Designing pandemic-resilient voting systems.
The 2020 general election occurred while many parts of the nation were under emergency orders related to the COVID-19 pandemic. This led to new requirements and considerations for voting systems. We introduce a model of the voting process to capture pandemic-related changes. Using a discrete event simulation case study of Milwaukee, WI, we study how to design in-person voting systems whose performance are robust to pandemic conditions, such as protective measures implemented during the COVID-19 pandemic. We assess various voting system designs on the voter wait times, voter sojourn times, line lengths at polling locations, voter time spent inside, and the number of voters inside. The analysis indicates that poll worker shortages, social distancing, and personalized protective equipment usage and sanitation measures can lead to extremely long voter wait times. We consider several design choices for mitigating the impact of pandemic-related changes on voting metrics. The case study suggests that long wait times can be avoided by staffing additional check-in locations, expanding early voting, and avoiding consolidated polling locations. Additionally, the analysis suggests that implementing a priority queue discipline has the potential to reduce waiting times for vulnerable populations at increased susceptibility to health risks associated with in-person voting.


Acid glycohydrolase in Chinese hamster with spontaneous diabetes. IV. Diabetes- and line-dependent variation in plasma enzyme activity.
The activity of five glycohydrolases was measured in the plasma of Chinese hamsters from eight highly inbred lines in the Upjohn colony. The diabetic animals showed elevated activities of plasma beta-D-galactosidase, N-acetyl-beta-D-glucosaminidase and N-acetyl-beta-D-galactosaminidase but similar activities of plasma alpha-D-glucosidase and alpha-D-galactosidase to the nondiabetic animals. Line-specific variation was observed in all five enzymes and anomalies were especially evident in N-acetyl-beta-D-glucosaminidase and N-acetyl-beta-D-galactosaminidase activity. In two diabetic lines, AC and Z, activities of these two enzymes were not elevated although significant correlation was found with blood sugar levels. The pronounced difference in the plasma activity of N-acetyl-beta-D-glucosaminidase in two diabetic lines, XA and AC, did not involve plasma inhibitors or activators, as evidenced by the coincidence in observed and calculated activities in mixed plasma samples, or specific isozymes, concluded from the similar elution profiles on ion-exchange column and thermostability curves. These data suggest that diabetes-related changes in plasma glycohydrolase activities are dictated by genetic factors and may be involved in the development of complications.


Evaluation of total antioxidant capacity of saliva and serum in caries-free and caries-active adults: an in-vivo study.
Oxidative stress is defined as an imbalance between the production of reactive oxygen species and antioxidant defense systems which are widely recognized as an important feature of many diseases including dental caries, suggesting that total antioxidant status may be of importance in determining the progression of caries. The aim of this study was to estimate the total antioxidant capacity (TAC) in saliva and serum of caries-free and caries-active adults and to correlate the TAC level with DMFT index (D = decayed, M = missing, F = filled, T = teeth). The present study included 100 healthy adults who were divided into four groups: Control, group I, group II, and group III, with a DMFT index 0, <3, <10, and >10, respectively. Saliva and serum samples were collected from all the four groups. The TAC of saliva and serum was estimated by phosphomolybdenum method. One-way analysis of variance (ANOVA) was used to compare the TAC of saliva and serum. Only differences with "P" < 0.05 were considered statistically significant. The mean TAC level of both saliva and serum increased significantly (P < 0.001) with the DMFT index. Total antioxidant capacity of saliva has a linear relation with caries, i.e., as the severity of caries increases, the TAC level also increases.


Influence of high-speed sintering protocols on translucency, mechanical properties, microstructure, crystallography, and low-temperature degradation of highly translucent zirconia.
Impacts of high-speed sintering on the optical and mechanical properties, microstructure, crystallography, and low-temperature degradation of commercial yttria-partially stabilized zirconia (Y-PSZ) were investigated. Five commercial Y-PSZ products (KATANA HT, KATANA STML, KATANA UTML, Zpex 4, and Zpex Smile) were investigated. Specimens were sintered following speed-sintering (~90 min) and conventional-sintering protocols (~7 h), and a group of KATANA STML was super-speed-sintered (18 min). Dimensions of the zirconia specimens after sintering were 14.5 mm (diameter) and 1.2 mm (thickness). Translucency was assessed using a colorimeter. Biaxial flexural strength was measured using a universal testing machine, followed by Weibull analysis. Scanning electron microscopy was used for microstructure assessments. X-ray diffraction was used to analyze the crystallography before and after hydrothermal aging. Low-temperature degradation (LTD) tests were performed at 134 °C under 2-3 bar water vapor in an autoclave. The translucency and flexural strength were not affected significantly by the sintering programs (p > 0.05). The conventionally sintered KATANA STML and speed-sintered Zpex 4 presented the highest and lowest Weibull modulus, respectively. The conventionally-sintered Y-PSZ had a larger average grain size and smaller fraction of fine grains than those of the speed-sintered specimens. The fractographic analysis of the speed- and conventionally sintered Y-PSZ yielded comparable results. The speed-sintered Y-PSZ exhibited a lower c-ZrO2 content than that of conventionally-sintered Y-PSZ, except for KATANA HT and KATANA STML. LTD tests indicated that some of the speed and conventionally-sintered Y-PSZ exhibited similar monoclinic volume fractions. Speed-sintering programs are acceptable for Y-PSZ zirconia.


Impact of different cadaveric donor age cut-offs on adult recipient survival after liver transplantation: a single-center analysis.
The increase in the number of patients awaiting liver transplantation (OLT) has forced the use of cadaveric donors (CD) with suboptimal characteristics. Of these, donor age is perhaps the most investigated parameter. Although excellent outcomes were observed for OLT using CD aged over 60 years, the European Liver Transplant Registry (ELTR) Group found an increased risk by using CD of more than 55 years. The Italian National Transplant Center has recently assumed that CD age more than 60 years is a potential risk factor for OLT. In this study, a single-center analysis was performed by stratifying CD by three age cut-offs (< or =55 or >55, < or =60 or >60, and < or =65 or >65 years) to evaluate effects on OLT outcome. Although no significant difference in 6-month and 1-year patient or graft survival occurred after stratification for each donor age cut-off, a better survival was observed with OLT performed using livers procured from CD >55 years. A significant increase in cold ischemia time (CIT) was observed among OLT performed with grafts procured from CD < or =55 and < or =65 years (P = .007), and there was an inverse correlation between overall CIT and donor age (R = -0.300; P = .0022). However, no impact on 1-year patient survival was observed by introducing CIT in univariate logistic regression models as well as donor age, recipient age, donor/recipient age ratio, donor/recipient sex mismatch, ELTR diagnostic categories, and UNOS status. The results of this study suggest the suitability of CD of more than 55 years for OLT and the need to further investigate the cut-off value for CIT-related risk.


Antimicrobial Photodynamic Therapy in the Nasal Decolonization of Maintenance Hemodialysis Patients: A Pilot Randomized Trial.
Infections are an important cause of mortality among patients receiving maintenance hemodialysis. Staphylococcus aureus is a frequent etiological agent, and previous nasal colonization is a risk factor for infection. Repeated antimicrobial decolonization reduces infection in this population but can induce antibiotic resistance. We compared photodynamic therapy, a promising bactericidal treatment that does not induce resistance, to mupirocin treatment among nasal carriers of S aureus. Randomized controlled pilot study. 34 patients receiving maintenance hemodialysis who had nasal carriage of S aureus. Patients were randomly assigned to decolonization with a single application of photodynamic therapy (wavelength of 660nm, 400mW/cm2, 300 seconds, methylene blue 0.01%) or with a topical mupirocin regimen (twice a day for 5 days). Nasal swabs were collected at time 0 (when the carrier state was identified), directly after treatment completion, 1 month after treatment, and 3 months after treatment. Bacterial isolates were subjected to proteomic analysis to identify the species present, and antimicrobial susceptibility was characterized. All 17 participants randomized to photodynamic therapy and 13 of 17 (77%) randomized to mupirocin were adherent to treatment. Directly after treatment was completed, 12 participants receiving photodynamic therapy (71%) and 13 participants treated with mupirocin (77%) had cultures that were negative for S aureus (risk ratio, 0.92 [95% CI, 0.61-1.38]; P=0.9). Of the patients who had negative cultures directly after completion of photodynamic therapy, 67% were recolonized within 3 months. There were no adverse events in the photodynamic therapy group. Testing was restricted to assessing nasal colonization; infectious complications were not assessed. Photodynamic therapy is a feasible approach to treating nasal carriage of S aureus. Future larger studies should be conducted to determine whether photodynamic therapy is equivalent to the standard of care with mupirocin. Government grant (National Council for Scientific and Technological Development process 3146682020-9). Registered at ClinicalTrials.gov with study number NCT04047914.


Science policy and science policy research.
This assessment of the value of science policy research in the making of policies is based on a lecture given at a meeting of the Sociology of Science Study Group of the British Sociological Association last March. The thoughts it contains are of course those of Dr Blume himself, and not of the Department of Education and Science or the Council for Scientific Policy.


Effect of modified fasting therapy on body weight, fat and muscle mass, and blood chemistry in patients with obesity.
The aim of this study was to investigate the effects and safety of modified fasting therapy using fermented medicinal herbs and exercise on body weight, fat and muscle mass, and blood chemistry in obese subjects. Twenty-six patients participated in a 14-day fast, during which they ingested a supplement made from fermented medicinal herbs and carbohydrates (intake: 400-600 kcal/d). The schedule included 7 prefasting relief days and 14 days of stepwise reintroduction of food. The patients also took part in an exercise program that incorporated Qigong, weight training, and walking exercises. The efficacy of treatments was observed by assessing body fat mass and muscle mass, and alanine aminotransferase (ALT), aspartate aminotransferase (AST), cholesterol, and triglycerides in each study period. Specific symptoms or side effects were reported. Body weight and body fat mass both decreased significantly by (5.16 ± 0.95) and (3.89 ± 0.79) kg (both P < 0.05), while muscle mass decreased by an average of (0.26 ± 0.22) kg, without statistical significance. ALT levels were significantly decreased (P < 0.05), while AST levels decreased without statistical significance (P = 0.052). The levels of total cholesterol and triglycerides were also significantly decreased (both P < 0.05). There were few adverse events except for mild dizziness, which did not affect everyday living. These results suggest that modified fasting therapy using fermented medicinal herbs and exercise could be effective and safe on obese patients.


