Interleukin-1 receptor antagonist reduced apoptosis and attenuated intestinal mucositis in a 5-fluorouracil chemotherapy model in mice.
The aim of this study was to investigate the relationship between changes in IL-1β expression and intestinal apoptosis after chemotherapy. And we further determine whether interleukin-1 receptor antagonist (IL-1Ra) reduces apoptosis in vivo after 5-fluorouracil (5-FU) chemotherapy in the small intestine. Intestinal mucositis was induced in mice by intraperitoneal injection of a single dose of 5-FU (200 mg/kg). IL-1Ra (1 mg/kg) was injected subcutaneously twice daily after 5-FU injection. 5-FU-induced intestinal apoptosis was detected by TUNEL assay. The expression of IL-1β induced by 5-FU in local intestinal tissue was examined by RT-PCR and immunohistochemistry. Assessment of 5-FU-induced mucositis (histology, diarrhea scores, bowel weight) was performed. The apoptosis-related proteins were investigated by western blotting analysis. The proliferation of intestine was examined by immunohistological staining of PCNA. Viability of IEC-6 cells was determined using the CCK-8 assay. The apoptosis of IEC-6 cells was examined by Hoechst 33342 staining. The variation of IL-1β expression induced by 5-FU was in accordance with the changes in intestinal apoptosis. Administration of IL-1Ra could block the destructive effect of IL-1β and reduce apoptosis in the small intestinal crypt after chemotherapy. The protection against apoptosis was in accordance with the reduction of the up-regulation of Bax and caspase 3 and the elimination of the down-regulation of Bcl-2 and Bcl-xL. Moreover, IL-1Ra attenuated the severity of intestinal mucositis induced by 5-FU and enhanced intestinal crypt proliferation. In vitro experiments showed that IL-1Ra suppressed apoptosis and increased cell viability in enterocyte IEC-6 cells treated with 5-FU. Additionally, IL-1Ra did not affect the chemotherapeutic effect of 5-FU in tumor CT-26 xenograft mice. Our studies elucidate that IL-1β is quite possibly involved in and mediated the course of intestinal apoptosis after 5-FU chemotherapy. Administered with IL-1Ra protects mice against intestinal apoptosis induced by 5-FU, relieves mucosal impairment of the small intestine, and facilitates the recovery of the intestinal mucosa. IL-1Ra treatment offers a novel promising strategy for the prevention and cure of chemotherapy-induced intestinal mucositis in clinical practice.


Effect of pulsed low-power ultrasound on growing tissues. II. Malignant tissues.
Pulsed ultrasound at 2.25 MHz was delivered by a transducer having an average power output of 1.5 mW to a transplantable mouse lymphosarcoma for 5 min. The transplantability of the tumor was reduced. No change in mitotic index as a result of insonation was noted.


Role of vitreous cytology in the diagnosis of primary central nervous system lymphoma: A report of an unusual presentation.
Primary central nervous system lymphoma (PCNSL) is a rare subtype of non-Hodgkin lymphoma confined to the brain, spinal cord, meninges, intraocular compartment, and cranial nerves. Intraocular lymphoma (IOL) is a rare subtype of PCNSL. Intravitreal involvement by a PCNSL is an infrequent but potentially fatal event. The role of vitreous cytology in diagnosing IOLs is vital but has been sporadically described in the literature due to its variable sensitivity. Herein, we present a case of PCNSL, who primarily presented with ocular symptoms and could be accurately diagnosed based on vitreous cytology and subsequently confirmed on stereotactic brain biopsy.


Relationship Between Hyperuricemia and Cardiovascular Disease Risk Factors in a Chinese Population: A Cross-Sectional Study.
To study the relationship between hyperuricemia and cardiovascular diseases (CVDs) risk factors in a Chinese population. Data analyzed in this study were from the Chinese Hyperuricemia and Gout Database. Indicators of serum uric acid (SUA) level, height, weight, systolic blood pressure (SBP), diastolic blood pressure (DBP), smoking status, alcohol consumption, blood glucose, cholesterol, and triglycerides were measured. T test, one-way analysis of variance, Pearson's correlation, multivariate linear regression, and multivariate logistic regression were used. Compared with normouricemic men, hyperuricemic men had greater height (P<0.01), weight (P<0.001), body mass index (BMI) (P<0.001), SBP (P<0.01), DBP (P<0.001), cholesterol (P<0.01), and triglyceride (P<0.001). Compared with normouricemic women, hyperuricemic women were older (P<0.01) and had greater weight (P<0.05), BMI (P<0.01), SBP (P<0.01), DBP (P<0.05), glucose (P<0.05), and triglyceride (P<0.001). In men, an increase of 1 mg/dL in SUA was associated with a 0.279 kg/m2 increase in BMI (P<0.001), a 2.438 mg/dL increase in cholesterol (P<0.05), a 10.358 mg/dL increase in triglyceride (P<0.001), and a 3.1 mg/dL decrease in glucose (P<0.01). In women, an increase of 1 mg/dL SUA was associated with a 0.168 kg/m2 increase in BMI (P<0.01) and a 3.708 mg/dL increase in triglyceride (P<0.01). After adjustment, SUA was strongly associated with obesity and hyperlipidemia in both sexes. Elevated serum uric acid concentration was strongly associated with obesity and hyperlipidemia in both men and women. These results indicated that, among hyperuricemia patients, we should pay more attention to the possibility of cardiovascular complications. These results might provide a novel target or a possible new treatment for cardiovascular diseases by lowering the level of serum uric acid.


Prevalence, predictors, and management for balloon uncrossable or undilatable lesions in patients undergoing percutaneous coronary intervention with in-stent restenosis chronic total occlusion.
Percutaneous coronary intervention for in-stent restenosis (ISR) chronic total occlusion (CTO) has been a great challenge. There are occasions when the balloon is uncrossable or undilatable (BUs) even though the guidewire has passed, leading to failure of the procedure. Few studies have focused on the incidence, predictors, and management of BUs during ISR-CTO intervention. Patients with ISR-CTO were recruited consecutively between January 2017 and January 2022 and divided into two groups based on the presence of BUs. The clinical data of the two groups (BUs group and non-BUs group) were retrospectively analyzed and compared to explore the predictors and clinical management strategies of BUs. A total of 218 patients with ISR-CTO were included in this study, 23.9% (52/218) of whom had BUs. The percentage of ostial stents, stent length, CTO length, the presence of proximal cap ambiguity, moderate to severe calcification, moderate to severe tortuosity, and J-CTO score were higher in the BUs group than in the non-BUs group (p < 0.05). The technical success rate and the procedural success rate were lower in the BUs group than in the non-BUs group (p < 0.05). Multivariable logistic regression analysis showed that ostial stents (OR: 2.011, 95% CI: 1.112-3.921, p = 0.031), the presence of moderate to severe calcification (OR: 3.383, 95% CI: 1.628-5.921, p = 0.024) and moderate to severe tortuosity (OR: 4.816, 95% CI: 2.038-7.772, p = 0.033) were independent predictors of BUs. The initial rate of BUs in ISR-CTO was 23.9%. Ostial stents, presence of moderate to severe calcification, and moderate to severe tortuosity were independent predictors of BUs.


Retroviral DNA H structures: displacement-assimilation model of recombination.
The avian retroviruses are unique among known RNA and DNA viruses in their extremely high frequencies of genetic recombination. We propose that these high frequencies can be explained by the facts that the closely associated RNA genomes of this diploid virus can be reverse-transcribed concurrently and that strand displacement is a fundamental property of the reverse transcription reaction. We have elaborated a specific model to describe this process that was suggested by the properties of novel structures observed with high frequency in the electron microscope: DNA duplexes in dimer arrangement that are linked at homologous regions by single-stranded DNA bridges. These structures are presumed to be intermediates of recombination, trapped because their generation in vitro prevents the subsequent resolution steps that would normally take place via the cellular apparatus during infection. The model generates several hypotheses whose exploration should help to test its accuracy.


Mutant FUS induces chromatin reorganization in the hippocampus and alters memory processes.
Cytoplasmic mislocalization of the nuclear Fused in Sarcoma (FUS) protein is associated to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Cytoplasmic FUS accumulation is recapitulated in the frontal cortex and spinal cord of heterozygous Fus∆NLS/+ mice. Yet, the mechanisms linking FUS mislocalization to hippocampal function and memory formation are still not characterized. Herein, we show that in these mice, the hippocampus paradoxically displays nuclear FUS accumulation. Multi-omic analyses showed that FUS binds to a set of genes characterized by the presence of an ETS/ELK-binding motifs, and involved in RNA metabolism, transcription, ribosome/mitochondria and chromatin organization. Importantly, hippocampal nuclei showed a decompaction of the neuronal chromatin at highly expressed genes and an inappropriate transcriptomic response was observed after spatial training of Fus∆NLS/+ mice. Furthermore, these mice lacked precision in a hippocampal-dependent spatial memory task and displayed decreased dendritic spine density. These studies shows that mutated FUS affects epigenetic regulation of the chromatin landscape in hippocampal neurons, which could participate in FTD/ALS pathogenic events. These data call for further investigation in the neurological phenotype of FUS-related diseases and open therapeutic strategies towards epigenetic drugs.


Polydiacetylene/triblock copolymer nanoblend applied as a sensor for micellar casein: A thermodynamic approach.
Polydiacetylene (PDA) and triblock copolymer nanoblends were synthesized to detect micellar casein (MC), the main milk protein and an indicator of milk quality. UV-Vis spectrum showed that MC induced blue-to-red transition in nanoblends. When nanoblends and MC were separated by dialysis membrane colorimetric response (CR) was similar, whereas a remarkable CR reduction was noticed after addition of dialyzed-MC, suggesting that small molecules present in MC (salts) caused PDA color change. Interaction enthalpy variation between nanoblends and MC showed an abrupt increase that coincided with MC concentration when colorimetric transition occurred. Copolymer hydrophobic/hydrophilic balance and presence of other molecules in the system affected nanoblends CR. MC salts were found to interact with nanoblends leading to color changes. MC concentration, MC salt release, copolymer hydrophobic/hydrophilic balance, and presence of other molecules in the system affected responses of the sensors. These results contribute to future applications of PDA/copolymer nanosensors to dairy models.


