[Determinants of Setting up a General Practice - a Qualitative Study].
In recent years, the motivation of the new generation of general practitioners to set up their own practice is decreasing. Knowledge of factors that promote and inhibit the process of setting up a practice can enable developing strategies to support this process. The aim of this study was to explore these determinants. Between April and October 2016, self-employed general practitioners from Baden-Württemberg were invited to participate in a qualitative interview study. Stratification of 553 physicians, who participated in a general practice support program between 2008 and 2011 and set up a practice in 2008 to 2014, was based on the agglomeration in rural areas, the peripheral zones around the agglomeration and the urban agglomerations themselves. The transcripts of the interviews were analyzed by two authors with the content analysis according to Mayring and summarized. In a second step, a consensus version was elaborated. A total of 23 general practitioners were recruited, 57% female and 42 years on average, and mostly working in group practices. The main motivation to set up a practice was the desire to improve the situation in relation to the daily clinical routine. These included a lower duty load and more family-friendly working hours. Relevant supportive factors during setting up a practice were family support, participation in a postgraduate training rotation network program and professional counseling. Inhibiting factors were fears of recourse and indebtedness, a complicated accounting system and a bureaucratic process of admission. On the one hand, the study shows that the many advantages of working as a general practitioner, such as its being family friendly, need to be better communicated to the doctors and their financial concerns alleviated. On the other hand, the need for courses on management of one's practice has also become clear. A standardized and optimized process of setting up a practice with an improved overview and a collegial contact person can facilitate the decision for and implementing the setting up a medical practice as a general practitioner.


Localization based on DEM matching using multiple aerial image pairs.
This paper proposes the localization algorithm that estimates translation parameters of an aircraft by comparing the sampled elevation map recovered from aerial sequence images, and the digital elevation model (DEM) with the given orientation and altitude parameters obtained from a gyroscope. It consists of two stages: recovering the sampled elevation map from multiple aerial image pairs and matching of the relative recovered elevation map (REM) with the relative DEM. Computer simulations with three real aerial image sequences show the effectiveness of the proposed algorithm.


Characterization of alpha-enolase as an interferon-alpha 2 alpha 1 regulated gene.
Interferons (IFNs) are multifunctional cytokines that after binding to the cell surface receptor induce the expression of a large number of genes, which in turn, mediate many biological processes including host defense, cell growth control, signaling, and metabolism. Here we show that IFN-alpha activates the mitogen-activated protein kinases (MAPK) ERK1/2 and the transcription factor CREB/ATF-1, which lead to the alpha-enolase (alpha-ENO) gene expression in fibroblasts. Alpha-ENO mRNA accumulation was apparent 6 h post-IFN stimulation and required both de novo protein synthesis and active gene transcription, which is typical of a secondary response gene. Alpha-ENO expression does not appear to be restricted to fibroblasts, since it was equally verified in peripheral blood mononuclear cells (PBMC). Furthermore, IFN-alpha stimulates the expression of the primary response genes c-fos and egr-1, which was followed by an increase in DNA binding activity of c-FOS and EGR-1 proteins, as verified by shift assays using the cis-acting elements AP-1 and EGR-1 localized at the alpha-ENO promoter. Finally, we also demonstrated that IFN treatment of PBMC cause an increase in both, alpha-ENO expression on the cell surface and plasmin generation followed addition of exogenous plasminogen.


Three steps to breaking immune tolerance to lymphoma: a microparticle approach.
In situ immunization aims at generating antitumor immune responses through manipulating the tumor microenvironment. On the basis of recent advances in the understanding of antitumor immunity, we designed a three-step approach to in situ immunization to lymphoma: (i) inducing immunogenic tumor cell death with the chemotherapeutic drug doxorubicin. Doxorubicin enhances the expression of "eat-me" signals by dying tumor cells, facilitating their phagocytosis by dendritic cells (DC). Because of the vesicant activity of doxorubicin, microparticles made of biodegradable polymer poly(lactide-co-glycolide) or PLGA can safely deliver doxorubicin intratumorally and are effective vaccine adjuvants, (ii) enhancing T-cell activation using anti-OX40 and (iii) sustaining T-cell responses by checkpoint blockade using anti-CTLA-4. In vitro, doxorubicin microparticles were less cytotoxic to DCs than to B lymphoma cells, did not require internalization by tumor cells, and significantly enhanced phagocytosis of tumor cells by DCs as compared with soluble doxorubicin. In mice, this three-step therapy induced CD4- and CD8-dependent systemic immune responses that enhanced T-cell infiltration into distant tumors, leading to their eradication and significantly improving survival. Our findings demonstrate that systemic antitumor immune responses can be generated locally by three-step therapy and merit further investigation as an immunotherapy for patients with lymphoma.


Indocyanine green-enhanced imaging of antigen-induced arthritis with an integrated optical imaging/radiography system.
To evaluate a combined indocyanine green-enhanced optical imaging/radiography system for the detection of arthritic joints in a rat model of antigen-induced arthritis. Arthritis of the knee and ankle joints was induced in 6 Harlan rats, using peptidoglycan-polysaccharide polymers. Three rats served as untreated controls. Optical imaging of the knee and ankle joints was done with an integrated optical imaging/radiography system before and up to 24 hours following intravenous injection of 10 mg/kg indocyanine green. The fluorescence signal intensities of arthritic and normal joints were compared for significant differences, using generalized estimating equation models. Specimens of knee and ankle joints were further processed and evaluated by histology. Immediately after administration, indocyanine green provided a significant increase in the fluorescence signal of arthritic joints compared with baseline values (P < 0.05). The fluorescence signal of arthritic joints was significantly higher compared with that of nonarthritic control joints at 1-720 minutes after intravenous injection (P < 0.05). Fusion of indocyanine green-enhanced optical imaging and radiography allowed for anatomic coregistration of the inflamed tissue with the associated joint. Hematoxylin and eosin staining confirmed marked synovial inflammation of arthritic joints and the absence of inflammation in control joints. Indocyanine green-enhanced optical imaging is a clinically applicable tool for detection of arthritic tissue. Using relatively high doses of indocyanine green, long-term enhanced fluorescence of arthritic joints can be achieved. This may facilitate simultaneous evaluations of multiple joints in a clinical setting. Fusion of indocyanine green-enhanced optical imaging scans with radiography increases anatomic resolution.


Therapeutic efficacy of antiglioma mesenchymal extracellular matrix 131I-radiolabeled murine monoclonal antibody in a human glioma xenograft model.
The development of Mabs, particularly those reactive with primary brain tumors but not with normal brain, provides a potential means of delivering therapeutic agents selectively to human malignant gliomas. Mab 81C6, an IgG2b immunoglobulin, which defines an epitope of the glioma-associated extracellular matrix protein tenascin, has been shown to bind to human glioma cell lines, glioma xenografts in nude mice, and primary human gliomas, but not to normal adult or fetal brain. To test the therapeutic potential of this Mab for targeted delivery of isotopes, nude mice bearing progressively growing s.c. xenografts of D-54 MG, a human glioma cell line, were given injections via the tail vein of either buffer, unlabeled 81C6, 131I-labeled 81C6, or 131I-labeled 45.6, a nonspecific control Mab of the same isotype. Specific activities of the Mab range from 6.0 to 15.5 mCi/mg with protein doses from 7.6 to 167 micrograms. The doses given by injection per animal for labeled 81C6 were 50, 250, 500, and 1000 mu Ci and 500 and 1000 mu Ci for 45.6. Tumor response was measured by growth delay in reaching 1000 or 5000 mm3 tumor volumes using the Wilcoxon rank sum test, and by comparing the proportion of tumors that had regression in volume after treatment using the Fisher exact test. Statistically significant growth delays at 1000 mm3 were noted in 1 of 3 experiments with 500 mu Ci 81C6 (P less than 0.001) and 2 of 3 for 1000 mu Ci 81C6 (P = 0.001 and less than 0.001). At 5000 mm3, statistically significant growth delays were seen with radiolabeled 81C6 in 2 of 2 experiments at 250 mu Ci (P = 0.01 and 0.02), 4 of 4 at 500 mu Ci (P = 0.03-less than 0.001), and 2 of 2 at 1000 mu Ci (P = less than or equal to 0.001) and with radiolabeled 45.6 in 1 of 1 at 1000 mu Ci (P = 0.01). The percentage of animals with tumor regression progressively increased with increasing doses of isotope. For radiolabeled 45.6, there were 0 of 10 regressors at 500 and 1 of 10 at 1000 mu Ci. For radiolabeled 81C6, there were 0 of 6 regressors at 50 mu Ci, 1 of 16 (6%) at 250 mu Ci, 7 of 38 (18%) at 500, and 15 of 28 (54%) at 1000 mu Ci. Statistically significant tumor regression was seen only at doses of 500 and 1000 mu Ci of 131I-81C6.(ABSTRACT TRUNCATED AT 400 WORDS)


Effects of Inhibition of miR-155-5p in Neural Stem Cell Subarachnoid Transplant on Rats with Cerebral Infarction.
Cerebral infarction is a leading cause of death, which calls for effective prevention and treatment. Transplant of neural stem cells (NSCs) is a potential therapeutic treatment to cerebral infarction although its efficacy still needs to be improved. Overexpression of hypoxia-inducible factor 1α (HIF-1α) has been shown to enhance the protective effects of stem cell transplant on cerebral infarction. The expression of HIF-1α is predicted to be regulated by miR-155-5p. Therefore, we regulated the expression of miR-155-5p in NSCs and evaluated the effects of miR-155-5p-regulated NSC transplant on cerebral infarction. We inhibited miR-155-5p expression in NSCs by overexpressing miR-155-5p inhibitor. HIF-1α expression, cell viability, and the expression of apoptosis markers were examined. We established the middle cerebral artery occlusion (MCAO) rat model, and the infarct volume, neurobehavioral outcomes, inflammation, and oxidative stress were evaluated after NSC transplant. miR-155-5p directly targeted HIF-1α and negatively regulated its expression. Inhibition of miR-155-5p enhanced cell viability and prevented cell apoptosis. Transplant of miR-155-5p-inhibited NSCs significantly decreased infarct volume and improved neurobehavioral outcomes of MCAO rats. Transplant of miR-155-5p-inhibited NSCs significantly inhibited inflammation and oxidative stress. Inhibition of miR-155-5p in NSCs resulted in enhanced protection against cerebral infarction after NSC transplant.


Differential acuity of the two eyes and the problem of ocular dominances.
While it has long been thought that no relationship exists between the eye of greater visual acuity and the eye favored in sighting, the data collected suggest the need for a re-examination of this issue. Sighting-dominance and acuity-dominance were associated. In addition, most individuals tested showed acuity-dominance of the left eye.


