Seed protection strategies of the brainy Elaeocarpus ganitrus endocarp: Gradient motif yields fracture tolerance.
Be it animals or plants, most of the organism's offspring come into existence after their embryos develop inside a protective shell. In plants, these hard protective shells are called endocarps. They serve the function of nourishing and protecting the seeds from external mechanical damage. Through evolution, endocarps of plants have developed various structural strategies to protect the enclosed seeds from external threats, and these strategies can vary according to the habitat or lifestyle of a particular plant. One such intriguing hard plant shell is the endocarp of the Elaeocarpus ganitrus fruit. It mostly grows in South Asia's mountainous forests, and its endocarps are known in the local communities as unbreakable and everlasting prayer beads. We report an in-depth investigation on microstructure, tomography, and mechanical properties to cast light on its performance and the underlying structure-property relation. The 3D structural quantifications by micro-CT demonstrate that the endocarp has gradient microarchitecture. In addition, the endocarp also exhibits gradient hardness and stiffness. The toughening mechanisms arising from the layered cellular structure enable the endocarps to withstand higher loads up to 5000 N before they fracture. Our findings provide experimental evidence of outstanding fracture tolerance and seed protection strategies developed by Elaeocarpus ganitrus endocarp that encourage the design of synthetic fracture tolerant structures. STATEMENT OF SIGNIFICANCE: Endocarps are low-density plant shells that exhibit remarkable fracture resistance and energy absorption when they encounter impact by falling from high trees and prolonged compression and abrasion by the predators. Such outstanding mechanical performance originates through structural design strategies developed to protect their seeds. Here we demonstrate previously undiscovered structural features and mechanical properties of Elaeocarpus ganitrus endocarp. We scrutinize the microstructure using high-resolution x-ray tomography scans and the 3D structural quantifications reveal a gradient microstructure which is in agreement with the gradient hardness and stiffness. The multiscale hierarchical structures combined with the gradient motif yield impressive fracture tolerance in Elaeocarpus ganitrus endocarp. These findings advance the knowledge of the structure-property relation in hard plant shells, and the procured structural design strategies can be utilized to design fracture-resistant structures.


Therapeutic vaccination with dendritic cells pulsed with tumor-derived Hsp70 and a COX-2 inhibitor induces protective immunity against B16 melanoma.
Prophylactic immunization of mice with autologous tumor-derived heat shock proteins (Hsp) generates effective anti-tumor immunity. However, this approach is ineffective when used therapeutically, partly due to the immunosuppressive effects of the growing tumor. Here we sought to overcome this problem by therapeutic vaccination with dendritic cells (DC) pulsed with Hsp70 and a COX-2 inhibitor. We found that Hsp70 induces IL-6 and IL-10 production and suppressed expression of CD40 on DC. Incubation of DC with tumor-conditioned medium attenuated Hsp70-induced expression of CD80 and induced expression of COX-2. Inhibition of COX-2 partially reversed the stimulatory effect of Hsp70 on DC IL-6 and IL-10 production and enhanced expression of CD80 and MHC classes I and II. Therapeutic administration of DC pulsed in vitro with Hsp70 in the presence of a COX-2 inhibitor significantly reduced progression of B16 tumors in mice and significantly enhanced survival. This was associated with a reduction in the frequency of IL-10-producing CD4(+) T cells and enhancement of IFN-gamma-producing CD8(+) T cells. Our findings provide a novel immunotherapeutic approach against cancer based on attenuation of COX-2-mediated immunosuppression using in vitro modulated DC.


Killing HIV-infected cells by transduction with an HIV protease-activated caspase-3 protein.
At present, treatment of HIV infection uses small inhibitory molecules that target HIV protease; however, the emergence of resistant HIV strains is increasingly problematic. To circumvent this, we report here a new 'Trojan horse' strategy to kill HIV-infected cells by exploiting HIV protease. We engineered a transducing, modified, apoptosis-promoting caspase-3 protein, TAT-Casp3, that substitutes HIV proteolytic cleavage sites for endogenous ones and efficiently transduces about 100% of cells, but remains inactive in uninfected cells. In HIV-infected cells, TAT-Casp3 becomes processed into an active form by HIV protease, resulting in apoptosis of the infected cell. This strategy could also be applied to other pathogens encoding specific proteases, such as hepatitis C virus, cytomegalovirus and malaria.


Associations between diet and cardiometabolic risk among Yup'ik Alaska Native people using food frequency questionnaire dietary patterns.
In previous analyses, we identified three dietary patterns from food frequency questionnaire data among a sample of Yup'ik Alaska Native people living in Southwest Alaska: a "subsistence foods" dietary pattern and two market-based dietary patterns "processed foods" and "fruits and vegetables". In this analysis, we aimed to characterize the association between the dietary patterns and cardiometabolic (CM) risk factors (lipids, blood pressure, glucose, adiposity). We used multilevel linear regression to estimate the mean of each CM risk factor, comparing participants in the 4th to the 1st quartile of each dietary pattern (n = 637). Models were adjusted for age, sex, past smoking, current smoking, and physical activity. Mean log triglyceride levels were significantly higher among participants in the 4th compared to the 1st quartile of the processed foods dietary pattern (β = 0.11). Mean HbA1c percent was significantly lower (β = -0.08) and mean diastolic blood pressure (DBP) mm Hg was significantly higher (β = 2.87) among participants in the 4th compared to the 1st quartile of the fruits and vegetables dietary pattern. Finally, mean log triglyceride levels and mean DBP mm Hg were significantly lower among participants in the 4th compared to the 1st quartile of the subsistence foods dietary pattern (β = -0.10 and β = -3.99 respectively). We found increased CM risk, as reflected by increased triglycerides, associated with eating a greater frequency of processed foods, and reduced CM risk, as reflected by lower triglycerides and DBP, associated with eating a greater frequency of subsistence foods.


Development of a microcomputer program for statistical evaluation of potential pharmacokinetic drug interactions.
A simple and self-explanatory program in BASIC for the statistical evaluation of potential pharmacokinetic drug interactions is described. This program, using the data (times and drug concentrations) obtained from two different populations, and with the help of graphic computing techniques, allows the determination and statistical comparison of pharmacokinetic parameters (disposition constants, transfer rate constants, area under the concentration-time curves, etc.) for one- and two-compartment open models after intravenous or extravasal administration. The program is organized in subroutines so that it can be easily modified or extended to other pharmacokinetic models by the user.


Atrial fibrillation and risk of stroke in dialysis patients.
Both stroke and chronic atrial fibrillation (AF) are common in dialysis patients, but uncertainty exists in the incidence of new strokes and the risk conferred by chronic AF. A cohort of dually eligible (Medicare and Medicaid) incident dialysis patients was constructed. Medicare claims were used to determine the onset of chronic AF, which was specifically treated as a time-dependent covariate. Cox proportional hazards models were used to model time to stroke. Of 56,734 patients studied, 5629 (9.9%) developed chronic AF. There were 22.8 ischemic and 5.0 hemorrhagic strokes per 1000 patient-years, a ratio of approximately 4.5:1. Chronic AF was independently associated with time to ischemic (hazard ratio [HR], 1.26; 99% confidence interval [CI], 1.06-1.49; P = .0005), but not hemorrhagic, stroke. Race was strongly associated with hemorrhagic stroke: African Americans (HR, 1.46; 99% CI, 1.08-1.96), Hispanics (HR, 1.64; 99% CI, 1.16-2.31), and others (HR, 1.76; 99% CI, 1.16-2.78) had higher rates than did Caucasians (all P < .001). Chronic AF has a significant, but modest, association with ischemic stroke. Race/ethnicity is strongly associated with hemorrhagic strokes. The proportion of strokes owing to hemorrhage is much higher than in the general population.


Identifying novel genes for amyotrophic lateral sclerosis by integrating human brain proteomes with genome-wide association data.
Genome-Wide Association Studies (GWAS) have identified numerous risk genes for Amyotrophic Lateral Sclerosis (ALS); however, the mechanisms by which these loci confer ALS risk are uncertain. This study aims to identify novel causal proteins in the brains of patients with ALS using an integrative analytical pipeline. Using the datasets of Protein Quantitative Trait Loci (pQTL) (NpQTL1 = 376, NpQTL2 = 152), expression QTL (eQTL) (N = 452), and the largest ALS GWAS (NALS=27,205, NControls = 110,881), we performed a systematic analytical pipeline including Proteome-Wide Association Study (PWAS), Mendelian Randomization (MR), Bayesian colocalization, and Transcriptome-Wide Association Study (TWAS) to identify novel causal proteins for ALS in the brain. Using PWAS, we found that the altered protein abundance of 12 genes in the brain was associated with ALS. Three genes (SCFD1, SARM1 and CAMLG) were identified as lead causal genes for ALS with solid evidence (False discovery rate < 0.05, in MR analysis; PPH4 > 80% for Bayesian colocalization). Specifically, an increased abundance of SCFD1 and CAMLG led to an increased risk of ALS, whereas a higher abundance of SARM1 led to a decreased risk of developing ALS. TWAS showed that SCFD1 and CAMLG were related to ALS at the transcriptional level. SCFD1, CAMLG, and SARM1 exhibited robust associations and causality with ALS. The study findings provide novel clues for identifying potential therapeutic targets in ALS. Further studies are required to explore the mechanisms underlying the identified genes.


Natural zeolite enhances anaerobic digestion of waste activated sludge: Insights into the performance and the role of biofilm.
Anaerobic digestion is widely employed for the treatment of waste activated sludge (WAS) due to its advantages like simultaneous energy recovery and sludge stabilization, promoting carbon-neutral operation of wastewater treatment plants. Natural zeolite, a low-cost and eco-friendly additive, has the potential to improve methane production from anaerobic digestion. This study investigated the effects of natural zeolite on anaerobic digestion when the substrate was WAS. It was found that methane production potential in response to natural zeolite was dosage-dependent. The optimal dosage was 0.1 g zeolite/g volatile suspended solids (VSS), with a methane yield of 181.89 ± 6.75 mL/g VSS, which increased by 20.1% compared to that of the control. Although the methane yields with other dosages of natural zeolite were higher than that of control, they were lesser than that with 0.1 g zeolite/g VSS. Natural zeolite affected transfer and conversion of proteins much more than polysaccharides in liquid phase and extracellular polymeric substances. In anaerobic digestion, natural zeolite had with little effects on WAS solubilization, while it improved hydrolysis, acidification, and methanogenesis. The dosages of natural zeolite did have significant effects on bacterial communities in biofilm rather than suspension, while the archaeal communities in biofilm and suspension were all greatly related to natural zeolite dosages. The developed biofilms promoted richness and functionality of microbial communities. The syntrophic metabolism relationships between methanogens and bacteria were improved, which was proved by selective enrichment of Methanosarcina, Syntrophomonas, and Petrimonas. The findings of this work provided some new solutions for promoting methane production from WAS, and the roles of natural zeolite in anaerobic digestion.