Phytol directly activates peroxisome proliferator-activated receptor alpha (PPARalpha) and regulates gene expression involved in lipid metabolism in PPARalpha-expressing HepG2 hepatocytes.
The peroxisome proliferator-activated receptor (PPAR) is one of the indispensable transcription factors for regulating lipid metabolism in various tissues. In our screening for natural compounds that activate PPAR using luciferase assays, a branched-carbon-chain alcohol (a component of chlorophylls), phytol, has been identified as a PPARalpha-specific activator. Phytol induced the increase in PPARalpha-dependent luciferase activity and the degree of in vitro binding of a coactivator, SRC-1, to GST-PPARalpha. Moreover, the addition of phytol upregulated the expression of PPARalpha-target genes at both mRNA and protein levels in PPARalpha-expressing HepG2 hepatocytes. These findings indicate that phytol is functional as a PPARalpha ligand and that it stimulates the expression of PPARalpha-target genes in intact cells. Because PPARalpha activation enhances circulating lipid clearance, phytol may be important in managing abnormalities in lipid metabolism.


Occurrence of Neospora caninum and Toxoplasma gondii infections in ovine and caprine abortions.
Neospora caninum and Toxoplasma gondii are closely related cyst-forming apicomplexan parasites identified as important causes of reproductive failure in cattle and small ruminants, respectively. Protozoan abortion in small ruminants is traditionally associated with T. gondii, but the importance of N. caninum remains uncertain. The aim of this study was to investigate the presence of N. caninum and T. gondii infections in abortion cases in small ruminants submitted for diagnosis. For this purpose, 74 ovine and 26 caprine aborted foetuses were recovered from different areas in Spain. Foetal histopathology was used to detect the presence of protozoal-associated lesions in brain. The presence of N. caninum and T. gondii was confirmed by PCR. Protozoal infection was detected in 17 out of 100 (17%) foetuses examined by at least one of the diagnostic techniques used. Lesions suggestive of protozoal infection were observed in 10.8% (8/74) and 15.4% (4/26) of the ovine and caprine abortions respectively. N. caninum and T. gondii infection was detected by PCR in 6.8% (5/74) and 5.4% (4/74) of sheep foetuses, respectively, of which five showed protozoal-associated lesions. N. caninum DNA was detected in 11.5% (3/26) of goat foetuses, of which two showed protozoal-associated lesions, whereas T. gondii DNA was detected in one goat foetus with no lesions. The simultaneous presence of N. caninum and T. gondii DNA was detected in one sheep foetus with severe lesions. This study demonstrates that N. caninum plays a significant role in abortion in small ruminants in the studied population. In addition, our results highlight the importance of differentiating between protozoa whenever characteristic lesions are observed.


Overnight glucose infusion suppresses renal ammoniagenesis and reduces hyperammonaemia induced by a simulated bleed in cirrhotic patients.
A simulated upper gastrointestinal (UGI) bleed in cirrhotic patients has been shown to induce hyperammonaemia. The kidney was the site of this exaggerated ammoniagenesis with alanine as substrate. Administration of alanine to decompensated cirrhotic patients did not change hepatic gluconeogenesis, but resulted in increased ammoniagenesis. We hypothesise that reduced hepatic glycogen stores result in hyperglucagonaemia which may drive increased renal gluconeogenesis and therefore alanine uptake and renal ammoniagenesis. To determine whether an overnight glucose infusion lowers renal ammoniagenesis by reducing hyperglucagonaemia and renal ammoniagenesis. Patients with decompensated cirrhosis were studied in a cross-over design. An UGI bleed was simulated via intragastric administration of an amino acids mixture mimicking the haemoglobin molecule after a 12-h overnight fast (F-group) or after a 12-h treatment with 20% glucose solution (G-group). Before the simulated bleed the glucagon levels were 21 (15-31) pmol/L in the F-group and 15 (9-21) pmol/L in the G-group (P < 0.01). After the simulated bleed, arterial ammonia levels increased in both groups [F-group: 73-118 μmol/L (P = 0.01); G-group 64-87 μmol/L (P = 0.01)]. The enhancement of hyperammonaemia was significantly higher in the F-group (45 [19-71] μmol/L) compared with the G-group (23 [13-39] μmol/L) (P = 0.01). The difference in renal ammoniagenesis during the simulated bleed in the F-group was 399 (260-655) nmol/kg/bwt/min and was significantly higher than in the G-group 313 (1-498) nmol/kg/bwt/min (P = 0.05). Overnight glucose infusion results in reduced renal ammoniagenesis and attenuates ammonia levels. These observations have implications for the development of nutritional strategies in hyperammonaemic patients.


Immunogenicity and protective potential of a Plasmodium spp. enolase peptide displayed on archaeal gas vesicle nanoparticles.
Plasmodium falciparum enolase has been shown to localize on the surface of merozoites and ookinetes. Immunization of mice with recombinant Plasmodium enolase (rPfeno) showed partial protection against malaria. Anti-rPfeno antibodies inhibited growth of the parasite in in vitro cultures and blocked ookinete invasion of mosquito midgut epithelium. It is hypothesized that parasite specific moonlighting functions (e.g. host cell invasion) may map on to unique structural elements of Pfeno. Since enolases are highly conserved between the host and the parasite, a parasite-specific epitope of enolase was displayed on novel protein nanoparticles produced by a halophilic Archaeon Halobacterium sp. NRC-1 and tested their ability to protect mice against live challenge. By genetic engineering, a Plasmodium-enolase specific peptide sequence (104)EWGWS(108) with protective antigenic potential was inserted into the Halobacterium gas vesicle protein GvpC, a protein localized on the surface of immunogenic gas vesicle nanoparticles (GVNPs). Two groups of mice were immunized with the wild type (WT) and the insert containing recombinant (Rec) GVNPs respectively. A third group of mice was kept as un-immunized control. Antibody titres were measured against three antigens (i.e. WT-GVNPs, Rec-GVNPs and rPfeno) using ELISA. The protective potential was determined by measuring percentage parasitaemia and survival after challenge with the lethal strain Plasmodium yoelii 17XL. Rec-GVNP-immunized mice showed higher antibody titres against rPfeno and Rec-GVNPs, indicating that the immunized mice had produced antibodies against the parasite enolase-specific insert sequence. Challenging the un-immunized, WT-GVNP and Rec-GVNP-immunized mice with a lethal strain of mice malarial parasite showed significantly lower parasitaemia and longer survival in the Rec-GVNP-immunized group as compared to control groups. The extent of survival advantage in the Rec-GVNP-group showed positive correlation with anti-rPfeno antibody titres while the parasitaemia showed a negative correlation. These results indicate that the parasite enolase peptide insert displayed on Halobacterium GVNPs is a good candidate as a protective antigenic epitope. The work reported here showed that the parasite-specific peptide sequence is a protective antigenic epitope. Although antibody response of B-cells to the guest sequence in Rec-GVNPs was mild, significant advantage in the control of parasitaemia and survival was observed. Future efforts are needed to display multiple antigens with protective properties to improve the performance of the GVNP-based approach.


Management of Third and Fourth-Degree Perineal Tears After Vaginal Birth. Guideline of the DGGG, OEGGG and SGGG (S2k-Level, AWMF Registry No. 015/079, December 2020).
Purpose This guideline provides recommendations for the diagnosis, treatment and follow-up care of 3rd and 4th degree perineal tears which occur during vaginal birth. The aim is to improve the management of 3rd and 4th degree perineal tears and reduce the immediate and long-term damage. The guideline is intended for midwives, obstetricians and physicians involved in caring for high-grade perineal tears. Methods A selective search of the literature was carried out. Consensus about the recommendations and statements was achieved as part of a structured process during a consensus conference with neutral moderation. Recommendations After every vaginal birth, a careful inspection and/or palpation by the obstetrician and/or the midwife must be carried out to exclude a 3rd or 4th degree perineal tear. Vaginal and anorectal palpation is essential to assess the extent of birth trauma. The surgical team must also include a specialist physician with the appropriate expertise (preferably an obstetrician or a gynecologist or a specialist for coloproctology) who must be on call. In exceptional cases, treatment may also be delayed for up to 12 hours postpartum to ensure that a specialist is available to treat the individual layers affected by trauma. As neither the end-to-end technique nor the overlapping technique have been found to offer better results for the management of tears of the external anal sphincter, the surgeon must use the method with which he/she is most familiar. Creation of a bowel stoma during primary management of a perineal tear is not indicated. Daily cleaning of the area under running water is recommended, particularly after bowel movements. Cleaning may be carried out either by rinsing or alternate cold and warm water douches. Therapy should also include the postoperative use of laxatives over a period of at least 2 weeks. The patient must be informed about the impact of the injury on subsequent births as well as the possibility of anal incontinence.


Influence of the diameter and taper of root canals on the removal efficiency of Thermafil Plus plastic carriers using ProTaper Retreatment Files.
This study aimed to investigate the influence of canal shape on the time required for the removal of Thermafil Plus plastic carriers (Dentsply Tulsa Dental, Tulsa, OK) using ProTaper Retreatment Files (Dentsply Maillefer, Ballaigues, Switzerland). Sixty simulated J-shaped canals in resin blocks were divided into six groups prepared differently in terms of apical size (25/04 or 35/06) and coronal enlargement (no coronal enlargement, using a K3 orifice opener [SybronEndo, Orange, CA] 25/08, or using Gates-Glidden drills [Mani, Tochigi, Japan] #1-4) and were filled with a Thermafil Plus of the same carrier size (size 25 or 35). The carriers were removed using ProTaper D1, D2, and D3 in a crown-down sequence, and removal time was measured. A similar experiment was performed using extracted mandibular incisors prepared to 25/04 with or without coronal enlargement using Gates-Glidden drills (n = 10 each). Simulated canals coronally enlarged with Gates-Glidden drills required a significantly longer removal time than other groups of identical apical size (p < 0.05). When groups with similar coronal enlargement were compared, those apically prepared to 35/06 required a significantly longer removal time than those prepared to 25/04 (p < 0.05). Coronally enlarged incisors also required a significantly longer removal time than those without coronal enlargement (p < 0.05). Canals with a larger diameter and/or taper required more time for the removal of Thermafil Plus plastic carriers.