Desmosome disassembly in response to pemphigus vulgaris IgG occurs in distinct phases and can be reversed by expression of exogenous Dsg3.
Pemphigus vulgaris (PV) is an epidermal blistering disorder caused by antibodies directed against the desmosomal cadherin desmoglein-3 (Dsg3). The mechanism by which PV IgG disrupts adhesion is not fully understood. To address this issue, primary human keratinocytes (KCs) and patient IgG were used to define the morphological, biochemical, and functional changes triggered by PV IgG. Three phases of desmosome disassembly were distinguished. Analysis of fixed and living KCs demonstrated that PV IgG cause rapid Dsg3 internalization, which likely originates from a non-junctional pool of Dsg3. Subsequently, Dsg3 and other desmosomal components rearrange into linear arrays that run perpendicular to cell contacts. Dsg3 complexes localized at the cell surface are transported in a retrograde manner along with these arrays before being released into cytoplasmic vesicular compartments. These changes in Dsg3 distribution are followed by depletion of detergent-insoluble Dsg3 pools and by the loss of cell adhesion strength. Importantly, this process of disassembly can be prevented by expressing exogenous Dsg3, thereby driving Dsg3 biosynthesis and desmosome assembly. These data support a model in which PV IgG cause the loss of cell adhesion by altering the dynamics of Dsg3 assembly into desmosomes and the turnover of cell surface pools of Dsg3 through endocytic pathways.


Comments on duck circovirus (DuCV) genotype definition.
A standardised methodology has been used to define genotypes based on pairwise sequence comparisons (PASC). PASC is a widely accepted method in virus taxonomy, which is based on the histogram of pairwised differences among sequences. Recently, Zhang et al. (2013) concluded that the average p-distance of duck circovirus (DuCV) between genotypes 1 and 2 was 0.170, and subtype distance thresholds were 0.032 in DuCV-1 and 0.018 in DuCV-2, respectively. However, there might be some concerns on the methodology application to define the genotype of DuCV. Taking into account the concerns mentioned above, our authors conducted the PASC analyses of 54 capsid gene (ORF2) and genomic sequences including all the sequences from Zhang et al. (2013). Our results confirmed the existence of two DuCV genotypes (1 and 2) and, we suggest that DuCV ORF2 and genomic distance genotype thresholds were 0.061 and 0.038, respectively.


[Endovascular prosthetic repair of abdominal aortic aneurysm. Part 1--selection of patients for endovascular treatment].
The work was aimed at choosing the criteria for selection of patients to undergo endovascular prosthetic repair of the abdominal aorta in aneurysms of the aorta and iliac arteries with due regard for the anatomical characteristics. According to the described methodology of assessing the technical success and the risk degree of the endovascular intervention we carried out a retrospective analysis of the findings of computed tomography in a total of 141 patients. Of these, the overwhelming majority--122 subjects were men over 65 years old. The total number of patients with anatomical parameters unfavourable for endovascular treatment amounted to 42 patients (29.8%). In forty (39.6%) from 101 patients endovascular intervention was possible only with occlusion of visceral iliac arteries.


Different Clinical Characteristics Between Distal Cholangiocarcinoma and Pancreatic Head Carcinoma With Biliary Obstruction.
The aim of this study was to compare the perioperative clinical characteristics between patients with distal cholangiocarcinoma (DCC) and pancreatic head carcinoma (PHC) with biliary obstruction. This study included patients who underwent pancreatoduodenectomy and were diagnosed with DCC (n = 85) or PHC (n = 90) by final pathological examination. Perioperative clinical characteristics were compared for patients with DCC versus PHC with biliary obstruction. Median coronal thickness of the pancreatic neck was significantly greater, whereas the main pancreatic duct diameter was significantly smaller in patients with DCC than patients with PHC. Most patients with DCC (95%) had a soft pancreas, whereas only 29% of patients with PHC had. The incidence rates of overall morbidity, infectious complications, and pancreatic fistula were significantly higher in patients with DCC than those in patients with PHC. Eleven DCC patients (12%) were preoperatively misdiagnosed with PHC. Among them, intraductal ultrasonography of the bile duct was performed in 7 patients, and the presence of PHC was suspected in 3 of these patients because intraductal ultrasonography detected a small intrapancreatic mass. This study clearly showed different perioperative characteristics between patients with DCC and PHC. It is not uncommon to misdiagnose PHC as DCC. Intraductal ultrasonography may be helpful in differentiating DCC and PHC.


Randomized controlled trials in pediatric surgery: could we do better?
Randomized controlled trials (RCTs) are accepted as the gold standard for assessing the effectiveness of clinical interventions but are rarely reported in pediatric surgery. Have RCTs submitted to the British Association of Paediatric Surgeons (BAPS) Annual Congress during the last 5 years been adequately designed and large enough to produce a valid result? Abstracts accepted by the Annual BAPS Congress meetings between 1996 and 2000 were examined in collaboration with a senior health services researcher. The quality of the design, methodology, statistical analysis and conclusions, and the adequacy of the sample size were assessed for all identifiable clinical RCTs. From 760 accepted abstracts, there were only 9 RCTs (1%) of clinical interventions. In only 4 trials was the relevant primary end-point specified at the outset of the study, and none documented the method of randomization. Only one abstract mentioned blinding with respect to the intervention or outcome measure. Sample sizes were inadequate to detect even large clinical differences. To date, only one of these RCTs has been published in an English-language, peer-reviewed journal. Clear guidelines exist for the conduct of RCTs, yet compliance with these standards was rarely documented in abstracts of pediatric surgical RCTs presented at BAPS. Sample sizes were inadequate. RCTs in pediatric surgery are difficult to perform, but the specialty would benefit from well-designed, carefully conducted, multicentre, clinical RCTs to advance evidence-based practice.


Metabonomics study on the effects of the ginsenoside Rg3 in a beta-cyclodextrin-based formulation on tumor-bearing rats by a fully automatic hydrophilic interaction/reversed-phase column-switching HPLC-ESI-MS approach.
The goal of this study was the application of a novel, fully automatic column-switching approach in a metabonomics study combining the orthogonal selectivities of hydrophilic interaction chromatography (HILIC) and reversed-phase chromatography. The temporal, pharmacodynamic effects of the ginsenoside Rg3 on the metabonome in urine of healthy and liver-tumor-bearing rats have been investigated. Within a total analysis time of 52 min we detected 5686 polar, and on the second column an additional 1808 apolar, urinary metabolite ions. The administration of a single, high dose of Rg3 in a beta-cyclodextrin-based formulation led to a considerable change of the metabolic pattern in cancer rats during 3 days studied. Seventeen biomarker candidates including three apolar metabolites, which were not retained on the HILIC column, were detected. Overall, the results suggest that the developed liquid chromatography-mass spectrometry strategy is a promising tool in metabonomics studies for global analysis of highly complex biosamples. It may not only increase the number of discovered biomarkers but consequently improve the comprehensive information on metabolic changes in a fully automatic manner.


Hypothalamo-pituitary-adrenal axis activity predicts disease progression in multiple sclerosis.
Clinical studies have shown that groups of multiple sclerosis (MS) patients exhibit a chronically activated hypothalamo-pituitary-adrenal (HPA) axis. However, the association of HPA axis activity and disease progression in MS is unknown. In this longitudinal study over a 3-year follow-up period, we report that patients who exhibited stronger HPA reactivity at baseline were significantly more likely to experience progression as measured by the Expanded Disability Status Scale (EDSS) during the follow-up period. Furthermore, HPA axis activity correlated with progression ratings and cognitive impairment three years later. Tests of HPA axis activity may be useful biomarkers for disease progression in MS.


Tracheobronchopulmonary carcinoid tumors: analysis of 40 patients.
Carcinoid tumors are a type of neuroendocrine tumors which usually involve the upper airways and the patients most often complain of cough and hemoptysis. This study was performed from 1990 through 2007 on 40 patients with carcinoid tumor who had been followed up for at least 3 years. The statistical analysis were based on tumor epidemiology, treatment and the 3-year survival. The factors influencing the survival were analyzed using SPSS and exact Fisher test. M/F was 16/24 with mean age 34 years. Their most common symptoms were coughing (90%) . The left main bronchus was the most common site of involvement (25%). 95% of all the cases underwent surgery and 5% of the patients underwent chemoradiotherapy due to distant metastasis . The most common surgical procedure was lobectomy or biloectomy (57.8%). Bronchial sleeve resection was performed on 10.4% of the patients. The most common pathology was the typical form (90%) and 5% of the madiastinal lymph nodes were involvd all of the atypical type. Carcinoid syndrome was seen in one patient (2.5%) and post operative adjuvant treatment was done in 5% of the patients after surgery because of mediastinal lymph node involvement. Post operative recurrence occurred in one patient (2.6%) of the atypical form with mediastinal lymph nodes involvement. The most common complication of surgery was a long- term air leakage (10.4%) and the surgical death rate was 0%. 3-year survival was 92.5%. The factors influencing the survival included the pathological type, distant metastasis and mediastinal lymph node involvement. Carcinoid tumors have mostly been responsive to surgical intervention, resulting in a long term survival.


Trichome dynamics and artemisinin accumulation during development and senescence of Artemisia annua leaves.
Artemisinin is a sesquiterpene lactone endoperoxide and an important antimalarial drug produced in Artemisia annua. To unravel the diverse processes determining artemisinin yield in A. annua crops, artemisinin accumulation during the development of individual leaves was studied in two field experiments. During the life cycle of a leaf, artemisinin was always present. Quantities were low at leaf appearance and increased steadily. In leaves studied until after senescence, maximum quantities and concentrations were achieved after the leaf had turned brown. The total quantity of possible artemisinin precursors per leaf (dihydroartemisinic acid and other upstream precursors) was highest early in the leaf cycle when the leaf was still expanding. Dihydroartemisinic acid was more abundant than the other compounds and its quantity declined during leaf development whereas that of artemisinin increased. Dihydroartemisinic acid was not converted directly into artemisinin, because on a per leaf basis the decline in molar quantity of precursors in the earliest formed leaves was not compensated for by a simultaneous increase in artemisinin. Our results suggest that a (putative) intermediate such as dihydroartemisinic acid hydroperoxide temporarily may have accumulated in considerable quantities. The number of mature, capitate trichomes on the adaxial leaf side increased after leaf appearance until the end of leaf expansion, and then decreased, probably due to collapse of trichomes. Artemisinin production thus (also) occurred when trichomes were collapsing. Later formed leaves achieved higher concentrations of artemisinin than earlier formed leaves, because of a higher trichome density and a higher capacity per trichome.