Time trends and regional differences in registration, stage distribution, surgical management and survival of breast cancer in Denmark.
The aim of this study was to analyse time trends, stage at diagnosis, survival and registration of population-based cohorts of breast cancer patients in selected Danish counties (in total 2504) in 1986 and 1996-1997. In 1986, no differences in the extent of disease were observed between the counties. Patients from one county (Funen) had centralised surgery, significantly more lymph nodes removed and a better survival in the multivariate analysis. In 1996-1997, mammographical screening had been implemented in Funen, leading to a significantly better stage distribution, whereas stage remained unchanged in the other counties. In Funen, survival was significantly better than in the other counties in univariate, but not in multivariate analysis. Survival increased significantly with time only in Funen. Inclusion in clinical trials increased over time and the coverage of the database in the Danish Breast Cancer Cooperative Group (DBCG) was high. However, patients not notified in DBCG had, beside older age, also worse stage of disease distribution and less extensive surgery. A difference in survival was observed between the counties. In 1986, this may be explained by a centralised surgical system in one county, whereas in 1996-1997 improvements could be due to an early diagnosis and other as yet unknown factors. The DBCG database cannot be considered as representative of the Danish population of breast cancer patients.


Diethyl Azelate for the Treatment of Brown Recluse Spider Bite, a Neglected Orphan Indication.
Brown recluse spider bite releases hemolytic and cytotoxic phospholipase D to the wound that may cause necrosis or even death. We examined diethyl azelate (DEA), a plasma membrane fluidizer with a broad range of immunomodulatory activities, as a potential treatment for the brown recluse spider bite. Topical DEA was used in emergency to treat brown recluse spider bites in a human subject. We subsequently evaluated the effects of DEA on hemolysis induced by the brown recluse spider venom, recluse recombinant phospholipase D (rPLD), and venoms from honey bee and moccasin snake, and on phospholipase A2 activity in the bee and snake venoms and in human urine. Topical DEA resolved the consequences of human brown recluse spider envenomation in two weeks. In vitro, DEA inhibited hemolysis caused by the brown recluse spider venom and rPLD and suppressed phospholipase A2 activity in a dose-dependent manner. DEA is a promising novel therapy for the brown recluse spider bite and perhaps even unrelated envenomations involving PLDs.


Advances in controlling hypertension in low-income patients.
Since hypertension is the foremost problem in minority and low-income populations treated in our community health centers, in 1976 we introduced a protocol that standardized diagnostic criteria and a step-care approach to the treatment of hypertension. In 1980, we modified the original protocol with guidelines for dietary management and an outline for improving physician-patient communication and health education. We hypothesized that implementing the protocol (and later modifications) would be associated with improved identification and control of hypertension. We conducted a cross-sectional study of hypertensive patients' charts in three community health centers in 1973, 1978, and 1982, and determined the status of blood pressure (BP) control of those patients by the end of the year. In 1973 (before protocol), 4 percent of hypertensives were undiagnosed and untreated, and 20 percent were lost to follow-up. Among those who remained under care, only 33 percent were under control (BP less than 160/95 mm Hg). In 1978, two years after the protocol was introduced, there were fewer undiagnosed and untreated patients (2 percent), but the number lost to follow-up increased to 31 percent. The proportion of hypertensives under control increased to 70 percent. In 1982, two years after the modifications to the protocol were introduced, the proportion of patients lost to follow-up decreased to 28 percent, and the proportion of patients with controlled blood pressure increased to 79 percent. The improved level of control was statistically significant at p less than .0001 (chi-square test).(ABSTRACT TRUNCATED AT 250 WORDS)


Tripartite motif containing 63, regulated by E26 transformation specific variant 4, facilitates the thyroid carcinoma progression and the AKT, p38, and ERK signaling pathways.
The current study aimed to investigate the role of tripartite motif containing 63 (TRIM63) in the progression of thyroid carcinomas. The results showed that TRIM63 was highly expressed in thyroid carcinomas tissues. TRIM63 knockdown inhibited the proliferation and induced the apoptosis of thyroid carcinoma cells, and overexpression of TRIM63 promoted the cell proliferation ability. These results were further confirmed by the in vivo growth of xenograft tumors. Subsequently, the underlying mechanism was explored. TRIM63 silencing repressed the AKT, p38, and ERK signaling pathways in thyroid carcinoma cells, and the contrary results were observed in TRIM63-upregulated thyroid carcinoma cells. Furthermore, we found that E26 transformation specific variant 4 (ETV4) regulated the transcription of TRIM63. The loss of TRIM63 reversed the ETV4 overexpression-induced promotion of proliferation in thyroid carcinomas cells. In conclusion, TRIM63, regulated by ETV4, activates the AKT, p38, and ERK signaling pathways and facilitates the thyroid carcinoma development.


Winter water relations of a deciduous timberline conifer, Larix lyallii Parl.
The degree of winter desiccation resistance exhibited by Larix lyallii Parl. was assessed by determination of water potential components and content of buds, xylem pressure potential (Ψ xylem) of twigs and amount of damage through winter at timberline in the Rocky Mountains of Canada. Comparative measurements were made on sympatric evergreen tree species to evaluate differences in winter desiccation avoidance and tolerance between evergreen and deciduous trees. Total (Ψ) and osmotic plus matric potentials (Ψ π + τ) of L. lyallii buds were lowest in December (-5.0 to-5.3 MPa and-6.6 to-7.0 MPa, respectively) when temperatures were lowest. Bud Ψ and water content increased in late winter while Ψ xylem of twigs continued to decline until March. The buds were isolated from the xylem from October through February, as indicated by large differences in water potential between the two organs during this time. Buds thus avoided desiccation as water was lost from the twigs. At the same time the buds were tolerant of very low Ψ and Ψ π + τ, a characteristic which is an important component of freezing damage resistance. Desiccation damage to buds of L. lyallii was much less than that to buds of similar-sized nearby trees of Abies lasiocarpa, although Ψ xylem of both species was similar. The deciduous habit apparently confers a significant advantate to L. lyallii, which dominated the upper timberline sites, in reduced susceptibility to winter desiccation damage. Other deciduous timberline species might also benefit from this advantage where winter conditions are desiccating.Seedlings of L. lyallii were also studded for their winter desiccation resistance because they have a large component of non-deciduous (wintergreen) needles that are photosynthetically active through two growing seasons and must overwinter as mature tissue. Experimental exposure of these needles, which are normally protected by the snowpack, caused nearly complete mortality of the wintergreen needles when twig Ψ xylem was only-3.9 MPa. The buds on these twigs were undamaged.


Prenatal dichlorodiphenyldichloroethylene (DDE) exposure and child growth during the first year of life.
Due to its long-term persistence in the environment and its ability to cross the placental barrier, prenatal p,p'-dichlorodiphenyldichloroethene (DDE) exposure continues to be a public health concern. This study aimed to evaluate the association between prenatal DDE exposure and child growth, at birth and during the first year of life. 253 pregnant women were recruited between January 2001 and June 2005 in a prospective cohort in Morelos, Mexico. Serum levels of DDE were measured during each trimester of pregnancy by gas chromatography with an electron capture detector. Using the generalized mixed-effects models, the association between DDE and child growth parameters (weight-for-age, length-for-age, weight-for-length, BMI-for-age and head circumference-for-age Z-scores) from birth to 1 year of age was assessed. Maternal dietary intake was considered as covariable among others. DDE levels were 6.3±2.8 ng/mL (first trimester), 6.6±2.9 ng/mL (second trimester), and 7.6±2.9 ng/mL (third trimester). After adjusting for potential confounder variables, no significant associations were observed with prenatal DDE exposure and each of the selected parameters. Our results show no evidence of an association between prenatal DDE exposure and child growth during the first year of life.


Fibrous metaphyseal defect.
The tendon and ligaments inserted into the perichondrium of the epiphyseal plate were examined in 152 autopsy specimens of tubular long bones. In the region of two areas where tendons were inserted (Ranvier's nodes), the normal medullary tissue is replaced by fibroblastic tissue. A retrospective radiological examination of 155 fibrous metaphyseal defects shows that they are situated at characteristic sites on the circumference of the metaphysis of long tubular bones. This can be related to the insertion of a tendon or ligament near the epiphyseal growth plate which corresponds to areas found in the morphological study and is the site of origin of fibrous metaphyseal defects.


A randomized trial comparing acetabular component fixation of two porous ingrowth surfaces using RSA.
Several new porous ingrowth surfaces for acetabular component fixation have recently been developed. The purpose of this study was to compare the in vivo fixation achieved by two different porosity ingrowth surfaces using radiostereometric analysis (RSA). Sixty-two patients undergoing primary total hip arthroplasty (THA) were randomized to receive a cementless acetabular component with either a 61% high porosity asymmetric titanium porous surface (StikTite, Smith and Nephew, TN, USA) or a 45% low porosity sintered bead porous surface (Roughcoat, Smith and Nephew, TN, USA). RSA and clinical follow-up examinations were done post-operatively, 6-weeks, 3-months, 6-months, 1-year and 2-years. Both the high porosity StikTite and lower porosity Roughcoat surfaces provided excellent biologic fixation.


Superoxide dismutase, glutathione peroxidase and catalase in the red cells of patients with malignant lymphoma.
Erythrocyte superoxide dismutase, glutathione peroxidase and catalase activities have been measured in patients with untreated malignant lymphomas. Marked deficiencies of superoxide dismutase (P less than 0.001) and glutathione peroxidase (P less than 0.001) were found, whereas catalase levels were normal. There was no apparent difference in enzyme activities between the different histological types of lymphoma.