Exploring Natura 2000 habitats by satellite image segmentation combined with phytosociological data: a case study from the Čierny Balog area (Central Slovakia).
Natura 2000 is a network of protected areas covering Europe's most valuable and threatened species and habitats. Recently, biota belonging to these networks have been threatened by both climate change and various human impacts. Regular monitoring is needed to ensure effective protection and proper management measures in these sites and habitats, but conventional field approaches are often time-consuming and inaccurate. New approaches and studies with different focuses and results are being developed. Our approach includes point data from field research and phytosociological databases as starting points for automatic segmentation, which has been developed just recently as a novel method that could help to connect ground-based and remote sensing data. Our case study is located in Central Slovakia, in the mountains around the village of Čierny Balog. The main aim of our case study is to apply advanced remote sensing techniques to map the area and condition of vegetation units. We focus on forest habitats belonging mainly to the Natura 2000 network. We concentrated on the verification of the possibilities of differentiation of various habitats using only multispectral Sentinel-2 satellite data. Our software NaturaSat created by our team was used to reach our objectives. After collecting data in the field using phytosociological approach and segmenting the explored areas in the program NaturaSat, spectral characteristics were calculated within identified habitats using software tools, which were subsequently processed and tested statistically. We obtained significant differences between forest habitat types. Also, segmentation accuracy was tested by comparing closed planar curves of ground based filed data and software results. This provided promising results and validation of the methods used. The results of this study have the potential to be used in a wider area to map the occurrence and quality of Natura 2000 habitats.


Aberrations of dermal connective tissue in patients with cervical artery dissection (sCAD).
Spontaneous cervical artery dissection (sCAD) is a common cause of stroke in patients below 55 years of age. Hereditary connective tissue disorders, including Ehlers-Danlos syndrome type IV, have been associated with sCAD and suprastructural abnormalities of both collagen fibrils and elastic fibers have been found by transmission electron microscopy in the dermis of about 50% of sCAD patients. Here, we investigated dermal connective tissue abnormalities using a novel method. Transmission and immunogold electron microscopy were used to study mechanically generated fragments of dermal matrix suprastructures, in particular collagen fibrils. Analysis of dermal tissue of sCAD patients revealed structurally abnormal collagen fibrils with irregularly contoured surfaces and increased diameters, often associated with a faint or absent banding pattern. Interestingly, only a small number of fibrils displayed short abnormal sections along the length of the fibril. Collagens I and III were present in normal as well as abnormal sections of the fibrils.However, immunogold labeling for the two proteins was strongly increased in abnormal sections.A systematic blinded investigation of skin biopsies of 31 sCAD patients and 17 controls revealed abnormal collagen fibrils in 7 sCAD patients but none of the controls. We conclude that approximately 20% of sCAD patients show collagen fibril alterations, establishing a promising basis for further investigation of connective tissue aberrations in skin biopsies of sCAD patients.


Interaction between surfaces decorated with like-charged pendants: Unravelling the interplay between energy and entropy leading to attraction.
The stronger motional coupling between monovalent counterions neutralizing homogeneously like-charged surfaces induced by an increase in charge density is known to foster inter-surface attraction. Compared to a uniformly distributed charge, point-like charges generate locally more intense fields, so that the correlation induced between counterions may be even stronger despite an identical total charge. It should thus be possible to induce surface attraction at lower charge densities than commonly expected. Monte Carlo simulations on primitive electrolyte models have been exploited to compute potential of mean force profiles and mobile ion densities for systems composed of two parallel surfaces bearing surface-tethered monovalent like-charged pendants as a function of the surface distance and pendant densities. Surfaces bearing like-charged pendants are found to attract each other over a wide range of distances despite the presence of very low charge densities. Notwithstanding the attractive contribution to the inter-surface forces provided by electrostatic interactions, the entropic component of the system Helmholtz energy is found to play the key role in defining the overall magnitude. The latter finding appears justified by an increase in the relative delocalization of counterions upon decreasing the surface distance.


Olfactory classical conditioning in neonatal mouse pups using thermal stimuli.
Mouse models are increasingly used to investigate genetic contributions to developmental disorders in children, especially newborns. In particular, early cognitive assessment in newborn mice is critical to evaluate pediatric drug efficacy and toxicity. Unfortunately, methods for behavioral tests in newborn mice are scarce. Therefore, developing such tests for newborn mice is a priority challenge for neurogenetics and pharmacological research. The aim of the present study was to develop a conditioning method well suited to high-throughput cognitive screening in newborn mice. To this end, we developed an odor-preference conditioning test using ambient temperature as an unconditioned stimulus (US) and artificial odors as conditioned stimuli (CS). First, we showed that mouse pups move toward the thermoneutral temperature when offered a choice between a thermoneutral and cold environment, thus showing thermotaxis. Second, we conducted a classical conditioning paradigm in pups aged six to ten days. In terms of central nervous system development, this period corresponds to extreme prematurity to early post-term period in humans. During acquisition, the pups were alternatively exposed to odor CS paired with either cold or warm temperatures. Immediately after acquisition, the pups underwent a two-odor choice test, which showed preference for the odor previously paired with the warm temperature, thus showing conditioning. The proposed paradigm is easy to conduct, and requires modest experimenter interference. The method is well suited for high-throughput screening of early associative disorders in newborn mice.


Cognitive deficits following stroke in the basal ganglia.
To examine the effect of a stroke in the basal ganglia on cognitive functioning. As part of a larger prospective study on the neuropsychological and psychosocial consequences of stroke, 12 patients with a stroke confined to the basal ganglia were examined. The patients were assessed in one of the three participating hospitals. The results of 12 patients with a stroke in the basal ganglia (mean age 55 years), were compared to 24 controls (mean age 54.3 years). Different aspects of memory, attention and concentration, visuospatial and visuoconstructive functions, language and arithmetic were assessed using neuropsychological tests. The data show a significant abnormality in cognitive functioning on all cognitive domains. The results stress the notion that subcortical damage may lead to substantial neuropsychological disorders and have clear implications for neurological rehabilitation.


Linkage and association of the CA repeat polymorphism of the IL6 gene, obesity-related phenotypes, and bone mineral density (BMD) in two independent Caucasian populations.
Genetic factors play an important role in osteoporosis and obesity, two serious public health problems in the world. We investigated the relationships between obesity-related phenotypes, bone mineral density (BMD) and the CA repeat polymorphism of the IL6 gene in two large independent samples using the quantitative transmission disequilibrium test (QTDT). The first sample consisted of 1,816 individuals from 79 multigenerational pedigrees. Each pedigree was identified through a proband with BMD Z-scores </=-1.28 at the hip or spine. The second sample was a randomly ascertained set of 636 individuals from 157 nuclear families. Ten alleles containing 9-18 CA repeats were identified in our Caucasian populations. For body mass index (BMI), fat mass and percentage fat mass (PFM), highly significant (P<0.01) or significant (P<0.05) results were found for linkage in our sample of nuclear families and for association in the multigenerational pedigrees. We also observed weak evidence for linkage (P=0.069) with spine BMD and for association with hip BMD in the sample of multigenerational pedigrees. Our results suggest that genetic variation in or near the IL6 locus may be involved in the etiology of obesity and osteoporosis.


Increased n-6 Polyunsaturated Fatty Acids Indicate Pro- and Anti-Inflammatory Lipid Modifications in Synovial Membranes with Rheumatoid Arthritis.
Emerging evidence suggests that fatty acids (FAs) and their lipid mediator derivatives can induce both beneficial and detrimental effects on inflammatory processes and joint degradation in osteoarthritis (OA) and autoimmune-driven rheumatoid arthritis (RA). The present study characterized the detailed FA signatures of synovial membranes collected during knee replacement surgery of age- and gender-matched OA and RA patients (n = 8/diagnosis). The FA composition of total lipids was determined by gas chromatography and analyzed with univariate and multivariate methods supplemented with hierarchical clustering (HC), random forest (RF)-based classification of FA signatures, and FA metabolism pathway analysis. RA synovium lipids were characterized by reduced proportions of shorter-chain saturated FAs (SFAs) and elevated percentages of longer-chain SFAs and monounsaturated FAs, alkenyl chains, and C20 n-6 polyunsaturated FAs compared to OA synovium lipids. In HC, FAs and FA-derived variables clustered into distinct groups, which preserved the discriminatory power of the individual variables in predicting the RA and OA inflammatory states. In RF classification, SFAs and 20:3n-6 were among the most important FAs distinguishing RA and OA. Pathway analysis suggested that elongation reactions of particular long-chain FAs would have increased relevance in RA. The present study was able to determine the individual FAs, FA groups, and pathways that distinguished the more inflammatory RA from OA. The findings suggest modifications of FA elongation and metabolism of 20:4n-6, glycerophospholipids, sphingolipids, and plasmalogens in the chronically inflamed RA synovium. These FA alterations could have implications in lipid mediator synthesis and potential as novel diagnostic and therapeutic tools.


Efficacy and safety of pirfenidone in the treatment of idiopathic pulmonary fibrosis patients: a systematic review and meta-analysis of randomised controlled trials.
Idiopathic pulmonary fibrosis (IPF) has been defined as a distinctive type of chronic fibrotic disease, characterised by a progressive decline in lung function and a common histological pattern of interstitial pneumonia. To analyse the efficacy and safety of pirfenidone in the treatment of IPF, a systematic review and meta-analysis was performed. This is a meta-analysis study. Patients were diagnosed as IPF. Use of pirfenidone. Progression-free survival (PFS), acute exacerbation and worsening of IPF and Impact on adverse events. The inverse variance method for the random-effects model was used to summarise the dichotomous outcomes, risk ratios and 95% CIs. A total of 9 randomised controlled trials with 1011 participants receiving pirfenidone and 912 controls receiving placebo were summarised. The pooled result suggested a statistically significant difference inall-cause mortality after pirfenidone use, with a summarised relative ratio of 0.51 (p<0.01). Longer PFS was observed in patients receiving pirfenidone compared with those who were given placebo (p<0.01). The IPF groups presented a high incidence of adverse events with a pooled relative ratio of 3.89 (p<0.01). Pirfenidone can provide survival benefit for patients with IPF. Pirfenidone treatment was also associated with a longer PFS, a lower incidence of acute exacerbation and worsening of IPF.