New test for the diagnosis of bacterial endophthalmitis.
Diagnosis of bacterial endophthalmitis (BE) often fails due to: (1) insufficient volumes of vitreous fluid (VF) and aqueous humour (AH); (2) lack of sensitivity of culture; (3) antibiotic treatments; (4) polymerase chain reaction (PCR) cross-contamination; and (5) limitations on the interpretation of the real-time PCR melting curve. We developed a fast real-time (f-real-t) PCR to improve the performance of the laboratory diagnosis of BE. The following samples were processed after adding an internal control: phosphate buffered saline (PBS); VF, AH and cell suspensions spiked with Bacteria (Bac); VF and AH from patients with endophthalmitis; and VF and AH from non-infective patients. DNA was extracted (MagNA Pure) and added to four tubes containing selected primers and probes for the identification and quantification of all Bac and eight genera by f-real-t PCR. Diagnostic performances based on direct microscopic examination, culture and f-real-t PCR were compared. The f-real-t PCR detected at least 0.01 colony-forming units (CFU) of Bac/microl with no cross-reactivity with fungi. Correlation with culture-positive results was 100%. Sixty per cent of BE samples tested culture-positive, but f-real-t PCR tested positive for 90%. Samples from non-infective cases were negative. The f-real-t PCR detected and quantified Bac, Staphylococci, Streptococci, Haemophilus, Pseudomonas, Enterobacteria, Acinetobacter, Propionibacteriacae and Corynebacteria in one run. Cultures required several hours to days (with a non-negligible number of false-negative results) and the f-real-t PCR was completed in 90 min. The f-real-t PCR is presented as a new tool for the diagnosis of BE: its usefulness requires validation with larger series of samples.


Modeling Cytostatic and Cytotoxic Responses to New Treatment Regimens for Ovarian Cancer.
The margin for optimizing polychemotherapy is wide, but a quantitative comparison of current and new protocols is rare even in preclinical settings. In silico reconstruction of the proliferation process and the main perturbations induced by treatment provides insight into the complexity of drug response and grounds for a more objective rationale to treatment schemes. We analyzed 12 treatment groups in trial on an ovarian cancer xenograft, reproducing current therapeutic options for this cancer including one-, two-, and three-drug schemes of cisplatin (DDP), bevacizumab (BEV), and paclitaxel (PTX) with conventional and two levels ("equi" and "high") of dose-dense schedules. All individual tumor growth curves were decoded via separate measurements of cell death and other antiproliferative effects, gaining fresh insight into the differences between treatment options. Single drug treatments were cytostatic, but only DDP and PTX were also cytotoxic. After treatment, regrowth stabilized with increased propensity to quiescence, particularly with BEV. More cells were killed by PTX dose-dense-equi than with PTX conventional, but with the addition of DDP, cytotoxicity was similar and considerably less than expected from that of individual drugs. In the DDP/PTX dose-dense-high scheme, both cell death and regrowth impairment were intensified enough to achieve complete remission, and addition of BEV increased cell death in all schemes. The results support the option for dose-dense PTX chemotherapy with active single doses, showing the relative additional contribution of BEV, but also indicate negative drug interactions in concomitant DDP/PTX treatments, suggesting that sequential schedules could improve antitumor efficacy. Cancer Res; 77(23); 6759-69. ©2017 AACR.


Assessment of stream water chemistry and impact of geothermal fluid in the up-Buyuk Menderes Basin, Turkey.
The discharge of geothermal fluid into the natural water environment may lead to serious damages. In this study, the impact of geothermal waste water on surface water has been investigated in the up-Buyuk Menderes River, Turkey. Thermal return water from district heating and from thermal bath in the Sandıklı region were the most important source of major solutes and trace elements to the up-Buyuk Menderes River and tributaries. The thermal contribution causes a drastic increase in Na, SO4 ions, EC, and temperature of surface waters. The concentrations of As, Al, B, Fe, Cr, Li, S, P, Pb, U, Mn, and Zn are increasing dramatically downstream of thermal water inputs in the Kufi Creek tributary. In addition to natural thermal water inputs, water quality was impacted by anthropogenic trace and major element inputs from surface waters. The increased of some trace elements (Al, As, B, Cu, Cd, Fe, Mn, P, U) in surface water are related to anthropogenic activities such as agricultural activities, sewage effluents, and stockyards in the study area. Additionally, surface water quality of the up-Buyuk Menderes River and tributaries was evaluated according to standards given by the Environmental Protection Agency of both Turkey and USA. Our study demonstrates the influence of thermal water inputs on water quality of surface waters.


A case report on complete cure of recurrent primary canaliculitis by 4-snip punctoplasty and canalicular curettage.
For the treatment of primary canaliculitis, 1,2,3-snip punctoplasty and canalicular curettage are commonly used; however, a recurrence rate of 6.6% to 22% has been reported. Herein, we describe a case of recurrent primary canaliculitis that was completely cured by 4-snip punctoplasty and canalicular curettage. A 53-year-old woman was admitted to our hospital with chief complaints of epiphora, discharge, eyelid flare up, and swelling near the inferior lacrimal punctum in the left eye, which initially presented 6 months earlier. Based on the aforementioned symptoms, the patient was initially diagnosed with bacterial conjunctivitis at a local ophthalmologic clinic and used antibiotic eye drops for 6 months. However, her symptoms did not improve and they worsened at 2 weeks prior to admission. She was subsequently diagnosed with chronic dacryocystitis and referred to our hospital for surgical treatment. Slit lamp examination results showed conjunctival congestion in the inner corner of the left eye, along with eyelid flare up, swelling near the inferior lacrimal punctum, and yellowish discharge and concretion from the lacrimal punctal orifice. Furthermore, punctal regurgitation was not observed in the lacrimal sac compression test. Thus, the patient was diagnosed with primary canaliculitis on the basis of her clinical symptoms and laboratory findings. Based on the diagnosis of primary canaliculitis, 1-snip punctoplasty and canalicular curettage were performed, and the patient was prescribed oral antibiotics for 2 weeks together with topical antibiotics for 4 weeks. Overall, the patient's symptoms improved after surgery, but epiphora and yellowish discharge from the lacrimal punctal orifice developed again 2 months after surgery during outpatient follow-up. Based on the diagnosis of recurrent primary canaliculitis, 4-snip punctoplasty and canalicular curettage were performed, and the patient was prescribed oral antibiotics for 2 weeks together with topical antibiotics for 4 weeks. Over a 6-month follow-up period, the symptoms disappeared completely and no other findings were observed. Four-snip punctoplasty and canalicular curettage are simple clinical procedures that can minimize the recurrence rate of primary canaliculitis. Hence, 4-snip punctoplasty and canalicular curettage should be considered as the 1st-line treatment for primary canaliculitis and recurrent cases.


Microbiological assay for the determination of azithromycin in ophthalmic solutions.
The validation of a simple, sensitive and specific agar diffusion bioassay, applying cylinder-plate method, for the determination of the antibiotic azithromycin in ophthalmic solutions is described. Using a strain of Bacillus subtilis ATCC 9372 as the test organism, azithromycin at concentrations ranging from 50.0 to 200.0 microg.mL(-1) could be measured in 1.6667 mg.mL(-1) ophthalmic solutions. A prospective validation of the method showed that the method was linear (r = 0. 999 9) and precise (RSD = 0. 70) and accurate (it measured the added quantities). The results obtained by bioassay method could be statistically calculated by linear parallel model and by means of regression analysis and verified using analysis of variance (ANOVA). We conclude that the microbiological assay is satisfactory for quantification of azithromycin in ophthalmic solutions.


Binding Interactions and Inhibition Mechanisms of Gold Complexes in Thiamine Diphosphate-Dependent Enzymes.
Thiamine diphosphate (ThDP)-dependent enzymes possess the unique ability to generate a carbene within their active site. In this study, we sought to harness this carbene to produce a Au(I) N-heterocyclic complex directly in the active site of ThDP enzymes, thereby establishing a novel platform for artificial metalloenzymes. Because direct metalation of ThDP proved challenging, we synthesized a ThDP mimic that acts as a competitive inhibitor with a high affinity (Ki = 1.5 μM). Upon metalation with Au(I), we observed that the complex became a more potent inhibitor (Ki = 0.7 μM). However, detailed analysis of the inhibition mode, native mass spectrometry, and size exclusion experiments revealed that the complex does not bind specifically to the active site of ThDP enzymes. Instead, it exhibits unspecific binding and exceeds the 1:1 stoichiometry. Similar binding patterns were observed for other Au(I) species. These findings prompt an important question regarding the inherent propensity of ThDP enzymes to bind strongly to Au. If this phenomenon holds true, it could pave the way for the development of Au-based drugs targeting these enzymes.


Drug design of GPCR ligands using physicogenetics and chemogenomics--principles and case studies.
An efficient computational method for hit and lead identification is described. The method that incorporate ligand information from physicogenetically related 7TM receptors, i.e. receptors with similar physicochemical features in the ligand binding pockets, have been developed to aid the construction of pharmacophore queries for mining of vendor and in-house databases to produce small focused libraries for a specific GPCR target. The physicogenetically related targets could be complementary to phylogenetically derived receptors and convey more relevance for the structure-based design approaches suitable for GPCR targets associated with no or limited ligand information. The approach is useful not only in identification of hits but also in the hit-to-lead process as constructed homology receptor models, SAR information and pharmacophore features are collectively utilized in the design of proprietary new lead series. This site-directed drug discovery approach of making smaller receptor-specific libraries displays important advantages over conventional HTS-based generation of hits. The methodology has been exemplified with the CRTH2 receptor, which was associated with minimal ligand information, to produce a small diverse library containing several useful hit series which were further converted into drugable lead series. The use of ligand and QSAR information in scaffold hopping was exemplified with MCH1R antagonists, which had been obtained via chemogenomics-enriched design. Finally, an example on how ligand relationships can be used in identifying receptor relationships was given with CCR2 antagonists to highlight the 3D relationships of GPCR targets not directly evident from either phylogenetic or physicogenetic relationships.