A novel treatment of bromelain and acetylcysteine (BromAc) in patients with peritoneal mucinous tumours: A phase I first in man study.
Bromelain (Brom) and Acetylcysteine (Ac) have synergistic activity resulting in dissolution of tumour-produced mucin both in vitro and in vivo. The aim of this study was to determine whether treatment of mucinous peritoneal tumour with BromAc can be performed with an acceptable safety profile and to conduct a preliminary assessment of efficacy in a clinical setting. Under radiological guidance, a drain was inserted into the tumour mass or intraperitoneally. Each patient could have more than one tumour site treated. Brom 20-60 mg and Ac 1·5-2 g was administered in 5% glucose. At 24 h, the patient was assessed for symptoms including treatment-related adverse events (AEs) and the drain was aspirated. The volume of tumour removed was measured. A repeat dose via the drain was given in most patients. All patients that received at least one dose of BromAc were included in the safety and response analysis. Between March 2018 and July 2019, 20 patients with mucinous tumours were treated with BromAc. Seventeen (85%) of patients had at least one treatment-emergent AE. The most frequent treatment-related AEs were CRP rise (n = 16, 80%), WCC rise (n = 11, 55%), fever (n = 7, 35%, grade I) and pain (n = 6, 30%, grade II/III). Serious treatment-related AEs accounted for 12·5% of all AEs. There were no anaphylactic reactions. There were no deaths due to treatment-related AEs. An objective response to treatment was seen in 73·2% of treated sites. Based on these preliminary results and our preclinical data, injection of BromAc into mucinous tumours had a manageable safety profile. Considerable mucolytic activity was seen by volume of mucin extracted and radiological appearance. These results support further investigation of BromAC for patients with inoperable mucinous tumours and may provide a new and minimally invasive treatment for these patients.


Self-amplification of nigral degeneration in Parkinson's disease: a hypothesis.
This review analyzes current evidence regarding possible mechanisms of nigral damage in idiopathic Parkinson's disease (iPD). In normal brain, a specific interplay among the blood-brain barrier (BBB), substantia nigra (SN), and locus coeruleus (LC) creates the condition for a self-accelerating damage to the SN. Three vicious circles involving SN-BBB, LC-SN-BBB, and histamine-BBB-SN interactions are described. In iPD, a self-accelerating loss of nigral cells can be triggered by brain hypoperfusion and by an increased blood histamine level. iPD-associated factors such as decreased CSF levels of substance P, somatostatin, and glutamate can aggravate the vicious-circle-induced damage to the SN.


Cytokines in exhaled breath condensate of children with asthma and cystic fibrosis.
Inflammatory mediators in exhaled breath condensate (EBC) indicate ongoing inflammation in the lungs and might differentiate between asthma and cystic fibrosis (CF). To evaluate the presence, concentration, and short-term variability of TH1- and TH2-mediated cytokines (interferon-gamma [IFN-gamma], tumor necrosis factor alpha [TNF-alpha], interleukin 10 [IL-10], IL-5, IL-4, and IL-2) in EBC of children with asthma or CF and in controls and to analyze the discriminating ability of inflammatory markers in EBC between children with asthma or CF and controls. Expired air was conducted through a double-jacketed glass tube cooled by circulating ice water. In 33 asthmatic children, 12 children with CF, and 35 control children, EBC was collected during tidal breathing. Cytokines were measured using flow cytometry. Interleukin 2, IL-4, IFN-gamma, and IL-10 were detected in 16%, 16%, 11%, and 9%, respectively, of all samples in asthma and CF. Interleukin 5 and TNF-alpha were not detected in children with CF. Cytokine concentrations did not differ significantly in children with asthma vs CF. In controls, IFN-gamma, TNF-alpha, and IL-10 were detected in 9%, 14%, and 3%, respectively; IL-2, IL-4, and IL-5 were not detected in controls. Cytokines such as IFN-gamma, TNF-alpha, IL-10, IL-5, IL-4, and IL-2 can be detected in EBC of children with asthma or CF. However, the concentrations found are close to the detection limits of the assay used. These findings emphasize the importance of developing more sensitive techniques for the analysis of EBC and of standardizing the EBC collection method.


Effect of boron element on photoaging in rats.
The present study further assessed the effects of oral and topical applications of boron, which is known to have antiinflammatory and wound healing effects, on photoaging. A total of 49 eight-week-old female Wistar albino rats randomly divided into seven groups (control, shaved control, shaved+UVB, topical dermabor 2% (D2), and %5 (D5), systemic sodium perborate tetrahydrate (SPT) 2% (SPT2) and 4% (SPT4). To induce an experimental photoaging, the rats were exposed to UVB at an emission spectrum of 290-320 nm. Biochemical, molecular, skin, histological, and collagen content analyzes were made at the end of the study. Increased skin inflammatory parameters (COX-2, IL-8, NF-KB, IL-6, and TNF-α) levels in UVB-exposed groups were inhibited in all treatment groups. The tissue level of hydroxyproline and elastase was found to decrease in all UVB-exposed group. The level of hydroxyproline was significantly higher in the D2 and D5 groups than in the SPT2 and SPT4 groups. The level of elastase was significantly lower in the D2 and D5 groups than in the SPT2 and SPT4 groups. In future, boron may be developed as a functionally protective treatment against photoaging caused by UVB, and may be included in sun protection systems.


The sympathetic innervation of the vocal cord. An experimental study in the guinea pig.
Formaldehyde-induced fluorescence and electron microscopy have been used to show the sympathetic innervation of the vocal cord in the guinea pig. The topographical distribution and morphology of the sympathetic fibres and endings are commented upon.


Impact of COPD exacerbation on cerebral blood flow.
We aimed to investigate the impact of chronic obstructive pulmonary disease (COPD) exacerbation on cerebral blood flow (CBF). In 21 COPD patients - in both exacerbation and stable phases -Doppler ultrasonographies of internal carotid artery (ICA) and vertebral artery (VA) were performed. There were significant differences in total, anterior and posterior CBF, ICA and VA flow volumes in exacerbated COPD compared to stable COPD. Total CBF was correlated with cross-sectional areas of left and right ICA, whereas independent predictor of total CBF was cross-sectional area of right ICA. Increased CBF might indicate cerebral autoregulation-mediated vasodilatation to overcome COPD exacerbation induced hypoxia.


Pre-donation water and salty snacks to prevent vasovagal reactions among blood donors.
Minimizing the risk of vasovagal reactions (VVRs) can prevent donor harms and improve donor return. We report the results of a program to reduce VVR rates. The program was implemented on June 11, 2017 and consisted in drinking water and eating a salty snack before donating blood, plasma, or platelets. All donations made during the "pre-program period" (October 11, 2015-June 10, 2017) and "post-program period" (June 11, 2017-May 11, 2019) were included. Study outcomes comprised VVRs (any severity) and syncopal VVRs, whether employee- or donor-reported. An interrupted time series (ITS) analysis proxied causality based on the "pre-program trend," the "immediate trend" (i.e., immediately before versus after the program), and the "post-program trend". The relative risk (RR) of VVR (along with confidence intervals [CIs]) was reported, overall and stratified by subgroups based on age, sex, donor type (i.e., first-time versus repeat), and donation type (i.e., whole blood versus apheresis). The monthly VVR rate (any severity) dropped from 4.6% in the pre-program period to 4.3% in the post-program period, and never reached its pre-program level. The ITS analysis revealed a statistically significant and increasing pre-program trend (RR [95% CI] = 1.011 [1.002-1.020]), a statistically significant and decreasing immediate trend (RR [95% CI] = 0.848 [0.743-0.969]), and a non-statistically-significant and stable post-program trend (RR [95% CI] = 0.999 [0.993-1.006]). Similar trends were observed for nearly all high- and low-risk subgroups. No statistically significant trend was observed for syncopal VVRs. These results suggest that the herein-described program durably reduced the incidence of VVRs (any severity) by ~15%.


Body size and skeletal muscle myoglobin of cetaceans: adaptations for maximizing dive duration.
Cetaceans exhibit an exceptionally wide range of body mass that influence both the capacities for oxygen storage and utilization; the balance of these factors is important for defining dive limits. Furthermore, myoglobin content is a key oxygen store in the muscle as it is many times higher in marine mammals than terrestrial mammals. Yet little consideration has been given to the effects of myoglobin content or body mass on cetacean dive capacity. To determine the importance of myoglobin content and body mass on cetacean diving performance, we measured myoglobin content of the longissimus dorsi for ten odontocete (toothed whales) and one mysticete (baleen whales) species ranging in body mass from 70 to 80000 kg. The results showed that myoglobin content in cetaceans ranged from 1.81 to 5.78 g (100 g wet muscle)(-1). Myoglobin content and body mass were both positively and significantly correlated to maximum dive duration in odontocetes; this differed from the relationship for mysticetes. Overall, the combined effects of body mass and myoglobin content accounts for 50% of the variation in cetacean diving performance. While independent analysis of the odontocetes showed that body mass and myoglobin content accounts for 83% of the variation in odontocete dive capacity.


Anti-senescence ion-delivering nanocarrier for recovering therapeutic properties of long-term-cultured human adipose-derived stem cells.
Human adipose-derived stem cells (hADSCs) have been used in various fields of tissue engineering because of their promising therapeutic efficacy. However, the stemness of hADSCs cannot be maintained for long durations, and their therapeutic cellular functions, such as paracrine factor secretion decrease during long-term cell culture. To facilitate the use of long-term-cultured hADSCs (L-ADSCs), we designed a novel therapeutic anti-senescence ion-delivering nanocarrier (AIN) that is capable of recovering the therapeutic properties of L-ADSCs. In the present study, we introduced a low-pH-responsive ion nanocarrier capable of delivering transition metal ions that can enhance angiogenic paracrine factor secretion from L-ADSCs. The AINs were delivered to L-ADSCs in an intracellular manner through endocytosis. Low pH conditions within the endosomes induced the release of transition metal ions (Fe) into the L-ADSCs that in turn caused a mild elevation in the levels of reactive oxygen species (ROS). This mild elevation in ROS levels induced a downregulation of senescence-related gene expression and an upregulation of stemness-related gene expression. The angiogenic paracrine factor secretion from L-ADSCs was significantly enhanced, and this was evidenced by the observed therapeutic efficacy in response to treatment of a wound-closing mouse model with conditioned medium obtained from AIN-treated L-ADSCs that was similar to that observed in response to treatment with short-term-cultured adipose-derived stem cells. This study suggests a novel method and strategy for cell-based tissue regeneration that can overcome the limitations of the low stemness and therapeutic efficacy of stem cells that occurs during long-term cell culture.