Liver transplantation and incidentally found hepatocellular carcinoma in liver explants: need for a new definition?
"Incidentally" identified hepatocellular carcinoma (iHCC) in liver explants after liver transplantation (LTx) is a frequently reported finding, which is characterized with a good prognosis. The purpose of this study was to evaluate the outcome of patients with these tumors in our series and in literature reports, and to compare their prognosis to that of HCC diagnosed preoperatively. From April 1998 to December 2003, 432 patients underwent deceased-donor LTx at our center for nonmalignant indications. An additional 31 patients with a preoperative known HCC (pkHCC) received deceased-donor grafts. A literature search was performed intending to estimate the incidence of iHCC in liver explants and the outcome after LTx. iHCC was found in 5 of the 432 patients. All five patients are currently alive without evidence of tumor recurrence after a median follow-up of 43 months. On the other hand, in the group of the 31 patients with pkHCC, 22 of them are at the moment alive in a median follow-up of 28 months. When comparing the two groups, no difference in survival could be found (P=0.1419 in log-rank test). Literature reports of 705 instances with iHCC over the past 20 years showed a statistical "better survival" in only 24 cases. Literature reports showed a remarkable "deviation" of the expected tumor characteristics for the iHCC. Obviously, this is because of a widely characterization of iHCC, including also tumors which are rather undetected HCC during the waiting time to LTx. A more precise definition for the iHCC is needed.


Biflorin inhibits the proliferation of gastric cancer cells by decreasing MYC expression.
Gastric cancer is the third leading cause of cancer-related death worldwide. To evaluate the anticancer potential and molecular mechanism of biflorin, a prenyl-ortho-naphthoquinone obtained from Capraria biflora L. roots, we used ACP02, a gastric cancer cell line established from a primary diffuse gastric adenocarcinoma. In this study, biflorin was shown to be a potent cytotoxic agent against ACP02 by Alamar Blue and Trypan Blue assays. Morphological analysis indicated cell death with features of necrosis. Furthermore, a decrease in colony formation, migration and invasion of ACP02 cells was observed after treatment with biflorin (1.0, 2.5 and 5.0 μM). Regarding the underlying molecular mechanism of biflorin in ACP02 cells, we observed a decrease in MYC expression and telomere length using FISH. Our findings suggest a novel molecular target of biflorin in ACP02 cells, which may be a significant therapeutic approach for gastric cancer management.


Gene disruption in Candida albicans using a synthetic, codon-optimised Cre-loxP system.
The development of the molecular toolbox for the fungal pathogen Candida albicans has been hampered by its lack of an exploitable sexual cycle, its diploid nature, and its non-canonical genetic code. We describe the adaptation of the Cre-loxP site-specific recombination system as a tool for the efficient and controlled disruption of C. albicans genes. We have validated this system by disrupting two C. albicans loci: ADE2 and MET15. Ade2 and met15 null mutants were made using loxP-flanked ARG4- and HIS1-based disruption cassettes. These markers were then resolved from the C. albicans genome using a synthetic codon-optimised cre recombinase gene, with near 100% efficiency. Finally, CIp plasmids containing the URA3, HIS1, and ARG4 markers were generated for the reintegration of markers and target genes in control strains. This system allows multiple and sequential genetic manipulations, which will facilitate the functional analysis of multigene families in C. albicans.


Heterojunction engineered bioactive chlorella for cascade promoted cancer therapy.
The hypoxic tumor microenvironment is one of most major hurdles restraining the anti-tumor efficiency of photodynamic therapy (PDT). Herein, active photosynthetic Chlorophyceae (Chlorella, Chl) functionalized with black phosphorus nanosheets (BPNSs) through polyaspartic acid (PASP) and Fe3+ mediating "Lego building method" are utilized for photocatalyzed oxygen-evolving to realize photosynthesis enhanced synergistic photodynamic/chemodynamic/immune therapy. The Chl cells with inherent photosynthesis and distinct metabolites are able to ameliorate tumor hypoxia, enhance immune cells infiltration, and stimulate the proliferation and maturation of immune cells. BPNSs loaded on the surface of Chl cells construct a type-II heterojunction with the chlorophyll in Chl cells, which improves the conversion efficiency of light through thoroughly separating photo-excited electrons and holes for 1O2 generation and O2 evolution, respectively. Additionally, the lock between "Lego bricks", Fe3+, can both consume glutathione (GSH) and catalyze Fenton reaction with H2O2 to generate ·OH, mediating chemodynamic therapy (CDT). Moreover, Chl@BP-Fe also exhibited high biocompatibility and potential biodegradability, guaranteeing high potential for clinic applications of this synergistic photodynamic/chemodynamic/immune therapy.


Severe Acute Respiratory Distress Syndrome in Potential Organ Donors-Rescue Prone Positioning: A Case Report.
Organ transplantation is a recognized treatment for many critical organ insufficiencies. One of the main problems in transplantation is the mismatch between organ donation and demand. It is very important to improve donor eligibility after brain stem death and to minimize insult to donatable organs by appropriate donor management. We present prone positioning as an effective supportive method of organ optimization in patients with acute respiratory distress syndrome with severe hypoxemia and hemodynamic instability.


Effects of peripheral transverse line markings on drivers' speed and headway choice and crash risk in car-following: A naturalistic observation study.
Rear-end crashes are closely related to car-following situation of vehicles. Speeding and insufficient headway are the major reasons as the drivers have not enough time to react to a sudden brake from the leading vehicle. Perceptual countermeasures, like speed reduction markings, are widely used in practice for accident prevention, and are verified with substantial effectiveness. However, compared with its practical application, the perceptual countermeasures are rarely analyzed in depth from the perspective of drivers' visual perception where the meaning of "perceptual" actually dwells. In addition, its effect on drivers' headway (distance) choice is almost ignored in previous research. Given this, the present study explored the effects of a certain type of perceptual treatment, i.e., the peripheral transverse line markings (PTLMs), on drivers' choice of speed and headway (distance) in car-following by a series of on-road experiments. In the on-road experiments, temporary line markings were installed on a real-world freeway in China to shape the PTLMs. The intersection angle (α) and the longitudinal spacing (λ) of the PTLMs were manipulated to attempt to associate the line markings with drivers' visual perception. Results of general and sectional relative differences of time headway (ηh, θh), speed (ηv, θv), and distance (ηd, θd) suggests that 1) the speed was reduced, the distance and time headway were increased significantly after the installation of PTLMs when compared with the original condition; 2) a larger intersection angle (α) and a smaller longitudinal spacing (λ) of PTLMs could lead to a greater variations in speed and headway (distance); in particular, the PTLMs in a form of α=150°, λ=2m resulted in 0.44 s increase in time headway, 1.33 m/s reduction in speed, and 4.07 m increase in distance in maximum; 3) the real-time crash risk variations under the influence of PTLMs were evaluated by two modified and extended surrogate safety indicators. The effects of PTLMs were discussed and explained considering the influences of optical illusion on lane width narrowing, edge rate on speed and "discontinuity effect" on distance, respectively. The findings of this study provide theoretical support for the perceptual countermeasures and suggest comparative advantages of PTLMs in dealing with rear-end crashes by intervening drivers' speed and headway choice.


Transdermal enhancement strategy of ketoprofen and teriflunomide: The effect of enhanced drug-drug intermolecular interaction by permeation enhancer on drug release of compound transdermal patch.
The aim of the present work was to develop compound transdermal patch containing teriflunomide (TEF) and ketoprofen (KTP) using permeation enhancement strategy; reveal the molecular mechanism by which Azone (AZ) promoted transdermal absorption of compound patch through the enhancement of drug-drug intermolecular interaction. The formulation was optimized using in vitro skin permeation study and confirmed with pharmacodynamics study, anti-inflammatory study and analgesics study. Enhanced drug-drug interaction by AZ was characterized using FT-IR, 13C NMR, molecular modeling and thermal analysis. The optimized formulation was composed of TEF (3%), KTP (2%), AZ (10%) and DURO-TAK® 87-4098 as adhesive matrix. The skin permeation amount of TEF-KTP combination was promoted by AZ about 1.9 times (594.2 ± 46.8 μg/cm2) and 1.2 times (502.92 ± 24.0 μg/cm2) compared with TEF-AZ and KTP-AZ individual patch. It was proved that the interaction between TEF and KTP via hydrogen bonding was further enhanced by AZ due to the increased molecular mobility of acrylate polymer (ΔTg = -17.7 °C), which was proved by FTIR and 13C NMR spectra. The enhanced drug-drug intermolecular interaction increased drug dispersed status and decreased the quantity of drug's hydrogen bonding site, thus increasing the drug release amount significantly. In conclusion, a compound transdermal patch containing KTP and TEF was developed successfully and a novel enhancement mechanism was clarified at molecular level, which provided reference for the development of novel compound transdermal patch.


Partially folded conformations in the folding pathway of bovine carbonic anhydrase II: a fluorescence spectroscopic analysis.
GdmCl-, urea-, and pH-induced unfolding pathways of bovine carbonic anhydrase II have been analyzed by using changes induced by different denaturing agents in intensity, anisotropy, life time, and parameter A value of intrinsic fluorescence as well as intensity and life time of ANS (ammonium salt of 8-anilinonaphthalene-1-sulfonic acid) fluorescence. The formation of several stable unfolding intermediates, some of which were not observed previously, has been established. This was further confirmed by representation of fluorescence data in terms of a "phase diagram", that is, I(lambda1) versus I(lambda2) dependence, where I(lambda1) and I(lambda2) are the fluorescence intensity values measured at wavelengths lambda(1) and lambda(2), respectively.


Interstitial deletion of the long arm of chromosome 6.
A de novo interstitial deletion of 6q21 was observed in a male baby with moderate microcephaly, facial dysmorphism, and psychomotor retardation. In situ hybridization with a c-myb probe showed that the gene was conserved on the deleted chromosome.


Energetic cost of web construction and its effect on web relocation in the web-building spider Agelena limbata.
Although spider webs may be effective in trapping prey, they require energy for construction. The design of webs varies in complexity from species to species. I assume that the energetic cost of web construction is significantly different among web types or species. This cost may constrain foraging tactics, particularly web relocation, because web relocation also requires energy to make a new web. To clarify the effect of the cost of web construction on web relocation, the energy cost of web construction and the rate of web relocation were estimated for the spider Agelena limbata. This spider constructs a sheet-funnel web consisting of a tight mesh of silk threads. This web was costly in terms of the energy needed for construction, which ranged from 9 to 19 times the daily maintenance energy. The daily rate of web relocation was below 1%, indicating high web-site tenacity. Relocation rates of species which built different types of web were compared in relation to cost of web construction. Orbweavers, which produce less costly webs than sheet-funnel weavers, relocate webs more frequently. Sheetweavers, which make webs of intermediate cost, appear to relocate webs more frequently than sheetfunnel weavers but less frequently than orbweavers. These results suggest that the energy cost of web construction is important in determining the frequency of web relocation.