Cervical cancer cell-derived angiopoietins promote tumor progression.
Metastatic or recurrent cervical cancer has limited treatment options and a high rate of mortality. Although anti-vascular endothelial growth factor drugs have shown great promise as a therapeutic target for treatment of advanced cervical cancer, drug resistance and class-specific side effects negate long-term benefits. The identification of alternative anti-angiogenic factors will be critical for future drug development for advanced or recurrent cervical cancer. In this study, we found that angiopoietins and Tie receptors were highly expressed in cervical cancer cells. Tie-2 expression in tumor cells predicted poorer prognosis. Wound closure assay and Transwell assay showed that upregulated or downregulated Ang-1 and Ang-2 expression promoted or reduced cervical cancer cell lines migration and invasion, respectively. In subcutaneous xenograft models of cervical cancer, downregulation of Ang-1 and Ang-2 attenuated tumor growth. The expression of vimentin and endomucin and microvessel density were all significantly decreased in the siAng-1 group and siAng-2 group relative to the infection control group. Our data support that dual inhibition of Ang-1 and Ang-2 may be an alternative target for anti-angiogenic adjuvant therapy in advanced or recurrent cervical squamous cell cancer.


[The gas chromatographic detection of acetylene in cadaveric material].
Acetylene traces were detected by gas chromatography in the cadaveric right crural muscle of a 30-year-old man dead from an explosion of an acetylene reservoir at a plant. Acetylene was identified using the absolute calibration method on 3 standard gas chromatographic columns, reaction gas chromatography, and acetylene "deduction" by silver sulfate on silicagel.


Chemical Constitute and Larvicidal Activity of Fractions of Ajuga chamaecistus tomentella Plant against Malaria Vector Anopheles stephensi.
The genus Ajuga, belongs to Lamiaceae family, is one of the exclusive subspecies in the flora of Iran. The plants of this genus are used traditionally for treatment of joints pain, gout, jaundice, and as insecticide. larvicidal activity of methanol 80% extract and partition fractions of hexane, chloroform, and ethyl acetate obtained from aerial parts of Ajuga chamaecistus subspecies tomentella against malaria vector An. stephensi was evaluated. Phytochemical study of active fraction was analyzed using column chromatography and spectroscopy. According to the results, among different fractions, hexane fraction has the most larvicidal activity with mortality rate of 100% in concentration of 102 ppm and LC50 of 95.66ppm. The structure of compound 1, main phytoecdysteroid compound separated from hexane fraction, was determined to be ajugalide-E. The results suggested that the hexane fraction of Ajuga chamaecistus subsp tomentella could be used as a natural and biodegradable insecticide.


Impact of an antimicrobial stewardship initiative to evaluate β-lactam allergy in patients ordered aztreonam.
An evaluation of the clinical and economic impact of an antimicrobial stewardship quality initiative (ASQI) focusing on allergy assessment in patients with a documented β-lactam allergy prescribed aztreonam was conducted. This retrospective study was executed at a hospital with an interdisciplinary antimicrobial stewardship program (ASP). A total of 186 patients with self-reported β-lactam allergies who were prescribed aztreonam while admitted during a 36-month time period surrounding the ASQI implementation were included. The primary study outcome was median time in hours to aztreonam discontinuation among nonanaphylactic patients. After implementation of the ASQI, the percentage of patients continued on aztreonam for the duration of therapy was nearly cut in half, and a greater percentage of patients were switched to β-lactam antibiotics. No adverse effects associated with β-lactam therapy were observed in any study patient. Antimicrobial cost savings was not associated with any difference in clinical outcomes. Overall, hospitalwide aztreonam prescribing and aztreonam use declined. Institutional aztreonam orders per 1000 patient-days decreased from 1.5 to 1 after implementation of the ASQI. Additionally, hospitalwide aztreonam days of therapy per 1000 patient-days was reduced from 3.6 in the pre-ASQI period to 1.8 in the post-ASQI period. An ASQI that included critical evaluation of patient-reported β-lactam allergies led to decreased aztreonam use, reduced antimicrobial expenditure, and similar clinical outcomes to those observed before implementation.


[Skin symptoms on the hands of female house-cleaning personnel].
Skin symptoms on the hands were studied in questionnaire-based studies conducted in 1989 and 1991 among female cleaners employed at Danish nursing homes, schools and offices. Eleven hundred and sixty-six participated in 1989 and 1011 of them participated in 1991. The average age was 45 years and the average length of five employed as a cleaner was ten years. Forty-three percent reported to have had at least one out of four skin symptoms during a one year period. Seventy percent reported improvement during week-ends and holidays. A positive correlation was found between hours per week spent with wet hands and skin symptoms. During the follow-up period the risk of developing skin symptoms was higher in the group who remained cleaners compared with the group who left the cleaning job. Similarly, the prognosis was better in the group which left the cleaning job compared with the group which remained cleaners. There is a future need to develop and implement new work organisation and cleaning methods to reduce the time spent with wet hands.


Secondary disclosure of parental HIV status among children affected by AIDS in Henan, China.
For children affected by AIDS, one psychological challenge is whether or how to disclose their parents' HIV status to others (secondary disclosure). The current study, utilizing data from 962 rural children affected by AIDS in central China, examines children's perceptions regarding secondary disclosure (intention of disclosure, openness, and negative feelings) and their association with children's demographic and psychosocial factors. The findings indicated that a high proportion of children preferred not to disclose parental HIV status to others, would not like to tell the truth to others in the situations of having to talk about parental HIV, and also had strong negative feelings about the disclosure. The study findings confirmed that keeping secrecy of parental HIV infection was associated with higher level of negative psychological outcomes (e.g., depression, loneliness, perceived stigma, and enacted stigma), and children's age was strongly associated with both their perceptions of secondary disclosure and psychological measures.


Axin1's mystique in manipulating microbiome amidst colitis.
Classically, Axin1 is considered a regulator of Wnt/β-catenin signaling. However, Axin1's roles in host-microbial interactions have been unknown. Our recent study has demonstrated that deletion of intestinal epithelial Axin1 in epithelial cells and Paneth cells protects the host against colitis by enhancing Akkermansia muciniphila. Loss of intestinal epithelial or Paneth cell Axin1 results in increased Wnt/β-catenin signaling, proliferation, and cell migration. This is associated with morphologically altered goblet and Paneth cells, including increased Muc2 and decreased lysozyme. Axin1 deletion specifically enriched Akkermansia muciniphila. Akkermansia muciniphila in Axin1 knockout mice is the driver of protection against DSS-induced inflammation. Here, we feature several significant conceptual changes, such as differences between Axin1 and Axin2, Axin1 in innate immunity and microbial homeostasis, and Axin1 reduction of Akkermansia muciniphila. We discuss an important trend in the field related to Paneth cells and tissue-specific Axin1 manipulation of microbiome in health and inflammation.


[Growth and biotin synthesis of Sporobolomyces pararoseus and Rhizopus delemar under different substrate ratios].
Biotin synthesis by the yeast Sporobolomyces pararoseus and the microscopic fungus Rhizopus delemar was studied in batch cultures at different substrate ratios in the medium. The overall (exocellular + endocellular) biotin content in the yeast was 4.5-6.0 micrograms per 1 g of biomass on different media and did not depend on the growth phase. The content of biotin in the fungus was 7.5-9.0 micrograms per 1 g of biomass and depended neither on the growth phase nor on the quantitative ratio between components of the growth medium. In contrast to the yeast, the content of exocellular biotin per 1 g of the mycelium increased with the fungal growth, and the yield of biotin was maximal (25-29 micrograms/g) at the stationary growth phase. The maximal rate of biotin synthesis by the both organisms coincided in time with their maximal growth rate.


2006 marketplace survey of trans-fatty acid content of margarines and butters, cookies and snack cakes, and savory snacks.
In recent years, newer technologies have been developed to reduce the trans-fat content of fats and oils used in manufacturing food products. To examine the implications of these changes on foods in the marketplace, a survey was conducted to assess current levels of trans and saturated fat in three food categories: margarines and butters; cookies and snack cakes; and savory snacks. A sampling of products from each category was conducted at a Wal-Mart Supercenter in the Minneapolis-St Paul, MN, metropolitan area in July of 2006. All information was obtained from product labels, except price, which was recorded from price listings on product shelving. Most margarines and butters (21 of 29), cookies and snack cakes (34 of 44), and savory snacks (31 of 40) were labeled as containing 0 g trans fat. However, some products contained substantial amounts of trans fat. Most notably, 3 of 40 savory snack products were labeled as containing > or =3 g trans fat. Significant inverse correlations were found between product price and the saturated and trans-fat content of margarines (r=-0.45) and savory snacks (r=-0.32). In conclusion, it appears that the food industry has made progress in reducing the trans-fat content in a variety of products. Nonetheless, consumers need to read product labels because the trans-fat content of individual products can vary considerably. Products that are lower in trans and saturated fat tend to cost more, which may be a barrier to their purchase for price-conscious consumers.


Causal effects of cardiovascular risk factors on onset of major age-related diseases: A time-to-event Mendelian randomization study.
Elucidating the causal effects of common intermediate risk factors on the onset of age-related diseases is indispensable for developing prevention and intervention procedures. We conducted two-stage time-to-event Mendelian randomization meta-analyses combining five large-scale longitudinal cohorts to investigate dynamic causal effects of cardiovascular disease risk factors including body mass index (BMI), systolic blood pressure (SBP), and lipids on the age-at-onset of age-related diseases. We constructed weighted polygenic scores based on genetic markers from previously reported genome-wide association studies as instrumental variables to estimate the causal effects. To avoid false positive due to potential pleiotropic effects of the genetic markers, we performed a leave-one-out sensitivity analysis and an MR-Egger sensitivity analysis that we expanded in the survival context. Our results show that elevated BMI increases the absolute risk of type 2 diabetes (T2D) (p=7.68e-04), heart failure (p=9.03e-03), and cardiovascular diseases (CVD) (p=1.69e-03) and the causal effects start at different ages. A significant association between BMI and the risk of stroke is observed; however, the sensitivity analyses suggest that the association is attributed to the potential pleiotropic effects of rs2867125 and rs1558902. Raised SBP levels are significantly associated with the development of atrial fibrillation (p=6.42e-03). Low-density lipoprotein cholesterol (LDL-C) levels are inversely associated with the age-at-onset of T2D (p=1.05e-02). In addition, LDL-C and triglycerides are inversely associated with the risks of cancer and T2D, respectively. Nevertheless, the sensitivity analyses suggest that these associations are probably due to pleiotropic effects of several single-nucleotide polymorphisms including rs4970834 and rs1260326. Our results highlight the involvement of BMI in the development of multiple age-related diseases. Some observed causal associations can attribute to pleiotropic effects of some genetic variations. These findings have important implications in unraveling causal effects of common risk factors on age-related diseases and guiding effective intervention strategies to reduce the incidence of these diseases.