Modelling the Effect of the Interaction between Vaccination and Nonpharmaceutical Measures on COVID-19 Incidence.
Since December 2019, the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread rapidly from Wuhan (China) across the globe, affecting more than 200 countries by mid-2021, with over 190 M reported cases and around 4 M fatalities. During the first year of the pandemic, affected countries implemented a variety of nonpharmaceutical interventions to control virus transmission. In December 2020, countries started administering several authorised vaccines under a limited supply scenario. In this context, the aim of this study was to develop a SEIR-type continuous-time deterministic disease model, to determine the impact of interaction between different vaccination scenarios and levels of protection measures on disease incidence. For this, the model incorporates (i) a protection measure including low (self-protection), medium (mobility limitation), high (closure of indoor facilities), and very high (lockdown) protection levels, (ii) quarantine for confirmed cases, and (iii) vaccination rate and efficacy of four types of vaccines (Pfizer, Moderna, Astra Zeneca, and Janssen). The model was verified and evaluated using the response timeline and vaccination strategies and rates in the Basque Country (N. Spain). Once the model performance was validated, different initial phase (when 30% of the population is vaccinated) vaccination scenarios were simulated, including (i) a realistic vaccine limited supply scenario and (ii) four potential full vaccine supply scenarios where a unique vaccine type is administered. Significant differences in disease prevalence and cumulative mortality were found between vaccination scenarios for low and medium-level protection measures. For high-level protection measures, any vaccine scenario is effective at limiting the virus transmission and disease mortality. The results obtained here may vary in further studies since there may be some unpredictable factors/covariates. With this in mind, the model here could be easily applied to other regions or countries, modifying the strategies implemented and initial conditions.


Investigating the Relationship Between Spiritual Health, Meaning in Life, and Death Attitudes among COVID-19 Patients Discharged from ICUs: A Cross-Sectional Study in Iran.
The COVID-19 pandemic has been shown to affect both physical and mental health. Because of this mental health burden, it is important to pay attention to issues such as the relationship between spiritual health, death attitudes and meaning in life - all issues made more prominent during the pandemic. This study was conducted to determine the correlation between these three factors - spiritual health, meaning in life, and death attitudes, among patients with COVID-19 discharged from the intensive care units of hospitals affiliated with Tehran University of Medical Sciences, Tehran, Iran.This cross-sectional, descriptive-analytical study was conducted between April 2020 and August 2021 with 260 participants. The data collection instruments were a demographic characteristics questionnaire, Polotzin and Ellison's Spiritual Health Questionnaire, The Meaning in Life Questionnaire (MLQ), and Death Attitude Profile-Revised (DAP-R).The correlation between meaning in life, spiritual health, and death attitudes was determined by Spearman's correlation coefficient. The research results showed that there is an inverse and significant correlation between spiritual health and death attitudes (p = 0.01); an inverse, but insignificant correlation between existential health and subscales of death attitudes, except for the subscales of approach acceptance and neutral acceptance (p > 0.05); and an inverse, but insignificant, correlation between spiritual health and death attitudes, (p > 0.05). In addition, there was an inverse and significant correlation between the presence of meaning in life and escape acceptance (p = 0.002); an inverse and significant correlation between the search for meaning in life and neutral acceptance (p = 0.007); and an inverse and significant correlation between the meaning in life and death attitudes (p = 0.04). Besides, the findings showed an inverse but insignificant correlation between all spiritual health subscales and the meaning in life subscales (p > 0.05). Spiritual health has an inverse correlation with death attitudes.Also, there is an inverse correlation between the total score of spiritual health and death attitudes. Regarding the subscales of spiritual health, there is an inverse correlation between existential health and death attitudes subscales, except for approach acceptance and neutral acceptance. Also, the results showed an inverse and significant correlation between meaning in life and death acceptance and avoidance subscales, and there was an inverse and significant correlation between the meaning in life and death attitudes. Finally, the increase in spiritual health reduces patients' risks of thinking about death. The research results double the significance of the role of nurses, especially those dealing with critically ill patients and those who have experienced severe disease conditions.


Effect of gender on the hearing performance of adult cochlear implant patients.
To evaluate the role of gender on the hearing performance of postlingually deafened adult patients with cochlear implants. Individual retrospective cohort study. There were 638 postlingually deafened adults (280 men and 358 women) selected for a retrospective evaluation of their hearing performance with cochlear implants. Both genders underwent the same surgical and rehabilitative procedures and benefited from the latest technological advances available. There was no significant difference in the age, duration of deafness, and preoperative hearing performance between the genders. The test battery was composed of the Freiburger Monosyllabic Test, Speech Tracking, and the Hochmair-Schulz-Moser (HSM) sentence test in quiet and in 10-dB noise. The results of 5 years of follow-up are presented here. Genders showed a similar performance in Freiburger Monosyllabic Test and Speech Tracking Test. However, in the HSM test in noise, men performed slightly better than women in all of the follow-up sessions, which was statistically significant at 2 and 4 years after implantation. Although normal-hearing women use more predictive cognitive strategies in speech comprehension and are supposed to have a more efficient declarative memory system, this may not necessarily lead to a better adaptation to the altered auditory information delivered by a cochlear implant. Our study showed that in more complex listening situations such as speech tests in noise, men tend to perform slightly better than women. Gender may have an influence on the hearing performance of postlingually deafened adults with cochlear implants.


Treatment of Functional Mitral Regurgitation in Heart Failure.
To analyze the current state of the art of functional mitral regurgitation (FMR) treatment. The first-line treatment of severe FMR consists of guideline medical therapy (GMT) and resynchronization therapy when indicated; the impact of new medical therapies like sacubitril/valsartan needs further assessment. Valvular intervention may be considered in FMR symptomatic patients despite GMT, and can be performed surgically or percutaneously. MitraClip is a safe percutaneous procedure associated with symptoms improvement. Recently, the COAPT trial showed superior outcomes for MitraClip versus GMT contrasting the MITRA-FR trial which showed no benefit of MitraClip compared with GMT. These results should be interpreted as complementary rather than opposite. The COAPT trial provided a "proof of concept" that percutaneous treatment of severe FMR in patients without too advanced left ventricular disease translates into a prognostic benefit. Careful patient selection will play a critical role in defining the clinical niche for successful interventions.


Prevention of nutritional rickets in Nigerian children with dietary calcium supplementation.
Nutritional rickets in Nigerian children usually results from dietary calcium insufficiency. Typical dietary calcium intakes in African children are about 200mg daily (approximately 20-28% of US RDAs for age). We sought to determine if rickets could be prevented with supplemental calcium or with an indigenous food rich in calcium. We enrolled Nigerian children aged 12 to 18months from three urban communities. Two communities were assigned calcium, either as calcium carbonate (400mg) or ground fish (529±109mg) daily, while children in all three communities received vitamin A (2500IU) daily as placebo. Serum markers of mineral homeostasis and forearm bone density (pDEXA) were measured and radiographs were obtained at enrollment and after 18months of supplementation. The overall prevalence of radiographic rickets at baseline was 1.2% and of vitamin D deficiency [serum 25(OH)D<12ng/ml] 5.4%. Of 647 children enrolled, 390 completed the 18-month follow-up. Rickets developed in 1, 1, and 2 children assigned to the calcium tablet, ground fish, and control groups, respectively (approximate incidence 6.4/1000 children/year between 1 and 3years of age). Children who developed rickets in the calcium-supplemented groups had less than 50% adherence. Compared with the group that received no calcium supplementation, the groups that received calcium had a greater increase in areal bone density of the distal and proximal 1/3 radius and ulna over time (P<0.04). We conclude that calcium supplementation increased areal bone density at the radius and ulna, but a larger sample size would be required to determine its effect on the incidence of rickets.


Mesquite pod extract modifies the reproductive physiology and behavior of the female rat.
Phytoestrogens are non steroidal compounds that can bind to estrogen receptors, mimicking some effects of estradiol (E(2)). These compounds are widespread among legumes, which are used as pasture, and their importance in animal agriculture has increased. Mesquite (Prosopis sp) is a widespread legume, widely used to feed several livestock species in Mexico. The main product of mesquite is the pod, which is considered high quality food. As a legume, it could be assumed that mesquite contains some amounts of phytoestrogens which might induce potential estrogenic effects. However, to our knowledge, there are no reports regarding the possible estrogenic activity of this legume either in livestock or in animal models such as the rat. Therefore, in this study, we evaluated the potential estrogenic effects of mesquite pod extract on several aspects of behavior and reproductive physiology of the female rat. The effects of the extract were compared with those of E(2) and two isoflavones: daidzein (DAI) and genistein (GEN). The following treatments were given to groups of intact and ovariectomized (OVX) female rats: vehicle; mesquite pod extract; E(2); GEN; DAI. Compared to vehicle groups, mesquite pod extract, DAI, GEN, and E(2) increased uterine weight and induced growth in vaginal and uterine epithelia. In intact rats, mesquite pod extract, GEN and DAI altered estrous cyclicity, decreased lordotic quotient and intensity of lordosis. In OVX rats, mesquite pod extract, DAI and GEN induced vaginal estrus, increased vaginal epithelium height, and induced lordosis, although its intensity was reduced, compared with intact rats in estrus and E2-treated rats. These results suggest that mesquite pod extract could have estrogenic activity. However, the presence of phytoestrogens in this legume remains to be confirmed.


Nosocomial outbreak caused by Serratia marcescens in a neonatology intensive care unit in a regional hospital. Analysis and improvement proposals.
Serratia marcescens (SM) may cause nosocomial outbreaks in Neonatal Intensive Care Units (NICU). We describe an outbreak of SM in a NICU and propose additional prevention and control recommendations. Between March 2019 and January 2020, samples were taken from patients in the NICU (rectal, pharyngeal, axillary and other locations) and from 15 taps and their sinks. Control measures were implemented including thorough cleaning of incubators, health education to staff and neonates'relatives, and use of single-dose containers. PFGE was performed in 19 isolates from patients and in 5 environmental samples. From the first case in March 2019 to the detection of the outbreak, a month elapsed. Finally, 20 patients were infected and 5 colonized. 80% of infected neonates had conjunctivitis, 25% bacteremia, 15% pneumonia, 5% wound infection, and 5% urinary tract infection. Six neonates had two foci of infection. Among the 19 isolates studied, 18 presented the same pulsotype and only one of the isolates from the sinkhole showed a clonal relationship with those of the outbreak. Initial measures established were ineffective to control de outbreak and were implemented with exhaustive cleaning, use of individual eye drops, environmental sampling and changing sinks. This outbreak presented a high number of neonates affected due to its late detection and torpid evolution. The microorganisms isolated from the neonates were related to an environmental isolate. Additional prevention and control measures are proposed, including routine weekly microbiological sampling.