Psychometric evaluation of the Sophia Observation withdrawal symptoms scale in critically ill children.
The Sophia Observation withdrawal Symptoms scale is an instrument for screening benzodiazepine and opioid withdrawal syndrome in pediatric critical care patients. The objectives of this study were to establish cutoff scores and to test sensitivity to change. Second, risk factors for withdrawal syndrome were explored. Prospective observational study with repeated measures. Level IV ICU at a university children's hospital. A total of 154 children with median age 5 months (interquartile range, 0-42 mo) who received continuous infusion of benzodiazepines and/or opioids for 5 or more days. None. Nurses repeatedly applied the Sophia Observation withdrawal Symptoms scale and the Numeric Rating Scale withdrawal when children were weaned off benzodiazepines and opioids. The latter represents the nurse's expert opinion. We analyzed 3,754 paired assessments; the median number per child was 15 (interquartile range, 7-31) over a median of 5 days (interquartile range, 3-11 d). Sensitivity and specificity were 0.83 and 0.93, respectively, for the Sophia Observation withdrawal Symptoms scale cutoff score of 4 or higher against a Numeric Rating Scale-withdrawal score of 4 or higher. Sensitivity to change was determined by comparing 156 Sophia Observation withdrawal Symptoms scale assessments (n = 51 patients) before and after additional sedatives or opioids. Multilevel regression analysis showed a mean decline of 1.5 points (at score range 0-15) after intervention (p < 0.0001). Logistic regression analysis identified duration of preweaning of midazolam, duration of weaning of midazolam, duration of preweaning of morphine, duration of weaning of morphine, and number of additional sedatives/opioids as statistically significant risk factors for withdrawal syndrome in these children. The Sophia Observation withdrawal Symptoms scale is a valid tool with good psychometric properties to assess withdrawal symptoms in PICU patients.


Cell adhesion induces overexpression of chromodomain helicase/ATPase DNA binding protein 1-like gene (CHD1L) and contributes to cell adhesion-mediated drug resistance (CAM-DR) in multiple myeloma cells.
Previous studies have shown that chromodomain helicase/ATPase DNA binding protein 1-like gene (CHD1L) exerts its anti-apoptotic function in many solid cancers. However, its role in human multiple myeloma (MM) has not been thoroughly elucidated. In this study, we investigate the role of CHD1L in MM. Preliminarily, up-regulation and down-regulation assay verified that CHD1L exerts its anti-apoptotic role through the apoptotic pathway involving caspase-9-caspase-3 apoptotic pathway in MM cells. In addition, we determined that CHD1L expression is increased when MM cells were adhered to fibronectin (FN) or bone marrow stromal cell line HS-5 cells and cell adhesion assay indicated that CHD1L siRNA reversed the high cell adhesion rate. Consistent with the reduced adhesion rate, the cells translated to a compromised cell adhesion-mediated drug resistance (CAM-DR) phenotype in MM. In summary, we will propose strategies for developing a CHD1L inhibitor for potential treatment of MM.


Determinants of female reproductive senescence: differential roles for the ovary and the neuroendocrine axis.
Aging in women is a complex process that begins with the transition into reproductive senescence and evolves to impact not just women's procreative potential but also multiple health-related parameters including longevity. Although somatic aging is an equal opportunity nemesis, certain disease states correlate highly with ovarian failure and the menopause, such as osteoporosis, diabetes, cardiovascular disease, and compromised cognitive function. Epidemiological studies suggest that a delayed natural menopause confers longevity and decelerates the appearance of many of the debilitating morbidities associated with the menopause. However, recent randomized clinical trials assessing the benefits of menopausal hormone therapy during the postmenopause clearly suggest that attenuation of the negative consequences of reproductive aging involves much more than a simple add back of ovarian steroids in the postmenopause. Conflicts between observations in epidemiological studies and in randomized clinical trials give good reason for continued innovative research focused on identifying the mechanisms that bring about the transition from peak reproductive potential to female reproductive quiescence. This article provides a brief update on our current understanding of the physiological and cellular mechanisms that precipitate and/or commit women to transit into reproductive senescence.


Immune checkpoint inhibitor-associated central nervous system autoimmunity.
Outcome and rechallenge data on central nervous system (CNS) autoimmunity triggered by immune checkpoint inhibitors (ICIs) are limited. We aim to describe a large series of patients with ICI-triggered CNS autoimmunity, and to compare these patients with spontaneous paraneoplastic syndromes (PNS). We retrospectively reviewed Mayo Clinic patients with ICI-triggered CNS autoimmunity (February 2015-June 2021). Clinical characteristics were compared to spontaneous PNS patients (with antineuronal nuclear antibody [ANNA]-1 or anti-Hu neurological autoimmunity, and/or neuroendocrine tumors [NET]) evaluated within the same period. Thirty-one patients were included (55% female, median age = 63 years, range = 39-76). Median time from ICI initiation was 3.65 months (range = 0.8-44.5). The most common associated malignancies were melanoma and small cell lung cancer. CNS manifestations included encephalitis (n = 16), meningoencephalitis (n = 8), cerebellar ataxia (n = 4), demyelinating syndrome (n = 2), and myelopathy (n = 1). Magnetic resonance imaging was abnormal in 62%. Cerebrospinal fluid was inflammatory in 70%. Neural autoantibodies were identified in 47%, more frequently in patients with NET (p = 0.046). ICI was discontinued in 97%; 90% received immunosuppressive treatment. After median 6.8 months follow-up (range = 0.7-46), 39% had unfavorable outcomes (grade ≥ 3). This was associated with higher severity degree at onset, shorter period from ICI to neurological symptom onset, and encephalitis. Four patients were rechallenged with ICI, and one relapsed. Patients with NET and with ANNA-1 ICI-triggered CNS autoimmunity had associated peripheral nervous system manifestations more frequently than their spontaneous counterparts (p = 0.007 and p = 0.028, respectively). One third of ICI-related CNS autoimmunity patients have unfavorable outcomes. Relapses may occur after ICI rechallenge. Neural autoantibodies are often present, more commonly in patients with NET.


Using co-cultures expressing fluorescence resonance energy transfer based protein biosensors to simultaneously image caspase-3 and Ca2+ signaling.
Fluorescence resonance energy transfer (FRET)-based protein biosensors allow the spatial and temporal imaging of signaling events in living cells. However, the simultaneous correlation of multiple events of a signaling pathway is hindered by the spectral cross-talk between fluorescent proteins. Here, we show, for signaling pathways that progress synchronously, multiple events can be correlated by using co-cultures expressing different FRET-based protein biosensors. As a demonstration, we investigated the simultaneous caspase-3 and Ca2+ signaling events involved in cell death of COS-7 cells induced by 10 mM H2O2. Interestingly, this H2O2 stimulus induced synchronous caspase-3 activation and Ca2+ signaling. In parallel to caspase-3 activation, cytosolic Ca2+ concentration, [Ca2+]c, gradually rises to its peak and then slowly drops. As cell shrinkage and rounding ensues, [Ca2+]c again gradually rises to its peak and then reaches a plateau. These observations reveal the relative timing and location of these signaling events in cell death induced by this stimulus of H2O2. Finally, our approach offers an exciting opportunity for spatial and temporal imaging of multiple events in a signaling pathway in living cells.


A systematic review of suggestive seizure induction for the diagnosis of psychogenic nonepileptic seizures.
Suggestive seizure induction is a widely used method for diagnosing psychogenic nonepileptic seizures (PNES). Despite seven decades of multidisciplinary research, however, there is still no unified protocol, no definitive agreement on the ethical framework and no consensus on diagnostic utility. This systematic review surveys the evidence at hand and addresses clinically relevant aspects of suggestive seizure induction. In addition to its use for facilitating the diagnostic process, its mechanism of action and utility in elucidating the psychopathology of PNES will be discussed.


Emerging mitochondrial signaling mechanisms in physiology, aging processes, and as drug targets.
Advances in research on mitochondria have elucidated their importance in cell survival and cell death regulation in addition to their function in energy production. Mitochondria are further implicated in various metabolic and aging-related diseases, which are now assumed to be caused by misregulation of physiological systems rather than pure accumulation of oxidative damage. Thus, the signaling mechanisms within mitochondria and between the organelle and its environment have gained interest as potential drug targets. Emerging mitochondrial signaling systems with potential for exploiting them for therapeutic intervention include, among others, the NAD(+)-dependent protein deacetylases of the Sirtuin family, the redox enzyme p66(Shc), and enzymes of the cyclic adenosine monophosphate (cAMP) signaling pathways. Here, we discuss functions of these signaling systems in mitochondria, their roles in aging processes and disease, and their potential to serve as therapeutic targets.


Case studies from two collaboratives on diabetes in Washington State.
Two individual teams, one from a small, rural clinic and one from a larger urban health system, were able to introduce innovations in care and realize improvement in patient outcomes.


Effectiveness of oncology nurse navigator on the incidence of postoperative pulmonary complications in gastric cancer patients undergoing radical gastrectomy.
Management of postoperative pulmonary complications (PPCs) can be challenging in gastric cancer patients undergoing radical gastrectomy and is always associated with poor prognosis. Even though oncology nurse navigator (ONN) provide effective and critical individualized care to patients, little is known about their impact on the occurrence of PPCs in gastric cancer patients. This study aimed to determine whether ONN decreases the incidence of PPCs in gastric cancer patients. This was a retrospective review in which data for gastric cancer patients at one centre was evaluated before and after an ONN hired. An ONN was introduced to patients at their initial visit to manage pulmonary complications throughout treatment. The research was conducted from 1 August 2020 to 31 January 2022. The study participants were divided into the non-ONN group (from 1 August 2020 to 31 January 2021) and the ONN group (from 1 August 2021 to 31 January 2022). The incidence and severity of PPCs between the groups were then compared. ONN significantly decreased the incidence of PPCs (15.0% vs. 9.8%) (OR = 2.532(95% CI: 1.087-3.378, P = 0.045)), but there was no significant difference in the components of PPCs including pleural effusion, atelectasis, respiratory infection, and pneumothorax. The severity of PPCs was also significantly higher in the non-ONN group (p = 0.020). No significant statistical difference was observed for the major pulmonary complications ([Formula: see text] 3) between the two groups (p = 0.286). Role of ONN significantly decrease the incidence of PPCs in gastric cancer patients undergoing radical gastrectomy.


