmented rabbits were anesthetized and TTT was performed on their right eye with a 810 nm diode laser (Iridis, Quantel-Medical (France)) (spot size: 1.3 mm). Three exposure durations (60, 30, or 15 seconds) were used with three ranges of power for each duration ("high," "mild," or "low"). A series of laser impacts was delivered to the posterior pole of the retina. Left eyes were used as controls. Twenty-four hours after laser irradiation, the animals were killed and histological study was performed on chorioretinal layers. Tissue samples were fixed in formalin and embedded in paraffin. A monoclonal antibody was used to detect Hsp70 immunoreactivity (mouse IgGl, SPA-810, Stress Gen, Victoria, BC, Canada), followed by a biotinylated goat anti-mouse antibody (Dako, Glostrup, Denmark), revealed by the avidin-biotin complex (Vectastain kit, Vector Laboratries, Burlingame, CA, USA) and the AEC chromogen. Retinal structures were further identified by HES coloration. During the experiments, the laser spots were not visible except for the strongest "high" powers for each exposure duration, where a whitening was discernable at the end of the laser exposures. A strong HSP70 immunoreactivity was detected in choroidal, non-pigmented cells for laser exposures lasting 60, 30, or 15 seconds with "mild" laser powers. On the contrary, rare HSP hyperexpression was detected with "high" or "low" laser powers lasting 60, 30, or 15 seconds. No HSP-70 immunoreactivity was detected on control eyes nor outside of the irradiated zones of treated eyes. Transpupillary laser irradiation lasting 15, 30, or 60 seconds induces an hyperexpression of HSP on choroidal layers. This could be a basis for the use of TTT with "short" laser exposures.


Formulation of mayonnaise with the addition of a bioemulsifier isolated from Candida utilis.
Biosurfactants have a number of industrial applications due their diverse properties, such as emulsification, foaming, wetting, and surface activity. The aim of the present study was to produce a biosurfactant from Candida utilis and employ it in the formulation of a mayonnaise. The biosurfactant was produced in a mineral medium supplemented with glucose and canola waste frying oil at 150 rpm for 88 h. The product was biologically tested on rats and in different formulations of mayonnaise, which were submitted to microbiological evaluations. The biosurfactant was added to the diet of the rats for 21 days. Greater consumption was found of the experimental diet. Moreover, no changes were found in the liver or kidneys of the animals, demonstrating the absence of a toxic effect from the biosurfactant. Six different formulations of mayonnaise were prepared and tested regarding stability with the addition of carboxymethyl cellulose and guar gum (combined and isolated) after 30 days of refrigeration. The most stable formulation with the best quality was obtained with combination of guar gum and the isolated biosurfactant, with an absence of pathogenic microorganisms. In conclusion, the potential and innocuousness of the biosurfactant isolated from C. utilis indicates its safe use in food emulsions.


Distribution, source, and contamination assessment of heavy metals in surface sediments of the Zhifu Bay in northern China.
In this study, 30 surface sediment samples were collected from Zhifu Bay in northern China and analyzed for heavy metals; in addition, their concentrations and pollution status were evaluated. The distributions of Cu and Zn were similar and mainly dominated by fine-grained sediments, whereas the other heavy metal distributions were not very regular. Al was positively correlated with Cu and Zn, and weakly correlated with Pb, As, and Hg. Except for some stations that showed minor enrichment and were unpolluted to moderately polluted by Cr, Cd, and Hg, the overall quality of sediments in the study area was good. Three principal components with eigenvalues >1 were estimated, accounting for 72.06 % of the total variability and representing natural sources, natural and anthropogenic, and anthropogenic sources, respectively.


The effects of dietary and physical activity interventions on tinnitus symptoms: An RCT.
Subjective tinnitus is defined as the perception of irregular sound at different frequencies. Although the underlying cause of tinnitus is unclear, increased body weight is known to increase tinnitus symptoms. The present study aimed to determine the effects of dietary and physical activity interventions on tinnitus symptoms. Sixty-three obese subjects with tinnitus aged 20 to 65 years were divided into diet + physical activity (P.A.) (n = 15), diet (n = 16), P.A. (n = 15), and control (n = 17) groups. Dietary records, anthropometric measurements, Tinnitus Handicap Inventory (THI), Beck Depression Inventory (BDI), Short-Form Health Survey (SF-36), and Visual Analogue Scale (VAS) of all individuals were recorded and compared at the baseline and at study completion. Body weight decreased in the diet + P.A. (-5.9 (3.5) kg), diet (-3.4 (0.9) kg), and P.A. (-2.0 (2.1) kg) groups compared to the baseline (p < 0.05). There was a more significant decrease in tinnitus frequency, tinnitus severity, and VAS scores in individuals with a weight loss of ≥ 5.0% than in those with < 5.0% (p < 0.05). A decrease of 1 kg/m2 in BMI decreased the BDI score by 0.485 units and the THI score by 0.523 units. Step counts were increased in the diet + P.A. (3562.3±739.9) and P.A. (3797.1 ± 1801.1) groups compared to baseline (p < 0.01). Each increase of 1000 steps increased the SF-36 score by 1.592 units and decreased the THI score by 0.750 units (p < 0.05). Dietary and physical activity interventions, alone or in combination, alleviated tinnitus symptoms and increased quality of life in individuals with tinnitus. Due to its contribution to obesity prevention and positive effects on tinnitus, organizing dietary and physical activity programs for obese individuals with tinnitus would improve these individuals' quality of life.