Antimycobacterial activity of azepanobetulin and its derivative: In vitro, in vivo, ADMET and docking studies.
The antimycobacterial investigation of azepanobetulin and its amide derivative was performed. Both compounds showed increased in vitro antibacterial activity on the H37Rv MTB strain in aerobic and anaerobic conditions. Basing on differences between MIC and IC50 values a predominant bactericidal effect for amide in contrast to azepanobetulin with a bacteriostatic antibacterial mechanism is defined. Both compounds showed a strong antibacterial effect against resistant MTB strains with amide derivative being slightly more active. Amide derivative also showed a higher antibacterial potency against non-tuberculous mycobacterial strains (M. avium, M. abscessus). Molecular docking studies showed that the inhibition of tuberculosinyl adenosine transferase (Rv3378c) could constitute an antimycobacterial mechanism of action for these triterpenic azepane derivatives. The pharmacokinetic profile was evaluated by ADMET studies and azepanobetulin showing the better results was evaluated by in vivo experiments. This compound has demonstrated a statistically significant antimycobacterial activity compared to control, but inferior to isoniazid. Our findings show that pentacyclic triterpene derivatives holding a seven-membered azepane A-ring are the promising template for the development of new agents with high antibacterial potential against M. tuberculosis H37Rv, non-tuberculous mycobacterial and drug- resistant strains.


Biological cost of fosfomycin resistance in Escherichia coli in a murine model of urinary tract infection.
Prevalence of fosfomycin resistance in E. coli clinical isolates from UTIs remains very low. Our hypothesis was that fosfomycin resistance may be associated with a biological cost. Three groups of strains of E. coli belonging to the B2 phylogenetic group were used: clinical wild-type (WT) isolates, clinical multidrug-resistant isolates and in vitro fosfomycin-resistant derivatives from the uropathogen clinical strain E. coli CFT073. In each group fosfomycin-susceptible and -resistant isolates were compared. In vitro, we found a significantly decreased growth rate for fosfomycin-resistant strains as compared with susceptible strains in the WT group. In a murine model of ascending UTI, there was a significant reduction in infection rates with fosfomycin-resistant isolates as compared with susceptible ones, in all 3 study groups, ranging from 28 to 39% (P<0.03). All fosfomycin-susceptible clinical strains were virulent in vivo (13/13), while fosfomycin-resistant clinical strains were either virulent (2/7) or non-virulent (5/7) (P<0.002). This difference was not explained by the number of virulence factors or pathogenicity-associated islands. In conclusion, fosfomycin resistance appears to carry some biological cost in E. coli, which may explain in part the apparent paradox of the low prevalence of fosfomycin resistance despite a high rate of spontaneous mutants.


Combined die-investment stone and die-stone cast for making resin-retained prostheses.
A technique has been presented for developing a combined die-investment stone/die stone-full arch working cast for use in making a resin-retained prosthesis. The advantage of the technique is that it affords the opportunity to articulate the working cast with a cast of the opposing arch and make the framework directly on a refractory material, while minimizing the subsequent need to trim the refractory material.


Chemoprophylaxis of Dirofilaria immitis (Leidy 1856) infection at a high challenge environment.
The frequency of canine heartworm infection in the state of Rio de Janeiro, Brazil was high before chemoprophylactic treatment was available, with one of the highest rates of infection (52.5 %) found among dogs living on the eastern shore of the state. Following the launch of a chemoprophylactic product, the rate of infection gradually decreased, and new infections were rarely reported. After 2005, outbreaks reported at the eastern shore as well as for new infections in other areas of high infection frequency were considered to possibly be related to reduced efficacy of macrocyclic lactones. Therefore, this study aimed to evaluate the efficacy of topical heartworm preventatives from different drug families at the high challenge area of the state of Rio de Janeiro. A total of 46 dogs, including animals negative for Dirofilaria immitis microfilariae and antigen (Snap 4 Dx, IDEXX Laboratories, USA) at the initial screening were randomly allocated to two monthly treatment groups. Dogs in one group received topical moxidectin + imidacloprid and dogs in the other group received topical selamectin for eight consecutive months. Blood samples were obtained for microfilariae and antigen detection until the eleventh month after the first treatment. Dogs becoming microfilaremic or antigenemic on or before day 180 were considered to be infected prior to the first dose and were excluded from the study. A total of 29 dogs completed the study, including 14 treated with moxidectin + imidacloprid and 15 treated with selamectin. No dogs treated with moxidectin + imidacloprid (0/14) became infected during the treatment period, whereas four dogs of the selamectin group (4/15) became infected. Topical moxidectin + imidacloprid is 100 % effective in preventing D. immitis infections in dogs living in a high challenge natural environment.


Factors affecting the incidence of wound infection in Neurosurgery.
A prospective survey of wound infection in a continuous series of 357 patients undergoing operations at a neurosurgical unit was made. The incidence of wound infection was 4.7 percent. Causative organisms were isolated in only 29.4 percent of the clinically infected cases. The type of suture material used did not affect the infection rate and neither did the coincidental use of steroids in the high doses employed in neurosurgical practice. Re-exploration does not carry an increased risk of infection. Use of systemic or topical antibiotics or both was not found to confer any protection against wound infection.


The effect of divalent metal cations on the inhibition of human coagulation factor Xa by plasma proteinase inhibitors.
The inactivation of human coagulation factor Xa by the plasma proteinase inhibitors alpha 1-antitrypsin, antithrombin III and alpha 2-macroglobulin in purified systems was found to be accelerated by the divalent cations Ca2+, Mn2+ and Mg2+. The rate constant for the inhibition of factor Xa by antithrombin III rose from 2.62 X 10(4) M-1 X min-1 in the absence of divalent cations to a maximum of 6.40 X 10(4) M-1 X min-1 at 5 mM Ca2+, 8.10 X 10(4) M-1 X min-1 at 5 mM Mn2+, with a slight decrease in rate at higher cation concentrations. Mg2+ caused a gradual rise in rate constant to 5.65 X 10(4) M-1 X min-1 at 20 mM. The rate constant for the inhibition of factor Xa by alpha 1-antitrypsin in the absence of divalent cations was 5.80 X 10(3) M-1 X min-1. Ca2+ increased the rate to 1.50 X 10(4) M-1 X min-1 at 5 mM and Mn2+ to 2.40 X 10(4) M-1 X min-1 at 6 mM. The rate constant for these cations again decreased at higher concentrations. Mg2+ caused a gradual rise in rate constant to 1.08 X 10(4) M-1 X min-1 at 10 mM. The rate constant for the factor Xa-alpha 2-macroglobulin reaction was raised from 6.70 X 10(3) M-1 X min-1 in the absence of divalent cations to a maximum of 4.15 X 10(4) M-1 X min-1 at 4 mM Ca2+, with a decrease to 3.05 X 10(4) M-1 at 10 mM. These increases in reaction rate were correlated to the binding of divalent cations to factor Xa by studying changes in the intrinsic fluorescence and dimerization of factor Xa. The changes in fluorescence suggested a conformational change in factor Xa which may be responsible for the increased rate of reaction, whilst the decrease in rate constant at higher concentrations of Ca2+ and Mn2+ may be due to factor Xa dimerization.


Evaluation of mesoporous borosilicate glass-ceramic composites as frits in reference electrodes.
The development of new mesoporous frits for reference electrodes to overcome the limitations of cross-contamination and screening effect is essential for many electrochemical measurements. Available frit-based reference electrodes (e.g., mesoporous, microporous) still suffer from cross-contamination and/or errors in electrochemical measurements. In this work, a mesoporous glass-ceramic composite is prepared to mitigate such limitations. Mesoporous glass-ceramic frits were prepared from low-cost materials (i.e., borosilicate and kaolin) at relatively low temperatures (750-850 °C). The prepared glass-ceramic frits were characterized using scanning electron microscopy (SEM), impedance measurements, and nitrogen sorption isotherms. The developed mesoporous glass-ceramic composites are characterized by a high chemical resistance against corrosive materials and a low thermal expansion. Reference electrodes constructed with the developed mesoporous glass-ceramic frits exhibited a low flow rate of 0.002 ± 0.001 to 0.41 ± 0.06 μL h-1 and high potential stability as well as very small potential drift of -2.4 ± 0.2 to -4.9 ± 0.2 μV h-1. Mesoporous glass-ceramic based reference electrodes exhibited average potential variations of 13 ± 3 mV over the concentration range of 1 mM to 0.1 M KCl. This indicates that mesoporous glass-ceramic frit-based reference electrodes exhibited a much lower flow rate compared to available microporous frit-based reference electrodes. Moreover, the developed mesoporous ceramic-based reference electrodes exhibited a 4-15-fold improvement in potential variations and a large improvement in potential stability in comparison with the reported mesoporous-frit-based reference electrodes.


Giardia lamblia aurora kinase: a regulator of mitosis in a binucleate parasite.
Giardia lamblia is a major cause of diarrhoeal disease worldwide. Since it has no known toxin, the ability of trophozoites to colonise the human small intestine is required for its pathogenesis. Mitosis in this protozoan parasite is a unique challenge because its two equivalent nuclei and complex cytoskeleton must be duplicated and segregated accurately. Giardial mitosis is a complex and rapid event that is poorly understood at the cellular and molecular levels. Higher eukaryotes have one to three members of the highly conserved Ser/Thr aurora kinase (AK) family that regulate key aspects of mitosis and cytokinesis. Giardia has a single AK orthologue (gAK) with 61% similarity to human AK A. In addition to the conserved active site residues, activation loop and destruction-box motifs characteristic of AKs, gAK contains a unique insert near the active site region. We epitope-tagged gAK at its C-terminus and expressed it under its own promoter. During interphase, gAK localises exclusively to the nuclei, but is not phosphorylated as shown by lack of staining with an antibody specific to phosphorylated AK A (pAK). In contrast, during mitosis pAK localises to the basal bodies/centrosomes and co-localises with tubulin to the spindle. During specific stages of mitosis, giardial pAK also localised dynamically to cytoskeletal structures unique to Giardia: the paraflagellar dense rods of the anterior flagella and the median body, whose functions are unknown, as well as to the parent attachment disc. Two AK inhibitors significantly decreased giardial growth and increased the numbers of cells arrested in cytokinesis. These inhibitors appeared to increase microtubule nucleation and cell-ploidy. Our data show that gAK is phosphorylated in mitosis and suggest that it plays an important role in the Giardia cell cycle. The pleiotropic localisation of AK suggests that it may co-ordinate the reorganisation and segregation of tubulin-containing structures in mitosis. We believe this is the first report of a signalling protein regulating cell division in Giardia.