Intra-articular Injectates: What to Use and Why.
Intra-articular injections are a nonsurgical treatment modality that can be used to manage osteoarthritis, naturally occurring or surgically induced acute synovitis, and intra-articular ligamentous or tendon injury. This option may be assistive for patients in which other conservative modalities are ineffective, or in conjunction with other forms of treatment. It may also be used as the primary treatment. Injectates labeled for use in companion animal joints include corticosteroids and viscosupplements. Additional injectates, that are not specifically approved for use in companion animals are but are reported in the literature, include orthobiologics and a radioisotope of Tin-117m.


Quinoline esters as potential antimalarial drugs: effect on relapses of Plasmodium cynomolgi infections in monkeys.
Two compounds of the quinoline ester series, WR 197236 (6-butyl-4-hydroxy-3-methoxycarbonyl-7-beta-phenoxyethoxyquinoline ) and WR 194905 (4-acetoxy-6-decyloxy-7-isopropoxy-3-methoxycarbonylquinoline++ +), exhibit anti-relapse activity against sporozoite-induced Plasmodium cynomolgi B infections in rhesus monkeys. Both the compounds have been found to be curative when given intramuscularly in 7 daily doses of 15 mg/kg, and no relapses were observed during the observation period of 120 d.


A preequatorial Gore-Tex sling to restore rectus muscle pathways in myopic strabismus fixus.
A 74-year-old woman with high myopia presented with a rapid-onset, large-angle esotropia consistent with myopic strabismus fixus, or fallen eye syndrome. We treated the patient with combined bilateral disinsertion of the medial rectus muscles and resection of the right lateral rectus muscle with bilateral repositioning of the displaced superior and lateral rectus muscles toward their normal anatomic positions using a polytetrafluoroethylene (Gore-Tex) sling. The eyes were held in the orthotropic position for 7 days after surgery using nylon traction sutures. After 7 months of follow-up, the patient remained orthotropic at distance with a residual esotropia of 12(Δ) at near and a persistent limitation of elevation.


A computer-aided automated methodology for the detection and classification of occlusal caries from photographic color images.
The aim of this work is to present a computer-aided automated methodology for the assessment of carious lesions, according to the International Caries Detection and Assessment System (ICDAS II), which are located on the occlusal surfaces of posterior permanent teeth from photographic color tooth images. The proposed methodology consists of two stages: (a) the detection of regions of interest and (b) the classification of the detected regions according to ICDAS ΙΙ. In the first stage, pre-processing, segmentation and post-processing mechanisms were employed. For each pixel of the detected regions, a 15×15 neighborhood is used and a set of intensity-based and texture-based features were extracted. A correlation based technique was applied to select a subset of 36 features which were given as input into the classification stage, where five classifiers (J48, Random Tree, Random Forests, Support Vector Machines and Naïve Bayes) were compared to conclude to the best one, in our case, to Random Forests. The methodology was evaluated on a set of 103 digital color images where 425 regions of interest from occlusal surfaces of extracted permanent teeth were manually segmented and classified, based on visual assessments by two experts. The methodology correctly detected 337 out of 340 regions in the detection stage with accuracy of detection 80%. For the classification stage an overall accuracy 83% is achieved. The proposed methodology provides an objective and fully automated caries diagnostic system for occlusal carious lesions with similar or better performance of a trained dentist taking into consideration the available medical knowledge.


Effect of specific foods, beverages, and spices on amount of ileostomy output in human subjects.
To measure the effect of various selected foods on the amount of ileal excreta, 37 metabolic balance studies were performed on seven subjects who had normal functioning ileostomies for ulcerative colitis. Although this investigation was conducted with the subjects living at home and selecting their own diet, metabolic balance techniques were carefully observed. The diet was identical in the 3-day control and 3-day experimental period except for the alteration of one aspect of the diet in the experimental period. The substances tested were those often either interdicted for or avoided by ileostomates. Only seven (five fruits, one vegetable, and prune juice) of the 37 dietary substances significantly increased the ileal effluent. Excessive water intake, alcohol beverages, fried foods, and spices did not increase ileostomy output. A small but significant loss of sodium and in some instances potassium was observed with prune juice and some fruits that statistically increased ileal output. Although a limited number of foods were studied, application of the results suggests that many dietary substances generally avoided by or interdicted for ileostomates did not significantly increase the amount of ileal excreta when objective measurements are made.


Ocular toxoplasmosis treatment and clinical monitoring of the patient.
A case of ocular toxoplasmosis is presented from the initial patient contact to the completion of treatment. A discussion follows which reviews the literature on ocular toxoplasmosis with emphasis on the typical pharmacological management of the disease.


Dielectric spectroscopy and electrophoretic mobility measurements interpreted with the standard electrokinetic model.
We report results from complementary electrokinetic measurements-dielectric relaxation and electrophoretic mobility-undertaken to test the applicability of the standard electrokinetic theory with a model system. Dielectric spectra were obtained at frequencies between 1 kHz and 40 MHz with a new, two-electrode cell design [Hollingsworth and Saville, J. Colloid Interface Sci. 257 (2003) 65-76]; mobility data were acquired with an electrophoretic light scattering instrument. Data from the two-electrode cell were collected at different electrode separations and interpreted with newly developed procedures to remove the influence of electrode polarization. Methodology A employs extrapolation to infinite electrode separation to compute the dielectric constant and conductivity as functions of frequency. The contributions from suspended particles are reported in terms of dielectric constant and conductivity increments. Methodology B uses a theoretical model of electrode polarization and the standard electrokinetic model in a nonlinear regression scheme. Results are presented in several forms: frequency-dependent dielectric constant and conductivity increments, frequency-dependent dielectric constants and conductivities, and the complex dipole coefficient. It is shown that the standard model provides a consistent methodology for interpreting particle behavior; zeta-potentials inferred from mobility and dielectric relaxation agree to within experimental error. Moreover, the cell design and interpretation are straightforward and provide relatively simple ways to obtain complementary measurements over a wide frequency range. The results unambiguously show that electrokinetic character of this dispersion follows the standard model.


Site-specific metal-induced damage of mitomycin C-crosslinked DNA fragments in the presence of sodium dithionite.
Purified singly mitomycin C-crosslinked DNA duplex fragments were treated with Cu(II) in the presence of sodium dithionite. Cleavage products were analyzed through single-nucleotide resolving denaturing polyacrylamide gel electrophoresis. In addition to the previously described non-specific cleavage, which may be attributed to the production of hydroxyl radical, a novel site-specific cleavage in the immediate vicinity of the MC-crosslink was observed. Possible mechanisms of this reaction are discussed.


Atrial septal aneurysms in infants and children.
Interatrial septal aneurysm (IASA) has been detected with increasing frequency since the advent of two-dimensional echocardiography (2DE). In this study, we investigated the prevalence, characteristics, and predisposing factors in IASA formation in 724 infants, children, and adolescents undergoing 2DE. Among this group, 12 patients had an IASA (prevalence = 1.7%). Eleven of the 12 patients had abnormal atrial hemodynamics as a result of either structural heart disease or significant supraventricular dysrhythmias. Follow-up 2DE performed in 10 of 12 patients, 1 to 48 months (mean 16.5 months) after the initial diagnosis, demonstrated diminution or resolution of the IASAs in those patients who had normal hemodynamics following surgical or spontaneous closure of their intracardiac defect, or medical control of their dysrhythmias. In contrast, IASAs became more prominent in those patients with persistent hemodynamic abnormalities. The high prevalence rate and subsequent involution of many IASAs in infants suggest that in the presence of abnormal atrial hemodynamics, the neonatal atrial septum may be prone to aneurysm formation because of inherent structural weaknesses of the neonatal septal tissue. In the absence of continued hemodynamic stress., the majority of these IASAs in infants resolve with maturational changes in the septum and normal cardiac growth.


Pharmacokinetics of ketorolac pentyl ester, a novel ester derivative of ketorolac, in rabbits.
Ketorolac is a potent nonsteroidal anti-inflammatory drug. Recently, a novel ester of ketorolac, ketorolac pentyl ester, was synthesized. When prepared in injectable oil, the new agent demonstrated a long duration of action. Ketorolac pentyl ester was synthesized using a prodrug design by esterification of ketorolac, and appeared to be a prodrug of ketorolac in vivo, which needed to be confirmed. The aim of the present study was to establish the prodrug's pharmacokinetics in vivo, and to confirm whether or not ketorolac pentyl ester was a prodrug of ketorolac. Pharmacokinetic profiles of intravenous ketorolac and its pentyl ester on an equal-molar basis in six rabbits were evaluated. A high-performance liquid chromatographic method was used to determine the plasma concentrations of ketorolac and its pentyl ester. We found that the plasma concentrations of ketorolac pentyl ester declined rapidly after injection and so did the conversion of ketorolac pentyl ester to ketorolac. Also, the conversion of ketorolac was proved complete when compared with intravenous ketorolac under an equi-molar basis. In conclusion, this in vivo pharmacokinetic study confirmed that keterolac pentyl ester was a prodrug of keterolac.


Anionic nanoparticles enable the oral delivery of proteins by enhancing intestinal permeability.
The oral delivery of bioactive peptides and proteins is prevented by the intestinal epithelial barrier, in which intercellular tight junction complexes block the uptake of macromolecules. Here we show that anionic nanoparticles induce tight junction relaxation, increasing intestinal permeability and enabling the oral delivery of proteins. This permeation-enhancing effect is a function of nanoparticle size and charge, with smaller (≤ 200 nm) and more negative particles (such as silica) conferring enhanced permeability. In healthy mice, silica nanoparticles enabled the oral delivery of insulin and exenatide, with 10 U kg-1 orally delivered insulin sustaining hypoglycaemia for a few hours longer than a 1 U kg-1 dose of subcutaneously injected insulin. In healthy, hyperglycaemic and diabetic mice, the oral delivery of 10 U kg-1 insulin led to a dose-adjusted bioactivity of, respectively, 35%, 29% and 23% that of the subcutaneous injection of 1 U kg-1 insulin. The permeation-enhancing effect of the nanoparticles was reversible, non-toxic, and attributable to the binding to integrins on the surface of epithelial cells.