The effects of a seatbelt-gearshift delay prompt on the seatbelt use of motorists who do not regularly wear seatbelts.
A seatbelt-gearshift delay was evaluated in two U.S. and three Canadian vehicles using a reversal design. The seatbelt-gearshift delay required unbelted drivers either to buckle their seatbelts or to wait a specified time before they could put the vehicle in gear. After collecting behavioral prebaseline data, a data logger was installed in all five vehicles to collect automated data on seatbelt use. Next the seatbelt-gearshift delay was introduced. The results showed that the delay increased all 5 drivers' seatbelt use, and that the duration of the delay that produced relatively consistent seatbelt use varied across drivers from 5 to 20 s. When the device was deactivated in four of the five vehicles, behavior returned to baseline levels.


Mucosal tolerance to E-selectin provides protection against cerebral ischemia-reperfusion injury in rats.
To study the effect of mucosal toleration to E-selectin on cerebral ischemia-reperfusion injury in rats and associated mechanisms. Rats were exposed to intranasal administration of E-selectin or PBS every other day for 10 days (single-tolerization group) or on two tolerization schedules separated by 11 days (booster-tolerization group). Control group received middle cerebral artery occlusion (MCAO) only. MCAO was performed 48 h after the last dose of E-selectin or PBS. After 2 h ischemia and 22 h reperfusion, the rats were killed. We examined the regional cerebral blood flow, neurological testing, frequencies of CD4+ T and CD8+ T lymphocytes in blood, plasma SOD activity, infarct volumes, and mRNA expressions of IL-10, TGF-beta(1), E-selectin, ICAM-1 and LFA-1 in the ischemic brain tissues. There were 30.25% (P<0.05) decreases of infarction volumes in the E-selectin booster group accompanied by decreased neurological deficit scores compared with PBS group. Compared with PBS-treated rats, CD8-positive cells were significantly decreased (27.4%, P<0.05), CD4-positive cells tended to increase (P>0.05), SOD activity was obviously increased (P<0.05), mRNA levels of IL-10 were markedly increased (21.0%, P<0.05) and TGF-beta(1) showed an upward trend (6.2%, P>0.05), mRNA levels of E-selectin were prominently decreased (28.7%, P<0.01) and ICAM-1 and LFA-1 had downward trends (P>0.05) in E-selectin booster animals. Mucosal tolerance to E-selectin after booster tolerization could relieve cerebral ischemia-reperfusion injury and induce ischemia tolerance in Wistar rats. The mechanisms may involve decreased frequencies of CD8+ T cells in blood, increased plasma SOD activity, heightened mRNA expression of IL-10 and lowered mRNA expression of E-selectin in the ischemic hemisphere.


The endoscopic retrograde cholangiogram and pancreatogram in chronic liver disease.
The endoscopic retrograde cholangiogram and pancreatogram of 22 patients with primary biliary cirrhosis, 33 patients with other forms of chronic liver disease and 28 'normal' controls were compared. The incidence of radiological intrahepatic duct abnormality is similar in patients with primary biliary cirrhosis and in other forms of liver disease, but is present in only a minority of both groups. A 'notch' or smooth indentation on the extrahepatic bile ducts at the porta hepatis was present in 58% of patients with primary biliary cirrhosis but in none in either of the other two groups. Three out of seven patients with sclerosing cholangitis showed minimal-change pancreatitis. Pancreatic abnormalities were otherwise infrequent.


Identification and characterization of a novel AA9-type lytic polysaccharide monooxygenase from a bagasse metagenome.
Lytic polysaccharide monooxygenases (LPMOs) are auxiliary enzymes catalyzing oxidative cleavages of cellulose chains in crystalline regions, resulting in their increasing accessibility to the hydrolytic enzyme counterparts and hence higher released sugars from biomass saccharification. In this study, a novel auxiliary protein family 9 LPMO (BgAA9) was identified from a metagenomic library derived from a thermophilic microbial community in bagasse collection site where diverse AA9 and AA10 putative sequences were annotated. The enzyme showed highest similarity to a glycoside hydrolase family 61 from Chaetomium thermophilum. Recombinant BgAA9 expressed in Pichia pastoris cleaved cellohexaose (DP6) into shorter cellooligosaccharides (DP2, DP3, and DP4). Supplementation BgAA9 to a commercial cellulase, Accellerase® 1500 showed strong synergistic effect on saccharification of Avicel® PH101, decrystallized cellulose, filter paper, and alkaline-pretreated sugarcane bagasse, resulting in 63-93% increase in the total reducing sugar yield after incubation at 50 °C for 72 h. Strong synergism was shown between BgAA9 and the cellulase with the highest total fermentable sugar yield obtained from 75:25% of Accellerase®1500:BgAA9 which released 39 mg glucose/FPU (filter paper unit) equivalent to 38.7% higher than Accellerase®1500 alone at the same total protein dosage of 5 mg/g substrate according to the mixture design study. The enzyme represented the first characterized LPMO from environmental metagenome and a potent auxiliary component for biomass saccharification. KEY POINTS: • BgAA9 represents the first characterized LPMO from metagenome. • 12 AA families were annotated in thermophilic bagasse fosmid library by NGS. • BgAA9 showed homology to Cel61 in Chaetomium thermophilum. • BgAA9 oxidized cellohexaose and PASC to DP2, DP4, and DP6. • BgAA9 showed strong synergism to Accellerase on bagasse hydrolysis.