Simultaneous expression of MMB-FOXM1 complex components enables efficient bypass of senescence.
Cellular senescence is a stable cell cycle arrest that normal cells undergo after a finite number of divisions, in response to a variety of intrinsic and extrinsic stimuli. Although senescence is largely established and maintained by the p53/p21WAF1/CIP1 and pRB/p16INK4A tumour suppressor pathways, the downstream targets responsible for the stability of the growth arrest are not known. We have employed a stable senescence bypass assay in conditionally immortalised human breast fibroblasts (CL3EcoR) to investigate the role of the DREAM complex and its associated components in senescence. DREAM is a multi-subunit complex comprised of the MuvB core, containing LIN9, LIN37, LIN52, LIN54, and RBBP4, that when bound to p130, an RB1 like protein, and E2F4 inhibits cell cycle-dependent gene expression thereby arresting cell division. Phosphorylation of LIN52 at Serine 28 is required for DREAM assembly. Re-entry into the cell cycle upon phosphorylation of p130 leads to disruption of the DREAM complex and the MuvB core, associating initially to B-MYB and later to FOXM1 to form MMB and MMB-FOXM1 complexes respectively. Here we report that simultaneous expression of MMB-FOXM1 complex components efficiently bypasses senescence with LIN52, B-MYB, and FOXM1 as the crucial components. Moreover, bypass of senescence requires non-phosphorylated LIN52 that disrupts the DREAM complex, thereby indicating a central role for assembly of the DREAM complex in senescence.


Liver alcohol and aldehyde dehydrogenase: inhibition and potentiation by histamine agonists and antagonists.
1. The in vitro effects of histamine, some other H1- and H2-receptor agonists and some antagonists were studied on the specific activities and kinetics of rat liver alcohol dehydrogenase (ADH), and cytoplasmic and mitochondrial liver aldehyde dehydrogenase (ALDH). 2. Histamine (H1- and H2-agonist) non-competitively inhibited ADH. There were no changes of cytoplasmic and mitochondrial liver ALDH activities in the presence of 2-(2-aminoethyl) pyridine. 3. Betazole (H2-receptor agonist) produced a competitive inhibition of mitochondrial ALDH but not of ADH or cytoplasmic ALDH. 4. Diphenhydramine (H1-receptor antagonist) non-competitively inhibited ADH at a lower concentration. It stimulated mitochondrial ALDH activity without changes in cytoplasmic ALDH from control values. 5. Burimamide (H2-receptor antagonist) produced a biphasic and dose-dependent stimulation and non-competitive inhibition of ADH and it non-competitively inhibited ALDH in both cytoplasmic and mitochondrial fractions. Metiamide (H2-receptor antagonist) non-competitively inhibited all ADH and ALDH of both liver fraction studied. 6. It is concluded that liver ADH and ALDH activity can be altered by compounds which affect both H1- and H2-histamine receptors and that these compounds may cause an in vivo potentiation and/or reduction of the toxic effect of ethanol.


Development and validation of a sensitive LC-MS/MS assay for simultaneous quantitation of ranolazine and its three metabolites in human plasma.
A rapid, sensitive and reliable LC-MS/MS method was developed and validated for the simultaneous determination of ranolazine and its three metabolites, CVT-2514, CVT-2738, and CVT-4786, in human plasma. The plasma samples were prepared by protein precipitation. Chromatographic separation was achieved on a Gemini C(18) column (50 mm × 2.0 mm, 5 μm) using methanol: 5 mM ammonium acetate as the mobile phase with gradient elution. Mass detection was carried out by electrospray ionization in both positive and negative ion multiple reaction monitoring (MRM) modes. The calibration curves were linear over a concentration range of 4-2000 ng/mL for ranolazine, 4-1000 ng/mL for CVT-2514 and CVT-2738 and 8-1000 ng/mL for CVT-4786. The intra-day and inter-day accuracy and precision were within the acceptable limits of ±15% at all concentrations. The method was successfully applied for the simultaneous estimation of ranolazine and its three metabolites in human plasma from a clinical pharmacokinetics study.


Development of angiogenic periglomerular microvessels after acute glomerular lesions in IgA nephropathy.
To clarify the clinicopathological characteristics and role of periglomerular angiogenesis in IgA nephropathy. The renal biopsy specimens of 114 patients with IgA nephropathy were examined. Among them, 46 (40%) showed periglomerular angiogenesis around the glomeruli. CD34 and α-smooth muscle actin (α-SMA) staining in serial sections revealed that these vessels contained CD34+ α-SMA+ microarterioles along with CD34+ α-SMA- capillaries. We termed these "periglomerular microvessels (PGMVs)". Patients with PGMVs (PGMV group) had clinically and histologically more severe disease than those without PGMVs (non-PGMV group) at the time of biopsy. Even after adjusting for age, there were significant differences in the degree of proteinuria and estimated glomerular filtration rate reduction between the PGMV and non-PGMV groups. The PGMV group showed a higher incidence of segmental and global glomerulosclerosis and crescentic lesions than the non-PGMV group (P < 0.01). Here, PGMVs were undetectable in the acute and active inflammation phase, but were observed in the acute to chronic or chronic glomerular remodelling phase. PGMVs mainly developed around glomerular adherent lesions to the Bowman's capsule with small or minimal glomerular sclerotic lesions. Conversely, they were rarely observed in segmental sclerosis areas. The PGMV group is clinically and pathologically more severe than the non-PGMV group; however, they were undetectable in segmental sclerosis with mesangial matrix accumulation. PGMVs might occur after acute/active glomerular lesions, suggesting that PGMVs may inhibit segmental glomerulosclerosis progression and could be a marker for good repair response after acute/active glomerular injury in severe IgA nephropathy cases.


Expression of urotensin-II in human coronary atherosclerosis.
The vasoactive peptide urotensin-II (U-II) is best known for its ability to regulate peripheral vascular and cardiac contractile function in vivo, and recent in vitro studies have suggested a role for the peptide in the control of vascular remodeling by inducing smooth muscle proliferation and fibroblast-mediated collagen deposition. Therefore, U-II may play a role in the etiology of atherosclerosis. In the present study we sought to determine the expression of U-II in coronary arteries from patients with coronary atherosclerosis and from normal control subjects, using immunohistochemistry and in situ hybridization. In normal coronary arteries, there was little expression of U-II in all types of cells. In contrast, in patients with coronary atherosclerosis, endothelial expression of U-II was significantly increased in all diseased segments (P<0.05). Greater expression of U-II was noted in endothelial cells of lesions with subendothelial inflammation or fibrofatty lesion compared with that of endothelial cells underlined by dense fibrosis or minimal intimal thickening. Myointimal cells and foam cells also expressed U-II. In most diseased segments, medial smooth muscle cells exhibited moderate expression of U-II. These findings demonstrate upregulation of U-II in endothelial, myointimal and medial smooth muscle cells of atherosclerotic human coronary arteries, and suggest a possible role for U-II in the pathogenesis of coronary atherosclerosis.


Large employers' selection criteria in purchasing behavioral health benefits.
To determine the criteria other than cost large employers use in selecting and monitoring behavioral health benefits, this study interviewed 31 of 44 (70.4%) randomly selected corporations employing at least 5,000 workers. While more than 60% of employers considered administrative efficiency and provider access to be very influential in their selection of behavioral health benefits, only 12.9% (95% confidence interval 0.7%-25.1%) considered clinical outcomes. Employers who considered clinical outcomes in their purchasing decision reported significantly greater satisfaction with the quality and cost of their behavioral health benefits. Following selection, 38.7% of corporations used employee complaints to monitor quality problems in their behavioral health benefits; 3.2% used clinical outcomes. If society expects employers to purchase behavioral health care on the basis of quality as well as cost, more employers need better indicators of quality.


Treatment of dye solutions by vacuum membrane distillation.
In this work, the vacuum membrane distillation (VMD) process has been applied to treat water containing different types of dyes. The influence of operating parameters, as feed temperature, feed flow rate, feed concentration, on the permeate flux and on rejection has been investigated. In all experimental tests, a complete rejection has been achieved and pure water has been recovered at the permeate side. Furthermore, experiments with water as feed have been carried out before and after the tests with dyes, in order to analyze the effect of fouling on the performance of the VMD. The water vapor fluxes immediately after the tests with dyes were higher than the values registered before the tests, probably due to an interaction with the polymeric membrane material which promotes a swelling of the membrane when in contact with the dye solutions. However, initial fluxes are recovered after prolonged cleaning with only water.


Prohibited, but still present: local and traditional knowledge about the practice and impact of forest grazing by domestic livestock in Hungary.
Forests have been grazed for millennia. Around the world, forest grazing by livestock became a controversial management practice, gradually restricted in many countries over the past 250 years. This was also the case in most Central and Eastern European countries, including Hungary, where forest grazing was a legally prohibited activity between 1961 and 2017. Until the 2010s, ecologists and nature conservationists considered it merely as a historical form of forest use. As a result, there is little contemporary scientific information available about the impact of forest grazing on vegetation and the traditional ecological knowledge associated with it. Our aim was to explore and summarize this type of knowledge held by herders in Hungary. We interviewed 58 knowledgeable herders and participated in forest grazing activities in 43 study locations across the country. The results were analysed qualitatively. We revealed a living ecological knowledge tradition and practice of forest grazing in native and non-native forest stands. The impact of livestock grazing on native and non-native forests is not considerably different, in the view of the herders. For both forest types, the greatest impact of grazing was the suppression of the shrub layer, while grazing also increased the dominance and palatability ("tameness") of the grasses. Livestock could cause significant damage to seedlings during forest grazing, but if done with care, grazing could also be an integral part of forestry management. Sustainability of current forest grazing practices depends on the depth of local and traditional knowledge applied and herders' stewardship. We stress the importance of collaborating with holders of local and traditional knowledge in order to gain a better understanding of the effects of livestock grazing on vegetation in temperate forests.


Validity of patients' self-reported drug use as a function of treatment status.
Recent reviews conclude that there is some evidence that drug abusers' self-reports are reliable and valid. However, there are wide variations among studies depending upon the samples and procedures used to obtain the data. The current study was conducted to extend the findings in this area. An examination of the intake interviews and same day urinalyses on 150 patients enrolling for outpatient opioid detoxification or maintenance revealed a fairly high agreement between drug use self-reports and urinalyses. A second study (N = 70) looking at the validity of self-reported drug use at intake and at 4 weeks follow-up revealed some noticeable changes in validity measures, suggesting that contingencies on positive urine results influence self reported drug use of addicts.