The COVID-19 Context Calls for a Broader Range of Healthcare Chaplaincy Models: An Exploratory Translational Study Utilizing Evolutionary Psychology and Social Neuroscience Loneliness Research.
Shifts in chaplain requests from patients and families and lack of engagement by staff in now traditional support forms in the COVID-19 context suggest that new insights and resourcing are needed. This exploratory translational study suggests that the evolutionary psychology of R. I. M. Dunbar and the social neuroscience of J. T. Cacioppo, his collaborators, and successors and their concerns for human loneliness have potential for use in development of effective healthcare chaplaincy practice in the COVID-19 context.


Bracken fern-induced malignant tumors in rats: absence of mutations in p53, H-ras and K-ras and no microsatellite instability.
Bracken fern (genus Pteridium) has been shown to induce tumors in domestic and experimental animals. Epidemiological studies have also shown an association between human exposure to bracken toxins and increased risk for the development of upper gastrointestinal tract tumors. Our aim in this study was to investigate possible genomic alterations in bracken fern-induced tumors of experimental animals searching for molecular markers that might be used for human epidemiological studies. Using human colorectal carcinogenesis as a molecular model, we examined eight malignant bracken fern-induced tumors of rats for mutations in the genes associated with the "classic pathway" of colorectal cancer, i.e. p53 and ras, and also in the "mutator pathway" by evaluating microsatellite instability. Exons 5-9 of the p53 gene and exons 1 and 2 of the K-ras and H-ras genes were examined by DNA sequencing and no mutations were found in any of the eight tumors. Amplification of five previously validated microsatellite loci (one with mono-, three with di- and one with tetra-nucleotide repeat motifs) in the malignant tumors and in the surrounding normal tissue did not reveal any instability. The involvement of epigenetic alterations or of mutations in other tumor suppressor genes or oncogenes should be further investigated in the search for human epidemiological markers.


PDE1 isozymes, key regulators of pathological vascular remodeling.
Pathological vascular remodeling is a hallmark of most vascular disorders such as atherosclerosis, postangioplasty restenosis, allograft vasculopathy, and pulmonary hypertension. Pathological vascular remodeling is a multi-cell-dependent process leading to detrimental changes of vessel structure and eventual vessel occlusion. Cyclic nucleotide signaling regulates a variety of vascular functions ranging from cell contractility to cell growth. Cyclic nucleotide phosphodiesterases (PDEs), a large family of structurally and functionally distinct isozymes, regulate cyclic nucleotide levels and compartmentalization through catalyzing their degradation reaction. Increasing evidence has suggested that one of the important mechanisms for specific cyclic nucleotide regulation is exerted through selective activation or inhibition of distinct PDE isozymes. This review summarizes the work done to characterize the role and therapeutic potential of PDE1 isozymes in pathological vascular remodeling.


Determination of the minimal phototoxic dose and colorimetry in psoralen plus ultraviolet A radiation therapy.
The use of an adequate initial dose of ultraviolet A (UVA) radiation for photochemotherapy is important to prevent burns secondary to overdosage, meanwhile avoiding a reduced clinical improvement and long-term risks secondary to underdosage. The ideal initial dose of UVA can be achieved based on the phototype and the minimal phototoxic dose (MPD). The objective measurement of constitutive skin color (colorimetry) is another method commonly used to quantify the erythematous skin reaction to ultraviolet radiation exposure. The aim of this study was to determine variations in MPD and constitutional skin color (coordinate L(*)) within different phototypes in order to establish the best initial dose of UVA radiation for photochemotherapy patients. Thirty-six patients with dermatological conditions and 13 healthy volunteers were divided into five groups according to phototype. Constitutional skin color of the infra-axillary area was assessed by colorimetry. The infra-axillary area was subsequently divided into twelve 1.5 cm(2) regions to determine the MPD; readings were performed 72 h after oral administration of 8-methoxypsoralen (MOP) followed by exposure of the demarcated regions to increasing doses of UVA. The majority of the participants were women (73.5%) and their mean age was 38.8 years. The MPD ranged from 4 to 12 J/cm(2) in phototypes II and III; from 10 to 18 J/cm(2) in type IV; from 12 to 24 J/cm(2) in type V and from 18 to 32 J/cm(2) in type VI. The analysis of colorimetric values (L(*) coordinate) and MPD values allowed the definition of three distinctive groups of individuals composed by phototypes II and III (group 1), types IV and V (group 2), and phototype VI (group 3). MPD and L(*) coordinate showed variation within the same phototype and superposition between adjacent phototypes. The values of the L(*) coordinate and the MPD lead to the definition of three distinct sensitivity groups: phototypes II and III, IV and V and type VI. Also, the MPD values bear a strong correlation to coordinate L(*) values. Mean MPD values described for each of the three major sensitivity groups were higher than the values commonly used in clinical settings for the different phototypes. Therefore, phototype alone is not a good parameter to define the initial UVA dose. MPD and colorimetry could be used in pre-treatment evaluation of patients who are to be submitted to photochemotherapy, in a non-invasive and more accurate way when compared with the classical phenotype clinical criteria.


Green supply chain decision of discarded drugs recycling: Evolutionary game and strategy simulation.
The research on the recycling of discarded drugs has become an important direction of the green supply chain in China. Faced with the great challenge of recycling discarded drugs in China, it is necessary to make clear the behavior choice of each recycling subject. This paper constructs an evolutionary game model among government, drugs recycling companies and consumers, describes the evolutionary game process, and analyzes the influence of the gain of government, drug recycling enterprises and consumers on the evolutionary stable strategy trend. By using Matlab simulation software to simulate the evolution of tripartite behavior, the final result is obtained: The government's choice of a strong regulatory strategy has an important positive role in guiding the entire discarded drug recovery market. Consumer's choice of active participation strategy and enterprise's choice of active participation strategy are most beneficial to the healthy development of the discarded drug recovery market. This study provides some valuable theoretical support and reference for the national decision-making of discarded drug recovery, helps to solve the problem of discarded drug recovery, and provides theoretical support and policy-making recommendations for the ultimate achievement of sustainable development goals.


The use of hypothermia in surgical pinealectomy of the neonate rat.
A technique is described in which rat pups (5-7 days old) are induced into a state of suspended animation by placing them in the freezing compartment of a refrigerator at -20 degrees C for 8-10 minutes. This induces cessation of respiration and heart beat for 12-15 minutes. Surgical pinealectomy is undertaken during this period. Postoperation the animal is gradually warmed and restored to its dam. The effectiveness of pinealectomy was checked after some 400 days by measurement of plasma dark cycle melatonin levels using radioimmune assay. The method is reliable, robust and the results predictable, no melatonin being detectable 400 days after surgery.


Mechanisms of Resistance to Immune Checkpoint Antibodies.
Immunotherapy using checkpoint inhibitors has changed the way we treat several aggressive cancers such as melanoma, non-small cell lung and head & neck cancers, among others, with durable responses achieved in the metastatic setting. However, unfortunately, the vast majority of patients do not respond to checkpoint inhibition therapy and a minority of patients, who do respond to treatment, develop secondary resistance and experience relapse by mechanisms still inadequately understood. Emerging evidence shows that alterations in multiple signaling pathways are involved in primary and/or secondary resistance to checkpoint inhibition. In this review we discuss how selected cancer-cell autonomous cues may influence the outcome of cancer immunotherapy, particularly immune checkpoint inhibition.


More than one glycan is needed for ER glucosidase II to allow entry of glycoproteins into the calnexin/calreticulin cycle.
Nascent and newly synthesized glycoproteins enter the calnexin (Cnx)/calreticulin (Crt) cycle when two out of three glucoses in the core N-linked glycans have been trimmed sequentially by endoplasmic reticulum (ER) glucosidases I (GI) and II (GII). By analyzing arrested glycopeptides in microsomes, we found that GI removed the outermost glucose immediately after glycan addition. However, although GII associated with singly glycosylated nascent chains, trimming of the second glucose only occurred efficiently when a second glycan was present in the chain. Consistent with a requirement for multiple glycans to activate GII, pancreatic RNase in live cells needed more than one glycan to enter the Cnx/Crt cycle. Thus, whereas GI trimming occurs as an automatic extension of glycosylation, trimming by GII is a regulated process. By adjusting the number and location of glycans, glycoproteins can instruct the cell to engage them in an individually determined folding and quality control pathway.


Interview- and questionnaire-based surveys on elderly patients' wishes about artificial nutrition and hydration during end-of-life care.
To promote advance directives, it is crucial to understand how many older persons have wishes related to end-of-life care. Additionally, it is important to understand how cognitive function or mood affect these wishes. For the interview-based survey, 99 inpatients aged 75 years or older were enrolled after excluding patients with a Mini-Mental State Examination score of 20 or less. For the questionnaire-based survey, 99 outpatients aged 75 years or older without dementia were enrolled. Both surveys comprised the same items on older patients' wishes related to artificial nutrition and hydration (ANH) during end-of-life care. Of the total enrolled patients, 76.8% participated in the interviews. Of these, 50.0% were against ANH during their end-of-life care, including the patients who were definitely against ANH (26.3%). In contrast, just 5.3% wished to receive ANH. In the questionnaire survey, 65.6% of the respondents were against ANH, and 4.9% wished to receive ANH. Aging and Mini-Mental State Examination scores of less than 24 were significantly associated with a higher tendency to decline from participating in the interview. However, the distribution of the interview answers was not associated with age, Mini-Mental State Examination or Geriatric Depression Scale scores. Of the interviewed patients, 84.2% agreed to their responses being preserved in their medical records. Although the majority of the elderly patients were against ANH during end-of-life care, many patients did not have definite wishes in Japan. The percentage of those who were against ANH was not associated with cognitive function or depressive state. Geriatr Gerontol Int 2016; 16: 1204-1210.


Corrigendum: Microalgae-based wastewater treatment for developing economic and environmental sustainability: Current status and future prospects.
[This corrects the article DOI: 10.3389/fbioe.2022.904046.].


A Novel Computer-Aided Method to Evaluate Scoliosis Curvature using Polynomial Math Function.
Scoliosis is a health problem that causes a side-to-side curvature in the spine. The curvature may have an "S" or "C" shape. To evaluate scoliosis, the Cobb angle has been commonly used. However, digital image processing allows the Cobb angle to be obtained easily and quickly, several researchers have determined that Cobb angle contains high variations (errors) in the measurements. Therefore, a more reproducible computer aided-method to evaluate scoliosis is presented. In this analytical study, several polynomial curves were fitted to the spine curvature (4th to 8th order) of thirty plain films of scoliosis patients to obtain the Curvature-Length of the spine. Each plain film was evaluated by 3 physician observers. Curvature was measured twice using the Cobb method and the proposed Curvature-Length Technique (CLT). Data were analyzed by a paired-sample Student t-test and Pearson correlation method using SPSS Statistics 25. The curve of 7th order polynomial had the best fit on the spine curvature and was also used for our proposed method (CLT) obtaining a significant positive correlation when compared to Cobb measurements (r=0.863, P<0.001). The Intraclass Correlation (ICC) was between 0.863 and 0.948 for Cobb method and0.974 to 0.984 for CLT method. In addition, mean measurement of the inter-observer COV (Coefficient of Variation) for Cobb method was of 0.185, that was significantly greater than the obtained with CLT method of 0.155, this means that CLT method is 16.2% more repeatable than Cobb Method. Based on results, it was concluded that CLT method is more reproducible than the Cobb method for measuring spinal curvature.