Broad-gain (Δλ/λ0</~0.4), temperature-insensitive (T<0~510K) quantum cascade lasers.
Broad-gain operation of λ~8.7 μm quantum cascade lasers based on dual-upper-state to multiple-lower-state transition design is reported. The devices exhibit surprisingly wide (~500 cm(-1)) electroluminescence spectra which are very insensitive to voltage and temperature changes above room temperature. With recourse to the temperature-insensitivity of electroluminescence spectra, the lasers demonstrate an extremely-weak temperature-dependence of laser performances: T0-value of 510 K, associated with a room temperature threshold current density of 2.6 kA/cm2. In addition, despite such wide gain spectra, room temperature, continuous wave operation of the laser with buried hetero structure is achieved.


Maternal Hepatitis B Virus Infection and Pregnancy Outcomes: A Hospital-based Case-control Study in Wuhan, China.
To examine the impact of maternal hepatitis B virus infection on pregnancy outcomes. Studies regarding hepatitis B virus infection and pregnancy outcomes are limited with inconsistent results, and none of them have evaluated the effect of maternal viral load in pregnancy on pregnancy outcomes. A hospital-based case-control study was conducted. In total, 1728 hepatitis B surface antigen (HBsAg)-positive women who delivered consecutively at Wuhan Women and Children Medical and Healthcare Center, Wuhan, China, from June 2008 to May 2015, were compared with 1497 HBsAg-negative women giving birth in the same hospital during the same period who were randomly identified and selected from the computerized medical record database in parallel. Univariate and multivariate logistic regression models were constructed. After adjusting for confounding variables, maternal HBsAg carriage was associated with increased risk of pregnancy-induced hypertension [adjusted odds ratio (aOR)=2.20; 95% confidence interval (CI), 1.30-3.73], fetal distress (aOR=1.40; 95% CI, 1.09-1.78), cesarean delivery (aOR=1.70; 95% CI, 1.45-1.99), and macrosomia (aOR=1.68; 95% CI, 1.19-2.37). Moreover, maternal viral load in the second trimester was significantly associated with risk of preterm birth (aOR for each log10 copy/mL increase, 1.18; 95% CI, 1.01-1.39) among HBsAg carriers after adjustment for maternal age, employment, parity, history of abortion, and prenatal body mass index. Maternal HBsAg carriage was associated with several adverse pregnancy outcomes. Furthermore, hepatitis B viral activity in pregnancy might have certain effects on pregnancy outcomes. Careful surveillance of maternal HBsAg status as well as viral activity in the second trimester among HBsAg carriers is warranted.


Genetic evidence and new morphometric data as essential tools to identify the Patagonian seahorse Hippocampus patagonicus (Pisces, Syngnathidae).
A genetic study to support morphometric analyses was used to improve the description and validate the Patagonian seahorse Hippocampus patagonicus (Syngnathidae) on the basis of a large number of specimens collected in the type locality (San Antonio Bay, Patagonia, Argentina). DNA sequence data (from the cytochrome b region of the mitochondrial genome) were used to differentiate this species from its relatives cited for the west Atlantic Ocean. Both phylogenetic and genetic distance analyses supported the hypothesis that H. patagonicus is a species clearly differentiated from others, in agreement with morphometric studies. Hippocampus patagonicus can be distinguished from Hippocampus erectus by the combination of the following morphometric characteristics: (1) in both sexes and all sizes of H. patagonicus, the snout length is always less than the postorbital length, whereas the snout length of H. erectus is not shorter than the postorbital length in the largest specimens; (2) in both sexes of H. patagonicus, the trunk length:total length (LTr :LT ) is lower than in H. erectus (in female H. patagonicus: 0·27-0·39, H. erectus: 0·36-0·40 and in male H. patagonicus: 0·24-0·34, H. erectus: 0·33-0·43) and (3) in both sexes, tail length:total length (LTa :LT ) in H. patagonicus is larger than in H. erectus (0·61-0·78 v. 0·54-0·64).


Linking development and aging.
Evolutionary theory predicts that the different life stages of organisms are coordinated to achieve maximal reproductive output. Moreover, aging can be seen as an evolutionary side effect of this selective process that applies to many living organisms. Hence, genetic, developmental, and physiological mechanisms resulting from this selection are expected to be conserved in diverse lineages. The insulin/insulin-like growth factor signaling (INS) pathway appears to be such a mechanism that regulates life span and reproduction in a variety of model organisms. Here I argue that the experimental tools of environmental manipulation and gene by environment interaction should be used more often both during the experimental organism's development and its adult life. This approach will help us to fully understand the functions of longevity-determining pathways and will determine the life stages during which these pathways exert their effects on adult life. These points are raised because of a recent Aging Cell publication by Tu and Tatar, in which the larval food environment was manipulated to determine the effects on adult reproduction, life span, aging, and INS. The results of this study are a promise of the usefulness of this approach for understanding the aging process.


Facile preparation of pyrimidinediones and thioacrylamides via reductive functionalization of amides.
The development of an efficient protocol for the reductive functionalization of amides into pyrimidinediones and amino-substituted thioacrylamides is presented. Enamines are generated in a highly chemoselective amide hydrosilylation reaction catalyzed by molybdenum hexacarbonyl in combination with 1,1,3,3-tetramethyldisiloxane. The direct addition of either isocyanate or isothiocyanate generates the corresponding pyrimidinediones and 3-aminothioacrylamides in high yields.


Barriers to screening, diagnosis and management of hyperglycaemia in pregnancy in Africa: a systematic review.
Gestational diabetes mellitus (GDM) complicates pregnancies in Africa. Addressing the burden is contingent on early detection and management practices. This review aimed at identifying the barriers to diagnosing and managing GDM in Africa. We searched PUBMED, Web of Science, WHOLIS, Google Scholar, CINAHL and PsycINFO databases in May 2020 for studies that reported barriers to diagnosis and management of hyperglycaemia in pregnancy. We used a mixed method quality appraisal tool to assess the quality and risk of bias of the included studies. We adopted an integrated and narrative synthesis approach in the analysis and reporting. Of 548 articles identified, 14 met the eligibility criteria. Health system-related barriers to GDM management were the shortage of healthcare providers, relevant logistics, inadequate knowledge and skills, as well as limited opportunities for in-service training. Patient-related barriers were insufficient knowledge about GDM, limited support from families and health providers and acceptability of the diagnostic tests. Societal level barriers were concomitant use of consulting traditional healers, customs and taboos on food and body image perception. It was concluded that constraints to GDM detection and management are multidimensional. Targeted interventions must address these barriers from broader, systemic and social perspectives.


Lps2: a new locus required for responses to lipopolysaccharide, revealed by germline mutagenesis and phenotypic screening.
Both forward and reverse genetic techniques have been used to define components of the mammalian lipopolysaccharide (LPS) receptor. TLR4, identified by a forward genetic approach as the product of the classical Lps locus, is the only known transmembrane component of the mammalian LPS receptor. Gene knockout work has also established that LPS signal transduction requires the integrity of CD14, MD-2, and, in part, MyD88, IRAK4, and TRAF-6. However, there is no reason to believe that these are the only proteins that make up the receptor/transducer apparatus. To examine the possibility that other proteins may be involved, we initiated a mutagenesis program, in which germline mutations are induced in mice using N-ethyl-N-nitrosourea (ENU), and macrophages from individual animals are screened for their competence to respond to LPS. We now report the existence of a new locus, Lps2, which is required for TNF production in response to LPS. The Lps2 mutation that we have identified is co-dominant, is similar in phenotypic effect to Lpsd, and does not represent a novel allele of any of the genes that are known to encode the 'core' LPS signaling apparatus. The Lps2 mutation does not preclude signaling initiated by peptidoglycan or unmethylated DNA. Hence, genetic data suggest that there is at least one 'missing' component of the LPS receptor complex that has yet to be found.


OSU-T315: a novel targeted therapeutic that antagonizes AKT membrane localization and activation of chronic lymphocytic leukemia cells.
Aberrant regulation of endogenous survival pathways plays a major role in progression of chronic lymphocytic leukemia (CLL). Signaling via conjugation of surface receptors within the tumor environmental niche activates survival and proliferation pathways in CLL. Of these, the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway appears to be pivotal to support CLL pathogenesis, and pharmacologic inhibitors targeting this axis have shown clinical activity. Here we investigate OSU-T315, a compound that disrupts the PI3K/AKT pathway in a novel manner. Dose-dependent selective cytotoxicity by OSU-T315 is noted in both CLL-derived cell lines and primary CLL cells relative to normal lymphocytes. In contrast to the highly successful Bruton's tyrosine kinase and PI3K inhibitors that inhibit B-cell receptor (BCR) signaling pathway at proximal kinases, OSU-T315 directly abrogates AKT activation by preventing translocation of AKT into lipid rafts without altering the activation of receptor-associated kinases. Through this mechanism, the agent triggers caspase-dependent apoptosis in CLL by suppressing BCR, CD49d, CD40, and Toll-like receptor 9-mediated AKT activation in an integrin-linked kinase-independent manner. In vivo, OSU-T315 attains pharmacologically active drug levels and significantly prolongs survival in the TCL1 mouse model. Together, our findings indicate a novel mechanism of action of OSU-T315 with potential therapeutic application in CLL.


Patient Preferences for Lung Cancer Interception Therapy.
Interception therapy requires individuals to undergo treatment to prevent a future medical event, but little is known about preferences of individuals at high risk for lung cancer and whether they would be interested in this type of treatment. To explore preferences of individuals at high risk for lung cancer for potential interception therapies to reduce this risk. This survey study used a discrete-choice experiment and included hypothetical lung cancer interception treatments with 4 attributes: reduction in lung cancer risk over 3 years, injection site reaction severity, nonfatal serious infection, and death from serious infection. Respondents were assigned to a baseline lung cancer risk of 6%, 10%, or 16% over 3 years. The discrete-choice experiment was administered online (July 13 to September 6, 2022) to US respondents eligible for lung cancer screening according to US Preventive Services Task Force guidelines. Participants included adults aged 50 to 80 years with at least a 20 pack-year smoking history. Statistical analysis was performed from September to December 2022. Attribute-level preference weights were estimated, and conditional relative attribute importance, maximum acceptable risks, and minimum acceptable benefits were calculated. Characteristics of respondents who always selected no treatment were also explored. Of the 803 survey respondents, 495 (61.6%) were female, 138 (17.2%) were African American or Black, 55 (6.8%) were Alaska Native, American Indian, or Native American, 44 (5.5%) were Asian or Native Hawaiian or Other Pacific Islander, 104 (13.0%) were Hispanic, Latin American, or Latinx, and 462 (57.5%) were White, Middle Eastern or North African, or a race or ethnicity not listed; and mean (SD) age was 63.0 (7.5) years. Most respondents were willing to accept interception therapy and viewed reduction in lung cancer risk as the most important attribute. Respondents would accept a greater than or equal to a 12.0 percentage point increase in risk of nonfatal serious infection if lung cancer risk was reduced by at least 20.0 percentage points; and a greater than or equal to 1.2 percentage point increase in risk of fatal serious infection if lung cancer risk was reduced by at least 30.0 percentage points. Respondents would require at least a 15.4 (95% CI, 10.6-20.2) percentage point decrease in lung cancer risk to accept a 12.0 percentage point increase in risk of nonfatal serious infection; and at least a 23.1 (95% CI, 16.4-29.8) percentage point decrease in lung cancer risk to accept a 1.2 percentage point increase in risk of death from serious infection. Respondents who were unwilling to accept interception therapy in any question (129 [16.1%]) were more likely to be older and to currently smoke with no prior cessation attempt, and less likely to have been vaccinated against COVID-19 or examined for skin cancer. In this survey study of individuals at high risk of lung cancer, most respondents were willing to consider interception therapy. These results suggest the importance of benefit-risk assessments for future lung cancer interception treatments.