Prevalence of IgE-mediated allergy and evaluation of Th1/Th2 cytokine profiles in patients with severe bronchial asthma.
The pathogenesis of asthma remains unclear, especially in cases of the severe disease. To explore IgE-mediated inhalant sensitization in severe asthma compared with a group of patients with chronic mild disease and evaluate the Th1/Th2 cytokine profiles in asthma by different disease severities. One hundred and fifty-four patients (age range: 28-69) with severe chronic asthma (study group) and 141 patients with chronic mild disease (control group) diagnosed according to GINA criteria were included in the study. Seventy-eight severe asthmatics and 43 subjects with mild disease were randomly selected for serum Th1/Th2 cytokine level estimation. The groups were matched in terms of age and atopy features (skin prick tests, specific and total serum IgE). Positive skin tests to at least one allergen were observed with comparable frequencies. Sensitization to Dermatophagoides pteronyssinus was the most prevalent positive result in both groups. An earlier onset of asthma together with a greater number of exacerbations was noted in severe asthmatics compared to patients with mild disease. Serum levels of interleukin 4 and 2 (IL-4 and IL-2) were detectable only in severe asthmatics irrespective of atopy features. The levels of interferon γ and tumour necrosis factor α were undetectable in both groups. IL-10 and IL-5 were detected in the serum of only 7 and 12 severe asthmatics, respectively. The serum level of IL-2 and IL-4 could be perceived as a marker of severe asthma. Neither IL-2 nor IL-4 levels in the serum could differentiate allergic and non-allergic asthma.


Selection-driven divergence after gene duplication in Arabidopsis thaliana.
Gene duplications are one of the most important mechanisms for the origin of evolutionary novelties. Even though various models of the fate of duplicated genes have been established, current knowledge about the role of divergent selection after gene duplication is rather limited. In this study, we analyzed sequence divergence in response to neo- and subfunctionalization of segmentally duplicated genes in the genome of Arabidopsis thaliana. We compared the genomes of A. thaliana and the poplar Populus trichocarpa to identify orthologous pairs of genes and their corresponding inparalogs. Maximum-likelihood analyses of the nonsynonymous and synonymous substitution rate ratio [Formula: see text] of pairs of A. thaliana inparalogs were used to detect differences in the evolutionary rates of protein coding sequences. We analyzed 1,924 A. thaliana paralogous pairs and our results indicate that around 6.9% show divergent ω values between the lineages for a fraction of sites. We observe an enrichment of regulatory sequences, a reduced level of co-expression and an increased number of substitutions that can be attributed to positive selection based on an McDonald-Kreitman type of analysis. Taken together, these results show that selection after duplication contributes substantially to gene novelties and hence functional divergence in plants.


[The urological complications of pelvic fractures: about 22 cases at the University Hospital, Brazzaville].
To analyze the epidemiology, injury mechanisms and therapeutic aspects of urological complications of fractures of the pelvic girdle. Retrospective study including 22 cases of urological complications of pelvic fractures analyzed between 2003 and 2010 at the University hospital, Brazzaville. Tile classification modified AO was used to understand the mechanisms underlying urological complications. The variables studied were: frequency, age, sex, origin, etiology, type of pelvic fracture, type of urological complications, clinical urological lesions, the therapeutic delay, the therapeutic method, the long-term prognosis. In total, 22 cases (11.40%) of urological complications were collected on 193 pelvic fractures. Men dominated the series with a sex ratio of 4.5, the average age was 33.8 years (12 to 64). Street accidents were the leading cause with 13 cases (59.09%). The urethra was the most affected in 16 cases (72.73%), the membranous portion in 10 cases (45.45%), the bladder in six cases (27.27%). Type A fractures were complicated four bladder lesions, types B, 12 urological lesions (1 bladder and urethra 11) and six type C lesions (1 bladder and urethra 5). Bone lesions were supported functionally in 18 cases (81.82%). Urethral injuries in men were repaired remotely by anastomotic urethroplasty. Urethral injury in females has been repaired urgently delayed. The bladder lesions were repaired by emergency laparotomy and suture of the breach, or urethral catheterization. In monitoring, seven patients had urological sequelae: erectile dysfunction in one case and urethral stenosis in six cases, they have been treated by dilatation (4 cases) and endoscopic internal urethrotomy (2 cases). The urological complications of pelvic fractures were rare in our experience, and must be systematically searched. Unstable fractures (types B and C) were the major providers of these complications. Remote processing was possible with good functional results.


Nanoscale and functional heterogeneity of the hippocampal extracellular space.
The extracellular space (ECS) and its constituents play a crucial role in brain development, plasticity, circadian rhythm, and behavior, as well as brain diseases. Yet, since this compartment has an intricate geometry and nanoscale dimensions, its detailed exploration in live tissue has remained an unmet challenge. Here, we used a combination of single-nanoparticle tracking and super-resolution microscopy approaches to map the nanoscale dimensions of the ECS across the rodent hippocampus. We report that these dimensions are heterogeneous between hippocampal areas. Notably, stratum radiatum CA1 and CA3 ECS differ in several characteristics, a difference that gets abolished after digestion of the extracellular matrix. The dynamics of extracellular immunoglobulins vary within these areas, consistent with their distinct ECS characteristics. Altogether, we demonstrate that ECS nanoscale anatomy and diffusion properties are widely heterogeneous across hippocampal areas, impacting the dynamics and distribution of extracellular molecules.


Guiding Nipple-Areola Complex Reconstruction: Literature Review and Proposal of a New Decision-Making Algorithm.
Nipple-areola complex reconstruction (NAR) most commonly represents the finishing touch to breast reconstruction (BR). Nipple presence is particularly relevant to the patient's psyche, beyond any shadow of doubt. Many reconstructive options have been described in time. Surgery is easy, but final result is often disappointing on the long run. The goal of this manuscript is to analyze and classify knowledge concerning NAR techniques and the factors that influence success, and then to elaborate a practical evidence-based algorithm. Out of the 3136 available articles as of August 8th, 2020, we selected 172 manuscripts that met inclusion criteria, which we subdivided into 5 main topics of discussion, being the various NAR techniques; patient factors (including patient selection, timing and ideal position); dressings; potential complications and finally, outcomes/patient satisfaction. We found 92 articles describing NAR techniques, 41 addressing patient factors (out of which 17 discussed patient selection, 14 described ideal NAC location, 10 described appropriate timing), 10 comparing dressings, 7 studying NAR complications, and 22 addressing outcomes and patient satisfaction. We elaborated a comprehensive decision-making algorithm to help narrow down the choice among NAR techniques, and choose the correct strategy according to the various scenarios, and particularly the BR technique and skin envelope. No single NAR technique provides definitive results, which is why we believe there is no "end-all be-all solution". NAR must be approached as a case-by-case situation. Furthermore, despite NAR being such a widely discussed topic in scientific literature, we still found a lack of clinical trials to allow for more thorough recommendations to be elaborated. This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews, and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies, and Experimental Studies. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.


Patellar tendon defect during the first year after anterior cruciate ligament reconstruction: appearance on serial magnetic resonance imaging.
The purpose of this study was to use magnetic resonance imaging to evaluate various parameters of the patellar tendon during the first year after harvest for anterior cruciate ligament (ACL) reconstruction. Twelve consecutive patients were serially imaged on a 1.5 Tesla GE magnet (GE Medical Systems, Milwaukee, WI) with a dedicated knee coil at 3 weeks, 3 months, 6 months, and 1 year after undergoing ACL reconstruction using a central one-third patellar tendon autograft. The tendon defect was not closed primarily, but the paratenon was approximated. The following measurements were performed: tendon width, defect width, cross-sectional area of the tendon, and tendon length. In addition, the patellar bone harvest site was evaluated for healing. The width of the tendon defect decreased by 62% over 12 months (P < .05). Only two patients showed complete closure of the defect. Tendon width was noted to decrease by 6.5% (P=.017). The ratio of defect width to overall tendon width (designated R) decreased by 58% (P < .05). Tendon length was noted to decrease during this by 8% (P=.037). The tendon cross-sectional area was noted to increase by 9% at 1 year, but this was not found to be statistically significant (P=.39). One year after ACL reconstruction using a central one-third patellar tendon, the tendon defect has begun to reconstitute itself but there is still a significant gap. This persistent defect must be taken into consideration when planning revision ACL surgery using reharvest of the central one third of the patellar tendon. The entire tendon also exhibits a reduction in width and length, while cross-sectional area increases slightly. Complete healing of the graft defect can not be assumed at 12 months post-ACL reconstruction.


Selective conversion of CO2 to isobutane-enriched C4 alkanes over InZrOx-Beta composite catalyst.
Direct conversion of CO2 to a single specific hydrocarbon with high selectivity is extremely attractive but very challenging. Herein, by employing an InZrOx-Beta composite catalyst in the CO2 hydrogenation, a high selectivity of 53.4% to butane is achieved in hydrocarbons (CO free) under 315 °C and 3.0 MPa, at a CO2 conversion of 20.4%. Various characterizations and DFT calculation reveal that the generation of methanol-related intermediates by CO2 hydrogenation is closely related to the surface oxygen vacancies of InZrOx, which can be tuned through modulating the preparation methods. In contrast, the three-dimensional 12-ring channels of H-Beta conduces to forming higher methylbenzenes and methylnaphthalenes containing isopropyl side-chain, which favors the transformation of methanol-related intermediates to butane through alkyl side-chain elimination and subsequent methylation and hydrogenation. Moreover, the catalytic stability of InZrOx-Beta in the CO2 hydrogenation is considerably improved by a surface silica protection strategy which can effectively inhibit the indium migration.


Effects of retinoic acid and staurosporine on the protein kinase C activity and the morphology of two related human neuroblastoma cell lines.
Studies on the involvement of protein kinase C in retinoic acid-induced differentiation of human neuroblastoma were carried out with two variants of the SK-N-SH cell line namely the SH-F subline, which differentiates to give a fibroblast-like phenotype, and the SH-N subline, which develops into the typical neuronal phenotype. In SH-F, a substantial increase in protein kinase C activity accompanied morphological differentiation. Accordingly, after 7 days of retinoic acid treatment, EDTA-extracted, cytosolic protein kinase C activity increased by slightly more than 2-fold over vehicle-treated controls. Again, detergent-extracted activity, representing membrane-bound or total protein kinase C, showed a similar 2.6- to 5.1-fold increase in treated cells. A time-course study revealed an earliest increase in total activity after two days of retinoic acid treatment which continued linearly for the first 6 to 8 days, and then levelled off. A study of the effect of retinoic acid on the protein kinase C in vitro with SH-F cell extracts showed only a slight increase in activity (of 25%) at the relatively high concentration of 10(-4) M; however, no significant differences were observed at lower concentrations. In contrast, the SH-N cell line responded to retinoic acid by a 45% decrease in EDTA-extractable, and a 63% decrease in detergent-extractable protein kinase C activity. Added to SH-F cell cultures, 15 nM staurosporine was found to inhibit protein kinase C in vivo and to a lesser extent, the protein kinase A. Present together with retinoic acid, staurosporine not only prevented the augmentation but caused a marked decrease of protein kinase C activity in this cell line. Morphological studies indicated that when SH-N cells are treated with staurosporine, or staurosporine and retinoic acid together, a neuronal phenotype similar to that produced by retinoic acid alone is observed. In contrast, when the SH-F cell line is treated with staurosporine or staurosporine and retinoic acid together, the flattened fibroblast-like cell type normally induced by retinoic acids is not observed. Instead, these cells display much smaller cell bodies and elaborate extensions resembling the neuronal phenotype produced by retinoic acid induced differentiation of the SH-N variant. These results suggest that changes in the protein kinase C activity may be involved in regulating the expression of the phenotype during cell differentiation.