Exploring Health Professionals' Perceptions on Health-ID, an Electronic Integrated Patient Progress Documentation System: A Qualitative Study in Indonesia.
Continuum of care relies on seamless communication across health professionals. Paper-based integrated patient care documentation is, therefore, obligated in hospitals in Indonesia to standardize information among health providers. However, there are several pitfalls with paper-based documentation. Reported issues regarding time, workload, incomplete patient charts, and delayed verification were seen as obstacles in the implementation of integrated patient progress notes. In an effort to tackle the issues, Health-ID (Health-Integrated Documentation) software was developed to resolve and organize health documentation to break communication boundaries between health professionals. This study was part of a system evaluation of the software program after its implementation in a hospital in Indonesia. The aim was to explore health professionals' perceptions of Health-ID. A qualitative study involving in-depth face-to-face interviews with five key informants and two focus group discussions was conducted. Thematic analysis was used to analyze the data. Thematic analyses of the interviews and focus group discussion revealed several main themes for each of the two topics that were explored in the discussions and interviews: (1) Perceptions on the use of Health-ID: innovative intervention; useful tool. (2) Perceived barriers to the implementation of the Health-ID: workload; organizational support; millennial gaps. The study revealed the potential of the Health-ID to generate effective communication and collaboration among health professions. Reported benefits were as follows: integrating technology in patient progress documentation has been shown to ease the work of health professionals, providing fast and reliable information on patient care updates.


Membrane lytic activity of antibacterial ionenes, critical role of phosphatidylcholine (PC) and cardiolipin (CL).
Understanding the mechanism by which an antibacterial agent interacts with a model membrane provides vital information for better design of future antibiotics. In this study, we investigated two antibacterial polymers, hydrophilic C0-T-p and hydrophobic C8-T-p ionenes, known for their potent antimicrobial activity and ability to disrupt the integrity of lipid bilayers. Our hypothesize is that the composition of a lipid bilayer alters the mechanism of ionenes action, potentially providing an explanation for the observed differences in their bioactivity and selectivity. Calcein release experiments utilizing a range of liposomes to examine the impact of (i) cardiolipin (CL) to phosphatidylglycerol (PG) ratio, (ii) overall vesicle charge, and (iii) phosphatidylethanolamine (PE) to phosphatidylcholine (PC) ratio on the activity of ionenes were performed. Additionally, polymer-bilayer interactions were also investigated through vesicle fusion assay and the black lipid membrane (BLM) technique The activity of C0-T-p is strongly influenced by the amount of cardiolipin, while the activity of C8-T-p primarily depends on the overall vesicle charge. Consequently, C0-T-p acts through interactions with CL, whereas C8-T-p modifies the bulk properties of the membrane in a less-specific manner. Moreover, the presence of a small amount of PC in the membrane makes the vesicle resistant to permeabilization by tested molecules. Intriguingly, more hydrophilic C0-T-p retains higher membrane activity compared to the hydrophobic C8-T-p. However, both ionenes induce vesicle fusion and increase lipid bilayer ion permeability.


Cytochrome bd Displays Significant Quinol Peroxidase Activity.
Cytochrome bd is a prokaryotic terminal oxidase that catalyses the electrogenic reduction of oxygen to water using ubiquinol as electron donor. Cytochrome bd is a tri-haem integral membrane enzyme carrying a low-spin haem b558, and two high-spin haems: b595 and d. Here we show that besides its oxidase activity, cytochrome bd from Escherichia coli is a genuine quinol peroxidase (QPO) that reduces hydrogen peroxide to water. The highly active and pure enzyme preparation used in this study did not display the catalase activity recently reported for E. coli cytochrome bd. To our knowledge, cytochrome bd is the first membrane-bound quinol peroxidase detected in E. coli. The observation that cytochrome bd is a quinol peroxidase, can provide a biochemical basis for its role in detoxification of hydrogen peroxide and may explain the frequent findings reported in the literature that indicate increased sensitivity to hydrogen peroxide and decreased virulence in mutants that lack the enzyme.


Health risk assessment of neonicotinoid insecticide residues in pistachio using a QuEChERS-based method in combination with HPLC-UV.
There is an increasing need to address the potential risks arising from combined exposures to multiple residues from pesticides in the diet. Pesticide residue-related pollution is a problem that arises because of the increased use of pesticides in agriculture to meet the growing demands of food production. In this study, pesticide residue data were obtained based on an optimized extraction method. For this purpose, we established a method based on quick, easy, cheap, effective, rugged, and safe (QuEChERS) extraction for simultaneous determination of imidacloprid (IMI) and acetamiprid (ACT) in pistachio nuts. The parameters influencing the QuEChERS method were the sample-to-water ratio and adsorbent amounts. As a result, both were optimized to improve the recovery of the analytes as well as the clean-up efficiency of the pistachio matrix. Our results indicated that a freeze-out step and use of primary and secondary amines as an adsorbent led to much cleaner chromatograms with lower baseline drift, without using graphitized carbon black and C18 -based adsorbent, which reduced both cost and time of analysis. Following extraction, the pesticide residues were separated and quantified by reverse-phase HPLC. For validation purposes, recovery studies were carried out using a concentration range from 20 to 2500 μg/L at nine levels. The suitable linearity, precision, and accuracy were obtained with HPLC-UV with recoveries of 70.37%-89.80% for IMI and 81.05%-113.57% for ACT, with relative standard deviations <12%. The validated method was successfully applied to the analysis of pistachio samples collected from a field trial to estimate maximum residue limits. There was no significant health risk for consumers via pistachio consumption.


Retrograde jejunogastric intussusception: report of 2 cases.
Two clinical variants of jejunogastric intussusception are described. In one, self-reduction is the rule, whilst in the other strangulation occurs and emergency surgery is mandatory. A case illustrating each variant is presented and its diagnosis and treatment are discussed.


Ternary Copper(II) Complexes With Indomethacin, a Potent Non-Steroidal Antiinflammatory Drug. Crystal Structure of Bis (Dimethylformamide)-Tetrakis[1-(4-Chlorobenzoyl)-5-Methoxy-2-Methyl-1-H-Indole-3-Acetato]Dicopper(II). Antiinflammatory Properties and Prevention of Gastrointestinal Side Effects by Nanocapsules.
Two ternary copper(ll) complexes of indomethacin [1-(4-chlorobenzoyl)-5-methoxy-2- methyl-1-H-indole-3-acetic acid] called hereafter lndo, were prepared and characterized by single crystal X-ray diffraction. The first complex Cu(2)(Indo)(4)(DMF)(2) I crystallizes in space group P-1 (a = 10.829(2), b = 13.379(2), c = 16.491(3) A; alpha = 105.58(2), beta = 101.06(2), gamma = 106.96(2) degrees ; V= 2104.6(6) A(3), Z= 1). The title molecule is a centrosymmetric binuclear complex, with Cu atoms bridged by the carboxylate moieties of four indomethacinate ligands. The four nearest O atoms around each Cu atom form a square planar arrangement with the square pyramidal coordination completed by the O atom of N,N'-dimethylformamide. Daily administration for seven days of 1 mg/kg of indomethacin, I and I encapsulated into liposomes induces a weak inflammation of rat gastrointestinal tract. I was less inflammatory than indomethacin but the better protection was brought by encapsulation of the compound. This might be of interest in sustained therapies of chronic inflammatory diseases.


Article and journal impact factor in various scientific fields.
We tried to provide the scientific community with data to answer the following simple question: What proportion of publications in the various scientific fields is published in journals with impact factor above the median and mean values of the distribution of journal impact factor? We analyzed and compared the distribution of the impact factor data reduced to the unit of science publication, the article. We calculated the proportion of articles published in journals with impact factor above the journal mean impact factor, journal median impact factor, and article mean impact. For all categories examined, at the article level, the mean impact factor was higher than the median (by 13.7% to 500% for the various scientific categories). The mean impact factor of journals was considerably lower than the mean impact factor of articles (by 0.3 to 6.4 units). The proportion of articles that were published in journals with impact factor above the journals' median impact factor was well above 50% in 17 of 19 scientific fields examined (all except mathematics and computer science). Our analysis shows that in most scientific fields examined, it is quite easier to publish an article in the top 50% of journals (based on impact factor calculations) than it is for the article to be included in the top 50% of published articles (based on the assumption made regarding the article' impact factor).


The E. coli immunosorbent as used in serodiagnosis of Legionella infections studied by crossed immunoelectrophoresis.
In this study we investigated an immunosorbent, E. coli blocking fluid (BF), proposed for use in the Legionella Indirect Fluorescent Antibody Test (IFA). With crossed immunoelectrophoresis (CIE) of clinically relevant Legionella species, only one heat-stable antigen (no. 1) cross-reacted with the BF preparation. Patients' sera with elevated Legionella IFA titres did not react with this antigen in CIE. Out of 23 IFA positive patients' sera, six had titres lowered significantly to negative, when BF was applied as serum diluent for the titration (IFA BF negative sera). All six sera were negative in the micro agglutination test (MA). None of the IFA BF negative sera contained any Legionella precipitins in CIE, whereas nine out of the remaining 17 IFA BF positive sera unchanged by BF contained one or more precipitins. CIE results could not explain the effect of BF in Legionella IFA, and further studies are needed to sufficiently define the use of immunosorbents in diagnostic Legionella serology.


Probing the functional limits of the norepinephrine transporter with self-reporting, fluorescent stilbazolium dimers.
A series of stilbazolium dimers were synthesized and investigated as sterically demanding ligands targeting the norepinephrine transporter (NET). The environmentally sensitive fluorescence of the dyes enables their use as self-reporting ligands; binding to and displacement from NET can be monitored by fluorescence microscopy.