The effectiveness of Hedyotis diffusa Willd extract in a mouse model of experimental autoimmune prostatitis.
Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a frustrating and often debilitating disease. Current studies have shown that Traditional Chinese Medicine (TCM) can improve patients' quality of life and alleviate CP/CPPS symptoms. In this study, the efficacy of Hedyotis diffusa Willd aqueous extraction in experimental autoimmune prostatitis (EAP) mice models was revealed. The C57BL/6 mice were randomly assigned to three groups. Except for the control group, all other groups were subcutaneously injected with 0.2 ml emulsion of T2 peptide, on day 0 and day 14, for inducing EAP models. After the EAP modelling, oral saline was given to the model group, while the H. diffusa group was treated with aqueous extract of H. diffusa Willd. Micturition habits and withdrawal response frequencies were measured. Haematoxylin and eosin staining and immunohistochemistry were used to investigate inflammatory cell infiltration and TNF-α in the prostate tissue respectively. TNF-α levels in the serum were evaluated by ELISA. The H. diffusa Willd aqueous extraction considerably reduced the urine spots number and increased the pain threshold in H. diffusa group. H. diffusa group showed significantly reduced inflammatory lesion and inflammatory cell infiltration than the model group. The levels of TNF-α in H. diffusa group were considerably reduced.


Characterization of a putative extracellular matrix protein from the beetle Tenebrio molitor: hormonal regulation during metamorphosis.
We used differential display to isolate epidermis cDNAs corresponding to juvenile-hormone analog-regulated mRNA from the beetle Tenebrio molitor. One of them encodes a putative extracellular matrix (ECM) protein, named Tenebrin. Indeed, the deduced protein sequence contains ECM typical features like the presence of a signal peptide, internal repeats, a RGD tripeptide sequence motif known to bind integrins and von Willebrand factor type c domains involved in protein-protein interactions. Northern blot analysis reveals a single transcript of about 11 kb with an expression pattern correlated to 20-hydroxyecdysone fluctuations during metamorphosis. In vivo injections of exogenous 20-hydroxyecdysone alone or combined with cycloheximide show that Tenebrin expression is directly induced by this hormone. Methoprene (a juvenile hormone analog) application experiments show that Tenebrin expression is rapidly induced by this analog. This gene is still up-regulated in the presence of protein synthesis inhibitor but, in these conditions, the mRNA induction level is not maximal.


Isolation and characterization of Populus xyloglucan endotransglycosylase/hydrolase (XTH) involved in osmotic stress responses.
Xyloglucan endotransglycosylase/hydrolase (XTH) belongs to the GH16 subfamily of the glycoside hydrolases of carbohydrate active enzymes and plays an important role in the structure and function of plant cell walls. In this study, 11 members of the XTH gene family were cloned from Populus tomentosa. A bioinformatics analysis revealed that 11 PtoXTHs could be classified into three groups, where PtoXTH27 and PtoXTH34 were most likely to exhibit XTH activity. Biochemical analyses of purified PtoXTHs demonstrated that PtoXTH27 and PtoXTH34 had detectable xyloglucan endotransglucosylase (XET) activity, while the others did not exhibit XET or XEH activity. Moreover, enzymatic assays revealed that the optimum reaction temperature of both PtoXTH27 and PtoXTH34 was 37 °C, while their optimum pH values differed, such that PtoXTH27 was 6.0 and PtoXTH34 was 5.0. Enzyme kinetic parameters indicated that PtoXTH34 had higher affinity for the receptor substrate, XXXG, implying that PtoXTH34 and PtoXTH27 in plants have different substrate structure specificity. Finally, heterologous expression of XTH significantly increased intracellular total sugar content and osmotolerance of yeast cells, indicating that PtoXTH27 and PtoXTH34 are potentially involved in osmotic stress responses. These results clearly demonstrate the enzymatic characteristics and putative role of XTH in osmotic stress responses.


Reactivity of normal airways to short-term exercise.
Reactivity of airways to short-term exercise was tested once in 15 healthy subjects and repeated on eight of the group using Stead-Wells and Wedge spirometers and body plethysmograph. The pulmonary function tests were performed at rest and shortly after exercise, and the data were studied by means of a randomized block analysis of variance. It was demonstrated that overall post-exercise pulmonary functions were not statistically different from the pre-exercise baseline.


Autophagy is critical for group 2 innate lymphoid cell metabolic homeostasis and effector function.
Allergic asthma is a chronic inflammatory disorder characterized by airway hyperreactivity (AHR) and driven by TH2 cytokine production. Group 2 innate lymphoid cells (ILC2s) secrete high amounts of TH2 cytokines and contribute to the development of AHR. Autophagy is a cellular degradation pathway that recycles cytoplasmic content. However, the role of autophagy in ILC2s remains to be fully elucidated. We characterized the effects of autophagy deficiency on ILC2 effector functions and metabolic balance. ILC2s from autophagy-deficient mice were isolated to evaluate proliferation, apoptosis, cytokine secretion, gene expression and cell metabolism. Also, autophagy-deficient ILC2s were adoptively transferred into Rag-/-GC-/- mice, which were then challenged with IL-33 and assessed for AHR and lung inflammation. We demonstrate that autophagy is extensively used by activated ILC2s to maintain their homeostasis and effector functions. Deletion of the critical autophagy gene autophagy-related 5 (Atg5) resulted in decreased cytokine secretion and increased apoptosis. Moreover, lack of autophagy among ILC2s impaired their ability to use fatty acid oxidation and strikingly promoted glycolysis, as evidenced by our transcriptomic and metabolite analyses. This shift of fuel dependency led to impaired homeostasis and TH2 cytokine production, thus inhibiting the development of ILC2-mediated AHR. Notably, this metabolic reprogramming was also associated with an accumulation of dysfunctional mitochondria, producing excessive reactive oxygen species. These findings provide new insights into the metabolic profile of ILC2s and suggest that modulation of fuel dependency by autophagy is a potentially new therapeutic approach to target ILC2-dependent inflammation.


Motor coordination uses external spatial coordinates independent of developmental vision.
The constraints that guide bimanual movement coordination are informative about the processing principles underlying movement planning in humans. For example, symmetry relative to the body midline benefits finger and hand movements independent of hand posture. This symmetry constraint has been interpreted to indicate that movement coordination is guided by a perceptual code. Although it has been assumed implicitly that the perceptual system at the heart of this constraint is vision, this relationship has not been tested. Here, congenitally blind and sighted participants made symmetrical and non-symmetrical (that is, parallel) bimanual tapping and finger oscillation movements. For both groups, symmetrical movements were executed more correctly than parallel movements, independent of anatomical constraints like finger homology and hand posture. For the blind, the reliance on external spatial factors in movement coordination stands in stark contrast to their use of an anatomical reference frame in perceptual processing. Thus, the externally coded symmetry constraint evident in bimanual coordination can develop in the absence of the visual system, suggesting that the visual system is not critical for the establishment of an external-spatial reference frame in movement coordination.


Passive smoking is a risk factor for esophagitis in children.
A case-control study was undertaken to determine whether esophagitis in children correlated with exposure to parental cigarette smoking. At least one parent smoked in 77 (79%) of 97 families in the study group, compared with 42 (38.9%) of the 108 families in the control group (p < 0.001). Passive smoking is a risk factor for the development of esophagitis in children, providing added support for public health efforts to restrict childhood exposure to tobacco smoke.


UNEP Chemicals' work: breaking the barriers to information access.
The global production and trade in chemicals was measured at 1.55 trillion US dollars in 1996, four times the amount of 1966. Chemicals represent 14% of imports and exports of OECD countries and the present decade has been characterised by the expansion of the production and use of chemicals in countries with economies in transition and developing countries. While some of these chemicals are benign at the levels we are usually exposed to them, others present risks to human health or the environment often across national boundaries. Failure to safely manage these risks could lead to serious and long-term consequences. The sound management of chemicals requires adequate information about their nature and use as well as their effects and control options. Much of this information can be culled from a variety of sources but that does not guarantee equal access to it by all those who are in need. To achieve equitable information distribution, the chemical unit of the United Nations Environment Programme (UNEP) operates many activities aimed at removing the geographical and technical barriers that prevent the free flow of chemical management information. These activities include the use of assorted media and activities to enhance countries' internal capacity to search and use the information available on the Internet.


Development of nanoRibo-seq enables study of regulated translation by cortical neuron subtypes, showing uORF translation in synaptic-axonal genes.
Investigation of translation in rare cell types or subcellular contexts is challenging due to large input requirements for standard approaches. Here, we present "nanoRibo-seq" an optimized approach using 102- to 103-fold less input material than bulk approaches. nanoRibo-seq exhibits rigorous quality control features consistent with quantification of ribosome protected fragments with as few as 1,000 cells. We compare translatomes of two closely related cortical neuron subtypes, callosal projection neurons (CPN) and subcerebral projection neurons (SCPN), during their early postnatal development. We find that, while translational efficiency is highly correlated between CPN and SCPN, several dozen mRNAs are differentially translated. We further examine upstream open reading frame (uORF) translation and identify that mRNAs involved in synapse organization and axon development are highly enriched for uORF translation in both subtypes. nanoRibo-seq enables investigation of translational regulation of rare cell types in vivo and offers a flexible approach for globally quantifying translation from limited input material.


Kinetics and interaction studies between cytochrome c3 and Fe-only hydrogenase from Desulfovibrio vulgaris Hildenborough.
Hydrogenases from Desulfovibrio are found to catalyze hydrogen uptake with low potential multiheme cytochromes, such as cytochrome c3, acting as acceptors. The production of Fe-only hydrogenase from Desulfovibrio vulgaris Hildenborough was improved with respect to the growth phase and media to determine the best large-scale bacteria growth conditions. The interaction and electron transfer from Fe-only hydrogenase to multiheme cytochrome has been studied in detail by both BLAcore and steady-state measurements. The electron transfer between [Fe] hydrogenase and cytochrome c3 appears to be a cooperative phenomenon (h = 1.37). This behavior could be related to the conductivity properties of multihemic cytochromes. An apparent dissociation constant was determined (2 x 10(-7) M). The importance of the cooperativity for contrasting models proposed to describe the functional role of the hydrogenase/cytochrome c3 complex is discussed. Presently, the only determined structure is from [NiFe] hydrogenase and there are no obvious similarities between [NiFe] and [Fe] hydrogenase. Furthermore, no crystallographic data are available concerning [Fe] hydrogenase. The first results on crystallization and X-ray crystallography are reported.


Combining MRI and clinical data to detect high relapse risk after the first episode of psychosis.
Detecting patients at high relapse risk after the first episode of psychosis (HRR-FEP) could help the clinician adjust the preventive treatment. To develop a tool to detect patients at HRR using their baseline clinical and structural MRI, we followed 227 patients with FEP for 18-24 months and applied MRIPredict. We previously optimized the MRI-based machine-learning parameters (combining unmodulated and modulated gray and white matter and using voxel-based ensemble) in two independent datasets. Patients estimated to be at HRR-FEP showed a substantially increased risk of relapse (hazard ratio = 4.58, P < 0.05). Accuracy was poorer when we only used clinical or MRI data. We thus show the potential of combining clinical and MRI data to detect which individuals are more likely to relapse, who may benefit from increased frequency of visits, and which are unlikely, who may be currently receiving unnecessary prophylactic treatments. We also provide an updated version of the MRIPredict software.