[Footballer's hip].
Although complaints and injuries in the knee and ankle joints are very prevalent in football, the hip has so far been given very little attention. Complaints in this area are often attributed to pathological changes in the inguinal region. However, intraarticular differential diagnoses are often not taken into consideration. This article gives an overview of possible hip pathology in footballers, as well as its diagnosis and treatment.


Matrix-assisted laser desorption ionization (MALDI) mass spectrometry: a novel analytical tool in molecular biology and biotechnology.
Matrix-assisted laser desorption ionization (MALDI) is a rather recent 'soft ionization' technique which produces quasimolecular ions of large organic molecules of up to several 100 kDa molecular mass. In combination with time-of-flight (TOF) mass spectrometry it has rapidly evolved as a valuable tool for the detection and characterization of biopolymers such as peptides, proteins, oligosaccharides and -nucleotides especially in mixtures and crude samples. MALDI-MS is remarkably tolerant towards common contaminants such as salts and buffers, requires sample loads in the subpicomolar range and features a mass accuracy (and precision) of 0.1-0.01%. Structural information on analyte molecules can be obtained by exploiting metastable post source decay (PSD) processes which allow extraction of sequence or substituent information on individual peptides contained, e.g., in an enzymatic digest. Thus, MALDI provides for an easy and straight forward elucidation of posttranslational modifications. The forseeable merging of MALDI with blotting and in situ degradation techniques give MALDI-MS a key role in future laboratory practice of biotechnology and molecular biology. The actual state-of-the-art is described, and selected examples are given with special emphasis on the aspects of analytical routine work.


Cerebrovascular diseases.
Conventional neuroradiological techniques, such as computed tomography (CT) and magnetic resonance imaging (MRI), make a fundamental contribution in both the acute and chronic phases of stroke. Recent years have witnessed the development of new imaging modalities, which include diffusion-weighted imaging (DWI), perfusion-weighted imaging (PWI), CT-angiography (CTA), MR-angiography (MRA), magnetic resonance spectroscopy (MRS), diffusion tensor imaging (DTI) and functional MRI (fMRI). While CTA, MRA, DWI and PWI are commonly used for clinical purposes, DTI, MRS and fMRI are becoming increasingly important in the field of experimental research of cerebrovascular diseases, but are still far from becoming of primary usefulness in the everyday clinical setting.


Study of the time of the visual system recovery.
The time of the visual system recovery was studied. The experimental method is presented. The results confirm a relationship between the duration of the threshold interval between pulses and the duration of light pulses. The type of this relationship is identified; the distribution of results of observations for groups is statistically evaluated.


Treatment outcomes in 3 modes of orthodontic practice.
This study examined differences in pretreatment severity and treatment outcome among orthodontic patients treated in 3 different practice-management modes. Samples of pretreatment (T1) and end of treatment (T2) study casts were selected from traditional private practices (TPP, 3 offices, 81 cases), a dental corporation (COMP, 2 offices, 53 cases), and a dental management service organization (DMSO, 1 office, 36 cases). Orthodontic specialists had treated all patients. Cases were initially selected on a consecutive start basis. From each practice, the first 30 cases satisfying the study criteria were included in the sample. The T1 and T2 study casts were evaluated with the PAR and HLD indexes. The PAR and HLD indexes showed a high level of agreement on T1 cast scores but not on the T2 casts. Mean T1 scores were highest in the COMP cases, followed by the DMSO and the TPP cases. T2 scores were lowest in the TPP cases, followed by the DMSO and the COMP cases. The percentage of PAR score reduction showed that, in all 3 modes, patients were treated to a high standard.


Based on 16 S rRNA sequencing and metabonomics to reveal the new mechanism of aluminum potassium sulfate induced inflammation and abnormal lipid metabolism in mice.
More and more discoveries have been made about the chronic toxic effects of aluminum, but the specific mechanism of action remains unclear. In this study, we explored the perturbation of aluminum on intestinal microflora and its effects on host and microbial metabolites through a more realistic nutrient absorption model. The microorganisms Turicibacter, Lactobacillus murinus, Lactobacillus_reuteri and Bifidobacterium pseudolongum may be the main targets of the aluminum affecting microbiota. Lysine, proline, putrescine, serotonin and cholesterol may be important metabolites affected by aluminum ions after the interference of intestinal flora composition, leading to abnormal metabolism pathways of amino acids and lipids in the body, and thus promoting inflammation and lesion. The possible mechanisms of aluminum action on the body: (1) Affecting immune cell response, ROS generation and production of a series of pro-inflammatory factors to promote inflammation; (2) Through the disturbance of intestinal microbiota composition structure, change the abundance of metabolites, and then affect amino acid metabolism, lipid metabolism pathways. The joint analysis of multiple omics showed significant difference in microbiome abundance and metabolomics expression between high dose group and the control group.


Arm raising at exposure-controlled multidetector trauma CT of thoracoabdominal region: higher image quality, lower radiation dose.
To evaluate the effect of arm position on image quality and effective radiation dose in an automatic exposure-controlled (AEC) multidetector thoracoabdominal computed tomography (CT) protocol in trauma patients. This retrospective study of the data of 177 trauma patients (117 male; median age, 39 years) was approved by the institutional ethics board, with informed patient consent waived. Patients underwent scanning by using an AEC 16-detector thoracoabdominal CT protocol in which both arms were raised above the shoulder region (standard-position group, 132 patients), one arm was raised and the other was down (one-arm group, 27 patients), or both arms were down (two-arm group, 18 patients). Objective and subjective image quality was assessed. Individual effective radiation dose was calculated from the effective tube current-time product per exposed section. For this purpose, section location-dependent conversion factors were derived by using a CT dosimetry calculator. The effect of arm position on effective dose was quantified by using linear regression analysis with correction for patient volume and attenuation. Compared with the image quality in the standard-position group, the image quality in the one- and two-arm groups was decreased but within acceptable diagnostic limits. The median corrected effective dose in the standard-position group was 18.6 mSv; the dose in the one-arm group was 18% (95% confidence interval: 11%, 25%) higher than this, and that in the two-arm group was 45% (95% confidence interval: 34%, 57%) higher. Omitting arm raising results in lower but acceptable image quality and a substantially higher effective radiation dose. Hence, effort should be made to position the arms above the shoulder when scanning trauma patients. Clinical trial registration no. NCT00228111.


[Role of crural inguinal lymphadenectomy and dynamic sentinel lymph node biopsy in lymph node staging in squamous-cell carcinoma of the penis. Our experience].
We determine the value of dynamic sentinel node biopsy for staging squamous cell carcinoma of the penis. During a period of 2 years 17 patients with penile cancer was performed after lymphoscintigraphy pre and intraoperatively with gamma ray detection probe at biopsy of the sentinel node with the aid of perilesional administered patent blue dye. After 20 days regional lymph node dissection was performed in all patients. Sentinel node metastasis was found in 5 patients; in one case lymphoscintigraphy not visualized sentinel node. All negative node biopsy was confirmed with the regional lymph node dissection. No major complication did occur after sentinel node biopsy. Occult lymph node metastases can be detected by dynamic sentinel node biopsy including preoperative lymphoscintigraphy, vital dye and gamma ray detection probe with a sensitivity of 78%, predictive negative value of 100% and with low morbidity.


Inhibition of prostaglandin delta 13 reductase activity in rabbit kidney cortex by glutathione disulfide.
t-Butyl hydroperoxide and H2O2-Fe(2+)-EDTA-glutathione system which produces hydroxyl radicals did not affect the 15-hydroxy prostaglandin dehydrogenase activity in rabbit kidney cortex. On the other hand, H2O2-Fe(2+)-EDTA-glutathione system inhibited the prostaglandin delta 13 reductase activity. Mannitol, a scavenger of hydroxyl radicals, had no effect on the inhibitory action of this system, indicating that the effect of H2O2-Fe(2+)-EDTA-glutathione system on the prostaglandin delta 13 reductase may not be due to produced hydroxyl radicals. As a result of further investigation, it was shown that glutathione disulfide, which is synthesized concomitantly with hydroxyl radicals from H2O2-Fe(2+)-EDTA-glutathione, inhibited the prostaglandin delta 13 reductase activity. These results suggest that hydroperoxides and hydroxyl radicals may not be likely candidates for the modulator of the catabolism of prostaglandins in the kidney cortex, and that glutathione disulfide has the potential to modulate the prostaglandin catabolism by affecting the prostaglandin delta 13 reductase activity.


Laser-Generated Proton Beams for High-Precision Ultra-Fast Crystal Synthesis.
We present a method for the synthesis of micro-crystals and micro-structured surfaces using laser-accelerated protons. In this method, a solid surface material having a low melting temperature is irradiated with very-short laser-generated protons, provoking in the ablation process thermodynamic conditions that are between the boiling and the critical point. The intense and very quick proton energy deposition (in the ns range) induces an explosive boiling and produces microcrystals that nucleate in a plasma plume composed by ions and atoms detached from the laser-irradiated surface. The synthesized particles in the plasma plume are then deposited onto a cold neighboring, non-irradiated, solid secondary surface. We experimentally verify the synthesizing methods by depositing low-melting-material microcrystals - such as gold - onto nearby silver surfaces and modeling the proton/matter interaction via a Monte Carlo code, confirming that we are in the above described thermodynamic conditions. Morphological and crystallinity measurements indicate the formation of gold octahedral crystals with dimensions around 1.2 μm, uniformly distributed onto a silver surface with dimensions in the tens of mm2. This laser-accelerated particle based synthesis method paves the way for the development of new material synthesis using ultrashort laser-accelerated particle beams.


Normal alkaline phosphatase in primary biliary cirrhosis.
A patient with primary biliary cirrhosis is described. Throughout her illness the serum alkaline phosphatase remained normal and this unique feature emphasizes the importance of histology in diagnosing the disease.