Changing times: DNA resequencing and the "nearly normal autopsy".
No matter how meticulous the autopsy, non-traumatic deaths in the young go unexplained from 5-10% of the time. The percentage is higher in children and young adults. Advances in molecular biology and DNA technology now make it possible to explain many of those deaths. This development is not without irony. At the same time that many clinicians are expressing frustration about the lack of tangible gains provided by the Human Genome Project [Greenhalgh T. The Human Genome Project. J R Soc Med. Dec 2005;98(12):545], and pathologists are wondering about the viability of their field, DNA technology is about to reshape the field of forensic pathology. Emerging evidence suggests that the underlying cause of death in many is genetic, and that both the heart and liver abnormalities can both play a role. The problem is that death from a wide variety of genetic defects may leave no histological markers. The ability to identify these "invisible diseases" with postmortem genetic testing has become a reality far more quickly than anyone had ever imagined. The US Food and Drug Administration is about to place "black box" warnings on warfarin advising doctors screen potential recipients for the ability to metabolize that drug and the American Heart Association has recently editorialized that because of genetic-induced variations in electrical conduction that all newborns should have a screening electrocardiogram before they leave the hospital. The introduction of large-scale genetic screening will have an enormous effect on the practice of forensic pathology, far beyond anything seen in our lifetimes. It will also change the practice of medicine as we know it. This paper reviews the current status of the problem.


Idiopathic pulmonary fibrosis.
Idiopathic pulmonary fibrosis (IPF) is a progressive devastating lung disease with substantial morbidity. It is associated with cough, dyspnea and impaired quality of life. If left untreated, IPF has a median survival of 3 years. IPF affects ∼3 million people worldwide, with increasing incidence in older patients. The current concept of pathogenesis is that pulmonary fibrosis results from repetitive injury to the lung epithelium, with fibroblast accumulation, myofibroblast activation, and deposition of matrix. These injuries, in combination with innate and adaptive immune responses, dysregulated wound repair and fibroblast dysfunction, lead to recurring tissue remodeling and self-perpetuating fibrosis as seen in IPF. The diagnostic approach includes the exclusion of other interstitial lung diseases or underlying conditions and depends on a multidisciplinary team-based discussion combining radiological and clinical features and well as in some cases histology. In the last decade, considerable progress has been made in the understanding of IPF clinical management, with the availability of two drugs, pirfenidone and nintedanib, that decrease pulmonary lung function decline. However, current IPF therapies only slow disease progression and prognosis remains poor. Fortunately, there are multiple clinical trials ongoing with potential new therapies targeting different disease pathways. This review provides an overview of IPF epidemiology, current insights in pathophysiology, diagnostic and therapeutic management approaches. Finally, a detailed description of current and evolving therapeutic approaches is also provided.


Phospholipid flippases: building asymmetric membranes and transport vesicles.
Phospholipid flippases in the type IV P-type ATPase family (P4-ATPases) are essential components of the Golgi, plasma membrane and endosomal system that play critical roles in membrane biogenesis. These pumps flip phospholipid across the bilayer to create an asymmetric membrane structure with substrate phospholipids, such as phosphatidylserine and phosphatidylethanolamine, enriched within the cytosolic leaflet. The P4-ATPases also help form transport vesicles that bud from Golgi and endosomal membranes, thereby impacting the sorting and localization of many different proteins in the secretory and endocytic pathways. At the organismal level, P4-ATPase deficiencies are linked to liver disease, obesity, diabetes, hearing loss, neurological deficits, immune deficiency and reduced fertility. Here, we review the biochemical, cellular and physiological functions of P4-ATPases, with an emphasis on their roles in vesicle-mediated protein transport. This article is part of a Special Issue entitled Lipids and Vesicular Transport.


Mechanisms of compensation for vestibular deficits in the frog. I. Modification of the excitatory commissural system.
In hemilabyrinthectomized frogs excitatory responses of central vestibular neurons to electrical stimulation of the remaining vestibular nerve were recorded extra- and intracellulary at different stages (0, 3, and 60 days) after the operation. The output pattern of ipsilateral vestibular neurons sending an axon across the midline via the vestibular commissure to the deafferented nucleus did not change postoperatively. The synaptic efficacy of these commissural axons ending on partially deafferented vestibular neurons on the lesioned side increased with time. This enhanced synaptic potency was associated with a shortening in time to peak and duration and an increase in amplitude of the evoked EPSPs. As a result most vestibular neurons were readily excited by single shock stimulation of the contralateral vestibular nerve, a finding which was rarely observed in control animals. These plastic changes are explained by the assumption of reactive synaptogenesis. The consequences of this modification for the readjustment of static and dynamic vestibular reflexes are discussed.


Ascorbate and dehydroascorbic acid as biomarkers of oxidative stress: validity of clinical data depends on vacutainer system used.
Ascorbate and dehydroascorbic acid are frequently used as biomarkers of oxidative stress, but their lack of stability ex vivo and rapid postsampling interconversion continue to result in erroneous reference values. One problem is the large variety of vacutainer devices used for blood sampling purposes and the basic question of plasma vs serum as matrix. This study acquired blood samples by using 9 different and commonly used vacutainer systems followed by acidic stabilization and analysis by a well-validated method with the purpose of identifying acceptable means of collecting samples for proper ascorbate/dehydroascorbic acid analysis. In comparison, K(3)-EDTA vacutainers were superior in maintaining low ex vivo oxidation of vitamin C.


Pro-Atrial Natriuretic Peptide: A Novel Guanylyl Cyclase-A Receptor Activator That Goes Beyond Atrial and B-Type Natriuretic Peptides.
The aim of this study was to determine if the atrial natriuretic peptide (ANP) precursor proANP is biologically active compared with ANP and B-type natriuretic peptide (BNP). ProANP is produced in the atria and processed to ANP and activates the guanylyl cyclase receptor-A (GC-A) and its second messenger, cyclic guanosine monophosphate (cGMP). ProANP is found in the human circulation, but its bioavailability is undefined. The in vivo actions of proANP compared with ANP, BNP, and placebo were investigated in normal canines (667 pmol/kg, n = 5/group). cGMP activation in human embryonic kidney 293 cells expressing GC-A or guanylyl cyclase receptor-B was also determined. ProANP processing and degradation were observed in serum from normal subjects (n = 13) and patients with heart failure (n = 14) ex vivo. ProANP had greater diuretic and natriuretic properties, with more sustained renal tubular actions, compared with ANP and BNP in vivo in normal canines, including marked renal vasodilation not observed with ANP or BNP. ProANP also resulted in greater and more prolonged cardiac unloading than ANP but much less hypotensive effects than BNP. ProANP stimulated cGMP generation by GC-A as much as ANP. ProANP was processed to ANP in serum from normal control subjects and patients with heart failure ex vivo. ProANP represents a novel activator of GC-A with enhanced diuretic, natriuretic, and renal vasodilating properties, and it may represent a key circulating natriuretic peptide in cardiorenal and blood pressure homeostasis. These results support the concepts that proANP may be a potential innovative therapeutic beyond ANP or BNP for cardiorenal diseases, including heart failure.


Diphenyl diselenide improves the antioxidant response via activation of the Nrf-2 pathway in macrophage cells.
Diphenyl diselenide [(PhSe)2] is an organoselenium compound that can mimic endogenous antioxidant enzymes, such as glutathione peroxidase (GPx), or be metabolized by thioredoxin reductase to form selenol intermediate, which can copy the function of the antioxidant selenoenzymes. This compound has shown potential role in preventing atherosclerosis and other oxidative stress-related diseases. The understanding of the underlying mechanism by which (PhSe)2 modulates the glutathione-related antioxidant defenses is a relevant question. Therefore, we tested its ability to promote the nuclear translocation of the nuclear factor (erythroid 2-like)-related factor 2 (Nrf-2), increasing the expression of enzymes related to the antioxidant system, such as heme oxygenase 1 (HO-1) and peroxiredoxin 1 (Prx-1), in addition to the main enzyme in the glutathione synthesis - gamma glutamylcysteine synthetase (?-GCS) - in murine J774 macrophage cells. (PhSe)2 (1µM) was able to promote nuclear translocation and increased the expression of the Nrf-2 factor in the nucleus in a time-dependent manner (1-24hours). In addition, this compound significantly increased the expression of HO-1 and Prx-1 at 24hours and GPx-1 after the first hour. Furthermore, (PhSe)2 was able to enhance GSH levels in a time-dependent manner, as well as GPx and GGCS activities. The increase in GPx and GGCS activities was dependent on the activation of PI3K, JNK, and p38MAPKs signaling pathways that may activate the Nrf2 factor. Altogether, these results show that (PhSe)2 improved the antioxidant defense by increasing the expression of HO-1 and Prx-1 and the synthesis of GSH as a consequence of the activation and nuclear translocation of Nrf-2 factor.


Trend of Body Compositions with Aging among Chinese Adolescents, Adults and Elders.
Rare reports can be found about sex- and age-specific body composition survey among Chinese population. The aim of this study is to explore the change of sex-specific body compositions with aging among Chinese adolescents, adults and elders. In a large-scale population survey about physiological constants and health conditions, 75,714 subjects who aged from 8 to 80 completed body composition array. Body mass index (BMI), percentage body fat (PBF), water percentage of body weight (WPBW), water percentage of lean body mass (WPLBM), fat-free mass index (FFMI) and basic metabolic rate were examined with Biodynamics BI-310 body composition analyzer. General obesity is defined as BMI equal to or greater than 28 kg/m2. The prevalence rates of general obesity were 9.4% for males and 7.7% for females respectively. With aging, PBF and FMI showed a U-shape curvilinear trend and WPBW showed a parabolic trend for males. At same age group: 18-19 age groups, PBF and FMI declined to the valley and WPBW rose to the peak. For females, PBF, WPBW and FMI changed in a linear trend. The values of WPLBM and FFMI showed same curvilinear trend for two genders. WPLBM changed in a U-shape trend and touched the valley in twenties for males and in 18-19 age groups for females. The value of FFMI was larger for older age groups in the younger generation but smaller in the older generation. A parabolic trend peaking was seen in the thirties for males and in the forties for females. Regression models with age as independent variable showed that the larger rate of increase of PBF and smaller rates of increase for WPBM and WPLBM with aging for males. This study presents detailed data about sex-specific body composition conditions. Different change trend with aging was found about body composition conditions.


A unified approach to dose-effect relationships in radiotherapy. II: Inhomogeneous dose distributions.
Conventional dose-effect relationships, such as those based upon the NSD or linear-quadratic concepts, do not account for dose inhomogeneities. Only a single "dose" value can be used in these equations and this can give rise to significant errors in the estimation of the "tolerance" dose in situations where dose distributions are inhomogeneous. This paper presents a method of "integrating" the biologically effective dose over the entire volume of each organ or tissue irradiated. Integral forms of the variable-exponent TDF and linear quadratic factor (LQF) models (ITDF and ILQF, respectively) can be used to determine whether or not any organ or tissue in an irradiated volume has exceeded tolerance, regardless of dose distribution non-uniformity. Several examples are given with comparisons to solutions obtained by conventional dose-effect models.