A crosssectional analysis of Facebook comments to study public perception of a new diagnostic test called the Cytosponge.
Social media provides a useful platform for informal discussions about healthcare. Acceptability is key to the uptake of diagnostic devices and this can be difficult to gauge from questionnaires and qualitative studies. The aim of this study is to investigate whether Facebook could be used to gauge public perception toward uptake of a new diagnostic test for Barrett's esophagus called the Cytosponge. We retrospectively reviewed Facebook comments relating to a video on the Cytosponge. We categorized comments into: (1) Positive, (2) Negative, (3) Unknown and (4) Questions. Recurring themes that arose were compared to a qualitative study on the Cytosponge. The video received 22.5 million views and 2837 comments within four months. Of these, 525 comments were positive, 215 were unknown, 179 were negative, 71 were questions, and 1847 were 'Tagged' comments. Among positive comments, recurrent themes were that it was innovative, could lead to early cancer-detection, and more favorable than endoscopy. Among negative comments, a recurring theme was concern about the risk of gagging and vomiting. Among 'questions', a recurring theme was related to the risk of Cytosponge detachment. We compared our analysis to a published qualitative study and found similar themes arose across both studies. Facebook provides a rich source of qualitative data, which could be used to augment studies to gauge public perception toward a new diagnostic test.


In situ normothermic regional perfusion for controlled donation after circulatory death--the United Kingdom experience.
Organs recovered from donors after circulatory death (DCD) suffer warm ischemia before cold storage which may prejudice graft survival and result in a greater risk of complications after transplant. A period of normothermic regional perfusion (NRP) in the donor may reverse these effects and improve organ function. Twenty-one NRP retrievals from Maastricht category III DCD donors were performed at three UK centers. NRP was established postasystole via aortic and caval cannulation and maintained for 2 h. Blood gases and biochemistry were monitored to assess organ function. Sixty-three organs were recovered. Forty-nine patients were transplanted. The median time from asystole to NRP was 16 min (range 10-23 min). Thirty-two patients received a kidney transplant. The median cold ischemia time was 12 h 30 min (range 5 h 25 min-18 h 22 min). The median creatinine at 3 and 12 months was 107 µmol/L (range 72-222) and 121 µmol/L (range 63-157), respectively. Thirteen (40%) recipients had delayed graft function and four lost the grafts. Eleven patients received a liver transplant. The first week median peak ALT was 389 IU/L (range 58-3043). One patient had primary nonfunction. Two combined pancreas-kidney transplants, one islet transplant and three double lung transplants were performed with primary function. NRP in DCD donation facilitates organ recovery and may improve short-term outcomes.


Canal-otolith interactions and detection thresholds of linear and angular components during curved-path self-motion.
Gravitational signals arising from the otolith organs and vertical plane rotational signals arising from the semicircular canals interact extensively for accurate estimation of tilt and inertial acceleration. Here we used a classical signal detection paradigm to examine perceptual interactions between otolith and horizontal semicircular canal signals during simultaneous rotation and translation on a curved path. In a rotation detection experiment, blindfolded subjects were asked to detect the presence of angular motion in blocks where half of the trials were pure nasooccipital translation and half were simultaneous translation and yaw rotation (curved-path motion). In separate, translation detection experiments, subjects were also asked to detect either the presence or the absence of nasooccipital linear motion in blocks, in which half of the trials were pure yaw rotation and half were curved path. Rotation thresholds increased slightly, but not significantly, with concurrent linear velocity magnitude. Yaw rotation detection threshold, averaged across all conditions, was 1.45 +/- 0.81 degrees/s (3.49 +/- 1.95 degrees/s(2)). Translation thresholds, on the other hand, increased significantly with increasing magnitude of concurrent angular velocity. Absolute nasooccipital translation detection threshold, averaged across all conditions, was 2.93 +/- 2.10 cm/s (7.07 +/- 5.05 cm/s(2)). These findings suggest that conscious perception might not have independent access to separate estimates of linear and angular movement parameters during curved-path motion. Estimates of linear (and perhaps angular) components might instead rely on integrated information from canals and otoliths. Such interaction may underlie previously reported perceptual errors during curved-path motion and may originate from mechanisms that are specialized for tilt-translation processing during vertical plane rotation.


The past, present, and future of sex segregation methodology.
We review the logic underlying margin-free analyses of sex segregation arrays. In the course of our review, we show that the Karmel-MacLachlan decomposition does not live up to its margin-free billing, as the index upon which it rests, Ip, is itself margin-sensitive. Moreover, because the implicit individualism of D is necessarily inconsistent with margin-free analysis, the field would do well to abandon not merely the Karmel-MacLachlan decomposition but all related efforts to purge marginal dependencies from D-inspired measures. The criticisms that Watts (1998) levels against our log-multiplicative approach are likewise unconvincing. We demonstrate that our preferred models pass the test of organizational equivalence, that the "problem" of zero cells can be solved by applying well-developed methods for ransacking incomplete or sparse tables, and that simple log-multiplicative models can be readily devised to analyze disaggregate arrays. We illustrate these conclusions by analyzing a new cross-national archive of detailed segregation data.


Methylation of INK4 and CIP/KIP families of cyclin-dependent kinase inhibitor in chronic lymphocytic leukaemia in Chinese patients.
INK4 (p15, p16, p18 and p19) and CIP/KIP (p21, p27 and p57) are two families of cyclin-dependent kinase inhibitors (CKI) targeting CDK4/6 and CDK2, respectively. To study the role of methylation in the inactivation of CKI in chronic lymphocytic leukaemia (CLL). Methylation-specific polymerase chain reaction was carried out on DNA obtained from the bone marrow of 56 newly diagnosed patients with CLL. Similar demographic features and clinical outcome were observed in our patients when compared with Caucasian patients, including an indolent clinical course (10-year overall survival 51%) and advanced Rai stage (p = 0.006), and a high-risk karyotype such as trisomy 12 and complex aberrations (p = 0.03). In the INK4 family, methylation in p15 and p16 occurred in 20 (35.7%) and 8 (14.3%) patients, respectively. In all, 5 (8.9%) CLL samples harboured concurrent methylation of both p15 and p16. Apart from an association of p16 methylation with higher presenting leucocyte count (64.5 x 10(9)/l in methylated p16 and 16.0 x 10(9)/l in unmethylated p16 patients; p = 0.016), there was no association between p15 and p16 methylation and age, sex and Rai stage. No difference was observed in the overall survival for patients with and without p15 and p16 methylation. By contrast, p18 and Rb were unmethylated in all samples. In the CIP/KIP family, apart from infrequent methylation of p57 in 4 (7.1%) patients, methylation of p21 and p27 was uniformly absent. p15 and, less frequently, p16 of the INK4 family of CKI, instead of the CIP or KIP family, were targeted by methylation in CLL. p16 methylation was associated with a higher lymphocyte count at presentation. This is the first comprehensive study of the epigenetic dysregulation of the INK4 and CIP/KIP families of CKI in Chinese patients with CLL.


De Novo Mutations of CCNK Cause a Syndromic Neurodevelopmental Disorder with Distinctive Facial Dysmorphism.
Neurodevelopment is a transcriptionally orchestrated process. Cyclin K, a regulator of transcription encoded by CCNK, is thought to play a critical role in the RNA polymerase II-mediated activities. However, dysfunction of CCNK has not been linked to genetic disorders. In this study, we identified three unrelated individuals harboring de novo heterozygous copy number loss of CCNK in an overlapping 14q32.3 region and one individual harboring a de novo nonsynonymous variant c.331A>G (p.Lys111Glu) in CCNK. These four individuals, though from different ethnic backgrounds, shared a common phenotype of developmental delay and intellectual disability (DD/ID), language defects, and distinctive facial dysmorphism including high hairline, hypertelorism, thin eyebrows, dysmorphic ears, broad nasal bridge and tip, and narrow jaw. Functional assay in zebrafish larvae showed that Ccnk knockdown resulted in defective brain development, small eyes, and curly spinal cord. These defects were partially rescued by wild-type mRNA coding CCNK but not the mRNA with the identified likely pathogenic variant c.331A>G, supporting a causal role of CCNK variants in neurodevelopmental disorders. Taken together, we reported a syndromic neurodevelopmental disorder with DD/ID and facial characteristics caused by CCNK variations, possibly through a mechanism of haploinsufficiency.


[Molecular factors of orthopoxvirus virulence].
Orthopoxviruses encode numerous virulence factors. Viral inhibitors of apoptosis of infected cells have been revealed in recent years. Viral inhibitors of the host's non-specific inflammatory reactions are shown to play an important role in effectively propagating the virus. A number of inhibitors of antiviral interferon action cause a high interferon resistance of orthopoxviruses. Some modulators of immune response of the infected body encoded by orthopoxviruses have been discovered in the past years. Viral growth factor, some proteins of the envelope of extracellular virions, etc. are shown to be important for viral dissemination in the host. A general scheme of synthesis of molecular factors of orthopoxviral virulence is discussed.