Management of proximal tibial stress fracture associated with advanced knee osteoarthritis: A systematic review.
Tibial stress fracture associated with knee osteoarthritis is an unusual and difficult clinical scenario. There is no clear existing treatment guideline for this uncommon clinical disease. The aim of this study is to review the impact of various treatment options for patients with advanced knee osteoarthritis associated with proximal tibial stress fracture. The study was performed using the databases of PubMed and Scopus. Methodological index for non-randomized studies score was used to evaluate the included studies' bias. The concluded data included the treatment approach, reported outcome measure, and time to fracture union. The literature search was started in December 2021 and accomplished at January 2022. A narrative description of the different methods and comparison of their results were done. Out of total assessed 69 studies, 9 studies were included in our review. The commonest treatment approach used was total knee arthroplasty by long tibial stem extension. The mean preoperative knee society score and knee functional score were 30.62 and 23.17, respectively. The mean postoperative knee society knee score was 86.87, while the functional score was 83.52. The average reported time to achieve fracture union was 4 months (ranging 2.07-5.50 months). The optimal clinical outcome for treating either acute or mobile tibial stress fracture in patients with advanced knee osteoarthritis can be achieved with long stem total knee arthroplasty. However, due to heterogeneity of data, comparison of different treatment options for chronic proximal tibial stress fracture mal-union/non-union coexisting with knee osteoarthritic and such inferences need to be judged cautiously.


Relationship of prefrontal brain lateralization to optimal cognitive function differs with age.
There is considerable debate about whether additional fMRI-measured activity in the right prefrontal cortex readily observed in older adults represents compensatory activation that enhances cognition or whether maintenance of youthful brain activity best supports cognitive function in late adulthood. To investigate this issue, we tested a large lifespan sample of 461 adults (aged 20-89) and treated degree of left-lateralization in ventrolateral and dorsolateral prefrontal cortex during a semantic judgment fMRI task as an individual differences variable to predict cognition. We found that younger adults were highly left-lateralized, but lateralization did not predict better cognition, whereas higher left-lateralization of prefrontal cortex predicted better cognitive performance in middle-aged adults, providing evidence that left-lateralized, youth-like patterns are optimal in middle age. This relationship was reversed in older adults, with lower laterality scores associated with better cognition. The findings suggest that bilaterality in older adults facilitates cognition, but early manifestation of this pattern during middle age is characteristic of low performers. Implications of these findings for current theories of neurocognitive aging are discussed.


Kinetics of the early recruitment of leukocyte subsets at the sites of tumor cells in the lungs: natural killer (NK) cells rapidly attract monocytes but not lymphocytes in the surveillance of micrometastasis.
Early host defense mechanisms play a critical role for the outcome of metastatic disease but most of the initial steps of such responses against tumor cells are still unknown. Here, the specificity and kinetics of leukocyte subsets in response to intravenous inoculation of vital dye labeled Fischer 344 rat syngeneic MADB106 tumor cells were monitored in lungs in situ by immunohistochemistry and image analysis over a time-period of 6 hr. In comparison with sham injections, tumor cell inoculation induces a dynamic sequence of rapidly increasing granulocyte (+40% at 5 min), NK and T cell (+60% at 15 min) as well as monocyte (+100% at 30 min) numbers in lung tissue. Already within the first minutes frequent colocalizations of granulocytes and NK cells with tumor targets were found in situ. Within the first hour NK cells selectively kill tumor targets, because depletion of NK cells in vivo drastically increases both the number of MADB106 cells retained in lungs and the emerging numbers of lung tumor colonies. In addition, the tumor-cell-induced increase of monocytes strictly depends on the presence of NK cells because NK-depletion completely abrogates the time specific response of monocytes. Under NK depleted conditions the tumor-induced recruitment of CD4(+) T cells is more pronounced suggesting a compensatory mechanism. In contrast, B cell numbers progressively decrease within hours after cell inoculation. These findings demonstrate that NK and T cells mediate the initial steps in the surveillance of lung metastasis. NK cells rapidly kill tumor cells and subsequently recruit monocytes in vivo.


Ajmaline induced intra-Hisian block.
Ajmaline-induced block within the atrioventricular bundle (intra-Hisian) is rare. We report a 59-year-old male with a left bundle branch block in whom intravenous Ajmaline unmasked a latent conduction abnormality within the atrioventricular bundle. Relevant literature is reviewed.


Advances in our understanding of gout as an auto-inflammatory disease.
Gout, the most common inflammatory arthritis, is the result of hyperuricemia and inflammation induced by monosodium urate (MSU) crystal deposition. However, most people with hyperuricemia will never develop gout, implying a molecular-genetic contribution to the development of gout. Recent genomic studies reveal links between certain genetic variations and gout. We highlight recent advances in our understanding of gout as an auto-inflammatory disease. We review the auto-inflammatory aspects of gout, including the inflammasome and thirteen gout-associated inflammatory-pathway genes and associated comorbidities. This information provides important insights into emerging immune-modulating targets in the management of gout, and future novel therapeutic targets in gout treatment. Cumulatively, this has important implications for treating gout as an auto-inflammatory disease, as opposed to a purely metabolic disease.


Respiratory studies on two benthic copepods Acanthocyclops viridis and Eucyclops agilis at environmental temperatures.
The rate of oxygen consumption in all developmental stages of two benthic cyclopoid copepod species, Acanthocyclops viridis (Jurine) and Eucyclops agilis (Koch, Sars) was investigated at temperatures between 5° C-20° C, which are reflective of the environmental temperature range of the benthic zone in Esthwaite Water, Cumbria, from which the organisms were derived. The larger species, A. viridis was found to have a temperature insensitive metabolism, whereas E. agilis showed a marked temperature response in respiratory function. Gravid and non-gravid females had similar rates of respiration except at 15° C-20° C in E. agilis. Males exhibited much lower respiration rates than females, but higher weight specific respiration rates; these differences were largely attributable to size differentials between the sexes. Estimates of swimming activity were made and these were related to the patterns of respiratory function observed.


Comparison of integrin, cadherin, and catenin expression in squamous cell carcinomas of the oral cavity.
In addition to their role in maintenance of tissue integrity, cell adhesion molecules regulate the growth and differentiation of stratified squamous epithelia. Reduced expression of E-cadherin and the alpha 2 beta 1, alpha 3 beta 1 and alpha 6 beta 4 integrins is already reported to correlate with poor histological differentiation in oral squamous cell carcinomas. However, it is not clear how closely cadherin and integrin loss are related in any given tumour, nor whether cadherin loss is correlated with changes in expression of the cytoplasmic regulatory proteins known as catenins. Double-label immunofluorescence has been used to stain a panel of 22 oral squamous cell carcinomas with antibodies to ten proteins, including E- and P-cadherin, the major keratinocyte integrin subunits, and alpha-, beta- and gamma-catenin. Overall, E-cadherin expression and integrin expression correlated well with tumour grade, while P-cadherin staining was more variable. All tumours, regardless of differentiation status, showed reduced staining for at least two of the catenins, implying that the adhesive function of E- and P-cadherin could be impaired even when cadherin expression is normal. It is concluded that in all squamous cell carcinomas, regardless of degree of histological differentiation, there is some perturbed expression of cell adhesion molecules and that integrin and E-cadherin loss are closely related.


Viral load dynamics of SARS-CoV-2 Delta and Omicron variants following multiple vaccine doses and previous infection.
An important aspect of vaccine effectiveness is its impact on pathogen transmissibility, harboring major implications for public health policies. As viral load is a prominent factor affecting infectivity, its laboratory surrogate, qRT-PCR cycle threshold (Ct), can be used to investigate the infectivity-related component of vaccine effectiveness. While vaccine waning has previously been observed for viral load during the Delta wave, less is known regarding how Omicron viral load is affected by vaccination status, and whether vaccine-derived and natural infection protection are sustained. By analyzing results of more than 460,000 individuals, we show that while recent vaccination reduces Omicron viral load, its effect wanes rapidly. In contrast, a significantly slower waning rate is demonstrated for recovered COVID-19 individuals. Thus, while the vaccine is effective in decreasing morbidity and mortality, its relatively small effect on transmissibility of Omicron (as measured here by Ct) and its rapid waning call for reassessment of future booster campaigns.


Immunological Analysis of Cryptococcal Meningoencephalitis in a Murine Model.
Cryptococcal meningoencephalitis (CM), caused by the fungal pathogen Cryptococcus neoformans species complex, can lead to high mortality or severe neurological sequelae in survivors that are associated with excessive inflammation in the central nervous system (CNS), especially in those who develop immune reconstitution inflammatory syndrome (IRIS) or postinfectious immune response syndrome (PIIRS). While the means to establish a cause-and-effect relationship of a specific pathogenic immune pathway during CM by human studies are limited, mouse models allow dissection of the potential mechanistic links within the CNS immunological network. In particular, these models are useful for separating pathways contributing predominantly to immunopathology from those important for fungal clearance. In this protocol, we described methods to induce a robust, physiologically relevant murine model of C. neoformans CNS infection that reproduces multiple aspects of human cryptococcal disease immunopathology and subsequent detailed immunological analysis. Combined with tools including gene knockout mice, antibody blockade, cell adoptive transfer, as well as high throughput techniques such as single-cell RNA sequencing, studies using this model will provide new insights regarding the cellular and molecular processes that elucidate the pathogenesis of cryptococcal CNS diseases in order to develop more effective therapeutic strategies.


Quality of life assessment in advanced pancreatic adenocarcinoma: results from a phase III randomized trial.
A phase III trial suggested that a PEFG (cisplatin, epirubicin, 5-fluorouracil, gemcitabine) regimen might improve the outcome compared to gemcitabine in advanced pancreatic adenocarcinoma. The analysis of treatment impact on quality of life (QOL) is reported. Patients completed the European Organization for Research and Treatment of Cancer QLQ-C30 and PAN-26 questionnaires at baseline and every second month of treatment until disease progression. The largest differences between arms favored PEFG. Expressed as improvement > or =10 points from baseline (PEFG/gemcitabine), these were: emotional function (43/18%), fatigue (41/17%), QOL (55/29%), pain (64/41%), and flatulence (50/26%). Only change in sexual function favored gemcitabine (19/42%). Physical function, fatigue, appetite, and satisfaction with healthcare improved in 40-46% of partial responders compared with 0-12% of patients with stable disease. Clinically relevant improvement in QOL from baseline was observed more often after PEFG than after gemcitabine, suggesting that the PEFG regimen did not impair QOL, Partial response was associated with improved QOL suggesting that effective treatment of pancreatic adenocarcinoma may have an important role in these patients.