Integration of Bioorthogonal Probes and Q-FRET for the Detection of Histone Acetyltransferase Activity.
Histone acetyltransferases (HATs) are key players in the epigenetic regulation of gene function. The recent discovery of diverse HAT substrates implies a broad spectrum of cellular functions of HATs. Many pathological processes are also intimately associated with the dysregulation of HAT levels and activities. However, detecting the enzymatic activity of HATs has been challenging, and this has significantly impeded drug discovery. To advance the field, we developed a convenient one-pot, mix-and-read strategy that is capable of directly detecting the acylated histone product through a fluorescent readout. The strategy integrates three technological platforms-bioorthogonal HAT substrate labeling, alkyne-azide click chemistry, and quenching FRET-into one system for effective probing of HAT enzyme activity.


Electronic tongue and cyclic voltammetric sensors based on carbon nanotube/polylactic composites fabricated by fused deposition modelling 3D printing.
In this work, 3D printed electrodes fabricated by blending Polylactic acid (PLA) with carbon nanotube (CNT), CNT/copper (Cu), CNT/zinc oxide (ZnO) composites were applied as cyclic voltammetric sensors for electronic tongue analysis. Porous rectangular rod-shape electrodes were fabricated by fused-deposition-modelling 3D printing of the CNT-based composites produced by a solution blending method. The physical and chemical properties of 3D printed electrodes were characterized by scanning electron microscopy, X-ray diffraction, Raman spectroscopy, Fourier transform infrared spectroscopy, four-point-probe electrical tests and thermoelectric measurements. The characterization results confirmed uniform distributions of CNTs, Cu particles and ZnO nanorods in the composites and high electrical conductivity of interconnected CNT networks. The additions of Cu and ZnO nanostructures slightly modified the electrical conductivity but significantly changed thermoelectric properties of the material. Cyclic voltammetric (CV) data demonstrated satisfactory stability of the composite materials under corrosive CV conditions. In addition, Cu and ZnO additives provided distinct electrochemical behaviors towards K4Fe(CN)6, H2O2 and nicotinamide adenine dinucleotide. Principal component analysis of CV features could effectively distinguish the three chemicals with various concentrations, illustrating the possibility to apply 3D printed CNT/PLA-based electrodes for electronic tongue applications.


Development of a homogeneous, fluorescence resonance energy transfer-based in vitro recruitment assay for peroxisome proliferator-activated receptor delta via selection of active LXXLL coactivator peptides.
The peroxisome proliferator-activated receptors (PPARs) are nuclear receptors activated by fatty acids and their metabolites. The PPARdelta subtype is believed to be involved in lipoprotein regulation and may have a role in reverse cholesterol transport. While the range of biological roles of PPARdelta still remains unclear, it is of therapeutic interest in cardiovascular diseases. Here we report a homogeneous in vitro assay for studying ligand activation of PPARdelta. We surveyed a panel of peptides containing the LXXLL motifs derived from coactivator protein sequences. Peptides with the best response were used to develop a sensitive and homogeneous recruitment assay for PPARdelta. The optimized assay has a signal-to-background ratio of about 8:1 and an assay quality parameter Z'-factor value of 0.8. The assay signal generated is stable for hours to even overnight. This simple recruitment assay can provide agonist and/or antagonist information that cannot be assessed by receptor-binding assay, and can be used for characterization and screening of ligands that modulate the activation of PPARdelta.


Cutaneous T-cell lymphoma is associated with increased risk of lymphoma, melanoma, lung cancer, and bladder cancer.
Patients with cutaneous T-cell lymphoma (CTCL) are at a higher risk of developing second malignancies. However, rates of incidence vary significantly across studies. A systematic review and meta-analysis of articles published between 1950 and 2019 was performed to evaluate the risk of second malignancies in patients with CTCL. We identified 10 eligible studies, including 12 patient cohorts, with 5.9% to 16.8% of patients developing second malignancies. All studies showed a male predominance for patients developing second malignancies. The mean age across the studies ranged from 44.6 to 68.0 years. The time between the diagnosis of CTCL and second malignancy ranged from 2.1 to 5.4 years (mean, 3.29 y; 95% confidence interval [CI], 2.69-5.15). Meta-analysis showed a standardized incidence ratio of 2.18 (95% CI, 1.43-2.93) for all malignancies. The standardized incidence ratios were 15.25 (95% CI, 7.70-22.79) for Hodgkin lymphoma, 4.96 (95% CI, 3.58-6.33) for non-Hodgkin lymphoma, 1.69 (95% CI, 1.18-2.21) for lung cancer, 1.72 (95% CI, 1.18-2.21) for bladder cancer, and 3.09 (95% CI, 1.77-6.43) for melanoma. We find that patients with CTCL are at increased risk of second malignancies, especially Hodgkin and non-Hodgkin lymphoma, lung cancer, bladder cancer, and melanoma. These findings provide evidence of a population at increased risk of malignancy. Early detection may decrease the morbidity burden of second malignancies, thus providing a strong rationale for prospective screening studies.


The effects of childhood adversity on treatment delays and its components in first-episode psychosis.
Apart from increasing risk for psychotic disorders, childhood adversity has been associated with worse outcomes. One way in which childhood adversity may worsen outcomes is by lengthening treatment delays, which are associated with negative impacts. We tested the influence of childhood trauma on treatment delays, measured as the duration of untreated psychosis (DUP), and its help-seeking and referral components, in a first-episode psychosis cohort (N = 203). We accounted for pertinent social (e.g., migrant status) and other determinants (i.e., age at onset, diagnosis, symptoms) of treatment delays. Multiple linear regression analyses revealed that for a one-unit increase in Childhood Trauma Questionnaire (CTQ) scores, average overall DUP increased by 25%. Higher CTQ scores also significantly predicted help-seeking and referral DUPs. Patients with schizophrenia-spectrum psychosis had longer help-seeking and total DUPs than those with affective psychosis. More severe positive symptoms predicted longer help-seeking DUPs, while more severe negative symptoms predicted longer referral DUPs. Indicators of social disadvantage did not affect DUP. Our results show that childhood trauma increases DUP by prolonging the help-seeking process and delaying access to mental healthcare even after help is sought. Early identification of psychosis among populations with trauma histories seems warranted and can likely positively impact outcomes.


[A regional comparison of outcomes quality and costs of general and specialized palliative care in Germany: a claims data analysis].
The main framework conditions for palliative care are set at the regional level. The scope of the forms of care used (outpatient, inpatient, general, specialized) varies widely. What is the quality of outcomes achieved by the palliative care provided on a federal states level? What are the associated costs of care? Retrospective observational study using BARMER claims data from 145,372 individuals who died between 2016 and 2019 and had palliative care in the last year of life. Regional comparison with regard to the following outcomes: proportion of palliative care patients who died in the hospital, potentially burdensome care in the last 30 days of life (ambulance calls, [intensive care] hospitalizations, chemotherapy, feeding tubes, parenteral nutrition), total cost of care (last three months), cost of palliative care (last year), and cost-effectiveness ratios. Calculation of patient/resident characteristic adjusted rates, costs, and ratios. Federal states vary significantly with respect to the outcomes (also adjusted) of palliative care. Palliative care costs vary widely, most strongly for specialized outpatient palliative care (SAPV). Across all indicators and the cost-effectiveness ratio of total cost of care to at-home deaths, Westphalia-Lippe shows favorable results. Regions with better quality and more favorable cost (ratios) can provide guidance for other regions. The extent to which the new federal SAPV agreement can incorporate the empirical findings should be reviewed. Patient-relevant outcome parameters should be given greater weight than parameters aiming at structures of care.


A running suture line for aortic valve replacement does not increase the rate of postoperative complete heart block.
Surgical implantation of a prosthetic aortic valve is typically done with multiple interrupted sutures. We adapted a running suture line technique for prostheses implantation to decrease the rate of complete heart block necessitating permanent pacemaker. 374 patients undergoing isolated aortic valve replacements were identified between 2015 and 2017. Patients with preoperative heart block, patients undergoing concomitant MAZE procedure and those undergoing multivalve procedures were excluded. Interrupted technique was performed with multiple non-pledgeted sutures. Running technique was performed with three 2-0 polypropylene sutures. Propensity-score matching (caliper distance = 0.10) was used to match based on patient age, gender, BMI, diabetes mellitus, renal failure, heart failure, arrythmias, use of anti-arrhythmics, and STS PROM. Propensity score matching yielded 103 pairs of running technique and interrupted technique patients for analysis. Within the propensity score-matched cohort, there were no differences in sustained complete heart block and need for pacemaker, 4 (3.8%) for running technique vs 3 (2.9%) for interrupted technique (p = 0.307). At 4 weeks, there was no difference in mean prosthetic aortic valve gradients calculated on transthoracic echocardiogram (6.39 ± 2.47 mmHg vs 6.46 ± 2.86, p = 0.850). There was no difference in paravalvular leak (0 (0%) vs 2 (1.9%), p = 0.070). Surgical implantation of a prosthetic aortic valve may be performed with a running suture technique without any significant increase in risk of heart block, need for permanent pacemaker or paravalvular leak. Long-term data will be critical to evaluate any development of paravalvular leaks in the future.


High-Sensitivity C-Reactive Protein and Risks of All-Cause and Cause-Specific Mortality in a Japanese Population.
High-sensitivity C-reactive protein (hsCRP) levels are lower in Japanese compared with Western subjects. Since it is uncertain whether hsCRP is a potent predictor of mortality at low CRP concentrations, the present study examined associations with all-cause and cause-specific mortality in a large population of Japanese. Subjects were 4,737 men and 6,343 women aged 49-76 years participating in the baseline survey of an ongoing cohort study of lifestyle-related diseases between February 2004 and July 2006. Hazard ratios for all-cause and cause-specific mortality associated with hsCRP levels were estimated using Cox proportional hazards regression. A total of 436 all-cause deaths occurred during a median follow- up of 8 years. The main cause of death was cancer. In men, hsCRP levels were positively associated with the risk of all-cause mortality as well as deaths from cancer and cardiovascular disease (CVD). All-cause mortality hazards for the 2nd (0.34-0.84 mg/L) and the 3rd (≥ 0.85 mg/L) tertiles of hsCRP were 1.27 (95% confidence interval [CI], 0.93-1.73) and 1.75 (1.30-2.37), respectively (p for trend=0.001). In women, increased risk of all- cause and cause-specific mortality associated with elevated hsCRP levels was observed, but the associations were not statistically significant. HsCRP may be an independent predictor of all-cause, cancer and CVD mortality in apparently healthy Japanese men, but not women. The differential effect of hsCRP in predicting mortality risk by sex warrants further investigation.