Incontinentia pigmenti: multisistemic genodermatosis.
Incontinentia pigmenti is an X-linked genodermatosis generally lethal in males; thus, it presents almost exclusively in females. It is caused by a loss-of-function mutation in the IKBKG (inhibitor of kappa polypeptide gene enhancer in B cells, kinase gamma) gene that prevents the NFкβ (nuclear factor kappa-light-chain-enhancer of activated B cells) protein from migrating to the nucleus to begin the transcription of factors that amplify the immune response and prevent apoptosis. Consequently, mutant cells become vulnerable to apoptosis when exposed to cytokines and, in turn, lead to vaso-occlusion and ischemia of tissues, such as the skin, the central nervous system and the retina. Dermatological lesions are characteristic and occur in 100% of patients; they are distributed along Blaschko lines, which follow the pattern of migration of skin cells in embryogenesis. The cutaneous manifestations follow a sequence of four phases since birth: vesicular, verrucous, hyperpigmented and hypopigmented. These lesions are relevant for the disease because they guide the clinician towards the diagnosis. Additionally, they are accompanied by neurological abnormalities, such as seizures, and multiple ophthalmological manifestations, such as retinal detachment. Incontinentia pigmenti patients with no clinically significant ophthalmic or neurological compromise have a good prognosis and a normal life expectancy. The abnormalities present are permanent, which can be a cause of concern for the patients.


Development of the early-life gut microbiome and associations with eczema in a prospective Chinese cohort.
Eczema is a major allergic disease in children, which is particularly prevalent in Chinese children during their first year of life. In this study, we showed that alterations in the infant gut microbiota precede the development of eczema in a prospective Chinese cohort. In particular, we discovered enrichments of the genera Clostridium sensu stricto 1 and Finegoldia in the cases at 3 and 1 month of age, respectively, which may represent potential targets for intervention to prevent eczema. Besides, we identified a depletion of Bacteroides from 1 to 6 months of age and an enrichment of Clostridium sensu stricto 1 at 3 months in the eczema cases, patterns also observed in C-section-born infants within the same time frames, providing first evidence to support a role of the gut microbiota in previously reported associations between C-section and increased risk of eczema in infancy.


Two-dimensional subwavelength imaging from a hemispherical hyperlens.
We report a hemispherical-shaped hyperlens with subwavelength resolution less than 100 nm. Simulations with the finite-element method show that with a 365 nm illumination, the hemispherical hyperlens isotropically magnifies the image along the radial direction. Under linearly polarized light, portions of an object can be resolved. A complete image of the object can be generated by superposing sufficient number of images obtained with incident light in different polarization directions. Such a hyperlens has great potential for realization of nanoscale imaging.


Electrical impedance tomography: a potential tool for intraoperative imaging of the tongue base.
Background. The presence of a tumor in the tongue is a pathology that requires surgical intervention from a certain stage. This type of surgery is difficult to perform because of the limited space available around the base of the tongue for the insertion of surgical tools. During the procedure, the surgeon has to stretch and then fix the tongue firmly in order to optimize the available space and prevent tissue movement. As a result, the preoperative images of the inside of the tongue no longer give a reliable indication of the position and shape of the cancerous tissue due to the deformation of the overall tissue in the area. Thus, new images are needed during the operation, but are very difficult to obtain using conventional techniques due to the presence of surgical tools.Objective. Electrical Impedance Tomography (EIT) is an imaging technique that maps the resistivity or difference of resistivity of biological tissues from electrical signals. The small size of the electrodes makes it a potentially interesting tool to obtain intraoperative images of the inside of the tongue. In this paper, the objective is to study the possibility of using EIT for this purpose is investigated.Main results. A detection method is proposed, including an original configuration of the electrodes, consistent with the anatomical specificities of the tongue. The proposed method is studied in simulation and then a proof of concept is obtained experimentally on a 3D printed test tank filled with saline solution and plant tissue.


The primary structure of two molecular species of porcine organ-common type acylphosphatase.
Electrophoretically homogeneous preparations of organ-common type acylphosphatase from porcine testis and brain were separated into two molecular species by reversed-phase liquid chromatography. From tryptic peptide map analysis, it was inferred that each of the two testis proteins is the same as the corresponding one of the two brain proteins. The complete primary structures of the two acylphosphatases from testis were then determined. The one molecular species consists of 100 amino acid residues: [sequence; see text] The other consists of 98 amino acid residues identical to the 3rd-100th residues of the above sequence and is also acetylated at the amino-terminal alanine. The 98-residue sequence has only 59% homology with porcine muscle acylphosphatase, but has 92% homology with human erythrocyte acylphosphatase. It was thus confirmed that the major acylphosphatases in testis, brain, and erythrocyte belong to the same organ-common type isoenzyme, distinct from the muscle type isoenzyme.


Identification of the first glyphosate-resistant wild radish (Raphanus raphanistrum L.) populations.
In Australia, glyphosate has been used routinely to control wild radish (Raphanus raphanistrum L.) for the past 40 years. This study focuses on two field-evolved glyphosate-resistant populations of wild radish collected from the grainbelt of Western Australia. Two wild radish biotypes were confirmed to be glyphosate resistant by comparing R/S of two suspected populations. Based on R/S from dose-response curves, the R1 and R2 populations were 2.3 and 3.2 times more resistant to glyphosate respectively. Dose response on glyphosate-selected progeny (>1080 g ha(-1)) demonstrated that the glyphosate resistance mechanism was heritable. When compared with the pooled mortality results of three known susceptible populations (S1, S2 and S3), the R1 and R2 subpopulations were 3.4-fold and 4.5-fold more resistant at the LD50 level respectively. Both populations were found to have multiple resistance to the phytoene desaturase inhibitor; diflufenican, the synthetic auxin; 2,4-D and the ALS inhibitors; chlorsulfuron, sulfometuron-methyl, imazethapyr and metosulam. This is the first report confirming glyphosate resistance evolution in wild radish and serves to re-emphasise the importance of diverse weed control strategies. Proactive and integrated measures for resistance management need to be developed to diversify control measures away from glyphosate and advance the use of non-herbicidal techniques.


[Identification of Bacteroides and Fusobacterium using antibiotic- and bile-impregnated disks].
Fifty-nine strains of gram-negative non-sporulating anerobic bacteria were identified to the genus. Comparison of the data on the biochemical identification with the phenotypes by sensitivity to antibiotics and bile showed, that the bacteroids of the fragilis group had the same phenotype. Sensitivity was determined with anaerodisks impregnated with antibiotics and bile. The other species of bacteroids and fusobacteria had several phenotypes. However, these phenotypes being non-specific for the species were characteristic of the genus: none of the bacteroid species had the fusobacteria phenotype. The presented table of the bacteroid and fusobacteria phenotypes by sensitivity to antibiotics and bile may be useful in identification of these organism.


Acute immune response in respect to exercise-induced oxidative stress.
The relationship between exhaustive exercise, oxidative stress, the protective capacity of the antioxidant defense system and cellular immune response has been determined. Exhaustive exercise in well-trained young men (n=19)-induced leukocytosis, decreased proportion of activated-lymphocyte subsets (CD4+ and CD8+) expressing CD69, decreased lymphocyte mitogenic response to concanavalin A (ConA) and phytohemagglutinin (PHA), increased lipid peroxidation, increased total antioxidant status (TAS) and catalase activity, immediately after exercise. Suppressed blood concentration of T-lymphocyte subsets (CD3+, CD4+, CD8+, NK), increased TAS and blood total glutathione (TGSH) in early recovery period (30 min after exercise) were found. Strong positive correlation was observed between TGSH and lymphocyte mitogenic response to ConA and PHA (r=0.85 and 0.85, respectively) immediately after exercise. Moderate positive correlation was observed between TAS and lymphocyte mitogenic response to PHA (r=0.59) immediately after exercise as well as between TAS and lymphocyte mitogenic response to PHA and ConA (r=0.69 and 0.54, respectively). Moderate to weak correlation was observed between TAS and conjugated dienes with exercise (r=0.66) as well as in 30-min recovery (r=0.50). After a short-term bout of exhaustive exercise, immune system was characterized by acute phase response, which was accompanied with oxidative stress. Suppression of the cellular immunity 30 min after exercise shows that this period is not enough for recovery after exhaustive exercise. The results suggest the interactions between exercise-induced oxidative stress and immune response.


Controlled release kinetics from a surface modified microgel-based reservoir device.
A device constructed by sandwiching a thin film of poly(N-isopropylacrylamide)-co-acrylic acid (pNIPAm-co-AAc) microgels between two thin layers of Au (all on a glass support) was used as a novel platform for controlled release of small molecules (drugs). In this submission, the model drug tris (4-(dimenthylamino)phenyl)methylium chloride (Crystal Violet, CV) was loaded into the microgel layer of the device by electrostatic interaction of its positive charge with the negative charges on the deprotonated AAc groups on the microgels at pH > 6.5. The upper Au layer of this device was coated with SiO2 generated by hydrolysis of tetraethyl orthosilicate (TEOS) catalyzed by ammonia at room temperature. Upon exposing the CV loaded devices to pH 3 solutions, the microgel AAc groups were neutralized, and the CV released. The release rate of the CV could be controlled by the thickness of the SiO2 layer coating the Au layer. Specifically, devices with thick silica layers slow the release rate and thin layers allow for faster release. This device represents an easily fabricated device for controlled and triggered release from a thin film with easily controlled release kinetics.


Aberrant epigenetic and genetic marks are seen in myelodysplastic leukocytes and reveal Dock4 as a candidate pathogenic gene on chromosome 7q.
Myelodysplastic syndromes (MDS) are characterized by abnormal and dysplastic maturation of all blood lineages. Even though epigenetic alterations have been seen in MDS marrow progenitors, very little is known about the molecular alterations in dysplastic peripheral blood cells. We analyzed the methylome of MDS leukocytes by the HELP assay and determined that it was globally distinct from age-matched controls and was characterized by numerous novel, aberrant hypermethylated marks that were located mainly outside of CpG islands and preferentially affected GTPase regulators and other cancer-related pathways. Additionally, array comparative genomic hybridization revealed that novel as well as previously characterized deletions and amplifications could also be visualized in peripheral blood leukocytes, thus potentially reducing the need for bone marrow samples for future studies. Using integrative analysis, potentially pathogenic genes silenced by genetic deletions and aberrant hypermethylation in different patients were identified. DOCK4, a GTPase regulator located in the commonly deleted 7q31 region, was identified by this unbiased approach. Significant hypermethylation and reduced expression of DOCK4 in MDS bone marrow stem cells was observed in two large independent datasets, providing further validation of our findings. Finally, DOCK4 knockdown in primary marrow CD34(+) stem cells led to decreased erythroid colony formation and increased apoptosis, thus recapitulating the bone marrow failure seen in MDS. These findings reveal widespread novel epigenetic alterations in myelodysplastic leukocytes and implicate DOCK4 as a pathogenic gene located on the 7q chromosomal region.