Knee acoustic emissions as a noninvasive biomarker of articular health in patients with juvenile idiopathic arthritis: a clinical validation in an extended study population.
Joint acoustic emissions from knees have been evaluated as a convenient, non-invasive digital biomarker of inflammatory knee involvement in a small cohort of children with Juvenile Idiopathic Arthritis (JIA). The objective of the present study was to validate this in a larger cohort. A total of 116 subjects (86 JIA and 30 healthy controls) participated in this study. Of the 86 subjects with JIA, 43 subjects had active knee involvement at the time of study. Joint acoustic emissions were bilaterally recorded, and corresponding signal features were used to train a machine learning algorithm (XGBoost) to classify JIA and healthy knees. All active JIA knees and 80% of the controls were used as training data set, while the remaining knees were used as testing data set. Leave-one-leg-out cross-validation was used for validation on the training data set. Validation on the training and testing set of the classifier resulted in an accuracy of 81.1% and 87.7% respectively. Sensitivity / specificity for the training and testing validation was 88.6% / 72.3% and 88.1% / 83.3%, respectively. The area under the curve of the receiver operating characteristic curve was 0.81 for the developed classifier. The distributions of the joint scores of the active and inactive knees were significantly different. Joint acoustic emissions can serve as an inexpensive and easy-to-use digital biomarker to distinguish JIA from healthy controls. Utilizing serial joint acoustic emission recordings can potentially help monitor disease activity in JIA affected joints to enable timely changes in therapy.


Identification of a protein Ser/Thr kinase cascade that regulates essential transcriptional activators in Myxococcus xanthus development.
Pkn8 is a membrane-associated protein Ser/Thr kinase (PSTK) of Myxoccocus xanthus that was previously found to associate with a novel cytoplasmic kinase, Pkn14. In the present study, MrpC, an essential transcription factor for fruA expression during fruiting body development, was identified using a genomic yeast two-hybrid screen with Pkn14 as bait. Our biochemical studies demonstrated that purified Pkn8 and Pkn14 are active kinases and that Pkn8 is able to phosphorylate Pkn14 that forms a tetramer via its C-terminal 41 residues. Moreover, Pkn14 phosphorylated purified MrpC, indicating that Pkn8 is a Pkn14 kinase and Pkn14 is an MrpC kinase. The pkn8 and pkn14 deletion strains (Deltapkn8 and Deltapkn14) developed into fruiting bodies significantly faster than that of the parent strain, DZF1. While mrpC expression was at a low level in DZF1 during vegetative growth, it was highly elevated in Deltapkn8 and Deltapkn14 during vegetative growth and development. Furthermore, FruA, usually induced at 6 h of development, was instead detected at the early stationary phase and accumulated faster during development in Deltapkn8 and Deltapkn14. Therefore, the developmental phenotype of Deltapkn8 and Deltapkn14 seems to be due to untimely FruA production mediated by elevated levels of MrpC in Deltapkn8 and Deltapkn14 during vegetative growth. As pkn14 expression was increased at the mid- and late-log. phases in DZF1 but decreased during development, the Pkn8-Pkn14 kinase cascade appears to negatively regulate mrpC expression by phosphorylating MrpC during vegetative growth. This is the first demonstration of a functional PSTK cascade in prokaryotes. mrpC expression has been proposed to be activated by MrpA and MrpB which belong to a two-component His-Asp phosphorelay signal transduction system and that MrpC autoregulate its own expression (Sun H. and Shi W., 2001 J Bacteriol 183: 4786-4795). Therefore, M. xanthus seems to utilize both eukaryotic PSTK cascade and prokaryotic His-Asp phosphorelay system to precisely regulate mrpC expression with specific timing during development.


Treatment of schistosome-induced glomerulonephritis. A case report and review of the literature.
A patient with membranoproliferative glomerulonephritis and renal dysfunction caused by Schistosoma mansoni was treated with oxamniquine. High levels of circulating immuno-complexes returned to normal following treatment, although renal function for the long term was unchanged. Specific antischistosomal therapy may be of partial benefit to patients with this disease.