Brain Linac-Based Radiation Therapy: "Test Drive" of New Immobilization Solution and Surface Guided Radiation Therapy.
To test inter-fraction reproducibility, intrafraction stability, technician aspects, and patient/physician's comfort of a dedicated immobilization solution for Brain Linac-based radiation therapy (RT). A pitch-enabled head positioner with an open-face mask were used and, to evaluate inter- and intrafraction variations, 1-3 Cone-Beam Computed Tomography (CBCT) were performed. Surface Guided Radiation Therapy (SGRT) was used to evaluate intrafraction variations at 3 time points: initial (i), final (f), and monitoring (m) (before, end, and during RT). Data regarding technician mask aspect were collected. Between October 2019 and April 2020, 69 patients with brain disease were treated: 45 received stereotactic RT and 24 conventional RT; 556 treatment sessions and 863 CBCT's were performed. Inter-fraction CBCT mean values were longitudinally 0.9 mm, laterally 0.8 mm, vertically 1.1 mm, roll 0.58°, pitch 0.59°, yaw 0.67°. Intrafraction CBCT mean values were longitudinally 0.3 mm, laterally 0.3 mm, vertically 0.4 mm, roll 0.22°, pitch 0.33°, yaw 0.24°. SGRT intrafraction mean values were: i_, m_, f_ longitudinally 0.09 mm, 0.45 mm, 0.31 mm; i_, m_, f_ laterally 0.07 mm, 0.36 mm, 0.20 mm; i_, m_, f_ vertically 0.06 mm, 0.31 mm, 0.22 mm; i_, m_, f_ roll 0.025°, 0.208°, 0.118°; i_, m_, f_ pitch 0.036°, 0.307°, 0.194°; i_, m_, f_ yaw 0.039°, 0.274°, 0.189°. This immobilization solution is reproducible and stable. Combining CBCT and SGRT data confirm that 1 mm CTV-PTV margin for Linac-based SRT was adequate. Using open-face mask and SGRT, for conventional RT, radiological imaging could be omitted.


Treatment of ocular disease in eczema herpeticum.
Individuals with atopic dermatitis are particularly susceptible to herpes simplex viral infection and may develop dissemination (eczema herpeticum). Additionally, they may develop severe and bilateral herpetic ocular disease. The keratitis is commonly complicated by stromal scarring and slow epithelial healing despite topical antiviral therapy. We treated three patients who had herpetic keratoconjunctivitis associated with eczema herpeticum. In all three cases the keratitis resolved promptly (48 to 72 hours) without residual scarring after treatment with systemic acyclovir and topical trifluridine. The combined use of systemic acyclovir and topical trifluridine may be of similar value in treating all cases of atopic herpetic keratitis.


The myelodysplastic syndromes.
The myelodysplastic syndromes constitute a fascinating model for monoclonal premalignant disorders. Haemopoiesis is 'dysplastic' with inefficient maturation of a slowly expanding or sometimes of a stable population, of blood cell precursors. About one third of the patients evolve into acute leukaemia, the result of either a progressive expansion of the original clone or a new mutation producing a more malignant subclone. The majority of patients suffer from the results of bone-marrow insufficiency, with pancytopenia and possibly immune deficiency. Characteristic karyotype anomalies involving mainly chromosomes 5, 7 and 8 are seen in half the patients. These same chromosomes are known to carry different oncogenes. The myelodysplastic syndrome occurs mainly in the aged and there is a moderate male preponderance. The incidence is still unknown but is probably similar to that of acute leukaemia. The etiology is also unknown; however, a secondary myelodysplastic syndrome precedes acute myeloid leukaemia, as a late consequence of chemo- and radio-therapy in treated Hodgkin's disease. This suggests that environmental mutagens might also be involved in primary myelodysplastic syndromes. Treatment remains highly unsatisfactory but a few recent developments improve prognosis, at least in the younger patient.


Relationship of varicocele to sperm output and fertility of male partners in infertile couples.
Both partners of 455 infertile couples seen consecutively were evaluated. When indicated the female partners were treated. Six semen specimens from each male subject were analyzed. A varicocele was diagnosed in 23.7 per cent of the men. More than 60 per cent of the men with a varicocele had sperm counts less than 40 million per ml., while 67 per cent without a varicocele had sperm counts more than 40 million per ml. The mean and total sperm counts of men with a varicocele were significantly lower than those without a varicocele. However, the pregnancy rates were not significantly different. The pregnancy rate was 46 per cent in couples whose male partners underwent a varicocelectomy, not significantly different from the pregnancy rate achieved in couples when the varicoceles were not corrected surgically (51 per cent). Varicocelectomy resulted in improvement in sperm count only when preoperative counts were more than 10 million per ml. Pregnancy rates for couples in which a varicocelectomy did or did not result in improvement in sperm count or motility were identical (45.1 and 45.5 per cent, respectively). These findings suggest that in male partners of infertile couples the presence of a varicocele is associated with compromised semen quality but not with diminished fertility when the female partners are treated. This observation emphasizes the importance of considering infertility as a problem of a couple, rather than a specific disorder of one of the partners.


Consolidative active scanning proton therapy for mediastinal lymphoma: selection criteria, treatment implementation and clinical feasibility.
Proton therapy (PT) represents an advanced form of radiotherapy with unique physical properties which could be of great advantage in reducing long-term radiation morbidity for cancer survivors. Here, we aim to describe the whole process leading to the clinical implementation of consolidative active scanning proton therapy treatment (PT) for mediastinal lymphoma. The process included administrative, technical and clinical issues. Authorization of PT is required in all cases as mediastinal lymphoma is currently not on the list of diseases reimbursable by the Italian National Health Service. Technically, active scanning PT treatment for mediastinal lymphoma is complex, due to the interaction between actively scanned protons and the usually irregular and large volumes to be irradiated, the nearby healthy tissues and the target motion caused by breathing. A road map to implement the technical procedures was prepared. The clinical selection of patients was of utmost importance and took into account both patient and tumor characteristics. The first mediastinal lymphoma was treated at our PT center in 2018, four years after the start of the clinical activities. The treatment technique implementation included mechanical deep inspiration breath-hold simulation computed tomography (CT), clinical target volume (CTV)-based multifield optimization planning and plan robustness analysis. The ultimate authorization rate was 93%. In 4 cases a proton-photon plan comparison was required. Between May 2018 and February, 2021, 14 patients were treated with consolidative PT. The main clinical reasons for choosing PT over photons was a bulky disease in 8 patients (57%), patient's age in 11 patients (78%) and the proximity of the lymphoma to cardiac structures in 10 patients (71%). With a median follow-up of 15 months (range, 1-33 months) all patients but one (out-of-field relapse) are without evidence of disease, all are alive and no late toxicities were observed during the follow-up period. The clinical implementation of consolidative active scanning PT for mediastinal lymphoma required specific technical procedures and a prolonged experience with PT treatments. An accurate selection of patients for which PT could be of advantage in comparison with photons is mandatory.


eIF4E phosphorylation regulates ongoing pain, independently of inflammation, and hyperalgesic priming in the mouse CFA model.
Mitogen activated protein kinase-interacting kinase (MNK)-mediated phosphorylation of the mRNA cap binding protein eIF4E controls the translation of a subset of mRNAs that are involved in neuronal and immune plasticity. MNK-eIF4E signaling plays a crucial role in the response of nociceptors to injury and/or inflammatory mediators. This signaling pathway controls changes in excitability that drive acute pain sensitization as well as the translation of mRNAs, such as brain-derived neurotrophic factor (BDNF), that enhance plasticity between dorsal root ganglion (DRG) nociceptors and second order neurons in the spinal dorsal horn. However, since MNK-eIF4E signaling also regulates immune responses, we sought to assess whether decreased pain responses are coupled to decreased inflammatory responses in mice lacking MNK-eIF4E signaling. Our results show that while inflammation resolves more quickly in mice lacking MNK-eIF4E signaling, peak inflammatory responses measured with infrared imaging are not altered in the absence of this signaling pathway even though pain responses are significantly decreased. We also find that inflammation fails to produce hyperalgesic priming, a model for the transition to a chronic pain state, in mice lacking MNK-eIF4E signaling. We conclude that MNK-eIF4E signaling is a critical signaling pathway for the generation of nociceptive plasticity leading to acute pain responses to inflammation and the development of hyperalgesic priming.


Possible inhibitory effect of lithium on peripheral conversion of thyroxine to triiodothyronine: a prospective study.
The effect of lithium on thyroid function was studied in 18 neuroleptic-treated male chronic schizophrenic in-patients. Lithium carbonate was administered for 8 weeks at a dosage giving a mean serum level of 0.79 mmol/l. Blood was obtained just before and after 8 weeks of lithium administration to determine the serum free thyroxine (free T4) levels, free triiodothyronine (free T3) levels and thyrotropin (TSH) levels. Overall, free T4 and TSH levels significantly increased whereas free T3 levels did not change. Two (11%) patients had abnormally increased free T4 levels and abnormally decreased free T3 levels after 8 weeks of lithium administration. These findings suggest that lithium may inhibit the peripheral conversion of free T4 to free T3 in some susceptible patients.


Enhanced loading regimen of teicoplanin is necessary to achieve therapeutic pharmacokinetics levels for the improvement of clinical outcomes in patients with renal dysfunction.
We evaluated the clinical efficacy and safety of teicoplanin according to the pharmacokinetics (PK) therapeutic level achieved in patients with renal dysfunction. Target trough concentration (Cmin) was ≥15-30 μg/ml which has been recommended in patients with normal renal function. Adult patients (estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m(2)) who were treated by teicoplanin were included in the study. We adopted two types of regimen for the initial 3 days: the conventional regimen, and the enhanced loading regimen (10 mg/kg twice daily on the 1st day, followed by 6.7-10 mg/kg once daily for the 2nd and 3rd days]. Two hundred and eighty-eight patients were evaluated for safety, and 106 patients with methicillin-resistant Staphylococcus aureus (MRSA) infections were evaluated for clinical efficacy. A significantly higher success rate was obtained in patients who achieved the target initial Cmin compared with those that did not (75.0 % vs 50.0 %, p = 0.008). In a multivariate analysis, initial Cmin ≥15 μg/ml was an independent factor for clinical success (adjusted odds ratio: 4.20, 95 % confidence interval: 1.34-13.15). In patients with 15-30 μg/ml of maximal Cmin during therapy, nephrotoxicity occurred in 13.1 %, and hepatotoxicity in 2.6 %, and these incidences were not significantly higher compared with those patients with <15 μg/ml. In conclusion, achievement of Cmin of 15-30 μg/ml without delay was necessary to improve clinical outcomes for the treatment by teicoplanin in patients with renal dysfunction. Further investigation is required regarding the optimal loading regimen to achieve the therapeutic levels in those patients.