Condensin-mediated chromosome organization and gene regulation.
In many organisms sexual fate is determined by a chromosome-based method which entails a difference in sex chromosome-linked gene dosage. Consequently, a gene regulatory mechanism called dosage compensation equalizes X-linked gene expression between the sexes. Dosage compensation initiates as cells transition from pluripotency to differentiation. In Caenorhabditis elegans, dosage compensation is achieved by the dosage compensation complex (DCC) binding to both X chromosomes in hermaphrodites to downregulate gene expression by twofold. The DCC contains a subcomplex (condensin I(DC)) similar to the evolutionarily conserved condensin complexes which play a fundamental role in chromosome dynamics during mitosis. Therefore, mechanisms related to mitotic chromosome condensation are hypothesized to mediate dosage compensation. Consistent with this hypothesis, monomethylation of histone H4 lysine 20 is increased, whereas acetylation of histone H4 lysine 16 is decreased, both on mitotic chromosomes and on interphase dosage compensated X chromosomes in worms. These observations suggest that interphase dosage compensated X chromosomes maintain some characteristics associated with condensed mitotic chromosome. This chromosome state is stably propagated from one cell generation to the next. In this review we will speculate on how the biochemical activities of condensin can achieve both mitotic chromosome compaction and gene repression.


Enzyme-assisted reforming of glucose to hydrogen in a photoelectrochemical cell.
Hydrogen gas has been produced by reforming glucose in a hybrid photoelectrochemical cell that couples a dye-sensitized nanoparticulate wide band gap semiconductor photoanode to the enzyme-based oxidation of glucose. A layer of porphyrin sensitizer is adsorbed to a TiO2 nanoparticulate aggregate sintered to a conducting glass substrate to form the photoanode. Excitation of the porphyrin results in electron injection into the TiO2, and migration to a microporous platinum cathode where hydrogen is produced by hydrogen ion reduction. The oxidized sensitizer dye is reduced by NADH, regenerating the dye and poising the NAD+/NADH redox couple oxidizing. The NAD+ is recycled to NADH by the enzyme glucose dehydrogenase, which obtains the necessary electrons from oxidation of glucose. The reforming of glucose produces gluconolactone, which hydrolyzes to gluconate; the electrochemical potential necessary to overcome thermodynamic and kinetic barriers to hydrogen production by NADH is provided by light. The quantum yield of hydrogen is approximately 2.5%.


Oral Supplementation with Hydrolyzed Fish Cartilage Improves the Morphological and Structural Characteristics of the Skin: A Double-Blind, Placebo-Controlled Clinical Study.
Collagen and its peptides are natural ingredients used in food supplements and nutricosmetics with the claim of providing benefits for skin health and beauty. In this context, the aim of the present study was to evaluate the clinical efficacy of oral supplementation with hydrolyzed fish cartilage for the improvement of chronological and photoaging-induced skin changes. A total of 46 healthy females aged 45 to 59 years were enrolled and divided into two groups: G1-placebo and G2-oral treatment with hydrolyzed fish cartilage. Measurements of skin wrinkles, dermis echogenicity and thickness, and morphological and structural characteristics of the skin were performed in the nasolabial region of the face before and after a 90-day period of treatment using high-resolution imaging, ultrasound, and reflectance confocal microscopy image analyses. A significant reduction in wrinkles and an increase of dermis echogenicity were observed after a 90-day period of treatment with hydrolyzed fish cartilage compared to the placebo and baseline values. In addition, reflectance confocal microscopy (RCM) image analysis showed improved collagen morphology and reduced elastosis after treatment with hydrolyzed fish cartilage. The present study showed the clinical benefits for the skin obtained with oral supplementation with a low dose of collagen peptides from hydrolyzed fish cartilage.


Effect of Diquafosol Ophthalmic Solution on Airflow-Induced Ocular Surface Disorder in Diabetic Rats.
To examine the effect of 3% diquafosol ophthalmic solution (DQS) on ocular surface disorders in diabetic model rats maintained in a continuous airflow condition. Goto-Kakizaki (GK) rats, a spontaneous model of type 2 diabetes, were exposed to constant airflow for 8 weeks. After the establishment of the animal model in this environment, DQS or saline was instilled six times a day into GK rat eyes for 6 weeks. Schirmer's test was performed before and after 6-week instillations. Corneal fluorescein staining was scored at 2-, 4-, and 6-week instillations. Touch thresholds for the cornea were also determined using a Cochet-Bonnet esthesiometer before and after 6-week instillations. The mean Schirmer's test score after instillation of DQS was twice higher than that recorded for saline alone. DQS significantly decreased corneal staining scores at 4- and 6-week instillations. No changes in touch thresholds were observed before and after 6-week instillations. These results suggest that DQS improves corneal epithelial damage by stimulating tear secretion without influencing corneal sensation in diabetic keratopathy. Thus, DQS may have potential for treatment of diabetic patients with dry eye.


Human type 5 adenovirus-based tuberculosis vaccine: is the respiratory route of delivery the future?
Despite progress in managing TB, there were 8.6 million new cases in 2012. To control TB will require a more effective vaccine than BCG, new drugs and better diagnostic tests. Recombinant replication-defective adenoviruses expressing foreign DNA have been studied as vaccines. We developed and evaluated a recombinant replication-deficient human Ad5 vector expressing Ag85A (Ad5Ag85A) as a TB vaccine in animal models and a Phase I human study. Animal models of Ad5Ag85A show markedly improved protection over BCG alone and immunization via the respiratory route provides the best type of protection. In humans, intramuscular vaccination was safe; Ad5Ag85A was immunogenic and stimulated polyfunctional T cell responses, more potently in previously BCG-vaccinated volunteers. Pre-existing Ad5 antibodies did not dampen the response. Given its potency, Ad5-based TB vaccines are well-positioned to be delivered to the respiratory tract, induce local lung immunity to control TB, and inform innovative approaches to new TB vaccination strategies.


Synthesis and reactivity of a PCcarbeneP cobalt(i) complex: the missing link in the cobalt PXP pincer series (X = B, C, N).
We report the first example of a cobalt PCcarbeneP pincer complex (1) featuring a central alkylidene carbon donor accessed through the dehydration of an alcoholic POP proligand. Complex 1 shares bonding similarities with cobalt PBP and PNP pincer complexes where the donor atom engages in π-bonding with the cobalt centre, and thus completes the PXP (X = B, C, N) pincer ligand series for cobalt (for X donors that partake in M-L π-bonding). As compared to PBP and PNP pincer complexes, which are known to be good hydride and proton acceptors (respectively), complex 1 is found to be an effective hydrogen atom acceptor. Complex 1 partakes in cooperative ligand reactivity, engaging in several small molecule activations with styrene, bromine, carbon disulphide, phenyl acetylene, acetonitrile, hydrogen, benzaldehyde and water (through microreversibility). The mechanism for the formation of complex 1 is studied through the isolation and computational analysis of key intermediates. The formation of 1 is found to avoid C-H activation of the proligand, and instead proceeds through a combination of O-H activation, hydrogen atom transfer, β-hydride elimination and hydrogen activation processes.


Thimerosal: clinical, epidemiologic and biochemical studies.
Thimerosal (or Thiomersal) is a trade name for an organomercurial compound (sodium ethyl-mercury (Hg) thiosalicylate) that is 49.55% Hg by weight, which rapidly decomposes in aqueous saline solutions into ethyl-Hg hydroxide and ethyl-Hg chloride. Developed in 1927, it has been and is still being used as a preservative in some cosmetics, topical pharmaceuticals, and biological drug products, including vaccines. Concerns have been voiced about its use because it is toxic to human cells. Although it is banned in several countries, it continues to be added to some vaccines in the United States and many vaccines in the developing world. This critical review focuses on the clinical, epidemiological, and biochemical studies of adverse effects from Thimerosal in developing humans. This review will include research that examines fetal, infant, and childhood death; birth defects; neurodevelopmental testing deficits in children; and neurodevelopmental disorders (attention deficit/hyperactivity disorder, autism spectrum disorder, tic disorder, and specific developmental delays). The review will also look at the research that examined the outcomes of acute accidental ethyl-Hg poisoning in humans. The studies that examine the underlying biochemical insights into the neuronal cellular damage will also be explored. The culmination of the research that examines the effects of Thimerosal in humans indicates that it is a poison at minute levels with a plethora of deleterious consequences, even at the levels currently administered in vaccines.


Identification of candidate genes for a factor regulating body weight in primates.
A weight gain of 20-30% above baseline, induced by gastrostomy overfeeding of subhuman primates or gavage overfeeding of rats, was found to completely suppress voluntary food consumption. When overfeeding was discontinued, body weight and oral intake returned in a coordinated fashion to baseline or "set point" values. This regulatory response could have been due to a circulating peptide that was secreted by adipocytes in proportion to the total body energy store and that mediated satiety at the level of the central nervous system. To search for this factor, a subtractive cDNA cloning strategy was developed, permitting the isolation of primate adipocyte genes with augmented expression in the overfed state. A 1.8-kb cDNA clone prepared by subtraction was found to hybridize to a 5-kb message expressed preferentially in the adipose tissue of overfed macaques and rats. This message, which was restricted in distribution among nonadipose tissues, was also detected in human subcutaneous fat. Candidate genes for satiety factors identified by this approach could be used in further studies of body weight regulation and obesity.


Measuring the impact of the COVID-19 pandemic on colorectal cancer presentation: a retrospective comparative study.
The Coronavirus disease 2019 (COVID-19) pandemic provided challenges to surgical care in Australia. This study aimed to measure the potential impact of COVID-19 on colorectal cancer presentation through surgical volume and cancer staging at a major tertiary referral hospital in the city of Sydney Australia. A retrospective cohort study was performed using routinely collected data from consecutive colorectal cancer patients undergoing surgery during the COVID-19 period (1 March 2020 to 1 October 2021) and compared with the pre-COVID-19 period (1 March 2018 to 1 October 2019). The main outcomes included patient demographics, surgical volume (including overall, elective and emergency) and cancer staging. Differences in outcomes between the two studied periods were compared using Pearson's chi-squared test, Fisher test or t-test. A total of 381 patients composed the COVID-19 group (Mean age = 62.4 years) and 364 patients composed the pre-COVID-19 group (Mean age = 65.6 years; P<0.001). No significant differences were observed for overall, elective or emergency surgical volumes. Patients in the COVID-19 group had a reduction in Stage I and an increase in Stage II and III disease, with Stage IV and recurrent disease being similar with a variation of <1% when compared to the pre-COVID-19 group (P<0.001). Disruptions in patient screening, diagnosis and management from elective surgery restrictions and patient hesitancy may not have resulted in observed changes to surgical volume, however, it may have contributed to an increase in Stages II and III colorectal cancer during COVID-19.