Gastrointestinal Care of the Parkinson Patient.
This article reviews the most common gastrointestinal (GI) problems that occur in patients with Parkinson disease, including weight loss, drooling, dysphagia, delayed gastric emptying, constipation, and defecatory dysfunction. Appropriate workup and treatment options are reviewed in detail in order to provide clinicians with a comprehensive and practical guide to managing these problems in Parkinson disease patients. GI adverse effects of commonly used Parkinson disease motor medications are also reviewed.


Towards Truly Sustainable Polymers: A Metal-Free Recyclable Polyester from Biorenewable Non-Strained γ-Butyrolactone.
The first effective organopolymerization of the biorenewable "non-polymerizable" γ-butyrolactone (γ-BL) to a high-molecular-weight metal-free recyclable polyester is reported. The superbase tert-Bu-P4 is found to directly initiate this polymerization through deprotonation of γ-BL to generate reactive enolate species. When combined with a suitable alcohol, the tert-Bu-P4 -based system rapidly converts γ-BL into polyesters with high monomer conversions (up to 90 %), high molecular weights (Mn up to 26.7 kg mol(-1) ), and complete recyclability (quantitative γ-BL recovery).


Renewable plant-derived lignin for electrochemical energy systems.
Lignin, as one of the most abundant natural polymers, has been proved to be a promising material for the construction of high-performance electrochemical energy systems, including electrodes, electrolytes, and separators, because of their low-cost and sustainable natures and unique structure with abundant functional group. In this review article, we outline some key contributions in this field such as fundamental principles and various electrochemical energy systems including rechargeable batteries, supercapacitors, solar cells, and fuel cells. At the same time, we also point out the significant scientific discussion and critical barriers for lignin-based materials for electrochemical energy systems and also provides feasible strategies for preparing new sustainable energy materials.


DNA lesion and mutagenesis induced in phageM13mp2 by UVA, UVB and UVC irradiation.
Sunlight is carcinogenic and mutagenic and its genotoxic effects are believed to be the result of UV light-induced lesions in DNA. These lesions include pyrimidine dimers and (6-4) photoproducts, but it is uncertain whether the pyrimidine modifications are the sole pre-mutagenic lesions induced by UV light. Previous studies indicate that some sunlight-induced mutations in the single-stranded DNA phage M13mp2 may not be caused by these photoproducts. In this work, purified single-stranded phage DNA was exposed to UVA, UVB and UVC and the induced mutations were analyzed. All 3 types of UV light increase the mutation frequency. The mutants were sequenced and the results suggest that UVA exposure may induce formation of a non-dipyrimidine lesion in DNA.


Percutaneous cholecystostomy and endoscopic cholecystolithotripsy in the management of acute cholecystitis.
Percutaneous cholecystostomy is a valuable alternative temporary measure for acute cholecystitis in elderly patients with severe underlying cardiopulmonary disease, but the subsequent management of gallbladder calculi is still controversial. Eleven patients treated with percutaneous endoscopic cholecystolithotripsy after percutaneous cholecystostomy were evaluated retrospectively. All patients showed clinical improvement after percutaneous cholecystostomy. Tract dilation succeeded in 9 patients. Complete stone clearance was achieved in seven patients over one to four sessions (average, two sessions). Stone extraction could not be completed in two patients because gallbladder access was lost in one patient, and the other refused further procedure. There were three complications, with two biliary fistulas and one major bile leakage leading to emergency cholecystectomy. The duration of the entire procedure ranged from 30 to 126 days (mean, 58 days). During the follow-up (mean 17.2 months), one patient had recurrent cholangitis and the others remained asymptomatic. Percutaneous cholecystolithotripsy after percutaneous cholecystostomy is a safe alternative in the management of high-risk elderly patients with acute cholecystitis.


Recent progress on the detection of animal-derived food stimulants using mass spectrometry-based techniques.
The misuse of animal-derived stimulants in food is becoming increasingly common, and mass spectrometry (MS) is used extensively for their detection and analysis. There is a growing demand for abused-substances detection, highlighting the need for systematic studies on the advantages of MS-based methods in detecting animal-derived stimulants. We reviewed the application of chromatography-mass spectrometry to the screening and detection of food stimulants of animal origin. Specifically, we analyzed four common animal sources of synthetic steroids, β-receptor agonists, zearalenol (ZAL), and glucocorticoids. We also explored the potential of using chromatography-mass spectrometry to detect and analyze animal-derived foods. We searched and screened the Web of Science and Google Scholar databases until April 2023. Our inclusion criteria included a publication year within the last 5 years, publication language of English, and the research fields of food analysis, environmental chemistry, and polymer science. Our keywords were "mass spectrometry," "anabolic androgenic steroids," "β-2agonists," "glucocorticoids," "zearalenone," and "doping." Although traditional techniques such as thin-layer chromatography and enzyme-linked immunoassays are simple, fast, and suitable for the initial screening of bulk products, they are limited by their relatively high detection limits. Among the methods based on MS, gas chromatography-mass spectrometry and liquid chromatography-tandem mass spectrometry are the most widely used for detecting food doping agents of animal origin. However, a sensitive method with high repeatability and a short analysis time for a large number of samples is still required. Advances in MS have enabled the detection of extremely low concentrations of these substances. Combining different techniques, such as high-resolution mass spectrometry, ultra-high performance liquid chromatography-tandem mass spectrometry, gas chromatography-combustion-isotope ratio mass spectrometry, ultra-high performance liquid chromatography-high resolution mass spectrometry, and two-dimensional chromatography, offers significant advantages for detecting trace illicit drugs in animal-derived foods. Due to advances in assay technology and sample preparation methods, sample collection and storage methods such as dried blood spots, dried urine spots, and volumetric absorptive microsampling are increasingly accepted because of their increased stability and cost-effectiveness. MS significantly improves the efficiency of detecting doping agents of animal origin. With the continuous development of MS technology, its application in the fields of doping detection and the analysis of doping agents of animal origin is expected to become more extensive.


The formation and management of middle ear granulation tissue in chronic ear disease.
Granulation tissue is an important pathogenic feature of all types of chronic ear disease, and it can be controlled and treated with good aural toilet, appropriate antibiotic therapy, topical steroids, and chemical cautery or surgical debridement.


A unique presentation of hyponatremia and seizures in a 2-month-old child with cystic fibrosis: a case report.
Cystic fibrosis is an autosomal recessive disorder that causes a broad range of clinical findings and can present unusually as electrolyte disturbance, such as hyponatremia that causes seizures in children. We report a case of a 2-month-old infant who presented with an episode of grand mal seizure induced by hyponatremia and moderate episodes of milky vomiting after breastfeeding. Proper investigations showed normal cardiac and renal functions. Ultrasonography showed no pathological changes. Laboratory tests performed showed hyponatremia, mild hypokalemia, and hypochloremia. Urinary electrolyte results were normal. While broadening the scope of differential diagnosis in order to reach a final diagnosis, the sweat chloride level was elevated, which confirmed the diagnosis of cystic fibroses. We aim to share our case to keep cystic fibroses in mind as a differential diagnosis when dealing with hyponatremic seizures in children.


Lipidomic analysis of human placental syncytiotrophoblast microvesicles in adverse pregnancy outcomes.
Syncytiotrophoblast microvesicles (STBM) are shed from placenta into the maternal circulation. STBM circulate in increased amounts in adverse pregnancies, e.g., preeclampsia and recurrent miscarriages (RM). Recently dysregulation of lipid metabolites has been proposed to be associated with their pathogenesis. Lipid composition of STBM in healthy and adverse pregnancies remains unknown. To determine lipid composition of STBM and whether STBM lipid composition differs in pathologic and normal pregnancies. Patients with Preeclampsia (n = 6) or history of RM (n = 9) (>2 consecutive losses <20 weeks) and gestational age-matched normal pregnant controls (same number as cases) were recruited. STBM were prepared from placental explant culture supernatant. Lipid profiling of STBM was performed by mass spectrometry in combination with liquid chromatography. We quantified ∼200 lipids in STBM including (i) glycerophospholipids (phosphatidylcholine, PC; phosphatidylethanolamine, PE; phosphatidylinositol, PI; phosphatidylglycerol, PG; phosphatidylserine, PS; phosphatidic acid, PA); (ii) sphingolipids (sphingomyelin, SM; ceramide, Cer; Glucosylceramide, GluCer; ganglioside mannoside 3, GM3); (iii) free cholesterol and cholesteryl esters, CE. The major lipid classes in STBM were SM, Chol, PS, PC and PI, along with PA and GM3 enrichments. SM/PC ratio showed a unique reversal (3:1) compared to that normally found in human cells or plasma. Level of total PS was significantly upregulated (p < 0.005) in preeclampsia patients, while PI (p < 0.0005), PA (p < 0.005), and GM3 (p < 0.05) were significantly downregulated. Similar trends were obtained in RM. Differential lipid expression of STBM in preeclampsia or RM includes those that are implicated in immune response, coagulation, oxidative stress, and apoptosis.


Multi-walled carbon nanotubes improved growth, anatomy, physiology, secondary metabolism, and callus performance in Catharanthus roseus: an in vitro study.
This study was conducted to monitor the physiological and molecular responses of Catharanthus roseus (rose periwinkle) to multi-walled carbon nanotube (MWCNT) incorporation into the culture medium. The seeds were grown on hormone-free MS medium supplemented with 0, 50, 100, and 150 mgL-1of MWCNT. The supplementations of culture medium with MWCNTs led to significant increases in plant growth indexes such as leaf width, leaf area, leaf fresh weight, root length, and total plant biomass). Slight increases were also observed in chlorophyll a (Chla), Chlb, and carotenoid contents (mean = 18.6%) in MWCNT-treated seedlings. Protein concentrations increased by an average of 34% relative to the control. The application of MWCNT resulted in twofold increases in the catalase and peroxidase activities. A similar trend was also observed in the phenylalanine ammonia lyase activities (by an average of 36.5%), soluble phenols (by 23%), and alkaloids (by 1.7-fold). Moreover, upregulations (mean = 37-fold) in the transcriptions of the DAT gene resulted from the MWCNT supplementations. Exposure to MWCNT improved cell sizes and xylem conducting tissue in treated seedlings. The applications of MWCNTs also stimulated the callus initiation and performance, implying their effects on proliferation and possible differentiation. This study has provided evidence of role MWCNT play in improving plant performance and production of pharmaceutical secondary metabolites.


Hepatitis B virus pre-genomic RNA and hepatitis B core-related antigen reductions at week 4 predict favourable hepatitis B surface antigen response upon long-term nucleos(t)ide analogue in chronic hepatitis B.
We investigated the dynamics of serum HBV pre-genomic RNA (pgRNA) and hepatitis B core-related antigen (HBcrAg) in patients receiving nucleos(t)ide analogues (NAs) and their predictability for favourable suppression of serum hepatitis B surface antigen (HBsAg). Serum viral biomarkers were measured at baseline, weeks 4, 12, 24, 36, and 48 of treatment. Patients were followed up thereafter and serum HBsAg level was measured at end of follow-up (EOFU). Favourable HBsAg response (FHR) was defined as ≤100 IU/mL or HBsAg seroclearance upon EOFU. Twenty-eight hepatitis B e antigen (HBeAg)-positive and 36 HBeAg-negative patients (median, 38.2 years old; 71.9% male) were recruited with median follow-up duration of 17.1 years (interquartile range, 12.8-18.2). For the entire cohort, 22/64 (34.4%) achieved FHR. For HBeAg-positive patients, serum HBV pgRNA decline at week 4 was significantly greater for patients with FHR compared to non-FHR (5.49 vs. 4.32 log copies/mL, respectively; P=0.016). The area under the receiver-operating-characteristic curve (AUROC) for week 4 HBV pgRNA reduction to predict FHR in HBeAg-positive patients was 0.825 (95% confidence interval [CI], 0.661-0.989). For HBeAg-negative patients, instead of increase in serum HBcrAg in non-FHR patients, FHR patients had median reduction in HBcrAg at week 4 (increment of 1.75 vs. reduction of 2.98 log U/mL; P=0.023). The AUROC for week 4 change of HBcrAg to predict FHR in HBeAg-negative patients was 0.789 (95% CI, 0.596-0.982). Early on-treatment changes of serum HBV pgRNA and HBcrAg at 4 weeks predict HBsAg seroclearance or ≤100 IU/mL in NA-treated CHB patients upon long-term FU.


Packing of sidechains in low-resolution models for proteins.
Atomic level rotamer libraries for sidechains in proteins have been proposed by several groups. Conformations of side groups in coarse-grained models, on the other hand, have not yet been analyzed, although low resolution approaches are the only efficient way to explore global structural features. A residue-specific backbone-dependent library for sidechain isomers, compatible with a coarse-grained model, is proposed. The isomeric states are utilized in packing sidechains of known backbone structures. Sidechain positions are predicted with a root-mean-square deviation (r.m.s.d.) of 2.40 A with respect to crystal structure for 50 test proteins. The rmsd for core residues is 1.60 A and decreases to 1.35 A when conformational correlations and directional effects in inter-residue couplings are considered. An automated method for assigning sidechain positions in coarse-grained model proteins is proposed and made available on the internet; the method accounts satisfactorily for sidechain packing, particularly in the core.


Hybrid mode atomic force microscopy of phase modulation and frequency modulation.
We propose hybrid phase modulation (PM)/frequency modulation (FM) atomic force microscopy (AFM) to increase the imaging speed of AFM in high-Q environments. We derive the relationship between the phase shift, the frequency shift and the tip-sample interaction force from the equation of motion for the cantilever in high-Q environments. The tip-sample conservative force is approximately given by the sum of the conservative force with respect to the phase shift in the PM mode and that with respect to the frequency shift in the FM mode. We preliminarily demonstrate that the hybrid PM/FM-AFM is a new and very promising AFM operation mode that can increase imaging speed.


Expression of cysteine proteinases and their inhibitor, cystatin beta, in cultured rat mesangial cells.
Matrix expansion in the glomerular mesangial area is observed in diabetic nephropathy. Intracellular breakdown of long-lived proteins was lower in mesangial cells in the high glucose medium than that in the control medium. Enzymatic activity of cathepsin L increased 1.4-fold after 6 h of treatment with the high glucose, and then declined gradually to 72% of control cells after treatment for 36 h. Change in the enzyme activity of cathepsin B showed a similar time course but less magnitude than that of cathepsin L. Immunoblot analysis with anti-cathepsin L antibody showed that change in the enzyme activity of cathepsin L was due to the change in the amount of cathepsin L, and that with anti-cathepsin B antibody showed no change in the amount of cathepsin B in the mesangial cells treated with high glucose. Intracellular cathepsin activities were controlled not only by the amounts but also by the inhibitor cystatin beta. Immunoblot analysis with anti-cystatin beta antibody showed that intracellular levels of cystatin beta increased slightly after 24 h of treatment with high glucose. These changes were derived from changes in mRNA level. These results, therefore, demonstrated that the decrease of intracellular protein breakdown in mesangial cells treated with high glucose medium was due to both suppression of cathepsins and increase of cystatin beta.


Long-term safety of anti-TNF-α in PsA patients with concomitant HCV infection: a retrospective observational multicenter study on 15 patients.
Psoriatic arthritis (PsA) is an inflammatory arthropathy associated with skin and/or nail psoriasis. TNF-α, in addition to its pro-inflammatory role, is an essential cytokine for the host's defense, and its depletion by treatment may facilitate the risk of viral infections or their reactivation. The aim of this study was to evaluate the efficacy and safety of TNF-α blockers in PsA patients with concurrent hepatitis C virus (HCV) infection. This is a multicenter study carried out in four Italian centers specialized in the diagnosis and treatment of PsA. At baseline and after 6 (T6) and 12 months (T12) of therapy, data concerning PsA activity and liver tests were registered. A total of 15 PsA patients with concomitant HCV infection were included in the study. At baseline, 13 patients had low viral load, and liver enzyme tests were within the normal range. During the observation period, these values remained stable. On the other hand, at baseline, a high viral load with slightly increased values of AST and ALT was detected in one patient. At T6 and T12, these values decreased. The remaining patient, at baseline, had low viral load, but with slightly increased AST and ALT values that normalized during the observation period. This is the greatest sample size available in the literature on this topic. The data suggests that anti-TNF-α agents are effective and safe in PsA patients with concomitant HCV. We suggest that the use of anti-TNF-α agents, accompanied by close monitoring, could be a therapeutic option.


Iron-iron oxide core-shell nanoparticles are active and magnetically recyclable olefin and alkyne hydrogenation catalysts in protic and aqueous media.
We report for the first time the use of iron-iron oxide core-shell nanoparticles for the hydrogenation of olefins and alkynes under mild conditions in ethanol and in an aqueous medium. This catalyst proves robust towards the presence of oxidants, such as oxygen and water, is magnetically recoverable and shows selectivity towards the less activated double bonds.


[Impact of the COVID-19 pandemic on patient safety incident and medication error reporting systems].
To determine the impact of the COVID-19 pandemic on the epidemiology of safety incidents (SI) and medication errors (ME) reported to the CISEMadrid notification system in the hospital and primary care settings of the Madrid Health Service (SERMAS). Observational and descriptive study with a retrospective analysis of data including all CISEMadrid notifications from 01-Jan-2018 to 31-Dec-2020, from 33 hospitals and 262 health care centres of the SERMAS. The two periods in 2020 with the greatest increase in COVID-19 cases were identified to compare incidents reported in the pre-pandemic and pandemic periods. 36,494 incidents were reported. Comparing both periods, an overall decrease in pandemic notifications of 60.7% was observed, being higher in primary care, falling to 33% of previous levels. The reduction in notifications was similar in the peaks and valleys of the waves. The three most frequent SIs in both periods and care settings were: diagnostic tests, medical devices/equipment/clinical furniture and organisational management/citations. In ME, dose failure and inappropriate selection were the most frequent in both settings and periods. There were no relevant differences in patient consequences in both periods. During the pandemic, patient safety notifications decreased although the most frequent types remained the same, as did their impact on the patient, both in hospitals and in primary care. The safety culture of organisations is a critical aspect for the maintenance of reporting systems.


The polymerase of negative-stranded RNA viruses.
Negative-sense (NS) RNA viruses deliver into cells a mega-dalton RNA-protein complex competent for transcription. Within this complex, the RNA is protected in a nucleocapsid protein (NP) sheath which the viral polymerase negotiates during RNA synthesis. The NP-RNA templates come as nonsegmented (NNS) or segmented (SNS), necessitating distinct strategies for transcription by their polymerases. Atomic-level understanding of the NP-RNA of both NNS and SNS RNA viruses show that the RNA must be transiently dissociated from NP during RNA synthesis. Here we summarize and compare the polymerases of NNS and SNS RNA viruses, and the current structural data on the polymerases. Those comparisons inform us on the evolution of related RNA synthesis machines which use two distinct mechanisms for mRNA cap formation.


Arterial switch operation after Mustard procedures in adult patients with transposition of the great arteries: is it time to revise our strategy?
After the Mustard or Senning procedure, adults with transposition of the great arteries may have right ventricular failure and require consideration of new therapies. A 2-stage arterial switch operation (ASO) may be performed as an alternative to heart transplantation. This procedure is relatively successful in children, but little is known about the 2-stage ASO in adults. We report our experience in adults undergoing pulmonary arterial banding as the first stage of a planned 2-stage arterial switch procedure after a failed Mustard operation. Three adult patients with systemic right ventricular failure late after Mustard procedures embarked, through pulmonary artery banding, on a course toward a 2-stage arterial switch at the Toronto General Hospital. Baseline clinical characteristics as well as preoperative hemodynamics were reviewed. Immediate perioperative and postoperative events, hemodynamic measurements, and clinical outcomes were also recorded. Two patients were banded acutely such that their morphologic left ventricular to right ventricular (LV/RV) systolic pressure ratios were >0.65 after the initial banding procedure. The subpulmonary left ventricle failed in both cases. In contrast, the third patient had a more gradual approach to pulmonary artery banding (PAB), with an initial LV/RV pressure ratio of 0.5, which eventually led to a successful conversion to an arterial switch procedure. Our evidence suggests that in adult patients expected to undergo a 2-stage arterial switch procedure after a failed Mustard operation, acute PAB achieving near-systemic subpulmonary LV pressure leads rapidly to ventricular failure and failure of this treatment strategy. A more gradual approach to PAB may be required to achieve a successful outcome.